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An imprint of Elsevier Inc.

2008, Elsevier Inc. All rights reserved.

First published 2008

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ISBN-13: 978-0-7216-2872-1

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List of Contributors

Arjang Abbasi DO Alvin K. Antony MD, FABPM&R, Lisa M. Bartoli DO, MS, FAAPMR Donatella Bonaiuti MD
Attending Physician FABPM Adjunct Clinical Assistant Professor Physiatrist
Interventional Pain Management and Director, Physiatry and Pain Head Team Physician USA Rugby Chief of Rehabilitation Medicine
Spine Rehabilitation Management Women’s National Team Department
Long Island Spine Specialists Advanced Centers for Orthopedic Center for Health and Healing S. Gerardo Hospital
Commack NY Surgery and Sports Medicine Department of Orthopedics Milan
USA Clinical Instructor, Department of Beth Israel Medical Center Italy
PM&R New York NY
Elsayed Abdel-Moty PhD Johns Hopkins University Medical USA Guiseppe Bonaldi MD
Research Associate Professor Center Director, Neuroradiology Department
Bonnie Lee Bermas MD Department of Neuroradiology
Department of Neurological Surgery Baltimore MD
Associate Rheumatologist Riuniti Hospital
The Rosomoff Comprehensive Pain USA
Robert B. Brigham Arthritis Center Bergamo
and Rehabilitation Center
Brigham and Women’s Hospital Italy
Miami Beach FL Charles N. Aprill MD
Boston MA
USA Clinical Professor
USA Joanne Borg-Stein MD
Physical Medicine and
Salahadin Abdi MD, PhD Assistant Professor of Physical
Rehabilitation Sarjoo M. Bhagia MD, MSc (Orth)
Professor of Clinical Anesthesiology Medicine and Rehabilitation
Interventional Spine Specialists Interventional Physiatrist
Chief, Division of Pain Medicine Department of Physical Medicine
Louisiana State University Health Department of Orthopedics and
University of Miami Pain Center and Rehabilitation, Harvard Medical
Science Center Rehabilitation
LM Miller School of Medicine School
Kenner LA Miller Orthopaedic Clinic
Miami FL Medical Director, Spaulding Wellesley
USA Charlotte NC
USA Rehabilitation Center
USA
Madhuri Are MD, BA Wellesley MA
David R. Adin DO Assistant Professor, Cancer Pain Amit S. Bhargava MD, MS USA
Spine and Sports Fellow Management Physician
Department of Physiatry Interventional Spine, EMG, Kenneth P. Botwin MD
Department of Anesthesiology and
Hospital for Special Surgery Arthritis, Pain and Sports Medicine Fellowship Director
Pain Medicine
New York NY Physical Medicine and Rehabilitation Florida Spine Institute
MD Anderson Cancer Center
USA Owings Mills MD Clearwater FL
University of Texas
USA USA
Houston TX
Sang-Ho Ahn MD, PhD USA Atul L. Bhat MD Craig D. Brigham MD
Associate Professor of Rehabilitation Clinical Instructor Physician
Medicine and Spine Center Joshua D. Auerbach MD Department of Physical Medicine and OrthoCarolina
Yeungnam University College Resident Rehabilitation Charlotte NC
of Medicine Department of Orthopaedic Surgery Tufts University School of Medicine USA
Daegu University of Pennsylvania Nashua NH
Republic of Korea Philadelphia PA USA Oleg Bronov MD
USA Clinical Instructor in Radiology
Klaus Birnbaum Priv.-Doz.
Venu Akuthota MD Department of Radiology/Neuro-
Physician
Director Giancarlo Barolat MD radiology Division
Orthopädie Hennef
The Spine Center Director and CEO University of Pennsylvania Medical
Hennef
and Associate Professor The Barolat Institute Center
Germany
Department of Rehabilitation Medicine Lone Tree CO Philadelphia PA
University of Colorado School of USA Nikolai Bogduk BSc(Med), MBBS, USA
Medicine PhD, MD, DSc, Dip Anat, MMed
Aurora CO Katrien Bartholomeeusen PT MSc (Pain Management) FAFRM, Lee Ann Brown DO
USA Manual Therapy, Dip ManipTher, FAFMM, FFDM (ANZCA) Physical Medicine and
MSc Sport PT Conjoint Professor of Pain Medicine Rehabilitation
William A. Ante MD Head of Private Practice for Manipula- Department of Clinical Research Florida Spine Institute
Attending Physiatrist tive PT and Sports PT The Newcastle Bone and Joint Institute Clearwater FL
Physical Medicine and Rehabilitation Faculty of Physical Education and University of Newcastle USA
Tri-State Orthopaedic Surgeons, Inc. Physiotherapy Newcastle
Evansville IN Lier Australia
USA Belgium

ix
List of Contributors

Mark D. Brown MD, PhD Larry H. Chou MD Gregory Day FRACS (Orth) Omar El-Abd MD
Professor and Emeritus Chairman Medical Director, Sports and Spine Associate Professor Clinical Instructor, Interventional
Department of Orthopaedics and Rehabilitation Division Department of Surgery Physiatrist
Rehabilitation Premier Orthopaedic and Sports School of Medicine Spaulding Rehabilitation Hospital
University of Miami School of Medicine Associates, LTD Bond University Harvard Medical School
Medicine Clinical Associate Professor of Queensland Wellesley MA
Miami FL Physical Medicine and Rehabilitation Australia USA
USA University of Pennsylvania Health
System Miles Day MD, FIPP, DABPM Mark I. Ellen MD, FAAPM&R
Thomas N. Bryce MD Philadelphia PA Associate Professor Medical Director and Section Chief
Assistant Professor USA Department of Anesthesiology and Physical Medicine and Rehabilitation
Department of Rehabilitation Pain Medicine Service
Medicine David W. Chow MD Texas Tech University Health Sciences Birmingham Veterans Administration
Mount Sinai Medical Center Medical Director Center Medical Center
New York NY California Spine Center Lubbock TX Birmingham AL
USA Walnut Creek CA USA USA
USA
Allen W. Burton MD Rick B. Delamarter MD Dawn M. Elliott PhD
Associate Professor Yung Chuan Chen MD Medical Director Associate Professor
Department of Anesthesiology and Physical Medicine and Rehabilitation The Spine Institute Department of Orthopaedic Surgery
Pain Medicine Specialist, Pain Physician Santa Monica CA and Department of Bioengineering
University of Texas Physical Medicine and USA University of Pennsylvania
MD Anderson Cancer Center Rehabilitation Philadelphia PA
Houston TX Michael J. DePalma MD USA
Spinal Diagnostics and Treatment
USA Associate Professor
Center
Director, VCU Spine Center Clifford R. Everett MD, MPH
Daly City CA
John A. Carrino MD, MPH Physical Medicine and Rehabilitation Assistant Professor of Orthopaedics
USA
Assistant Professor of Radiology Virginia Commonwealth University Physical Medicine and Rehabilitation
Harvard Medical School Gianluca Cinotti MD Richmond VA Department of Orthopaedics
Department of Radiology Registrar USA University of Rochester
Brigham and Women’s Hopsital Orthopaedic Surgery Rochester NY
Boston MA Richard Derby MD USA
Clinical Orthopedics
USA Medical Director
Universita of Rome
Spinal Diagnostics and Treatment Center Amir H. Fayyazi
Italy
Bojun Chen MD, PhD Adjunct Clinical Associate Professor Assistant Professor
Clinical Instructor Steven P. Cohen MD Division of Physical Medicine and Department of Orthopedics
Department of Rehabilitation Associate Professor Rehabilitation Institute for Spine Care
Medicine Department of Anesthesiology and Stanford University Medical Center Syracuse NY
Mount Sinai Medical Center Critical Care Medicine Daly City CA USA
New York NY John Hopkins School of Medicine USA
USA Baltimore MD Claudio A. Feler MD, FACS
Timothy R. Dillingham MD, MS Semmes-Murphey Neurologic and
USA
Yung Chuan Chen MD Professor and Chairman Spine Institute
Physical Medicine and Rehabilitation Paul Cooke MD, FABPM&R Dept of Physical Medicine and Associate Professor
Specialist, Pain Physician, Physiatrist Assistant Attending Physiatrist Rehabilitation Department of Neurosurgery
Physical Medicine and Rehabilitation Hospital for Special Surgery The Medical College of Wisconsin University of Tennessee Health
Spinal Diagnostics and Treatment Attending Physician, The Medical Brookfield WI Science Center
Center Center of Princeton USA Memphis TN
Daly City CA Princeton, NJ USA
USA USA Carol A. Dolinskas MD, FACR
Clinical Associate Professor of Radiology Julius Fernandez MD
Cynthia Chin MD University of Pennsylvania Semmes-Murphey Neurologic and
Anthony R. Cucuzzella MD
Associate Professor of Clinical Philadelphia PA Spine Institute
Medical Staff
Radiology USA Assistant Professor
Christiana Care Health System
Department of Radiology Department of Neurosurgery
Christiana Spine Center
University of California, San Francisco Jonathan A. Drezner MD University of Tennessee Health
Newark NJ
San Francisco CA Associate Professor, Team Physician Science Center
USA
USA Associate Director, Sports Medicine Memphis TN
Richard J. Daniels MD Fellowship USA
Kingsley R. Chin MD Department of Family Medicine
Staff Interventional Radiologist
Assistant Professor of Orthopaedic Hall Health Sports Medicine
University Hospital Pennsylvania Robert Ferrari MD, FRCPC, FACP
Surgery University of Washington
Philadelphia PA Clinical Professor
Division of Spine Surgery Seattle WA
USA University of Alberta Hospital
Hospital of the University of USA Edmonton AB
Pennsylvania Kenny S. David MS(Orth) Canada
Philadelphia PA Thomas Edrich MD, PhD
Consultant
USA Instructor of Anesthesia Jeffrey S. Fischgrund MD
Department of Orthopaedic
Surgery Department of Anesthesiology Attending Orthopaedic Surgeon
Christian Medical College Brigham and Women’s Hospital William Beaumont Hospital
Vellore Boston MA Royal Oak MI
India USA USA

x
List of Contributors

David A. Fishbain MD, BSc (Hon), Robert J. Gatchel PhD, ABPP Stephen Hanks MD Stefan Hellinger MD
MSc, FAPA Professor and Chairman Assistant Professor of Clinical Orthopaedic Surgeon, Spine
Professor of Psychiatry and Department of Psychology Orthopaedic Surgery Surgeon
Adjunct Professor of Neurological College of Science, University of Texas Department of Orthopaedic Surgery Department of Orthopaedics
Surgery at Arlington University of Arizona Health Sciences Isar Klinik Munich
University of Miami Arlington TX Center Munich
Rosomoff Pain Center USA Pittsburgh PA Germany
Miami Beach FL USA
USA Peter Gerner MD Steven Helper MD
Assistant Professor of Matthew Hannibal MD Physiatrist
Colleen M. Fitzgerald MD Anesthesiology Orthopedic Surgeon Penn Spine Fellow
Medical Director, Women’s Health Department of Anesthesiology San Francisco Orthopedic Surgeons University of Pennsylvania
Rehabilitation Brigham and Women’s Hospital San Francisco CA Philadelphia PA
Rehabilitation Institute of Chicago Boston MA USA USA
Assistant Professor USA
Physical Medicine and Mouchir Harb MD Harry N. Herkowitz MD
Rehabilitation Peter C. Gerszten MD, MPH, FACS Attending Physician Chairman
Northwestern University Feinberg Associate Professor of Neurological Spring Valley Hospital Department of Orthopaedic Surgery
School of Medicine Surgery Las Vegas NV William Beaumont Hospital
Chicago IL Department of Neurological USA Royal Oak MI
USA Surgery USA
Presbyterian University Hospital Donal F. Harney MD, Dip Pain Med,
Yizhar Floman MD Pittsburgh PA CARCSI, FCARCSI Harish S. Hosalkar, MD,
Professor of Orthopedic Surgery USA Department of Anesthesiology MBMS(Orth), FCPS (Orth), DNB
Israel Spine Center Pain Management and Research (Orth)
Assuta Hospital Russell V. Gilchrist DO Center Pediatric Orthopedic Surgeon
Tel Aviv Assistant Professor University Hospital Maastricht Department of Orthopedic Surgery
Israel Department of Physical Medicine and Maastricht University of Pennsylvania
Rehabilitation The Netherlands Philadelphia PA
Edward J. Fox MD University of Pittsburgh Medical USA
Assistant Professor of Orthopaedic Center Mark A. Harrast MD
Surgery Pittsburgh PA Clinical Associate Professor of Reha- Kenneth Hsu MD
Division of Orthopaedic Oncology USA bilitation Medicine and Orthopaedics Attending Orthopaedic Surgeon
Hospital of the University of and Sports Medicine Spine Center
Pennsylvania Robert S. Gotlin DO, FAAPMR University of Washington St. Mary’s Hospital and Medical
Philadelphia PA Director, Orthopaedic and Sports Seattle WA Center
USA Rehabilitation USA San Francisco CA
Assistant Professor, Rehabilitation USA
Michael B. Furman MD, MS Medicine Syed Anees Hasan MD
Clinical Assistant Professor Albert Einstein College of Medicine at Spine Fellow Raymond D. Hubbard MD
Department of Physical Medicine and Yeshiva University Penn Spine Center, HUP Pre-doctoral Fellow
Rehabilitation Department of Orthopaedic Surgery University of Pennsylvania Health Department of Bioengineering
Temple University School of Continuum Center for Health and System University of Pennsylvania
Medicine Healing Philadelphia PA Philadelphia PA
Philadelphia PA New York NY USA USA
USA USA
Sara Ruth Sanne Haspeslagh, MD, Christopher W. Huston MD
Rollin M. Gallagher MD, MPH, M. Sean Grady MD FIPP Consultant to Phoenix Suns, Mercury
DABPM Professor and Chairman Anesthesiologist, Pain Specialist and Arizona Rattlers
Director of Pain Management Department of Neurosurgery Department of Anesthesiology The Orthopedic Clinic Association
Department of Anesthesiology University of Pennsylvania School of AZ Sint-Augustinus Hospital Phoenix AZ
Philadelphia Veterans Affairs Medical Medicine Wilrijk USA
Center Philadelphia PA Belgium
Victor W. Isaac MD, FAAPMR
Philadelphia PA USA
James Heavner PhD, DVM Associate Director
USA
Richard D. Guyer MD Professor Center for Spine, Joint and Neuro-
Steven R. Garfin MD Associate Clinical Professor Department of Anesthesiology muscular Rehabilitation
Professor and Chair Department of Orthopedics Texas Tech University Health Sciences Brentwood TN
Department of Orthopedics University of Texas Center USA
University of California San Diego PlanoTX Lubbock TX
United States Zacharia Isaac MD
San Diego CA USA
Instructor
USA
Andrew J. Haig MD, FAAEM, Johannes Hellinger MD Physical Medicine and
Timothy A. Garvey MD FAAPMR Professor of Orthopaedics, Spine Rehabilitation
Staff Surgeon Associate Professor Surgeon Harvard Medical School
Twin Cities Spine Center Physical Medicine and Department of Orthopaedics Chestnut Hill MA
Minneapolis MN Rehabilitation Isar Klinik Munich USA
USA and Orthopedic Surgery Munich
University of Michigan Germany
Ann Arbor MI
USA

xi
List of Contributors

James D. Kang MD Daniel H. Kim MD, FACS Joseph M. Lane MD Donald Liss MD
Professor of Orthopaedic and Neuro- Assistant Clinical Professor Professor Orthopaedic Surgeon Assistant Clinical Professor of
logical Surgery Department of Orthopaedic Surgery Orthopaedic Surgery Rehabilitation Medicine
Department of Orthopaedic Surgery The Boston Spine Group Hospital for Special Surgery Columbia University College of
University of Pittsburgh School Boston MA New York NY Physicians and Surgeons
of Medicine USA USA New York NY
Pittsburgh PA and Attending Physician
David H. Kim MD Hoang N. Le MD
USA The Physical Medicine and
Assistant Clinical Professor Clinical Instructor in Neurosurgery Rehabilitation Center
Brinda S. Kantha DO Department of Orthopaedic Surgery Department of Neurosurgery Englewood NJ
Attending Physician Tufts University Medical School Stanford Medical Center USA
New Jersey Institute of Minimally New England Baptist Hospital Palo Alto CA
Invasive Spine Surgery The Boston Spine Group USA Howard Liss MD
West Orange NJ Boston MA Assistant Clinical Professor of
USA USA Kathryn E. Lee Rehabilitation Medicine
Pre-doctoral Fellow Columbia University College of
Frederick S. Kaplan MD Mark A. Knaub MD Department of Bioengineering Physicians and Surgeons
Isaac and Rose Nassau Professor of Assistant Professor of Orthopaedics University of Pennsylvania New York NY
Orthopaedic Molecular Medicine and Rehabilitation Philadelphia PA and Attending Physician
Department of Orthopaedic Surgery Penn State Milton S. Hershey Medical USA The Physical Medicine and
University of Pennsylvania School of Center
Sang-Heon Lee MD, PhD Rehabilitation Center
Medicine Penn State College of Medicine
Physiatrist Englewood NJ
Philadelphia PA Hershey PA
Research Physician USA
USA USA
Spinal Diagnostics and Treatment
Brian J. Krabak MD, MBA Steven M. Lobel MD
Jaro Karppinen MD, PhD, BSc Center
Clinical Associate Professor Fellow
Professor of Physical and Daly City CA
Department of Rehabilitation Georgia Pain Physicians Training
Rehabilitation Medicine USA
Medicine Program
Department of Occupational Atlanta GA
University of Washington David A. Lenrow MD, JD
Medicine USA
Seattle WA Vice Chair of Clinical Affairs
Finnish Institute of Occupational
USA Associate Professor
Health Carmen E López-Acevedo MD
Department of Physical Medicine
Oulu Associate Professor
Elliot S. Krames MD and Rehabilitation
Helsinki Department of Physical Medicine,
Medical Director Hospital of the University of
Finland Rehabilitation and Sports Medicine
Department of Anesthesiology Pennsylvania
Pacific Pain Treatment Centers University of Puerto Rico School of
Yoshiharu Kawaguchi MD, PhD Philadephia PA
San Francisco CA Medicine
Assistant Professor USA
USA San Juan
Department of Orthopaedic Surgery Paul H. Lento MD Puerto Rico
Toyama Medical and Pharmaceutical Assistant Professor, Northwestern
Per O. J. Kristiansson MD, PhD
University Medical School and Susan M. Lord BMedSc, BMed, PhD,
Associate Professor of General
Toyama Attending Physician, Center for Spine, FANZCA, FFPMANZCA
Practice
Japan Sports and Occupational Staff Specialist, Pain Medicine
Department of Public Health and
Rehabilitation Division of Anaesthesia, Intensive
Christina Kerger Hynes MD Caring Sciences
Rehabilitation Institute of Chicago Care & Pain Management
Attending Physician, Women’s Health Uppsala University
Chicago IL John Hunter Hospital
Rehabilitation Uppsala
USA New Lambton Heights NSW
Rehabilitation Institute of Chicago Sweden
Australia
Instructor, Physical Medicine and Isador H. Lieberman BSc, MD, MBA,
Rehabilitation Jukka-Pekka Kouri MD FRCS(C) William W. Lu PhD, MHKIE
Northwestern University Feinberg Specialist in Physical Medicine and Professor of Surgery Associate Professor
School of Medicine Rehabilitation Spine Institute Department of Orthopaedics and
Chicago IL Pain Specialist Cleveland Clinic Traumatology
USA Helsinki Cleveland OH The University of Hong Kong
Finland USA Hong Kong
Byung-Jo Kim MD, PhD China
Associate Professor of Neurology Richard D. Lackman MD, FACS Julie T. Lin
Department of Neurology Associate Professor and Chairman Assistant Professor Keith D. K. Luk
Korea University College of Department of Orthopaedic Surgery Department of Rehabilitation Professor of Orthopaedic Surgery
Medicine Hospital of the University of Medicine Department of Orthopedic Surgery
Seongbuk-Gu Pennsylvania Weill Medical College of Cornell Duchess of Kent Children’s Hospital
Seoul Philadelphia PA University University of Hong Kong
Korea USA New York NY Hong Kong
USA China
Choll W. Kim MD, PhD Francis P. Lagattuta MD
Assistant Professor, Minimally Fellowship Director Jason S. Lipetz MD Gregory E. Lutz MD
Invasive Orthopaedic Surgery LAGS Spine and Sportscare Medical Assistant Professor Physiatrist-in-Chief
Department of Orthopaedic Surgery Center, Inc. Department of Rehabilitation Medicine Hospital for Special Surgery
University of California Santa Maria CA Albert Einstein College of Medicine New York NY
San Diego CA USA East Meadow NY USA
USA USA

xii
List of Contributors

Jean-Yves Maigne MD Ian Bruce McPhee FRACS (ortho) Michael Ray Moore MD Ashley Lewis Park MD, FACP
Head, Department of Physical Associate Professor Orthopaedics Clinical Assistant Professor of Clinical Assistant Professor of Medicine
Medicine Division of Orthopaedics Surgery Department of Internal Medicine
Hôtel-Dieu Hospital The University of Queensland The Bone and Joint Center Division of Rehabilitation
Paris Queensland The University of North Dakota University of Tennesee College of
France Australia School of Medicine and Health Medicine
Sciences Staff Physician, Campbell
Gerard A. Malanga MD Samir Mehta MD Bismarck ND Orthopaedic Clinic
Director, New Jersey Sports Institute Resident USA Germantown TN
New Jersey Medical School Department of Orthopaedic Surgery USA
West Orange NJ University of Pennsylvania Michael H. Moskowitz MD MPH
USA Philadelphia PA Assistant Clinical Professor Vikram Parmar MD
USA Anesthesiology and Pain Medicine Physician
Julie Marley PT, Dip MDT University of California Davis Opelousas General Health System
Physical Therapist Renée S. Melfi MD
Sacramento CA Opelousas LA
Spine Center Physician
and Bay Area Pain Medical Associates USA
Christiana Spine Center Physical Medicine and Rehabilitation
Mill Valley CA
Newark NJ Orthopaedic Associates of Central Rajeev K. Patel MD
USA
USA New York Assistant Professor Orthopaedics
Syracuse NY S. Ali Mostoufi MD Department of Orthopaedics
Richard Materson MD USA Interventional Physiatrist University Orthopaedic Associates
Clinical Professor, Physical Medicine MGH Spine Center Pittsford NY
and Rehabilitation Thomas Metkus BS
MGH Pain Clinic USA
Baylor College of Medicine and Associate Professor
Boston MA
University of Texas Medical School Department of Neurosurgery Andrew Perry MD
USA
and Chairman of the Board, Institute University of Pennsylvania School of Orthopaedic Resident
for Religion and Health Medicine Scott F. Nadler DO University of California San Diego
Texas Medical Center Philadelphia PA Formerly, Professor San Diego CA
Houston TX USA Physical Medicine and Rehabilitation USA
USA Randolph NJ
Mathew Michaels MD Frank M. Phillips MD
USA
Christopher J. Mattern MD Consultant Professor of Orthopaedic Surgery
Orthopaedic Resident Georgia Pain Physicians, PC Stefano Negrini MD Rush University Medical Center
Hospital for Special Surgery Atlanta GA Scientific Director Chicago IL
New York NY USA Italian Scientific Spine Institute (ISICO) USA
USA Milan
William F. Micheo MD Robert J. Pignolo MD, PhD
Italy
Eric A.K. Mayer MD Chairman and Professor Assistant Professor of Medicine
Physician Department of Physical Medicine, Markus Niederwanger MD Department of Medicine
Productive Rehabilitation Institute of Rehabilitation and Sports Medicine Fellow Division of Geriatric Medicine
Dallas for Ergonomics University of Puerto Rico School of Georgia Pain Physicians Training University of Pennsylvania School of
Dallas TX Medicine Program Medicine
USA San Juan Atlanta GA Philadelphia PA
USA USA USA
Tom G. Mayer MD
Medical Director, Productive Evan R. Minkoff DO Conor W. O’Neill MD Christopher T. Plastaras MD
Rehabilitation Institute of Dassas Physician Comprehensive Spine Diagnostics Assistant Professor
for Ergonomics Desert Pain and Rehabilitation Medical Group, Inc Physical Medicine and Rehabilitation
Clinical Professor of Orthopedic Associates Daly City CA Feinberg Northwestern School of
Surgery Palm Desert CA USA Medicine
University of Texas Southwestern USA Chicago IL
Medical Center Donna D. Ohnmeiss Dr.Med USA
Peter J. Moley MD President
Dallas TX
Assistant Attending Physiatrist Texas Back Institute Research Franco Postacchini MD
USA
HSS Affiliated Physician’s Office Foundation Professor of Orthopaedic Surgery
Frank McCabe MPT Cert. MDT Old Greenwich CT Plano TX Clinical Orthopedics
Physical Therapist USA USA University of Rome ‘La Sapienza’
Physical Therapy Rome
Marco Monticone MD Raymond W.J.G Ostelo PhD, PT
Wallace, Glick and McCabe Physical Italy
Researcher Doctor of Epidemiology
Therapy and Fitness
Italian Scientific Spine Institute Institute for Research in Extramural Roberto Postacchini MD
Montgomery PA
Milan Medicine (EMGO) Professor of Orthopaedic Surgery
USA
Italy Institute VU Medical Centre Clinica Ortopedica
Colleen McLaughlin BSRT Amsterdam University of Rome ‘La Sapienza’
Gul Moonis MD
Radiology Technologist The Netherlands Rome
Assistant Professor of Radiology
Penn Spine Center Italy
Department of Radiology/Neuro- Jeffrey Ostrowski PT
University of Pennsylvania Health
radilgy Division Physical Therapist Ben B. Pradhan MD, MSE
System
University of Pennsylvania Medical Excel Physical Therapy Director of Clinical Research
Philadelphia PA
Center Philadelphia PA The Spine Institute
USA
Philadelphia PA USA Santa Monica CA
USA USA

xiii
List of Contributors

Joshua P. Prager MD, MS, DABPM Ryan S. Reeves MD Terry C. Sawchuk MD Ramnik Singh MD
Director Medical Director, Spine Team Texas Adjunct Professor Attending Physician
Department of Anesthesiology and Attending Physiatrist, Spine Team Intermountain Spine Institute Institute for Spinal Disorders
Internal Medicine Texas University of Utah Cedars-Sinai Medical Center
UCLA Pain Medicine Center Southlake TX Salt Lake City UT Los Angeles CA
Los Angeles CA USA USA USA
USA
Luke Rigolosi MD Jerome Schofferman MD Clayton D Skaggs DC
Heidi Prather DO Physical Medicine and Rehabilitation Director of Research and Associate Professor of Research
Associate Professor New Jersey Medical School Education Logan University
Chief, Section of Physical Medicine University of Medicine and Dentistry Spine Care Medical Group Adjunct Instructor
and Rehabilitation of New Jersey San Francisco Spine Institute Department of Obstetrics
Department of Orthopedics University Hospital Daly City CA Washington University
Washington University School of Newark NJ USA St Louis MO
Medicine USA USA
St Louis MO James Schuster MD, PhD
USA Hubert L. Rosomoff MD, DMedSc, Jan Slezak MD
Assistant Professor
FAAPM Medical Director of Northeast Pain
Department of Neurosurgery
Adriana S. Prawak DO Medical Director Research Center
The Hospital of the University
Attending Physician and Partner The Rosomoff Comprehensive Pain Interventional Spine Medicine
of Pennsylvania
Sports and Spine Rehabilitation and Rehabilitation Center Barrington NH
Philadelphia PA
Division Miami Jewish Home and Hospital at USA
USA
Premier Orthopaedic and Sports Douglas Gardens
Medicine Associates, LTD Miami Beach FL Eric D. Schwartz Curtis W. Slipman MD
Havertown PA USA Associate Professor of Radiology Director, Penn Spine Center
USA Department of Radiology/Neuro- Associate Professor of Physical
Renee Steele Rosomoff RN, BSN, radiology Division Medicine and Rehabilitation
Joel M. Press MD MBA University of Pittsburgh Medical University of Pennsylvania Health
Attending Physician Program Director Center System
Spine and Sports Rehabilitation The Rosomoff Comprehensive Pain Pittsburgh PA Philadelphia PA
Center, Rehabilitation Institute of and Rehabilitation Center USA USA
Chicago Miami Beach FL
and Associate Professor USA Rinoo Vasant Shah MD, DABPMR, Wesley L. Smeal MD
Department of Physical Medicine and DABPMR (Pain), DABPM Attending Physician, Spine and
Rehabilitation Sarah M. Rothman Assistant Professor Sports Rehabilitation Center
Northwestern University Pre-doctoral Fellow Department of Anesthesiology Rehabilitation Institute of Chicago
Feinberg School of Medicine Department of Bioengineering Guthrie Clinic Instructor, Department of Physical
Chicago IL University of Pennsylvania Horseheads NY Medicine and Rehabilitation
USA Philadelphia PA USA Northwestern University – Feinberg
USA School of Medicine
G. X. Qiu MD Parag Sheth MD Chicago IL
Professor of Orthopaedic Surgery Assistant Professor of Medicine
Anthony S. Russell MA, MBBChir, USA
Department of Orthopaedic Surgery Department of Rehabilitation Medicine
FRCP, FRCPC, FACP
Peking Union Medical College Mount Sinai School of Medicine
Professor of Medicine Jennifer L. Solomon MD
Hospital New York NY
University of Alberta Clinical Instructor
Beijing USA
Edmonton AB Physical Medicine and
PR China Canada Rehabilitation
Frederick A. Simeone MD, FACS
Gabor B. Racz MD, DABA, FIPP, Weill Medical College of Cornell
Emeritus Professor of Neurosurgery
Bjorn Rydevik MD, PhD University
ABMP, ABIPP University of Pennsylvania School of
Professor of Orthopaedic Surgery New York NY
Professor and Chair Medicine
Department of Orthopaedics USA
Department of Anesthesiology and Philadelphia PA
Salgrenska University Hospital
Pain Management USA
Gothenburg Hillel M. Sommer MD, FRCPC, CSPQ,
Texas Tech University
Sweden Dip. Sport Med
Lubbock TX Alexander C. Simotas MD
USA Assistant Professor of Rehabilitation Associate Professor
Durgadas Sakalkale MD Physical Medicine and
Medicine
Kristjan T. Ragnarsson MD Clinical Instructor Rehabilitation
Physical and Rehabilitative Medicine
Professor and Chairman Department of Orthopaedics and University of Manitoba
Weill Medical College of Cornell
Department of Rehabilitation Medicine Rehabilitation Winnipeg MB
University
Mount Sinai Medical Center Yale University School of Medicine Canada
New York NY
New York NY New Haven CT USA
USA USA Brad Sorosky MD
Gurkirpal Singh BS, MBBS, MD Clinical Instructor
Raj D. Rao MD Robert Savarese DO Adjunct Clinical Professor of Medicine Department of Physical Medicine and
Director of Spine Surgery Physician Division of Gastroenterology and Rehabilitation
Department of Orthopedic Surgery Jacksonville Orthopedic Institute Hepatology Northwestern Feinberg School of
Medical College of Wisconsin Jacksonville FL Stanford University School of Medicine Medicine
Milwaukee WI USA Stanford CA Chicago IL
USA USA USA

xiv
List of Contributors

Daniel Southern MD Carlos F. Tirado MD Christophe Van de Wiele MD, PhD Douglas S. Won MD
Danbury Orthopedic Associates Clinical Research Fellow in Addiction Department of Nuclear Medicine Attending Spine Surgeon
Danbury CT University of Pennsylvania Treatment University Hospital Gent Southwest Spine Institute
USA Research Centre Gent Irving TX
Philadelphia PA Belgium USA
Gwendolyn A. Sowa MD, PhD USA
Assistant Professor of Physical Maarten van Kleef Kirkham Wood MD
Medicine and Rehabilitation John E. Tobey MD Head of Department of Anesthesiol- Associate Professor
Center for Sports, Spine and Clinical Instructor, Department of ogy and Pain Management Department of Orthopaedics
Occupational Rehabilitation Physical Medicine and Rehabilitation Pain Management and Research Center Massachusetts General Hospital
Pittsburgh PA University of Colorado Health University Hospital Maastricht Boston MA
USA Sciences Center Maastricht USA
Boulder CO The Netherlands
Milan P. Stojanovic PhD USA Chandra S Yerramalli PhD
Director, Interventional Pain Program Jan Van Zundert MD, PhD, FIPP Department of Orthopaedic Surgery
HMS Anaesthesia Daisuke Togawa MD, PhD Head of Multidisciplinary Pain Centre McKay Orthopaedic Research Laboratory
Massachusetts General Hospital Adjunct Staff Anesthesiologist, Department of University of Pennsylvania
Boston MA Spine Centre Anesthesiology, Pain Management Philadelphia PA
USA Hakodate Central General Hospital and Research Centre, USA
Hakodate City University Hospital Maastricht
William J. Sullivan MD Hokkaido Maastricht Anthony T. Yeung MD
Assistant Professor Japan The Netherlands Orthopedic Surgeon
Department of Physical Medicine Arizona Institute for Minimally
and Rehabilitation Jesse T. Torbert MD, MS Kamen Vlassakov MD Invasive Spine Care
University of Colorado at Denver and Orthopaedic Tumour Post-Doctoral Director, Division of Orthopaedic and Arizona Orthopedic Surgeons
Health Sciences Centre Research Fellow Regional Anesthesia Phoenix AZ
Aurora CO Pennsylvania Hospital Brigham and Women’s Hospital USA
USA Philadelphia PA Boston MA
USA Christopher Alan Yeung MD
USA
Gul Koknel Talu MD Voluntary Clinical Instructor
Carlo Trevisan MD
Associate Professor of Anesthesiology John B. Weigele MD, PhD Department of Orthopedic Surgery
Medical Specialist Surgeon in
Department of Algology Assistant Professor of Radiology University of California San Diego
Orthopedics
Medical Faculty of Istanbul University Department of Radiology School of Medicine
Clinical Orthopedics
Istanbul Hospital of the University of Phoenix AZ
University of Milan–Bicocca
Turkey Pennsylvania USA
Monza
Philadelphia PA
Andrea Tarquinio RN Italy
USA Way Yin MD
Head Nurse John J. Triano DC, PhD, FCCS(C) Medical Director
Penn Spine Center Director William C. Welch MD Spinal Diagnostics; Interventional
Hospital of the University of Chiropractic Division Chief of Neurosurgery, Pennsylvania Pain Management
Pennsylvania Texas Back Institute Hospital Interventional Medical Associates of
Philadelphia PA Plano TX Professor of Neurosurgery Bellingham, PC
USA USA Clinical Practices of the University of Bellingham WA
Pennsylvenia USA
Philip Tasca MD Mark D. Tyburski MD University of Pennsylvania Health
Assistant Clinical Professor of Physiatrist System Faisel M. Zaman MD,
Rehabilitation Medicine Department of Physical Medicine and Philadelphia PA FAAPMR&ABPM
Columbia University Medical Center Rehabilitation USA Interventional Physiatrist
New York NY Spine Clinic Intermountain Spine Institute
and Interventional Physiatrist Roseville CA C. Y. Wen MMedSc MBBS Affiliate Faculty, University of Utah
The Physical Medicine and USA Department of Orthopaedics and Division of Physical Medicine and
Rehabilitation Center, PA Traumatology Rehabilitation
Englewood NJ Mohammad N. Uddin MD Clinical Science Building Salt Lake City UT
USA Pain Management Physician Prince of Wales Hospital USA
APAC Centers for Pain Management Hong Kong
Santhosh A. Thomas DO, FAAPM&R Chicago IL China James F. Zucherman MD
Medical Director, Spine Center USA Medical Director
Co-Director, Medical Spine Fellowship Robert E. Windsor MD FAAPMR Orthopedic Spine Surgeon
Cleveland Clinic Foundation Alexander Vaccaro MD, FACS FAAPM FAAEM St Mary’s Spine Center
Westlake OH Professor and Co-chief, Spine Division President San Francisco CA
USA Department of Orthopaedic Surgery Georgia Pain Physicians, PC USA
Rothman Institute Atlanta GA
Issada Thongtrangan MD Philadelphia PA USA
Department of Neurosurgery USA
Stanford University Medical Center Beth A. Winklestein PhD
Vijay B. Vad MD
Palo Alto CA Assistant Professor of Bioengineering
Assistant Professor
USA and Neurosurgery
Department of Rehabilitation Medicine Department of Bioengineering
Weill Medical College of Cornell University of Pennsylvania
University Philadelphia PA
New York NY USA
USA

xv
Preface

Two decades ago, the notion that the variety of disciplines that practice can be managed with medications, therapy and possibly injection
spine care would universally embrace the concept of a comprehensive or other percutaneous procedures. We want the reader to under-
algorithmic approach was an anathema. While this methodical, step- stand when surgery can be delayed, when it should be avoided, and
wise approach had been practiced by the spine surgical community when it is required. It is also our hope that this text will provide a
the other specialties treating patients with spinal disorders have had a stepwise approach for those patients that have disorders that fall
haphazard orientation. Some disciplines offered a singular technique, under the former two situations. Some of our algorithms are uni-
which was used to treat all painful conditions, while others used ‘a versally accepted, while others represent the idiosyncratic approach
little of this, and a little of that’. As the years passed, a variety of in- of the author. In fact, there are several instances in which the same
fluences have irrevocably changed the perspective that conservative problem is attacked in a different way by two authors. Since the
care cannot be appropriately integrated with the surgical approach. science of medical rehabilitation and interventional spine care is
Among the propelling factors have been cohort and randomized stud- evolving, it is no surprise that spine practitioners may have differ-
ies of patients undergoing medical rehabilitation and interventional ent views regarding which tests to request, the order of diagnostic
spine care; an explosion in the number of physicians who practice and treatment interventions and which therapeutic alternatives are
interventional spine/pain medicine; education of the lay communi- best. However, within that expected and reasonable diversity of
ty, which has been accelerated by the internet, and their desire to opinion a central belief should be conveyed to the reader. Patients
pursue the least aggressive treatment available; and malpractice law- deserve the least aggressive care feasible, but the alternatives must
suits predicated on surgery having been performed without adequate be chosen by the individual spine practitioners’ interpretation of the
conservative treatment. This book represents the culmination of the literature and their clinical experience. When this is accomplished,
growth and development of the diagnosis and treatment of patients an algorithmic approach can be offered that adequately balances
with spinal pain. Indeed, the composition of editors underscores the the potential outcomes and known side effects or complications.
importance this integrated approach has taken. As our understanding of painful spinal disorders evolves we should
Our focus has been to write about algorithmic approaches for a expect that most patients with a particular disorder will be treated
variety of conditions. A basic premise and a central theme of this in a similar fashion and we believe this textbook places us closer to
text is that certain disorders require immediate surgery, but most this penultimate goal.
Curtis W. Slipman
2007

xvii
Acknowledgments

The development and production of a textbook of this scope is an Jackson, Zac Isaac, Atul Bhat, Russell Gilchrist, Mike Frey, Phil
enormous task and requires the assistance of numerous individuals. Tasca, Sarjoo Bhaggia, Omar el Abd, Michael DePalma, Raj Patel,
My appreciative comments begin with my residency at Columbia David Chow, Frank Bender, Carl Shin, Amit Bhargava, Aleya Salem,
Presbyterian Medical Center and its residency director, Erwin Victor Isaac, Faisel Zaman, Serge Menkin, Steven Helper, and Paul
Gonzalez. During the past 24 years he has served as a mentor and Singh. Their enthusiasm, intellect and hard work have created the
enthusiastic supporter. In 1992 when I was recruited to develop opportunity to see a large volume of patients, conduct research and
the Penn Spine Center, it was Alfred Fishman who had the vision, refine my views on interventional spine care. There have been a few
political prowess and guidance to insure that interventional physiatry individuals who as medical students shared their time, enthusiasm
would thrive in an academic setting. Concurrently, Ron Wisneski, and intellect who deserve recognition, Larry Chou, Chris Plastaras,
whose tenure of chief of orthopedic spine surgery temporarily over- Alfred Campbell, Catherine Loveland-Jones and Jason Berke. My
lapped with my presence at The University of Pennsylvania, helped current chairman, Richard Salcido, and a number of staff members
formulate the idea of an algorithmic approach to neck and back pain. at the Penn Spine Center were particularly supportive of the time
Since my arrival at Penn an exponential growth in my education of and effort I needed to devote to the writing and editing of this
spine care occurred. Richard Herzog provided the foundation and text including Andrea Tarquinio, Colleen McLaughlin and Lynette
nuances for the interpretation of radiological studies, Ron Wisneski Rundgren. The editorial staff at Elsevier, Joanne Scott, Amy Head,
and Ed Vresilovic shared the surgical perspective and were open to Cecilia Murphy, Susan Pioli, Dolores Meloni and Rolla Couchman
learning and employing a Physiatric perspective. Of course there deserve enormous thanks for their dedication, attention to detail
were and remain many physicians with whom I have practiced that and perseverance. Without their effort and guidance this book
have a played a key role in my understanding of spinal disorders. would not exist. I want to thank the physicians who have been the
Among them are Lori Loevner, Evan Siegelman, Robert Grossman, pioneers and leaders in interventional spine for the last two decades.
Murray Dalinka, Robert Hurst, Paul Marcotte, David Lenrow, Fred These individuals created the opportunity all of us are now enjoy-
Kaplan, Mark Ellen, Larry Chou, Dawn Elliot, and Beth Winklestein. ing. Join me in extending appreciative thoughts to Scott Nadler,
Several physicians who practiced outside of Penn were instrumen- Rick Derby, Nic Bogduk, Jeff Saal, Stan Herring, Joel Press, Charles
tal in the growth of the Penn Spine Center and in my spine edu- Aprill, Guisseppe Bonaldi, Paul Dreyfus, and Stu Weinstein. Finally
cation including Fred Simeone and Giancarlo Barolat. Perhaps the a deep heartfelt thanks to the co-editors of this text, Rick Derby,
single most valuable contribution to my understanding of spine care Fred Simeone, Tom Mayer, David Lenrow, Kingsley Chin, Salahadin
comes from the Penn Spine Center Fellows; Elliot Sterenfeld, Chris Abdi and Larry Chou. Their input has been invaluable and their
Huston, David DeDanious, Randy Palmitier, Jason Lipetz, Howard energy irreplaceable.
Curtis W. Slipman
2007

xix
To Jared
PART 1 GENERAL PRINCIPLES
Section 1 Introduction

CHAPTER
Past, Present, and Future
1 of Interventional Physiatry
Richard Materson

THE PAST War One, however, produced sufficient casualties, many with mus-
One might inquire what a history and philosophical chapter is doing culoskeletal injuries, that would become chronic and which seemed
in an evidence-based clinical textbook. Interventional spine proce- to improve when treated with physical modalities including hydro-
dures by physiatrists at first glance seem simply to be an outgrowth therapy and therapeutic exercise and newly harnessed portions
of physical medicine, a clinical right turn justified by new informa- of the electromagnetic spectrum. With the lead of the American
tion similar to other changes in medical practice such as interven- Medical Association in the 1915–21 time frame, a group of physical
tional cardiology. But the role of the practitioner is so fundamentally modality experts were called together to see how more physicians
changed from previous roles that a deeper inquiry is invited. How might learn about and put to use these procedures. The AMA Board
do such striking ‘about-faces’ occur in medicine? What and who pro- of Trustees approved this group, called the American Congress of
motes these changes and how are they accomplished? After all, a hos- Physical Therapy, in September 1921. It was not to be the start of
pital-based practitioner can’t simply announce one day that he or she a new specialty, but rather a task force to enhance knowledge and
is going to have entry to a surgical suite or intervention room and skills. It consisted of physicians from medicine, most of whom were
do new procedures. The author is grateful to the many early mem- attached to academic centers and who had studied and advocated for
bers of the Physiatric Association of Spine Sport and Occupational these methods. The AMA had previously and subsequently stimu-
Rehabilitation (PASSOR) who were willing to e-mail to the author lated and assisted the creation of the American College of Surgeons
their observations regarding how they became involved is this move- (ACS) and the American College of Physicians (ACP) and several
ment, who influenced them, and in which directions they believe we surgical and medical specialty organizations. With the American
are evolving. Association of Medical Colleges (AAMC) and the Association of
Most of organized medicine, including its Boards, Academies and Teaching Hospitals, the AMA, ACP, and ACS, the idea of creden-
educational hierarchy, justify their existence by including words such tialing individuals who were willing to subject themselves to addi-
as ‘in the public interest …’ in their constitution or bylaws preamble. tional postgraduate education, training, and experience and who
None should believe that such baser needs such as ego, power, control, were willing to put their knowledge and skills to a test, thereby
and economic well-being and keeping a practice away from ‘the other identifying properly trained ‘specialists’ for the public. The medi-
guy’ do not play a role as well. The trick to good organizational manage- cal schools came under the supervision of the Liaison Council for
ment and maintenance of the voluntary system of medical accredita- Medical Education (LCME), the residencies under residency review
tion is to be sure the balance favors public good a great deal more than committees (RRCs) appointed jointly by the AMA section councils
the practitioner benefit. and specialty societies and supervised by the Accreditation Council
The development of interventional physiatry represents a model on Graduate Medical Education (ACGME) and the American Board
study of how change is reasonably brought about in medical practice. of Medical Specialties (ABMS), continuing education led by the
If one reviews the history of the practice of medicine in the United Council on Medical Specialty Societies (CMSS). The various liaison
States since Flexner’s report,1 the complex story of organized medi- groups had representation from practitioners, academicians, hospi-
cine is found to be the string in the supersaturated sugar solution (the tals, boards, and medical and surgical academies. When federal dol-
great mix of knowledge, attitudes, and practices) allowing the for- lars became prominent in support of medical education and practice,
mation of rock candy (the roles of the various medical and surgical government representatives were added, but control was always in
specialties). An approach through organized medical channels is the the hands of physician volunteers who were either elected by or
‘way’ to get desired changes. Change does not occur quickly, nor par- appointed by their peers to represent them.
ticularly smoothly; however, the system seems to work. Perseverance In its earliest days practitioners of physical medicine often shared
pays. Such has been the case for interventional physiatry. an interest in the newly developed area of ionizing radiation. In 1923,
Osler in medicine, and Halstead and others in surgery are names the American College of Radiology and Physiotherapy became the
known by every internist and surgeon. These pioneers opined that first physical medicine society. As radiology established itself as a
4 years of matriculation through even the best medical school curri- separate discipline, the organization’s name was changed to drop radi-
culum was inadequate to teach the volume and complexity of knowl- ology; however, the first journal was titled the Archives of Physical
edge, skills, and behaviors required to properly care for patients with Therapy, X-ray and Radium. In 1930, the organization became the
significant illness. Postgraduate medical education at the bedside was American Congress of Physical Therapy and in 1945, as the practice
required, and the development of a capacity for life-long professional of physical therapy became its own discipline, the name changed to
learning. the American Congress of Physical Medicine. By 1954, the World War
During the first 20 years of the twentieth century there was no Two-developed team concept of care, espoused by Howard Rusk and
such thing as a physical medicine and rehabilitation doctor. World George Deaver, caused another name change to Physical Medicine

1
Part 1: General Principles

and Rehabilitation. By 1967, the ‘team concept of rehabilitation’ funding at a time of virtual nonfunding for musculoskeletal disorders
devotees were of sufficient number to cause the name to change and research. These currents influenced the practitioners and their
to the American Congress of Rehabilitation Medicine. Their jour- representatives in the American Academy of Physical Medicine and
nal became the Archives of Physical Medicine and Rehabilitation. Rehabilitation. Those physicians with a more physical medicine orien-
Upon action from an AMA advisory council on medical specialties, tation often complained of inadequate attention and resource sharing
on June 6, 1947, eleven physiatrists became the first American Board in the Academy. In general, the physical medicine oriented physiat-
of Physical Medicine with Krusen as its first chairman and Zeiter as rists gravitated towards care of more acute neuro-musculo-skeletal
vice-chairman. A few physiatrists were ‘grandfathered’ and a total disorders including ever more ubiquitous spine related pain. In the
of 103 became the first listed Board Diplomats. In 1949 the board military, the training programs focused on physical medicine, with
name was changed to the American Board of Physical Medicine and rehabilitation to occur in the Veterans Administration system. In this
Rehabilitation following the trend towards rehabilitation. setting, and in the growing private musculoskeletal practice setting,
The group that was to become the American Academy of Physical the physiatrist saw acute patients and often provided full diagnostic
Medicine and Rehabilitation (PM&R) began in 1938–39 as an invita- and therapeutic care, referring to other specialties as was appropriate.
tion-only membership of 42 physical therapy physicians with an intent This conflicted with the rehabilitation model in which practitioners
of limiting membership to 100 physicians. After 1952, all Diplomats were describing their domain as ‘the third phase of medicine after
of the American Board of Physical Medicine and Rehabilitation were preventive medicine and acute care.’ In the latter paradigm, the phys-
invited to become members. In 1957, a conference was held to deter- iatrist did not have access to the patient except upon referral from a
mine the proper roles of the Academy versus the American Congress. physician or surgeon who were the primary practitioners.
The Congress was to control the journal, to provide interdisciplinary In preparation of this chapter, a call was sent to founding PASSOR
rehabilitation education, and to reach out to nonphysiatrist physi- members to identify the influences upon them to become members.
cians interested in the field. The Academy was to bring their mem- Perhaps the most frequently cited was the desire to become a pri-
ber physiatrists into closer collaboration with other physician peers mary practitioner for musculoskeletal patients. They were influenced
and concentrate on physiatric education and policy. The Academy by orthopedists such as James Cyriax, Arthur White, John Fromoyer,
was to represent the field in the AMA House of Delegates. Later, Malcolm Pope, W.H. Kirkaldy-Willis, and Alf Nachemson and some-
after considerable negotiation, the Archives of PM&R ownership times encouraged to become ‘nonoperative orthopedists’ in lieu of
were split by the Congress with the Academy for a purchase price physiatrists. They were also influenced by independent minded
of ‘$1.00 and considerations.’ Editorial Boards represented each physiatrists whose credentials in physical medicine were rich and
organization under an editor-in-chief. As the Academy grew, and as who were expert in use of modalities and therapeutic exercise, clini-
the various allied professions became more independent with policy cal kinesiology, and the newly developing field of electrodiagnostic
interests different at times from physicians, physiatric membership medicine such as V. Lieberson, Carl Granger, Justus Lehman, Ernest
in the Congress declined. Several attempts were made to work out Johnson, Myron Laban, Erwin Gonzalez, Ian MacLean, Joe Honet
ways to stay allied and share a common central office but a split and others. Henry Betts was identified as a facilitator sympathetic
was inevitable. The Congress now is independent of the Academy, to growth in this arena. Newer generations of PASSOR members
smaller in membership and has refocused itself to interdisciplinary were greatly influenced by Jeffrey and Joel Saal and their associ-
rehabilitation research. The Council of Academic Societies (CAS) ate Stan Herring. These physiatrists were often themselves sports-
of the Association of American Medical Colleges in 1967 rejected men whose interests gravitated in this direction. To this group add
the American Academy of Physical Medicine and Rehabilitation as those physiatrists whose practices included large numbers of injured
too broadly based to be a constituent member but at the same time workmen. Many of these patients suffered spine-related pain disor-
recognized the newly formed Association of Academic Physiatrists ders. The musculoskeletal physiatrists included also those who fol-
(AAP) to represent undergraduate and graduate medical education lowed the work of Janet Travell and Dave Simons in dealing with
interests and academic policy. the clinical entity of myofascial pain syndrome and those whose
The history of the specialty of Physical Medicine and Rehabilitation interests gravitated to arthritis and related disorders. Many of these
is covered in detail elsewhere and should be reviewed for a more com- physicians tended to feel that the Archives of Physical Medicine and
plete story.2–6 Elkins, Knapp, Bennett, Bierman, Kovacs, Molander, Rehabilitation, especially those issues sponsored by the American
Coulter, Zeiter, Krusen Ewerhardt and others were among the origi- Congress of Rehabilitation Medicine, did not adequately represent
nators of the field followed by Rusk, Deaver, Johnson, Lehman, their spine and musculoskeletal interests and did not believe the
Kottke, Stillwell and many more than can be mentioned here. Review Archives was well regarded by spine and sports peers in medicine.
will be rewarding to observe how a small group of dedicated The policy issues facing the main field of rehabilitation, which were
physicians gave much volunteer time and attention to the multiple primarily government regulatory-related, were of little concern to the
facets necessary for growth of a medical specialty. physical medicine practitioner who was not practicing in rehabilita-
One should appreciate that what began as a ‘physical medicine’- tion facilities but was more often office or clinic based. Furthermore,
oriented body of knowledge transitioned to a medical rehabilitation the educational offerings of the Academy were felt to slight the need
orientation over time. Physical medicine was never ‘lost;’ it was simply for both basic and advanced material from the musculoskeletal area,
less visible with the overriding mass appeal of rehabilitation as popu- especially spine and sport, and not to pay adequate attention to the
larized by Rusk.7 New York philanthropist Bernard Baruch played office practice needs of these physiatrists. The earliest and common
a major role in stimulating development of 12 departments that practice model, which continues today, was for the physiatrist to asso-
matriculated nearly 60 early physiatric pioneers. Baruch convinced ciate with an orthopedist or orthopedic group practice, becoming the
President Truman of the field’s contribution to the war and postwar member who did not perform surgery, but attended to diagnostics
effort. The President ordered military medical authorities to embrace and postoperative care. Government and insurance bodies tended to
the field. Civilian interest followed. Large infusions of federal dollars ‘bundle’ preoperative care, surgery, and limited postoperative care into
from the Medicare program followed. During the DeBakey era, heart one standard surgical fee. The surgeon now had a financial incentive to
disease and stroke held the top-tiered research support position. This pass on care to another specialist. Furthermoe, additional members
funding resulted in increased medical rehabilitation demands and in a group practice made investment in practice-owned diagnostic

2
Section 1: Introduction

imaging equipment and laboratories inviting and increased the fre- second. Both of these physiatrists were strongly identified with the
quency of use of the equipment. As physiatrists became competent movement to enhance the place of spine, sports and occupational
in interventional spine procedures, more struck out on their own or rehabilitation in the field. The Rosenthal award served not only to
became part of single-specialty (physiatric spine medicine) practice recognize outstanding and innovative practitioners such as the two
groups. Several academic programs became involved. Orthopedists mentioned and those Rosenthal awardees who followed, but indicated
and family practitioners laid claim to sports medicine, although sev- real interest on the part of the many physiatrists who overflowed the
eral physiatrists have become professional and school team physicians meeting rooms to hear these lectures. The Academy leadership had
and are highly regarded for their work. Physiatrists have become to be impressed with the quality of the presentations and the pro-
increasingly attractive to insurers and re-insurers as the physicians fessionalism of those who were listening. This was not simply some
of choice for industrial musculoskeletal injuries and post-trauma soft start-up group of malcontents, but rather a real wave of practitioners
tissue injuries. These physicians offer thorough history and physi- with like clinical interests.
cal examination, astute diagnostic capabilities, nonsurgical (read less Jeff Saal, MD, became the first physician at Stanford University
expensive) remediative and rehabilitative care, ability to collaborate to begin facet and image-guided epidural spinal injections. By 1987,
when surgery is indicated, and disability evaluation and management he, together with his brother Joel and associate Stanley Herring,
all in one place. The capacity to perform electromyography and diag- MD, began to teach two-day spinal injection courses which attracted
nostic and therapeutic blocks in carefully selected patients was an a larger number of applicants than could be accommodated. This
added benefit. type of course was integrated into Academy offerings. Short courses
During the 1980s the Academy of PM&R attempted to address were recognized to be inadequate to gain competency but served as
these musculoskeletal and related issues by permitting the develop- an introduction and facilitated the need for curricular design and
ment of special interest groups (SIGs) which became responsible Fellowship development. In 1989, the Saal brothers again made a
for developing education appropriate to their interest and promot- major contribution to understanding the rationale for antiinflam-
ing policy concerns to Academy Board attention. During the annual matory use in disc disease by describing disc disease treatment with
meeting, the Academy met the first part of a week, the Congress the epidural steroids and stabilization exercises and elaborating on the
second part, with the middle weekday for supposed integrated blend. inflammatory enzymes involved (PLA2). This attracted great addi-
Time and organizational collaboration was inadequate to meet the tional interest in interventional physiatry. The new data were particu-
needs of either party and disenchantment grew. There was even con- larly welcome in an era of ‘low back losers’ and Nachemsen’s articles
sideration of development of a new group outside of the Academy of regarding the great divergence of surgical rates between the United
PM&R to represent the interests of these musculoskeletal-oriented States and Sweden and describing the long-term natural course of
physiatrists. disc disease. By now the journal Spine was becoming well recognized
At the same time, the Academy Board, and in fact much of orga- as a place to publish spine-related material.
nized medicine, was involved in a great debate regarding subspecial- From 1983, a succession of Academy of PM&R Presidents (Grant,
ization and the credentialing of subspecialists. To the degree that Kraft, LaBan, Materson, Gonzalez, MacLean) were particularly impressed
groups identified special added competence, the issues of territori- with the need to reach out to their colleagues, pressing this move-
ality appeared, i.e. limitation to one kind of practitioner or open to ment, and were themselves interested in musculoskeletal medicine
members of vorious Boards of Specialty. Added to this were issues practice. Drs Opitz, de Lateur, Christopher, and Demopoulos were
of curriculum content definition and development of a critical mass interspersed with these others and, while personally more rehabilita-
of expert educators and clinical facilities to achieve the educational tion medicine oriented or balanced, paved the way for ascendancy of
standards. Would specialization prevent the general Diplomat from this area from a SIG to a higher-level entity within the Academy.
practice in the defined area? Would that in effect drive out com-
petition and be inflationary? Would subspecialty educational offer-
ings be available to all (generally making the offerings entry level)
THE PRESENT
or be at advanced level, good for the specialist but beyond benefit With the urging of LaBan, Honet and Gonzalez, Saal and others, the
to the generalist? Would an added credential become a requirement concept of making this group an official body of the Academy with
for hospitals and certifying organizations to allow privileges or access the ability to raise dues, put on educational offerings, and self-govern
to practitioners or for courts to recognize expertise? The Academy became real with the official creation of the Physiatric Association
(and medicine) resolved these issues differently in various areas such of Spine, Sports and Industrial Rehabilitation (PASSOR) in 1993
as pediatric rehabilitation, electrodiagnostic medicine, spinal cord with Jeff Saal, MD, as its first president. A three-year probationary
injury, and head injury rehabilitation. period for new councils was defined in the Academy Bylaws. PASSOR
There was waxing and waning of support for the musculoskeletal Founding members and Charter members are listed in Table 1.1 and
specialization at the Academy Board level depending on the rela- Table 1.2. The Founding members in particular all played important
tive representation of rehabilitation primary versus physical medi- roles in getting the organization established, supported the educational
cine primary practitioners on the Board. Quick fixes allowing SIGs programs and special courses as organizers and faculty, took leadership
greater access to program content met with resistance from program in the definition of a Fellowship curriculum, contributed to defini-
committee members who felt their control and ability to meet their tions for proper billing and procedure codes for this subspecialty, and
responsibilities challenged. At the same time, division over owner- represented the subspecialty to outside organizations and journals.
ship and editorial control of the Archives of PM&R raged on at a time They also contributed to the writing of the PASSOR Constitution
when the two organizations were growing ever more apart in their and Bylaws. Worried that feisty PASSOR leaders might lead a move-
aspirations and needs. ment to ‘jump ship’ from the Academy if their needs were not imme-
In 1983, the Richard and Hinda Rosenthal Foundation indicated diately met, the then Academy president appointed Joe Honet and
its wish to identify physiatrists less than 50 years of age who would Dick Materson, former Academy presidents, to an Advisory Board
be outstanding leaders in the clinical nonoperative care of low back for PASSOR and Myron LaBan as a Board Liaison. Their job was to
pain. An AAPM&R Rosenthal Lectureship was created with Myron see that ‘cooler heads’ prevailed and that PASSOR was given good
M. LaBan, MD, as the first recipient and Jeffery A Saal, MD, as the information on the best strategies to assure its needs were met. As an

3
Part 1: General Principles

Table 1.1: PASSOR Founding Members Table 1.2: PASSOR Charter Members

Jeffrey A. Saal, MD, Founding Chairman Terence P. Braden, III, DO


Richard P. Bonfiglio, MD Mark Steven Carducci, DO
Robert S. Gamburg, MD James P. Foydel, MD
Steve R. Geiringer, MD Michael Fredericson, MD
Erwin G. Gonzalez, MD Kenneth W. Gentilezza, MD
Peter A. Grant, MD Michael C. Geraci, Jr., MD
Andrew J. Haig, MD Jerel H. Glassman, MPH, DO
Stanley A. Herring, MD Richard A. Goldberg, DO
Gerald P. Keane, MD Robert S. Gotlin, DO
Francis P. Lagattuta, MD Robert Iskowitz, MD
Edward R. Laskowski, MD John Keun-Sang Lee, MD
Joel M. Press, MD Aaron M. Levine, MD
Joel S. Saal, MD Howard I. Levy, MD
Curtis W. Slipman, MD Donald Liss, MD
Barry S. Smith, MD Howard Liss, MD
William James Pesce, DO
Bernard M. Portner, MD
attendee at a majority of the subsequent board meetings, this author Stephen R. Ribaudo, MD
will testify as to the maturity, wisdom, professionalism, and dedica-
Robert D. Rondinelli, MD, PhD
tion of the founding officers and those leaders who have followed to
this date. Sridhar V. Vasudevan, MD
With Jeff Saal, MD, as Founding President of PASSOR and Erwin John C. Vidoloff, MD
Gonzalez his successor, administration of PASSOR and its transition
to a fully functioning academic organization proceeded at a remarkable
pace, withstanding the trials and tribulations of meeting the individual
desires of its well ego-defined Board personalities. A dues structure medicine and industrial medicine topics could be interspersed with
was necessary in order to put on programs, develop and disseminate those dealing with the spine (which was always highlighted by the
academic and marketing materials, enhance membership, promote Rosenthal Lecture presentation).
research, and reward visiting faculty for contributions. An initial Typical of similar organizations, a committee structure was seen
dues of US$300 per member per annum was agreed upon to which as desirable. Committees dealing with Constitution and Bylaws;
would be added the revenues from the successful and oversubscribed Nominations and Membership were first, followed by Education and
cadaver courses on injection techniques (now named the PASSOR Program, Research, Marketing and Communication, Medical Practice,
Spinal Procedures Workshop Series) and annual meetings fees. and Information Systems. Unlike too many other organizational com-
Disputes regarding the size of the economic commitment of mem- mittees, PASSOR members served faithfully and enthusiastically,
bership and its effect on both PASSOR membership and Academy with appropriate and timely reports requiring careful management
membership numbers, and access of PASSOR materials and educa- of board meetings to remain on course and on time. The presidents
tional events to non-PASSOR Academy members caused animated rose to the occasion so that motions were acted upon, either being
debate but were resolved. AAPM&R Bylaws stated Councils could
self-govern; however, all policy and procedure were required to be
consistent with Academy policy and subject to their overall approval.
The PASSOR Board controlled finances, but dues were collected and Table 1.3: PASSOR Past Presidents
finances reviewed and approved at Academy Board levels.
Jeffrey A. Saal, MD 1993–1994
Subsequent PASSOR presidents (see Table 1.3, PASSOR past
presidents) each identified major areas of emphasis for their presi- Erwin G. Gonzalez, MD 1994–1995
dential years. As frequently happens in similar organizations, discus- Joel S. Saal, MD 1995–1996
sion began to consider lengthening the presidential term to 2 years to
Joel M. Press, MD 1996–1997
allow task completion, as presidents discovered the tasks were great
and the time short. (A single-year term prevailed, encouraging presi- Robert E. Windsor, MD 1997–1998
dential efficiency). As PASSOR members demonstrated their ability Andrew J. Cole, MD 1998–1999
to plan and conduct highly valued educational offerings for the annual
Barry S. Smith, MD 1999–2000
AAPM&R session, they were allocated additional program time and
responsibility, evolving towards greater control of all musculoskeletal Gerard A. Malanga, MD 2000–2001
offerings. Aside from standard lectures and symposia, clinical demon- William F. Micheo, MD 2001–2002
strations were scheduled and some (such as joint examination) video-
Bruce E. Becker, MD 2002–2003
taped for future use. Topics were purposefully varied so that sports

4
Section 1: Introduction

approved, disapproved, or tabled, and with meaningful but limited curriculum, capacity, means of credentialing, and its effect on oth-
debate encouraged. This was carried out efficiently and with good ers and the public. Further pursuit by PASSOR members is active,
humor, with a minimum of bruised egos, which can be a part of such especially in the sports medicine arena.
undertakings. A review of the board meeting minutes, minutes of Confusion over the meaning of, pronunciation of, and marketing
telephone conferences, annual meetings, and reports to members usefulness of the term physiatrist has come up recurrently. A ‘nam-
demonstrate a continued thread of progress of important PASSOR ing’ organization was hired to study the issue and present choices
business. This was facilitated by outstanding administrative support for new name consideration and adoption. Observations of member’s
in the person of Dawn M. Levreau, staff liaison assigned by Academy practices and member interviews and polls were carried out with no
Executive Director Ronald A. Henrichs, CAE. Ms. Levreau was real consensus. Older members preferred to stay with ‘physiatrist,’
an Illinois State University graduate with a BS in economics and a younger members wished a name change. ‘Externist,’ ‘orthomyolo-
minor in Speech Communication who began work at the Academy in gist,’ ‘orthologist’ and others were discussed. The name was to apply
April, 1994. Her educational background, and 12 years of experience to muscuolskeletal-interested physiatrists, not replace ‘physiatrist.’
in association management, made her an invaluable contributor to The PASSOR board agreed that 90% of the members should favor
PASSOR growth. Those who serve in volunteer medical organization a change and polls were taken. Response was never adequate to be
roles recognize just how important good staffing is to an organization’s determinative, and in the interim, marketing could not be delayed.
success. Board and Committee and Task Force packets were prepared With time and exposure, more members seemed to be comfortable
in orderly fashion, agendas planned, meetings, speakers, meeting and with ‘physiatrist.’
exhibit space planned and carried out with flexibility and positive The AAPM&R Board decided to dip into reserves and launch a
attitude. The Academy board, other councils, committees, and staff major marketing program for the field. After considerable discussion
developed a pride in their work with PASSOR and sparked member the PASSOR Board decided also to invade reserves and make a major
enthusiasm with benefits. Rarely do members speak up when things financial and creativity contribution to the effort. The Academy
go well in organizations; rather, their loud protests are heard if some- Marketing and Communication staff was geared up for the effort
one is perceived to ‘muck up.’ In PASSOR’s history, praise for leader- and PASSOR members made outstanding contributions to brochure
ship and staff assistance has been a constant. development, newspaper inserts, speaker bureaus, and develop-
PASSOR members became interested in defining a model mus- ment of desktop office marketing materials aimed at patients, medi-
culoskeletal curriculum and muscuoskeletal physical examination cal colleagues, insurance companies, and adjusters. A USA Today
competencies for use in Fellowships and generally in postgraduate insert was highly regarded. The program was a remarkable success.
PM&R training programs. Evidence of a generally unsatisfactory low The PASSOR goal was to identify the physiatrist as the physician of
level of history taking and physical examination skills observed at choice (experts) for functional musculoskeletal rehabilitation. Drs K
Fellowship entry has propelled this into a major project. Plans to edu- Ragnarsson and Joel Press played major roles.
cate the instructors, identified in collaboration with the Association for Education has always been a mainstay of PASSOR. Officers and
Academic Physiatrists, were seen as a precursor to organizing curri- members generously gave of their time to produce AAPM&R annu-
cula and instructional materials. A traveling Fellowship was proposed al meeting muscuoskeletal programs and demonstrations. Mid-year
and is being explored so that a Fellow might gain from the varied advanced-level courses were offered with varied success in attract-
strengths of more than one teaching program. So as not to tread on ing attendance despite the high order of materials and lecturers. An
prerogatives of credentialing bodies, RRC, and Boards, these materi- exception was the PASSOR Spinal Procedures Workshops Series that
als were seen as approaches or guidelines rather than requirements was sufficiently popular to be offered at or about the time of the
for certification. Annual AAPM&R meeting and at mid-year on a regional basis.
Since fellowships were not formally defined, Dr. Slipman, in his Joel Press started the idea of a special bibliography with a sports
capacity of Chair of the Education Committee of PASSOR, developed topic while he chaired the first education committee. The work con-
the concept that a single credible reference source was necessary for tinued through Curtis Slipman’s chair of the committee and the two
residents who wished to seek elective fellowships of value. Together served as the editors of the final product. Following Brian A Casazza,
with committee member Terry Sawchuk he produced the first res- MD, and Jason Lipetz and others, the medical education committee
ident’s Fellowship Guide. Rob Windsor subsequently recognized saw to the development of bibliographies regarding major musculosk-
the need to differentiate between Fellowships PASSOR recognized eletal topics including Lower Extremity, Lumbar Spine, and Cervical
and those which it did not. Modest criteria for PASSOR recognition Spine as the initial three. All Fellowship Chairs are to review and
were set but the idea was set in motion that all Fellowships were not contribute to these documents. The bibliographies were placed in
created equal. More recently, Jason Lipetz, in his role as Education the PASSOR website as the new millennium brought PASSOR to the
Committee Chair, further raised the bar, as the entry requirement cyber-education age. Musculoskeletal and EMG case studies were
includes scholarly criteria (publications and scientific presenta- added after the pioneering contributions of Ian C. MacLean, MD,
tions). These materials were developed and disseminated and have to make the EMG case studies available for this methodology. These
become a valuable resource for trainees. PASSOR promulgated its continue to be contributed by Jason Lipetz, MD, and his medical
criteria for Fellowship Directors and model curricular content of education committee members who have also attempted to add a
fellowships. Programs could voluntarily supply information for the cyber journal club to the offerings. The Fellowship Guide and other
guide but PASSOR found itself incapable of policing the accuracy references were also made available online.
of the data even if it were desirable to do this. Nevertheless, the Informally, PASSOR members contributed to the Academy’s cyclic
guide has been highly valued by residents exploring such programs Study Guide sections promulgated through the Academy of PM&R’s
and informal truth-telling networks developed by resident’s ‘circuits’ Medical Education Committee (MEC). They also contributed to the
complemented the guides. Issues of practice privileges at hospitals Resident and Practitioner Self-Assessment materials published by
and institutions began to develop, with some physiatrists denied priv- the Academy’s MEC subcommittee on self-assessment (SAE-R and
ileges. This spurred investigation of formal subspecialization creden- SAE-P). Earlier, some papers authored by PASSOR members were
tials through the RRCs, the Boards, and the ABMS. Subspecialization developed and distributed as educational mini- monographs; however,
is a complex issue as previously alluded to in this chapter dealing with this has been discontinued. PASSOR Educational Guidelines for the

5
Part 1: General Principles

Performance of Spinal Injection Procedures was produced and addi- expertise to take learners through a well-devised curriculum and
tional education guides are planned. Promulgation of ‘practice guide- practical clinical demonstrations and experience. These courses were
lines’ was considered and rejected for a myriad of reasons including organized and carried out by PASSOR members with the capable
copyright and legal issues as well as an inability to keep such papers assistance of Academy staff. Professional meetings companies expert
current. Collaboration with the information steering function of the in the delicate arrangements for such courses helped arrange the
Agency for Health Care Research and Quality (AHRQ – formally cadaver courses. Space does not permit listing all of these outstanding
the Agency for Health Care Policy Research [AHCPR] of the educators; however, a few are mentioned here: Curtis Slipman, Jeff
Department of Health and Human Services) and other organizations and Joel Saal, Robert Windsor, Andrew Haig, Andrew Cole, Gerard
such as the American Association of Electrodiagnostic Medicine and Malanga, William Micheo, Francis Lagattuta, Paul Dreyfuss, Jeffrey
The American Academy of Neurology was considered more appropri- Young, Stanley Herring, Stuart Weinstein, Scott Nadler, Heidi
ate for practice guidelines. Several coalitions of spine and musculosk- Prather, Jeff Pavell, Anthony Cucuzzella, Bruce Becker, Joel Press,
eletal societies developed including the National Association of Spine Michael Furman, David Bagnall, Jay Smith, Sheila Dugan, Barry
Societies (NASS), the Council of Spine Societies (COSS), and the Smith, Ann Zeni, Venu Akuthota, Lori Wasserburger, Kurt Hoppe,
Joint Commission on Sports Medicine. PASSOR members regularly Susan Dreyer, Terry Sawchuk, Frederick McAdam, Erwin Gonzalez,
contributed in ever increasing numbers to the peer-reviewed medi- Jerrold Rosenberg, Krystal Chambers, Christopher Huston, Edward
cal literature in the Archives of Physical Medicine and Rehabilitation Rachlin, James Atchison, and Joseph Feinberg.
and other journals. After considerable investigation and debate a Research was recognized as the key to successful incorporation of
formal affiliation with and sponsorship of the Clinical Journal of this subspecialty into accepted practice. This needed to be evidence-
Sports Medicine began with Stuart Weinstein, MD, as Senior Editor. based, primarily clinical, research. PASSOR elected to support the
However this affiliation was dropped at the end of the first contract newly reformatted Foundation for Physical Medicine with a signif-
term in 2003. PASSOR paid the subscription price for its members icant donation from reserves and personal commitment to a chal-
during the contract. lenge grant by all Board members. PASSOR tightened its criteria for
The PASSOR Spinal Procedure Workshop Series and the musculo- award of the Rosenthal Awardees (Table 1.4 – Rosenthal Lecturers).
skeletal and sports education courses were the paradigm of PASSOR Recently, the Saal Family Foundation has announced its sponsorship
members giving extraordinarily generously of their time and personal of spine research. A PASSOR Research Grant Award for US$10 000

Table 1.4: Richard and Hinda Rosenthal Foundation Lecturers

The Richard and Hinda Rosenthal Foundation Lecture is presented by a young physiatrist who has demonstrated noteworthy advancement in
the nonsurgical care of low back pain. This prestigious lectureship was established through the generosity of the Richard and Hinda Rosenthal
Foundation.
Lecturer Year Rosenthal Lecture Title
Scott F. Nadler, DO 2003 Core Strength: What is it all about?
Stuart M. Weinstein, MD 2001 The 21st Century Physiatrist: Seasoned Veteran or Rookie Sensation.
Cancelled due to 9/11
Joseph D. Fortin, DO 2000 Interventional Physiatry: The ‘Cardiology’ Approach to Musculoskeletal Medicine
Curtis W. Slipman, MD 1999 Controlling Our Future: Managing the Dilemmas Facing Physiatry
Susan J. Dreyer, MD 1998 The Forgotten Spinal Epidemics: Osteoporosis
Andrew J. Cole, MD 1997 Education and Mentoring: Physiatric Core Values
Paul H. Dreyfuss, MD 1996 Diagnosis Driven Spine Care in the 21st Century
Joel M. Press, MD 1995 The Future of Physiatric Low Back Care
Andrew J. Haig, MD 1994 New Job for an Old Test: Needle Electromyography of the Paraspinal Muscles
James Rainville, MD 1993 Uncoupling Pain and Impairment – Maximizing the Potential of Chronic Low Back Pain in Patients
Maury Ellenberg, MD 1992 Radiculopathy Secondary to Disc Herniation: Does it Require Surgery?
Nicolas E. Walsh, MD 1991 Research Design in Low Back Pain
Joel S. Saal, MD 1990 The Biochemistry and Pathophysiology of Lumbar Degenerative Disc Disease: A Rationale
for Non-Operative Care
Stanley A. Herring, MD 1989 Stanley A. Herring, MD The Physiatrist as the Primary Spine Care Specialist, Implications for Training
and Education
Avital Fast, MD 1988 Low Back Pain in Pregnancy
Irina Barkan, MD 1987 Lumbar Outlet Syndrome and Myofascial Back Syndrome: Diagnosis and Treatment
Patricia E. Wongsam, MD 1986 Biomechanics of the Lumbar Spine: Some Recent Advances
Jeffery A. Saal, MD 1985 Advances in Conservative Care in the Lumbar Spine: Correlation of SNR Block and Clinical EMG Findings
Myron M. LaBan, MD 1983 Vesper’s Curse’ Night Pain – The Bank of Hypnosis
Note that Dr. Nadler passed away in December 2004.

6
Section 1: Introduction

Table 1.5: PASSOR Research Grant Recipients

2004 Jay Smith, MD Electromyographic Activity in the Immobilized Shoulder Girdle Musculature during Ipsilateral and
Contralateral Upper Limb Motions
2003 Julie Lin, MD Functional Impact of the Posture Training Support in Elderly Osteoporotic Patients
2002 Michael Fredericson, MD The Effect of Running on Bone Density and Bone Structure in Elite Athletes
2001 Heidi Prather, DO Vertebral Compression Fractures Related to Cancer Patients and Treatment with Vertebroplasty
2000 Anne I. Zeni, DO PT Does Athletic Amenorrhea Induce Cardiovascular Changes?
1999 Gregory E. Lutz, MD The Biomechanical and Histological Analysis of Intradisc Electrothermal Therapy on Interventional Discs
1998 Thierry H.M. Dahan, MD Double blind randomized clinical trial examining the efficacy of modified Bupivacaine suprascapular nerve
blocks in the treatment of chronic refractory painful subacromial impingement syndrome

‘seed money’ Research Award was created. (See Table 1.5 for awardees must be appreciated and not shunned. Some members opine that
and topics.) there is often no need for ancillary assistance when a skilled physiat-
Organizations Awards highlight PASSOR values. Aside from rist can ‘provide it all,’ and state that physical therapists, chiroprac-
the Presidential awards, Research Grant Award, and Rosenthal tors, and others do not truly represent competition if physiatrists are
Lectureships, the PASSOR Board created the PASSOR Distinguished good at all that they lay claim to be good at.
Clinician Award to honor members who have achieved distinction on This author is in agreement with colleague Bernie Portner, MD,8
the basis of their outstanding performance in musculoskeletal patient who observes, ‘… that much of what is done today is way off mark.
care, their scholarly level of teaching, and who have contributed There is, in the book on the History of Medicine, a chapter entitled
significantly to the advancement of the specialty through participa- ‘blood letting, the four humors, the hypothymic syndrome and other
tion in PASSOR activities (see Table 1.6 – Distinguished Clinician nonsensical, yet commonly held, tomfoolery of days gone by …’ and
Awardees). A Distinguished PASSOR Member Award was also cre- then gives his personal opinion of some of today’s practices. Each of
ated to honor PASSOR members who have provided invaluable ser- us could make a list of those things that we do which may not be
vices to the specialty through participation in PASSOR activities (see adequately supported by evidence-based research, or which appear to
Table 1.7). These awards were to be directed to members who were have greater physician emollient benefit than good patent outcome.
not serving on the Board in the three years prior to the award. Often, procedures are promulgated with much greater enthusiasm
than for which evidence of their long-term success exists. Polls of
THE FUTURE spines surgeons have indicated that financial incentives alone for doing
added procedures, not careful medical individualization, have made
PASSOR has had a recent strategic plan which redefines its mission, laminectomy without fusion relatively rare. We must support and uti-
goals, and objectives and which seeks to reintegrate PASSOR into lize evidence-based medical literature, starting with this textbook, and
the mainstream of the Academy of PM&R. This would eliminate dis- look for carefully done outcomes research. Despite the requirement
tinct dues or meeting fees and necessitate creative ways to maintain for resource constraint considerations and cost–benefit analysis, as a
funding and momentum. It remains to be seen if this is not sim- profession we must guard against primarily economic-driven clinical
ply another change in the flow of organizational makeup and if the decision-making, or the public will demand diminishment of medical
good will and resources necessary to meet the needs of all members autonomy and substitution of creativity-stifling regulation.
is present. A number of members have opined that simply being a To this end, NIH, NIDRR, and other recognized funders of research
nonoperative orthopedist eschews the valuable education, training, (including private endowments) must support bona fide musculosk-
and experience of general physiatrist rehabilitation training. The eletal clinical and research models.
proper value of team care and methodologies, and attention to psy- Regarding progress in academia, Curtis Slipman founded the
chosocial, vocational and disablement issues for selected patients first interdisciplinary academic spine program at the university of
Pennsylvania in 1992 at a time when physiatrists were being blocked
by anesthesia and orthopedics. His program included direct par-
ticipation of ortho spine, neurosurg spine, and radiology, and all
saw patients in the same facility, and created the first academic
Table 1.6: PASSOR Distinguished Clinician Award
Recipients

The PASSOR Distinguished Clinician Award honors PASSOR members


who have achieved distinction on the basis of their outstanding Table 1.7: Distinguished PASSOR Member Award
performance in musculoskeletal patient care, their scholarly level of Recipients
teaching, and have contributed significantly to the advancement of
the specialty through participation in PASSOR activities.
PASSOR members who have provided invaluable service to the
Robert E. Windsor, MD 2003 specialty through participation in PASSOR activities.
Francis P. Lagattuta, MD 2002 Erwin G. Gonzalez, MD 2002
Paul H. Dreyfuss, MD 2001 Jeffrey A. Saal, MD 2001
Jeffrey L. Young, MD 2000 Robert E. Windsor, MD 2000

7
Part 1: General Principles

interventional physiatric fellowship in 1993. Slipman’s emphasis had leaders act today to create the history of tomorrow. Congratulations
also been on developing leaders of interventional physiatry that could colleagues, you’ve produced an enviable history.
go on to develop academic programs with top-notch fellowships. He
has been able to place a group of incredibly productive young physiat-
rists in academic centers. These physiatrists include: Zacharia Isaac
at Harvard, Omar el Abd at Harvard, Jason Lipetz at Einstein in NY, References
Michael dePalma at the Medical College of Virginia, Raj Patel at the 1. Flexner A. Medical education in the United States and Canada: A report to the
Carnegie Foundation for the advancement of teaching. Bulletin No 4. New York:
University of Rochester, David deDanious at the Medical College of
Carnegie Foundation for the Advancement of Teaching; 1910.
Wisconsin, Russell Gilchrist at the University of Pittsburgh, and Amit
2. Materson R. Introduction. In: Grabois M, Garrison S, Hart K, Lehmkuhl D, eds.
Bhargavia at the University of Maryland. The University of Michigan Physical medicine and rehabilitation. The complete approach. Malden, Mass: Black-
program was founded by Andrew Haig, MD, and emphasized the well Science; 2000:1–16.
critical importance of research to this field. 3. Kottke F, Knapp ME. The development of physiatry before 1950. Arch Phys Med
Another prediction that has been observed to be coming true is Rehab 1988; 69:4–14.
that young women physiatrists who were themselves athletes during 4. Krusen FH. Historical development in physical medicine and rehabilitation during
their school years have become attracted to this arena and see oppor- the last forty years. Arch Phys Med Rehab 1969; 50:1–5.
tunity in the hands-on approach to interventional spine treatment, 5. Martin GM, Opitz J, eds. The first 50 years: The American Board of Physical Medi-
and welcome the opportunity to contribute to the medical literature cine and Rehabilitation. Arch Phys Med Rehab 1997; 78(supp 2):1–68.
dealing specifically with women’s issues 6. Opitz J, ed. Fifty years of physiatry; the forging of the chain. Arch Phys Med Rehab
Physiatry will continue to evolve as science warrants and practitio- 1988; 69: 1–3.
ners are willing. Organizations such as PASSOR, collaborating with 7. Rusk HA. A world to care for. New York: Random House; 1972.
organized medicine, will facilitate the needed changes as new young 8. Porner B. e-mail communication to Materson. May 2004.

8
PART 1 GENERAL PRINCIPLES
Section 1 Introduction

CHAPTER
Epidemiology
2 David A. Lenrow

INTRODUCTION
Incidence is the rate of occurrence of spine pain or a specific sub-
Epidemiology is the branch of medicine that deals with the study set of spine pain in the population being studied. Incidence is always
of the causes, distribution, and control of disease in populations.1 in relation to a defined period of time. It refers to new episodes or
Epidemiology of spine pain provides insight into the scope of the occurrences. To determine incidence in a specific population it is
problem and allows us to evaluate the impact of various treatment necessary to sample an appropriate cross-section of the population
methods and preventative strategies. Without reliable epidemiologic when they are symptom free and then to follow them for occurrence
data it is impossible to evaluate treatment or prevention with any of symptoms over a specific time period.
accuracy. In reviewing the literature on the epidemiology of spine Prevalence and incidence of spine pain allow us to better define the
pain, it quickly becomes evident that there are significant gaps in scope of the problem. They also allow for the formulation of theories
our knowledge which require sound evidence-based medicine for of etiology by analysis of associated factors. They do not determine
resolution. Until we have reproducible data with set criteria for spine causation.3 The estimates of costs to society further define the prob-
pain, in general and specific populations, we will be unable to accu- lem and include economic, medical, and disability-related costs.
rately define its natural history or the benefit of selected treatments.
Historically, the medical profession has held a variety of opinions on
the cause of spine pain with associated treatments. This led to the
CHALLENGES
teaching of treatments without any clear scientific evidence and has The collection of epidemiologic data on spine pain presents difficul-
propagated potentially ineffectual approaches to ill-defined causes of ties on several levels. The inclusion criteria for an episode of spine
spine problems. The long history of opinion-based clinical medicine pain vary. Without clear and standardized criteria for an episode of
and medical education is coming to a close. In this era of evidence- spine pain, or a specific syndrome, it is not possible to generalize or
based medicine it is essential to determine the epidemiology of spine combine the data from studies. An example is an attempt to compare
problems so we can proceed to focusing on effective treatment and point prevalence across studies that define episodes of spine pain as
prevention. having a duration of at least 2 weeks to studies which count any epi-
Understanding the epidemiology of spine pain will establish the sode of spine pain, even fleeting pain. These studies are not compa-
extent of the problem in the population, and its natural history. The rable and the information in each is at best only generalizable to the
next level of studies should be aimed at determining the relationship specific population of the study.
between specific factors, both external and internal, which are associ- Consistency among studies with clearly defined criteria for an
ated with spine pain. It is likely that this will vary with specific etiolo- episode of spine pain would allow for comparison and pooling of
gies of spine pain, so the studies of causation will be intimately linked data. Fleeting, transient, mild neck pain should not be evaluated in
with research aimed at determining the pain generators in specific the same category as severe, intense, disabling, chronic neck pain.
syndromes. Only when we have reached this level of understanding The study should include the question used and how it was admin-
will researchers be able to systematically develop methods of treat- istered. The length of the particular questions used and the method
ment and prevention which elevate the care of these patients from of administration can alter the responses obtained. The prevalence
opinion-based to evidence-based medicine. period must be defined. Only the same prevalence periods should
The terms often used in studying the effect of spine pain on popula- be compared. Point prevalence represents the most reliable infor-
tions are incidence and prevalence. Prevalence is the percentage of a mation to obtain in survey studies since memory is not required.
population that is affected with a particular disease or symptoms at a The longer the recall period the more this is apt to be affected by
given time or during a specific set time interval. There are many factors memory.4 This can cause errors in both directions. Memory may
contributing to prevalence including, but not limited to, the number of fade with time or events may be remembered as occurring more
new cases, the duration of symptoms, and individuals with spine pain recently than they actually occurred.5,6 Point prevalence avoids this
moving in or out of the study population.2 The determination of preva- issue.
lence only requires sampling at one time point. A cross-section of the Self-reporting of spine pain has been criticized for being subjective
population of interest should be sampled to ensure that the data will be and not as reliable as direct observation or examination. With pain,
generalizable to the population as a whole. The study population must and specifically spine pain, there is no objective test to determine
reflect the population to which the information will be applied or the the existence of symptomatic pain. When assessing the outcomes of
information will have little or no utility. Point prevalence is thought to a treatment, we rely substantially on our patients’ reported symp-
be fairly accurate when obtained in surveys, whereas prevalence over toms, and perhaps in research that is also our best tool with the least
long periods of time or an individual’s lifetime is often less accurate. misperception. What has been called a weakness of many studies may
Memory fades with time, particularly if pain has resolved. be its strength.

9
Part 1: General Principles

Generalizability of the information from a study population is fre- A British study with 12 907 respondents to a survey found a
quently the goal. To allow for the extrapolation of findings from the 1-year prevalence of 34% and a weekly prevalence of 20% for neck
sampled population to the larger population requires that the sample pain.14 Of the total respondents, 11% reported neck pain within the
population be representative of the group as a whole. It is essential past year that interfered with their normal activities. An episode was
that the study population be a random sample of the target popula- defined as pain lasting 1 day or longer.
tion. It is important to define the population prior to sampling so the In one of the few prospective studies the lifetime and annual prev-
outcome is relevant. alence of low back pain in the UK was 59% and 42%, respectively.15
It is time to standardize the methodology of performing epide- This was a mailed survey with 1455 respondents. An incidence rate
miologic studies for spine pain. We need widespread use of standard- of 4% was found. Age was associated with increased prevalence. An
ized scales for data collection, appropriate population samples and episode of back pain was defined as lasting longer than 1 day and not
valid, reliable outcome measures. If the measures used have not been associated with menstrual cycle, pregnancy, or febrile illness.
validated, the data are of questionable value at best. Guez, in a Swedish study of 4392 adults, found an 18% preva-
lence of chronic neck pain with continuous pain lasting longer than
Scope of the problem 6 months.16 Of the subjects with neck pain, 30% had a history of
trauma. No data were reported on the interval between trauma and
Spine pain is nearly ubiquitous in industrial societies. It is among the
neck pain. The definition of neck injury was injury that was severe
most common medical problems in developed countries. It is present
enough to lead to a physician visit. In another Swedish population
in rural workers and in sedentary through heavy-duty occupations. In
study with 6000 respondents, 48% of men and 38% of women
the majority of cases causation remains muddled. The often repeated
reported neck pain on a self-administered questionnaire.17 The preva-
causal factors including obesity, heavy work, leg length discrepancy,
lence as a whole was 43% with women having a significantly higher
and others have not been proven. The data for low back pain vary
prevalence than men. Chronic neck pain defined as lasting greater
but the lifetime prevalence in industrial nations is high, 50–85%
than 6 months was reported in 22% of women and 16% of men. A
or greater.7,8 The annual incidence is approximately 5% with some
history of head or neck trauma was present in 25% of the subjects
reports up to 15%.8 Back pain accounted for 15 million physician
who developed chronic neck pain. Linton, in a Swedish study, sur-
visits in 1990 in the US.9 It is a major factor in lost work days and the
veyed 3000 persons and found a 2-year prevalence of 73% for low
first or second most common cause of disability.10 In people under 45
back pain.18 Of these, 17% utilized sick time and another 14% had
year of age it is the most common cause of disability in the US.10
been off work but did not use sick time.
The societal costs are enormous. The prognosis for a single episode
In the Mini-Finland Health Survey 8000 people were inter-
of back pain is excellent, with 90–95% of acute episodes resolving
viewed and examined.19 Lifetime prevalence of neck pain was 71%.
fully. Resolution of symptoms usually occurs within 3 months. The
Chronic neck pain was diagnosed in 9.5% of the men and 13.5% of
patients who do not recover are often noted to be the major cost
the women. An association was found between neck pain and history
in disability and medical care. It is becoming evident that there is
of injury and mental and physical stress at work. In a survey study
a significant recurrence rate for acute back pain with an associated
of 10 000 Norwegians, the 1-year prevalence rate of neck pain was
progression to chronic pain. With surveys, participants have been
34.4%.20 Neck pain lasting for more than 6 months had a prevalence
found to forget up to 25% of episodes of back pain for which they
of 13.8%.
sought medical attention, making recurrence rates difficult to deter-
In a telephone survey of 1964 participants in Catalonia, Spain,
mine. The epidemiology of neck pain is much less often the target of
the 6-month prevalence of low back pain was 50.9%.21 Back pain
studies, but it appears to be nearly as prevalent as back pain.
was more common in women, manual workers and less-educated
respondents. Back pain limited the daily activities in 36.7% and
History was responsible for time off work in 17% and disability pension in
Back pain has been present since the earliest of recorded time. In 6.5%.
the Edwin Smith papyrus circa 1500 BCE there is a description of In a Belgian study of 618 blue collar workers in the steel industry,
back pain, including the examination and diagnosis. Neanderthal skel- lifetime prevalence was 66%, 1-year prevalence was 53%, and 1-week
etons and Egyptian mummies revealed degenerative spine changes. prevalence was 25%.22 An episode was any ‘problem in the low back.’
Hypocrites (460–370 BC) noted that back pain with sciatic pain Most of these episodes were mild and categorized as fatigue or com-
lasted about 40 days and affected men 40–60 years old.11 Historically, mon low back pain. Only 17% sought medical advice and only 11%
chronic back pain was not thought to be secondary to injury until the were limited in their occupational or domestic activities.
mid nineteenth century. This was the time of the industrial revolu- In the Netherlands in a survey with 3664 respondents, low back
tion and the building of the railways. It was called railway spine and pain had a prevalence of 26.9% and neck pain 20.6%. Low back pain
thought to be related to work, or even travel on the railroad, even if was the most common musculoskeletal pain and neck pain was the
there was no identifiable injury.12 This led to the acceptance of spine third most common.23
pain as an occupational injury.

STATISTICS North America


National Health and Nutrition Examination Survey-CDC (NHANES
Europe 1999–2000) found the prevalence of low back pain (LBP) within the
In Britain, a study in the general population with 4515 respondents past 3 months to be 37.44% with a sample size of 4880.24 Neck pain
from three general practices determined the prevalence of neck and over the previous 3 months lasting at least 1 day revealed a preva-
back pain.13 An episode of spine pain was defined as lasting at least 1 lence of 18.46%. Deyo analyzed the NHANES II data (1976–1980)
week in duration. The 1-month prevalence of all spinal pain was 29%. with a survey population of 27 801 and found a lifetime prevalence
The prevalence for back pain was 24.5% for women and 21.3% for in the US of LBP of 13.8% and prevalence in the previous year of
men. For neck pain the prevalence was 16.5% for women and 10.7% 10.3%.25 In the Deyo study an episode of LBP was defined as lasting
for men. Of the total spine pain, 40% was disabling. at least 2 weeks.

10
Section 1: Introduction

Canada has been the site for many epidemiologic studies for both Asia
lumbar and cervical ailments. Cassidy et al., with 1131 respondents to
In a cross-sectional study of garment workers, battery/kiln workers,
a mailed survey in Saskatchewan, found 28.4% point prevalence and
and teachers in Shanghai, People’s Republic of China, the overall
84.1% lifetime prevalence of back pain.26 The 6-month prevalence
yearly prevalence of back pain was 50%.30 The number of subjects in
was graded into five intensities and disability categories. This was
this study was 383. This was self-reported back pain with symptoms
an attempt to stratify the prevalence so that transient nondisabling
lasting a minimum 24 hours. Garment workers had the highest yearly
pain could be differentiated from disabling back pain. Low intensity/
prevalence of 74% while teachers had a prevalence of 40%. The
low disability back pain accounted for 48.9% of the population that
7-day prevalence was 45% for garment workers and 22% for teachers.
had back pain in the previous 6 months. High intensity/high disability
The different occupations were thought to account for the variation
back pain was reported by 10.7% of this population. The remain-
in prevalence.
ing 12.3% of the subjects in the 6-month prevalence group reported
In a study of 800 workers in Russia, the lifetime prevalence was
high intensity/low disability back pain. Women were twice as likely
48.2%, point prevalence was 11.5%, and the 1-year prevalence was
as men to report severe disabling back pain; low intensity was equal
31.5%. The vast majority (88.2%) had pain for less then 2 weeks.
between genders. The authors conclude that general prevalence is
Only 1.8% had pain for longer than 12 weeks.31
not terribly useful information since the majority of responders who
had episodes of back pain had low intensity/nondisabling episodes of
back pain.
Cote et al. looked at the prevalence of neck pain in the same ran- Low-income countries
dom survey of the Saskatchewan population.27 The lifetime preva- Studies to determine statistics for spine pain in low-income
lence of neck pain was 66.7% and point prevalence was 22.2%. Neck countries are much less common than in wealthy industrialized
pain was defined as any pain between the occiput and third thoracic nations. The literature on back pain is primarily from high-income
vertebrae as detailed on a mannequin diagram. Subjects were strati- countries accounting for less then 15% of the world population.
fied by intensity of pain and disability in a fashion similar to the study In an attempt to test the hypothesis that in low-income coun-
on back pain. Women experienced more neck pain than men in all tries, since physical labor is more common, back pain should have
severity groups. Women had a 58.8% 6-month prevalence and men a higher prevalence, a systematic review of the literature for low-
had a 47.2% 6-month prevalence. The 6-month prevalence of low income countries was performed.5 The point prevalence was the
intensity/low disability neck pain was 39.75% and 10.1% for high benchmark and used for comparison. Interestingly, high-income
intensity/low disability neck pain. A total of 4.6% of the surveyed countries had 2–4 times the point prevalence found in rural, low-
population reported highly disabling neck pain for the previous income countries. The variation within both the high-income and
6-month period. Interestingly, low intensity/low disability neck pain low-income groups was twofold. This large disparity within cate-
was found to decrease with age. High disability neck pain was more gories of countries puts the methodology and therefore strength of
prevalent in women than in men. the study into question. Notwithstanding the methodologic issues,
Kopec et al., in a longitudinal study of households in 10 provinces manual labor does not appear to correlate with back pain. Perhaps
in Canada, were able to determine the incidence of back pain.10 physical activity is protective or even serves as treatment. This
The interval of the two surveys was 2 years and the sample size study in a general way lends evidentiary support to exercise as a
was 11 063 subjects age 18 years or older. An episode of back pain treatment modality.
was defined as lasting longer than or equal to 6 months in duration Harlow found a 29.8% prevalence of low back pain, a 38.3%
or expected duration. The 2-year incidence in females was 9.0% prevalence of upper back pain, and a 26.4% prevalence of neck
and in males was 8.1%. Of note is that this was a self-adminis- pain in women in Tijuana, Mexico. 32 In a study in urban Zimbabwe
tered survey but the question was ‘Have you been diagnosed by a of 10 839 respondents, back pain was the second most disabling
health professional with back problems, excluding arthritis?’ One condition after headaches.33 Omokhodion, in 840 Southwest
could envision several potential biases of this longitudinal prospec- Nigerian office workers, found a 12-month prevalence of low
tive study. The question asked is not defined in terms of intensity back pain of 38% and point prevalence of 20%.34 The overall rate
but only duration. The duration maybe 6 months or longer or in of disability was 5.6%. In a cross-sectional study in rural Tibet
the alternative be expected to last 6 months or longer. This opin- with n=499, the point prevalence of low back pain was 34.1%,
ion on expected duration is that of the subjects. The diagnosis of the 12-month prevalence was 41.9%. 35 Subjects also reported
back problems by health professionals is being self-reported by the functional disability related to their pain. In rural China 36 the
subject and not by health professionals or their records. The valid- prevalence was found to be 12.1% and in Nepal 37 18.4% for low
ity of this second-hand information is unclear. George, in another back pain. Sharma reported that 23% of patients seen for medi-
Canadian survey with 1131 respondents, showed an 8% 6-month cal care in outdoor rural India were seen for back pain.38 The
incidence of clinically significant low back pain by the Chronic Pain information from rural nations may be helpful in our understand-
Questionnaire.28 ing of the factors important in developing spine pain and its pre-
The prevalence of low back pain in North America, as elsewhere, vention.
varies by study. In an attempt to reconcile the variability and deter- The prevalence and incidence of spine pain is a large problem
mine reliable prevalence rates a methodological review of the lit- internationally regardless of compensation systems and culture. The
erature was performed to identify acceptable studies and compare variability both in the same populations and across populations is sub-
prevalence rates.29 They found 13 studies from 1981–1998 method- stantial. Even with this large variation in prevalence and methodol-
ologically acceptable, but with variable assessments and definitions ogy the statistics remain staggering. Before we hypothesize on why
of an episode of back pain. The range of point prevalence in the stud- these variations are found, both in different groups of subjects and
ies varied from 4.4% to 33.0%. One-year prevalence rates ranged in time, we must determine the value of the data we are comparing.
from 3.9 to 63%. The explanation for the variability is partially The methodology and generalizability of the individual studies must
blamed on the differing durations of back pain required to constitute be sound and comparable before there is any value in formulating
a reportable episode. reasons for the differences noted.

11
Part 1: General Principles

COST practices in Manchester. The relative risk was 1.5 for men and 2.2 for
women who had poor general health.
The cost of back pain to various societies is hard to quantify. This is
due to the lack of central data collection and variation in methodol- Weight
ogy. Extrapolating data from worker’s compensation claims in the US
Weight has often been cited as a risk factor in spine pain, most often
and then projecting to the population as a whole reveals staggering
in low back pain. Webb found an association between obesity and
costs.39 In 1988 the estimate was 22.4 million cases of back pain with
back pain with disability but not with neck pain or low-intensity back
149.1 million lost work days. This loss of workdays alone is estimated
pain.13 Kopec et al. found no significance but weight was close to sig-
to cost more than US$13.3 billion. This does not take into account
nificant as a factor in women.10 Croft found weight to be a significant
health care, personal expenses, and insurance costs. Estimates of total
factor for women but not men.49 Gyntelberg, in a study of Danish
cost in the US range from US$50 to US$100 billion per year. A
men, found an association between height and low back pain but not
Swedish study found that 6% of sufferers accounted for over 50%
weight.50
of the costs.18 In Australia the cost is estimated at US$10 billion per
year with a lifetime prevalence of 80%.40 In the Netherlands back
pain is the most common cause of lost days at work and disability. In Occupation
1991 the direct costs of medical care for back pain in the Netherlands In a British survey with 12 907 respondents, no association for neck
was US$367.6 million and the indirect costs were US$4.6 billion.41 pain was found for lifting, vibratory tool use, or professional driv-
In a 2003 study in the US, back pain was the second most common ing.14 There was an association found with above-the-shoulder activ-
pain condition resulting in lost time from work after headache.42 Out ity for >1 hr/day. Stronger associations were found with tiredness
of the total work force, 3.2% lost time from work as a result of back or frequent stress. Occupations with the highest prevalence were,
pain. Pain-related loss of productive work time cost an estimated in descending order; construction workers, nurses, armed services
US$61.2 billion. The majority was because of decreased productivity members, and the unemployed. No association was found between
while at work and not due to absence from work. physical workload, postures, or exposure to vibration and low back
pain in steel workers.22
FACTORS In a study in the Netherlands, scaffolders had a 60% 12-month
back pain prevalence.51 Supervisors had similar rates for back pain
The cause of most episodes of spine pain is uncertain. The purported and perceived disability but less severe back pain and lower absence
risk factors are numerous. Heavy lifting, particularly on a repetitive rates than scaffolders.
basis, has often been suggested as an inciting event. Age, gender, and Ehrlich opines that most spine pain is not related to work activi-
psychological distress have all been implicated, but not consistently. ties but may be related to psychosocial factors.52 Job dissatisfac-
Cigarette smoking and obesity have been related to back pain in some tion, stress, the system of compensation, and hiring a lawyer are all
studies.43–46 Socioeconomic status has been identified as a risk factor reported to decrease return-to-work rates. Hadler states how back
in some studies43,47 but not all studies.10 Before leaping from associ- pain is dealt with determines if it is disabling or not; secondary gain
ated factors to causation and postulated mechanisms, we must have such as workers’ compensation increases the morbidity.53
better data for prevalence and incidence so the significance of these
potentially inconsequential associations can be adequately evaluated. Secondary gain
Cote et al. analyzed the Saskatchewan Health and Back Pain Survey
There is a long-standing controversy regarding the role of secondary
data to determine the factors associated with neck pain and disabil-
gain in spine pain and disability. Disability from spine pain was not a sig-
ity.48 In the sample population, 15.9% reported prior neck injury in
nificant problem until the industrial revolution. Cassidy et al. analyzed
a motor vehicle accident. This history and headaches were strongly
the effect of compensation on whiplash injury in Saskatchewan.54 On
associated with all grades of neck pain. Subjects with cardiovascular
January 1, 1995, the tort compensation system for traffic injuries was
or digestive problems had a higher 6-month prevalence of disabling
changed to a no-fault system eliminating recovery for pain and suf-
neck pain but not milder neck pain. There was an association between
fering. This provided natural data collection points. It is important to
low back pain and neck pain.
note that Saskatchewan was the only insurer for motor vehicle injuries
The Mini-Finland Health Survey found chronic neck pain strongly
in the Province and all residents benefit from state health insurance.
associated with back pain and shoulder disorders, but only weakly
For the last 6 months of the tort claim system the 6-month cumula-
associated with osteoarthritis, cardiovascular, and mental disorders.19
tive incidence was 417 per 100 000 persons compared to 302 and 296
Trauma to the neck or low back was associated with chronic neck
per 100 000 in the first and second 6-month periods of the no-fault
pain.
system. This equates to a 28% decrease in claims for whiplash injury.
Kopec et al., in a prospective study, tried to identify factors in the
The time from the date of injury to claim closure decreased from 409
development of back pain in the general population.10 General health
days to 194 days in the same time interval. During this same period
and psychosocial factors were important in both sexes. Other factors
there was an increase in the number of vehicle-damage claims and
in men were age, usual activity pattern, lack of gardening, and height.
distance driven.
For women the other factors were self-reported arthritis or rheuma-
tism and a history of psychological trauma. If a woman has none of
these identified factors her risk of developing back pain in a 2-year Psychological
period is 6%. For a woman who has activity restriction, has been diag- The development of back pain has often been associated with psy-
nosed with arthritis or rheumatism, has two or more traumatic events chological factors.55–57 In the Manchester study, psychological factors
in childhood, and reports a high level of personal stress, her risk of were found to be predictive of low back pain.57 This was a prospec-
developing back pain is 32% in a 2-year period. tive study of 4501 surveyed subjects. Subjects with no back pain but
General health was a strong predictor of back pain in a study in the high scores for psychological distress were more likely to develop
UK by Croft et al.49 They studied 2715 individuals from two general back pain than individuals with low scores.

12
Section 1: Introduction

Perez found an association prospectively between psychological respondents reporting persistent annual low back pain.15 Acute epi-
factors and back pain in healthy workers.56 The only factors related sodes recurred and in some patients turned into chronic, constant
to back pain in that study were age, depression, and general stress. pain.
Kopec et al. found general stress to be a factor in men and personal
stress (a subset of general stress) a factor in women, as well as a
history of psychological trauma in women.10 In a Finnish study, an
DISABILITY
association between depression and neck and back pain was found in Spine pain is a major cause of disability. It has been estimated that
both men and women.58 Power, in a British cohort study looking at 1% of the population is disabled by back pain. It is the leading cause
early life variables, found psychological distress at age 23 to be the of disability in the US for the population under 45 years old and
strongest predictor of low back pain.59 This doubled the risk of back the second cause for those 45–65 years old.46 Back pain accounts for
pain later in life. In rural India 67%, of patients seen for low back approximately one-fourth of worker’s compensation claims in the
pain had psychosocial issues, and 38% were dissatisfied with their US. In a survey of 30 074 respondents 5256 subjects, or about 17.5%,
current job.38 self-reported back pain lasting at least 1 week.39 Construction workers
in males and nurses aides in females had the highest prevalence rates
Smoking of 22.6% and 18.8%, respectively. Subjects reported missing work or
changing jobs in 12.1% of those with reported pain. Extrapolating this
Smoking has be implicated as a factor in developing spine pain.45,59
to national estimates yields staggering numbers of cases of back pain
The Manchester study,49 Kopec et al.10 and Guez et al.16 among oth-
and lost work days.
ers did not find an association between spine pain and smoking. In
There is little known about the extent of the disability spine pain pro-
a systematic review of the literature for 1976–1997 an association
duces in less-industrialized nations. In Nigerian office workers, only 5%
between smoking and non-specific back pain was found.45 The results
of those surveyed reported lost days due to back pain, with a mean of 4.7
revealed an association between smoking and back pain in men in 18
days per year.34 The incidence of back pain was similar to that in industri-
of 26 studies and in 18 of 20 studies in women. It is not clear if smok-
alized nations but the absence from work was not as significant.
ing preceded back pain or if there is a close relationship. The finding
The history of spine pain and disability helps illuminate some of the
of a positive association does not imply causation.
factors that transform spine pain, as an accepted part of life, into a
disabling condition. Allan and Waddell review the history of back pain
Age and disability.11 There was very little written about spine pain caus-
The highest prevalence of low back pain occurs between 40 and 60 ing disability until the industrial revolution. Early reports of spine dis-
years of age. Kopec et al., in one of the few studies looking at inci- ability in railway workers led to much more frequent spine disability
dence and age, showed a peak incidence at 45–64 years of age.10 Rates in the early twentieth century. This was coupled with the concept
of back pain seem to increase during adult life until age 65 and then of compensation for work-related injury. During WWI the US draft
they decrease. board rejected recruits that had static problems of the spine to avoid
Predicting back pain by knowing the causation and associated fac- backache. Recruits still developed backache, but could be made fit for
tors would allow for an intelligent, scientific approach to prevention. service by special training battalions. This suggested that back pain
The data currently available are often contradictory and difficult to might be a fitness problem and not a medical problem. In the British
explain. In one study, gardening is associated with a lower risk of armed forces there was a fivefold increase in withdrawal from duty for
low back pain.10 In other studies sports and nonoccupational home back pain between WWI and WWII. In Britain in 1911 and the US in
improvement increased the risk.49 Is gardening really associated with 1949, workers were covered for injury by Workman’s Compensation
lower incidence of back pain or do people prone to back pain not Insurance. As the breadth of compensation increased so did the extent
garden? We must ask the right questions to determine the association of disability for back pain. The author’s concluded that disability is not
between risk factors and the development of spine pain. Perhaps these a natural sequelae of back pain, but is secondary to how we compen-
are just chance associations. Without precise methodology, reproduc- sate, manage, and treat patients with these aliments.
ibility, and multiple studies in agreement, the true associated factors
remain uncertain and true causation beyond our reach.
CONCLUSION
Spine pain is a widely prevalent condition. Spine disorders account
RECURRENCE for a tremendous cost both in lost productivity and medical care to
The traditional notion that the great majority of episodes of non- industrial societies. Back pain is one of the top two reasons persons
specific back pain resolve has come under scrutiny. There is good seek medical care, superceded only at times by respiratory infection.
evidence that a substantial fraction of back problems have recurrent The prevalence is variable across studies but there is no standard-
symptoms. Miedema found that 28% of patients with an episode ized methodology to study spine pain. Definitions of spine problems
of back pain, for which they consulted their physician, went on to vary greatly as do methods of obtaining data. These variables make it
develop chronic back pain.41 Only 1 in 5 people with back pain con- impossible to compare statistics across studies even if the populations
sult their physician. were identical. Spine pain is not a specific disease or one etiology of
In a review of the literature the 1-year recurrence rate for low back pain, which makes it difficult to address. It is most often of non-spe-
pain was 20–44%.8 Lifetime recurrence rates were up to 72%. These cific cause, or more accurately an as yet unidentified cause.
studies were prospective studies for occupational back pain. Nurses The rate of surgery varies by regions and by country with up to a 15-
and drivers had the highest recurrence rates while white collar work- fold variation within the US. The use of various treatments including
ers had the lowest recurrence rates. In general, men had higher rates COX-2 antiinflamatory drugs, spinal injections, IDET and percutane-
of recurrence than women. In a longitudinal cross-sectional study ous discectomies, just to name a few treatments, vary greatly by geo-
in the UK there was a 59% lifetime prevalence, with 42% of those graphic area. Treatment trends have changed throughout the history

13
Part 1: General Principles

of medicine. The factors driving these shifts are, unfortunately, not 19. Makela M, Heliovaara M, Sievers K, et al. Prevalence, determinants and conse-
quences of chronic neck pain in Finland. Am J Epidemiol 1991; 134:1356–1367.
always scientific in basis or in the patient’s best interest. This is per-
haps driven more in the US by reimbursement trends and patients 20. Bovim G, Schrader H, Sand T. Neck pain in the general population. Spine 1994;
19:1307–9.
desire for specific treatments. The lay press and insurance industry
21. Bassols A, Bosch F, Campillo M, et al. Back pain in the general population of Cata-
fuel this, and not necessarily scientific evidence. Once these treat-
lonia (Spain). Prevalence, characteristics and therapeutic behavior. Gac Sanit 2003;
ment modalities become common and patients ask for them, it is very 17(2):97–107.
difficult to study their effectiveness. The first step to evidence-based 22. Masset D, Malchaire J. Low back pain, epidemiologic aspects and work-related fac-
medicine in the treatment of spine pain is the collection of valid, tors in the steel industry. Spine 1994: 19(2):143–146.
consistent, epidemiologic data. This will serve as the foundation on 23. Picavet HSJ, Schouten JSAG. Musculoskeletal pain in the Netherlands: prevalenc-
which to build rational treatment in the future. es, consequences and risk groups, the DMC3-study. Pain 2003; 102:167–178.
The study of the epidemiology of spine pain is essential to under- 24. http://www.cdc.gov/nchs/about/major/nhanes/frequency/mpq.htm
standing the scope of the problem, factors implicated in causation, 25. Deyo RA, Tsui-Wu YJ. Descriptive epidemiology of low back pain and its related
and the natural history. The next step is to control causative factors or medical care in the United States. Spine 1987; 12:264–268.
comorbid conditions with possible etiologic associations, to see if the 26. Cassidy JD, Carroll LJ, Cote P. The Saskatchewan health and back pain survey: The
incidence of these conditions can be altered. Basing our treatment of prevalence of low back pain and related disability in Saskatchewan adults. Spine
spine disorders on poor epidemiologic studies amounts to opinion- 1998; 23(17):1860–1866.
based medicine rather than rational treatment with evidence as its 27. Cote P, Cassidy JD, Carroll L. The Saskatchewan health and back pain survey: The
foundation. The charge to this generation of researchers and medical prevalence of neck pain and related disability in Saskatchewan Adults. Spine 1998;
23(15):1689–1698.
professionals is to base treatment on scientific evidence. To do so, we
must first focus on accurate epidemiology with consistent definitions 28. George C. The six-month incidence of clinically significant low back pain in the
Saskatchewan adult population. Spine 2002; 27(16):1778–1782.
of episodes of spine pain and durations that are significant.
29. Loney PL, Stratford PW. The prevalence of low back pain in adults: A methodologi-
cal review of the literature. Physical Therapy 1999; 79:384–396.
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15
PART 1 GENERAL PRINCIPLES
Section 2 Spinal Pain

CHAPTER
Inflammatory Basis of Spinal Pain
3 James D. Kang and Stephen Hanks

INTRODUCTION in resisting the high pressure of the nucleus, as well as maintaining


Low back pain with or without radiculopathy continues to be a sig- stability against rotational forces. Cutting all fibers of the same ori-
nificant clinical entity causing major disability in patients. However, entation, while preserving fibers of the other direction, results in a
the etiology of low back pain and the exact pathophysiology remains greater increase in the axial rotation of the isolated motion segments
elusive. Intervertebral disc degeneration has been implicated as one than does removal of both facet joints. The inner anulus fibers attach
of the key factors associated with low back pain. The intervertebral directly to the cartilaginous endplate whereas the outer fibers attach
disc continues to be a structure of great interest because its degen- directly to the vertebral body via Sharpey’s fibers.
eration or failure may influence a variety of structures in processes The nucleus pulposus is centrally located and consists of a rela-
believed to play a role in low back pain. There has been a large body tively random network of collagen and hydrated proteoglycans. The
of recent work focusing on the interaction between biomechanics and lumbar nucleus occupies 30–50% of the total disc area in cross-sec-
the biochemistry of disc degeneration and their seemingly coupled tion. Water content varies from 70% to 90%, is highest at birth, and
interaction. decreases with advances in age as the concentration of proteoglycans
Low back pain is undoubtedly one of the largest health problems also decreases. The intervertebral disc is composed of a collection of
affecting society, both individually and as a whole. It is the sec- macromolecules that include mostly collagen and proteoglycan. The
ond most common reason listed for a doctor’s office visit and the matrix of the outer anulus consists of approximately 80% of type I col-
lifetime prevalence is estimated at 91%. Of the total Workmen’s lagens and small amounts of type V collagen. Inside the outer anulus,
Compensation expenditure nationwide, it accounts for somewhere the concentrations of type II collagen and proteoglycan become pro-
between 70% and 90%. It is the second leading cause of disability gressively greater toward the center of the disc as the concentration
worldwide and its incidence is increasing disproportionately to the of type I collagen decreases. Inside the nucleus, the concentration of
population growth and other disabling conditions. type II collagen approaches 80% while type I is absent. Type II fibers
For these important reasons, characterizing the underlying causes are more hydrophilic than type I fibers and therefore are 25% more
of low back pain has become more important in the scientific litera- hydrated. Most of the data on the mechanical behavior of discs have
ture in the last 7–10 years. been obtained from in vitro studies of spine specimens obtained at
autopsy. There is evidence that the hydration in discs changes quickly
after death, including transfer of water from the outer to inner anulus,
THE INTERVERTEBRAL DISC and this may affect testing results in research using cadavers.
The intervertebral disc has many functions including stabilization of The presence of degenerative discs, as mentioned, is nearly univer-
the spine by attaching vertebral bodies together and allowing move- sal as humans age. All disc tissue ages from birth to death, with the
ment between these bodies giving the spine its flexibility. With the most marked changes occurring in the nucleus pulposus where the
facet joints, the spine bears the entire compressive load to which proteoglycan concentration, water content, and the number of viable
the trunk of the body is exposed. Discs within the lumbar spine are cells all decrease. These changes are accompanied by fragmentation
exposed to three times or more the weight of the trunk while in the of the aggregating proteoglycans. Although all discs eventually show
sitting position and this number can double during certain activities these same changes, the rate at which they show them varies not only
such as jumping, lifting out of position, or trauma. Changes within from person to person, but within discs from the same individual.
the disc as humans age affects the ability of the spine to respond to
the loads to which it is subjected. Disc biomechanics
In general, tissue failure occurs because the loads to which they
Disc structure are exposed as stresses generated exceed the strength of the tissue.
The intervertebral disc is composed of four concentrically arranged These can be tensile, compressive, or shear forces contributing to the
layers including (1) the outer anulus fibrosus, (2) the fibrocartilagi- damage. Stokes and Greenapple demonstrated strains of 6–10% dur-
nous inner anulus fibrosus, (3) the transition zone between the anulus ing extremes of flexion and axial rotation in lumbar disc fibers.1 The
fibrosus and the nucleus pulposus, and (4) the nucleus pulposus. The strains were greater in the posterolateral areas than in the anterior
outer anulus is composed of approximately ninety collagen sheaths regions. While pure axial compression, even in testing at very high
bonded together in concentric laminated bands within which the loads, does not cause herniation of the nucleus pulposus, cyclic load-
fibers are arranged in the helicoid manner. ing can cause annular tears that may eventually lead to disc hernia-
These sheaths are oriented at about 30° to the disc plane and at tion. Discs are known to exhibit creep, relaxation, and hysteresis. In
about 120° therefore in alternate bands. This orientation is important these studies, the amount of hysteresis was shown to increase with

17
Part 1: General Principles

load and decrease with age. These studies also demonstrate that non- region from vascular dilatation. Swelling results from edema which
degenerative discs creep less slowly than degenerative discs. This may is the accumulation of fluid in the extravascular space and from the
indicate that there is less physiologic elasticity in degenerative discs. physical mass of the inflammatory cells migrating to the area. Pain is
Finite element analysis has effectively modeled the functional spi- one of the best-known features of acute inflammation and it results
nal unit (FSU). It has been shown that in compression the load is partly from the stretching and distortion of tissues due to the edema
transferred from one vertebra to another through the endplates via in the area. Chemical mediators of acute inflammation including bra-
the nucleus pulposus and the anulus fibrosus. The application of a dykinin, the prostaglandins, and serotonin are also known to induce
load causes pressure to develop within the disc, pushing fibers out pain. Loss of function is a well-known consequence of inflammation
and away from the center of the disc. Rupture of the annular fibers added by Virchow to the list originated by Celsus. Movement of an
was seen posterolaterally in the innermost layer during progressive inflamed area is consciously and reflexively inhibited by pain, while
failure analysis in compression and in shear loads at various rotations. severe swelling or local muscle spasm may limit movement of the
The rupture progressed toward the periphery, with increased loads area.
up to the maximum used in the analysis. The acute inflammatory response involves three changes or pro-
These structural changes to the disc and functional spinal unit can cesses. Changes in the vessel size and flow, increased vascular per-
be readily seen with modern imaging techniques. However, mechani- meability and the formation of the fluid exudate, and migration or
cal phenomena or biomechanical changes are inadequate to explain de-margination of polymorphonuclear leukocytes (PML) into the
some of the clinical observations made in the patients who have low extravascular space are characteristic processes of acute inflamma-
back pain or radiculopathy. These include clinical improvement after tion. Briefly, these early stages involve small blood vessels adjacent to
treatment with powerful antiinflammatory medications, clinical the area of the tissue damage, which become dilated with increased
improvement in the absence of a change in the pathologic anatomy of blood flow. As blood flow begins to slow, the endothelial cells swell
the disc, and the lack of correlation between symptoms or neurologic and partially retract so that they form a leaky continuum within the
signs and the size of the disc herniation. blood vessel. The vessels become leaky, which permits the passage
of water, salts, and small proteins into the damaged area. One of the
main proteins to leak out during this period is fibrinogen. Circulating
INFLAMMATION PMLs initially adhere to the swollen endothelial cells and then migrate
Acute inflammation is a response of living tissue to damage and it through these channels created by the retracted endothelial cells and
has three functions. The inflammatory exudates formed carry protein through the basement membrane, passing into the area of tissue dam-
and fluid in cells from blood vessels to the damaged area to mediate age. Later on, blood monocytes (macrophages) migrate in a similar
local defenses. It also helps eliminate any infective agent that is pres- way. The microcirculation consists of a network of small capillaries
ent in the area, and helps break down damaged tissue, facilitating its that lie between the arterioles. These microcapillaries initially experi-
removal from the site of the damage. Acute inflammation may result ence an increased blood flow following the initial phase of arteriolar
from physical damage, chemical substances, microorganisms, or constriction, which is transient. Blood flow to the injured area may
other agents. The response results in changes in local blood flow and increase up to tenfold during this time, but then blood flow begins
increased permeability of blood vessels that facilitates the escape of to slow down, allowing the leukocytes to de-marginate into the area.
proinflammatory cells from the blood into the tissues. These changes The slowing of this blood flow, which follows the phase of hyperemia,
are essentially the same whatever the cause and wherever the site. is due to increased vascular permeability and allows plasma to escape
Usually, acute inflammation is a short-lasting process. However, the into the tissues while blood cells stay within the blood vessels. Blood
length of the process is probably dependent on the inciting cause. viscosity is therefore relatively increased as the percentage of red cells
Hypersensitivity reactions are another cause of acute inflamma- relative to white cells and other proteins increases. The increased
tion, as are physical agents such as tissue damage from trauma, ultra- vascular permeability increases capillary hydrostatic pressure as well
violet or ionizing radiation, burns, or frostbite. Irritants and corrosive as allowing the escape of plasma proteins in the extravascular space.
chemicals can cause inflammation and tissue necrosis. Lack of oxygen Instead of the usual return of fluid into the vascular space, however,
or necrosis is another mechanism by which acute inflammation can proteins act to increase the colloid osmotic pressure in the extravas-
propagate. In this particular cause, the reduction of oxygen and nutri- cular space. Consequently, more fluid leaves the vessel than comes
ents resulting from inadequate blood flow or infarction is a potent back and the net escape of protein rich fluid is called exudation.
inflammatory stimulus. Experimental work has demonstrated three patterns of increased
Celsus described the four principal effects of acute inflammation vascular permeability. There is an immediate response that is tran-
nearly 2000 years ago (Table 3.1). These include redness from acute sient, lasting 30–60 minutes, mediated by histamine acting on the
dilatation of small blood vessels within the area. Heat, or warmth, is endothelium directly. A delayed response starts 2–3 hours after injury
usually seen only in the peripheral parts of the body such as the skin. and may last for up to 8 hours. This is mediated by factors synthe-
It is also due to the increased blood flow or hyperemia through the sized by local cells such as bradykinin or factors from the complement
cascade, or those released from dead neutrophils in the exudate. A
third response that can be prolonged for more than 24 hours is seen
if there is a direct necrosis of the endothelium. In the later stages of
acute inflammation where movement of neutrophils becomes impor-
Table 3.1: Celsus’s original description of the tant, experimental evidence has shown purposeful migration of neu-
characteristic signs of inflammation trophils along a concentration gradient. This movement appears to be
mediated by substances known as chemotactic factors diffusing from
Erythema (rubor)
the area of damage. The main neutrophil chemotactic factors are C5a,
Warmth (calor) LTB4, and bacterial components. These factors, when bound to the
Pain (dolor) receptor on the surface of a neutrophil, activate secondary messenger
systems stimulating increased cytosolic calcium with the assembly of
(Loss of function was added by Virchow)
cytoskeletal specializations that are involved in their ability to move.

18
Section 2: Spinal Pain

The spread of the inflammatory response following injury to a small The PML is the characteristic cell in acute inflammation. Its abil-
area of tissue suggests that chemical substances are released from the ity to move in a response to a concentration gradient of chemotactic
injured tissues spreading out to uninjured areas. These chemicals are factors has been well demonstrated and is mediated by cytosolic cal-
called endogenous mediators and contribute to the vasodilatation, cium. Neutrophils are able to bind to bacterial components via their
de-margination of neutrophils, chemotaxis, and increased vascular Fc receptor and are able to phagocytose various particles or organisms
permeability. Chemical mediators released from the cells include his- and partially liquefy them with toxic compounds contained within
tamine, which is probably the best-known chemical mediator in acute lysosomes.
inflammation. It causes vascular dilatation in the immediate transient Following tissue damage or loss from any cause, including damage
phase of increased vascular permeability. This substance is stored in due to the inflammatory process, there may be resolution, regenera-
mast cells, basophils and eosinophils, as well as platelets. Histamine tion, or repair. All of these processes may occur in the same tissue or
released from those sites is stimulated by complement components begin as soon as there is significant tissue damage. Healing does not
C3a and C5a, and by lysosomal proteins released from neutrophils. wait for inflammation or other mechanisms to subside, but usually
Lysosomal compounds are released from neutrophils and include takes place concurrently. The outcome depends on which of these
cationic proteins that may increase vascular permeability and neu- three processes predominate and on a number of factors. Resolution
tral proteases, which may activate complement. Prostaglandins are tends to occur when there is little tissue destruction as well as a limited
a group of long-chain fatty acids derived from arachidonic acid and period of inflammation and short, successful treatment. Regeneration
synthesized by many cell types. Some prostaglandins potentiate the occurs when lost tissue is replaced by a proliferation of cells of the
increase in vascular permeability caused by other compounds. Part of same type reconstructing the normal architecture. Regeneration pro-
the antiinflammatory activity of drugs such as aspirin and nonsteroi- ceeds based on cell type, and cells are usually classified into three
dal antiinflammatory drugs (NSAIDs) is attributable to inhibition of groups based on their ability to regenerate. Labile cells are those that
one of the enzymes involved in prostaglandin synthesis. Leukotrienes are normally associated with high rate of loss and replacement and
are also synthesized from arachidonic acid, especially in neutrophils, therefore have a high capacity for regeneration. Stable cells do not
and appear to have vasoactive properties. SRS-A (slow-reacting sub- normally proliferate to a significant extent but can be stimulated to
stance of anaphylaxis) involved in type I hypersensitivity is a mixture do so after they have been damaged. Permanent cells are unable to
of leukotrienes. Serotonin (5-hydroxytryptamine) is present in high divide after their initial development and therefore cannot regenerate
concentration in mast cells and platelets and is a potent vasocon- when lost (i.e. neurons).
strictor. Lymphokines are a family of chemical messengers released Tissue architecture is also important. Simple structures are easier
by lymphocytes. Aside from their major role in type IV sensitivity, to reconstruct following damage than complex ones. An imperfect
lymphokines also have vasoactive or chemotactic properties. attempt at regeneration can have important clinical consequences
Within the plasma are four enzymatic cascade systems including such as the cirrhosis that results after damage to the liver and the
the complement system, the kinins, the coagulation factors, and resulting abnormal nodular architecture from the repair. This pro-
the fibrinolytic system, which are interrelated and produce various cess is also dependent on the amount of tissue loss. There must be
inflammatory mediators. The complement system is a cascade system cells left in the area to regenerate, as well as a reasonable volume
of enzymatic proteins and can be activated during the acute inflam- to regenerate prior to scar formation. In repair, the process results
matory reaction in various ways. In tissue necrosis, enzymes capable in formation of a fibrous scar from the granulation tissue. Following
of activating complement are released from dying cells. During infec- the acute inflammation and phagocytosis of necrotic debris and other
tion, the formation of antigen–antibody complexes can activate com- foreign material, blood vessels proliferate and fibroblasts assemble
plement via the classical pathway, while endotoxins of Gram-negative at the edge of the damaged area. As the endothelial cells and fibro-
bacteria activate complement via the alternative pathway. Products blasts grow into the damaged area, vascularization also proceeds.
of the kinin, coagulation, and fibrinolytic systems can also activate Fibroblasts continue to proliferate, producing collagen and giving the
complement. The products of complement activation that are most tissue mechanical strength; eventually a scar consisting of dense col-
important in acute inflammation include C5a, which is chemotactic lagen results. Factors influencing healing include the rate of healing,
for neutrophils, increases vascular permeability, and releases hista- the presence of foreign material or of continuing inflammation, inad-
mine from mast cells. C3a has similar properties to those of C5a, but equate blood supply, abnormal motion, or certain medications that
is less active. C5, 6, and 7 are all chemotactic for neutrophils and, in inhibit this process. Systemically, the healing process becomes less
combination with 8 and 9, have additional cytolytic activity. Finally, effective and slower with increasing age. Nutritional deficiencies play
C4b, C2a, and C3b are all important in the opsonization of bacteria, an important role as well as metabolic diseases such as renal failure
which facilitates phagocytosis by macrophages. or diabetes mellitus. Some patients with ongoing malignancies are
The kinin system includes the kinins, which are peptides of 9 to actually in a catabolic state and unable to heal even simple wounds.
11 amino acids that are important in increasing vascular permeabil- Additionally, corticosteroids are important systemic inhibitors of
ity. The most important of these is bradykinin. The kinin system is wound healing.
activated by coagulation factor XII. Bradykinin is also an important
chemical mediator of pain, which is a cardinal feature of acute inflam-
mation. The process of inflammation
Within the coagulation system, factor XII, once it has been acti- Inflammation is a complex, stereotypical reaction of the body in
vated by contact with extracellular materials, will activate the response to damage of cells in vascularized tissues. In avascular tis-
coagulation, kinin, and fibrinolytic systems directly. This system is sue such as the normal cornea or within the disc space, true inflam-
responsible for the conversion of soluble fibrinogen into fibrin, which mation does not occur. The cardinal signs of inflammation presented
is the major component of the acute inflammatory exudate. These earlier, including redness, swelling, heat, pain and deranged func-
fibrin degradation products result from the lysis of fibrin in the pres- tion, have been known for thousands of years. The inflammatory
ence of plasmin. response can be divided temporally into hyperacute, acute, sub-
Within the fibrinolytic system, the fibrin degradation products acute, and chronic inflammation. The response can be based on the
have effects on local vascular permeability. degree of tissue damage, such as superficial or profound, or on

19
Part 1: General Principles

the immunopathological mechanisms such as allergic, or inflam- Eosinophils


mation mediated by cytotoxic antibodies, or inflammation medi- Eosinophils are terminally differentiated end-stage leukocytes that
ated by immune complexes, or delayed-type hypersensitivity reside predominantly in submucosal tissue and are recruited at the
reactions. As presented earlier, the development of inflammatory sites of specific immune reactions including allergic diseases. Like
reactions is controlled by cytokines, by products of the plasma other granulocytes, they possess a polymorphous nucleus, although
enzyme systems (complement, the coagulation system, the kinin with only two lobes and no nucleus. The eosinophil cytoplasm con-
and fibrinolytic pathways), by lipid mediators (prostaglandins tains large ellipsoid granules. Recently, it has been recognized that
and leukotrienes) released from different cells, and by vasoac- eosinophils are capable of elaborating cytokines that include those
tive mediators released from mast cells, basophils, and platelets. with potential growth factor activities and those with potential roles
These inflammatory mediators controlling different types of reac- in acute and chronic inflammatory responses. Cytokines produced by
tions differ from one another. Fast-acting mediators such as the human eosinophils that have activity in acute and chronic inflamma-
vasoactive amines and the products of the kinin system modulate tory responses include IL-1α, IL-6, IL-8, TNF-α, and both transform-
the immediate response. Later, newly synthesized mediators such ing growth factors TGF-α and TGF-β. In addition to the acute release
as leukotrienes are involved in the accumulation and activation of of protein, cytokine, and lipid mediators of inflammation, eosinophils
other cells. Once the leukocytes have arrived at the site of inflam- likely contribute to chronic inflammation including the development
mation, they release mediators that control the later accumulation of fibrosis. Additional roles for the eosinophil modulating extracel-
and activation of other cells. However, it is important to realize lular matrix deposition and remodeling are suggested by studies of
that in inflammatory reactions initiated by the immune system the normal wound healing. During dermal wound healing, eosinophils
ultimate control is exerted by the antigen itself, in the same way as infiltrate into the wound site and sequentially express TGF-α early
it controls the immune response itself. For this reason, the cellular and TGF-β later during wound healing.
accumulation at the site of a chronic infection or in an autoimmune
reaction is quite different from that at sites where the antigenic
stimulus is rapidly cleared. Neutrophils
Inflammation can become chronic. In certain settings, the acute Neutrophils, also known as polymorphonuclear leukocytes, repre-
process, characterized by neutrophil infiltration and edema, gives sent 50–60% of the total circulating leukocytes and constitute the
way to a predominance of mononuclear phagocytes and lymphocytes. first line of defense. Once an inflammatory response is initiated,
This probably occurs to some degree with the normal healing pro- neutrophils are the first cells to be recruited. Neutrophils contain
cess that becomes exaggerated and chronic when there is an effective granules which contain antimicrobial or cytotoxic substances, neutral
elimination of foreign material as in some infections, or introduction proteinases, acid hydrolases, and a pool of cytoplasmic membrane
of foreign bodies, or deposition of crystals, or persistent inflamma- receptors. The granules contain, in addition to other substances,
tory product secretions such as disc herniations. serine proteases such as elastase and cathepsin-G, which hydrolyze
protein in cell envelopes. Substrates of granulocyte elastase include
collagen crosslinks and proteoglycans, as well as elastin components
Inflammatory cells of blood vessels, ligaments, and cartilage. Cathepsin-G cleaves carti-
lage proteoglycans while granulocyte collagenases are active against
Mast cells and basophils type I, and to a lesser degree type III collagen from bone, cartilage,
Mast cells and basophils play a central role in inflammation and imme- and tendon. Collagen breakdown products have chemotactic activ-
diate allergic reactions. They are able to release potent inflammatory ity for neutrophils, monocytes, and fibroblasts. Although neutrophils
mediators such as histamine, proteases, chemotactic factors, cyto- are essential to host defense, they have also been implicated in the
kines, and metabolites of arachidonic acid that act on the vasculature, pathology of many chronic inflammatory conditions and ischemia–
smooth muscle, connective tissue, mucous glands, and inflammatory reperfusion injury. This may be triggered by substances released from
cells. Mast cells settle in the connective tissue and usually are not damaged host cells or as a consequence of superoxide generation
circulating in the bloodstream. Basophils are the smaller circulating through xanthine oxidase.
granulocytes that settle into the tissues upon stimulation. Both these Neutrophils, macrophages, endothelial, and other cells produce
types of cells contain special cytoplasmic granules which store these two types of free radicals. The first type is represented by reactive
mediators of inflammation. The release of these mediators is known oxygen intermediates that are formed in neutrophils by the activity of
as degranulation and can be induced by physical destruction such NADPH oxidase. The second type includes reactive nitrogen inter-
as mechanical trauma, or chemical substances such as proteases, or mediates such as nitric oxide. Reactive nitrogen intermediates have
endogenous mediators including tissue proteases or cationic proteins been of some interest in low back-associated pain. These are some-
derived from eosinophils and neutrophils, or immune mechanisms times called reactive oxynitrogen intermediates. The pathway by
which may be IgE dependent or IgE independent. Neutral proteases, which they are originated is an oxidative process in which short-lived
which account for the vast majority of the granule protein, serve as nitric oxide is derived from the guanidino nitrogen in the conversion
markers of mast cells and different types of mast cells. The newly of L-arginine to L-citrulline. This reaction is catalyzed by nitric oxide
generated mediators, often absent in resting mast cells, are typically synthase (NOS) and, like the respiratory burst, it involves oxygen
produced during IgE-mediated activation and consist of arachidonic uptake. Three distinct isoforms of nitric oxide synthase represent-
acid metabolites, principally leukotriene C4 (LPC4), and prostaglan- ing three distinct gene products have been isolated and purified.
din D2 (PGD2), and cytokines. Of particular interest in humans is The three isoforms vary considerably in their subcellular location,
the production of tumor necrosis factor (TNF-αγ, IL-4, IL-5, and structure, kinetics, regulation, and hence functional roles. Two of
IL-6). In the cytoplasm of both mastocytes and macrophages are the enzymes are constantly present and termed constitutive NOS
special granules called lipid bodies where metabolism of arachi- (cNOS). The endothelial cNOS is mostly membrane bound and
donic acid occurs and where their products, including leukotrienes, formed only in endothelial cells. The neuronal cNOS was identified
may be stored. in cytosol or central and peripheral neurons. The third isoform is an

20
Section 2: Spinal Pain

inducible form that is not present in resting cells. Cytokines are a bradykinin and histamine, they contribute to edema and pain induc-
potent stimulus for iNOS production or suppression. Those with an tion. Thromboxane (TXA2) is considered an inflammatory mediator
apparent stimulating effect include IFN-γ, IL-1, IL-6, TGF-α, GM- that facilitates platelet aggregation and triggers vasoconstriction.
CSF, and PAF (platelet activating factor) while suppression has been Neovascularization is an important component of inflammatory
observed by IL-4, IL-8, IL-10, TGF-β, PDGF (platelet derived growth reactions and subsequent repair and remodeling processes. Some
factor), and MDF (macrophage deactivating factor). Cytokines are diseases such as arthritis are maintained by persistent neovasculariza-
basic regulators of all neutrophil functions. Many of them, including tion. Macrophages are very important to this process. The angiogenic
somatesthetic growth factors and pyogens, have shown to be potent activity of macrophages is associated with their secretory activity in
neutrophil priming agents. Neutrophils are also capable of de novo an active state. Macrophages become angiogenic when exposed to
synthesis and secretion of small amounts of some cytokines including low oxygen conditions or to wound-like concentrations of lactate,
IL-1, IL-6, IL-8, TNF-α and GM-CSF. pyruvate, or hydrogen ions. They can also be activated by cytokines
Bioactive lipids originate mainly from arachidonic acid which is an such as IFN-γ, GM-CSF, PAF, or MCP (monocyte chemoattractant
abundant constituent of neutrophil membranes. Arachidonic acid is protein).
metabolized to prostaglandins, leukotrienes, and lipoxins. LTB4 is a
strong neutrophil chemoattractant that may play a role in the prim-
ing process. Vasoactive leukotrienes LTC4, LTB4, and LTE4 increase Mediators of inflammation
microvascular permeability and may contribute to ischemia–reper- In addition to the previously mentioned cell types, there are several
fusion injury. In contrast to leukotrienes, prostaglandins suppress chemical mediators of inflammation. There is considerable redun-
most neutrophil functions, possibly through their ability to elevate dancy of these mediators. The most important vasoactive mediators
intracellular cyclic AMP. stored in mast cells and basophil granules are histamine and sero-
tonin. These are both also present in human platelets. Histamine has
diverse functions including dilation of small vessels, locally increased
Macrophages vascular permeability by endothelial cell contraction, chemotaxis for
Macrophages can be divided into normal and inflammatory mac- eosinophils, and blocking of key T-lymphocyte function. Serotonin is
rophages. A macrophage population in a particular tissue may be also capable of increasing vascular permeability, dilating capillaries,
maintained by three mechanisms: the influx of monocytes from the and producing contractions of nonvascular smooth muscle.
circulating blood, local proliferation, and biologic turnover. Under
normal steady-state conditions, the renewal of tissue macrophages
occurs through local proliferation of progenitor cells and not by Lipid mediators
monocyte influx. Inflammatory macrophages are present in various The major constituents of cell membranes are phospholipids. Cellular
exudates. Very specific markers such as peroxidase activity may char- phospholipase, especially phospholipase A2 and C, are activated dur-
acterize them and, since they are derived exclusively from monocytes, ing inflammation and degrade phospholipids to arachidonic acid.
they share similar properties. Macrophages are generally a population Arachidonic acid has a short half-life and can be metabolized by two
of ubiquitously distributed mononuclear phagocytes responsible for major routes, the cyclooxygenase and the lipoxygenase pathways.
numerous homeostatic, immunologic, and inflammatory processes. The cyclooxygenase pathway produces prostaglandins, prostacyclins,
Their wide tissue distribution make these cells well suited to provide and thromboxanes. The lipoxygenase pathway produces either leu-
an immediate defense against foreign elements prior to leukocyte kotrienes or lipoxins.
immigration. The prostaglandins are a family of lipid-soluble hormone-like mol-
Macrophages display a wide range of functional and morphologic ecules produced by different cell types in the body. For example,
phenotypes. The term activated macrophages is reserved for mac- macrophages and monocytes are large producers of both PGE2 and
rophages possessing specifically increased functional activity. There PGF2. Neutrophils produce moderate amounts of PGE2, and mast
are two stages of macrophage activation. The first is a prime stage cells produce PGD2. PGE2 enhances vascular permeability, is pyro-
in which macrophages exhibit enhanced MHC class II expression, genic, and increases sensitivity to pain. Prostaglandins must be syn-
antigen presentation, and oxygen consumption, but reduced prolif- thesized and released in response to an appropriate stimulus and do
eration. The agent that primes macrophages for activation is IFN-γ, not exist free in tissues.
a product of stimulated TH1 and TH0 cells. Other factors including Thromboxin A2 is produced by monocytes and macrophages as
IFN-α, IFN-β, IL-3, M-CSF, GM-CSF, and TNF-α can also prime well as platelets. It causes platelets to aggregate and vasoconstriction.
macrophages for select functions. Primed macrophages respond to These effects are somewhat opposed by the action of prostacyclin
secondary stimuli to become fully activated, the stage defined by which is a potent vasodilator. Leukotrienes LTD4 and 5-hydroxy-
their inability to proliferate, high oxygen consumption, killing of eicosatetranoate (5-HETE) cause the chemotaxis and chemokine-
facultative and intercellular parasites, tumor cell lysis and maximal sis of several cell types including neutrophils. They are spasmogenic
secretion of the mediators in inflammation including TNF-α, PGE2, and cause contraction of smooth muscle and have effects on mucous
IL-1, IL-6, and reactive oxygen species of nitric oxide production by secretion. Lipoxins LXA4 and LXB4 stimulate changes in microcircu-
iNOS. lation.
Macrophages are important producers of arachidonic acid and its
metabolites. Upon phagocytosis, macrophages release up to 50%
of their arachidonic acid for membranous esterified glycerol phos- Products of the complement system
pholipid. It is immediately metabolized into different types of pros- Complement is a complex system containing more than 30 different
tanoids. From them, prostaglandins, especially PGE2 and prostacyclin glycoproteins present in the serum in the form of components, factors,
(PGI2), are characterized as proinflammatory agents. They induce or other regulators, and on the surface of different cells in the form
vasodilation, act synergetically with complement components C5a of receptors. The components of the classical pathway are numbered
and LTB4, and mediate myalgia response to IL-1. In combination with 1–9 and in prefix by the letter ‘C.’ All these pathways use C5–C9

21
Part 1: General Principles

that form the membrane attack complex (MAC). Activation of each other cells including epithelial cells, endothelial cells, smooth muscle
of the components results from the proteolytic cleavage event in a cells, myeloid, erythroid, and lymphoid cells.
cascade mechanism. The complement system influences the activity
of numerous cells, tissues, and physiologic mechanism of the body.
The result of cytotoxic complement reaction may be beneficial or Chemokines
harmful to the body. The complement system is a potent mechanism Chemokines represent a superfamily of chemotactic cytokines act-
for initiating and amplifying inflammation. This is mediated through ing as initiators and potentiators of antiinflammatory reactions. They
fragments of complement components. Tissue injury following isch- are active over a high concentration range, and are produced by a
emic infarction may also cause complement activation and abundant wide variety of cell types. Exogenous irritants and endogenous media-
deposition of membrane attack complex may be readily seen in tissue tors such as IL-1, TNF-α, PDGF and IFN-γ induce the production
following ischemic injury. of chemokines, and because they bind to specific cell surface recep-
tors they are considered second-order cytokines. Additionally, most
chemokine molecules share structural similarities and function, and
Cytokines mediating inflammatory functions are attractants for many different types of cells.
Cytokines are soluble glycoproteins that act nonenzymatically through
specific receptors to regulate cell functions. Cytokines make up the
fourth major class of soluble intercellular signaling molecules with
BIOCHEMISTRY OF DISC DEGENERATION
neurotransmitters, endocrine hormones, and autocoids. Cytokines The biochemical events that occur with intervertebral disc degenera-
are synthesized, stored, and transported by many different cell types. tion and, in particular, the role of biochemical mediators of inflam-
Lymphokines are cytokines that are secreted mainly by activated T mation and tissue degradation, have received more attention in the
lymphocytes and monokines are produced by activated macrophages literature over the last 10 years. Matrix metalloproteinases (MMPs),
and monocytes. In order to unify the terminology of these factors, prostaglandin E2 (PGE2), and a variety of cytokines have been shown
the term interleukin was accepted. Besides the term expressing to play a role in the degradation of articular cartilage. Nitric oxide is
their origin, cytokines can also be named according to their func- another mediator.
tion as are interferons and others. Cytokines are directly responsible The clinical presentation of acute lumbar radiculopathy is most
for the temporal amplitude and duration of the immune response often attributed to a compressed lumbar nerve root by a herniated
as well as tissue remodeling. Individual cytokines can have widely intervertebral disc.
varying responses and functions depending on cell type, concentra- It is well-known and something of a paradox that some patients
tion, and the synergistic or modulating effects of other cytokines. with large herniations have no radicular symptoms and, in contrast,
The information that an individual cytokine conveys depends on a some patients with no evidence of disc herniations have severe radic-
pattern of regulators to which a cell is exposed and not on just a ulopathy. While the mechanics of nerve root compression undoubt-
single cytokine. There is no doubt that cytokines contribute to the edly play a role in the pain, it probably only partially explains the
signs, symptoms, and pathology of inflammatory, infectious, auto- exact pathophysiology of the radiculopathy.
immune, and malignant diseases. TNF-α is an excellent example.
Locally, it has important regulatory and antitumor activities but when
TNF-α circulates in higher concentrations it may be involved in the MMPs, cytokines, and nitrous oxide
pathogenesis of endotoxic shock, cachexia, and other serious dis- Matrix metalloproteinases (MMPs) are thought to be responsible for
eases. Inflammation is dependent on both pro- and antiinflammatory the turnover of the extracellular matrix within the nucleus pulposus
cytokines. Proinflammatory cytokines are produced predominantly and anulus fibrosus. Their activity is controlled on at least three lev-
by activated macrophages and are involved in the upregulation of els. First, they are upregulated by cytokines such as interleukin-1 via
inflammatory reactions. Antiinflammatory cytokines belong to the gene expression, and also by TNF-αγ. Next, MMPs are latent in their
T-cell-derived cytokines and are involved in the downregulation of proform, requiring activation prior to reaching their full degradative
inflammatory reactions. potential. And lastly, MMPs are inhibited in connective tissue by a
The central role in inflammatory responses involves IL-1 and TNF- number of TIMPs (tissue inhibitors of metalloproteinases).
α. Antagonists to IL-1 (IL-1ra) and TNF-α may become important MMPs come in several different varieties. The most commonly
clinically in the treatment of some rheumatologic conditions such as investigated ones in terms of intervertebral disc degeneration have
ankylosing spondylitis and rheumatoid arthritis. IL-1 and TNF-α with been MMP2 (gelatinase-α) and MMP3 (stromelysin). Kang investi-
IL-6 serve as endogenous pyrogens. The upregulation of inflammatory gated stromelysin production as well as production of nitric oxide
reactions is also performed by IL-11, IFN-α, IFN-β, and especially by IL-6 and PGE2, comparing 18 herniated lumbar discs with 8 control
the members of the chemokines superfamily. On the other hand, anti- discs obtained from patients undergoing anterior surgery for scoliosis
inflammatory cytokines (IL-4, IL-10, and IL-13) are responsible for and burst fractures.2 Kang examined gelatinase, stromelysin, as well as
the downregulation of the inflammatory response. The production of collagenase activity. His group found a nearly sixfold increase in gela-
most lymphokines and monokines such as IL-1, IL-6, and TNF-α is tinase among the herniated disc samples compared to the controls.
also inhibited by TGF-β. However, TGF-β has a number of proin- Collagenase production was absent in the control subjects and nonsig-
flammatory activities including chemoattractant effects on neutro- nificantly elevated in the herniated discs. Caseinase (or stromelysin
phils, T lymphocytes, and nonactivated monocytes. TGF-β has been – MMP3) showed an approximately fourfold increase in the herniated
demonstrated to have in vivo immunosuppressive and antiinflam- samples compared with the control discs. This early finding and the
matory effects, as well as proinflammatory and selected immunoen- activity of MMPs in herniated disc samples was interesting, especially
hancing activities. When administered systemically, TGF-β acts as an in the case of caseinase (stromelysin) which is known to degrade the
inhibitor, but if given locally it can promote inflammation. Generally, core protein of cartilage proteoglycans. The progressive loss of these
TGF-β stimulates neovascularization and the proliferation and activi- proteoglycans within the nucleus pulposus is believed to be one of the
ties of connective tissue cells, and is a pivotal factor in scar formation central reasons behind its desiccation and failure to retain its water
and wound healing. But TGF-β has antiproliferative effects on most content. The high levels found in the herniated discs probably repre-

22
Section 2: Spinal Pain

sent the levels found in the degenerative discs compared to the lower intervertebral discs was significantly higher than in nonprolapsed
level of MMP activity in the normal discs. It is likely that the smaller discs. The same study used an anti-TIMP1 monoclonal antibody to
or lower activity of the MMPs in the normal discs reflects a basal demonstrate the normal presence of MMP3 and TIMP1 together in
amount of MMP activity responsible for ongoing remodeling of the the degenerative intervertebral discs and hypothesized that an imbal-
disc architecture. The high MMP production in the herniated discs ance between MMP3 and TIMP may induce degeneration.
is likely a result of the increased inflammatory mediators produced IL-1 is a known mediator of mesenchymal cells and probably has
within the discs or in the immediate area of the discs because of the a central role in disc degeneration. It is one of the key inflammatory
inflammation. mediators and it has been found in mononuclear cells responding to
IL-1 is known to have a positive modulating response on the MMPs. disc herniations. The studies on human disc tissue have had difficulty
In the presence of a high IL-1 concentration and a low or relatively demonstrating IL-1β in the intervertebral disc tissues, but when disc
low TIMP concentration, the degradative enzymes may be expected cells were stimulated with lipopolysaccharide, elevated levels of IL-
to flourish. In a follow-up study to this article, Kang et al. reported on 1β were found. Both MMP2 (gelatinase) and MMP3 (stromelysin)
the effect of interleukin-1β on control and herniated discs using sam- respond to IL-1. In an experiment using ovine disc cells, Shen et al.
ples from the lumbar and cervical spine.3 They showed significantly demonstrated the ability of IL-1 to enhance the in vitro production
elevated MMP production in the form of gelatinase and stromely- of MMP2 and MMP3 by cells of the nucleus pulposus.5 However, the
sin by normal nondegenerated disc specimens after the addition of active form of MMP3 predominated over the active form of MMP2 in
IL-1β. The basal levels of gelatinase and stromelysin were already this model of IL-1 activation. This suggests that, in the presence of IL-1
increased in the lumbar and cervical degenerative disc specimens and as an inflammatory mediator, MMP3 may be more intimately involved
the addition of IL-1β to these cultures did not significantly increase with ongoing intervertebral disc degeneration than is MMP2.
them. Collagenase activity was not detected. Therefore, the MMPs appear to be key factors in disc degeneration
An interesting control in this last study was the use of L-NMA (n- (Fig. 3.1).
3. They are the active form of the enzymes that they produce,
monomethyl-L-arginine) to block endogenously produced NO. Cells and are capable of degrading constituents of the extracellular matrix
were cultured (control and diseased) in the presence of L-NMA in and basement membrane at physiologic pH values. Substrates for these
order to study the effects of endogenously produced nitrous oxide on MMPs are present in abundance in the disc: collagens II and III are
the other mediators. When L-NMA was added to the nondegenerate substrates for MMP1, MMP8 and MMP13, as well as their proteoglycans
control specimens that had been stimulated with IL-1β, the produc- and other minor collagens which are substrates for MMP2 and MMP9.
tion of gelatinase was significantly decreased, but not the produc- Compared with healthy discs, degenerative discs have been noted to
tion of stromelysin. When this same effect was studied in herniated have higher activities of not only MMP3 and MMP7, but also TIMP1.
lumbar discs that were stimulated with IL-lβ, both gelatinase and MMP3 activity has been correlated to the size of osteophytes present
stromelysin were significantly reduced. Interestingly, the same study in disc degeneration. Inhibitors of MMPs have been found in low levels
done on the herniated cervical discs stimulated with IL-1β had no and are constitutively expressed. TIMP2 appears to be released by most
significant effect on gelatinase or stromelysin.3 cell types within the discs, whereas TIMP1 appears to be exclusively
Several other authors have studied MMPs and their association with overexpressed in discs with degenerative disease. These expressions
intervertebral disc degeneration. Fujita et al. studied autopsy speci- of MMPs and TIMPs have also been measured in spines with pre-
mens of degenerative discs.4 They first discovered serine elastases sumed abnormal biomechanical loading characteristics such as those
with high activity in the endplate and nucleus pulposus of degenera- with scoliosis. Handa et al. showed that proteoglycans and inhibitors of
tive discs. Another group using a monoclonal antibody against MMP3, MMPs were produced in increased amounts under hydrostatic condi-
found the MMP3-positive cell ratio was significantly correlated with tions when loads were increased to within a normal range.6 Taking these
the magnetic resonance imaging grade of intervertebral disc degen- loads to abnormally high pressures resulted in decreased proteoglycan
eration. The MMP3-positive cell ratio observed in prolapsed lumbar production and an increased production of MMP3.

Resident chondrocytes IL-1 (Many sources)

Upregulation ↓ ↓
MMP-7 MCP-1 TNF-α Nitric oxide MMP3/TIMP MMP2/MMP3 Nitric oxide IL-6/PGE2
TNF-α IL-8

Macrophage Neuro- Nerve Matrix Matrix Nerve


infiltration of vascular- conduction degradation degradation effects
disc tissue ization velocity response to
reduction abnormal
loading
Factories for Nerve Nerve
production of ingrowth sensitization
inflammatory DRG
mediators sensitization
(TNF-α, IL-1,
IL-6, NO)
Back pain Radiculopathy Disc degeneration Back pain Radiculopathy Fig. 3.1 MMPs as key factors in
disc degeneration.

23
Part 1: General Principles

Much of the work involving the study of MMP activation and mea- The support for macrophage-mediated cellular response in herni-
surement has been done using tissue obtained from patients oper- ated disc tissue is also supported by another study by Haro. While
ated on for herniated discs. Therefore, many of these publications macrophage invasion appears to accompany and participate in the
include the fact that the assay was done on disc tissue that had been inflammatory response, the likely end to this is reabsorption of the
presumably exposed to some type of a burst of inflammation after herniated disc tissue. Groups have proposed neovascularization of
exposure to the epidural space. It has been proposed that patients these disc tissues as the means by which this happens. Previous stud-
with herniated, sequestered, or noncontained herniations may have ies have shown that resorption may be mediated by neovasculariza-
a more severe inflammatory reaction and pain response. Nygaard tion as measured through Gd-DTPA MRI. Komori showed that the
et al. looked at 37 patients undergoing surgery for lumbar disc her- tendency of these herniated disc tissues to spontaneously resorb was
niation.7 They divided the patients into those who had a bulging disc, proportional to the degree of Gd-DTPA enhancement, which sug-
a contained or incomplete herniation, or a noncontained or seques- gests that the resorption was mediated by a vascular event.13 Haro
tered free disc fragment. Unfortunately, they were unable to recruit and his group have shown that, in an in vitro co-culture system they
enough patients with bulging discs to investigate this phenomenon have used previously, an increase in macrophage VEGF protein (vas-
statistically. In looking at the two groups with the largest number cular endothelial growth factor) and mRNA expression was observed
of patients, including the contained herniation group which had 25 after they exposed disc tissue to the co-culture.14 They found TNF-α
members and the noncontained herniation group which had 9 mem- was required for induction of VEGF protein and conclude that this
bers, there was a significant difference in the mean concentrations of may be one mechanism for resorption for herniated disc tissue.
LTB4, with the noncontained group having almost double the concen- Further evidence for the involvement of the macrophage and its
tration versus the contained herniation group. As well, thromboxane importance is shown in the paper by Burke et al.15 This group studied
B2 was significantly higher in the noncontained versus the contained the production of monocyte chemoattractant protein-1 (MCP1) and
herniation group. Although the measured concentration of these two interleukin-8 (IL-8) by intervertebral discs removed after surgery.
proinflammatory cytokines was lower in the bulging disc, their num- Burke found that MCP1 and IL-8 were detected in both the control
bers were too small to be included in the statistical analysis. This and herniated disc specimens and that the noncontained herniated
study seems to support the theory that there are different inflamma- samples contained higher levels of these chemokines than those with
tory characteristics of different degrees of disc herniations. an intact anulus. They proposed that the MCP1 production attracts
One of the other paradoxes in the delineation of an inflamma- the macrophages while IL-8 may influence the angiogenesis or the
tory response for disc herniation has to do with the atypical cellular neovascularization that is seen in these samples. Although the stimu-
response when compared to inflammation occurring at other places lus for MCP1 in this in vitro experiment was not investigated and is as
in the body. Neutrophils are the sine qua non of acute inflamma- yet unknown, this may represent a physiologic mechanism for initia-
tion; however, they have really only been found in noncontained or tion of macrophage infiltration after disc prolapse and the process of
sequestered disc fragments where neovascularization may be occur- disc resorption. IL-8 was also strongly influenced by the noncontained
ring. Most of the cellular elements that have been identified and are morphology of these samples. In addition to the angiogenic proper-
proposed to be the source or factories for most of the inflammatory ties of IL-8, it is also chemotactic for T cells that have been identified
cytokines are macrophages. Gronblad,8 Nojara,9 Yasuma,10 and Haro11 in the chronic inflammatory filtrate around disc herniations.
have identified macrophages as well as vascular proliferation in the In addition to TNF activation of or paracrine/autocrine effects gov-
granulation tissue of herniated discs. Haro additionally found that erning MMP production, TNF-αγ has long been regarded to be a key
inflammatory cells were more abundant in the noncontained group player in mediating the sensitization of nerve roots by material from
of disc herniations than in the contained group. Inflammatory cells the nucleus pulposus, and other effects such as edema, intervascu-
are known to act in an autocrine or paracrine type fashion with regard lar coagulation, reduction in blood flow, and the splitting of myelin.
to their effect on resident cells in the inflammatory process. This TNF-αγ is known to be released from the chondrocyte resident cells
must also be true for the degenerative disc. The intervertebral disc, in the nucleus pulposus. In a local application of TNF-αγ, it induced a
which is normally nourished through diffusion, can become neovas- reduction in nerve conduction velocity in a porcine experiment done
cularized to some extent after exposure to the epidural space. These by Aoki et al.16 In this study, applications of interleukin-1β and inter-
discs display granulation tissue with macrophage and T-lymphocyte feron-γ induced a very small reduction of nerve velocity compared
infiltration not observed in healthy discs. Haro et al. have proposed with epidural fat. In a follow-up study to this, Olmarker and Rydevik
that the natural resorption of a herniated disc appears to occur by a demonstrated that local blockers to TNF-αγ prevented the reduc-
vascularization-mediated process and is correlated with macrophage tion of nerve conduction velocity and seemed to limit the nerve fiber
infiltration. injury and intercapillary thrombus formation, as well as the intraneu-
It is also known that chondrocytes replace proteoglycans within the ral edema seen in the absence of the inhibitor.17 These authors have
nucleus pulposus and these cells have been proposed to play a very suggested that TNF-αγ inhibitors may be important therapeutically
important role in the inflammatory process in regards to production in the future. Presently, synthesis of TNF-αγ can be blocked with
of abnormal types of collagen as well as MMPs and TIMPs in response systemic corticosteroids, IL-10, TGF-βγ or by other drugs such as
to abnormal loading characteristics. Haro et al. reported their results chlorpromazine, pentoxifylline, or ciclosporin. However, these drugs
in a co-culture system of chondrocytes and macrophages and demon- are non-specific inhibitors and may result in side effects that would
strated a marked upregulation of MMP3 by disc chondrocytes with be undesirable. Presently, there are anti-TNF agents being used in
the addition of macrophages to the culture system. This resulted in the treatment of rheumatoid arthritis. The first of these, infliximab
eventual resorption of the disc through macrophage action. They fur- (Remicade), was quickly followed by etanercept (Enbrel). Recently,
ther used MMP-null mice to determine that the production of MMP3 a monoclonal antibody against TNF-αγ, adalimumab (Humira), has
by the chondrocytes was required for macrophage infiltration in disc been released. These agents are not presently approved for treatment
resorption. In a more recent study, this same group has shown that of sciatic pain, but have given sufferers of rheumatoid arthritis a fur-
the production of MMP7 by macrophages was found to be required ther dimension for their treatment.
for infiltration into disc tissue through a mechanism involving the Another potent inflammatory mediator that is also induced by
release of soluble TNF-α.12 TNF-αγ is nitric oxide. Nitric oxide is a particularly interesting

24
Section 2: Spinal Pain

Table 3.2: Temporal relationships in disc degeneration

Pre-adolescence Adolescence Early Adulthood Middle Adulthood Late Adulthood


Matrix remodeling for Highest period of weightbearing Continued matrix Continued structural Structural loss of height
‘slow growth’ linear growth imbalance imbalances stable
No inflammogenic Matrix remodeling imbalances Collagen isotype Chronic and acute on In vivo collapse and
changes switch chronic inflammation autofusion or
↑chondrocyte nests
Loss of proteoglycan Inflammogenic events Desiccation and breakdown In vivo collapse with
(e.g. injury, abnormal of anulus facet joint incompetence
motion) and instability
Onset of early degeneration Structural changes – Changes contributing to
loss of height DJD or stenosis

compound in that it has been shown to act in various ways depend- as well as the neovascularization that both potentiates the response
ing on the tissues that in which it resides. In bone, mechanical stress and serves as a nidus for nerve invasion of the outer anulus.
affects intracellular cyclic AMP, calcium, and PGE2 levels, as well as Inflammatory mediators such as bradykinin, nitric oxide, and
having effects on matrix synthesis. It has been demonstrated that TNF-αγ may directly affect local nerves having effects on conduction
nitric oxide is a key mediator of these processes. Articular chondro- velocity and sensitizing nerve endings to normally benign motion. As
cytes have been shown to produce large amounts of nitric oxide. As well, the effect on perineural vascularity and edema is pronounced in
described in the preceding sections introducing the inflammatory the presence of these mediators. These proinflammatory contribu-
process, nitric oxide is produced in several forms including the induc- tors may help explain the previously mentioned paradox concerning
ible form that is present in chondrocytes. Kang et al. first showed a lack of evidence supporting compression per se in causing spinal
the spontaneous production of nitric oxide from human lumbar discs nerve pain.
and that this production was higher in herniated discs than normals.2 Researchers continue to unravel the temporal relationships as well
In a follow-up study, Kang et al. examined the effects of IL-1β on as new ways of treating this common entity. Solution of the a priori
normal and herniated disc tissue. They found that the addition of ‘first cause’ for degenerative disc disease will probably await our abil-
IL-1βγ caused a significant increase in the production of nitric oxide ity to genetically replace damaged discs. Such research is ongoing in
as well as IL-6 and PGE2.3 While these inflammatory mediators were several centers and deserves support.
sharply increased in both normal and herniated disc tissue, the inter-
esting point to this paper was that MMP production did not change
in the herniation disc material, while the normal disc showed a sharp
increase in the production of MMPs. It is also noted by this group
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Invest 1986; 77:645–648. lagen types in differentiated and dedifferentiated articular chondrocytes. Biochim
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Eyre DR, Muir H. Quantitative analysis of types I and II collagens in human interverte- Melrose J, Ghosh J, Taylor TKF. Neutral proteinases of the human intervertebral disc.
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Melrose J, Ghosh J, Taylor TKF, et al. The serine proteinase inhibitory proteins of the Roberts S, Menage J, Duance V, et al. 1991 Volvo Award in Basic Sciences. Collagen
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27
PART 1 GENERAL PRINCIPLES
Section 2 Spinal Pain

CHAPTER
Transduction, Transmission
4 and Perception of Pain
Sarah M. Rothman, Raymond D. Hubbard, Kathryn E. Lee
and Beth A. Winkelstein

Painful spinal disorders are common problems in society, affecting an models, including behavioral sensitivity, local structural changes, and
estimated 50 million Americans. The societal costs (including litiga- cellular and molecular changes in the CNS, as they provide insight
tion, work lost, treatment, and disability) for such disorders of the into understanding pain mechanisms.
spine are staggering. For example, the cost of low back pain alone has It is important to define, at the outset, relevant distinctions in ter-
been estimated at US$40–50 billion annually.1,2 Chronic neck pain minology. ‘Pain’ is a complex perception that is influenced by prior
has a similarly high cost of nearly US$30 billion in health-related experience and by the context within which the noxious stimulus
expenses.3 Until a better understanding of the pathomechanisms of occurs. Likewise, ‘nociception’ is the physiologic response to tissue
pain and the injuries which produce them are defined, the effective damage or prior tissue damage. Similarly, for discussion in this chap-
prevention and treatment of these disorders and their symptoms will ter, ‘hyperalgesia’ is defined as enhanced pain to a noxious stimulus.4
remain elusive. Further, distinguishing those physiologic mechanisms Strictly speaking, this is a leftward shift of the stimulus–response
which lead to persistent pain from those which differentially pro- function relating pain to intensity. The corresponding pain thresh-
duce only transient symptoms is also important in understanding and old is lowered and there is enhanced response to a given stimulus.
managing these syndromes. It is the intent of this chapter to highlight Hyperalgesia is mediated by nociceptor sensitization, where ‘sensiti-
traditional and emerging theories of pain detection and transmission zation’ describes a corresponding shift in the neural response curve
in the context of spine-related syndromes. A brief discussion of the for stimulation. Sensitization is characterized by a decrease in thresh-
neurophysiology of pain highlights concepts of local responses, pain old, an increased response to suprathreshold stimulus, and spontane-
transduction, signal transmission, and processing and is integrated ous neural activity.
with more recent hypotheses of the central nervous system’s (CNS) For this chapter, many of the examples are drawn from painful
neuroimmunologic involvement in persistent pain. injuries related to the cervical or lumbar spine. These include both
This chapter focuses on the sensory system, presenting the gen- low back and neck pain from radiculopathy and facet-mediated
eral anatomy of the spinal cord, nerve roots, and nerves. There are injury. While it is recognized that these examples are by no means all-
many physiologic mechanisms by which pain is detected and through inclusive of pain related to the spine, they do provide an ideal context
which they can elicit nociception and ultimately the perception for discussing many of the broader mechanisms presented here.
of pain. Mechanisms of pain detection are presented with specific
points related to transmission of pain signals. In persistent pain, CNS
changes can produce hypersensitivity or central sensitization. In addi-
RELEVANT NEURAL ANATOMY
tion to the electrophysiologic changes leading to central sensitization, Before presenting and discussing pain mechanisms, it is first neces-
the spinal cord and brain mount a series of neuroimmune responses sary to describe the relevant anatomical structures, biological connec-
which may further contribute to sensitization and persistent pain tions, and relationships of neural sensory and processing components.
symptoms. Findings related to neuroimmunity are briefly reviewed These are reviewed only briefly here to provide appropriate context; a
here to form a basis for discussing more recent views of mechanisms more detailed presentation can be found in texts specifically focused
of persistent pain. in neural science and pain.4,5
Physiologic mechanisms, together with neurochemical responses, The primary afferents, which relay pain signals from injured or
are addressed and discussed in the context of findings from animal stimulated tissues, terminate in the dorsal horn of the spinal cord.
models of persistent pain in which behavioral hypersensitivity is pro- At each level in the spinal cord, the dorsal nerve roots carry sensory
duced. In particular, studies examining mechanical injuries to differ- information from the periphery into the spinal cord. Dorsal roots
ent anatomical structures of the spine and which lead to persistent contain sensory neurons, whose cell bodies make up the enlarged
pain symptoms are used here to provide a comparative discussion of dorsal root ganglion (DRG) (Fig. 4.1). In contrast, the ventral root
pain detection and transmission and perception, in the context of fac- contains the axons of neurons whose cell bodies are within the ventral
tors for consideration in the spine. As such, findings with radiculopa- horn of the spinal cord and transmits efferent signals. At each spinal
thy models of nerve root compression are presented and compared level, the dorsal and ventral nerve roots come together, outside of
for discussion of potential differences in mechanisms of transient the spinal column and distal to the DRG, and combine to form the
and persistent sensitivity (pain). In addition, findings from the cervi- nerve which communicates with the peripheral nervous system. The
cal radiculopathy model are directly compared to those behavioral spinal nerves further branch into smaller nerves in the periphery and
responses for a facet-mediated distraction pain model in the cervi- innervate bones, ligaments, joints, discs, muscles, organs, and many
cal spine. These behavioral studies provide a platform for exploring other tissue types.
similarities and differences in pain responses for different types of Structurally, three protective layers surround the spinal cord, which
tissue injuries. Measures of injury responses are presented for these are themselves extensions of the cranial meninges: the dura mater

29
Part 1: General Principles

cell populations. The gray matter, which has a darker appearance,


contains the cell bodies of spinal neurons and makes up the central
region of the spinal cord. It is surrounded by the white matter which
contains the axons of the spinal neurons. The columnar tracts of the
spinal cord are regionally specialized according to information they
carry (see Fig. 4.2). The lateral column contains motor neurons; the
dorsal column carries information related to mechanoreception; and
the ventrolateral column houses neurons which communicate infor-
mation regarding pain, temperature, and motor signals. In general,
the sensory system ascending pathway comprises the dorsal portion
of the spinal cord, while the descending pathway of the motor control
system comprises the ventral aspect of the cord.
Afferents of the dorsal nerve root enter the spinal cord dorsolater-
ally and branch in the white matter, with collaterals which terminate
in the gray matter. Nerve fibers mediating pain pass through the tract
of Lissauer and have branches which terminate in the most super-
ficial regions of the dorsal horn, laminae I and II. Neurons in these
laminae synapse on secondary neurons in laminae IV–VI of the dorsal
horn and these secondary neurons cross the midline before ascending
to the brain contralaterally in the anterolateral region of the cord.
Lamina X, which is located in the gray matter region closest to the
central canal, also receives sensory inputs related to pain. The neu-
rons of the substantia gelatinosa receive information from Aδ and C
fibers; Aβ afferents terminate in the deeper laminae. After injury, it
is believed that Aβ afferents sprout from the deeper lamina into the
dorsal horn where they make synaptic contacts with neurons.6,7
Nociceptive information is transmitted from the spinal cord to
Fig. 4.1 Axial section of dorsal and ventral C7 nerve root stained with supraspinal sites, primarily in the pons, medulla and thalamus. The
osmium tetroxide. Small- and large-diameter fibers are apparent in the anterolateral ascending system has three tracts: spinothalamic, spin-
dorsal root (bottom), as well as cell bodies of the dorsal root ganglion. oreticular, and spinomesencephalic. The spinothalamic is the most
Scale bar is 100 μm.
prominent of the tracts. Briefly, the spinothalamic and spinoreticular
tracts mediate noxious sensations, with axons terminating on neu-
rons in the reticular formation of the medulla and pons. From there,
(outermost), the arachnoid mater, and the pia mater (innermost layer signals are relayed to the thalamus, and then, neurons project to the
closest to the spinal cord). Within the spinal column, the lumbar dor- somatosensory cortex.
sal and ventral nerve roots extend below the spinal cord and this Each regional level of the spinal cord receives sensory information
neural tissue, collectively called cauda equina, fills the sacral spinal from specific regions of the body, known as dermatomes. Typically,
column. The spinal cord is anatomically composed of two regions nerves from approximately two spinal levels innervate any given
(Fig. 4.2). These are distinguished by their appearance, function, and region of the skin’s surface. These surfaces have been divided into
discrete regions, providing a dermatomal map relating each region
of the skin to a corresponding spinal level.8 Clinically, dermatomal
maps are used to identify the origin of painful symptoms. However,
Dorsal root Tract of Lissauer I Dorsal column nerve endings which innervate internal organs can also produce cuta-
(primary afferents) II neous sensation. This ‘referred pain’ sensation is experienced at sites
Gray matter
X other than its source and is due to the fact that nearly all spinal neu-
Dorsal horn
rons that innervate internal organs also are associated with cutaneous
sensation.

Lateral column
Ventrolateral column
TRANSDUCTION
Nociceptive afferents are specific for sensing different noxious stim-
uli: thermal, mechanical, and chemical stimuli. Some nociceptors
are polymodal and sense all types of stimuli. Broadly, sensory nerve
Ventral root fibers range in diameter from <0.05 μm to 20 μm. These fibers are
either unmyelinated or myelated with thick or thin myelin sheathes
enclosing them. Their conduction velocities can range from 0.5 m/s
to 120 m/s, depending on their axon diameter and/or the presence of
Central canal White matter
myelination. A fibers are myelinated and can evoke sharp and prick-
Fig. 4.2 Schematic illustration of the spinal nerve roots, spinal cord, and ing pain sensation; they can also convey sensations of aching pain.
its regions of gray and white matter. Also indicated are columns of the The largest, myelinated sensory axons, Aβ, are generally classified
neuronal tracts in the white matter. Those regions of the gray matter as mechanoreceptive. Aβ fibers are primarily proprioceptive (sensing
(laminae) of particular relevance to pain sensation and transmission are mechanical movement in joints and muscles). Their diameters are
indicated. approximately 10 μm; these fibers have slower conduction velocities

30
Section 2: Spinal Pain

than Aδ fibers. The smallest myelinated fibers are Aγ fibers, which edema as part of the healing process, these same immune processes
primarily mediate pin-prick, itching, and other mechanical sensations that provide healing also sensitize nociceptors and recruit new noci-
of pain. Unmyelinated C fibers mediate thermal sensation, in addi- ceptors that enhance pain.11,12 In particular, cytokines are released
tion to mechanical pain. Stimulation of C fibers can also induce a in the periphery in association with tissue injury and inflammation.
burning sensation. C and some A fibers are the primary high-thresh- These small proteins, in turn, contribute to the local inflammatory
old noceiceptors. The A fibers exhibit greater response frequencies response, while further modulating electrophysiologic responses
than C fibers and have more communications to the spinal cord. of nerve fibers and altering nociception. Additional details regard-
Pain results most often from direct tissue injury or from inflam- ing specific biochemical mediators of pain and their mechanisms
mation which alters the local peripheral chemical milieu. For a given of action throughout the pain signaling pathway (i.e. injury site and
insult, local nociceptors become activated; this occurs when the nerve spinal cord) are provided in a later section specifically addressing
endings of the Aδ and C fibers are stimulated. Conduction velocities biochemical mediators of pain.
of Aδ fibers are approximately 10 times those of C fibers (5–30 m/s
and 0.5–2 m/s, respectively) due to the saltatory conduction medi-
ated by their myelin sheathing. As a consequence of this difference
TRANSMISSION
in conduction velocity, a sharp pain is first detected in response to a In general, injury to a variety of tissues, including muscle, disc, liga-
stimulus, followed by a longer-lasting, dull and burning pain, which is ment, and neural tissue, can induce many cascades and physiological
mediated by the C fibers. signals which lead to pain transmission (Fig.4.3). During this pro-
Pain detection and signaling begin at the injury site where Aδ and cess, neuroplasticity and subsequent CNS sensitization responses
C fibers are activated by thermal, chemical, mechanical, and/or produce altered functions of chemical, electrophysiological, and
electrical stimuli. These nociceptors can become sensitized, lower- pharmacological systems throughout the periphery and central
ing their thresholds for firing and increasing their firing rates when systems.4,13–17 This cascade of biochemical and molecular reactions
stimulated.9 Further, damaged cells at the site of injury release ATP causes changes in gene transcription, post-translational modifica-
and free protons. Briefly, a complex series of reactions also occur, tions, and culminates with the transmission of pain.18 The interplay
including altered blood flow, release of neuropeptides from the affer- of these system responses involves complicated cross-system effects
ent fiber itself, and a generalized host of biochemical and cellular between injury and changes in both the peripheral and central ner-
responses typical of an immune response. For painful tissue injuries, vous systems. The integration of multiple physiologic systems, as
inflammation is induced in an effort to promote healing and recov- occurs with pain transmission (see Fig. 4.3), contributes to the over-
ery. In this process, inflammatory mediators such as prostaglandin E, all challenges in preventing such syndromes since a given insult may
serotonin, bradykinin, and histamine, among others, can alter fiber initiate a host of different responses which can be established and
responses. These and other mediators directly activate nociceptors maintained remote from the actual site of injury. Regardless, there
or can sensitize those nociceptors which are already responding to is a generalized series of responses which occurs following a painful
stimuli. This further induces increased neuronal activity. Specifically, injury in the periphery.
bradykinin, serotonin, excitatory amino acids, and hydrogen ions are A chemical insult in the periphery causes direct activation of
all responsible for directly activating afferents.9,10 Similarly, prosta- sensory neurons; voltage-gated sodium channels are integral for ini-
glandins, serotonin, noradrenaline, adenosine, nitric oxide, and nerve tiating and propagating pain signals in these sensory neurons. Two
growth factors can sensitize nociceptors. separate types of such channels have been designated as SNS and
In addition to altered electrical activity, and the local synthesis SNS-2, respectively. The SNS subtype is present on both C and some
and release of inflammatory mediators that induce inflammation and A fibers; SNS-2 channels are exclusively present on unmyelinated

Pain

Afferent fibers

Injury
Fig. 4.3 Schematic diagram detailing the
broad collection of physiologic mechanisms
which initiate and contribute to pain. While
Local site of injury/pathology CNS the schematic suggests a simple linear
Electrophysiologic cascade (from left to right) of events which
Structural and material responses signalling Dorsal horn excitability lead to pain, these responses are quite
Decreased threshold,
Edema Increased response to stimuli, dynamic in nature and involve aspects
Ongoing spontaneous activity of electrophysiology, immunology, and
Inflammation and immune responses their interplay. The degree to which these
Neuroimmune activation and inflammation alterations occur is variable and dependent
Neuromodulator release Glial activation, on both the nature of the injury and the
Cytokine and chemokine upregulation/release, type of response. Moreover, many of these
Altered synaptic transmission
individual responses affect each other (small
Algesic mediator induction and release arrows) and are themselves directly altered
SP, CGRP, prostaglandins, glutamate, NO by confounding physiologic, anatomical, and
mechanical factors.

31
Part 1: General Principles

neurons. The vanilloid receptor (VR1) is spatially co-localized with is constitutively expressed by both neurons and endothelial cells. Of
these channels. note with regard to pain signaling, neuronal NOS (nNOS) is par-
Calcium concentrations play a critical role in mediating pain in the ticularly potent due to its activity being enhanced in the presence
central nervous system by controlling and regulating levels of nitric of intracellular calcium (see above). While the main source of NO
oxide synthase (NOS), prostaglandins, and changes in their gene tran- in the CNS is through the activity of neurons in pathological states
scription.19 An increase in calcium causes enhanced release of neu- such as inflammation and/or pain, microglia and inflammation can
rotransmitters, as well as an increase in activity of neuronal nitric oxide also produce NO.
synthase. Because changes in intracellular calcium occur through the While nitric oxide acts primarily at the site of its synthesis, it can
actions of several different channel types, it is possible to isolate the also serve as a neurotransmitter, having direct influence on trans-
effects of calcium based on which channel opened. For example, in stri- mission of painful stimuli. Dorsal horn neurons can respond to NO
atal neurons, the population of calcium that activates nNOS is derived signaling in pain, directly initiating phosphorylation of membrane
from opening of a voltage-gated calcium channel. In addition, increases proteins and changes in gene transcription within these neurons. In
in intracellular calcium via NMDA receptor influx causes increases in the dorsal horn, NO can feed back to the presynaptic terminals of
arachidonic acid which can enable COX and prostaglandin produc- primary afferents where it promotes the release of glutamate and
tion. This process sensitizes neurons of the dorsal horn by a protein substance P. This action accentuates nociceptive signaling. As well,
kinase C pathway; this second messenger can induce neurons to release NO can stimulate glial cells to produce prostaglandins and cytokines,
substance P and glutamate and provide nociceptive transmission. which leads to nociception.
Primary afferents communicate with spinal neurons via synaptic Bradykinin is a hormone intimately involved in inflammation and
transmission. A variety of neurotransmitters (i.e. glutamate, NMDA, vascular responses that also contributes to pain signaling. This pro-
substance P) modulate postsynaptic responses, with further trans- tein works through a series of transmembrane G protein-coupled
mission to postsynaptic spinal neurons and supraspinal sites via receptors: bradykinin B1 is implicated in chronic pain and bradykinin
the ascending pathways.9 Peripheral signals of injury pain generate B2 is involved in acute inflammation and pain.25 Both receptors are
increased neuronal excitability in the spinal cord.17 Associated with expressed on primary sensory neurons where they can directly par-
this sensitization are a decreased activation threshold, increased ticipate in the primary effects of nociception. Bradykinin sensitizes
response magnitude, and increased recruitment of receptive fields.4 nociceptors, which produces hyperalgesia. While the B2 receptor is
The continuous input from nociceptive afferents can drive spinal constitutively expressed, the B1 receptor is induced in tissue that
circuits and lead to central sensitization, maintaining a chronic pain is damaged by either infection, disease, or injury. For example, as
state.15 These neuroplastic changes are accompanied by other electro- early as 48 hours after a peripheral nerve injury, B2 receptor mRNA
physiological manifestations that cause neurons to fire with increased increases, while B1 expression does not reach similar levels until 14
frequency and even to fire spontaneously.16 Spinal processing is fur- days later.25 B2 receptor kinetics are comparatively fast relative to B1,
ther directly altered by descending inhibitory and facilitory pathways including the processes of ligand binding, release, and internalization.
that can provide additional modulation of spinal interneurons.20 Through the B2 receptor, bradykinin causes the release of substance
Ultimately, persistent pain results from the sensitization of the P and calcitonin gene-related peptide from primary sensory neurons.
central nervous system. While the exact mechanism by which the This release is further increased in the presence of prostaglandins,
spinal cord reaches a ‘hyperexcitable’ state of sensitization is not which are upregulated at the site of insult.
fully known, many hypotheses have emerged. Here, only highlights Prostanoids are a class of pronociceptive molecules such as pros-
of these theories are provided as an overview. More extensive and taglandin E2 that are produced when arachidonic acid is metabolized
detailed discussions can be found elsewhere in the literature.17,21–23 by the COX enzyme, which exists in isoforms COX-1 and COX-2.
Central hyperexcitability is characterized by a ‘wind-up’ response of Specifically, the COX-2 isoform is dramatically upregulated in the
repetitive C fiber stimulation, expanding receptive field areas, and spinal cord after injury in the periphery. The release of prostaglan-
spinal neurons taking on properties of wide dynamic-range neurons.24 din E2 which occurs in response to the upregulation of that enzyme
Low threshold Aβ afferents, which normally do not transmit pain, causes a shift in the peripheral terminal of the nociceptor, lowering
begin to signal spontaneous and movement-induced pain.22 Aβ fibers its threshold and increasing its excitability.
stimulate postsynaptic neurons to transmit pain, where these Aβ There is a host of other inflammatory-related mediators which
fibers previously had no effect. This plasticity of neuronal function in have direct and indirect effects on pain and nociception. Serotonin
the spinal cord contributes to central sensitization. is released from platelets downstream from mast cell degranulation,
as occurs during inflammation. Serotonin directly modulates pain by
activating primary afferents and also enhances sensitivity of sensory
BIOCHEMICAL MEDIATORS OF PAIN responses to bradykinin. Leukotriene B4 is a neutrophil attractant
Many chemical mediators are involved in the transduction and trans- that can sensitize afferents.
mission of pain, including local sensory terminals, synaptic transmitters, Substance P is a pronociceptive neurotransmitter, which is released
afferent sensitizers in the periphery, neuronal activators and modula- in the periphery following afferent activation. It mediates inflamma-
tors, and mediators of spinal cord signaling. Many of these mediators are tion by causing vasodilation and the release of prostaglandin E2 and
endogenous; some are inducible. In addition, many of these chemicals cytokines. These actions impact local inflammation, directly modu-
are directly involved in pain, while some are primarily inflammatory with lating nociception. Substance P can cause a release of calcium from
secondary actions of nociception. Their properties and interactions are intracellular stores and lead to NO production, neuronal excitability,
eloquently detailed in the previous chapter.4 A brief synopsis of the pri- and long-term sensitization.26,19 Substance P has been shown to have
mary mediators affecting nociception is provided to create context for a role in pain in the central nervous system. Administration of antago-
understanding the complexities of pain signaling. nists to the substance P receptor, neurokinin-1 (NK-1), can induce
Nitric oxide (NO) is a pleiotropic pronociceptive messenger, with antinociception in the central nervous system following chronic
both intracellular and extracellular mechanisms of action. It can also painful mechanical nerve constriction.28
serve directly as a neurotransmitter. NO is formed when L-arginine Calcitonin gene-related peptide (CGRP), a neuropeptide often co-
is catabolized to L-citrulline, by nitric oxide synthase (NOS). NOS localized with substance P in the spinal cord, contributes to sensiti-

32
Section 2: Spinal Pain

zation. It regulates nociceptive responses by promoting the release (iNOS) and constitutive (cNOS), whereas microglia are only respon-
of substance P and glutamate from primary afferents, while imped- sible for inducible NOS.39 TNF-α and IL-1β control the stimulation
ing the metabolism of substance P.28,29 CGRP alone causes a slow of iNOS in both astrocytes and glia, therefore inducing the produc-
membrane depolarization in sensory neurons and an influx of cal- tion of NO from those cell types. Alternatively, TGF-β suppresses
cium through voltage-gated calcium channels. These actions enhance NO production in both astrocytes and microglia whereas IL-10 only
sensitization and promote NK-1 and NMDA activation.19 Antibodies affects NO production in astrocytes.
to substance P and CGRP can attenuate pain symptoms in inflam-
matory models of carageenan-induced hyperalgesia and painful nerve
injury;26,30 these studies strongly implicate both such neuropeptides
CNS NEUROIMMUNE RESPONSES IN PAIN
in pain transmission. While central sensitization contributes to nociceptive mechanisms
Excitatory amino acids, such as glutamate, have potent roles in of persistent pain in the CNS, recent research has demonstrated
pain, both at the site of injury and in the central nervous system. the potent role of spinal neuroimmune responses in the generation
Indeed, both non-neuronal and neuronal cells in the periphery pro- of chronic pain.40 CNS immune changes have been demonstrated to
duce glutamate. Both of these sources act on primary afferents by occur in the setting of persistent pain.33,36–38,41,42 Among the disor-
activating them when bound to any of the NMDA, kainite, AMPA, or ders in which this phenomena has been observed are radiculopathy,
metabotropic glutamate receptors.4 Certainly, this positive feedback neuropathy, diabetes, and HIV. These immunological alterations
mechanism of nociceptor excitation leads to peripheral sensitiza- provide evidence that implicates a role for centrally produced pro-
tion and to altered afferent signaling into the spinal cord. Glutamate inflammatory cytokines, glial activation, and leukocyte trafficking in
receptors are expressed in dorsal root ganglion cells,30 suggesting its rodent pain models of lumbar radiculopathy.38,43–46 From this body
direct involvement in afferent signaling to the cord. As the NMDA of work, a cascade of events in the CNS has been proposed fol-
glutamate receptor has a key role in regulating synaptic efficacy, there lowing injury.14,40 Glial cells and neurons become activated and can
is also a direct role for this receptor in the spinal plasticity changes produce and release cytokines, which in turn can lead to increased
associated with central sensitization and persistent pain. activation of these cell types. As well, they lead to increased release
In a normal resting state, NMDA receptors are blocked by the of pain mediators.33,34,36 Glial and/or neuronal proinflammatory
presence of a magnesium ion, and glutamate is free to bind only to cytokines can sensitize peripheral nociceptive fields47 and cells in
low-affinity AMPA receptors. For a neuronal depolarization, the mag- the dorsal root ganglia.48
nesium ion blocking the NMDA receptor becomes liberated, which Events that induce behavioral hypersensitivity also activate cen-
allows glutamate to bind in its place. This binding activates a com- tral and peripheral immune cells that mediate chronic pain.25,34,36,49,50
plicated cascade, allowing an influx of a host of ions, including cal- Cytokines and growth factors have been strongly implicated in the
cium. These events, in turn, activate a kinase cascade. Each NMDA generation of pathological pain states throughout the nervous system.
receptor is composed of two subunits: the NR1 subunit and the NR2 Specifically, proinflammatory cytokines, such as IL-1, IL-6, and TNF,
subunit. The NR2B subunit has been specifically implicated in pain are upregulated both locally and in the spinal cord.32,33,35 Immune acti-
transmission via research findings from a variety of knockout stud- vation with cytokine production may indirectly induce the expression
ies,31 and its ability to be more readily phosphorylated than the other of many pain mediators such as glutamate, nitric oxide, and prosta-
NR subunits. NMDA receptors are found both post- and presynapti- glandins in the CNS. In conjunction with this neuroimmune acti-
cally. Presynaptic NMDA receptor activation causes the release of vation, neuroinflammatory actions, in which immune cells migrate
substance P from small-diameter primary afferent fibers. The open- from the periphery into the CNS in association with pain, occur.14,40,45
ing of the NMDA receptor also increases the synaptic strength of Such infiltration may lead to further nociceptive changes in the CNS
neurons in the dorsal horn by activating the kinase cascade. These and potentially to central sensitization. Infiltrating immune cells alter
events, which can directly potentiate neuronal fiber sensitization, pro- and compound neuronal activation, and promote algesic mediator
duce the ‘wind-up’ responses described for dorsal horn neurons.17,24,32 release, further perpetuating the maintained excitability and sensi-
However, despite the known involvement of the NMDA receptor tization in the CNS, leading to pain and behavioral sensitivity in the
in pain signaling, little clinical success has been demonstrated for case of in vivo models. The spinal immune response of nociception
NMDA antagonists in ameliorating pain, due to profound side effects has many facets, forming a complicated cascade of events leading to
such as memory or coordination deficits. pain (see Fig. 4.3). It is important to recognize, though, that while
Cytokines can directly and indirectly regulate biochemical cas- quite potent, these immune responses are only one aspect of noci-
cades leading to the transmission and modulation of pain. Broadly, ception and the effects of these cellular and chemical sequelae can
cytokines include both proinflammatory and antiinflammatory pro- themselves directly modulate many other potent pathways of pain
teins, both of which are upregulated in painful injuries.33–37 In par- signaling in the CNS.
ticular, in models of neural injury either distal (peripheral injury) or
proximal (nerve root injury) to the DRG, spinal IL-1β, IL-6, IL-10,
and TNF-mRNA have all been observed to be significantly elevated INJURY AND BIOMECHANICAL FACTORS
for persistent pain.38 Not all of these factors are proinflammatory. MODULATING NOCICEPTION AND PAIN
For example, IL-10 has been shown to suppress NO production in PERCEPTION
cultured astrocytes and also suppress proliferation in macrophages,39
which in turn has antiinflammatory effects. The presence of cyto- Electrophysiologic and neuroimmune responses of the CNS likely
kines can further stimulate their own production, as demonstrated work together to affect pain for spinal syndromes, with local biome-
by IL-1 stimulating its own production.36 Cytokines mediate cellu- chanics at the site of an injury modulating both such responses. Low
lar processes through the production or suppression of nitric oxide. back pain is an ideal syndrome to use as an illustrative example for
NO has an immunoregulatory role in the central nervous system. Its discussing these mechanisms and cellular response cascades of pain.
production leads directly to hyperalgesia, as previously mentioned. In this discussion, injury conditions are presented as examples of how
Cytokines regulate NO by interfering with the production of NOS. mechanical loading modulates nociception in low back pain, with par-
Astrocytes produce each of the two main forms of NOS, inducible ticular emphasis on nerve root injury (i.e. radiculopathy). In addition,

33
Part 1: General Principles

throughout the following text comments will be made where appli-


cable to other spinal regions such as the cervical spine.
In vivo studies of animal models of pain report altered electrophys-
iologic and cellular function for graded cauda equina compression.
Applied compression increases endoneurial pressure locally in the rat
sciatic nerve and DRG in proportion to the degree of mechanical
loading.51,52 It has been shown that edema patterns and intensity are
modulated by the nature of the mechanical insult.52–55 Loading to the
nerve root can produce changes in electrical impulse propagation and
conduction velocity56–58 and repetitive neuronal firing in the dorsal
horn of the spinal cord,57,59 which are physiologic correlates leading to
spinal sensitization and, consequently, persistent pain. This collective
body of research suggests an electrophysiological and neuronal mech-
anism of spinal cord plasticity and central sensitization for mechani-
cal injuries. It is only inferential for understanding the production and
maintenance of pain symptoms.
Imaging techniques have been used in a rodent model of painful
lumbar radiculopathy to quantify nerve root tissue deformation for
A
an applied root ligation. In that study, Winkelstein et al. examined the
injury parameter of tissue deformation in the context of pain (behav-
ioral hypersensitivity).60,61 Local injury mechanics were found to
modulate pain behaviors. There was a significant positive correlation
in that pain model between behavioral sensitivity and the amount of
tissue compression.60 This observation led to a mechanical compres-
sive deformation threshold for pain behaviors and hypersensitivity that
were defined based on the amount of nerve root compression.27 More
recent work examining cervical nerve root compression magnitude
and behavioral sensitivity in the forepaw suggests that a force-based
threshold may be more sensitive than deformation for predicting pain
symptoms. It has been suggested that a load below 10 g may be suf-
ficient to elicit persistent pain for cervical dorsal nerve root compres-
sion.49 Interestingly, while work in the cervical spine suggests that
tissue loading may more directly influence pain symptoms, neural
tissue is a very soft material and, as such, can undergo extreme tis-
sue deformations before establishing any perceivable load. Continued
research is needed to fully define those exact mechanisms through B
which direct mechanical loading/deformation of the cervical root can
be transduced to produce persistent pain. Nonetheless, recent find-
ings of evidence of neuronal degeneration local to the insult (Fig. 4.4) Fig. 4.4 Fluoro jade-B staining of nerve root and DRG for control (A)
suggest that local changes in the region of injury are robust and occur and injured (B) conditions demonstrating the lack of degeneration in the
as early as 1 day after direct insult. Together, mechanical parameters control sample where there is no fluorescence. In contrast, the image on
defining painful injuries provide added utility for clinicians in diagnos- the right is a DRG 1 day following a painful compression to the root. The
noticeable dots in the DRG indicate degenerating cells and may suggest
ing painful injuries, directly linking the injury event to the likelihood
a mechanism of pain symptoms in this model.
of pain symptoms. Moreover, in the future, it will hopefully provide
insight into predicting clinical outcomes for this class of injuries.
While defining the relationship between spinal tissue insult and pain cal nerve root injuries and pain mechanisms, findings suggest similar
is necessary for understanding the clinical context of painful patholo- cytokine responses may be evident throughout the spine (i.e. lumbar
gies, understanding the specific and relevant nociceptive responses is versus cervical injuries).
crucial for characterizing the central mechanisms of persistent spine Spinal microglial activation has been demonstrated to be more
pain. Using RNase Protection Assays to detect spinal mRNA of a panel intense for greater nerve root deformation at injury in lumbar inju-
of cytokines (TNF-α, IL-1αβ, IL-6, IL-10) in lumbar radiculopathy, ries,44,62 which is consistent with the graded behavioral responses
a statistically significant correlation was found between mRNA levels and spinal cytokine expression according to injury severity.44,60,61
at postoperative day 7 and the degree of tissue deformation for lum- Interestingly, in these same studies, astrocytic activation did not
bar root compression.60 This observation suggests a modulatory effect follow injury magnitude, suggesting that biomechanics at injury in
of injury magnitude on one aspect of spinal nociception. IL-1β has lumbar radiculopathy models may differentially modulate some neu-
been reported to depend on nerve root compression intensity.44 This roimmune responses and not others.62 Recent work from the authors’
observation suggests preservation of these changes at both the mes- laboratory has examined these same spinal glial responses in two dif-
sage and protein level spinal cytokines involved in chronic low back ferent cervical spine injuries.49,50 In these studies of nerve root com-
pain. In comparative models of cervical nerve root injury created by pression and facet joint tension different astrocytic responses were
either compression or transection, spinal IL-6 protein at day 1 follow- observed. In the nerve root compression model spinal astrocytic
ing radicular injury was elevated, implying a potential relationship to expression was elevated compared to sham and followed the behav-
hypersensitivity on the day of assay.35 While continued research into ioral hypersensitivity patterns.49 Astrocytic activation did not show a
these and other cytokine responses is needed for understanding cervi- dependence on mechanical force magnitude. In our facet-mediated

34
Section 2: Spinal Pain

painful injury model spinal astrocytic activation did demonstrate a Increased allodynia (sensitivity) = “more pain”
significant correlation with injury magnitude and behavioral sensi- 10
tivity.50 This finding may suggest that different spinal immune cas- 9
cades exist for mechanical injuries to different tissue types. In a Facet joint injury
8
study directly comparing behavioral hypersensitivity produced for Facet sham

# of paw withdrawals
7
these nerve root compressions and facet-mediated injuries, no dif- 10g root injury
6
ferences were observed (Fig. 4.5). Both insults produced symptoms Root sham
immediately that were sustained for almost 5 weeks depending on 5
the insult. Moreover, within the first 2 weeks following injury, there 4
was no difference in symptom intensity between the two scenarios. 3
However, for this pilot study, the joint-mediated pain appeared to be 2
sustained for a longer duration than the neural tissue injury. Together
1
with the CNS glial findings for these two models of neck pain, these
behavioral outcomes suggest that pain symptoms (perception) may 0
be mediated differently depending on the source of the insult or sig- 0 10 20 30 40
naling. This comparative work from the authors’ lab suggests that for Post-operative time (days)
injuries in the cervical spine direct damage to neural tissue may be
Fig. 4.5 Mechanical allodynia (behavioral sensitivity) produced in the
perceived the same as for a nondestructive ligament loading scenario.63
ipsilateral forepaw for cervical radicular (10 g root) and facet distraction
These observations and suppositions highlight the need for continued (facet joint) injuries. Both injuries produce immediate increases in
integrative research to identify common and different physiologic allodynia compared to sham procedures. The increased sensitivity (pain)
mechanisms for injuries within the musculoskeletal system. is sustained for almost 3 weeks and even longer for the facet injury.

multidisciplinary approaches will help define nociceptive responses


SUMMARY in these and other spinal disorders.
It is recognized that the pathologies presented are by no means the In the typical response of an acutely painful episode for spinal con-
only chronically painful syndromes of the spine. As such, it should ditions, the balance of injury, repair, and healing is achieved and the
be noted that many of the theories described above may assist with cascade of electrophysiologic and chemical events resolves follow-
developing a more broad understanding in the context of pain in ing inflammation and injury. However, for persistent pain, the local,
the spine. While many factors modulate electrical signaling patterns spinal, and even supraspinal, responses are undoubtedly altered from
(amplitude, frequency) and local tissue changes (edema, pressure), that described above (Fig. 4.6). Based on the discussion presented
and the neuroimmune cascade for painful radiculopathy, their effects here regarding persistent pain, a comprehensive picture is emerging
for other painful syndromes may be similar. Continued integration of for spinal injuries and CNS responses of nociception: spinal cytokine

Dorsal root Injury or insult


Dorsal

Dorsal root
ganglion (DRG)
Spinal nerve

Ventral root
Ventral
Local root responses

Axonal injury DRG responses


Altered electrophysiology
Spinal responses Neuronal degeneration Neuronal degeneration
Myelin disruption/breakdown ↑ membrane permeability
Neuropeptide expression Altered fiber caliber Altered Na+ channels
Altered electrophysiology Local glia responses Neuropeptide expression
Immune changes – debris removal Local glia plasticity
– glial cell activation – cytokine release −growth factor release Fig. 4.6 Nociceptive responses are complicated
– cytokine release −neuropeptide release and involve a host of changes both locally and
Central sensitization −cytokine release in the central nervous system. Some responses
are self-regulating and can promote healing
processes which produce resolving pain, while
Persistent Acute other changes occur both at the site of injury
pain? pain? and in the spinal cord and CNS and can be
sustained, leading to persistent pain symptoms.

35
Part 1: General Principles

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The authors gratefully acknowledge the following for financial sup- orphin in the dorsal horn of rats with nerve injury or inflammation. Neuroscience
2003; 121:681–690.
port: National Institute of Arthritis and Musculoskeletal and Skin
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37
PART 1 GENERAL PRINCIPLES
Section 2 Spinal Pain

CHAPTER
Central Influences on Pain
5 Michael H. Moskowitz

INTRODUCTION face of neurons and their synapses. This has been a trend in neurology
Understanding central influences on pain is crucial if acute pain is and psychiatry, as well as in pain research. As a result of this research
to be prevented from becoming chronic and chronic pain is to be we have an ever more precise grasp of neurotransmitters, neurorecep-
brought under effective control. Central influences on pain exem- tors, positive and negative feedback loops, excitatory and inhibitory
plify neuroplasticity and, as such, help distinguish between pain as influences, and modulation of these processes by second messengers
a disease and pain as a symptom. One cannot fully grasp the con- and comodulating neurotransmitters. More recent discoveries about
cepts of central pain influences without detailing the contribution neuroglia, microglia, and the specialized cells of the blood–brain
of peripheral pain processes to their development and perpetuation. barrier focus upon far more complex processes than passive support
While they are most often tied in to structural changes in the periph- and protection. More sophisticated understanding of downstream
eral (PNS) or central nervous system (CNS), central changes that events addresses intracellular processes and how the genome is influ-
occur in chronic pain establish it as a separate, but connected, process enced to create changes in the proteome. This provides us with the
to the structural injury. Despite our focus in pain research on spinal basic building blocks of neuroplasticity and a refocus of our tradi-
cord action in development of neuroplasticity, brain nuclei respon- tional understanding of pharmaceutical targets and effects. This new
sible for the manufacture and axonal transport of neurotransmitters understanding of intracellular mechanisms also allows for develop-
and membrane placement of neuroreceptors place the brain in the ment of specific therapeutics aimed at influencing the genome for
command position for regulating central pain. Appreciation of the more pinpoint treatment, opening up a new potential for managing
brain’s adaptation to afferent signals altered at the dorsal horn and neuroplastic events in specific anatomical areas and precise synaptic
the synergism of brain-based, top-down modulation of these spinal targets. Ultimately, if we can change the ways that specific cells in
cord events represents the next frontier of therapeutic targets, espe- specific areas turn on and turn off production of neurotransmitters,
cially as our understanding of the genome’s effect upon the proteome neuroreceptors, nerve growth factors, enzymes, and neurohormones,
matures. Finally, it is through the common pathways and common we will be able to realize the dream of getting the runaway process of
neuroplastic events of centrally maintained pain and major affective chronic pain back into its normal physiologic harness.
disorder that the link between chronic pain and chronic affective dis-
order can be established at a molecular level. NEUROPLASTICITY AND THE DISEASE
OF PAIN
CENTRAL INFLUENCES ON PAIN It is important for physician and patient alike to distinguish pain as
Perhaps the best place to begin is to look at what is meant by cen- a symptom from pain as a disease. The symptom of pain is an essen-
tral influences on pain. Although the definition in the literature has tial fact of life and helps guide us to immobilize an injured part of
ranged from specific damage to brain or spinal cord to intracellular the body, seek help, and direct care. Pain is one of the most com-
processes that occur in the CNS, for the purpose of this chapter cen- mon symptoms aiding physicians in diagnosis and treatment. It is
tral influences involve the reaction of the CNS to acute and chronic also disturbing enough for most people who have it to require some
pain of any origin. While central influences on acute pain must be action, usually a cessation of activity. Successful treatment aimed
understood to explain the maladaptive processes involved in chronic- at the source of the pain often eliminates it. In fact, the body has
ity, this chapter will focus on the type of reorganization that occurs in physiologic mechanisms designed to diminish pain quickly after most
the CNS at the anatomic, neurophysiologic, intracellular, and molec- tissue injuries.
ular levels, as influenced by chronic activation of the nociceptive sys- The disease of pain, however, is quite different. It is the underlying
tem. Research into the anatomy of the spinal cord and the brain over condition and the extensive pathology of that condition distinguishes
the last several decades has revealed an increasing awareness of the the disease of pain from the symptom of pain. Although there are
complexity of the perception of pain as an unpleasant physical and definitions of pain becoming a chronic problem based upon duration
emotional experience. Not only are we progressively more aware of of injury, nerve damage, or frequency of flare-ups, the best definition
the built-in areas of pain processing, but also of the interconnections views the disease process from the standpoints of phenomenology
of the circuits that run to and from these regions. The result is that and neurophysiology.
we have a much better idea of how the brain and spinal cord work Phenomenologically, the disease of pain represents a concatena-
together to control nociception and how this process breaks down in tion of biological, psychological, and social events that disrupt the
chronic pain disorders. We also have a clearer understanding of where life of the patient. Cascades that occur in each area result in the
to target treatment and why effective treatment of peripheral stimu- experience of chronic pain. When people experience pain, there is an
lus is not always successful in resolving pain problems. Increasingly, expectation that it will eventually stop as the body heals. If this fails
our therapeutic targets of long-term treatment of chronic pain are to occur there are consequences that occur throughout the individ-
directed toward the intercellular mechanisms that occur at the inter- ual’s life. Mersky and Bogduk define pain in the following manner:

39
Part 1: General Principles

‘Pain is an unpleasant sensory and emotional experience associated acids results in wind-up pain, driven by the extreme peripheral and
with actual or potential tissue damage or described in terms of such central input. Wind-up appears to be the direct product of activation
damage.’1 The reason that this definition stands the test of time is that it of N-methyl D-aspartate (NMDA) receptors in the superficial dorsal
succinctly reflects the ambiguity of pain and unifies the physical and horn neurons.7 After nerve injury, reorganization directed by the dor-
the emotional, actual injury and potential damage, expectations and sal root ganglion (DRG) results in dorsal horn atrophy of nociceptive
experience, while highlighting the unpleasantness of pain. What it (Aδ and C-fibers) end-terminals, as well as phenotypic changes in
fails to take into account is the distinction of the symptom of acute non-nociceptors (Aβ fibers) so that they produce nociceptive neu-
pain and the disease of chronic pain. Donald Price describes acute rotransmitters and grow and reconnect into areas that are normally
pain as a two-staged event of desire to avoid harm and expectation populated by nociceptive (C-fiber) nerve terminals.8 The brain itself
that harm will be avoided. Price points out that when a person is goes through major changes at both a molecular and anatomic level.
injured, immediate concern about tissue damage is replaced with Actual apoptosis occurs in the brain in different regions for different
anxiety about healing and ‘threat to the self.’2 He describes fear chronic pain states, resulting in nerve cell loss and dendritic prun-
and anger as emotional aspects of acute pain and despair, frustra- ing.9 Functional MRI and MR spectroscopy in complex regional pain
tion, hopelessness and depression as common affective experiences syndrome (CRPS) and in chronic low back pain have demonstrated
of persistent pain. While this expands the understanding of pain this phenomenon.10
from the IASP definition it still lacks the necessary social perspec-
tive. For this we must turn to the biopsychosocial model developed
by George Engel. Engel’s view of the biomedical model was that
ACUTE PAIN
it ignored anything beyond reductionistic science and did not con- Acute pain is pain that is of recent origin, is related to specific injury
sider patients in the context of their psychology or as a larger part of or illness, is of short duration, and is accompanied by time-limited, if
society. In his paper, ‘Clinical Application of the Biopsychosocial any, disability. Acute pain is an important indicator that alerts us to
Model,’ Engel stated, ‘The biomedical model can make provision for the presence of a problem and tells us to stop using the injured body
neither the person as a whole nor for data of a psychological or social part to avoid further injury and allow healing. It is caused by nor-
nature . . . The triumphs of the biomedical model all have been in mal activation of pain nerve receptors, known as nociceptors. These
the areas for which the model has provided a suitable framework for specialized nerve endings are embedded throughout the body and
scientific study. The biopsychosocial model extends that framework respond to penetrating wounds, chemical irritations or burns, heat,
to heretofore neglected areas.’3 To integrate the ideas of Price and cold, pressure, nerve injury, inflammation, muscle spasm, fractures,
Engel with those of Bogduk and Mersky it makes more sense to view infections, edema, expansion or rupture of visceral tissue, ischemia,
persistent pain as an unpleasant emotional and sensory experience overuse, erosion, and degeneration. This covers almost all of the pain
associated with actual or potential threat to the integrity of one’s conditions that present medically, and, in fact, pain is one of, if not
entire life and described in terms of that threat. the most common presenting medical complaint to primary care
Why is it important to understand phenomenology in a textbook physicians’ practices.
on interventional spine and what is this doing in a chapter entitled Pain is often the symptom that helps us pinpoint the pathology,
Central Influences on Pain? Patients do not present to pain special- or at least helps us to begin to develop a differential diagnosis. At
ists with declarations about discs or nerves or neuroplasticity, but the same time, pain can be quite confounding both for diagnosis and
do come with descriptions of the disruptive nature of their pain to treatment. It is not an uncommon experience to find the underly-
their ability to be comfortable, to be happy, to relate to others, to ing pathology, treat it effectively, and still be left with residual pain
work, and to play. Understanding central influences on pain requires complaints. Although this occurs less frequently with acute pain, and
that physicians distill the biopsychosocial information brought in by more often when that pain becomes chronic, it may point to mis-
the patient down to the molecular changes occurring in the central diagnosis and a revision of treatment plans in acute pain problems.
nervous system, with the goal of crafting a plan to address these Although most acute pain clears up with treatment of the underly-
central neuroplastic changes in order to reestablish homeostasis in ing condition, it is important to treat the pain concomitantly with
the patient’s life. the healing of the structural and physiologic pathology. Treating acute
Neuroplasticity develops in response to injury. This is usually a pain decreases the unpleasantness of the experience, which if left
temporary state aimed at reestablishing the homeostatic balance of activated can have serious consequences to psychological and neuro-
both the PNS and CNS. Peripherally, the immune system responds transmitter homeostasis. Additionally, when the pain does not clear
to injured tissue with release of inflammatory chemicals, such as up, more aggressive means should be employed, to prevent that pain
bradykinins, prostaglandins, and histamines to isolate the injury from becoming chronic. Once chronicity sets in, the pain is much
from healthy tissue and increase the number, availability, and activa- more difficult to treat.
tion of peripheral opioid receptors.4 When this works well, healing When a peripheral nociceptor is activated an action potential is
occurs and the CNS and PNS quickly remodel to normal molecular, generated and sent down the axon to cell bodies in the dorsal root
physiologic, and anatomic status. When there is unrelenting periph- ganglion. The incoming signal results in the DNA encoding the mes-
eral stimulation or a breakdown in adaptive function, neuroplastic senger RNA to instruct ribosomes in the cytoplasm to manufacture
changes that occur at the peripheral injury, dorsal horn of the spinal substance-P (SP), a neurotransmitter and calcitonin gene related pep-
cord, and the brain result in the disease of pain, also known as mal- tide (CGRP), a neuropeptide. SP is constantly being manufactured
dynia.5 This is very different from the symptom of pain, eudynia. In at the ribosome in response to pain signals. It is then sent to nerve
maldynia pathological processes developing at the site of the periph- terminals where it is released. It is important to remember that the
eral injury, and discussed in much greater detail in Chapters 3 and 4, pain signal’s effect upon the nerve cell body causes the manufacture
include excessive activity of sodium and calcium channels, ectopy of more SP. SP is released at nerve endings synapsing on second-order
through the alteration of neurotransmission from orderly ion chan- nociresponsive neurons within the spinal cord. There it activates neu-
nel transductions to rapid-fire stimulus encoding, and recruitment rokinin-1 receptors (NK-1R) in the spinal cord dorsal horn cells and
of non-nociceptors proximal and distal to the site of injury.6 At the a new action potential is generated.11 In acute pain the signal at these
dorsal horn of the spinal cord, excessive activity of excitatory amino dorsal horn neurons is typically equivalent in strength to the signal

40
Section 2: Spinal Pain

Fig. 5.1 In acute pain the incoming pain signal is passed on unaltered at the dorsal horn and is further passed to arousal, emotional,
neuroendocrine, somatosensory, and autonomic centers, resulting in activation of descending pathways from many of the same centers. This
countersignal is sent down to the dorsal horn, where the incoming signal is downwardly modulated.

coming into the CNS. This signal is then passed predominantly to and the dorsal horn interneurons. On the interneuron membranes
either the neospinothalamic tract or the paleospinothalamic tract and SP activates NK-1R in the spinal cord dorsal horn cells and new
sent to midbrain, thalamic, hypothalamic, and limbic structures in action potentials are generated. At the dorsal horn the SP/NK-1R
the brain. These are passed further to other deep and cortical struc- complex is incorporated into the cytoplasm of the neuron, where
tures in multiple regions of the brain resulting in a broad stimulation it is ultimately broken down into its constituent components and
of pain sensation, arousal, autonomic pathways, somatosensory cen- recirculated. The action of the SP/NK-1R complex also depolarizes
ters, and neuroendocrine pathways. This allows for a response to a the membrane wall of the neuron and causes the removal of magne-
painful stimulus, which is sensory and emotional and produces physi- sium ions from NMDA receptors. Magnesium ions normally block
ologic activity that is orchestrated through the interplay of far-flung these receptors, keeping them inactive. This results in activation of
areas of the brain and culminates in a countersignal from other wide- normally dormant NMDA receptors via reception of the ubiquitous
spread regions of the brain via descending pathways to dampen and excitatory neurotransmitter, glutamate, which in turn allows calcium
ultimately to help to extinguish the incoming signals (Fig. 5.1).12 ions to pass into the interneuron cytoplasm, causing the signal to be
amplified in frequency and duration (wind-up).15 This amplified sig-
CHRONIC PAIN nal is then passed through Lissauer’s tracts to the neospinothalamic
tract and/or the paleospinothalamic tract and sent to brain stem, mid-
Chronic pain is best thought of as persistent pain that has no signifi- brain, thalamic, hypothalamic, and limbic structures in the brain. To
cant chance of being altered by usual treatment modalities or natural complicate matters further, other pathways engaged in chronic pain
healing. This is pain that often has been amplified by the severity of by unknown, but documented, mechanisms augment these classical
pain signals reaching the CNS and causing a wind-up phenomenon at spinal cord tracts.16 These signals are passed further to other deep
the dorsal horn of the spinal cord.13 It may even involve rapid depolar- and cortical structures in multiple regions of the brain resulting in
ization and ectopy at the site of injury or the cell bodies in the dorsal a broad stimulation of pain sensation, arousal, autonomic responses,
root ganglia. Sympathetic coupling, antidromic neurogenic inflam- somatosensory activation, and neuroendocrine alteration. This results
mation, CNS immune cell mediated inflammation, limbic kindling, in an extreme response to a painful stimulus, which is sensory and
activation of the neuromatrix, or other forms of central sensitization emotional and produces physiologic activity that is modulated by sen-
may also be involved.9 Finally, anxiety, depression, or other psycho- sory input from multiple areas of the brain.17 The brain’s attempt to
social factors are influenced by and influence pain perception.14 The diminish this signal is thwarted due to the ongoing process of wind-
result is pain that is physiologically amplified and often psychologi- up pain at the dorsal horn of the spinal cord (Fig. 5.2).
cally augmented, while conversely activating psychological responses.
The patient experiences pain that feels overwhelming and represents
an unwelcome change in life.
When a peripheral nociceptor is chronically activated, SP, CGRP,
CENTRAL PAIN
and adenosine triphosphate (ATP), which targets the P2X3 subtype Trauma to specific areas of the central nervous system can result in
purinergic receptor, are released from the nociceptor and in turn severe pain that may be immediate or delayed for months to years
activate non-nociceptive touch, movement, position, temperature after the damage occurs. The term often used for this is central pain,
and mechanical receptors. Action potentials are generated and sent and although many central pain processes drive this type of pain, the
down the axon to their cell bodies in the dorsal root ganglion. The name actually describes the location of pain in the CNS. Central pain
incoming signal results in the DNA encoding the messenger RNA to can be a problem in a number of different pathological CNS processes.
instruct ribosomes in the cytoplasm to make SP in cells that normally Strokes in areas of the brain that involve ascending or descending
do not produce this neuropeptide. In particular, SP is released at the pain pathways or the thalamus itself are frequently marked by severe
dendritic end-terminals into the synapses between the dendritic tree and unrelenting pain. Demyelinating illnesses may cause central

41
Part 1: General Principles

Fig. 5.2 In chronic pain the incoming pain signal winds up and increases in frequency, resulting in a more intense signal at the dorsal horn and
is further passed to arousal, emotional, neuroendocrine, somatosensory, and autonomic centers. As with acute pain, descending pathways are
activated. This countersignal is sent down to the dorsal horn, where it cannot downwardly modulate the incoming stimulus, due to continued wind-
up in dorsal horn neurons. The result is continued broad, intense, and relentless stimulation of brain centers.

pain. Trauma to the spinal cord can also result in chronic pain. This
type of pain is subject to the same problems noted in centralization
WIND-UP PAIN
of peripheral pain, including neurotransmitter, neurocircuit, and Wind-up pain is one of the main features of central pain plasticity that
neuroreceptor plasticity. Central pain of this type can be rather distinguishes chronic pain from acute pain as a disease process rather
difficult to treat due to limited utility of a number of medications. than a symptom. Wind-up is a highly complex problem related to
Different studies show that after injury to the spinal cord, anywhere activation of NMDA receptors in second order neurons in the dorsal
from 18% to 94% (with an average of 69%) of patients will develop horn of the spinal cord and third-, fourth-, and fifth-order neurons in
chronic pain disorders and that chronic pain ranks high on the list the brain. The activation of NMDA receptors results in a pain signal
for patients with difficult post-traumatic sequelae of spinal cord injury, amplification through several processes culminating in hypersensitiv-
right behind paralysis, sexual dysfunction, and incontinence. Recent ity of the NMDA receptor-activated neuron to even minimal input
studies show that about one-third of patients who develop post- from presynaptic sites.
spinal cord injury pain will suffer from severe pain.18 Syringomyelia The process of wind-up pain is driven by the peripheral stimu-
is an example of central pain that develops slowly over time due lus, but can continue independently even if the peripheral stimulus
to deafferentation, a physiologic interruption of input to CNS is well controlled. Activation of central processes caused by wind-up
neurons resulting in loss of excitation, inhibition, and modulation of pain can maintain high pain levels. This is another reason why extinc-
information to the receptive neurons. In syringomyelia more than tion of peripheral processes via various medication and invasive pro-
90% of patients will develop pain disorders, but the time of onset cedures may not extinguish or even diminish severe pain perception
averages 4–9 years after development of the syrinx.19 This delay in caused by peripheral injury.
symptoms can obfuscate the etiology of the pain and has led to the Normally, NMDA receptors are located on all CNS neurons, but
incorrect conclusion by some researchers that syringomyelia is rarely are in an inactive state due to a magnesium block. They serve the
painful. Studies done over time on patients with syrinx show that purpose of destroying dying nerve cells by apoptosis to promote
development of chronic pain is a common phenomenon. removal of cells and pruning back of dendrites to make room for cell
Melzak’s latest theory views deafferentation pain as a problem of replacement with new cells and rearborization of the dendritic tree.
hypervigilant brain function, via a concept he labels the neuromatrix. Apoptosis is best understood as programmed cell death and consists of
Deafferentation occurs when the normal input to central nociceptors complex intracellular process that lead to activation of NMDA recep-
is interrupted. This brain-based matrix consists of neurons, circuits, tors on the cell membrane and influx of calcium into the cytosome,
and dendrites in the thalamus, cortex, and limbic system, constantly resulting in pinpoint neuronal death, dendritic pruning, and ultimate
cycling signals, allowing the brain to generate body image with or replacement with new neurons, arborization, and synaptogenesis. It
without sensory input. Interruption of normal peripheral input forces is this way that the CNS makes new connections, new pathways, and
these centers of the brain to provide information to other areas of the reduces dead and redundant cells and circuits. Without this process,
brain. When consistent input to the matrix is interrupted, it works the vibrant interplay of anatomic, physiologic, emotional, and experi-
to reestablish balance by approximating output consistent with that ential events could neither be sustained nor adaptively altered.21
previous input. Melzak further theorizes that a second output neuro- To understand wind-up pain it is essential to understand the role
matrix sends information to the PNS and its innervations, resulting of neurocircuits at the junction of the PNS to the dorsal horn, tracts
in perception of movement, spasm, and pain even if these sites are from the spinal cord to the brain, intracranial connections, and path-
denervated (spinal root avulsion) or amputated. At the same time, ways from the brain back to the dorsal horn. Furthermore, the role of
the output neuromatrix sends signals to the emotional centers of the neurotransmitters and neuromodulators must also be appreciated, as
brain, evoking emotional response to pain. The neuromatrix preserves the combination of ubiquitous compounds with more focal substances
the image of self at the cost of unrelenting pain. Thus, the failure of results in the picture of adaptive processes gone wrong. Ultimately,
brain-based homeostatic mechanisms leads to central pain.20 intracellular processes that result in exertion of genomic shifts in

42
Section 2: Spinal Pain

the proteome determine when and where neurotransmitters, neuro-


receptors, neuropeptides, and neurohormones will be dispatched.
I
The dorsal horn is organized in lamina with second-order neurons II
serving as receptors for incoming signals from PNS nerve terminals. IV
III
There are ten lamina identified as part of the organization of the spi- V
nal cord with lamina I–VI as part of the dorsal horn.22 Lamina I, II, VI
IV, and V are the main nociceptive regions of the spinal cord.11 Fast
VII
excitatory postsynaptic potentials are produced by excitatory amino
acid neurotransmitters and slow excitatory postsynaptic potentials X
are produced by neuropeptides (Fig. 5.3).23 IIX
VIII IX
Information from these terminals is passed to the several different
nerve tracts that course through the white matter of the spinal cord, IX
IX
with the most significant nociceptive tracts being the paleospinotha-
lamic tract and the neospinothalamic tract. In the dorsal horn there are
nociceptive-specific (NS) neurons and wide dynamic range (WDR)
neurons. As indicated by their names, the former are activated only
by lightly myelinated Aδ fiber (first pain) and unmyelinated C-fiber
(second pain) input, while the latter receive A-δ fiber, C-fiber, and Fig. 5.3 Lamina I, II, IV, and V of the dorsal horn of the spinal cord are
heavily myelinated Aβ fiber (mechanoreceptor) input. Additionally, the main nociceptive receiving and transmitting levels. It is in lamina I
WDR neurons are capable of increasing response to increasing input. and II where C-fibers and Aδ fibers terminate, while terminations of C,
Aδ and Aβ fibers occur in lamina IV and V. These lamina are not only the
In turn, both NS and WDR neurons send axons to multiple brain-
anatomical source of normal CNS pain processes, but it is here where
based sites, including brainstem and midbrain reticular formation,
wind-up from peripheral stimulus occurs.
the superior colliculus, the periaquaductal gray, parabrachial nuclei,
hypothalamus, ventrolateral, and medial thalamus. In turn, these
deep brain structures send further connections to the insula, anterior
cingulate cortex, supplementary motor area, somatosensory cortex, This complexity of anatomy, physiology, cellular mechanisms, genetic
posterior parietal cortex, posterior cingulate cortex, and prefrontal processes, and constant remodeling determines the complexity of the
cortex.24 Even this complex set of connections and inputs is an over- pain experience and pain behaviors (Fig. 5.4).
simplification made more complex by variable collateral branching Afferent pain systems tell only part of the story. These must be
to other brain regions, afferent and efferent two-way connections placed into the context of the activity of efferent pathways as well.
between brain nuclei, modulating negative feedback loops, excit- Once pain enters the CNS, it does not become cut off from the PNS
atory, inhibitory and comodulating neurotransmitters, activation of any more than the brain and spinal cord function in isolation. The
brain-based apoptosis and regeneration, dendritic pruning and rear- experience of pain unpleasantness requires a multitude of responses
borization, and dynamic shifts in blood–brain barrier permeability.25 including reflexive recoil, voluntary motor responses, conscious

Supplementary motor cortex Posterior cingulate cortex


Anterior cingulate cortex 1st somatosensory cortex
2nd somatosensory cortex

Posterior
Insula parietal
complex
Fig. 5.4 Various regions of the brain and
Ventroposterior their connections to the paleospinothalamic
Frontal
lateral nucleus tract (PST) and neospinothalamic tract
cortex
(NST), demonstrating the complexity of the
afferent CNS connections of major pain
Periaquaductal gray processing pathways. It must be noted that
Parabrachial nucleus in chronic pain disorders, other spinal tracts
are recruited to pass on nociceptive signals.
(VPL, ventroposterior lateral nucleus; PAG,
Amygdala periaquaductal gray matter; AMYG, amygdala;
HYP, hypothalamus; VMpo, ventromedial
Ventromedial posterior complex Paleospinothalamic tract posterior complex; ACC, anterior cingulate
Hypothalamus Neospinothalamic tract cortex; SMA, supplementary motor cortex;
Medial dorsal nucleus: ventrocaudal part MDvc, medial dorsal nucleus: ventrocaudal
part; S1, first somatosensory cortex; S2, second
somatosensory cortex; PPC, posterior parietal
cortex; PCC, posterior cingulate cortex; PB,
parabrachial nucleus)

43
Part 1: General Principles

avoidance, emotional awareness, and intellectual assessment and of magnesium from membrane depolarization and glutamate attaches
planning. The brain mounts a counteroffensive against the incoming to external and internal sites in the NMDA receptor, promoting the
activation of nociceptors in an attempt to turn the excessive activity influx of calcium into the cell. Calcium activates L-argenine to break
down in a process of synergy that involves dampening of output from down to nitric oxide (NO). This diffuses across the synapse and
peripheral dendritic terminals, release of nociceptive neurotrans- stimulates the release of more SP and glutamate, perpetuating this
mitters synapsing on dorsal horn neurons, and hyperpolarization of vicious cycle. The action of intracellular calcium also results in the
dorsal horn membrane potentials.26 Anatomically, pain-modulating breakdown of prostanoids to arachidonic acid, resulting in activation
pathways in the brain originate in the cerebral cortex, amygdala, and CNS inflammation (Fig. 5.6).15,29
hypothalamus and synapse in the periaquaductal and periventricular Recent research has shown that a very similar, but brain-based
gray nuclei. These converge to other synaptic connections in the ros- process occurs in chronic affective disorder, including bipolar disor-
troventral medulla and from there course down bulbospinal tracts der, major depressive disorder, generalized anxiety disorder, panic
to synapse with presynaptic primary end-terminals and dorsal horn disorder, and post-traumatic stress disorder.30 Most of this research has
second order neurons.27 Additionally interneurons in the dorsal horn been done independently of pain research, but converges on the same
play an important role in modulation of pain (Fig. 5.5). basic processes in the CNS for this set of disorders. Primary dementia
Wind-up pain occurs with constant stimulation of C-fiber afferents also has been examined from the standpoint of NMDA receptor acti-
resulting in increased dorsal horn receptive field size due to activation vation and apoptosis, with treatment for memory loss being focused
of NMDA receptors, loss of Aβ fiber inhibition of nociception, phe- increasingly upon NMDA receptor blockade. Additionally long-term
notypic Aβ terminal change to SP production and release and neu- mu opioid stimulation of PK-C production and activation appears
ropathy induced sprouting of Aβ fibers into more superficial levels to be a major process involved in the development of tolerance to
of the dorsal horn.28 Although constant input is needed to start this opioid medications and as such presents us with a possible strategy
process, very little, if any input is needed to maintain it, thus creat- for improving pain control by decreasing tolerance.
ing a nightmare of positive feedback with minimal or even absent
peripheral stimulus.
It is the unrelenting bombardment of the dorsal horn neurons that
MOLECULAR PAIN PROCESSES
perverts the adaptive function of NMDA receptor activation into a As with any bodily process, pain transmission occurs due to molecular
maladaptive disease process. The release of SP and glutamate from processes. We know far more about molecular pain processes than we
presynaptic nerve endings arising from peripheral, primary-order neu- have in the past, but unraveling this mystery is still in its early stages
rons results in activation of NK-1 receptors and non-NMDA (AMPA and there is far more to understand. What we do know is that molec-
and kainate) glutamate receptors. The normal restraining influence of ular changes in cell function occur with nociceptive and neuropathic
gamma aminobutyric acid (GABA) and the endorphin systems is over- injury and that these changes may go on to further changes common
whelmed. Without this brake upon the activity of glutamate, NK-1 in chronic intractable pain. Some of the neurotransmitters involved
receptors are stimulated excessively and cause depolarization of cell are SP and glutamate, but also include dopamine, norepinephrine,
membranes of NS and WDR neurons, rich in dormant NMDA recep- serotonin, histamine, and acetylcholine. Other molecules brought
tor populations. In turn, this process activates NMDA receptors by into play are nerve growth factors, calcium, sodium, potassium, and
causing them to release their magnesium block due to the migration chloride ions, μ-opioid receptors, protein kinase-C (PK-C), c-fos

Supplementary motor cortex

Periventricular gray

Frontal
cortex

Periaqueductal gray

Fig. 5.5 Descending pathways from the brain


Amygdala modulate pain signals coming into the CNS from
Rostroventral the PNS. Many of the same areas involved in
Hypothalamus medulla ascending pathways are involved in top-down
modulation of pain. The spinal bulbar tract runs
from the brain down to the dorsal horn. (SMA,
supplementary motor cortex; HYP, hypothalamus;
PAG, periaquaductal gray matter; PVG,
periventicular gray matter; RMV, rostroventral
medulla; AMYG, amygdala)

44
Section 2: Spinal Pain

Substance-P

Glutamate
P P
Glutamate P Activated
P P P
P NMDA receptor P P
Ca Ca
Ca
P
Mg
Mg P P
Mg P
Ca Ca
Ca Substance-P
AMPA Activated
NMDA NK-1 Mg
Mg Activated
receptors Mg AMPA
receptors receptors NK-1
receptors
Released receptors
MU-opioid receptor magnesium
(post-synaptic)

A B

P P
P P
PP P PP P
P P P P
P P

Ca Ca
Ca PKC Ca
Ca Ca++ activated PKC Ca
PKC influenced mRNA

mRNA
PKC PKC
PKC PKC
New NMDA
receptors

C D

Fig. 5.6 (A) Presynaptic terminals release glutamate and SP into synapse. Postsynaptic nerve cells show magnesium-blocked NMDA receptors,
AMPA, and NK-1 receptors. (B) Glutamate attaches to AMPA receptors and SP attaches to NK-1 receptors. Long-term depolarization of cell
membrane causes the magnesium block to be removed from the NMDA receptor. Glutamate attaches to external and internal sites resulting in
calcium influx to the cytosome. (C) Inactive PKC is activated by calcium. (D) Activated PKC influences mRNA to instruct the proteome to create more
NMDA receptors, which are sent to the cell membrane.
(Continues)

45
Part 1: General Principles

Nitric oxide
Glutamate
NO NO
P Induced and
P activated NMDA P
PP P receptors P P
P P P P
P P P P
P P P
Substance-P
Ca NO Activated
Ca Ca NO AMPA Activated
Ca Ca Ca Nitric oxide PKC NK-1
Ca Ca receptors
Ca Ca receptors
Ca
Ca Ca Ca
mRNA Ca
PKC mRNA
PKC

E F

Fig. 5.6—cont’d (E) Intracellular PK-C causes magnesium blocks to be removed from NMDA receptors, activating them. More calcium flows into the
cytosome. Calcium transforms cytosomal L-argenine via nitric oxide. (F) NO diffuses across the synapse to the presynaptic cytosome, causing release
of SP and glutamate. This results in increased pain and perpetuation of the vicious cycle of wind-up.

protein, prostanoids, arachidonic acid, interleukin-1, tumor necro- centerpiece of this process is activation of NMDA receptors in the
sis factor-α (TNF-α), peripheral and central bradykinins and brain- dorsal horn and the brain. The process is described elsewhere in this
derived neurotrophic factor (BDNF). Holding the whole excitatory chapter. What is important to understand is that NMDA activation
process back is GABA (Table 5.1). is a process that actually leads to several other intracellular processes
In nerve injury, excessive sodium and calcium channel activity that develop into manufacture, membrane placement, and constant
leads to a markedly increased production of SP in DRG neurons and turnover of newly activated NMDA receptors. Thus, a vicious cycle
massive release of SP at dendritic terminals. Interestingly, neuron leads to ongoing production and replacement of postsynaptic NMDA
morphology in the DRG neurons changes, but there is almost no cell receptors. These cause an incoming pain signal to become relent-
death, due to production of nerve growth factors, especially BDNF less, constant, and self-perpetuated, even absent significant ongo-
by these cells after axotomy.31 A more startling development is that ing peripheral stimulus. In a further piece of biological irony, the
cells in the dorsal horn replace C-fiber nociceptors with Aβ fiber endogenous opioid receptors that serve best to regulate pain become
non-nociceptors, which in turn make new synaptic connections in the contributors to wind-up through this same NMDA receptor activa-
superficial lamina of the dorsal horn.32 We know that A-beta nerve tion and turnover, because opioid action on μ-opioid receptors in the
fibers do produce SP and CGRP after nerve injury. It is likely that spinal cord and brain results in further processes that keep sequenc-
activation of synapses by phenotypically changed Aβ fibers leads to ing this vicious cycle. We are faced with the paradox of SP/NK-1
allodynia and involves nerve growth factors to establish these synaptic receptor-bound complexes causing activation and proliferation of
reconnections. NMDA receptors resulting in increased production and release of
Central neuroplasticity in chronic intractable pain disorders is not presynaptic SP and glutamate and the primary treatment to prevent
only complex, but serves to confound many interventions, as well SP release and attachment to NK-1 receptors, exogenous opioids and
as diminish effectiveness of successful treatment over time. The endogenous opioid (endorphin) release, also perpetuating the same

Table 5.1: Some of the Major Molecules Involved in Nociception

Amino acids Brain Amines Nerve Growth Factors Ions Inflammatory Mediators Others
Glutamate Norepinephrine NGF-1, 2, 3 Sodium Prostanoids Substance-P (neurokinen)
GABA Serotonin Brain derived neurotropic factor Potassium Arachidonic acid c-fos protein (gene)
Dopamine Calcium Interleukin μ-opioid receptor
Histamine Chloride Tumor necrosis factor-α Protein kinase-C (enzyme)
Acetylcholine Bradykinins

46
Section 2: Spinal Pain

changes at the NMDA receptor.33 This then is at least a partial molec- are activated allowing for orderly apoptosis and related dendritic
ular explanation of opioid tolerance, i.e. NMDA receptor activation tree pruning. Thus, the individual’s life experience and internal brain
and turnover. In fact, several animal studies have demonstrated the development remain connected and interactive.43 Additionally, acti-
activation of NMDA receptors with ongoing opioid treatment.34–36 vation of NMDA receptors throughout the life of an individual allows
At this point we need to step back from the physiologic process of for apoptotic activity with dying nerve cells, ultimately culminating
wind-up pain and look at the neurotransmitters and neuromodula- in removal and replacement with new neurons. It also appears that
tors that play roles in its occurrence. It is here also that one sees the activation of NMDA receptors leads to long-term potentiation, which
molecular interplay of pain and chronic affective disorder due to the appears critical to development and laying down of new memory.44
action of many of these very same molecules, especially when viewed It is the abnormal activation of these NMDA receptors and the
through the perspective of the aforementioned phenomenology and damage caused by excitatory glutamate to the cells affected that lead
anatomy of pain and affective centers. to chronic pain, chronic affective disorders, primary dementia, and
The CNS is dominated by two neurotransmitters, glutamate and opioid tolerance.
GABA, although the latter is more classically seen as a neuromod- The most important restraint to both the PNS and CNS is the
ulator. These two molecules make up 90% of neurotransmitters in activity of GABA upon peripheral nerve terminals interfacing with
the CNS. They are collocated in all areas, although usually on dif- dorsal horn second-order neurons, as well as multiple sites in the
ferent neurons. They are involved in homeostasis of excitatory and brain. GABA is the second most ubiquitous neurotransmitter in the
inhibitory neurotransmission, respectively. GABA is almost entirely CNS and is released at dorsal horn sites in balance with glutamate
synthesized from glutamate via the enzymatic action of glutamate release. It acts as the brake upon CNS activation from glutamate.
decarboxylase. Glutamate and GABA also have the most extensive On the presynaptic nociceptor terminal it prevents excessive release
distribution of any neurotransmitters in the CNS. While there are of glutamate and SP. In the CNS, GABA serves to oppose excita-
other excitatory and inhibitory neurotransmitters (e.g. aspartate and tion of brain neurons activated in pain, chronic stress, depression,
glycine), glutamate and GABA should be viewed as the molecular and anxiety. It also restrains the release of glutamate and SP from
heavyweights of CNS neurotransmitter homeostasis, with all other presynaptic terminals. Three types of GABA receptors are known
neurotransmitters aimed at fine tuning their activity.37 GABA-a, GABA-b and GABA-c. Little is known of GABA-c, but it
Glutamate is an excitatory amino acid that is released at synap- appears that GABA-a receptors are mostly located in the brain and
tic end terminals and in turn activates several types of postsynaptic GABA-b mostly in the dorsal horn of the spinal cord. Over 150 000
receptors. These include ionotropic AMPA (α-amino-3-hydroxy-5- subtypes of GABA receptors have been identified. Some GABA neu-
methylisoxazole-4-proprionic acid), kainate, and NMDA, as well rons are excitatory because they inhibit other inhibitory pathways,
as metabatropic receptors. Ionotropic receptors regulate ion flow so the picture can be quite complicated.45 This is the process that
into and out of the cytosome through activated receptor channels. appears to be at work in the sleep center of the hypothalamus. When
Metabatropic receptors work by activating second messengers in the histaminic wake promoter neurons activate neighboring GABAergic
cytosome that effect long-term changes in the proteome through pathways, this results in inhibition of sleep promoter neurons which
complex intracellular and intranuclear activity. Glutamate’s role in leads to GABAergic inhibition of wake promoter neurons result-
acute pain is unclear, but it likely has a significant effect upon this via ing in sleep.46 This process goes awry in chronic pain disorders, and
excitatory activity on AMPA and kainate receptor types, due to the increased sleep latency, decreased sleep time, and decreased deep
fast component of excitatory postsynaptic potentials (EPSP) upon stage 3 and 4 sleep are hallmarks of chronic pain. Insomnia is con-
stimulation by glutamate. AMPA receptors are distributed on the sidered a comorbid condition at best and a contributor to chronic
same neurons as NMDA receptors. Magnesium ions serve to func- pain and chronic affective disorders at worst.47 As the main inhibitory
tionally block activation of NMDA receptors. Once the magnesium neuromodulator of glutamate and SP release, GABA inhibits A-delta
block is removed from NMDA receptors, they can become activated fibers (first pain mixed nociceptors), C-fibers (second pain nocicep-
by glutamate, resulting in the slow component of EPSP and establish- tors), and Aβ fibers (phenotypically altered nociceptors). Apparently,
ment of the gateway to neuroplasticity.38 Evidence-based animal and GABA plays a key role in preventing hyperalgesia and allodynia, but it
human studies have established the activation of NMDA receptors as also appears that when NMDA receptors are pathologically activated,
central to development and maintenance of chronic pain and opioid the ability of GABA to keep excitatory processes in check becomes
tolerance in the CNS, whether or not peripheral stimuli persist.39,40 compromised (Fig. 5.7).48
An obvious question is that of what purpose these receptors play in The neuropeptide SP has been implicated as one of the main neuro-
normal CNS function. Researchers believe that the NMDA receptor transmitters involved in the experience of pain for several decades.
is essential to normal neurodevelopment, through molecular, physi- SP is synthesized in the DRG with 80% being sent down axons to
ologic, and anatomic remodeling throughout the life an organism. the periphery and 20% to the end-terminals for release to targets in
Humans are born with two to three times the number of brain-based the dorsal horn. The highest prevalence of SP is in hypothalamus,
nerve cells we will end up with during adulthood. The circuits con- substantia nigra, dorsal horn of spinal cord, spinal ganglia, autonomic
necting these neurons are rudimentary and expand through processes nerves, and the sympathetic trunk. SP is a neurokinin and binds pref-
such as intellectual stimulation, emotional experience, developmen- erentially to NK-1R, but also binds to NK-2R and NK-3R. SP/NK-1R
tal task mastery, establishment of relationships, new learning, and binding is associated with pain, emesis, depression, and anxiety. In the
motor skill development. These neurocircuits connecting neuron PNS, SP is associated with antidromic neurogenic inflammation. The
centers with neuron targets are generally completed during the first amygdala, locus ceruleus, hypothalamus, substantia nigra, and pedun-
10 to 15 years of life, followed by a period of apoptosis and dendritic cular nuclei all stain intensively for SP. Moderate staining occurs in
pruning over the next decade or two, resulting in the framework of caudate putamen, nucleus accumbens, raphe nuclei, and lamina 1 of
neurons, neurocircuits, and neuroreceptors we will use for the rest of the spinal cord, with low levels in cerebral cortex, cerebellum, and
our lives.41 These, in turn, must die and be replenished to continue hippocampus. Even in areas of high density, SP is limited to 5% or
to allow further development and maintain life.42 NMDA receptors less of neurons. SP localizes to synapses, released by dendrites and
play a central role in the pruning process. When internal cellular pro- cell bodies. The distribution of NK-1 roughly corresponds to that
cesses signal a need to destroy or replace a cell, NMDA receptors of SP. Rapid binding of SP occurs with closely apposed NK-1R and

47
Part 1: General Principles

Activity of opioids at the μ receptor increases


GABA vesicle PK-C in its inactive form. This is activated by
intracellular calcium, leading to increased
GABA production and activation of NMDA receptors
neuron
GABA
GABA GABA
neuron

P
P P P
P
P
P P

Mg
Mg Opioids
Mg

AMPA
NMDA NK-1
receptors Ca
receptors receptors
Ca Opioids
Fig. 5.7 Under normal physiologic conditions GABA restrains the Ca
excitatory influence of glutamate. They are neurotransmitters in
harmony with one another, resulting in homeostatic CNS activity. The
activity of GABA on presynaptic glutamate and SP-containing neurons
is to balance the release and reuptake of each by its own action and
reuptake on interneurons and neurons from central command centers.

subsequent internalization to cell within 5 minutes via the action of


endosomes. Scientists have observed basolateral amygdala internal- Fig. 5.8 Opioid activation of PK-C at the μ-receptor.
ization in rats experiencing maternal separation. The degree of SP
release and SP/NK-1R internalization is directly proportional to the
intensity and duration of stressors. Previous exposure to painful or are four types of EP receptors, EP1–4. EP1, EP2, and EP4 receptors are
stressful stimuli results in a more robust release of SP. Repeated or stimulated by spinal cord release of PGE2, resulting in central sen-
more intense stimuli result in diffusion of SP to distant sites with up sitization. It also appears that once this process has occurred PGE2
to 3–5 times activation of NK-1 receptors. Several animal models attaching to a subtype of EP3 receptors (EP3α receptors) decreases
show increased anxiety in SP agonist stimulation.49 Ablation of NK-1 central hyperalgesia.55
neurons with the potent neurotoxin saporin bound to SP in the dorsal Serotonin, norepinephrine, and dopamine in brain pathways ascend
horn resulted in markedly decreased nociception.50 Animal models into the cortical, limbic, hypothalamic, and basal ganglia/cerebellar
using SP antagonists or genetically altered SP knockout mice show centers from the medulla and pons, regulating mood, wakefulness,
decreased anxious correlates to rodent behavior. There is high colo- vegetative function, executive function, and pleasure. Serotonergic
calization of SP and NK1 in emetic and emotional centers of brain, as and noradrenergic pathways descend to the spinal cord from the
well the superficial lamina of the dorsal horn.49 medulla and regulate painful stimuli. Serotonergic downward modu-
The intracellular compound PK-C serves as a second messenger lating circuits may have positive or negative effects on pain process-
system in central nervous system hyperalgesia.51 PK-C is activated ing in the dorsal horn, but noradrenergic stimulation of α2 receptors
after NMDA receptors in the dorsal horn and the brain are turned clearly down-modulates painful stimuli.56 Normal function of sero-
on by incorporation of the SP/NK-1R transmitter/receptor complex tonin and norepinephrine in the brain promotes genome production
into the cytosol. As described earlier in this chapter, this results in of BDNF. Current research indicates that BDNF production and
depolarization of the cell membrane and loss of affinity of the mag- dissemination is most likely the common denominator between the
nesium block for the dormant NMDA receptor. After magnesium positive effect upon depression by such varied approaches as seroto-
migrates into the cytosol, the NMDA receptor is activated. Once PK- nergic and noradrenergic antidepressants, valproic acid, lithium, and
C is activated it migrates from the cytosol to the cell membrane, electroconvulsive therapy (ECT).30 Increased systemic circulation of
where PK-C further sensitizes NMDA receptors and more calcium is glucocorticoids has been detected in pain disorders and chronic affec-
transported through these open NMDA channels into the cell.52 It is tive disorders. Excessive serum glucocorticoid activity causes overac-
the action of glutamate upon these newly activated NMDA channels tivity of glutamate in the hippocampus, amygdala, hypothalamus, and
that causes inwardly generated currents to produce wind-up pain.53 brainstem. It appears that BDNF reverses this excessive and destruc-
The action of opioids on μ-opioid receptors also increases the activa- tive activity of glutamate on NMDA, AMPA, and kainate receptors.
tion of PK-C resulting in more sensitization of NMDA receptors and It has been demonstrated that SSRIs, valproic acid, lithium carbon-
more calcium influx into the cytosol. This appears to play a criti- ate, and ECT are neuroprotective and neurotrophic, actually growing
cal step in the intracellular development of tolerance to opioids, as back damaged neurons and promoting dendritic branching, through
blocking these receptors with NMDA receptor antagonists reverses activation and release of BDNF.
opioid tolerance (Fig. 5.8).54 The ascending reticular activating system (ARAS) is one of the
Prostanoids present another problem of CNS hyperalgesia. When major components of normal executive function. This system is made
inflammation occurs in the periphery, prostaglandin E2 (PGE2) up of noradrenergic, serotonergic, dopaminergic, and cholinergic neu-
attaches to prostanoid (EP) comorbid receptors. This causes hyperal- rons and their common circuits coursing to the frontal lobes. This
gesia and widens the nociceptive field in dorsal horn neurons. There system works via release of these neurotransmitters in the frontal

48
Section 2: Spinal Pain

cerebral cortex and should be seen on a direct continuum with the Reactive gliosis occurs when brain microglia release cytokines
amount of neurotransmitters released. Low release results in depres- in response to anatomic, physiologic, molecular, or genetic insult.
sion, anxiety, poor concentration and attention, and diminished Immune cytokines, including tumor necrosis factor-α (TNF-α) and
executive function. Normal release results in euthymia and normal interleukin-1 (IL-1) enhance glucocorticoid activity in the pituitary.
attention concentration and executive function. High release results In turn, this induction of glucocorticoids reduces apoptosis from
in fight or flight response, panic, and hypervigilance. One of the TNF-α.59 Since circulating glucocorticoid elevations can result in
major problems in both chronic affective disorders and chronic pain NMDA-induced apoptosis in the limbic system in chronic affective
disorders is that of poor sleep. Sleep is negatively affected in length disorder, theoretically one problem of this neuroinflammatory/neuro-
and architecture, exhibiting insomnia, hypersomnolence, and various endocrine induction could occur when chronic CNS inflammation
dyssomnias. While this relates in part to dysfunction of the ARAS, results in chronically elevated CNS glucocorticoid levels. The point
histaminic neurons in the tuberomamillary region of the hypothala- is that these normally adaptive processes may lead to maladaptive
mus are also involved. Unlike the variable response ARAS neurons, secondary responses if chronicity sets in and is not curbed.
histaminic neurons function as a threshold system that is either on or The pain responsive molecular systems also have other built-in
off. These two systems must work together to promote proper initia- peripheral and central restraints. Ultimately, these can be exploited.
tion and maintenance of sleep (Fig. 5.9).57 There are peripheral opioid receptors that respond to endorphins,
Molecular cross-talk plays another role in connections between the which are endogenous opioids. They are synthesized in the DRG and
pain and emotional systems, as well as between inflammation and transported down axons to the peripheral nociceptors. Peripheral
neuroendocrine mediators. Dopamine is a neurotransmitter involved opioid receptors are increased in number during inflammation.
in mood control, executive function, cognitive processes, pleasure, Inflammation increases cyclic AMP, which decreases nociceptor
energy, and movement. It appears that much of this effect is con- excitability via opioid receptor stimulation. Peripheral nocicep-
trolled via dopaminergic control of glutamate action in several differ- tor sprouting increases in inflammation, creating more opioid sites.
ent brain regions via several different mechanisms. There is evidence Activation of peripheral opioid, sites leads to decreased excitability,
for dopamine effects synaptically and extrasynaptically in prefron- decreased release of excitatory neuropeptides and decreased nerve
tal cortex neurons. This region also shows control of glutamate by firing. It also appears that local immune cells, activated by inflam-
dopamine’s activation of GABAergic restraint on glutamate release. mation, produce endogenous opioids. corticotrophin releasing factor
Glutamate neurons from the prefrontal cortex innervate populations and IL-1, increased in inflammation, stimulate endorphin release and
of dopamine neurons in their originating sites in the brainstem teg- attachment to receptors in inflamed nociceptors, but not to normal
mentum. Finally, dopamine and glutamate neurons send convergent tissue. Inflammatory chemicals also increase permeability of the peri-
dendrites to synaptic and extrasynaptic sites in basal ganglia, prefron- neurium so that endorphins can attach to receptors on nociceptors
tal cortex and amygdala.58 The high level of neuromodulation that and their axons.60
occurs between dopamine and glutamate suggests potential problem Endogenous opioids are also of benefit in the CNS. Endogenous
areas of neuroplasticity, which will require further study, but also opioids are released and activated in the dorsal horn of the spinal cord
opens possibilities for therapeutic intercession. with nociceptive and neuropathic pain. They are sent to the area of
excessive stimulation and attach to μ-, δ-, and κ-opioid receptors.56,61
Rapid deactivation is also considered a hallmark of endogenous opioid
effects and limits their benefit in chronic pain states. If medication
can be found to extend the activity of endorphins, these endogenous
molecules might have greater utility in the treatment of chronic pain
disorders.
Another endogenous antinociceptive process that controls pain
peripherally and centrally is the stimulation of α2 adrenergic recep-
tors by endogenous norepinephrine. This occurs at the junction of
peripheral nerve terminal interface with the dorsal horn of the spinal
cord. Norepinephrine release in the brainstem can cover several dif-
ferent areas of the brain, but also is sent to the dorsal horn of the
spinal cord. It has its effect on nociception at the presynaptic termi-
nal and the dorsal horn NS and WDR neuron. When norepinephrine
Histamine
attaches to α2 adrenoreceptors at the peripheral nerve terminals, it
Ascending Dopamine prevents the release of SP and glutamate, diminishing their stimula-
reticular Serotonin tion of NK-1 and NMDA receptors in the dorsal horn of the spinal
activating Acetyl choline cord. Furthermore, when norepinephrine stimulates α2 receptors on
system Norepinephrine
the dorsal horn neurons, potassium ions are released from the intra-
cellular space to the extracellular space, resulting in hyperpolariza-
Fig. 5.9 Ascending reticular activating system (ARAS) neurons consist tion and limited firing of NS and WDR neurons (Fig. 5.10).62
of neuron centers in the medulla and pons. Among other areas of the One of the notions that has fallen out of favor is the old idea of
brain, these neurons send tracts to the frontal cortex and release their neurotransmission of one transmitter for one specific target neuron.
neurotransmitters at these sites. The ARAS tracts run parallel with a We now know that diffusion of neurotransmitters occurs to targets
tract from histaminic neuron centers in the tuberomamillary region of
distant from the intended cells, as in the massive release of SP in
the hypothalamus. The action of dopamine, serotonin, norepinephrine,
acetylcholine, and histamine allow for normal executive function,
patients with neuropathic pain. The result is that of both a precise
including normal energy, problem solving, and creativity. If these and a diffuse effect of neurotransmitters. Additionally, it is also
neurotransmitter levels are low, patients experience fatigue, depression, known that neurotransmitters have a greater effect upon the biology
loss of motivation. If the neurotransmitters are too high, problems occur of the cell than we understood previously. The action of neurotrans-
with panic, fear, and external vigilance. mitters on membrane-located neuroreceptors is not only related

49
Part 1: General Principles

Norepinephrine releases from Norepinephrine attaches to alpha-2a


descending neurons from medulla receptors on interneuron and Potassium
and attaches to alpha-2 receptors. egress occurs, hyperpolarizing cell.
Calcium influx is blocked and Neurotransmission is prevented.
release of substance-P and
glutamate is inhibited

K+ K+
K+ K+

+
K+ K
K+ K+

A B

Fig. 5.10 (A) Presynaptic action of α2 agonism blocks release of SP and glutamate. (B) Postsynaptic action of α2 agonism hyperpolarizes neuron via
potassium (K) efflux.

to propagation of action potentials, but also results in neuroplas- this information can be passed to distant sites via still unknown glial
tic change by affecting cytoplasmic RNA. This results in coding of mechanisms resulting in alteration of neurons that are not physically
nuclear mRNA by DNA. Subsequently, mRNA instructs cytoplasmic connected to each other. It appears that glia communicate chemically
ribosomes to manufacture neurotransmitters, neuroreceptors, nerve by secreting substances that are only picked up by other glia, ulti-
growth factors, neurokinins, and neuromodulators. DNA coding of mately influencing these distant sites. This slow form of information
the mRNA also directs these new substances to various deployment processing allows for adjustments to synaptic strength, blood–brain
sites on the cell membrane, in the cytoplasm of the neuron or at barrier permeability, and neuronal apoptosis and replenishment.64
nerve terminals or peripheral nociceptors.63 None of this is orches- We have far more to learn and it is inevitable that our emerging
trated randomly. Peripheral injury to nerve tissue and inflammatory knowledge of the human genome will reveal a treasure trove of infor-
activation of nociception results in changes in CNS transcription mation about these processes. Through unraveling the information in
factors, such as c-jun, and sequence-specific binding factor nuclear the genome we will gain accuracy in developing therapeutics to alter
factor-κB in the nuclei of neurons, with subsequent neuropeptide processes in a precise and temporally controlled fashion.
changes occurring over the next 5–7 days.7 Other neurotransmitters,
neuropeptides, second messengers, and neuromodulators are known
to take part in this incredibly complex orchestration of neuroplastic-
CONCLUSION
ity in the CNS. Central influences on pain are best understood in terms of adaptive
Adding to the complexity of neuronal information processing is the systems that allow peripheral stimuli to alert us to ‘an unpleasant
emerging knowledge we are gaining about the function of glial cells, physical and emotional experience,’ and to respond to that experience
the other 90% of brain and spinal cord cells. Long known to serve sup- by reestablishing homeostasis. While in the vast majority of cases this
portive, insulating, and nutritional function, we now are beginning to system performs its task well, when CNS-mediated wind-up pain
unravel the far more complex function of glia in neurotransmission. It leads to hyperalgesia and allodynia, the adaptability of this system goes
has become apparent in the last 15 years of research of glia that they awry, shifting to maladaptive consequences that reverberate through-
communicate with each other through calcium imbibition respon- out the CNS. This chapter attempts to describe some of the impor-
sive to neuronal firing. Glial cells then feed back to neuronal net- tant breakthroughs in our understanding of these processes. Research
works by releasing increased neurotransmitters to increase synaptic in this field is still in its infancy and ranges outside the area of pain
strength and the number of new synaptic connections. Furthermore, medicine to neurology, psychiatry, basic neuroscience, and genetics.

50
Section 2: Spinal Pain

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pathic behavior: evidence for plasticity and non-specificity. Neuroscience 2002; 45. Roberts E. Adventures with GABA: Fifty years on. In: Martin D, Oslen R, eds.
115(2):403–413. GABA in the nervous system. Philadelphia: Lippincott, Williams and Wilkins;
17. Maier SF. Bi-directional immune-brain communication: implications for understand- 2000:1–24.
ing stress, pain, and cognition. Brain Behav Immun 2003; 17(2):69–85. 46. Horvath TL, Diano S, Van den Pol A. Synaptic interaction between hypocretin
18. Willis W. Possible mechanisms of central neuropathic pain. In: Yezierski R, Bur- (orexin) containing neurons and arcuate nucleus NPY-producing cells in rodent
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IASP Press; 2002:85–115. 19:1072–1087.

19. Williams G. Post-traumatic syringomyelia, an update. Parapolegia 1990; 28:296– 47. Moldofsky H. sleep and pain. Sleep Med Rev 2001; 5(5):385–396.
293 48. Todd A, Maxwell D. GABA in the mammalian spinal cord, GABA in the nervous
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50. Nichols ML. Transmission of chronic nociception by spinal neurons expressing the 58. Sesack SR, et al. Anatomical substrates for glutamate-dopamine interactions:
substance P receptor. Science 1999; 286(5444):1558–1561. evidence for specificity of connections and extrasynaptic actions. Ann NY Acad
51. Basbaum A. Distinct neurochemical features of acute and persistent pain. PNAS Sci. 2003;1 003:36–52.
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52. Chen L, Huang L. Protein kinase-C reduces Mg2+ block of NMDA-receptor chan- D, ed. Molecular neurobiology of pain. Seattle: IASP Press; 1997:45–58.
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53. Wolfe C. Synaptic remodeling and pain. In: Borsook D, ed. Molecular neurobiology of pain. Seattle: IASP Press; 1997:25–43
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52
PART 1 GENERAL PRINCIPLES
Section 3 General Diagnostic Technique

CHAPTER
Radiology
6 John B. Weigele, Eric D. Schwartz, Oleg Bronov and Gul Moonis

INTRODUCTION Disadvantages
Remarkable advances in diagnostic imaging of the spine have occurred Plain films have intrinsically poor contrast resolution. Only materi-
over the last several decades. Since magnetic resonance imaging als with markedly different X-ray attenuations such as metal, bone,
(MRI) was introduced into clinical practice in the mid 1980s it has soft tissue/water, fat, and air can be distinguished. Conventional
rapidly assumed the preeminent role in spinal imaging as a result of radiographs cannot discriminate among various soft tissue structures,
its abilities to display exquisite anatomic images and to accurately discs, ligaments and cerebrospinal fluid (CSF). As a result, many
characterize a broad spectrum of diseases encompassing degenera- disorders such as herniated discs, tumors, and myelopathies are not
tive, inflammatory, infectious, traumatic, neoplastic, and congenital visible. In addition, conventional radiographs represent a two-dimen-
disorders.1–3 Nonetheless, MRI has limitations. Conventional radio- sional projection of the anatomy. Three-dimensional relationships are
graphs (plain films), computed tomography (CT), and myelography not demonstrated as they are on multiplanar tomographic CT and
combined with postmyelography computed tomography (myelo CT) MRI images. This lack of multiplanar tomographic imaging limits the
also play important roles in the evaluation of spine pathology.4 In this assessment of many clinical questions. Plain films are obtained with
chapter the roles, advantages, disadvantages, and techniques for each ionizing radiation.
of these imaging modalities will be discussed, followed by consider-
ations of imaging the normal spine and a number of spinal disorders Technique
commonly evaluated and treated by the spine interventionist.
A standard complete cervical spine radiographic examination includes
anteroposterior (AP), lateral, bilateral oblique, and open mouth
IMAGING MODALITIES views. A ‘swimmers’ lateral with one shoulder elevated and the other
depressed is used for trauma if C6 and C7 are not well visualized
Conventional radiographs (plain films, X-rays) on the conventional lateral view. For thoracic spine evaluation AP
Roles and lateral views are usually sufficient. Lumbar spine radiographs are
Diagnostic imaging of the spine usually begins with conventional radio- tailored to the indication. A full examination consists of AP, both
graphs. Plain films provide an inexpensive and rapid screening of skeletal oblique, and lateral views. The oblique view provides the ‘Scotty dog’
anatomy and potential abnormalities to guide further clinical evalua- image that is most useful to evaluate the pars interarticularis for a
tion and imaging. Primary care patients with low back pain who were defect (spondylolysis) and the facet joints (Fig. 6.1). In some, cases
screened with plain films and rapid MRI had nearly identical clinical out- such as for surgical guidance or for a postoperative assessment, one
comes, and plain film screening was less expensive.5 The spinal segments or two views may suffice.
are readily counted and the alignment, size and shape of the vertebral
bodies are easily assessed. Plain films screen for degenerative disease Magnetic resonance imaging
that can be demonstrated by disc interspace narrowing, osteophytes, and
Roles
endplate sclerosis. Grossly destructive neoplastic or infectious/inflam-
matory processes can be diagnosed by cortical bone destruction or verte- MRI has become the most valuable method to image the spine. After
bral collapse. Plain films of the lumbar spine readily depict pars defects screening plain films, MRI is the next imaging study of the spine usu-
(spondylolysis) and spondylolisthesis. Conventional radiographs provide ally obtained. It is considered the most useful modality for the evalu-
rapid and cost effective evaluation of skeletal spine trauma although ation of myelopathy, radiculopathy, and back pain requiring advance
CT is assuming an increasingly important role.6,7 Flexion and extension imaging. CT and CT-myelography are usually reserved for patients
plain films evaluate spinal stability in trauma and postsurgical cases. For with a contraindication to MRI or for the investigation of specific
the interventionist this study is particularly important for patients who questions raised or remaining unanswered by the MRI.
experience pain during extension or show evidence of spondylolisthe-
sis with plain films. Conventional radiographs provide intraoperative Advantages
guidance and postoperative assessment of surgical hardware, bone grafts, The superior contrast resolution of MRI depicts the soft tis-
alignment, and stability. sue anatomy of the spine better than plain films and CT. MRI is
comparable to CT and bone scans for most pathologic processes
Advantages causing neurological compromise and is better than CT for the
Conventional radiographs have high spatial resolution and are widely detection of systemic diseases.1 The spinal cord, nerve roots, CSF,
available, rapidly and inexpensively obtained. Flexion–extension vertebrae, discs, and ligaments can be exquisitely resolved and
views to evaluate spinal stability are easy to acquire. distinctly visualized.6 Multiplanar tomographic imaging optimally

53
Part 1: General Principles

Fig. 6.1 Pars defect.


Oblique plain film of
the lumbosacral spine
A
demonstrates a L5
pars defect (arrow),
and a normal L4
pars interarticularis
(arrowhead) for
comparison.

displays three-dimensional anatomic relationships. MRI is able


to reveal inflammatory, traumatic, and infectious processes using
image acquisitions that are sensitive to edema such as fat-sup- Fig. 6.3 Bony neural
foraminal stenosis.
pressed T2-weighted fast spin echo (FSE) and short tau inversion
Axial cervical spine
recovery (STIR) pulse sequences.6 Gadolinium-enhanced images bone window CT image
display inflammatory processes (with fat-suppression) (Fig. 6.2), (A) and T2-weighted
tumors, and distinguish scar from disc in postoperative patients. gradient-echo MRI image
Ionizing radiation is not used. There are no known risks of MRI (B) demonstrate bony
for patients without a contraindication except for exceedingly rare B neural foraminal stenosis
allergic reactions to gadolinium injections. (arrows).

Disadvantages patient in the scanner is limited and the introduction of ferromag-


MRI is expensive and the examination time is longer than for plain netic objects into the strong magnetic field can be hazardous. This
films and CT scans. MRI may not display bony pathology such as makes a MRI examination of unstable and critically ill patients more
cervical foraminal stenosis as well as CT (Fig. 6.3).6 Access to the difficult. Rapid patient access and resuscitation can be compromised.
Some individuals experience severe claustrophobia inside the bore of
the magnet. It is dangerous to place patients with cardiac pacemakers
and ferromagnetic implants into the strong magnetic field of the MRI
scanner. Most cochlear implants, ocular implants, and neurostimula-
tors as well as some aneurysm clips are not MRI compatible. Most of
the orthopedic hardware, surgical clips, and staples currently in use
are safe. Cardiac valve prosthesis, vascular stents, wires, and coils are
usually MRI compatible but require different amount of time after
placement before the patient can be safely placed in the magnetic
field. In general, a published resource such as the ‘Reference Manual
for Magnetic Resonance Safety, Implants and Devices’ or the man-
ufacturer should be consulted if the patient reports any implanted
medical device or retained metallic foreign body. Knowledge of the
exact name and manufacture of a device is necessary to determine its
safety; if this information is not available, it is recommended that the
patient not undergo MRI scanning.8
Fig. 6.2 Discitis and Images in the region of surgical hardware may be nondiagnostic.9
osteomyelitis. Fat
There is limited experience with dynamic studies of the spine and
suppressed contrast-
enhanced T1-weighted
studies with physiological spine loading, and these examinations are
thoracic spine MRI not readily available at most centers.
image reveals marked
enhancement Technique
of two adjacent
Lumbar spine MRI exams typically include both sagittal and axial
vertebrae (arrows)
with destruction acquisitions using T1- and T2-weighted pulse sequences. Sagittal
of the intervening images should be carried from one neural foramen to the other
disc and endplates neural foramen with thin slices and a minimal interslice gap. Sagittal
(arrowheads). and axial T1-weighted spin echo images are useful to evaluate the

54
Section 3: General Diagnostic Technique

It can also image skeletal anatomy not adequately visualized on plain


films in trauma patients, in particular the C1–2 and C6–7 regions. CT
can be used to as a less expensive alternative to MRI to screen patients
with lumbar radiculopathy. CT is routinely used to characterize bony
tumors of the spine due to its exquisite depiction of bony detail and
ability to display calcifications, osseous and cartilaginous matrix.
Fig. 6.4 Normal
cervical foraminal Advantages
nerve roots. Axial 3-D
T2-weighted gradient CT provides high-resolution detail of trabecular and cortical bone
echo cervical spine MRI and is able to differentiate soft tissue, disc, CSF, and fat. Images
image demonstrates acquired in the axial plane on modern helical CT scanners can be
normal nerve roots in reconstructed in other planes. Exquisite three-dimensional models
the neural foramina of the bony anatomy can be reconstructed for surgical planning. CT
(arrows) surrounded by is less severely degraded by imaging artifact from surgical hardware
bright CSF in the nerve than MRI. In the cervical spine, CT provides a more accurate repre-
root sleeves. sentation of bony stenoses of the central canal and neural foramina
vertebral body marrow, epidural, and foraminal fat. T2-weighted than MRI. A CT scan takes less time than a MRI examination. The
fast spin echo (FSE) images evaluate the disc space, nerve roots, and patient is more accessible within the scanner, facilitating the study of
facets. CSF is brighter than discs, nerve roots, cartilage, bone, and uncooperative, critically ill, and unstable individuals. Patients are less
ligaments on a T2-weighted FSE acquisition. Axial 3–5 mm images likely to be claustrophobic in a CT scanner than in the typical high-
are angled parallel to the disc interspace to optimally evaluate disc field MRI gantry. Obese patients who cannot fit in the MRI bore and
morphology. The images are carried from the pedicle above the disc those with pacemakers and other MRI-incompatible hardware can be
interspace to the pedicle below to look for migrated free fragments. successfully imaged on the typical CT scanner. CT is also very useful
Since fat is relatively bright on T2-weighted FSE images, the sagit- for guiding spinal interventions.
tal T2-weighted FSE images can be obtained with fat-suppression to
evaluate the vertebrae for edema associated with trauma, infection, Disadvantages
or inflammation. Postgadolinium (contrast enhanced) axial and sagit- CT cannot distinguish soft tissues with very similar X-ray attenu-
tal T1-weighted images are obtained for specific indications, includ- ations. CT is therefore much less sensitive than MRI in detecting
ing postoperative evaluations to distinguish a disc herniation from pathologic processes such as infection and tumor. MRI is also much
scar tissue, possible infection/inflammation, and tumors. more sensitive to intrinsic spinal cord pathology. Scar, disc material,
MRI pulse sequences for cervical spine imaging typically include and other soft tissue can have similar attenuation values on unen-
sagittal and axial T1-weighted, axial and sagittal T2-weighted FSE, hanced CT scans and can be difficult to distinguish. Spinal cord,
and axial three-dimensional T2-weighted gradient echo images. T1- nerve roots, and CSF cannot be distinguished without intrathecal
weighted sagittal images assess the vertebrae for size, shape, and contrast. Patients are exposed to ionizing radiation.
alignment and for marrow signal intensity. T2-weighted axial and
sagittal FSE images evaluate the spinal cord, nerve roots, and facets.
Thin section (e.g. 1.5 mm) axial three-dimensional T2-weighted gra- Technique
dient echo images are valuable in the cervical spine. On these images, Spiral CT of the spine is currently performed with 1–3 mm collima-
the disc is variably moderate in intensity, CSF is very bright, and tion depending on the region being evaluated and the specifications
bone is dark. The nerve root sleeves containing CSF in the neural of the CT scanner. In the cervical spine 1–1.5 mm collimation is rou-
foramina are optimally visualized (Fig. 6.4). This is important since tinely used on multislice row detectors. Images are reviewed in both
T1-weighted images are not as useful to evaluate the cervical neural soft tissue and bone windows. Sagittal and coronal reconstructions
foramina as for the lumbar spine because there is less fat. Compression are obtained when indicated. Computed tomography utilizes a highly
of the nerve roots or spinal cord by osteophytes or disc herniations is collimated X-ray beam, which is registered by the detector after
demonstrated with high sensitivity. Gradient echo images, however, passing through the patient. The original CT developed by Godfrey
can artifactually accentuate the apparent degree of bony stenosis due Hounsfield in 1972 had one X-ray source and one detector rotating
to susceptibility effects. The FSE images are less sensitive to suscep- around the patient. Current CT scanners have many rotating X-ray
tibility effects; therefore, the degree of bony central canal stenosis tubes and detectors that acquire data as the patient is continuously
is best estimated on sagittal T2-weighted FSE images. Sagittal short advanced through the bore of the scanner (helical or spiral scanning).
tau inversion recovery (STIR) images are valuable to evaluate the soft X-ray sources and detectors can be aligned in several rows, which
tissues, especially the ligaments, in trauma cases.10 allow simultaneous image acquisition at several levels. This configura-
tion can obtain thinner slices in a shorter time. Attenuation values of
Computed tomography (noncontrast) the X-ray beam passing through the tissue at many various angles are
computed using a projection reconstruction technique and a number
Roles is assigned to every pixel (picture element); these calculated values
Noncontrast CT may answer important clinical questions not answered of relative attenuation are called Hounsfield units. By one conven-
by MRI, particularly about bony detail such as the integrity of the tion, 0 is the Hounsfield number of water and 1000 is the Hounsfield
posterior vertebral body cortical bone in a patient with a malignant number for air. Materials such as bone and metal that attenuate more
compression fracture being evaluated for vertebroplasty. Bony steno- of the X-ray beam are assigned higher numbers. Assigning each pixel
ses of the neural foramina in the cervical spine are depicted more a grayscale value based on its Hounsfield number creates images.
accurately than on MRI.6 Noncontrast CT often depicts subtle frac- Window level refers to the Hounsfield number at the middle of the
tures and displacements such as facet jumps better than plain films.7 grayscale range and window width refers to the number of Hounsfield

55
Part 1: General Principles

units that span the grayscale range from black to white. If the win- Standard myelogram films include AP, oblique, and lateral views.
dow width is large, there is less contrast between tissues with rela- Standing, flexion, and extension images may be useful.
tively close attenuation values, but many different tissues with a wide The postmyelogram lumbar CT is obtained with the patient prone
range of attenuation parameters will be shown in different grades of if tolerated to allow the contrast to pool in the ventral thecal sac and
gray. A narrow window helps to demonstrate even small differences in the nerve root sleeves. Thin section images are obtained parallel
in tissue attenuation within the chosen window, but all of the tis- to each disc interspace from the pedicle above to the pedicle below
sues with Hounsfield units above or below the window limits will be so a free fragment will not be missed. In the cervical spine, contigu-
completely white or black. Specific windowing protocols vary among ous thin-section CT images are obtained. Images are reviewed in soft
scanners and manufacturers. A typical soft tissue window level is 50 tissue and bone windows.
and window width is 450, while a typical bone window level is 350
and window width is 2000. Different mathematical reconstruction Nuclear medicine
algorithms can be applied to increase contrast between structures. A
Nuclear medicine imaging of the spine is discussed in Chapter 7.
bone algorithm is particularly helpful to accentuate bony margins and
interfaces of bone with air and soft tissues.
Discography
Myelography and postmyelography CT Discography is reviewed in Chapter 25.
Roles
Myelography and postmyelography CT are used to study patients
IMAGING OF THE NORMAL SPINE
with surgical hardware that renders MRI images nondiagnostic, and Spinal cord and nerve roots
as problem solving tool for patients with equivocal or discordant
The spinal cord extends from the caudal aspect of the medulla oblon-
findings on MRI, and for patients with a contraindication to having
gata at the upper border of the first cervical vertebra (C1) to its infe-
a MRI examination. Myelography and postmyelography CT pro-
rior termination as the conus medullaris occurring variably from the
vides additional information to that obtained from a MRI in exam
twelfth thoracic vertebra (T12) to the second lumbar vertebra (L2).
33% of patients with lumbar degenerative disease.11 It is often the
The filum terminale is a fibrous cord that extends caudally from the
definitive imaging study for cervical myelopathy and radiculopathy
tip of the conus. It initially travels intradurally and then merges with
since it is the gold standard for detecting osteophytic impingement
the dura to insert in the coccyx. The nerve roots extending inferior to
on cervical nerve roots. Myelography and postmyelography CT can
the conus are called the cauda equina. The sacral roots are positioned
be useful to detect small tumor implants on nerve roots and also
centrally and posteriorly within the thecal sac; the lumbar roots are
arachnoiditis.
located anterolaterally.14
There are two regions of normal spinal cord expansion, one in the
Advantages lower cervical cord extending approximately from C4 to T1 and the
Postmyelography CT provides the definitive assessment of central other in the lower thoracic cord extending approximately from T9
stenosis and the degree of cord compression in the cervical spine. to T12. These normal regions of cord enlargement supply the bra-
Myelography and postmyelography CT can demonstrate herniated chial and lumbosacral plexuses, and should not be misinterpreted as
discs in the cervical spine neural foramina missed on MRI. Subtle pathologic.14
compression of nerve roots in the lumbar lateral recesses is demon- The spinal cord gives rise to 31 paired sets of spinal nerves: 8 cer-
strated better on myelography than postmyelography CT or MRI.12 vical, 12 thoracic, 5 lumbar, and 5 sacral, and 1 coccygeal. The first
Myelography and postmyelography CT provide better assessment of cervical spinal nerve is purely sensory and exits the spinal canal above
the spinal canal and nerve roots than MRI in the region of surgi- the ring of C1; the second spinal nerve exits into the C1–2 neural
cal hardware. Myelographic films can be obtained with the patient foramen above the C2 pedicle, and so on to the seventh cervical spi-
standing and during flexion and extension to evaluate dynamic abnor- nal nerve exiting into the C6–7 neural foramen. The eighth cervical
malities during physiologic loading.13 spinal nerve exits into the C7–T1 neural foramen. In the cervical
region the nerve roots occupy the lower portion of the foramen at
Disadvantages the same level as the disc interspace. Each thoracic and lumbar spinal
nerve exits the canal beneath its like-numbered pedicle so that the
Myelography and postmyelography CT require puncture of the thecal
first thoracic spinal nerve exits beneath the T1 pedicle into the T1–2
sac with a spinal needle (usually lower lumbar, occasionally at C1–2)
neural foramen, the first lumbar spinal nerve exits beneath the L1
and instillation of nonionic iodinated contrast into the subarachnoid
pedicle into the L1–2 neural foramen, and so on. Sensory (dorsal)
space. Although complications are uncommon, they include headache
and motor (ventral) nerve roots arising from the spinal cord join to
(occasionally due to a CSF leak requiring a blood patch), contrast
form the spinal nerves. The dorsal root ganglion contains the sensory
reaction, seizure, infection, and hemorrhage. The procedures and
nerve cell bodies and lies in the neural foramen near the junction of
recovery period is lengthy. Patients are exposed to ionizing radiation.
the dorsal and ventral roots. A conjoined root consists of two nerve
roots traveling in the same dural sleeve; it is a normal anatomic vari-
Technique ant occurring in approximately 5% of patients. The conjoined roots
The patient typically lies prone and a standard lumbar puncture is per- may exit through the same or different neural foramina.14
formed with a 22–25-gauge spinal needle. Nonionic iodinated contrast In the lumbar spine each nerve exits the thecal sac enclosed in a
is instilled into the subarachnoid space during fluoroscopic monitoring root sleeve of variable length entering the lateral recess (subarticular
to confirm the correct needle position. Twelve to 15 cc of Omnipaque space) bounded by the vertebral body anteriorly, the pedicle laterally,
180 is instilled for lumbar myelography and 10–12 cc of Omnipaque and the superior articular process posteriorly (Fig. 6.5).14 The mini-
300 is instilled for cervical myelography. For a cervical myelogram, the mum normal diameter of the lateral recess is 3–4 mm. The lateral
patient is briefly tilted head-down on the table to facilitate the gravity- recesses are best imaged on axial CT and MRI images. The nerve root
dependent flow of the contrast into the cervical subarachnoid space. passes inferiorly and laterally into the upper portion of the neural

56
Section 3: General Diagnostic Technique

Vertebrae
The spine contains 7 cervical, 12 thoracic, and 5 lumbar vertebrae, the
sacrum (consisting of 5 fused elements), and the coccyx. Except for the
uniquely shaped first and second cervical vertebrae, the vertebrae have
a generic shape that consists of an anterior cylindrically shaped vertebral
body and the posterior elements consisting of the pedicles, transverse
processes, superior and inferior facets, lamina, and spinous process.14
There are important regional variations in the morphology and size
of the vertebrae. The first and second cervical vertebrae have unique
shapes. The first cervical vertebra (the atlas) does not have a dis-
Fig. 6.5 Normal lumbar
crete body; it consists of a ring comprised of anterior and posterior
lateral recesses. Axial
CT demonstrates
arches connected by lateral masses that articulate with the occipi-
normal L4–5 lateral tal condyles above and the second cervical vertebra below. The axis,
recesses (arrows). the second cervical vertebra, has a unique superior projection (dens)
extending from the C2 vertebral body to articulate with the anterior
foramen above the level of the disc interspace surrounded by fat. arch of C1, secured by the transverse and subsidiary ligaments.14 The
The neural foramen is keyhole-shaped and widest superiorly (Fig. distance between the posterior border of the anterior arch of C1 and
6.6).15 The neural foramen is optimally examined on sagittal MRI, the anterior border of the dens should be 3 mm or less in an adult and
reconstructed sagittal CT, and oblique plain films. 5 mm or less in a child.
On T1-weighted MRI the spinal cord and nerve roots have a uni- The cervical vertebrae from C3 to C7 are conventionally shaped
form intermediate signal intensity that is brighter than the surround- and increase in size progressing caudally. They have unique uncinate
ing relatively low signal intensity CSF (Fig. 6.7A). On T2-weighted processes that extend superiorly from the lateral aspects of the verte-
images, the spinal cord and intrathecal nerve roots are extremely well bral bodies to articulate with the vertebra above forming the uncover-
visualized as relatively hypointense structures bathed in bright sur- tebral joints (joints of Luschka). Spurs extending from the uncinate
rounding CSF (Fig. 6.7B). The nerve roots in the cervical foramina processes may compromise the nearby neural foramen. The superior
are best seen on high-resolution three-dimensional T2-weighted axial and inferior facets are fused into the articular pillars. The vertebral
images outlined by surrounding bright CSF in their nerve root sleeves arteries pass through foramina in the transverse processes of C1 to
(see Fig. 6.4). In the lumbar foramina the nerve roots are visualized C6.14 The central canal of the cervical spine is triangular, measuring
best on axial and especially sagittal T1-weighted images surrounded a minimum AP diameter of 15 mm at C1–2 and 12 mm in the lower
by the hyperintense fat within the foramen (see Fig. 6.6).16 The cervical region.
spinal cord normally does not enhance; however, enhancement of The 12 conventionally shaped thoracic vertebrae are larger than the
normal spinal nerve roots has been reported. Extensive nerve root cervical vertebrae and increase in size from T1 to T12. The interpe-
enhancement, thickening, and nodularity are abnormal. dicular distance decreases to T6, and then increases to T12. The trans-
On CT images the spinal cord and nerve roots are difficult to dis- verse processes of the thoracic vertebrae articulate with the ribs.
tinguish from surrounding CSF unless intrathecal contrast is used The 5 lumbar vertebrae are the largest. The lumbar spinal canal
(Fig. 6.8). The spinal cord and nerve roots are silhouetted by intra- usually is triangular in shape; less frequently it may be oval. The mini-
thecal contrast on myelogram radiographs. mal normal AP diameter of the lumbar spinal canal is 11.5 mm and

Fig. 6.6 Normal lumbar neural foramen.


Sagittal T1-weighted lumbar spine MRI image
(A) demonstrates the typical keyhole-shaped
L4–5 neural foramen containing the L4 nerve
superior to the disc level and surrounded by
hyperintense fat (arrow). Sagittal lumbar CT
image in bone window (B) demonstrates the L3–4
A B neural foramen (arrow) and the L3 articular facets
(arrowheads)

57
Part 1: General Principles

Fig. 6.7 Normal cervical spine. Sagittal


T1-weighted (A) and T2-weighted (B) cervical
spine MRI images reveal normal vertebrae, disc
interspaces, spinal canal, and spinal cord. The
normal cervical enlargement serving the brachial
plexus is evident. CSF is hypointense on
A B T1- and hyperintense on T2-weighted images. The
cerebellar tonsils are in normal position.

the minimal cross-sectional area is 1.45 mm2 (Fig. 6.9). The interpe- gradually converting to yellow (nonhematopoietic) by adolescence.17
dicular distance increases slightly from L1 to L5. Normal adult yellow bone marrow is relatively hyperintense on T1-
The MRI appearance of the vertebrae is age dependent.17 The weighted images due to the fat, and should always be brighter than the
vertebral marrow is normally red (hematopoietic) during childhood, intervertebral discs. Marrow fat distribution can be heterogeneous,
so some mild signal heterogeneity on the T1-weighted images is
common. The vertebrae are hypointense on conventional T2-weighted
spin echo sequences; the normal intervertebral discs are brighter. On
fast spin echo (FSE) T2-weighted sequences the marrow is more
hyperintense and lesions causing bone edema may be obscured unless
fat suppression is used. The vertebrae display mild homogeneous
enhancement after gadolinium administration. Since there are few
mobile protons to provide MRI signal in the cortical bone, it appears
as a thin, uniform, dark line outlining the bone marrow.

Fig. 6.8 Cervical nerve


root avulsions. Coronal Fig. 6.9 Normal lumbar
cervical myelogram CT spinal canal. Sagittal
demonstrates normal helical CT image of the
left-sided cervical nerve lumbar spine in the
roots (arrows). The midline reveals normal
right-sided cervical nerve alignment, vertebral
roots were traumatically body heights, lordosis,
avulsed. and spinal canal.

58
Section 3: General Diagnostic Technique

Intervertebral discs, anterior and posterior


longitudinal ligaments
The discovertebral complex consists of the cartilaginous endplate,
anulus fibrosus, and nucleus pulposus. The well-hydrated nucleus
pulposus is a fibrocartilage remnant of the primitive notocord. It is
less well structured than the outer anulus fibrosus, occupies a large
portion of the disc during childhood, and is bright on T2-weighted
images (Fig. 6.10). With progression though adolescence into early
adulthood, a horizontal low signal band develops in the center of the
nucleus on T2-weighted images that corresponds to the develop-
ment of higher collagen concentration in the equatorial region. This
is called the intranuclear cleft and is a part of normal maturation
(Fig. 6.11).
Fig. 6.11 Intranuclear
The surrounding anulus fibrosus consists of multilayered (up to cleft. Sagittal
15) dense parallel fibrous bands. The outer ring of the anulus fibrous T2-weighted lumbar
contains peripheral lamellae that insert into the bony ring apophy- spine MRI image
sis (Sharpey’s fibers) (see Fig. 6.10A). The outer anulus is relatively demonstrates a
dark on T1- and T2-weighted images. The inner ring of the anulus normal T2 hypointense
is brighter on T2-weighted images and gradually merges with the L5–S1 intranuclear cleft
nucleus. Both the nucleus and anulus have similar signal intensities (arrow).
on T1-weighted images and are difficult to distinguish. The nucleus
is eccentrically located toward the posterior aspect of the disc. The
posterior anular fibers are thinner and smaller in number. The outer ventral epidural space and lies just anterior (ventral) to the thecal sac
annular fibers merge with the anterior and posterior longitudinal (Fig. 6.12). A midline septum attaches the PLL to the periosteum
ligaments. of the posterior vertebral body and serves to compartmentalize the
The lumbar intervertebral discs increase in width from L1–2 to ventral epidural space.18
L4–5. The L5–S1 disc thickness is variable and may be less. The tho- The cartilaginous endplate is composed of hyaline cartilage that
racic discs are uniformly thinner than the lumbar discs. The cervical covers the bony endplate of the vertebral body and is bound to it by
discs are more wide anteriorly than posteriorly.14 Cervical discs have multiple fibrous attachments. The margin of the cartilaginous end-
a less well-defined nucleus and anulus with less of a discrete poste- plate attaches to the ring apophysis. The osseous endplate has perfo-
rior anulus. rations and numerous vascular channels to the disc interspace.
The anterior (ALL) and posterior (PLL) longitudinal ligaments
are dense fibrous bands that are low signal intensity on T1- and T2-
weighted MRI images. The ALL lies adjacent to the anterior sur- Posterior elements
face of the vertebral bodies and intervertebral discs. It forms a layer The pars interarticularis and the facet joints are well demonstrated
that is attached to the outer anulus and provides some fibers that on oblique plain films, sagittal and axial MRI, and CT images. The
attach to the vertebral body. The PLL merges with the outer anulus articular cartilage is best seen on sagittal MRI. The posterior liga-
at the disc interspace (Fig. 6.12). The PLL is separated from the mentous complex (interspinous ligaments, ligamentum flavum, facet
posterior surface of the vertebral body by the venous plexus in the joint capsules) is imaged best with MRI.

Fig. 6.10 Normal lumbar disc. Sagittal (A) and


axial (B) T2-weighted MRI images of a lumbar disc
demonstrate the hyperintense central nucleus
A B pulposus (arrowheads) surrounded by the
hypointense peripheral anulus fibrosus (arrows).

59
Part 1: General Principles

Within the degenerative/traumatic subcategories, a number of


more specific terms are defined.19 Annular tears (annular fissures)
are separations between annular fibers, avulsion of fibers from verte-
bral attachments, or breaks in the fibers that extend radially, trans-
versely, or horizontally through the lamellae.19
Herniation is defined as a localized displacement of disc material
(any combination of nucleus, anulus, endplate, cartilage, or bony ring
apophysis) beyond the limits of the disc interspace involving less than
Fig. 6.12 Normal 50% of the disc circumference. The disc interspace is defined cranio-
posterior longitudinal caudally by the edges of the vertebral endplates and laterally by the
ligament. Sagittal outer margins of the ring apophyses, without the inclusion of osteo-
T2-weighted lumbar phytes. Herniations are further described as focal (involving <25% of
spine MRI image the disc circumference) or broad-based (involving 25–50% of the disc
demonstrates the thin,
circumference). Generalized disc displacements involving >50% of the
linear hypointense
disc circumference are called bulges.19 Despite the obvious utility of
posterior longitudinal
ligament (arrows) standardized nomenclature, experienced interpreters demonstrate sig-
separated from the nificant interobserver variability describing lumbar spine disc disease.20
posterior vertebral A herniation can be subcategorized as a protrusion or extrusion on
bodies by the epidural the basis of its shape. A herniation is defined as a protrusion if the
venous plexus and distance between the edges of disc material beyond the interspace
attached to the outer is always less than the distance between the edges of the base of
aspects of the anulus the herniation in the same plane. A herniation is called an extru-
fibrosus. sion if any distance between the edges of the disc material beyond
the interspace is greater than the distance between the edges of the
base of the herniation in the same plane. Protrusion and extrusion
IMAGING OF THE ABNORMAL SPINE are defined solely on a morphological basis; the terms do not refer to
whether or not the anulus is intact.19
Degenerative disease A sequestration (free fragment) is a subtype of an extrusion where
Nomenclature the displaced disc material has lost continuity with the parent disc.
The use of ambiguous terminology to describe findings on spine imag- Migration refers to displacement of the disc material away from the
ing has interfered with clear and precise communication between site of the extrusion, whether or not it is sequestrated. Craniocaudal
radiologists and clinicians. To address this significant problem, cooper- disc herniations through the vertebral body endplate are called inter-
ative multispecialty task forces of the North American Spine Society, vertebral herniations (Schmorl’s nodes). Disc herniations are con-
American Society of Spine Radiology, and the American Society of tained if covered by an intact anulus and uncontained if not covered.
Neuroradiology have proposed standardized nomenclature for lum- MRI frequently cannot distinguish contained from uncontained her-
bar disc pathology.19 These recommendations have been endorsed by niations. Discography can demonstrate an uncontained herniation.19
the parent societies of the task forces, the Joint Section on Disorders Standard bony landmarks can be used to define the location of a
of the Spine and Peripheral Nerves of the American Association of disc herniation. In the axial plane, the following zones can be defined
Neurological Surgeons, and the Congress of Neurological Surgeons, from medial to lateral: central – between the medial edges of the
and the CPT and ICD coding Committee of the American Academy articular facets; subarticular – from the medial edge of the articu-
of Orthopedic Surgeons.19 lar facets to the medial edge of the pedicle; foraminal – from the
The definitions recommended by the task forces are based on anat- medial edge of the pedicle to the lateral edge of the pedicle; and extra-
omy and pathology and are not intended to imply etiology or clinical foraminal (far lateral) – lateral to the lateral edge of the pedicle. In
significance. Although these definitions were developed specifically the sagittal plane, herniation location can be described to be discal,
for lumbar disc pathology, it seems logical to extrapolate the use of infrapedicular, suprapedicular, and pedicular.
these terms to the thoracic and cervical spine.19 The volume of the herniation can be categorized on the axial image
The lumbar disc is classified into the following general diagnostic showing the most significant impact on the canal. Compromise
categories: normal, congenital/developmental variation, degenera- of less than one- third of the canal is defined as mild, compromise of one-
tive/traumatic, infectious/inflammatory, neoplastic, and morphologic third to two-thirds of the canal is moderate, and compromise of more
variant of uncertain significance.19 than two-thirds of the canal is severe.19
The normal category includes a morphologically normal disc in a The description of a disc herniation can include the following:
young adult and does not include degenerative, developmental, and morphology (protrusion, extrusion, broad-based, focal), status of
adaptive changes that may be considered clinically normal, such as containment (by the outer anulus), continuity (sequestered or free),
the changes typically associated with aging.19 relationship with the PLL (subligamentous), volume (spinal canal
The congenital/developmental variation category includes congeni- or foraminal compromise), composition (disc, cartilage, bone, and
tally abnormal discs and adaptive disc changes in response to abnor- ligament), and location.19 Some consider a recurrent disc contained if
mal biomechanical forces, for example, morphological disc changes it is limited by scar tissue.
due to scoliosis or spondylolisthesis.19 The term degeneration includes the findings of disc desiccation,
The degenerative/traumatic category includes the subcategories fibrosis, and narrowing, numerous annular tears, mucinous annu-
of annular tear, herniation, and degeneration. This category includes lar degeneration, endplate sclerosis, and osteophytes. Two distinct
degenerative changes that may be part of normal aging and not nec- degenerative patterns have been described. The first pattern, spon-
essarily pathologic. Degenerative changes considered pathologic are dylosis deformans, affects the anulus fibrosus and adjacent ring
also included. apophysis. It is believed to be a consequence of normal aging with

60
Section 3: General Diagnostic Technique

findings that include anterior and lateral osteophytes, disc dehydra- Intervertebral osteochondrosis
tion without disc interspace narrowing, small transverse and concen- Intervertebral osteochondrosis refers to degenerative changes that
tric annular tears, and small amounts of gas in the annular entheses. are considered pathologic and not due to normal aging, including
Posterior osteophytes are not considered to be an element of spon- desiccation and narrowing of the disc, extensive gas in the disc, disc
dylosis deformans. The second pattern, intervertebral osteochondro- bulging, radial annular tears, posterior osteophytes, endplate sclero-
sis, affects the nucleus pulposus and the endplates. It is considered sis and erosions, and chronic bone marrow changes adjacent to the
pathologic, not due to normal aging. Intervertebral osteochondrosis disc interspaces. Radial annular tears are failures of multiple annular
may or may not be symptomatic. It includes desiccation and narrow- layers. They are bright on T2-weighted images and may enhance (Fig.
ing of the disc, extensive gas in the disc, disc bulging, posterior osteo- 6.13). Such high-intensity zones on MRI have a high specificity for
phytes that can narrow the spinal canal and neural foramina, endplate painful annular tears on discography; however, the sensitivity is low.21
sclerosis and erosions, and chronic bone marrow changes adjacent to Disc desiccation and loss of water content causes decreased disc
the disc interspaces.19 height and decreased signal intensity on T2-weighted images. Juxta-
The other categories are inflammatory/infection, neoplasia, and endplate changes (Modic types 1–3) may be present (Fig. 6.14).
morphologic variant of unknown significance. The inflammation/ Modic type 1 corresponds to increased vascularity in the juxta-end-
infection category includes infection, inflammatory discitis, and plate vertebra. Its MRI appearance reflects increased water content:
inflammatory spondylitis. Modic type 1 changes are included in this dark on T1-weighted images and bright on T2-weighted images (Fig.
category. The neoplasia category includes morphologic disc changes 6.14A, B). Modic type 2 represents increased fatty marrow: bright
due to primary or metastatic tumor. Structural abnormalities of the on T1-weighted and dark on fat-suppressed T2-weighted FSE images
disc without sufficient data to define are placed in the category of (Fig. 6.14C, D). Modic type 3 denotes sclerotic changes: dark on
morphologic variant of unknown significance.19 both T1- and T2-weighted images (Fig. 6.14E, F).22 Posterior osteo-
phytes are also dark on both T1- and T2-weighted images and can
Spondylosis deformans narrow the spinal canal and neural foramina. Extensive gas in the disc
(vacuum disc) can be seen on plain films and CT, and sometimes seen
Spondylosis deformans refers to degenerative changes that are asso-
on MRI.19
ciated with the normal aging process, including small concentric
and transverse annular tears, decreased hydration of the disc, ante-
rior and lateral osteophytes, and small amounts of gas in the annu- Disc herniations
lar entheses. Concentric tears have fluid or mucoid material that is On CT, disc herniations are similar to the density of the parent
bright on T2-weighted images between lamellar layers. Transverse disc and are higher density than the CSF. On myelogram radio-
tears occur at the insertion of the anulus into the ring apophysis, and graphs, disc herniations are diagnosed by effacement of a nerve
may contain fluid that is bright on T2-weighted images or gas that root sleeve or by compression of the thecal sac (extradural
is visible on plain films or CT. The discs have decreased water con- defect). Myelography is relatively insensitive to lateral (foraminal)
tent due content to a decreased glycosaminoglycan/collagen ratio and disc herniations and also central herniations at L5–S1 since the
are moderately less bright on T2-weighted images without a loss in thecal sac is farther from the disc interspace. Postmyelography CT
height of the disc interspace. Osteophytes are dark on both T1- and detects small disc herniations and herniations at L5–S1 missed on
T2-weighted images.19 myelography.23

Fig. 6.13 Annular tear. Sagittal (A) and axial (B) T2-
A B weighted MRI images reveal a peripheral annular
tear (arrow).

61
Part 1: General Principles

On T1-weighted MRI images, lumbar spine disc herniations are images is an important sign (Fig. 6.16). Sagittal T2-weighted images
usually iso- to slightly hyperintense relative to the parent disc (Fig. demonstrate loss of continuity of a sequestered lumbar disc hernia-
6.15A, B). Disc herniation signal intensity on T2-weighted FSE tion with its parent disc (Fig. 6.17).26 MRI cannot reliably distinguish
images is variable; the herniation is often iso- to hypointense to the supraligamentous from subligamentous lumbar disc herniations.27
parent disc (Fig. 6.15C, D). Posterior disc herniations are often con- Thoracic disc herniations are quite rare, representing less than
tiguous with a radial tear. Anterior disc herniations are less common 1% of all disc herniations (Fig. 6.18). They present insidiously with
and more frequently asymptomatic. Posterior and posterolateral disc myelopathy, back pain, or radiculopathy.28 Myelopathy occurs more
herniations usually affect the descending nerve root in the lateral commonly than radiculopathy because of the lordotic curve in the
recess, e.g. the L4 nerve root is affected by a L3–4 disc herniation thoracic spine. Calcified thoracic disc herniations may be difficult to
(Fig. 6.15) whereas lateral (foraminal) herniations affect the exiting diagnose on MRI. Myelo-CT may be more definitive in this setting.
nerve root, e.g. the L3 nerve root is affected at L3–4 (Fig. 6.16). A Cervical disc herniations occur most frequently at C5–6 and at
prominent localized venous plexus of epidural veins can look simi- C6–7 (Fig. 6.19).29,30 Lateral cervical disc herniations are rare because
lar to a disc herniation on MRI and can cause radicular symptoms.24 the uncovertebral joints (joints of Luschka) block the herniation from
MRI anatomically characterizes foraminal and extraforaminal hernia- extending in this direction. The nomenclature designed for lumbar
tions best.25 Effacement of foraminal fat on the sagittal T1-weighted disc pathology also can be used to describe cervical disc disease.

A B C

D E F

Fig. 6.14 Juxta-endplate changes. Sagittal T1-weighted and T2-weighted MRI images display Modic type 1 (A, B) and Modic type 2 (C, D) changes
(arrows). Sagittal T1-weighted MRI image (E) and sagittal CT image (F) display Modic type 3 changes (arrows).

62
Section 3: General Diagnostic Technique

A B

Fig. 6.15 Lumbar disc


herniation. Sagittal (A)
and axial (B) T1-
weighted, sagittal (C),
and axial (D) T2-
weighted MRI images
demonstrate an L5–S1
disc extrusion (arrow)
impinging on the
C D S1 nerve root in the
lateral recess.

The natural history of disc herniations is varied. Disc herniations experienced interpreter may provide the most useful correlation
clearly can decrease over time with conservative management and with the clinical presentation. As general guidelines, lumbar central
clinical improvement can be seen. The mechanisms for this are canal is considered abnormal if the area is less than 1.5 cm2 or the
unknown. Possible factors include disc fragmentation, shrinkage, AP diameter is less than 11.5 mm. The narrowed lower lumbar canal
and phagocytosis. Inflammation and neovascularity around the disc often has a trefoil or ‘T’ shape from posterior spurs, disc bulges, facet
margin may promote resorption.31,32 hypertrophy, and thickened ligamentum flavum. The trefoil shape
is accentuated by congenitally short pedicles. The lateral recess is
narrowed if it is less than 4 mm in AP diameter. Hypertrophy of the
Spinal stenosis superior articular facet frequently narrows the lateral recess. Lateral
Spinal stenosis is the term for clinically symptomatic narrowing of recess narrowing may compress the exiting nerve root. The normal
the spinal canal or neural foramen. These symptoms include radicu- ligamentum flavum is 2–4 mm in thickness. Thicker than 5 mm it is
lopathy, myelopathy, and neurogenic claudication due to nerve root considered hypertrophied.
compression.33–35 Lumbar spinal stenosis is frequently evaluated with MRI. Both sagit-
There are a number of causes of spinal stenosis. In children and tal and axial planes, and both T1- and T2-weighted pulse sequences
young adults these include achondroplasia, mucopolysaccharidoses, provide valuable information. Axial-loaded MRI can reveal more
congenitally short pedicles, spondylolisthesis, congenital spinal lipo- severe central canal stenosis and modify the treatment plan.36 The
mas, and disc herniations. Degenerative disease is the most common lumbar neural foramen is best evaluated on sagittal T1-weighted
cause of spinal stenosis in older adults. images.37 Sagittal images display the foramen in optimal profile. The
The typical degenerative lumbar spine with spinal stenosis has lumbar foramen is predominately filled with bright fat that contrasts
varied combinations of degenerative bulges/herniations, osteophytes well with surrounding disc, ligament, and bone. The normal foramen
that form from stresses exerted on the ring apophysis by the disc has a ‘key-hole’ shape; the superior aspect of the foramen is larger than
after Sharpey’s fibers have torn, facet hypertrophy due to osteoar- the inferior aspect. The inferior aspect of the foramen usually narrows
thritis of the synovial facet joint, and hypertrophy of the ligamentum first (Fig. 6.20). The superior portion of the foramen containing the
flavum. The degree of canal compromise may be accentuated by the nerve root usually narrows later. Positional MRI of the lumbar spine
presence of congenitally short pedicles or spinal lipomatosis. with patients seated and imaged in flexion and extension demonstrates
In the lumbar spine, there are three zones to consider: the cen- minor neural foraminal compromise better than conventional supine
tral spinal canal, the lateral recesses, and the neural foramina.34,35 MRI and correlates with positional pain differences.38
Suggested values in the literature for the normal measurements of There is still an important role for conventional myelography in
these regions vary; the subjective evaluation of the images by an the evaluation of patients with lumbar radiculopathy. Lumbar root

63
Part 1: General Principles

Fig. 6.16 Foraminal


lumbar disc herniation.
Sagittal (A) and axial
(B) T1-weighted and
axial T2-weighted
(C) MRI images reveal
a foraminal (lateral)
lumbar disc herniation
(arrow) impinging
on the nerve root
and ganglion, and
A C obliterating the
foraminal fat.

A B C

Fig. 6.17 Free disc fragment. Sagittal T2-weighted (A), axial T1-weighted (B), and axial T2-weighted (C) MRI images demonstrate a disc sequestration
(arrow) impinging on the thecal sac and nerve root in the lateral recess.

64
Section 3: General Diagnostic Technique

Fig. 6.20 Bony lumbar


foraminal stenosis.
Sagittal T1-weighted
MRI image reveals
bony foraminal
encroachment at
multiple levels (arrows).

compression in the lateral recess caused by degenerative changes


is demonstrated by myelography with greater sensitivity than post-
myelography CT or MRI. Surgically confirmed nerve root compres-
sion in the lumbar lateral recess was missed on MRI in 28%, missed
on postmyelography CT in 38%, but only missed on conventional
myelography in 6%.12
Causes of cervical spinal canal narrowing include osteophytes,
ligamentous thickening (posterior longitudinal ligament and ligamen-
tum flavum), disc herniations, and bulges. The cervical spine canal
is considered narrow if the anteroposterior diameter measures less
than 11 mm. On MRI, this is most accurately determined on sagittal
Fig. 6.18 Thoracic disc
herniation. Sagittal T2-weighted images. MRI can overestimate the degree of stenosis
T2-weighted MRI compared to postmyelography CT.39 Kinematic MRI demonstrates
image displays that spinal stenosis and cervical cord impingement increases in flex-
a thoracic disc ion and extension as degenerative disease progresses.40 Bony stenosis
herniation (arrow). of the cervical neural foramina is displayed best by CT (Fig. 6.21).

A B C

Fig. 6.19 Cervical disc herniation. Sagittal (A) and axial (B) T2-weighted fast spin echo MRI images and an axial T2-weighted gradient echo MRI image
(C) demonstrate a cervical disc herniation (arrow) impinging on the exiting nerve root.

65
Part 1: General Principles

consideration. There is an increased incidence of juxta-articular cysts


in spondylolisthesis. CT facet arthrography can be useful to confirm
the diagnosis in some cases.44 Rare thoracic and cervical juxta-articu-
lar cysts have been reported.6,45,46 Synovial cysts can also be caused by
calcium pyrophosphate deposition disease.47
Fig. 6.21 Bony cervical
foraminal stenosis. Correlation of imaging and clinical evaluation
Axial bone window CT It is exceedingly important that careful correlation is carried out
image demonstrates between the imaging findings and the presenting symptoms and signs
marked foraminal before causality is assumed. A positive correlation between imaging
stenosis caused by findings and the clinical presentation of patients with back pain is
uncinate process
often absent. In addition, morphologic abnormalities are frequently
(arrowhead) and facet
(arrow) hypertrophy.
detected on imaging studies of clinically asymptomatic individuals.48–52
Lumbar disc bulges and protrusions but not extrusions are found on
Spinal cord myelopathy caused by spinal stenosis is bright on T2- MRI in many asymptomatic individuals. Annular tears, Schmorl’s
weighted images (Fig. 6.22). Different patterns have been described nodes, and facet arthropathy are also common.52,53 Therefore, the
and correlated with surgical outcomes. Well-defined and intense imaging abnormalities found in patients with back pain may be coin-
intramedullary high signal on T2-weighted images is associated with cidental and unrelated to the pain. In addition, asymptomatic people
a poor surgical prognosis.41 with lumbar spine abnormalities on MRI do not have a higher prob-
ability of developing back pain in the future.54 Cervical spine abnor-
malities are also frequently found in asymptomatic individuals.50
Juxta-articular cysts
Juxta-articular cysts are associated with degenerative disease and Failed back syndrome
occur in a characteristic location, extending anteromedially into Failed back syndrome refers to continued or recurrent back pain after
the canal from the lumbar facet joint forming a round postero- spinal surgery. It has been variably reported to occur in 5–40% post-
lateral extradural mass.42,43 The majority is true synovial cysts; how- operative patients. The pain can be caused by scar tissue, residual
ever, a few are ganglion cysts and contain a connective tissue capsule. or recurrent disc herniation, insufficient decompression with central
Juxta-articular cysts most commonly occur at L4–5 and at L5–S1, or foraminal stenosis, instability, spondylolisthesis, hematoma, post-
more often on the right side. They may present with radicular pain operative fluid collection, operation at the wrong level, CSF leak,
and neurological deficits. The juxta-articular cyst is diagnosed by infection, and arachnoiditis.55–60
its characteristic position in the posterolateral aspect of the spinal The MRI appearance of the postoperative spine evolves over time.
canal abutting the anterior aspect of the facet joint and by associated In the first week after surgery, there is usually more mass effect vis-
degenerative changes in the facet joint including joint space narrow- ible at the operated level than before the procedure. The degree of
ing, sclerosis, and osteophytes. The imaging appearance can vary. The mass effect does not correlate with the eventual clinical outcome
contents may have characteristics of fluid or blood with varied MRI and the mass effect typically begins to decrease after the first week.
signal intensities (Fig. 6.23). The periphery can calcify and enhance. Granulation tissue, the instrumented disc, and the adjacent vertebrae
A posterolateral disc extrusion is the primary differential diagnostic all normally enhance after surgery. Surgicel placed for hemostasis can
markedly compress the posterior thecal sac in the immediate post-
operative period in patients who are clinically doing well.61 The imaging
diagnosis of a residual or recurrent disc is therefore difficult in the
immediate postoperative period.60,62
After the immediate postoperative period, gadolinium-enhanced
MRI reliably differentiates postoperative epidural scar from a residual
or recurrent disc herniation (Figs 6.24, 6.25). On nonenhanced T1-
weighted images, scar and disc are indistinguishable (Fig. 6.25A, B).
On T2-weighted images, epidural scar may be slightly brighter than
disc material.63 On gadolinium-enhanced T1-weighted images per-
formed immediately after the contrast injection, postoperative scar
enhances avidly and homogeneously, while disc material does not (Fig.
6.25C, D).64 In patients who are studied more than 6 weeks after
surgery, MRI is 96% accurate in differentiating scar tissue and disc
herniation.64 Fat suppression is useful because both enhancing epidu-
ral scar and fat are bright on nonfat-suppressed T1-weighted images.65
The periphery of a disc herniation can enhance immediately follow-
ing injection, but the central portion does not. Severely fragmented
Fig. 6.22 Spinal discs can display rapid diffuse enhancement similar to epidural scar.
stenosis-induced
A recurrent disc may exert mass effect on a nerve root but epidural
myelopathy. Sagittal
scar usually does not. On delayed imaging after injection, contrast can
T2-weighted cervical
spine MRI image diffuse into a disc herniation causing it to be confused with enhanc-
demonstrates ing scar tissue. Interestingly, one recent study has suggested con-
spinal stenosis and trast-enhanced MRI imaging does not improve diagnostic accuracy in
myelopathy (arrow). patients with prior lumbar surgery.66

66
Section 3: General Diagnostic Technique

A B C

Fig. 6.23 Synovial cyst. Sagittal T1-weighted (A) and T2-weighted (B) lumbar spine MRI images, and an axial T2-weighted MRI image (C) display a
left-sided L4–5 synovial cyst (arrow).

Fig. 6.24 Postoperative epidural scar. Axial pre-


(A) and postgadolinium (B) T1-weighted MRI
images demonstrate enhancing epidural scar tissue
A B surrounding the nerve root in the lateral recess
(arrow).

Postoperative nerve root enhancement may be a marker of active menopausal women. Additional causes include metastases, multiple
neural inflammation associated with radiculopathy.67 Lumbar nerve myeloma, leukemia, lymphoma, malignant and benign primary verte-
roots, however, can enhance in patients that have not had surgery and bral neoplasms, trauma, osteomyelitis, osteomalacia, osteitis cystica,
there is no correlation with radiculopathy.68 and hemochromatosis.
Postoperative discitis and osteomyelitis are difficult to diagnose on The World Health Organization defines osteoporosis as bone min-
MRI in the first 6 months after back surgery. Asymptomatic patients eral density more than 2.5 standard deviations below the mean in a
can have an imaging appearance identical to infection with a disc and normal young adult population. Osteoporosis may be primary (asso-
adjacent vertebrae that are dark on T1-weighted images, are bright ciated with aging) or secondary to corticosteroids, hyperthyroidism,
on T2-weighted images, and demonstrating diffuse enhancement. multiple myeloma, oophorectomy, male hypogonadism, paralysis,
anticonvulsants, and alcoholism. Thirty percent of postmenopausal
white women in the United States are estimated to have osteopo-
Vertebral compression fractures rosis; this is associated with bone fragility and an increased risk of
Vertebral compression fractures are defined by a loss of more than fractures. The cumulative lifetime risk of developing a symptomatic
15% of normal vertebral body height. Osteoporosis is the most com- vertebral compression fracture is 16% in white women and 5% in
mon cause of compression fractures and occurs most often in post- white men.69,70

67
Part 1: General Principles

A B

Fig. 6.25 Postoperative disc herniation. Sagittal


and axial T1-weighted MRI images pre- (A, B)
and postgadolinium (C, D) demonstrate a
postoperative disc herniation. The disc herniation
(arrow in C and D) is surrounded by enhancing
scar/granulation tissue (arrowheads in C) and
C D impinges on the nerve root (arrowhead in D) in
the lateral recess.

The clinical presentation and course of osteoporotic compression cally reinforce the pathologically weakened vertebra. Cement poly-
fractures is quite varied. Although spine imaging often detects inci- merization strengthens and stabilizes the vertebral body. Mechanical
dental, asymptomatic compression fractures in elderly people, pain- stabilization is thought be the primary mechanism for pain relief;
ful compression fractures are quite common. It is estimated there however, neurotoxic effects from the methylmethacrylate mono-
more than 700 000 symptomatic osteoporotic compression fractures mer and heat from the exothermic polymerization reaction may
occur each year in the United States associated with 115 000 hospital also contribute by destroying nociceptive receptors and nerves.
admissions, 161 000 physician visits and five million days of restricted Vertebroplasty has successfully treated painful vertebral compression
activity.71 The pain associated with osteoporotic compression fractures fractures caused by osteoporosis, hemangiomas, metastases, multiple
usually lasts 2 weeks to 3 months, but may persist indefinitely and can myeloma, and lymphoma.72
significantly impair physical, functional, and psychosocial performance. Patients are typically screened with plain films to identify the pres-
Many compression fractures are associated with severe pain that is ence, number, and positions of the vertebral compression fractures.
refractory to conventional forms of therapy such as immobilization, If there are serial examinations, the interval development of new
bracing, and analgesics. Patients commonly experience a profoundly compression fractures can be determined and correlated with the
negative impact on the quality of their lives, and potentially life-threat- clinical history. MRI usually is obtained next, to obtain more infor-
ening secondary medical problems can develop such as deep venous mation about the age and etiology of the compression fractures, and
thrombosis, pulmonary embolism, pneumonia, constipation, decubi- also to exclude other causes for the patient’s symptoms. CT and bone
tus ulcers, and depression. Vertebral compression fractures associated scans are obtained in selected cases to answer specific questions.
with benign and malignant tumors also frequently cause severe pain The MRI appearance of osteoporotic compression fractures var-
and disability that is refractory to conventional therapies. ies with time. The bone marrow in a vertebra with an acute benign
Percutaneous vertebroplasty is a relatively new and effective mini- compression fracture has edema and inflammation that is dark on
mally invasive technique to treat painful compression fractures. The T1-weighted images and bright on STIR and T2-weighted images.
procedure was first performed in France in 1984; it consists of the This bone edema usually resolves in 4–6 weeks. The bone marrow
percutaneous insertion of a relatively large-gauge bone needle into signal intensity returns to normal with resolution of the bone edema
a vertebral body and the injection of a viscous liquid mixture of and is bright on T1-weighted images reflecting fatty marrow.73,74 This
polymethyl methacrylate cement under fluoroscopic guidance. The return to normal-appearing bone marrow is diagnostic of a benign
procedure is usually performed for pain relief, but may also mechani- cause and excludes a malignant compression fracture.

68
Section 3: General Diagnostic Technique

A B C

Fig. 6.26 Malignant compression fracture. T1-weighted (A), fat-suppressed T2-weighted (B), and fat-suppressed contrast-enhanced T1-weighted
(C) sagittal lumbar spine MRI images demonstrate a malignant L4 compression fracture (arrows).

A malignant vertebral compression fracture is also dark on nant compression fracture. Large regions of posterior cortical destruction
T1-weighted images and variably bright on T2-weighted images (Fig. 6.28) increase the risk of cement extravasation causing spinal cord
(Fig. 6.26). Unlike a benign compression fracture, the low signal or nerve root compression and are associated with higher vertebroplasty
intensity on T1-weighted images will only return to normal following complication rates. Such cortical destruction is rare in osteoporotic
radiation therapy. Benign and malignant compression fractures can compression fractures and occurs more commonly in cases of malignant
look identical on MRI, and definitive diagnosis may require a biopsy; compression fractures due to metastases. If the CT demonstrates this
however, there are some distinguishing characteristics. As previ- type of destruction the vertebroplasty technique can be modified or the
ously noted, the benign compression fracture marrow signal inten- procedure might not be performed. CT is the most accurate method to
sity usually returns to normal in about 6 weeks, while the malignant evaluate the distribution of the polymethyl methacrylate cement after a
compression fracture marrow does not. A malignant compression vertebroplasty, especially important in a patient with a new radiculopathy
fracture often has abnormal signal throughout the vertebra, and can or myelopathy that may be due to extravasated cement.79
have abnormal signal in the pedicles and the rest of the posterior ele-
ments. The abnormal signal in benign compression fractures usually Arachnoiditis
does not involve the entire vertebral body or the posterior elements.
Arachnoiditis is a result of leptomeningeal inflammation that may be
Large paravertebral or epidural masses are common with malignant
caused by any source of subarachnoid blood (surgery, trauma, ruptured
and uncommon with benign compression fractures.73,74
arteriovenous malformation, and aneurysm), infection (tuberculous and
Patients who are referred for vertebroplasty often have multiple
bacterial meningitis), and other inflammatory disorders. Arachnoiditis
osteoporotic compression fractures of indeterminate ages with nonlo-
used to be common following myelography with Pantopaque (iophen-
calizing physical examinations. Identifying the compression fractures
dylate) but is rare with currently used nonionic contrast agents.80
that are responsible for the pain that will respond to vertebroplasty
Arachnoiditis can be the source of significant back pain and has been
can be difficult. The presence of increased uptake on a bone scan in
reported to cause 6–16% of the cases of failed back syndrome.81
an osteoporotic compression fracture is a good predictor for a positive
The findings of arachnoiditis are variable and well seen on sagittal
clinical response to vertebroplasty. Of 27 patients with 35 osteoporotic
and axial T2-weighted FSE images, myelogram films, and postmyelog-
compression fractures that demonstrated increased activity on bone
raphy CT images. Obliteration of nerve root sleeves is an early finding.
scan, 93% had a significant decrease in pain following vertebroplasty.75
More severe cases display irregular clumping of the nerve roots (Fig.
All of the 14 patients evaluated for mobility had a significant improve-
6.29), distortion of the thecal sac and adhesion of the nerve roots to
ment after vertebroplasty. The presence of bone edema on MRI can
the thecal sac giving the ‘empty sac’ sign. Thoracic arachnoid cysts can
distinguish painful acute/subacute from asymptomatic chronic osteo-
occur. Enhancement is variable. Tuberculous arachnoiditis has a distinc-
porotic compression fractures and correlates with a clinical benefit
tive pattern with leptomeningeal thickening and nodules on the spinal
from vertebroplasty.76 The sagittal STIR pulse sequence detects bone
cord and nerve roots (differential diagnosis: metastases, sarcoid).
edema with the greatest sensitivity. T2-weighted FSE images are almost
as sensitive. MRI can also demonstrate the fluid-filled cavity within
a vertebra seen in Kümmel’s disease (vertebral body osteonecrosis) Dural ectasia
(Fig. 6.27), which responds well to vertebroplasty.77,78 Dural ectasia is abnormal enlargement of the thecal sac or nerve root
Although CT is not used as commonly as plain films and MRI for the sleeves at any level but most commonly in the lumbosacral region.
evaluation of vertebroplasty patients, it has roles. CT is useful to evalu- Causes include Marfan syndrome, Ehlers-Danlos syndrome, neurofi-
ate the integrity of the posterior bony cortex of a vertebra with a malig- bromatosis, and ankylosing spondylitis.82 Findings include scalloping

69
Part 1: General Principles

Fig. 6.27 Avascular necrosis. Sagittal helical CT


image (A) and sagittal fat-suppressed T2-weighted
MRI image (B) demonstrate an air- and fluid-filled
A B subchondral cavity (arrows) in the L4 vertebral
body.

Fig. 6.28 Posterior


cortical destruction.
Axial lumbar spine Fig. 6.29 Arachnoiditis.
CT in bone window Axial CT-myelogram
demonstrates a demonstrates
vertebral body clumping of the
metastasis with lumbar nerve
posterior cortical roots (arrow) and a
destruction (arrows). laminectomy defect.

of the posterior vertebral bodies (Fig. 6.30A), increased interpedicu- edema and inflammation (Fig. 6.31).83,84 An enhancing paravertebral
late distances (Fig. 6.30B), widened neural foramina, thinning of the mass (phlegmon) or frank abscess may be present. Renal spondyloar-
cortex of the pedicles and lamina, and meningoceles. thropathy can look similar but there is usually less edema and no clinical
evidence of infection. Destruction of the endplates on plain films is an
Infection insensitive but relatively specific sign of infection. CT often demonstrates
Spine infections, including discitis, osteomyelitis, and epidural abscess, endplate irregularities and bony juxta-endplate sclerosis. The MRI find-
are best detected and characterized by MRI.6 Bacteria that cause disci- ings can persist long after successful antibiotic therapy and do not reflect
tis are most often spread by hematogenous dissemination, followed by therapeutic failure. The MRI appearance of tuberculous osteomyelitis is
direct introduction during surgical procedures. The most common organ- variable and may be more suggestive of tumor than infection.85
ism is Staphylococcus aureus. Pneumonia and urinary tract infections are Epidural abscesses are caused by direct extension of discitis/osteo-
typical sources. The infection spreads from the endplate into the disc myelitis and also by hematogenous dissemination. Intravenous drug
and adjacent subchondral vertebral marrow. The clinical presentation is abuse, immunosuppression, AIDS, endocarditis, pneumonia, and
varied; an acute infection may cause severe back pain and fever, while an urinary tract infections are common settings. Patients present with
indolent infection may cause remarkably subtle symptoms. The lumbar fever, back pain, and tenderness. Neurological deficits can be due to
spine is the most common site. Spinal cord and nerve root dysfunction mass effect or septic thrombophlebitis.
may evolve as the infection progresses from either direct compression or On MRI, an epidural abscess is dark on T1-weighted images and
septic thrombophlebitis. An elevated erythrocyte sedimentation rate and bright on T2-weighted images. Enhancement can be diffuse (phleg-
an elevated white blood cell count are usually present. mon) or peripheral (pus surrounded by an enhancing pseudocapsule)
Bacterial discitis and vertebral osteomyelitis is detected on MRI (Fig. 6.32). The abscess is positioned more frequently in the poste-
with 96% sensitivity, 93% sensitivity, and 94% accuracy.83 On rior epidural space than anterior.
MRI, the disc interspace and the adjacent vertebrae are dark on Facet synovitis may be sterile (inflammatory) or infectious. MRI
T1-weighted images, bright on T2-weighted images and enhance due to can accurately diagnose pyogenic facet joint infection.86 Staphylococcus

70
Section 3: General Diagnostic Technique

Fig. 6.30 Dural ectasia


associated with
neurofibromatosis
type 1. Sagittal
T2-weighted thoracic
spine MRI image (A)
shows scalloping of
posterior vertebral
bodies (arrows).
Anteroposterior thoracic
spine plain film (B)
demonstrates widening
A B of the interpediculate
distances (arrows).

aureus is the most common organism. Most occur in the lumbar spine. and its involvement can range from virtually asymptomatic to dis-
An epidural abscess is associated in 25%. It is best seen on sagittal abling, which may require urgent surgery due to progressing neu-
images. Fat-suppressed T2-weighted FSE images may show fluid in rological deficits and instability. Rheumatoid arthritis can cause
the synovial joint space and edema in the adjacent subcortical bone. atlantoaxial subluxation due to transverse ligament laxity as a result
The joint space may enhance on postgadolinium fat-suppressed T1- of synovial inflammation. The synovitis may evolve from a joint effu-
weighted images. Biopsy may be necessary for definitive diagnosis.87 sion into a fibrous pannus. Odontoid erosions occur frequently due to
synovial inflammation between the dens and the atlas.
Conventional radiographs are relatively insensitive to rheumatoid
Rheumatoid arthritis arthritis of the cervical spine. Bony erosions can be seen in atlas
Rheumatoid arthritis typically involves multiple joints in the upper and axis. Atlantoaxial subluxation manifests as increase of anterior
and lower extremities. Involvement of the cervical spine is not uncom- atlanto-odontoid distance, which is due to laxity and/or disruption of
mon; however, the thoracic and lumber spine are rarely affected. transverse ligament. Vertical and lateral subluxation is more difficult
The craniocervical junction is the most vulnerable area of the spine to detect on plain radiographs.88

Fig. 6.31 Discitis and osteomyelitis. Sagittal


T2-weighted (A) and fat-suppressed contrast-
enhanced T1-weighted (B) thoracic spine MRI
images demonstrate a destroyed, fluid-filled disc
interspace with peripheral enhancement (arrows)
A B as well as marked bone edema and enhancement in
the adjacent vertebrae.

71
Part 1: General Principles

CT is the test of choice to evaluate for bony changes in rheu-


matoid arthritis of the cervical spine (Fig. 6.33). Imaging of rheu-
matoid arthritis reveals disc space narrowing, osseous irregularities,
and erosions without osteophytes. Even small erosions can be seen
with thin-section spiral CT. C1 and C2 are routinely involved
(see Fig. 6.33A, B). The odontoid process is affected in 14–35%
of patients with rheumatoid arthritis. Subchondral erosions can
also be seen at other levels of the cervical spine involving the end-
plates and facet joints. Erosion and/or destruction of the spinous
processes also can be present. Inflammatory facet arthropathy is
not uncommonly seen. Osteophytes are not a feature of rheuma-
toid arthritis, although in elderly individuals rheumatoid arthritis
and osteoarthritis often coexist. Sagittal and coronal reformatted
images are useful to evaluate for vertical and lateral dislocation at
Fig. 6.32 Epidural
abscess. Sagittal
the craniocervical junction, and can also demonstrate subluxations
contrast-enhanced at lower levels, particularly at C3–4 and C4–5. Rheumatoid arthri-
T1-weighted cervical tis can cause significant narrowing of the spinal canal by pannus
spine MRI reveals a (Fig. 6.33C). Detection of pannus on CT can be augmented by
peripherally enhancing the use of intravenous contrast, although the soft tissues are now
ventral epidural usually evaluated by MRI.89
abscess (arrows) MRI is the best imaging test for visualization of inflamma-
and prevertebral tory changes in the soft tissues, including the ligaments and the
inflammation synovium. MRI signal characteristics and enhancement pattern
(arrowheads).
can reliably distinguish different stages of pannus formation.

Fig. 6.33 Rheumatoid arthritis. Sagittal


(A) and axial (B) bone window CT
images demonstrate erosions of the
odontoid and anterior arch of C1.
Axial soft tissue window CT image (C)
C demonstrates pannus (arrowheads)
narrowing the spinal canal.
72
Section 3: General Diagnostic Technique

Hypervascular pannus is hyperintense on T2-weighted images, Ankylosing spondylitis


vividly enhances with gadolinium, and retains enhancement over Ankylosing spondylitis is an inflammatory spondyloarthropathy with
5–10 minutes. Hypovascular pannus demonstrates intermediate a reported incidence of 1.4%; it occurs in young adults with a strong
T2 signal and has moderate enhancement that mildly decreases male predominance (4:1). More than 97% of patients are HLA-B27
over 5–10 minutes. Fibrous pannus is usually hypointense on positive. An inflammatory infiltrate of plasma cells and lymphocytes
T2-weighted images and demonstrates mild or absent enhancement. causes vascularization and ossification of ligamentous attachments
Nonenhanced T1-weighted images are not helpful as all types of pan- to bone (enthesopathy) and inflammation of synovial and carti-
nus are hypointense.90 MRI also reveals mass effect on the spinal cord laginous articulations. The sacroiliac joints are universally involved.
and medullocervical junction, including spinal canal stenosis and cord This process in the outer anulus, ALL, and PLL results in multi-
compression. level vertebral fusion and ossification (syndesmophytes). The plain
film appearance is called the ‘bamboo spine’ (Fig. 6.34A, B). The

B
C

Fig. 6.34 Ankylosing spondylitis. AP (A) and


lateral (B) plain films demonstrate a bamboo
spine with syndesmophytes. A sagittal T1-
weighted MRI image (C), and sagittal (D), and
axial (E) T2-weighted MRI images reveal abnormal
marrow, dural ectasia, and arachnoiditis with
D the empty sac sign and clumping of nerve roots
(arrows).
73
Part 1: General Principles

vertebrae lose their normal anterior convexity and appear squared. at the disc interspaces while OPLL is a continuous process along the
The upper and lower corners of the anterior vertebral body become posterior longitudinal ligament.
sclerotic. Calcification of the discs is common. There is fusion of the Diffuse idiopathic skeletal hyperostosis (DISH), also known as
facet and sacroiliac joints. On MRI, the vertebral bodies are dark on Forestier disease, demonstrates exuberant calcification of the ALL
T1-weighted images, bright on T2-weighted images, and enhance without significant disc disease or ankylosis of the facet joints.
(Fig. 6.34C, D). Calcified discs can be dark or bright on T1-weighted Bony bridging of at least four contiguous vertebrae is characteristic.
images. Spinal fractures, deformity, subluxation, rotatory instability, Hyperostosis also occurs at ligamentous and tendonous insertions,
and stenosis occur.91,92 Stress fractures through the disc interspace and juxta-articular ossifications are present.
with nonunion cause an unstable pseudoarthrosis. Destruction of
the disc interspace with adjacent zones of bony sclerosis is evident.
Ankylosing spondylitis is associated with arachnoiditis and dural Spondylolysis and spondylolisthesis
ectasia (Fig. 6.34D, E). Spondylolysis is defined as a fracture through the pars interarticu-
laris (pars defect). The etiology of spondylolysis is unknown; stress
Ossification of the posterior longitudinal fractures and congenital defects are considered possible causes.
Spondylolysis is a common source of chronic back pain in children
ligament and diffuse idiopathic skeletal and young adults. Pars defects are readily demonstrated on plain
hyperostosis films as a fracture through the neck of the ‘Scotty dog’ on the oblique
Ossification of the posterior longitudinal ligament (OPLL) is an view (see Fig. 6.1) and on CT on both axial and reconstructed sagittal
inflammatory degenerative process associated with cervical spine images (Fig. 6.36A, B). Diagnosis of pars defects on MRI is more dif-
degenerative disease that affects both men and women, usually in ficult.94 On sagittal T1-weighted images, a break in the bony cortex
middle age.93 OPLL occurs in 50% of patients with diffuse idiopathic or the marrow signal of the pars interarticularis can be seen;95 how-
skeletal hyperostosis (DISH). OPLL can cause central spinal canal ever, 25% of pars defects are missed on MRI (Fig. 6.36C, D).
stenosis, compress the spinal cord, and cause myelopathy. CT with Spondylolisthesis is anterior or posterior displacement (transla-
sagittal reconstructions accurately displays the extent and severity tion) of a vertebra relative to an adjacent vertebra. Anterolisthesis
of the process (Fig. 6.35A, B). OPLL can be difficult to diagnose on refers to anterior displacement of a vertebra relative to the adjacent
MRI since the ossified ligament is dark on both T1- and T2-weighted caudal (inferior) vertebra while retrolisthesis refers to posterior dis-
images (Fig. 6.35C). OPLL may contain bone marrow that will placement. Severity is graded by the percentage of the vertebral
change its MRI appearance. Deformity and compression of the spinal body that is displaced. Grade I is less than 25%, grade II is 25–50%,
cord on sagittal T2-weighted images may suggest the diagnosis. The grade III is 50–75%, and grade IV is greater than 75%. A number
differential diagnosis of OPLL includes posterior osteophytes, calci- of conditions that destabilize the posterior column can cause
fied discs, and meningiomas. Differentiation of OPLL from posterior spondylolisthesis. These include congenital disorders (dysplastic and mis-
osteophytes is usually straightforward since osteophytes occur focally oriented articular processes, kyphosis, spina bifida), spondylolisthesis,

A B C

Fig. 6.35 OPLL. Sagittal (A) and axial (B) CT images and a sagittal T2-weighted MRI image (C) demonstrate ossification of the posterior longitudinal
ligament (arrows).

74
Section 3: General Diagnostic Technique

A B

Fig. 6.36 Spondylolysis and spondylolisthesis.


Sagittal (A) and axial (B) CT images, sagittal
T1-weighted (C), and axial T2-weighted (D) MRI
C D images demonstrate pars defects (arrows) and
grade I anterolisthesis of L5 on S1.

degenerative facet arthropathy, the surgically fused spine, trauma (pedi- side. The mass forms a well-defined meniscus with the subarachnoid
cle fractures), and destructive processes (tumor, infection, osteoporosis, contrast on the myelogram radiographs. Intradural–intramedullary
osteopetrosis). Spondylolisthesis frequently causes neural foraminal nar- masses originate within the spinal cord. The spinal cord is expanded
rowing best evaluated on reconstructed sagittal CT images and sagittal T1- and the subarachnoid space is circumferentially narrowed. These
weighted MRI images. The normal shape of the neural foramen is altered; include tumor (astrocytoma, ependymoma, metastases), syringohy-
the longest axis of the foramen changes from vertical to horizontal. The dromyelia, infection, and inflammatory/demyelinating lesions.
sagittal MRI can demonstrate foraminal stenosis, obliteration of forami- The superior soft tissue contrast resolution of MRI has markedly
nal fat, and nerve root compression and/or kinking. A fibrocartilaginous enhanced the detection and characterization of neoplastic disease
mass may be seen around the nonhealed pars fracture. A disc herniation of the spinal cord and canal.2,6 The use of i.v. gadolinium contrast
is more common at the level above the spondylolisthesis than at the same is essential since the large majority of tumors enhance while many
level. The anterior displacement of the upper vertebra relative to the disc inflammatory/demyelinating lesions do not.
confers the artifactual appearance of a disc bulge or herniation (pseudo-
bulge or herniation). Neither isthmic nor degenerative spondylolisthesis Intramedullary neoplasms
appears to be associated with instability or hypermobility when studied
Intramedullary neoplasms usually expand the spinal cord, are of high sig-
with kinematic MRI.96
nal intensity on T2-weighted images, and enhance. Ependymomas and
astrocytomas are the most common primary spinal cord tumors.97,98
Neoplastic disease
Technique Ependymoma
Prior to MRI, myelography was the primary method to evaluate Ependymomas represent approximately one-half of spinal cord
masses involving the spinal canal and spinal cord. On myelography, tumors and are the most common intramedullary tumor in adults,
masses are differentiated into extradural, intradural–extramedul- usually occurring in the third to fifth decade of life. They arise from
lary, and intradural–intramedullary locations. Extradural masses arise the ependymal cells of the central canal. They are unencapsulated,
from the disc (herniation), epidural space (infection, tumor), or ver- benign, well-circumscribed, slowly growing tumors. Cervical and
tebral body (osteophytes, benign and malignant tumors, retropulsed cervical–thoracic locations are most common. Ependymoma is the
fracture fragments). The thecal sac and spinal cord are displaced most common primary spinal cord neoplasm of the distal spinal cord,
away from the mass. Intradural–extramedullary masses arise within conus medullaris, and filum terminale (6.5% of all ependymomas)
the thecal sac and outside the spinal cord. Meningiomas and nerve (Fig. 6.37). Myxopapillary ependymoma is a particular histological
sheath tumors (neurofibroma and schwannoma) are the most com- variant occurring in this region. These are mucin-containing tumors
mon intradural–extramedullary masses. These enlarge the ipsilat- that can calcify or hemorrhage. These are often hyperintense on T1-
eral subarachnoid space and displace the spinal cord to the opposite weighted images, likely due to a high mucin content.99 Ependymomas

75
Part 1: General Principles

Fig. 6.37 Conus medullaris ependymoma.


Sagittal T2-weighted (A) and contrast-enhanced
T1-weighted (B) lumbar spine MRI images
A B demonstrate a heterogeneous T2-hyperintense,
contrast-enhancing conus mass.

typically are iso- to hypointense on T1-weighted images, and hyper- present acutely in the fourth to sixth decade due to hemorrhage. MRI
intense on T2-weighted images, usually with multinodular high signal is the most sensitive diagnostic imaging study. The lesions appear simi-
intensity throughout the cord that may be focal (over several verte- lar to cavernous malformations in the brain and are typically rounded
brae) or diffuse (up to 15 vertebrae). They frequently hemorrhage and in shape with a mixed signal intensity core containing regions of T1
may contain dark areas on T2-weighted images representing hemosid- and T2 high signal intensity due to methemoglobin surrounded by a
erin from old bleeds. Sharply marginated regions of enhancement are T2 low signal intensity rim of hemosiderin (Fig. 6.39). They are typi-
typically seen; however, enhancement patterns can be quite varied.99 cally not visualized on spinal angiography (angiographically occult vas-
Most ependymomas have associated cysts that are usually not tumoral. cular malformation) although occasionally late pooling of contrast or
abnormal draining veins can be demonstrated. Histologically proven
Astrocytoma intramedullary arteriovenous malformations can have the same clini-
cal presentation and imaging characteristics.100
Astrocytomas comprise approximately 40% of spinal cord tumors.
They are the most common intramedullary tumor in children. In chil-
dren, the tumors are grade I pilocytic astrocytomas with a good prog- Other uncommon intramedullary tumors
nosis. Astrocytomas also occur in adults with a mean age of 29 years Less common intramedullary tumors include ganglioglioma/ganglio-
and are more common in men. In adults the tumors are usually low- cytoma and metastases. Ganglioglioma/gangliocytoma usually occurs
grade infiltrative astrocytomas with a poorer prognosis, and generally in children and adolescents. The cervical spinal cord is the most
not resectable. The tumors extend on average over 7 vertebrae. They common location. They typically display mixed signal intensity on
occur most commonly in the thoracic spinal cord. The tumors are T1-weighted images, high signal intensity on T2-weighted images,
iso- to hypointense on T1-weighted images, and hyperintense on T2- and patchy peripheral enhancement. A minority does not enhance.
weighted images (Fig. 6.38A). Uneven enhancement is usually present Prominent tumoral cysts are common. Intramedullary metastases are
(Fig. 6.38B). Cysts (usually tumoral) and syrinxs can be associated. usually dark on T1-weighted images, bright on T2-weighted images,
and demonstrate intense, homogeneous enhancement. There is
Hemangioblastoma usually marked edema surrounding the tumor.
Hemangioblastoma is the third most common intramedullary tumor
(1–7%). It is a vascular tumor that usually has solid and cystic compo- Intradural–extramedullary neoplasms
nents; however, 25% are entirely solid. The solid component typically Meningioma
enhances intensely. There is usually associated edema. The tumors can
Intradural–extramedullary neoplasms typically compress and dis-
be eccentric and can appear extramedullary. Hemorrhage is common.
place the cord away from the tumor and enlarge the ipsilateral
Prominent vascular flow voids can be seen. Approximately one-third
subarachnoid space next to the mass (Fig. 6.40). Meningiomas rep-
of patients with hemangiomas have von Hippel-Lindau syndrome.
resent about 25% of spinal canal tumors. There is an association with
The hemangiomas can be multiple in these patients.
neurofibromatosis type 2. They occur more frequently in women
than men, most often in the thoracic spine. Meningiomas are well cir-
Cavernous malformation cumscribed and dural based. They are usually iso- to slightly hypoin-
Spinal cord cavernous malformations are uncommon neoplastic vas- tense on T1-weighted images and may be heterogeneous. The tumors
cular lesions. They have a strong female predominance, and usually are similar intensity or slightly hyperintense to the spinal cord on

76
Section 3: General Diagnostic Technique

Fig. 6.38 Spinal cord astrocytoma. Sagittal


T2-weighted (A) and contrast-enhanced T1-
weighted (B) cervical spine MRI images reveal
marked spinal cord expansion, pathologic
A B heterogeneous T2 hyperintensity, and
enhancement (arrows).

T2-weighted images. Intense, homogeneous enhancement is charac- Schwannoma and neurofibroma are indistinguishable by MRI
teristic. Calcification can occur. appearance, although solitary lesions are usually schwannomas, and
schwannomas are more commonly associated with vascular changes,
Nerve sheath tumors hemorrhage, cysts, and fatty degeneration.
Nerve sheath tumors (schwannoma and neurofibroma) may be intra-
dural–extramedullary, both intradural and extradural, or completely Extradural tumors
extradural. Schwannomas are associated with neurofibromatosis Metastatic disease
type 2. Neurofibromas are associated with neurofibromatosis type 1. The vertebrae are the most common location of metastatic disease in
Both types of tumors are usually isointense on T1-weighted images the spine. Most metastases begin in the vertebral body but they may
and hyperintense on T2-weighted images, and enhance. Combined grow through the pedicles into the posterior elements. The most com-
intradural–extradural tumors often enlarge the neural foramen mon primary sources of vertebral metastases are breast, lung, renal,
(Fig. 6.41) and can display a characteristic dumbbell shape. and prostate carcinomas. Leukemia, lymphoma, multiple myeloma,
melanoma, and sarcomas also commonly involve the spine.
Plain films and CT are relatively insensitive for the early detection of
spine metastases. Most metastases are osteolytic and eventually cause a
radiolucent geographic defect or a combined osteolytic and osteoblas-
Fig. 6.39 Spinal cord tic lesion. A relatively specific, but insensitive plain film finding is loss
cavernoma. Axial of a pedicle. Common osteoblastic metastases include prostate, breast,
T2-weighted gradient
ovarian, and transitional cell carcinoma, lymphoma, and carcinoid.
echo MRI image of the
MRI is more sensitive than plain films and CT in detecting spi-
cervical spine reveals
a typical peripherally nal metastatic disease.2,6 The T1-weighted acquisition is the most
T2-hypointense lesion sensitive MRI pulse sequence. Tumor deposits are usually well cir-
with susceptibility cumscribed and darker than the normally bright adult fatty mar-
effects caused by row on T1-weighted images see (Fig. 6.26A). On postgadolinium
hemosiderin (arrow). T1-weighted images, enhancing tumor can be equally bright as the

77
Part 1: General Principles

Fig. 6.40 Meningioma. Sagittal T2-weighted


(A) and contrast-enhanced T1-weighted (B)
thoracic spine MRI images demonstrate a mildly
A B T2 hyperintense, mildly enhancing intradural
extramedullary mass (arrows).

surrounding normal fatty marrow and may be obscured.65 This pit- common and typically larger with malignant compression fractures.
fall can be avoided by obtaining nonenhanced T1-weighted images. On CT, benign compression fractures typically are not associated with
Fat suppression on the postgadolinium images is also helpful (see cortical bone destruction while malignant compression fractures may
Fig. 6.26C).65 Tumor contains more water than fatty marrow and usually be associated with destruction of a pedicle, cortical, or cancellous
is relatively bright on fat-suppressed T2-weighted images (see Fig. 6.26B). bone. Biopsy may be necessary for definitive diagnosis.
On non-fat suppressed T2-weighted images tumor and fatty marrow can CSF dissemination of tumor to the leptomeninges occurs in a num-
have very similar signal intensities and can be difficult to distinguish. ber of childhood and adult malignancies. The leptomeningeal spread
Osteoblastic metastases are dark on both T1- and T2-weighted images. can be from drop metastases from a primary central nervous system
Several criteria have been described for MRI and CT findings to (CNS) malignancy or from systemic metastatic disease. Diagnosis
distinguish benign and malignant compression fractures. Osteoporotic can be made both with MRI and myelography and postmyelography
compression fractures are low signal intensity on T1-weighted images CT. On MRI the pial surface of the spinal cord can display nodular
in the acute phase, but typically return to normal over the course of or linear enhancement and the contour of the cord can be irregular.
4–6 weeks. Malignant compression fractures remain low signal inten- Extensive covering of the pial surface has been called ‘sugar-coating’
sity indefinitely unless treated with radiation therapy. Malignant (Fig. 6.42). Tumor nodules can be seen on nerve roots (‘Christmas
compression fractures are more likely to have abnormal signal through- balls’). Contrast-enhanced MRI detects leptomeningeal metastases
out the entire vertebra and the posterior elements are more commonly in 50% of high-risk patients with initially negative CSF serology.101
involved. Epidural masses are common with malignant and uncommon
with benign compression fractures. Paravertebral masses are more Vertebral body hemangioma
The vertebral body hemangioma is the most common benign tumor of
the osseous spine. It is present in approximately 11% of population and
multiple in 4%.102 The tumor is composed of adult-type blood vessels
and is often an incidental finding on a CT or MRI scan performed for
unrelated reasons. The tumor may be a focal lesion or fill the entire
vertebral body and extend into the posterior elements. On plain films
the typical incidental hemangioma has a characteristic radiographic
appearance of prominent vertical striations within in vertebra that rep-
resent thickened bony trabeculae. These thickened bony trabeculae
have a characteristic spotted appearance on axial CT images. The bony
cortex is usually intact. MRI detects even small hemangiomas with
great sensitivity. The typical hemangioma is bright on both T1- and
T2-weighted images due to increased fat and water content. There
Fig. 6.41 Schwannoma. is variable enhancement after gadolinium administration. A fat-sup-
Axial cervical spine MRI pressed T2-weighted image will differentiate a hemangioma from focal
image demonstrates an fatty replacement. An occasional hemangioma can appear hypointense
expansile hyperintense on T1-weighted images and might be confused with another tumor
mass in the neural such as a metastasis. In case of uncertainty, a CT can demonstrate the
foramen (arrow). characteristic features of a hemangioma (Fig. 6.43C).

78
Section 3: General Diagnostic Technique

Fig. 6.42 Drop metastases from glioblastoma


multiforme. Sagittal T2-weighted lumbar spine
MRI image (A) demonstrates nodular tumor
deposits in the cauda equina (arrows). Contrast-
enhanced T1-weighted lumbar spine image
(B) shows diffuse, thickened enhancement of
the pial surface of the conus (arrowheads), linear
and nodular enhancement of the cauda equina,
A B and thickened, enhancing lumbar nerve roots
(arrows).

Most symptomatic or aggressive hemangiomas are located in tebral hemangiomas have been successfully treated with percutane-
the thoracic spine.103 Neurological deficits are produced by large ous vertebroplasty.79 Aggressive hemangiomas have been successfully
tumors that have epidural extension causing spinal canal stenosis or treated with percutaneous alcohol sclerotherapy.104
neural foraminal narrowing with resultant spinal cord or nerve root
compression (Fig. 6.43A, B). The epidural component usually has Osteochondroma
low signal intensity on T1-weighted images and enhances with gado- Osteochondromas are relatively rare in the spine in comparison to the
linium (Fig. 6.43B). Hemangiomas also cause painful compression long tubular bones. They commonly involve the lumbar or thoracic
fractures (Fig. 6.43A, C). Painful compression fractures due to ver- spine; the cervical spine is least often affected.105 These benign tumors

A B C

Fig. 6.43 Aggressive spinal hemangioma. Sagittal fat-suppressed T2-weighted MRI image (A) demonstrates a hyperintense vertebral and epidural
mass (arrows) and a superior endplate fracture. The vertebral, epidural (arrow), and paravertebral (arrowheads) mass enhances on an axial
postgadolinium T1-weighted MRI image (B). Sagittal helical CT image (C) demonstrates a superior endplate fracture and thickened, vertically
oriented trabeculae.

79
Part 1: General Principles

usually originate from the posterior elements, most commonly from the Chordoma
spinous process. A vertebral body origin is quite unusual. Symptoms The chordoma is an uncommon, slowly growing, locally invasive bone
are usually related to mass effect and compression of adjacent struc- tumor arising from primitive notochord cells. The tumor occurs most
tures. Conventional radiographs demonstrate an exophytic lesion that often in the clivus and the sacrum. The cervical spine is the next most
has direct contiguity with cortex of the native bone with a broad or common location. There is 2:1 male to female predominance. A chor-
pedunculate attachment. CT shows similar findings but can delineate doma can present at any age and there is no characteristic age peak.111
fibrous cap to better advantage. The lesion has a heterogeneous MRI Although the chordoma is histologically benign, it may behave in a
appearance due to it mixed bony and cartilaginous content. The car- malignant fashion and can even metastasize. Metastases are uncom-
tilaginous components are bright on T2-weighted images. The ossified mon in clival and sacral tumors, but are seen more often in verte-
components are dark on all pulse sequences. MRI can be useful to assess bral chordomas. Conventional radiographs demonstrate a destructive
mass effect in cases of spinal canal compromise. An osteochondroma osseous lesion with amorphous calcifications, which involves more
may occasionally undergo malignant degeneration into a chondrosar- then one vertebra in almost 50% of cases. CT is superior in dem-
coma. This is much more common in individuals with multiple lesions onstrating the bone destruction and calcified matrix.112 MRI is less
due to multiple hereditary exostosis disease. Features suspicious for sensitive for the bony details but can accurately depict epidural and
malignant degeneration include new pain, rapid growth, lytic changes, paravertebral extension. MRI signal characteristics are non-specific.
and disappearance of calcifications that were previously present.106 The tumor is usually hypo- or isointense on T1-weighted images and
hyperintense on T2-weighted images. Heterogeneity of signal may be
Osteoid osteoma due to calcifications, cystic changes, and prior hemorrhage.113
The spine is the second most common location for this benign lesion
following the metaphyses of long tubular bones. Osteoid osteomas Giant cell tumor
occur most often in the lumbar spine. They occur half as often in the
Giant cell tumor rarely occurs in the spine except for the sacrum. On
cervical spine and rarely in the thoracic spine. The lesion is confined
plain films the tumor appears as a lytic, expansile mass with a thinned
to the posterior elements 75% of the time. The lamina, articular pro-
bony cortex. CT is non-specific and reveals an expansile, hypodense
cesses, and pedicles represent the most typical sites of involvement.107
mass usually lacking internal calcifications. The MRI findings are also
There is a 2:1 to 4:1 male to female predominance. They occur in
non-specific. The tumor typically is hypointense on T1-weighted
adolescents and young adults, and are rarely seen after 30 years of
images, hyperintense on T2-weighted images, and enhances with gado-
age. Pain is the usual presenting symptom, classically described as
linium. Occasionally, the tumor may aggressively invade the surround-
occurring at night and relieved by aspirin. Unexplained focal pain in
ing soft tissues, mimicking a malignant neoplasm. MRI is the preferable
the region of the spine in a young individual without prior trauma
imaging modality to assess extension into the soft tissues.114
should raise the possibility of an osteoid osteoma.
Plain films can demonstrate a lytic lesion that can contain calci-
fications surrounded by sclerosis. Due to superimposition of differ- Aneurysmal bone cyst
ent structures on plain films, a small lesion can easily be overlooked. Aneurysmal bone cyst (ABC) is a benign osseous lesion usually diag-
In case of high clinical suspicion, a nuclear bone scan with SPECT nosed before 20 years of age. There is no clear sex predilection. The
imaging is a sensitive and cost-efficient way to make the diagnosis. If spine is a relatively common location. The typical presenting com-
a focal area of increased radiotracer uptake is detected in the bony plaint is pain. On occasion, patients present with findings caused by
spine, targeted CT is performed to better characterize this finding. spinal cord or nerve root compression. The posterior elements are
The CT typically reveals a well-defined focal hypodensity in the involved in the majority of cases; however, involvement of the ver-
posterior elements measuring less than 1.5 cm in diameter representing tebral body is also common (Fig. 6.44). Less than 25% of the lesions
the nidus. The nidus may contain internal calcifications and is usually extend into paraspinal soft tissues. Plain films show an expansile lytic
surrounded by bony sclerosis. Administration of intravenous contrast lesion with a thinned cortex; sometimes septations can be detected.
results in avid, prompt enhancement due to hypervascularity within
the nidus.108 MRI usually is not required, but if performed it dem-
onstrates a heterogeneous, well-defined lesion. Hypointense foci on
both T1- and T2-weighted sequences may be seen if calcifications are
present. Marked enhancement with gadolinium defines the nidus.

Osteoblastoma
The osteoblastoma is histologically similar to osteoid osteoma but is larger
in size; the tumor nidus measures more than 1.5 cm in diameter. It is a rare
benign bone lesion with clear predilection for the spine where it routinely
involves the posterior elements, most commonly the spinous process.108
It may occur in infants to the elderly with a 2:1 male to female predomi-
nance. Plain films usually demonstrate an expansile, well-defined lytic
Fig. 6.44 Aneurysmal
mass causing thinning of the cortex. Cortical destruction occurs fairly
bone cyst. Sagittal
often. Dense sclerotic margins can occasionally be seen. Radiographic T2-weighted thoracic
features suggest malignancy in 12% of the cases. The primary differential spine MRI reveals
diagnosis is osteosarcoma.109,110 CT will show similar findings. MRI signal a multiloculated,
characteristics are non-specific. Heterogeneous signal intensity is usually hyperintense,
observed due to the presence of calcifications and intratumoral blood expansile mass in the
products. Tumor extension within the spinal canal and paraspinal soft posterior elements and
tissues is better defined on MRI. in the vertebral body.

80
Section 3: General Diagnostic Technique

CT demonstrates the same findings but can also demonstrate any nantly hyperintense on T2-weighted images with enhancement after
soft tissue extension. Septations and a multilocular appearance may gadolinium administration.121
be evident on CT; fluid levels sometimes can be seen in several com-
partments, which is highly suggestive of an ABC. MRI more read- Leukemia
ily demonstrates the septations and multiple fluid levels of different
signal intensities due to presence of blood products of different age. Leukemia is the most common malignancy in children; however,
These findings correlate well with the histopathologic composition, adults of different ages are also commonly affected. Acute lympho-
which consists of several cavernous spaces filled with blood prod- blastic leukemia is predominant in children and constitutes about
ucts. MRI often demonstrates a thin, dark rim around the lesion on 80% of all cases.122 Imaging studies, plain radiographs, and CT dem-
T1-weighted images. Enhancement of the septae after gadolinium onstrate osteopenia/osteoporosis throughout the spine, sometimes
administration is generally seen.115 with compression fractures. Extreme compression deformity of
the vertebral body (vertebra plana) sometimes can be seen. Lucent
bands within the vertebrae may be present. Sclerotic foci occasion-
Osteosarcoma ally can be noted.123 MRI clearly demonstrates diffuse bone marrow
Primary osteosarcoma of the spine is rare; although overall it is the signal abnormality, dark on T1- and bright on T2-weighted images,
most common primary malignant neoplasm of the bone. It is usually due to the replacement of fatty bone marrow by leukemic cells.
diagnosed in adolescents and young adults. There is approximately a Enhancement with gadolinium is a common feature.124 An unusual
2:1 male predilection.116 Osteosarcoma of the spine has non-specific presentation of myelogenous leukemia (chloroma) can occur in the
appearances on all imaging studies. Plain radiographs show a lytic or spine as an expansile mass often extending into the soft tissues and
mixed lytic/sclerotic lesion sometimes with disruption of cortex. CT typically isointense on T1-weighted images.
can better delineate bony changes including cortical interruption as
well as calcified bony matrix and periosteal reaction if present.117 MRI
Lymphoma
usually demonstrates a heterogeneous mass that is hypointense on T1-
weighted and predominantly hyperintense on T2-weighted images. Primary non-Hodgkin’s lymphoma can involve the spine, but met-
The tumor enhances after gadolinium administration. Extension astatic lesions from primary lymphoma elsewhere in the body are
into the spinal canal and paravertebral soft tissues can be appreci- much more common. Non-Hodgkin’s lymphoma most commonly
ated on MRI.118 Metastatic disease to the spine from osteosarcoma occurs in middle-aged and elderly patients. It is two times more
elsewhere in the body is much more common than primary vertebral common in men. In primary spinal lymphoma plain radiographs
osteosarcoma. usually demonstrate lytic or permiative bone destruction, though
occasionally sclerotic areas may be seen. CT findings are concordant
with plain films. MRI typically shows T1 hypointensity within the
Chondrosarcoma involved bone marrow. The T2-weighted images can demonstrate
Chondrosarcoma is a malignant bone neoplasm arising from carti- slightly hyperintense, isointense, or even hypointense signal charac-
lage. The majority of cases involve middle-aged individuals. Males teristics as in other hypercellular tumors.125
are involved two times more often than females. Chondrosarcoma
can arise as primary lesion or as a result of malignant transformation Ganglioneuroma, ganglioneuroblastoma and neuroblastoma
of a benign cartilage-containing tumor such as an osteochondroma or
enchondroma. The spine is rarely a primary site of chondrosarcoma. Ganglioneuroma, ganglioneuroblastoma, and neuroblastoma consti-
The cervical spine and cervicothoracic junction are involved in about tute a group of tumors originating from primitive neural crest tumors
40% of cases. Conventional radiographs show a lytic destructive and differ by degree of cell differentiation, ganglioneuroma being the
lesion often containing calcified matrix. Radiographic differentiation most benign. These tumors are seen almost exclusively in children.
from osteosarcoma can be difficult. CT is excellent for depiction Adrenal origin is most common, followed by paraspinal tumors aris-
of bony details, cortical breakthrough, and nature of the calcifica- ing from the sympathetic chain ganglia. The cervical spine is affected
tions. Soft tissue extension can be seen on CT, but MRI is the best much less commonly than lumbar and thoracic spine.126 Because of
imaging modality to assess paraspinal and epidural involvement. The their paraspinal location, these tumors can grow through the neural
tumor usually appears as a heterogeneous mass predominantly hypo- foramina into the spinal canal, causing impingement on the thecal
intense on T1-weighted and hyperintense on T2-weighted images. sac, and sometimes grow into the epidural space. Plain radiographs
Intratumoral calcifications and blood products from prior hemor- can demonstrate a paraspinal mass. Several radiographic features are
rhage contribute to heterogeneity. Enhancement with gadolinium is suggestive of tumor extension into the spinal canal through a neural
commonly present. foramen, including widening of the neural foramen, erosion of the
pedicle, and widening of the spinal canal. Other radiographic findings
include thinning and scalloping of the ribs, widening of the intercos-
Ewing’s sarcoma tal distance, and scalloping of the vertebral body. CT provides addi-
Ewing’s sarcoma is a primary bone malignancy predominantly affect- tional information regarding the bony changes and also demonstrates
ing children and young adults. Spine involvement is rare, but spinal the tumor and its relationship with adjacent structures. Extension of
metastases from the distant tumor in the long or flat bones are quite the tumor into the spinal canal can be seen on CT, but differentia-
common.119,120 Plain radiographs demonstrate lytic changes, often tion of the tumor from spinal cord can be difficult. MRI is best to
permiative destruction, and cortical disruption. Periosteal reaction evaluate for tumor extension into the spinal canal and epidural space
is commonly present, sometimes with characteristic ‘onion peel’ and is crucial for surgical planning. Neuroblastoma is usually of low
appearance. CT can show the same findings to better advantage plus signal intensity on T1-weighted images and low to intermediate sig-
presence of soft tissue mass. MRI can excellently demonstrate extent nal intensity on T2-weighted images because of its hypercellularity
of the tumor within the bone and surrounding soft tissues as well and low water content. Heterogeneity may be seen due to areas of
as epidural disease, but signal characteristics are quite non-specific: necrosis, hemorrhage, and intratumoral calcifications. These tumors
hypointense on T1-weighted images and heterogeneous but predomi- usually enhance after gadolinium administration. The spinal cord

81
Part 1: General Principles

may have abnormal signal when compressed by tumor within the based on the clinical course of disease. ADEM is a monophasic illness
spinal canal.127 while MS typically has recurrent episodes.

Multiple sclerosis Sarcoidosis


Multiple sclerosis (MS) is a demyelinating disease of the CNS that Sarcoidosis is granulomatous disease of unknown etiology, which can
most commonly affects young to middle-aged adults with a female affect almost any organ or system. The lungs are the most commonly
predominance, but it can occur at any age and occasionally devel- affected sites, although patients often remain asymptomatic when lung
ops in children and in the elderly. The brain is the most commonly involvement is detected on a chest X-ray performed for unrelated rea-
affected site, often accompanied by spinal lesions. Isolated involve- sons. CNS involvement (neurosarcoidosis) is present in approximately
ment of the spinal cord occurs in 5–24% of cases.128–130 There is no 5% of patients. Neurosarcoidosis is a great mimicker, as it can involve
direct correlation between the radiographic appearance of MS and both the brain and its coverings with different radiographic presenta-
the clinical condition of the patient. More then 50% of detected tions. Primary involvement of the spinal cord is rare.135 Only 6–8%
spinal cord lesions are located in the cervical spine. A single lesion of patients with neurosarcoidosis have spinal cord involvement, most
is visualized more commonly than multiple plaques.131 The typical commonly in the cervical region. Nodules may be present on the pial
MS plaque in the spinal cord is peripherally located, involves both surface mimicking tumor deposits. Intramedullary lesions are usually
gray and white matter and spans less then 2 vertebral bodies in its bright on T2-weighted images with patchy enhancement postgadolin-
vertical extent. Expansion or atrophy of the spinal cord is seen in ium and commonly associated with focal expansion of the cord. Pial
minority of cases. T2-weighted sequences are superior for detection enhancement is often present and in the appropriate clinical setting
of MS lesions. Unenhanced T1-weighted sequences are not sensi- can help establish a diagnosis.136
tive for MS plaques and usually appear normal. T2-weighted images
demonstrated a hyperintense lesion eccentrically located within the Behçet’s syndrome
cord (Fig. 6.45A). An FSE T2-weighted pulse sequence is almost Behçet’s syndrome is uncommon disease characterized by recurrent
as sensitive as a conventional T2-weighted spin echo sequence.132 ulcerations of the oral and genital mucosa, uveitis, and iridocyclitis.
Fast STIR images can sometimes detect additional lesions not clearly Involvement of CNS is present in less then 50% of cases and occa-
seen other sequences.133 Approximately 56% of spinal cord plaques sionally can be the only manifestation of disease. Involvement of
seen on MRI enhance after gadolinium contrast administration spinal cord is less common than the brain and usually demonstrates
(Fig. 6.45B).131 non-specific T2-hyperintense intramedullary lesions that are not
visible on T1-weighted images; some lesions may enhance with gado-
linium. Focal cord expansion or atrophy can be present depending on
Acute disseminated encephalomyelitis chronicity of the process.137
Acute disseminated encephalomyelitis (ADEM) is an acute mono-
phasic CNS inflammatory demyelinating process that usually follows Systemic lupus erythematosus
a viral infection or a vaccination, although sometimes the underlying
Systemic lupus erythematosus (SLE) can affect almost any organ or
etiology (possibly a subclinical infection) cannot be identified. The
system and the CNS is not an exception. SLE is 8 times more com-
brain is affected much more commonly than the spinal cord. Spinal
mon in females. Transverse myelitis is a rare complication of SLE.
cord symptoms usually manifest as an acute transverse myelitis. On
Transverse myelitis usually occurs in patients with positive antiphos-
MRI, the spinal cord lesions are undistinguishable from MS plaques.
pholipid antibodies. Radiologic findings in SLE-induced transverse
The lesions are bright on T2-weighted images, commonly enhance
myelitis are non-specific and include bright signal abnormality within
with gadolinium, and can cause cord expansion. T1-weighted images
the spinal cord on T2-weighted sequences with possible cord expan-
usually are normal.134 Differentiation between MS and ADEM is
sion and enhancement.138

Fig. 6.45 Spinal cord multiple sclerosis. Sagittal


T2-weighted (A) and contrast-enhanced
T1-weighted (B) cervical spine MRI images reveal
A B an eccentric T2 hyperintense MS plaque with
peripheral curvilinear enhancement (arrows).

82
Section 3: General Diagnostic Technique

Radiation myelopathy
Radiation myelopathy is an uncommon complication of radiation
therapy. It usually occurs when a significant radiation dose is deliv-
ered to the structures adjacent to the spinal cord, and the spinal cord
cannot be excluded from the radiation port; the most typical exam-
ple is a radiation therapy for a nasopharyngeal carcinoma. There are
two distinctive time peaks for development of radiation myelopathy,
12–14 months and 24–28 months after the radiation treatment. A
larger radiation dose leads to earlier development of clinical symp-
toms.139 There are distinct histologic categories of radiation-induced
spinal cord abnormalities, including white matter parenchymal lesions
(type 1), primary vascular lesions (type 2), and a combination of both
(type 3). White matter abnormalities unusually demonstrate demy-
elination, while vascular lesions are characterized by hyalinization or
fibrinoid necrosis of vessel walls.140 In the acute phase of postradiation
myelopathy there is spinal cord edema, which appears hypointense
on T1-weighted and hyperintense on T2-weighted images. Areas of
necrosis may be seen in severe radiation injury. Spinal cord expansion
and enhancement with gadolinium may be present that sometimes
has an appearance of intramedullary neoplasm. Occasionally there is
extension of the signal abnormality above and below the level of radi-
ation exposure, which may be related to propagation of extravasated
fluid along the white matter tracts. In the chronic phase the signal
abnormalities may reverse and be replaced by cord atrophy.139

Gout
The spine is much less commonly involved with gout than the appen-
dicular skeleton. Spinal involvement usually occurs in long-standing
disease. Any area of the spine can be affected. Plain films are not
sensitive for detecting gout in the spine. CT can demonstrate bony
changes including erosions and soft tissue calcifications. MRI bet- Fig. 6.46 Syringo-
ter visualizes gouty tophi. The tophi are low to intermediate signal hydromyelia. Sagittal
intensity on T1-weighted images and heterogeneous, predominantly T2-weighted
hyperintense signal intensity on T2-weighted images. The tophi thoracic spine MRI
contain small, discrete, dark areas on all pulse sequences. Diffuse reveals extensive
syringohydromyelia.
or peripheral enhancement is seen. The tophi are typically juxta-
articular in location associated with joint erosions.141

Neurenteric cyst
Syringohydromyelia
The neurenteric cyst (enterogenous cyst) is caused by inclusion of
Syringohydromyelia refers to CSF-filled cavities within the spinal endodermal elements in the spinal canal during embryogenesis. Most
cord (Fig. 6.46). Cystic dilatation of the central canal is called hydro- are intradural-extramedullary in location although rare intramedul-
myelia, whereas fluid cavities within the cord parenchyma are called lary neurenteric cysts occur. They are typically positioned ventral or
syringomyelia. Since it is often difficult to make this distinction on ventrolateral to the spinal cord with variable dural attachment. There
the basis of the imaging appearance, the general term syringohydro- may be communication with an extraspinal component. Vertebral
myelia (syrinx) is often used to include all CSF-containing cystic anomalies are often associated. On MRI, a smooth unilocular CSF
cavities within the spinal cord. signal intensity cyst is typically seen ventral to the cord, possibly dis-
Hydromyelia most commonly occurs in association with con- placing and compressing it. High protein concentration in the cyst
genital malformations, most commonly the Chiari malformations. may increase the signal on T1-weighted images. The neurenteric cyst
Other causes include narrowing of the foramen magnum second- does not enhance, distinguishing it from a neoplasm.143
ary to achondroplasia and tumor. Syringomyelia can be caused by
intramedullary tumors, trauma, ischemia, and arachnoiditis or may
be idiopathic. Arachnoid cyst
On MRI, syringohydromyelia appears as a cystic intramedullary col- Spinal arachnoid cysts are rare causes of spinal cord or nerve root
lection that usually has CSF signal intensity on all pulse sequences compression. The cysts may be intradural or extradural in location;
(Fig. 6.46). A high protein concentration can increase the signal inten- intradural cysts are less common. Both forms can present with back
sity on T1-weighted images. Benign syringes are typically fusiform in pain, sensory changes, weakness, and bowel or bladder dysfunction.
shape, with tapered proximal and distal margins. Tumor syringes are The severity of symptoms often varies dramatically with changes in
frequently more rounded or oval in shape. The cavities can be mul- posture. A fluctuating clinical course with remissions and exacerba-
tiple and can be incompletely septated, appearing beaded (Fig. 6.46). tions is common, and can be confused with multiple sclerosis.144,145
Gliotic changes may be present at the ends of the syrinx. Gadolinium- Intradural spinal arachnoid cysts affect men and women equally,
enhanced images are essential to look for any underlying tumor.142 usually presenting in the third to fifth decade. The majority (80%)

83
Part 1: General Principles

are located in the thoracic spine, typically posterior to the spinal cord. other dermal components including hair follicles, sebaceous and sweat
They may be single or multiple. A number of etiologies have been glands. Most of these cysts are intradural-extramedullary in location;
proposed, including congenital, inflammation (arachnoiditis), and pre- they occur most commonly in the lumbar spine. Their MRI appearance
vious surgery or trauma. Plain films are usually normal. On myelogra- is variable. Dermoids typically are bright on T1-weighted images due to
phy and postmyelography CT the cysts may demonstrate immediate fatty elements and are heterogeneous in appearance. Epidermoids are
filling with contrast, delayed filling (12–24 hours), or may never fill. often iso- to hyperintense to CSF on T1-weighted images and are vari-
Cysts that fill immediately may be difficult to visualize. On MRI, the ably iso- to hyperintense to CSF on T2-weighted images. MRI cannot
cysts are isointense to CSF on all pulse sequences and can be difficult reliably differentiate between dermoid and epidermoid cysts.142,146
to discriminate from the normal subarachnoid space. Absence of pul-
sation artifact within the cyst may help identify it. Sagittal views can Tarlov (perineural) cysts
show anterior displacement of the spinal cord with possible flattening,
Tarlov or perineural cysts are nerve root lesions that occur most
and widening of the posterior CSF space (Fig. 6.47).144
frequently in the sacrum. Tarlov first described them in 1938. The
Extradural arachnoid cysts are the result of a congenital defect in
cysts arise from the junction of the dorsal ganglion and nerve root
the dura through which the arachnoid membrane herniates. These
between the endoneurium and perineurium. Possible etiologies
cysts have a connection (pedicle) with the subarachnoid space. They
include increased hydrostatic pressure and trauma. Most are asymp-
occur most often in the mid- to lower thoracic spine and less com-
tomatic and are incidentally detected, although symptomatic Tarlov
monly in the lumbar spine lying posterior or posterolateral to the
cysts occur rarely. On myelography and postmyelography CT there
thecal sac. There is a 2:1 male predominance; they usually present in
is delayed filling of the cyst with contrast reflecting the absence of
the second decade. Plain films typically show widening and erosion
a direct connection with the subarachnoid space; this delayed filling
of the spinal canal, erosion of pedicles, foraminal enlargement, and
differentiates the Tarlov cyst from a meningeal diverticulum. Sacral
vertebral body scalloping. On myelography and postmyelography CT
foramina are enlarged on plain films and CT. The cysts are isoin-
there is an extradural mass that fills with contrast. If the connecting
tense to CSF on all MRI pulse sequences. Patients with neurological
pedicle is narrow the filling may be delayed. MRI demonstrates an
deficits related to Tarlov cysts larger than 1.5 cm in diameter may
extradural mass posterior or posterolateral to the thecal sac that is
benefit from surgical resection of the cyst wall.147
isointense to CSF on all pulse sequences. The thecal sac is displaced
anteriorly and compressed. The cyst abuts the epidural fat at the
cranial and caudal margins.145 Transdural spinal cord herniation
Transdural spinal cord herniation is rare and may occur spontaneously,
Dermoid and epidermoid cysts after surgery, or following trauma. Patients can present with myelop-
Dermoid and epidermoid cysts are rare spinal tumors that result from athy, radiculopathy, sensory deficits, and Brown-Sequard syndrome.
inclusion of ectodermal cells during neural tube closure between the MRI demonstrates a locally displaced spinal cord with a dilated sub-
third and fifth weeks of embryogenesis. They can also result from arachnoid space opposite the herniation. Associated intramedullary
implantation of cells during lumbar puncture and surgery. Epidermal high signal on T2-weighted images, a vertebral body nuclear trail sign,
cells line the wall of epidermoid cysts while dermoids also contain and syringohydromyelia have been reported.148 The imaging appear-
ance of a transdural spinal cord herniation can be confused with an
arachnoid cyst.

Spinal vascular lesions


Spinal vascular lesions can be categorized into vascular neoplasms
(hemangioblastoma, cavernous malformation), aneurysms, and arte-
riovenous lesions. Varied nomenclatures for arteriovenous lesions
have been proposed. Spinal vascular malformations have been divided
into type I (spinal dural arteriovenous fistula), type II (intramedul-
lary arteriovenous malformation), type III (combined intradural and
extradural or juvenile arteriovenous malformation), and type IV (spi-
nal cord arteriovenous fistula). A more recent modified classification
scheme divides these arteriovenous lesions into arteriovenous fistulas
(direct arteriovenous connection without an intervening nidus) and
arteriovenous malformations (containing a vascular nidus), with sub-
divisions of these broad categories. Arteriovenous fistulas are subdi-
vided into extradural, intradural-ventral, and intradural-dorsal types.
Arteriovenous malformations are subdivided into extradural-intradu-
ral and intradural types. The intradural arteriovenous malformations
are further categorized as intramedullary compact, intramedullary
diffuse and conus medullaris arteriovenous malformations.149
The spinal dural arteriovenous fistula (type I arteriovenous malfor-
mation, intradural dorsal arteriovenous fistula) is the most common
spinal vascular malformation and most controversial in terms of etiol-
ogy, pathophysiology, diagnosis, and treatment.149 A fistula forms in a
Fig. 6.47 Spinal arachnoid cyst. Sagittal T2-weighted thoracic spine MRI spinal dural nerve root sleeve supplied by a branch of the correspond-
images demonstrate a CSF intensity expansile cystic mass dorsal to the ing radiculomedullary artery with arterialized venous drainage into
spinal cord remodeling the posterior elements. the coronal venous plexus surrounding the spinal cord. Lower thoracic

84
Section 3: General Diagnostic Technique

and upper lumbar nerve root sleeves are the most common locations, Intramedullary spinal cord arteriovenous malformations (type
although the fistula can form in any spinal nerve root sleeve. Multiple II arteriovenous malformations) are supplied by branches of the
feeding arteries can occur. This lesion typically presents in the fifth to anterior and posterior spinal arteries.149 There is an intraparenchy-
sixth decade of life with a strong (>5:1) male predominance and is mal nidus (compact or diffuse) drained by the spinal veins. The
often associated with intervertebral osteochondrosis, suggesting it is angioarchitecture is similar to brain arteriovenous malformations.
acquired. Venous hypertension induced in the coronal venous plexus Intranidal or feeding artery aneurysms may be present. These lesions
induces progressive myelopathy (spinal cord edema, ischemia, and usually present acutely secondary to intraparenchymal hemorrhage.
eventual infarction) known as the Foix-Alajouanine syndrome. Compression-induced myelopathy and progressive myelopathy due to
Clinically, these patients typically present with an insidious, slowly vascular steal also occur. Diagnosis on MRI is usually straightforward.
progressive myelopathy that results in severe disability if not treated Prominent, tortuous feeding and draining vessels and a vascular nidus
by endovascular or surgical obliteration. Neurological deterioration that contain flow voids and enhancement are visible. Conventional
is usually not reversible, so an expedient diagnosis is essential. This angiography is usually necessary for complete characterization.
diagnosis can be challenging since the clinical presentation can mimic Extradural-intradural arteriovenous malformations (juvenile,
other spine disorders such as degenerative disc disease and the imag- metameric, type III arteriovenous malformations) are rare lesions
ing findings can be subtle. On MRI, the spinal cord can be normal in that do not respect tissue boundaries and typically involve the spi-
size or enlarged. Intramedullary high signal intensity on T2-weighted nal cord, vertebral body, and extraspinal structures.149 They usually
images is typically but not invariably visible (Fig. 6.48A). Peripheral become symptomatic during childhood or adolescence and require
T2-weighted hypointensity in the spinal cord can be seen and may a multidisciplinary approach to treatment, and have a poor progno-
increase the specificity for the diagnosis of venous hypertension.150 sis. Extensive involvement of the spinal cord, spine, and surrounding
Prominent vessels along the dorsal aspect of the spinal cord are usu- structures is typically seen on MRI.
ally but not always visible (Fig. 6.48A, B). These vessels and the spi- The spinal cord arteriovenous fistula (type IV arteriovenous mal-
nal cord can enhance (Fig. 6.48B). All patients with an otherwise formation) is an intradural ventral arteriovenous fistula located on
unexplained progressive myelopathy and any suggestive MRI findings the anterior pial surface comprised of a direct arteriovenous connec-
should undergo a comprehensive spinal angiogram that includes all tion involving the anterior spinal artery and an enlarged venous net-
intercostal and lumbar segmental arteries, and the subclavian, ver- work.149 Clinical presentations include progressive myelopathy and
tebral, thyrocervical, costocervical, median sacral, and internal iliac acute subarachnoid hemorrhage. MRI demonstrates prominent pial
arteries. vessels with flow voids without a parenchymal nidus.

Fig. 6.48 Spinal dural fistula. Sagittal T2-weighted


(A) and contrast-enhanced T1-weighted
(B) thoracic spine MRI images demonstrate
multiple serpiginous tubular T2 flow voids with
enhancement dorsal to the spinal cord consistent
with pathologically enlarged perimedullary veins
(arrows), and thoracic spinal cord T2-hyerintensity
A B and enhancement caused by venous hypertension
and interstitial edema (arrowheads).

85
Part 1: General Principles

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127. Siegel MJ, Jamroz GA, Glazer HS, et al. MR imaging of intraspinal extension of aging and clinical spectra [see comment]. Am J Neuroradiol 1998; 19(7):1337–
neuroblastoma. JComput Assist Tomogr 1986; 10(4):593–595. 1344.
128. Honig LS, Sheremata WA. Magnetic resonance imaging of spinal cord lesions in 149. Spetzler RF, Detwiler PW, Riina HA, et al. Modified classification of spinal cord
multiple sclerosis. J Neurol Neurosurg Psychiatr 1989; 52(4):459–466. vascular lesions [see comment]. J Neurosurg 2002; 96(2 Suppl):145–156.
129. Tartaglino LM, Friedman DP, Flanders AE, et al. Multiple sclerosis in the spinal 150. Hurst RW, Grossman RI. Peripheral spinal cord hypointensity on T2-weighted MR
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195(3):725–732. Am J Neuroradiol 2000; 21(4):781–786.

88
PART 1 GENERAL PRINCIPLES
Section 3 General Diagnostic Technique

CHAPTER
Nuclear Medicine Imaging
7 With an Emphasis on Spinal Infections
Christophe Van de Wiele

tive nuclei, will combine with an electron from the surroundings and
INTRODUCTION annihilate it. Upon annihilation, both the positron and the electron
Nuclear medicine imaging assesses pathophysiologic processes such are then converted to electromagnetic radiation in the form of two
as regional perfusion, permeability, accumulation of white blood high-energy photons which are emitted 180 degrees away from each
cells, bone turnover, etc. These processes precede morphological other. It is this annihilation radiation that can be detected externally
changes as assessed by radiologic imaging. As such, it accounts for and is used to measure both the quantity and the location of the
the high sensitivity of nuclear medicine procedures, but also for the positron emitter. Simultaneous detection of two of these photons by
low specificity in differential diagnosis of different diseases with detectors on opposite sides of an object places the site of the anni-
similar pathophysiologic characteristics. As an established infection- hilation on or about a line connecting the centers of the two oppos-
imaging modality, nuclear medicine plays a vital healthcare role in ing detectors. At this point, mapping the distribution of annihilations
the diagnosis and subsequent effective treatment of infection of the by computer is conducted. If the annihilation originates outside the
spine. Various radiopharmaceuticals have been shown to significantly volume between the two detectors, only one of the photons can be
aid diagnosis of infection of the spine: single photon emitting agents detected, and since the detection of a single photon does not satisfy
for single photon emission computerized tomography (SPECT), the coincidence condition, the event is rejected. Since radioisotopes
bone scanning agents, 111In-oxine-, 99mTc-hexamethylpropyleneamine suitable for PET have a short half-life (e.g. 110 min for 18F), an on-site
oxime-, and 99mTc-stannous fluoride colloid-labeled leukocytes, 99mTc- cyclotron is needed for production of such isotopes.4
Fanolesmab and 67Ga-citrate; and more recently 18fluorodeoxyglu- Special radiosynthesis facilities are required, restricting the avail-
cose (FDG) for positron emission tomography (PET). This chapter ability of noncommercially available PET radiopharmaceuticals
describes and evaluates available data on FDG PET for assessment of to specialized centers. In contrast to PET, the synthesis of SPECT
infection of the spine as opposed to SPECT and radiologic examina- radiopharmaceuticals is much less expensive. As the half-lifes of the
tions. First, technical aspects of PET and SPECT are described fol- isotopes used in SPECT are longer than those of isotopes used in
lowed by a brief overview of routinely available radiopharmaceuticals PET (hours versus minutes), longer acquisition times are possible in
of relevance for imaging infection of the spine. Subsequently, results SPECT. On the other hand, the resolution of a conventional PET
obtained in clinical studies are described. camera is twice as good as that of a conventional gamma camera
and PET allows for more accurate quantification when compared to
PET AND SPECT SPECT.

The gamma camera or SPECT camera is a camera that is able to


detect scintillations (flashes of light) produced when gamma rays,
resulting from radioactive decay of single photon emitting radioiso-
RADIOPHARMACEUTICALS
topes, interact with a sodium iodide crystal at the front of the camera. AND METHODOLOGY
The scintillations are detected by photomultiplier tubes, and while
the areas of crystal seen by tubes overlap, the location of each scin-
99m
Tc-MDP/HDP
tillation can be computed from the relative response in each tube.1 Bone scintigraphy makes use of 99mTc-labeled organic analogues of pyro-
The energy of each scintillation is also measured from the response phoshate which are characterized by P-C-P bonds and predominantly
of the tubes, and the electrical signal to the imaging computer con- absorb at kinks and dislocation sites on the surface of hydroxyapatite
sists of the location and photon energy. In front of the crystal resides crystals. The most commonly used diphosphonate agents are 99mTc
a collimator which is made of lead and usually manufactured with hydroxyethylene diphosphonate (99mTc HDP) and 99mTc methylene
multiple elongated holes (parallel-hole collimator). The holes allow diphosphonate (99mTc MDP). The major physiologic determinants of
only gamma rays that are traveling perpendicularly to the crystal face bone uptake of these phosphate agents are the rate of bone turnover
to enter. The gamma photons absorbed by the crystal therefore form and blood flow, and the bone surface area involved.5 When performed
an image of the distribution of the radiopharmaceutical distribution for osteomyelitis, the study is usually done in three or four phases.
in front of the camera. By rotating the camera around the patient and Three-phase bone imaging consists of a dynamic imaging sequence,
acquiring images at different angles, tomographic images, or SPECT the flow or perfusion phase, followed immediately by static images
images, can be generated through the use of specific reconstruction of the region of interest, which is the blood-pool or soft-tissue phase.
algorithms.2 The third, or bone phase, consists of planar static images of the area
As with SPECT, PET relies on computerized reconstruction pro- of interest, acquired 2–4 h later. SPECT is performed when deemed
cedures to produce tomographic images, but by means of indirectly necessary by the nuclear medicine physician. The usual injected dose
detecting positron emission.3 Positrons, when emitted by radioac- for adults is 740–925 MBq (20–25 mCi) of 99mTc-MDP. The nor-

89
Part 1: General Principles

mal distribution of this tracer, by 3–4 h after injection, includes the IgG1 (Granuloscint; CISBio International) that binds to non-specific
skeleton, genitourinary tract, and soft tissues.6 cross-reactive antigen-95 present on neutrophils. Studies generally
become positive by 6 h after injection; delayed imaging at 24 h may
increase lesion detection.11 Another agent that has been investigated is
67
Ga
a murine monoclonal antibody fragment of the IgG1 class that binds to
67
Ga-citrate has been used for localizing infection for more than three normal cross-reactive antigen-90 present on leukocytes (LeukoScan;
decades. 67Ga, which is cyclotron produced, emits 4 principal rays Immunomedics). Sensitivity and specificity of this agent range from
suitable for imaging: 93, 184, 296, and 388 keV. Several factors gov- 76% to 100% and from 67% to 100%, respectively.12
ern uptake of this tracer in inflammation and infection. When injected
intravenously, 67Ga binds primarily to transferrin a β-globulin respon- 18
sible for transporting iron. Increased blood flow and increased vascu-
F FDG
18
lar membrane permeability associated with inflammation/infection Fluorodeoxyglucose is a fluorinated glucose analogue that, like glu-
result in increased delivery and accumulation of transferrin-bound cose, passes through the cell membrane. Following subsequent phos-
67
Ga at inflammatory foci. At the site of infection or inflammation, phorylation by glucose-6-hexokinase it is trapped within the cell.13–15
67
Ga can then bind to lactoferrin, which is present in high concentra- Although FDG PET is reported to be a sensitive and specific tech-
tions in inflammatory foci, attach to leukocytes, or may be directly nique in oncological imaging, it is well known that inflammatory and
taken up by bacteria. Siderophores, low molecular weight chelates infectious lesions can cause false-positive results.16 Various types of
produced by bacteria, have a high affinity for 67Ga. The siderophore– inflammatory cells such as macrophages, lymphocytes, and neutro-
67
Ga complex is presumably transported into the bacterium, where phil granulocytes as well as fibroblasts have been shown to avidly take
it remains until phagocytosed by macrophages.7 Imaging is usually up FDG, especially under conditions of activation. It even appears
performed 18–72 h after injection of 185–370 MBq of 67Ga-citrate. that on autoradiography, the FDG distribution in certain tumors is
The normal biodistribution of 67Ga, which can be variable, includes highest in the reactive inflammatory tissue, i.e. the activated macro-
bone, bone marrow, liver, genitourinary and gastrointestinal tracts, phages and leukocytes surrounding the neoplastic cells.7,8
and soft tissues.7
INFECTION OF THE SPINE
Radiolabeled leukocytes Vertebral infection represents 2–4% of all cases of osteomyelitis
Neutrophils concentrate in large numbers, up to 10% of the total and its incidence is increasing.17 In order to prevent clinically sig-
number of neutrophils per day, at sites of infection. Their accumu- nificant consequences which include neural compromise and late
lation is stimulated by the presence of lactoferrin, local neutrophil spinal deformities, early diagnosis and prompt treatment are essen-
secretions, and chemotactic peptides. Several techniques for in vitro tial. Causative pyogenic microorganisms in decreasing order of fre-
radiolabeling of isolated leukocytes have been reported; the most com- quency are Staphylococcus aureus, Streptococcus and Pneumococcus
monly used procedures make use of the lipophilic compounds 111In- and Gram-negative bacteria.18 Tuberculous spondylitis is an impor-
oxyquinoline (oxine) and 99mTc hexamethyl propyleneamine oxine tant form of nonpyogenic granulomatous infection. The routes of
(HMPAO).8 The lipophilic oxine binds bi- and trivalent ions such spinal infection include hematogenous spread, postoperative infec-
as 111In. Following diffusion of 111In-oxine across the cell membrane, tions, direct implantation during spinal punctures, and spread from a
111
In is released from oxine, which leaves the cell and binds intracel- contiguous focus.
lularly. HMPAO forms a small neutral lipophilic complex with 99mTc
that readily crosses the cell membrane and changes into a secondary
hydrophilic complex that is trapped in cells. The radiolabeling pro-
Acute osteomyelitis and spondylodiscitis
cedure takes about 2–3 h. The usual dose of 111In-labeled leukocytes The combination of physical examination and biochemical alterations
is 10–18.5 MBq (300–500 μCi); the usual dose of 99mTc-HMPAO- in combination with three-phase bone scanning, and especially MRI,
labeled leukocytes is 185–370 MBq (5–10 mCi). A total white count have a high sensitivity (>90%) for the detection of acute osteomy-
of at least 2000/mm3 is needed to obtain satisfactory images. Usually, elitis and spondylodiscitis.19–21 Accordingly, in the absence of compli-
the majority of leukocytes labeled are neutrophils, and hence the cating factors, the added value of scintigraphic imaging techniques
procedure is most useful for identifying neutrophil-mediated inflam- will be limited. Nevertheless, FDG PET especially may have a role
matory processes, such as bacterial infections. The procedure is less in doubtful cases, albeit rarely. For instance, it may play a role in dif-
useful for those illnesses in which the predominant cellular response ferentiating spondylodiscitis from erosive degenerative disc disease, a
is other than neutrophilic, such as tuberculosis.9 At 24 h after injec- condition occasionally displaying a false-positive MRI and bone scan
tion, the usual imaging time for 111In-labeled leukocytes, the normal findings.20,22–24 When confronted with a negative PET scan in this
distribution of activity is limited to the liver, spleen, and bone mar- clinical situation, infection can be excluded.
row. The normal biodistribution of 99mTc-HMPAO-labeled leukocytes
is more variable. In addition to the reticuloendothelial system, activ- Chronic osteomyelitis
ity is also normally present in the genitourinary tract, large bowel
Patients with chronic osteomyelitis may present with a variety of
(within 4 h after injection), blood pool, and occasionally the gallblad-
symptoms, including localized bone and joint pain, erythema, swell-
der.10 The interval between injection of 99mTc-HMPAO-labeled leu-
ing, fevers, night sweats, etc. Laboratory tests, such as leukocyte
kocytes and imaging varies with the indication; in general, imaging is
count, estimated sedimentation rate, and C-reactive protein can be
usually performed within a few hours after injection.
helpful in diagnosis but lack sensitivity and specificity in low-grade
99m
infections.25–28 C-reactive protein is also useful for gauging response
Tc-labelled antibodies to therapy.
Considerable effort has been devoted to developing in vivo methods Many imaging modalities have been proposed for the noninva-
of labeling leukocytes using peptides and antigranulocyte antibodies/ sive evaluation of chronic osteomyelitis.29 Radiographs are helpful
antibody fragments. One method makes use of a murine monoclonal in the diagnosis and staging of the patient. However, changes are

90
Section 3: General Diagnostic Technique

often subtle. Conventional radionuclide scans can also be useful in evaluation due to the lack of histopathological data. The histopatho-
the diagnosis but do not aid in preoperative planning of resection. logical findings revealed osteomyelitis or inflammatory spondylitis
Combined three-phase bone scintigraphy and leukocyte scan has a in all 15 patients: seven patients had acute osteomyelitis and eight
good clinical accuracy (79–100%) when considering the peripheral patients had chronic osteomyelitis or inflammatory spondylitis. FDG
skeleton;19,30–35 however, its accuracy decreases (1) in low-grade PET yielded 15 true-positive results. However, the absence of nega-
chronic infections(lower sensitivity);25,27 (2) in the presence of tive findings in this series may raise questions concerning selection
periskeletal soft tissue infection due to the limited resolution of criteria.
conventional nuclear imaging (lower sensitivity and specificity); (3) De Winter et al. reported on 60 patients suffering from a vari-
in the central skeleton due to the presence of normal bone marrow ety of suspected chronic orthopedic infections.42 In this prospective
and the possibility of so-called ‘cold lesions’ (lower sensitivity and study, the presence or absence of infection was determined by surgi-
specificity);24,31–35 and (4) after trauma or surgery due to the presence cal exploration in 15 patients and long-term clinical follow-up in 28
of ectopic hematopoietic bone marrow (lower specificity). To avoid patients. As opposed to the study by Guhlmann et al., patients with
false-positive studies due to ectopic bone marrow, the combination of recent surgery were not excluded. Considering only those patients
leukocyte scanning with bone marrow scanning (99mtechnetium sul- with suspected chronic osteomyelitis, FDG PET was correct in 40 of
fur colloid) has been proposed.36 Congruency between leukocyte and 43 patients. There were three false-positive findings, 17 true-negative
bone marrow scanning indicates the presence of bone marrow, while findings, and no false-negative findings. This resulted in a sensitivity
the presence of a positive leukocyte scan and negative marrow scan of 100%, a specificity of 85%, and an accuracy of 93%. Two of three
suggests the presence of infection. Using this technique, diagnostic false-positive findings occurred in patients who had been operated on
accuracy of up to 96% has been reported. In the vertebral column, a recently (6 weeks and 4 months, respectively).
combination of bone and gallium scan has been proposed to improve Zhuang et al. studied the accuracy of FDG PET for the diagnosis
both sensitivity and specificity.37 However, the need for two or even of chronic osteomyelitis.43 Twenty-two patients with possible osteo-
three (bone scan/leukocyte scan/bone marrow scan or bone scan/gal- myelitis (5 in the tibia, 5 in the spine, 4 in the proximal femur, 4 in
lium scan) techniques is not practical, adds to the cost and patient the pelvis, 2 in the maxilla, and 2 in the feet) that underwent FDG
radiation dose, and is time consuming. PET imaging and in whom operative or clinical follow-up data were
Computed tomography is used to identify a sequestered infection available were included for analysis. The final diagnosis was made by
and for preoperative resection planning. Similarly, MRI is useful for surgical exploration or clinical follow-up during a 1-year period. FDG
surgical planning because it delineates intraosseous and extraosse- PET correctly diagnosed the presence or absence of chronic osteo-
ous involvement. CT and MRI are, however, of limited value in the myelitis in 20 of 22 patients but produced two false-positive results,
presence of metallic implants as well as for discriminating between respectively two cases of recent osteotomies, resulting in a sensitivity
edema and active infection after surgery.21,29,30 of 100%, a specificity of 87.5%, and an accuracy of 90.9%. It is, how-
Overall, in spite of the available armamentarium of imaging modal- ever, unclear from their report in how many patients histopathologic
ities, clinicians are often confronted with an indeterminate diagno- or microbiologic studies were available.
sis and the clinical strategy adopted is often limited to a ‘wait and Chako et al. retrospectively analyzed the accuracy of FDG PET for
see’ policy or empirical antibiotic treatment.25,38,39 Accordingly, novel diagnosing infection in a large population of patients and in a variety
imaging modalities with a very high accuracy for identification of of clinical circumstances, including suspicion of chronic osteomyelitis
sites of chronic osteomyelitis are of major interest. Several authors in 56 patients.44 Final diagnosis was made on the basis of surgical
have addressed the value of FDG PET for this purpose. Guhlman pathology and clinical follow-up for a minimum of 6 months. Among
et al. studied 51 patients suspected of having chronic osteomyelitis the patients suspected of having chronic osteomyelitis, the accuracy
in the peripheral (n=36) or central (n=15) skeleton prospectively was 91.2%.
with static FDG PET imaging and combined 99mTc-antigranulocyte
Ab/99m
Tc-methylene diphosphonate bone scanning within 5 days.40
Obtained images were evaluated in a blinded and independent man-
CONCLUSION
ner by visual interpretation, which was graded on a five-point scale Although limited, available data on FDG PET for imaging of the spine
of two observers’ confident diagnosis of osteomyelitis. Receiver oper- are promising, displaying a higher accuracy for diagnosing osteomy-
ating characteristic (ROC) curve analysis was performed for both elitis when compared to other imaging modalities for this purpose,
imaging modalities. The final diagnosis was established by means of including conventional nuclear medicine examinations. For instance,
bacteriologic culture of surgical specimens and histopathologic analy- in the study by Guhlman et al., comparing the combination of bone
sis (n=31) or by biopsy and clinical follow-up over 2 years (n=20). scan and leukocyte scan with FDG PET, the latter proved signifi-
Of 51 patients, 28 had osteomyelitis and 23 did not. According to the cantly more accurate for the diagnosis of osteomyelitis in the central
unanimous evaluation of both readers, FDG PET correctly identified skeleton. The fact that FDG PET is not disturbed by the presence of
27 of the 28 positives and 22 of the 23 negatives (IS identified 15 metallic implants and is able to differentiate between scar tissue and
of 28 positives and 17 of 23 negatives, respectively). On the basis of active inflammation constitutes a major advantage when compared to
ROC analysis, the overall accuracy of FDG PET and immunoscintig- CT and MRI. As opposed to radiolabeled leukocytes or radiolabeled
raphy in the detection of chronic osteomyelitis were 96%/96% and antibodies, FDG is likely to penetrate easier and faster in lesions than
82%/88%, respectively. cellular tracers or antibodies.45 Aside from the potential for higher
Kälicke et al. evaluated the clinical usefulness of fluorine-18 fluoro- sensitivity, taking into account available data, a negative PET scan
deoxyglucose positron emission tomography (FDG PET) in acute and virtually rules out osteomyelitis.42,44
chronic osteomyelitis and inflammatory spondylitis.41 The study pop- Initially, it was thought that the specificity of FDG PET for detec-
ulation comprised 21 patients suspected of having acute or chronic tion of infection of the spine may be limited by the fact that this
osteomyelitis or inflammatory spondylitis. Fifteen of these patients tracer also accumulates in benign lesions and tumors. More recent
subsequently underwent surgery. FDG PET results were correlated papers, however, focusing on fractures, hemangioma, Paget’s disease,
with histopathological findings. The remaining six patients, who and endplate abnormalities of and in the spine, tend to contradict
underwent conservative therapy, were excluded from any further this hypothesis. Following traumatic fracture or surgical intervention,

91
Part 1: General Principles

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43. Zhuang H, Duarte PS, Pourdehand M, et al. Exclusion of chronic osteomyelitis 50. Hatayama K, Watanabe H, Ahmed AR, et al. Evaluation of hemangioma by positron
with F-18 fluorodeoxyglucose positron emission tomography. Clin Nucl Med 2000; emission tomography: role in a multimodality approach. J Comput Assist Tomogr
25:281–284. 2003; 27:70–77.
44. Chacko TK, Zhuang H, Stevenson K, et al. The importance of the location of fluoro- 51. Stumpe KD, Zanetti M, Weishaupt D, et al. FDG positron emission tomography for
deoxyglucose uptake in periprosthetic infection in painful hip prostheses. Nucl Med differentiation of degenerative and infectious endplate abnormalities in the lumbar
Commun 2002; 23: 851–855. spine detected on MR imaging. Am J Roentgenol 2002; 179:1151–1157.

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PART 1 GENERAL PRINCIPLES
Section 3 General Diagnostic Technique

CHAPTER
Electrodiagnostic Approach to Patients
8 with Suspected Radiculopathy
Timothy R. Dillingham

INTRODUCTION C8, C7, and C5 radiculopathies. In subjects with C6 radiculopathies,


half the patients showed findings similar to those with C5 radicu-
Cervical and lumbosacral radiculopathies are conditions involving lopathies and the other half demonstrated C7 patterns. This surgical
a pathological process affecting the spinal nerve root. Commonly, group was more severely affected than patients who do not require
this is a herniated nucleus pulposus that anatomically compresses surgical interventions, and this pattern may not hold for less symp-
a nerve root within the spinal canal. Another common etiology for tomatic patients.
radiculopathy is spinal stenosis resulting from a combination of In the lumbar spinal region dorsal and ventral roots exit the spi-
degenerative spondylosis, ligament hypertrophy, and spondylolisthe- nal cord at about the T11–L1 boney level and travel in the lumbar
sis. Inflammatory radiculitis is another pathophysiological process canal as a group of nerve roots in the dural sac. This is termed the
that can cause radicular pain and/or radiculopathy. It is important ‘horse’s tail’ or cauda equina. This poses challenges and limitations
to remember, however, that other more ominous processes such as to the EMG examination. A destructive intramedullary (spinal cord)
malignancy and infection can present with the same symptoms and lesion at T11 can produce EMG findings in muscles innervated by
signs of radiculopathy as the more common causes. any of the lumbosacral nerve roots and manifest the precise findings
This chapter deals with the clinical approach used in an electrodi- on needle EMG as those seen with a herniated nucleus pulposus at
agnostic laboratory to evaluate a person with neck pain, lumbar spine any of the lumbar disc levels. For this reason, the electromyogra-
pain, or limb symptoms which are suggestive of radiculopathy. The pher cannot precisely determine the anatomic location of a lumbar
indications for referring for testing as well as the limitations of testing intraspinal lesion producing distal muscle EMG findings in the lower
are discussed to give a greater understanding of this important diag- limbs. The needle EMG examination can only identify the root or
nostic procedure. This is not intended to be a basic chapter dealing roots that are physiologically involved, but not the precise anatomic
with how to perform electrodiagnostic studies. site of pathology in the lumbar spinal canal. This is an important
Given the extensive differential diagnosis for limb and spine symp- limitation requiring correlation with imaging findings to determine
toms, it is important for electrodiagnosticians to develop a concep- which anatomic location is most likely the offending site. This can be
tual framework for evaluating these referrals with a standard focused difficult in elderly persons with foraminal stenosis as well as moder-
history and physical examination and a tailored electrodiagnostic ate central canal stenosis at more than one site.
approach. Accurately identifying radiculopathy by electrodiagnosis In a prospective study of 100 patients with lumbosacral radiculop-
whenever possible, provides valuable information that helps guide athy who underwent lumbar laminectomy, EMG precisely identified
treatment and minimizes other invasive and expensive diagnostic and the involved root level 84% of the time.3 Needle EMG failed to accu-
therapeutic procedures. rately identify the compressed root in 16%. However, at least half of
the failures were attributable to anomalies of innervation. Another
SPINE AND NERVE ROOT ANATOMY: component to this study involved stimulating the nerve roots intraop-
DEVIATIONS FROM THE EXPECTED eratively with simultaneous recording of muscle activity in the lower
limb using surface electrodes. These investigators demonstrated vari-
Spinal anatomy is discussed in detail in Chapters 46 and 80 by Russell ations in root innervation, such as the L5 root innervating the soleus
Gilchrist and will not be emphasized here. From an electrodiagnostic and medial gastrocnemius, in 16% of a sample of 50 patients. Most
perspective, however, there are several specific anatomical issues that subjects demonstrated dual innervation for most muscles.3
merit further discussion. These findings underscore the limitations of precise localization
At all levels the dorsal root ganglion (DRG) lies in the interver- for root lesions with EMG. The electrodiagnostician should main-
tebral foramen. This anatomical arrangement has implications for tain an appreciation of these anatomic variations to better convey the
clinical electrodiagnosis of radiculopathy, namely that sensory nerve level of certainty with respect to diagnostic conclusions.
action potentials (SNAPs) are preserved in most radiculopathies as
the nerve root is affected proximal to the DRG. PHYSICAL EXAMINATION
Regarding the cervical nerve roots and the brachial plexus, there are
many anatomic variations. Perneczky1 described an anatomic study of The electrodiagnostic examination is an extension of the standard
40 cadavers. In all cases, there were deviations from accepted cervi- clinical examination. The history and physical examination are vital
cal root and brachial plexus anatomy. Levin, Maggiano, and Wilbourn2 initial steps in determining what conditions may be causing the pre-
examined the pattern of abnormalities on electromyography (EMG) senting symptoms. Most radiculopathies present with symptoms in
in 50 cases of surgically proven cervical root lesions. A range of needle one limb. Multiple radiculopathies such as are seen in cervical spinal
EMG patterns was found with EMG demonstrating less specificity stenosis or lumbar stenosis may cause symptoms in more than one
for the C6 root level, but more specificity and consistent patterns for limb. A focused neuromuscular examination that assesses strength,

95
Part 1: General Principles

reflexes, and sensation in the affected limb and the contralateral limb mal electrodiagnostic studies, indicating that clinicians should not
is important, providing a framework for electrodiagnostic assess- curtail electrodiagnostic testing simply because the physical exami-
ment. nation is normal. For lower limb symptoms, loss of a reflex or weak-
An algorithmic approach to utilizing physical examination and ness dramatically increased the likelihood of having a radiculopathy
symptom information to tailor the electrodiagnostic evaluation is by EMG. Losing the Achilles reflex, for instance, resulted in an odds
shown in Figure 8.1. In this approach, symptoms and physical exami- ratio of 8.4 (p<0.01), in other words eight times the likelihood of
nation signs create a conceptual framework for approaching these having a radiculopathy by EMG with this physical examination find-
sometimes daunting problems. Admittedly, there are many excep- ing compared to someone without loss of this reflex.4 Similar findings
tions to this approach with considerable overlap in medical disor- were noted for upper limb symptoms; if a reflex was lost or weakness
ders which might fall within multiple categories. Radiculopathies and was noted the likelihood of having a cervical radiculopathy confirmed
entrapment neuropathies are examples of such conditions with a vari- by EMG was many times greater.5 Combinations of findings, particu-
ety of clinical presentations and physical examination findings, such larly weakness plus sensory loss or plus reflex changes, resulted in a
that they are included in both focal symptom categories with and ninefold greater likelihood of cervical radiculopathy and two to three
without sensory loss. In the case of a person with lumbosacral radicu- times greater likelihood of lumbosacral radiculopathy.4,5
lopathy, a positive straight leg raise test may be noted in the absence
of motor, reflex, or sensory changes. Conditions such as myopathies The American Association of Neuromuscular
and polyneuropathies better fit this algorithmic approach, given that
symptoms and physical examination signs are more specific. Figure
and Electrodiagnostic Medicine Guidelines for
8.1 also contains musculoskeletal disorders and denotes how they Radiculopathy Evaluation
fall into this conceptual framework. The electrodiagnostician must The American Association of Neuromuscular and Electrodiagnostic
be willing to modify the electrodiagnostic examination in response Medicine (AANEM) guidelines recommend that for an optimal evalu-
to nerve conduction and EMG findings and adjust the focus of the ation of a patient with suspected radiculopathy, a needle EMG screen
examination in light of new information. of a sufficient number of muscles and at least one motor and one
The implications of symptoms and signs on electrodiagnostic sensory nerve conduction study should be performed in the involved
findings were investigated by Lauder and colleagues for suspected limb.6 The nerve conduction studies are necessary to exclude poly-
cervical and lumbosacral radiculopathies.4,5 Even though physical neuropathy. The sufficiency of the EMG screen and a recommended
examination findings were better at predicting who would have a number of muscles is discussed in detail below. An EMG study is
radiculopathy, many patients with normal examinations had abnor- considered diagnostic for a radiculopathy if EMG abnormalities are

Fig. 8.1 Algorithmic approach to structuring the electrodiagnostic examination based upon physical examination signs and the location of the
patient’s symptoms. Focal symptoms refer to single limb symptoms whereas generalized symptoms are present when the patient complains of
symptoms affecting more than one limb.

96
Section 3: General Diagnostic Technique

found in two or more muscles innervated by the same nerve root, and and the clinical scenario before attributing H-reflex abnormalities to
different peripheral nerves, yet muscles innervated by adjacent nerve the aging process.
roots are normal.7 This assumes, of course, that other generalized In patients with upper limb symptoms suggestive of cervical radicu-
conditions such as polyneuropathy are not present. lopathy, H-reflexes and F-waves are not useful in diagnosis but rather
It is often necessary to study bilateral limbs, particularly if a single help exclude polyneuropathy as an underlying cause of symptoms.
limb shows EMG findings suggestive of radiculopathy and the patient One study by Miller and colleagues14 examined the H-reflexes in the
has symptoms in both the studied and the contralateral limb. If bilat- upper limb in a set of patients defined by a combination of clinical
eral limbs are involved, the electrodiagnostician should have a low criteria (no imaging or EMG studies) as having definite or probable
threshold for studying selected muscles in an upper limb (if the lower cervical radiculopathy. They tested the H-reflex for the FCR, the
limbs are abnormal on EMG) or a lower limb (if both upper limbs ECR, the APB, and the biceps heteronymous reflex. The later reflex
are abnormal) to exclude a generalized process such as polyneuropa- is derived by stimulating the median nerve in the cubital fossa and
thy or motor neuron disease. Likewise, additional nerve conduction recording over the biceps brachii muscle, averaging 40–100 trials.
studies are appropriate to exclude other suspected conditions and These reflex studies had a 72% sensitivity overall for the group with
the electrodiagnostician should have a low threshold for expanding 100% for the subset of patients with definite cervical radiculopathy.
the study. In contrast, needle EMG demonstrated 90% sensitivity for the defi-
nite group. Although these findings suggest a possible role for these
H-REFLEXES, F-WAVES, AND NERVE upper limb H-reflexes, they are highly specialized, time consuming,
and difficult to consistently elicit. They may have a role in sensory
CONDUCTION radiculopathies where needle EMG will not be positive and imaging
Nerve conduction studies, H-reflexes, and F-waves are not very use- findings are equivocal. Further studies are necessary to clarify whether
ful for confirming radiculopathy. They are useful, however, to exclude the findings of Miller et al.14 can be duplicated at other centers.
polyneuropathy or mononeuropathies.

F-waves
H-reflexes F-waves are late responses involving the motor axons and axonal pool
H-reflexes have commonly been used to determine whether a at the spinal cord level. They can be assessed and classified by using
radiculopathy demonstrates S1 involvement.7 It is a monosynaptic the minimal latency, mean latency, and chronodispersion or scatter.7
reflex that is an S1-mediated response and can differentiate to some As in the case of H-reflexes, they demonstrate low sensitivities and
extent L5 from S1 radiculopathy. Many researchers have evaluated are not specific for radiculopathy; rather, they are a better screen
their sensitivity and specificity with respect to lumbosacral radicu- for polyneuropathy. Published sensitivities range from 13% to 69%;
lopathies and generally found a range of sensitivities from 32% to however, these studies suffer from many of the same shortcomings
88%.7–12 However, many of these studies suffered from lack of a con- that are found in the H-reflex studies.8,15,16
trol group, imprecise inclusion criteria, or small sample sizes. London and England17 reported two cases of persons with neu-
Marin et al.12 prospectively examined the H-reflex and the exten- rogenic claudication from lumbosacral spinal stenosis. They dem-
sor digitorum brevis reflex in 53 normals, 17 patients with L5, and 18 onstrated that the F-wave responses could be reversibly changed
patients with S1 radiculopathy. Patients included in the study had all after 15 minutes of ambulation, which provoked symptoms. This
of the following: (1) radiating low back pain into the leg, (2) reduced suggested an ischemia-induced conduction block in proximal motor
sensation or weakness or positive straight leg raise test, and (3) either neurons. A larger-scale study of this type might find a use for F-waves
EMG evidence of radiculopathy or structural causes of radiculopa- in the identification of lumbosacral spinal stenosis and assist with the
thy on magnetic resonance imaging (MRI) or computed tomography delineation of neurogenic from vascular claudication.
(CT) imaging. The maximal (2 SD) value for the H-reflex side-to-
side latency difference was 1.8 ms as derived from the normal group.
They analyzed the sensitivity of the H-reflex for side-to-side differ- Motor and sensory nerve conduction studies
ences greater than 1.8 ms or a unilaterally absent H-reflex on the Standard motor and sensory nerve conduction studies are not helpful
affected side. The H-reflex only demonstrated a 50% sensitivity for in identifying a cervical or lumbosacral radiculopathy. However, they
S1 radiculopathy, 6% for L5 radiculopathy, but had a 91% specificity. should be performed to screen for polyneuropathy and exclude common
Amplitudes were not assessed in this study. These results suggest that entrapment neuropathies if the patient’s symptoms could be explained
the H-reflex has a low sensitivity for S1 root level involvement. by a focal entrapment. Remember that based upon the anatomy of the
H-reflexes may be useful to identify subtle S1 radiculopathy, yet dorsal root ganglion, sensory responses should be normal in most radicu-
there are a number of shortcomings related to these responses. They lopathies. If they are absent, this should raise suspicion for another diag-
can be normal with radiculopathies12 and, because they are mediated nosis such as polyneuropathy, plexopathy, or mononeuropathy.
over such a long physiological pathway, they can be abnormal due to Plexopathies often pose a diagnostic challenge as they are similar to
polyneuropathy, sciatic neuropathy, or plexopathy.7 They are most radiculopathies in symptoms and signs. In order to distinguish plexop-
useful in the assessment for polyneuropathy. athy from radiculopathy, sensory responses which are accessible in a
In order to interpret a latency or amplitude value and render a limb should be tested. In plexopathy, they are likely to be reduced
judgment as to the probability that it is abnormal, precise popula- in amplitude, whereas in radiculopathy they are generally normal. If
tion-based normative values encompassing a large age range of normal substantial axonal loss has occurred at the root level, the compound
subjects must be available for comparison of these nerve conduction muscle action potential recorded in muscles innervated by that root
findings. Falco et al.13 demonstrated in a group of healthy elderly may be reduced in both plexopathies and radiculopathies. This is usu-
subjects (60–88 years old) that the tibial H-reflex was present and ally when severe axonal loss has occurred such as with cauda equina
recorded bilaterally in 92%. Most elderly are expected to have nor- lesions or penetrating trauma that severely injures a nerve root. The
mal H-reflex studies and, when abnormalities are found in these per- distal motor latencies and conduction velocities are usually preserved
sons, the electrodiagnostician should critically evaluate these findings as they reflect the fastest conducting nerve fibers.7

97
Part 1: General Principles

SOMATOSENSORY EVOKED POTENTIALS, Dumitru and colleagues,23 in a study involving persons with uni-
lateral and unilevel L5 and S1 radiculopathies, evaluated DSEPs
DERMATOMAL SOMATOSENSORY EVOKED and segmental SEPs. History, physical examination, imaging studies,
POTENTIALS, AND MAGNETIC EVOKED and electrodiagnostic medicine evaluations clearly defined patients
POTENTIALS with unilateral/unilevel L5 or S1 nerve root compromise. Regression
equation analysis for cortical P1 latencies evaluating age and height
The AANEM guidelines recently examined the literature and con- based on comparable patient and control reference populations
cluded that somatosensory evoked potentials (SEPs) may be useful revealed segmental and dermatomal sensitivities for L5 radiculopa-
for cervical spondylosis with cord compression. Likewise, in lumbo- thies to be 70% and 50%, respectively, at 90% confidence intervals.
sacral spinal stenosis, dermatomal somatosensory evoked potentials Similar sensitivities were obtained for 2 standard deviation mean
(DSEPs) may be useful in defining levels of deficits.6 These tests are cortical P1 latencies. Side-to-side cortical P1 latency difference
not necessary for electrodiagnostic testing for persons with suspected data revealed segmental and dermatomal sensitivities for S1 radicu-
radiculopathies and their usefulness is limited to special circum- lopathies to be 50% and 10%, respectively, at 2 standard deviations.
stances. These tests are not recommended for the routine evaluation These investigators questioned the clinical utility of both segmental
of persons with suspected radiculopathy. and dermatomal SEPs in the evaluation of patients with suspected
DSEPs can document physiological evidence of multiple or single unilateral/unilevel L5 and S1 nerve root compromise, finding little utility
root involvement in lumbosacral spinal stenosis and may be useful for these tests in persons with single-level lumbosacral radiculopathy.
in the case where spinal canal narrowing is minimal and the patient
has symptoms. This testing also complements standard needle EMG.
Snowden et al.18 found that for single and multilevel lumbosacral spi- PURPOSE OF ELECTRODIAGNOSTIC
nal stenosis, DSEPs revealed 78% sensitivity relative to spinal imag- TESTING
ing. In this well-designed prospective study, DSEP criteria as well as
inclusion criteria were precisely defined. The predictive value for a Electrodiagnostic testing is expensive and uncomfortable for patients and
positive test was 93%. so it is important to understand why it is performed and the expected
Yiannikas, Shahani, and Young19 demonstrated that SEPs may be outcomes. Electrodiagnostic testing serves several important purposes:
useful for cervical myelopathy. In this study of 10 patients with clini- (1) It effectively excludes other conditions that mimic radiculopathy
cal signs of myelopathy, all 10 had abnormal peroneal SEPs and seven such as polyneuropathy or entrapment neuropathy. Haig and col-
had abnormal median SEPs. leagues24 demonstrated that the referring diagnostic impression is
Maertens de Noordhout et al.20 examined motor and SEPs in often altered with electrodiagnostic testing.
55 persons with unequivocal signs and symptoms of cervical spinal (2) Electrodiagnostic testing can, to some extent, suggest severity or
myelopathy. In this group 87% showed gait disturbances, and 82% extent of the disorder beyond clinical symptoms. Involvement of
showed hyperreflexia. MRI was not the diagnostic standard as these other extremities can be delineated or the involvement of multi-
authors felt that MRI was prone to overdiagnosis; rather, metrizamide ple roots may be demonstrated, such as in the case of lumbosacral
myelography showed unequivocal signs of cervical cord compression spinal stenosis.
for all of these patients. Magnetic stimulation of the cortex was per- (3) There is utility in solidifying a diagnosis. An unequivocal radicu-
formed and the responses measured with surface electrodes. In these lopathy on EMG in an elderly patient with non-specific or mild
subjects 89% demonstrated abnormalities in magnetic evoked poten- lumbar spondylosis or stenosis on MRI reduces diagnostic uncer-
tial (MEP) to the first dorsal interosseus muscle and 93% had one tainty and identifies avenues of management such as lumbar ste-
MEP abnormality. At least one SEP abnormality was noted in 73%. roid injections or decompression surgery in certain situations.
Tavy et al.21 examined whether MEPs or SEPs assisted in identify- (4) Outcome prediction may be possible. If surgical intervention is
ing persons with radiological evidence of cervical cord compression planned for a lumbosacral radiculopathy, a positive EMG preop-
but who were without clinical markers for myelopathy. All patients eratively improves the likelihood of a successful outcome postop-
had clinical symptoms of cervical radiculopathy, but not myelopathy. eratively (see below). This is an area that deserves more research
In this group, MEPs were normal in 92% and SEPs were normal in attention.
96%. These investigators concluded that MEPs and SEPs are normal
in most cases of persons with asymptomatic cervical stenosis. This USEFULNESS OF ELECTRODIAGNOSTIC
indicates that abnormal MEPs and SEPs are likely to be true-positive
findings and not false positives related to mild asymptomatic cord
TESTING
compression. It is important to remember that cervical spondylosis is The value of any test depends upon the a priori certainty of the diag-
a process that causes a continuum of problems including both radicu- nosis in question and this principle applies to electrodiagnostic test-
lopathy and myelopathy. ing. For a condition or diagnosis for which there is great certainty
The inherent variability and difficulty in determinations of what before additional testing, the results of the subsequent tests are of
constitutes normal SEPs prompted investigation. Dumitru and col- limited value. This concept, diminishing returns on the road to diag-
leagues22 examined the variations in latencies with SEPs. In 29 normal nostic certainty, is important.
subjects, they examined the ipsilateral intertrial variations, arithmetic For instance, in a patient with acute-onset sciatica while lifting, L5
mean side-to-side differences, and maximum potential side-to-side muscle weakness, a positive straight leg raise, and an MRI showing a
differences with stimulation of the superficial peroneal sensory nerve, large extruded L4–5 nucleus pulposus, an EMG test will be of lim-
sural nerve, and L5 and S1 dermatomes with respect to P1 and N1 ited value in confirming the diagnosis of radiculopathy.
latencies and peak-to-peak amplitudes. Considerable ipsilateral inter- In contrast, an elderly diabetic patient with sciatica, limited physi-
trial variation was observed and side-to-side comparisons revealed a cal examination findings, and equivocal or age-related MRI changes
further increase in this inherent variation regarding the above mea- presents an unclear picture. In this case electrodiagnostic testing is of
sured parameters. They suggested an additional parameter with which high value, placing in perspective the imaging findings and excluding
to evaluate SEPs: the maximum side-to-side latency difference. diabetic polyneuropathy as a confounding condition.

98
Section 3: General Diagnostic Technique

ELECTROMYOGRAPHY AND DIAGNOSTIC nosis was underscored by Robinson.25 It is apparent that EMG is not a
very good screening test. In terms of screening tests, MRI is better for
SENSITIVITIES identifying subtle structural abnormalities, with EMG to assess their
The need for EMG, particularly in relationship to imaging of the clinical relevance and to exclude other disorders.
spine, has been recently highlighted.25 Needle EMG is particularly
helpful in view of the fact that the false-positive rates for MRI of PARASPINAL MUSCLE EXAMINATION
the lumbar spine are high, with 27% of normals having a disc pro-
trusion.26 For the cervical spine, the false-positive rate for MRI is Several reports suggested high rates of false-positive fibrillations in
much lower, with 19% of subjects demonstrating an abnormality, lumbar paraspinal muscles.28,29 Dumitru, Diaz, and King30 conducted a
but only 10% showing a herniated or bulging disc.27 Radiculopathies well-designed study to examine whether or not fibrillations are found
can occur without structural findings on MRI, and likewise without in the lumbar paraspinal muscles of normal asymptomatic volunteers.
EMG findings. The EMG only evaluates motor axonal loss or motor These investigators examined lumbosacral paraspinal muscles and
axon conduction block and for these reasons a radiculopathy effect- intrinsic foot muscles with monopolar EMG and recorded potentials
ing the sensory root will not yield abnormalities by EMG. If the rate for analysis. Regular firing rate was required in order for classification
of denervation is balanced by reinnervation in the muscle, then spon- as fibrillation potentials. They found many irregularly firing poten-
taneous activity is less likely to occur. tials with similar waveform characteristics as fibrillations and positive
The sensitivity of EMG for cervical and lumbosacral radiculopathies sharp waves (PSW). By excluding these irregularly firing potentials
has been examined in a number of studies. The results of some of (atypical endplate spikes) they found much lower false-positive para-
these studies are displayed in Table 8.1, which lists the ‘gold standards’ spinal fibrillation prevalences than other investigators. Only 4% of
against which these EMG findings were compared. Studies using a these normal subjects had lumbar fibrillations or PSW potentials by
clinical standard may reflect a less severe group, whereas those using EMG testing. The investigators felt that the higher prevalences of
a surgical confirmation may indicate a more severely involved group. spontaneous activity reported by other investigators28,29 were due to
The sensitivity for EMG is unimpressive, ranging from 49% to 92% in not fully appreciating the similarity between innervated and dener-
these studies. Electromyography is not a sensitive test, yet likely has vated spontaneous single muscle fiber discharges. This well-designed
higher specificity. The issue of specificity and its value in electrodiag- quantitative study underscores the need to assess both firing rate

Table 8.1: Selected studies evaluating the sensitivity of EMG relative to various ‘gold standards’

Study Sample Size Gold Standard EMG Sensitivity


Lumbosacral radiculopathy
Weber and Albert59 42 Clinical + imaging HNP 60%
Nardin et al. 29
47 Clinical 55%
Kuruoglu et al. 8
100 Clinical 86%
Khatri et al.60 95 Clinical 64%
Tonzola et al.61 57 Clinical 49%
Schoedinger62 100 Surgically proven 56%
Knutsson 46
206 Surgically proven 79%
Young et al. 3
100 Clinical and imaging 84%a
Linden and Berlit10 19 Myelography and CT 78%
Lumbosacral spinal stenosis
Hall et al.48 68 Clinical + myelogram 92%
Johnsson et al.63 64 Clinical + myelogram 88%b
Cervical radiculopathy
Berger et al.64 18 Clinical 61%
Partanen et al. 65
77 Intraoperative 67%
Leblhuber et al. 9
24 Clinical + myelogram 67%
So et al.66 14 Clinical 71%
Yiannikas et al. 19
20 Clinical and/or radiographic 50%
Tackman and Radu. 16
20 Clinical 95%
Hong et al.67 108 Clinical 51%
a
Both fibrillations or large motor units >8 mV were considered positive.
b
This study assessed EMG parameters and used quantitative EMG with a unique grading scale not used in clinical practice. Fibrillations were infrequent.
This limits the generalizability of this otherwise strong study.
Unless otherwise stated the EMG parameters used in sensitivity calculations were fibrillation potentials.

99
Part 1: General Principles

and rhythm as well as discharge morphology when evaluating for level. Because of the screening nature of the EMG exam, electro-
fibrillations and positive waves in the lumbar paraspinal muscles. diagnosticians with experience should look for more subtle signs of
Electrodiagnosticians should take care not to overcall fibrillations in denervation and, if present in the screening muscles, then expand
lumbosacral paraspinal muscles by mistaking irregularly firing end- the study to determine if these findings are limited to a single myo-
plate spikes for fibrillations. tome or peripheral nerve distribution. If they are limited to a single
Paraspinal muscles may be abnormal in patients with spinal cancers31–33 muscle, the clinical significance is uncertain.
or amyotrophic lateral sclerosis,34 and following spinal surgery35 or
lumbar puncture.36 In fact, fibrillations can be found years after lumbar
laminectomy.35 The absence of paraspinal muscle fibrillations in such
The cervical radiculopathy screen
patients is helpful, but finding fibrillations in someone after laminec- Dillingham et al.41 conducted a prospective multicenter study evalu-
tomy is of uncertain relevance as these fibrillations may be residual ating patients referred to participating electrodiagnostic laboratories
from the previous muscle damage or relatively new denervation. with suspected cervical radiculopathy. A standard set of muscles were
Investigations over the last decade have provided insights into bet- examined by needle EMG for all patients. Those with electrodiag-
ter quantification and examination of lumbosacral paraspinal mus- nostically confirmed cervical radiculopathies, based upon EMG find-
cles. The lumbar paraspinal muscle examination has been refined ings, were selected for analysis. The EMG findings in this prospective
through investigations that used a grading scale for the findings.37–40 study also encompassed other neuropathic findings: (1) positive sharp
The ‘mini PM’ score provides a quantitative means of deriving the waves, (2) fibrillation potentials, (3)complex repetitive discharges
degree of paraspinal muscle denervation.40 It distinguishes normal (CRD), (4) high-amplitude, long-duration motor unit action poten-
findings from persons with radiculopathy. This novel and quantita- tials, (5) increased polyphasic motor unit action potentials, or (6)
tive technique may prove useful to identify subtle radiculopathies or reduced recruitment. There were 101 patients with electrodiagnosti-
spinal stenosis with greater precision. cally confirmed cervical radiculopathies representing all cervical root
Cervical and lumbar paraspinal muscles should only be exam- levels. When paraspinal muscles were one of the screening muscles,
ined for insertional activity and spontaneous activity while at rest. five-muscle screens identified 90–98% of radiculopathies, six-muscle
Recruitment findings and motor unit morphology for these muscles screens identified 94–99%, and seven-muscle screens identified
has not been established and consequently we do not know for sure 96–100% (Tables 8.2 and 8.3). When paraspinal muscles were not
what constitutes normal. Examiners should not overcall radiculopa- part of the screen, eight distal limb muscles recognized 92–95% of
thies based upon ‘reduced recruitment’ or ‘increased polyphasicity’ radiculopathies. Six-muscle screens, including paraspinal muscles,
in the paraspinal muscles. Paraspinal muscles either show sponta- yielded consistently high identification rates, and studying additional
neous activity and therefore localize the lesion to the root level or muscles lead to only marginal increases in identification. Individual
they do not. There is considerable overlap in paraspinal muscles with screens useful to the electromyographer are listed in Tables 8.2 and
single roots innervating fibers above and below their anatomic levels. 8.3. In some instances a particular muscle cannot be studied due to
For this reason, the level of radiculopathy cannot be delineated by wounds, skin grafts, dressings, or infections. In such cases the elec-
paraspinal EMG alone, but rather is based upon the root level that tromyographer can use an alternative screen with equally high iden-
best explains the distribution of muscles demonstrating fibrillations. tification. These findings were consistent with those derived from a
large retrospective study.42
IDENTIFICATION AS A SEPARATE CONCEPT
FROM SENSITIVITY The lumbosacral radiculopathy screen
A similar prospective multicenter study was conducted at five insti-
Electrodiagnostic testing is uncomfortable and expensive. Because tutions by Dillingham et al.43 Patients referred to participating elec-
electrodiagnosis is a composite assessment composed of various tests, trodiagnostic laboratories with suspected lumbosacral radiculopathy
a fundamental question is; when has the point of diminishing returns were recruited and a standard set of muscles examined by needle
been reached? Some radiculopathies cannot be confirmed by nee- EMG. Patients with electrodiagnostically confirmed lumbosacral
dle EMG, even though the signs and symptoms along with imaging radiculopathies, based upon EMG findings, were selected for analy-
results suggest that radiculopathy is present. A screening EMG study sis. As described above for the prospective cervical study, neuropathic
involves determining whether or not a radiculopathy, if present, can findings were analyzed along with spontaneous activity. There were
be confirmed by EMG. If the radiculopathy cannot be confirmed, 102 patients with lumbosacral radiculopathies representing all lum-
then presumably no number of muscles can identify the radiculopa- bosacral root levels. When paraspinal muscles were one of the screen-
thy. If it can be confirmed, then the screen should identify this pos- ing muscles, four-muscle screens identified 88–97%, five-muscle
sibility with a high probability. The process of identification can be screens identified 94–98%, and six-muscle screens 98–100% (Tables
conceptualized as a conditional probability: given that a radiculopathy 8.4–8.6). When paraspinal muscles were not part of the screen, iden-
can be confirmed by needle EMG, what is the minimum number of tification rates were lower for all screens and eight distal muscles
muscles which must be examined in order to confidently recognize were necessary to identify 90%. If only four muscles can be tested
or exclude this possibility? This is a fundamentally different concept due to limited patient tolerance, as seen in Table 8.4, and if one of
from sensitivity. It involves understanding and defining the limita- these muscles are the paraspinals, few electrodiagnostically confirm-
tions of a composite test (group of muscles). able radiculopathies will be missed. A large retrospective study noted
consistent findings, concluding that five muscles identified most
HOW MANY AND WHICH MUSCLES electrodiagnostically confirmable radiculopathies.44
Dillingham and Dasher45 re-analyzed data from a study published by
TO STUDY Knutsson almost 40 years earlier.46 In this detailed study, 206 patients
The concept of a screening EMG encompasses identifying the possi- with sciatica underwent lumbar surgical exploration. All subjects
bility of an electrodiagnostically confirmable radiculopathy. If one of underwent standard EMG by the author (Knutsson) with a standard
the muscles in the screen is abnormal, the screen must be expanded set of 14 muscles using concentric needles. The examiner was blinded
to exclude other diagnoses, and to fully delineate the radiculopathy to other test results and physical examination findings. In addition to

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Section 3: General Diagnostic Technique

Table 8.2: Five-muscle screen identifications of patients Table 8.3: Six-muscle screen identifications of the patients
with cervical radiculopathies with cervical radiculopathies

Muscle screen Neuropathic Spontaneous activity Muscle Screen Neuropathic Spontaneous Activity
Without paraspinals Without paraspinals
Deltoid, APB, FCU 92% 65% Deltoid, APB, FCU 93% 66%
Triceps, PT Triceps, PT, FCR
Biceps, triceps 85% 54% Biceps, triceps, FCU 87% 55%
EDC, FCR, FDI EDC, FCR, FDI
Deltoid, triceps 84% 58% Deltoid, triceps 89% 64%
EDC, FDI, FCR EDC, FDI, FCR, PT
Biceps, triceps 91% 60% Biceps, triceps, EDC 94% 64%
PT, APB, FCU PT, APB, FCU
With paraspinals With paraspinals
Deltoid, triceps, PT 98% 80% Deltoid, triceps, PT 99% 83%
APB, PSM APB, EDC, PSM
Biceps, triceps, EDC 95% 73% Biceps, triceps, EDC 96% 75%
FDI, PSM FDI, FCU, PSM
Deltoid, EDC, FDI 90% 73% Deltoid, EDC, FDI 94% 77%
PSM, FCU PSM, FCU, triceps
Biceps, FCR, APB 95% 77% Biceps, FCR, APB 98% 79%
PT, PSM PT, PSM, triceps
The screen detected the patient with cervical radiculopathy if any muscle Muscle abbreviations, identification criteria, and definitions are
in the screen was one of the muscles which were abnormal for that described in Table 8.2.
patient.
Neuropathic findings for nonparaspinal muscles included positive
waves, fibrillations, increased polyphasic potentials, neuropathic
recruitment, increased insertional activity, CRDs, or large amplitude/long LUMBAR SPINAL STENOSIS
duration motor unit action potentials.
With the aging population in the United States and the increasing
For paraspinal muscles the neuropathic category included fibrillations,
increased insertional activity, positive waves, or CRDs. Spontaneous prevalence of lumbar spinal stenosis that occurs in the elderly, this
activity referred only to fibrillations or positive sharp waves. condition takes on greater public health significance. In fact, an
APB, abductor pollicis brevis; FCU, flexor carpi ulnaris; FCR, flexor carpi entire edition of the Physical Medicine and Rehabilitation Clinics of
radialis; PSM, cervical paraspinal muscles; FDI, first dorsal interosseous; North America was recently dedicated to this complex topic.47 There
PT, pronator teres, supra-supraspinatus, infra-infraspinatus; EDC, are few studies involving spinal stenosis and electromyography. For
extensor digitorum communis.
lumbosacral spinal stenosis, Hall and colleagues48 showed that 92% of
Adapted with permission, Dillingham et al.41
persons with imaging-confirmed stenosis had a positive EMG. They
also underscored the fact that 46% of persons with a positive EMG
study did not demonstrate paraspinal muscle abnormalities, only dis-
the EMG and surgical information, myelogram and physical examina-
tal muscle findings. In 76%, the EMG showed bilateral myotomal
tion data were derived. In this contemporary re-analysis, screens of
involvement.48 These results suggest that in such patients, distal limb
four muscles with one being the PSM yielded an identification rate of
findings may be the most prominent and electromyographers should
100%, a 92% sensitivity with respect to the intraoperative anatomical
not expect fibrillations in lumbosacral paraspinal muscles.
nerve root compressions, and an 89% sensitivity with respect to the
In the United States, diabetes is on the increase, with increas-
clinical inclusion criteria.45 This study, using data from four decades
ing prevalence and incidence.49 Diabetes often confounds accu-
ago, confirmed that four-muscle screening examinations provide high
rate diagnosis of radiculopathy and spinal stenosis.50,51 Inaccurate
identification. These findings are consistent with contemporary work
recognition of sensory polyneuropathy, diabetic amyotrophy, or
showing that screens with relatively few muscles (six) are optimal.
mononeuropathy can lead to unnecessary surgical interventions.
As described above, these research efforts were undertaken to
In a recent prospective study by Adamova and colleagues,50 the
refine and streamline the EMG examination. The strongest studies,
value of electrodiagnostic testing was assessed. There were three
contemporary prospective multicenter investigations, provide the
groups; one group composed of 29 persons with imaging confirmed
best estimates for a sufficient number of muscles.41,43 In summary,
clinically mild lumbar spinal stenosis, 24 subjects with both diabe-
for both cervical and lumbosacral radiculopathy screens the optimal
tes and polyneuropathy, and 25 healthy age-matched volunteers
number of muscles appears to be six muscles, including the paraspi-
served as control subjects. In this well-designed study, sural sen-
nal muscles and muscles that represent all root level innervations.
sory amplitudes distinguished the diabetic polyneuropathy group
When paraspinal muscles are not reliable, then eight nonparaspinal
(an amplitude of 4.2 microvolts or less was found in 47% of dia-
muscles must be examined. Another way to think of this:
betic patients and only 17% of stenosis patients). The ulnar F-wave
‘To minimize harm, six in the leg and six in the arm’ was prolonged in polyneuropathy patients and not lumbar stenosis

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Part 1: General Principles

Table 8.4: Four-muscle screen identifications of patients Table 8.6 Six-muscle screen identifications of patients
with lumbosacral radiculopathies with lumbosacral radiculopathies

Screen Neuropathic Spontaneous Screen Neuropathic Spontaneous


Activity Activity
Four muscles without paraspinals Six muscles without paraspinals
ATIB, PTIB, MGAS, RFEM 85% 75% ATIB, PTIB, MGAS, RFEM, SHBF, LGAS 89% 78%
VMED, TFL, LGAS, PTIB 75% 58% VMED, TFL, LGAS, PTIB, ADD, MGAS 83% 70%
VLAT, SHBF, LGAS, ADD 52% 35% VLAT, SHBF, LGAS, ADD, TFL, PTIB 79% 62%
ADD, TFL, MGAS, PTIB 80% 67% ADD, TFL, MGAS, PTIB, ATIB, LGAS 88% 79%
Four muscles with paraspinals Six muscles with paraspinals
ATIB, PTIB, MGAS, PSM 97% 90% ATIB, PTIB, MGAS, PSM, VMED, TFL 99% 93%
VMED, LGAS, PTIB, PSM 91% 81% VMED, LGAS, PTIB, PSM, SHBF, MGAS 99% 87%
VLAT, TFL, LGAS, PSM 88% 77% VLAT, TFL, LGAS, PSM, ATIB, SHBF 98% 87%
ADD, MGAS, PTIB, PSM 94% 86% ADD, MGAS, PTIB, PSM, VLAT, SHBF 99% 89%
The screen identified the patient if any muscle in the screen was VMED, ATIB, PTIB, PSM, SHBF, MGAS 100% 92%
abnormal for that patient. The muscle either demonstrated neuropathic
VMED, TFL, LGAS, PSM, ATIB, PTIB 99% 91%
findings or spontaneous activity.
Neuropathic findings for nonparaspinal muscles included positive ADD, MGAS, PTIB, PSM, ATIB, SHBF
waves, fibrillations, increased polyphasic potentials, neuropathic
recruitment, increased insertional activity, CRDs, or large amplitude long Abbreviations and definitions of muscle abnormalities are the same as
duration motor unit action potentials. Spontaneous activity referred in Table 8.4.
only to fibrillations or positive sharp waves.
For paraspinal muscles the neuropathic category included fibrillations