Painful Peripheral

Neuropathy

Division of Pain Medicine

Department of Anesthesiology
University Hospitals of
Cleveland

Salim Hayek, MD, PhD

Painful Peripheral Neuropathy

Salim Michel Hayek, MD, PhD

Division of Pain Medicine
Department of Anesthesiology
University Hospitals of Cleveland
 Conflicts of Interest

None Relevant to this talk

 Learning Objectives

Pathophysiology
Epidemiology
Diagnosis
 Peripheral Neuropathies
Large Fiber (LFN)
Small Fiber (SFN)
Most common painful neuropathy
Distal painful peripheral neuropathy
 Painful Feet and later may  hands
Burning pain, pins and needles: + symptoms
Numbness: -symptoms
Mixed Fiber Neuropathies (MFN)

Gorson KC, Ropper AH. Idiopathic distal small fiber neuropathy. Acta Neurologica
Scandinavica. 1995;92(5):376-382
Nerve Fiber Types
Aβ C, Aδ
 Peripheral Neuropathy
15 to 20 million people in the United
States over age 40 have some type of
peripheral neuropathy
Non-Painful
Painful: Small Fiber Neuropathy (SFN)
pain, burning, tingling, and numbness in a
length-dependent or stocking-glove
distribution

Gregg EW et al., Diabetes Res Clin Pract 2007; 77:485–488

 SFN—Clinical Finding

Often normal
Neurologic exam
EMG Aα fibers
NCS Aβ fibers
 Erroneous diagnoses:
Plantar fasciitis
Vascular insufficiency
Degenerative lumbosacral spine disease
Tavee J & Zhou L, Cleve Clin J Med. 2009 May;76(5):297-305
 SFN Prevalence
Sjogren’s: 45% have pure SFN with
burning pain
Diabetes: neuropathy in 50-70%, not all
with burning pain
Inferred prevalence:
Diabetes is at approx 6% of population (CDC)
Distal burning pain occurs in 15-20% of
diabetics, or ~1% of entire population
Of patients referred for the evaluation of
SFN, about 1/3 have diabetes 3-5%
Italian study found prevalence of 3% (Beghi,
1995)
Lopate G et al., Muscle Nerve. 2006 May;33(5):672-6
Low PA et al., Diabetes Care. 2004 Dec;27(12):2942-7.
 SFN Pathophysiology
Degeneration of small
Unmyelinated C-Fibers
Thinly myelinated A-δ Fibers
~Autonomic fibers
When progression from small fiber to large
fiber neuropathy occurs, a symptomatic
change from "positive" to "negative"
neuropathic symptoms is observed clinically

Gorson KC, Ropper AH. Idiopathic distal small fiber neuropathy. Acta Neurologica
Scandinavica. 1995;92(5):376-382
Distal Symmetric Polyneuropathy:
Small Fiber
• First: pain and hyperalgesia
• Later: loss of sensitivity
oHeat/Cold Aδ & C fibers
oLight touch/pinprick Aβ fibers
• Predisposes to diabetic foot
disease
• Electrophysiology may not
detect nerve damage
• Autonomic symptoms

Vinik. In:Diabetes and Carbohydrate Metabolism. 2002.

 SFN Symptoms
Vague discomfort, length-dependent
 numbness in toes, “pebbles”
 burning pain: stocking/gloves
Worse at night
“tightness” around feet
 SFN Exam
Allodynia
Hyperalgesia
 pinprick/thermal sensation
Mild  in vibratory sense
Motor strength, DTR and
proprioception are WNL
 Autonomic Symptoms
History
Dry eye, dry mouth, orthostatic dizziness,
constipation, bladder incontinence, sexual
dysfunction, trouble sweating, skin
discoloration (red or white)
Physical Exam
Orthostatic hypotension, dry, shiny and
discolored atrophic skin (vasomotor or
sudomotor abnormalities)
Tavee J & Zhou L, Cleve Clin J Med. 2009 May;76(5):297-305.
 Autonomic  Prognosis is poor

If an autonomic neuropathy is part of

the small fiber neuropathy, the
prognosis is quite poor
5 Studies conducted between 1980
and 1993 showed 23% to 56%
mortality at 5 years!

Rathmann W et al., Diabet Med. 1993 Nov;10(9):820-4

 Distal Symmetric Polyneuropathy:
Large Fiber
Sensory and/or motor nerves
Feet usually affected first
Vibration perception
Position sense (proprioception)
Muscle Wasting (hammertoes)
~Deep seated gnawing pain
May interfere with ADL
Abnormalities detected by EMG
Vinik In: Diabetes and Carbohydrate Metabolism, 2002
 Causes of SFN
 Diabetes mellitus/pre-DM
 Dysthyroidisms
 Alcoholism
 Amyloidosis
 B12 deficiency
 Celiac disease
 Paraproteinemia
 Restless leg syndrome
 Paraneoplastic syndrome Not length-dependent
 Neurotoxic drug exposure
 Hereditary
 Infectious
 HIV
 Hepatitis C
 Autoimmune diseases
 Sjögren's disease
 Scleroderma
 SLE
 Idiopathic SFN
 ~50% of cases, no etiology can be found despite extensive medical work up
 SFN often precedes Diabetes

Impaired glucose tolerance (IGT) 2nd hour

>140 mg/dl and <200 mg/dl (75 gm dextrose)
1/3 patients with painful sensory neuropathy
~50% of patients with idiopathic SFN
Pre-DM  risk factor for SFN
IGT  SFN at initial presentation vs.
DM progression into MFN in 50% of pts
Tavee J & Zhou L, Cleve Clin J Med. 2009 May;76(5):297-305
Sumner CJ et al., Neurology 2003; 60:108-111
 Why Early Nerve Involvement?
Pancreatic Peri-Islet Schwann Cells

Winer S et al. Nature Medicine 9:198, 2003

T-cells attack Schwann cells
before pancreatic Beta-cells

Green = T-cells (CD3)

Red = Schwann cell (GFAP)
Blue = Beta-cell (Insulin)

Winer S et al. Nature Medicine 9:198, 2003

 Metabolic Syndrome
HTN + Hyperlipidemia + Obesity +
Insulin Resistance (DM or pre DM)
Risk factor for
Cardiovascular disease
Cerebrovascular disease
Small Fiber Neuropathy (more important
role for dyslipidemia)

Tesfaye S et al., N Engl J Med. 2005 Jan 27;352(4):341-50

Smith AG et al., J Neurol Sci. 2008 Oct 15;273(1-2):25-8
Diagnosis: Skin Biopsy (IENFD)
IntraEpidermal Nerve Fiber Density
IENFD
Skin
Biopsy
2 mm
punch
biopsies
stained/
small
fibers
counted
 Skin Biopsy Correlates with Exam
 106 patients & 45 control
subjects
 Defined as a syndrome of
 Idiopathic symmetric
burning,
 Paresthesias, hyperalgesia,
or allodynia in a length-
dependent distribution
 Normal strength, reflexes,
and nerve conduction
 Excluded DM, B12
 Divided into nl & abnl
sensation to pin & vibration
 Best discrimination
occurred at 8/mm
 Modest correlation
foot/calf
Walk D et al., Neurol Sci. 2007 Apr 15;255(1-2):23-6
 Key Points
Small Fiber Neuropathy (SFN) is a major
cause of neuropathic pain
Diabetic Painful Neuropathy is ~ SFN
Pre-diabetic neuropathy is a frequent
cause of SFN
Skin biopsy (IENFD) is important in
diagnosis
Behavioral modification, Pharmacotherapy
and SCS are potential treatments
Thank You!!