Introduction to Clinical Medicine

(ICM)
Diseases of the Musculo-skeletal System

Prepared by:
Robert W. Wilhoite M.D.
Diagnosis and Evaluation of a patient with
arthritis or musculoskeletal disorders
Two Clinical Clues:
Joint pattern
Is inflammation present?
How many joints are involved?
What joints are involved?
Presence or absence of extra-articular
manifestations
Arthrocentesis
Arthrocentesis
Gross:
Clarity
hemorrhage
Cell count:
Non-inflammmatory (<2000 WBC/ml
Inflammatory (2,000 75,000 WBC/ml
Purulent (> 100,000 WBC/ml.
Microscopic exam:
Polarization
Gram stain
Culture:
Case # 1
This 58 year old white woman has noted pain in
several bones of her body including pelvis,
spine and skull. Only recently has she
developed pain in her right lower leg and an x-
ray revealed a chalk stick fracture.
Laboratory studies revealed an elevated
alkaline phosphatase level.
Following this a skeletal survey was done and a
biopsy was performed.
The x-ray is of her pelvis and the slide is
representative of her lesion.
Case # 1
Findings:
Multiple bone pain
Fracture
Elevated alkaline phosphatase level
Case # 1
1. Describe the morphologic features of
the biopsy specimen.
The slide shows an abnormal arrangement
of lamellar bone resembling a jig-saw puzzle
separated by cement lines resulting in a
mosiac pattern.
2. What is your differential diagnosis?
Pagets disease of bone
Osteogenic sarcoma*****

Case # 1
How would you define Pagets disease?
A chronic disease of bone characterized by
enlargement and lytic lesions of bone
followed by disorganized and excessive bone
formation.
(matrix formation)

Case # 1
What are the clinical manifestations of Pagets
disease of bone?

Pain
Skull lesions with osteolysis
Fracture
High output failure due to increased blood supply
Osteogenic sarcoma***
Case # 1
3. What are the various stages through which
this condition progresses
-Hot or osteoclastic resorption stage
- Mixed osteoblastic and osteoclastic stage in which there is seen thickening of
the cortex
- Cold or burnt out stage
4. What are some of the complications that may
occur in association with this lesion?
- chalk stick fracture
- leontiasis ossea over growth of cranial-facial skeleton
- platybasia - invagination of base of skull with compression of post. fossa
- osteogenic sarcoma or giant cell tumor
- high output cardiac failure due to hypervascularity of pegetoid bone
there is increased blood flow (AV shunt) and hihg output failure



Case # 1
Comments:
The osteoclast is the pathologic cell seen in
Pagets disease and contrary to normal
osteoclasts Pagetoid ostcoclasts will contain
multiple nuclei (up to 100)

Case # 1
Final diagnosis

Pagets disease of bone
Case # 2
This 46 year old woman has a long standing history
of chronic renal disease secondary to chronic
pyelonephritis. More recently she has developed
paresthesias in her finger tips with her thumb
exhibiting a red-blue color and possible ischemic
change.
Initial laboratory findings:
Serum phosphorous 6.0
Serum calcium 7.6
BUN 57
Creatinine 3.0
A bone biopsy was performed.
Case # 2
Findings:
Chronic renal disease
Chronic pyelonephritis
Paraesthesias of fingers
Elevated chemistries

Case # 2
What is your interpretation of the
laboratory findings?
Phosphorous 6.0
Calcium 7.6
BUN 57
Creatinine 3

Case # 2
1. What is your interpretation of the bone
biopsy specimen?
Increased osteoclasts
Giant cells emeshed in a background fibrous stroma
Represents the so-called brown tumor of
bone osteitis fibrosa cystica
2. What do you believe is the underlying cause
of this womans problem?
Chronic renal failure with secondary
hyperparathyoidism

Case # 2
Describe the physiologic events that
occur in the evolution of this disease
process.
Due to chronic renal failure there is a decreased excretion of
of phosphorous resulting in hyperphosphatemia
This in turns leads to increased loss of calcium
The hypocalcemia stimulates the parathyoid gland to produce more
parathormone.
The increased PTH levels are detected by receptors on the osteoblasts which
in turn release molecules that stimulate osteoclastic bone resorption
How do you explain the ischemic changes
in her fingers?
Calciphylaxis this is due to vascular calcification of skin and
subcutaneous tissues resulting in ischemic changes

Final diagnosis

Chronic renal failure
With
Secondary hyperparathyroidism
Case # 3
This 15 year old young man complains of pain
in his left tibia.
Physical exam reveals an apparent soft tissue
mass beneath the skin in the area of his pain.
The mass is warm and the swollen.
An x-ray of of the leg shows a lytic process
involving the distal tibia
Laboratory findings:
Hemoglobin 11.0
WBC 15,000
Sedimentation rate 62
A biopsy of the bone was performed

Case # 3
Findings:
15 year male
Pain in left tibia with soft tissue mass
X-ray osteolytic lesion
Elevated sed rate

Case # 3
1. Describe the histologic findings in the
microscopic section.
The slide shows malignant appearing, small, round blue cells
without gland formation
2. What is your differential diagnosis?
Ewing sarcoma
Malignant lymphoma T and B cell markers
Rhabdomyosarcoma strap cells
Neuroblastoma pseudo-rosette formation
Small cell carcinoma of the lung immunofluorsescent stains
3. Would you order any special stains to
support your primary diagnosis?
PAS cells are rich in glycogen
Final diagnosis

Ewings sarcoma


Case # 4*****
This 42 year old woman has a history of type II
diabetes mellitus since the age of 30.
She now consults with her physician because of
pain in her ankle.
Physical exam reveals an obvious ulcer with
drainage of a purulent material.
An x-ray of the area reveals a sub-periosteal
abscess as well as a focal area of necrotic bone.
Case # 4
Findings:
History of diabetes mellitus
Pain in ankle with discharge
Ulcer with subperiosteal abscess

Case # 4
1. Would you order any additional lab tests?
Blood culture and wound culture
2. What would be your preliminary diagnosis?
Chronic osteomyelitis
3. Describe the sequence of events that may be seen in
the bone is this condition persists.
With the destruction of bone it is initially
surrounded by a sequestrum
Subsequent to this new bone is formed to create a
sheath around the necrotic segment - involucrum

Case # 4
4. What are the most common causes of
this disease process?
Pyogenic (bacterial) osteomyelitis
Staphy 80-90 %****; E. coli, Pseudo, Klebsiella
Tuberculous osteomyelitis
Get infection of the spine which may rupture
producing a cold abscess (psoas muscle). This
may dissect to emerge through the skin of the
inguinal area resulting in a draining sinus
Syphilis
Final diagnosis
Final diagnosis

Chronic osteomyeloitis
Case # 5
This 18 year old man complains of severe pain
in his right knee.
Physical exam reveals a swollen knee which is
warm to the touch.
An x-ray (picture # 1) reveals destruction of the
cortical bone as well as an adjacent soft tissue
mass.
A resection was performed and the microscopic
slide is representative of the lesion.
(slides # 2-3)
Case # 5
Findings:
18 year old man with pain in right knee
X-ray cortical bone destruction
Case # 5
1. Describe the microscopic findings seen in the
biopsy.
They show malignant osteoblasts which are forming
new bone.
2. What is your differential diagnosis?
Osteogenic sarcoma osteolytic and osteoblastic
Chondrosarcoma cartilagenous matrix
Ewings sarcoma small round blue cells
Fibrosarcoma spindle shaped cells
What other tumors will produce lytic and blastic
mets?
Prostate and breast

New bone formation
Malignant osteoblasts
Case # 5
3. What other conditions may be
associated with the development of this
disease process?
Pagets disease of bone
Bone infarct
Retinoblastoma of the eye
(the Rb gene due to germ line mutation exhibits
the risk of osteogenic sarcoma 1000 X)
Final diagnosis

Osteogenic sarcoma***
Case # 6****
This 38 year old woman has noted progressive
pain in both hands and her right knee over the
past two years. This pain had initially
responded to ASA and NSIAD but more
recently she now describes a lessening effect of
these drugs and progressive morning stiffness
of her joints.
Physical exam shows her hand joints to be
warm and swollen.
An x-ray of her hands was obtained and a
synovial biopsy of the knee joint was
performed.
Case # 6
Findings:
Progressive pain in hands and knee
Morning stiffness
Warm and swollen joints

Case # 6
Findings:
Morning stiffness of joints
Painful swollen joints


Case # 6
1. What is your interpretation of the x-ray?
2. Describe the histologic changes seen in the synovial
biopsy.
Villous proliferation of the synovial membrane
Leukocytic infiltration with lymphoid nodules
Formation of a pannus which erodes the articular cartilage
3.What is your differential diagnosis?
SLE
Osteoarthritis
Psoriatic arthritis
Gout
Connective tissue disease
Rheumatoid arthritis
Septic arthritis
Polymyalgia rheumatica and Lyme disease


Joint narrowing with erosion and osteoporosis
Proximal interphangial joints (PIP)
What is Rheumatoid Arthritis?
A systemic, chronic inflammatory
disorder that affects primarily joints but
also soft tissues, skin, blood vessels, heart,
lung and muscle.
Produces a non-suppurative synovitis
leading to destruction of articular
cartilage
A disease of women 20 40; F:M 4:1
Clinical Features
Slow and progressive disease
Hands and wrist most commonly
involved; joints red and swollen, painful
Bilateral and symmetrical
Causes bone erosion and osteoporosis
Swan neck deformity: hyperextension of
PIP and flexion of DIP
Joint effusions
Clinical Features
Formation of joint mice
Due to small fractures with dislodged pieces of
cartilage into joint space
Cyst formation with osteophytes
Pain becomes worse with use
Limitation of mobility
Joint effusions are common
Rheumatoid nodules
Herberdens nodes
Case # 6
Rheumatoid nodule:
Seen in 20 % of patients with RA
Central area of necrosis surrounded by
epitheloid histiocytes and lymphocytes
Microscopic findings
Hyperplasia of synovial lining with multi-
nucleated giant cells
Synovial lining shows villous-like and
frond-like folds that fill the joint space
Perivascular inflammatory changes with
fibrinoid necrosis
Juxta- articular erosion with pannus
formtion
Case # 6
What is the RA factor?
An IgM antibody

Is it specific for rheumatoid arthritis?
No! Also can be positive in sarcoidosis,TB,
autoimmune diseases, parasitic infections,
SLE

Diagnosis of RA
Need four criteria to make the diagnosis:
Morning stiffness
Arthritis in hands and joints
Symmetric arthritis
Rheumatoid nodules
Positive RA factor
Typical radiographic findings
Syndromes:
Feltys syndrome: RA+splenomegaly+neutropenia
Caplins syndrome: RA+pneumoconioses
Amyloidosis

What are the extra-articular
manifestations of RA
Blood vessels: rheumatoid vasculitis, palmar
erythema
Skin: rheumatoid nodules
Lung: rheumatoid nodules, pulmonary fibrosis
Spleen: amyloidosis
Heart:
Aorta: aortitis
Other organs
Case # 6
How would you distinguish RA from
Stills disease?
Juvenile arthritis
(Still s disease)****
A chronic inflammatory arthritis seen in
children under the age of 16
Female predominance
RA factor is absent
No rheumatoid nodules
May show positive ANA
70 90 % will recover
Regressive disease state
Case # 6
What are classical findings in making a
diagnosis of rheumatoid arthritis?
-morning stiffness
-arthritis in 3 or more joints
-arthritis of typical hand joints
-symmetric arthritis
-rheumatoid nodule
-serum rheumatoid factor (RA)
-typical radiographic changes
Note: you need four or more of these criteria to
support your diagnosis.

Final diagnosis

Rheumatoid arthritis
Case # 7
This 62 year old man has had repeated attacks
of acute arthritis involving several joints in his
body. This has progressed to the point where
he now suffers chronic arthritic pain. This past
week he developed an acute pain in his right
foot.
Physical exam reveals the foot to be
exquisitively tender.
An x-ray was taken
A biopsy was performed
Case # 7
Initial laboratory findings:
WBC 45,000
Hgb 9.5
RBC 3.0
Uric acid 12.0
Case # 7
Findings:
Repeated attacks of arthritis in multiple
joints
Acute pain in foot

Case # 7****
What is your differential diagnosis?
Gout
Pseudogout
Case # 7
What are the causes of hyperuricemia ?
Gout
High cell turnover e.g. acute leukemia
Recent ingestion of contaminated meat

Case # 7
1. What is your interpretation of the x-
ray?
A tophaceous deposit which has destroyed
the 1 st MP joint.
2. What is your interpretation of the
microscopic section?
There is a tophus containing uric acid
crystals

Gouty arthritis
Risk factors:
Age (M>)
Genetic predisposition
Alcohol, drugs, thiazides, lead, obesity
Micro:
Basic defect elevated uric acid level
Deposition of monosodium urate cyrstals in joints
(needle-like crystals), birefringent
Multi-nucleated giant cells
Gout and Gouty Arthritis
Types of Gout:
Primary: enzymatic defect overproduction of uric
acid
Secondary: assoc. with diseases with cellular
breakdown (e.g. leukemias, renal disease)

Clinical course:
Asymptomatic hyperuricemia
Acute gouty arthritis
Intercritical gout asymptomatic intervals
Chronic tophaceous gout
Gouty Tophus
Complications of Gout
Tophi:
Chalky, cheesy, yellow white pasty deposits
of mono-sodium urate crystals
Renal colic: deposition of uric acid
Chronic renal failure: common cause of
death (20 %)
Hypertension:
Pseudogout
(chondrocalcinosis)
Primary type:
Hereditary in origin, early onset
Secondary type:
Occurs in the elderly
Self-limited attacks of acute arthritis
Commonly associated with:
Hyperparathyroidism, ochronosis,diabetes,
hypothroidism, hypomagesemia
Morphology of Pseudogout
Deposition of calcium pyrophosphate
crystals in joint space
They exhibit a positive birefringence
Rhomboid shaped crystals
Macrophages and fibrosis
No gouty tophi
Final diagnosis

Gouty arthritis
Case # 8
This 70 year old post-menopausal woman
has complained of arthritis over the past
4 years. Two days ago she suffered a
compression fracture of her vertebra. **
Laboratory studies:
Serum calcium, phosphorous, alkaline
phosphatase and PTH are all normal.
An x-ray of her femur was taken.
Case # 8
Findings:
Post-menopausal female
Four year history of arthritis
Compressionn fracture
Calcium, phosphorous ,AP and PTH are
normal

Case # 8
What is the basic problem in this case?

Demineralization of bone!

Rate of bone formation may be normal
Rate of bone resorption is increased
Case # 8
What additional tests would you order?
Bone densitometry (DXA)
(note: cannot differentiate osteoporosis from
osteomalacia)
Quantitative serum vitamin D
Note: calcium and phosphorous levels not
always helpful!

Case # 8
What is your differential diagnosis?
Osteoporosis
Osteomalacia
Hormone deficiency ( lack of estrogen)
Cushings syndrome(hormone excess)
Immobolization
Hyperparathyroidism
Multiple myeloma
Excessive vitamin D
Osteoporosis
1) Peak bone mass 30 years of age
2) Average loss 0.7 %/ year
Pathogenesis of osteoporosis:
Age related osteoblasts have reduced capacity to
make bone senile osteoporosis
Genetic factors inherited deficiency of vitamin D
receptors
Nutritional status calcium deficiency
Hormonal influence post menopausal bone loss

Osteoporosis
Osteoporosis compression fracture
Case # 8
What factors are associated with the
development of osteoporosis?
Age literally worn out osteoblasts
Decreased physical activity
Genetic factors
Calcium nutritional status
Hormones estrogen deficiency
(you will see a 35 % loss of cortical bone over 20
years post-menopausal.)
What is osteomalacia?
Inadequate mineralization of newly
formed bone matrix
Clinically difficult to diagnose
Non-specific complaints weakness, aches
and pain
Frequently made after fracture femoral
neck and spine
Case # 8
How would you distinguish osteoporosis
from osteomalacia?
Painful proximal muscle weakness, bone
pain and tenderness
Decreased bone density
Elevated alkaline phosphatase in
osteomalacia

Osteomalacia
Related to vitamin D metabolism:
Low 25(OH) vitamin D
Inadequate exposure to sun light
Deficiency dietary intake young girls
Defective GI absorption
Hypocalemia, hypophasphatemia

Case # 8
Final diagnosis

Osteoporosis

Case # 9
This 58 year old woman has gained 30 pounds
over the past year. She has noted progressive
articular stiffness which has been periodic in
nature but now has become more prominent.
It is made worse by activity but relieved by
rest. More recently these symptoms tend to
limit the range of motion of her knees. She also
complains of progressive back pain.
X-rays of her hip and knee are illustrated
Joint space marrowing
Case # 10
What additional tests would you order?
RA
ANA
Case # 9
What is your differential diagnosis?
Osteoarthritis
Rheumatoid arthritis
SLE
Gout
Pseudogout
What is your final diagnosis?
Osteoarthritis
Case # 9
Osteoarthritis:
A degenerative disease
Most common form of arthritis
Characterized by loss of articular cartilage,
formation of new bone and osteophytes
No systemic manifestation
Asymmetric involvelment with localization to only a
few joints
Most commonly affects weight bearing joints
Pain worsens with activity, relieved by rest
Osteoarthritis
A slowly progressive destruction of the
articular cartilage
Most common form of arthritis >women
Primary or idiopathic type
Seen from 20- old age
A wear and tear arthritis degenerative joint dis.
Secondary type
Seen in younger individuals
Due to trauma, joint injury or secondary disease
(e.g. diabetes, ochronosis, hemochromatosis, obesity)
Clinical Features
Formation of joint mice
Due to small fractures with dislodged pieces
of cartilage into joint space
Cyst formation with osteophytes
Pain becomes worse with use
Limitation of mobility
Joint effusions are common
Herberdens nodes
Femoral Head Fracture
Osteoarthritis
Final diagnosis

Osteoarthritis
Case # 10
This 36 year old AfroAmerican woman
consults her PMD because of a gradual
increase of pain in her joints. These are
primarily noted in the bones of the
ankles, knees and fingers and appear to
be symmetrical . More recently she gives
a history of pleuritic pain. There is a past
history of hypertension which has been
controlled by hydralazine.
Case # 10
Initial laboratory findings revealed:
Hgb 9.0
WBC 2,300
Sed rate 53
Urinalysis 2-3 RBCs, 3+ protein
Platelet count 100,000
Case # 10
Findings:
Afro-American
Symmetric pain in small joints
Pleuritic pain
Hypertension
Hydralazine therapy
Case # 10
What is your differential diagnosis?
Connective tissue diseases:
SLE
Systemic sclerosis
Polymyositis,dermatomyositis
Mixed connective tissue disease
Rheumatoid arthritis
Vasculidities
Drug induced SLE
Sjogrens syndrome

Case # 10
What additional tests would you order?
ANA
Is a positive ANA specific for any
diagnosis?
No! can be elevated in the following:
SLE, scleroderma, RA, dermatomyosytitis
Wegeners



Case # 10
Antibody profile:
ANA titer >180 98 %
SLE
Anti Sm (15 %) anti double stranded DNA
Systemic sclerosis
Anti-Sci (40 %)
Polymyositis
Anti-Jo (25 %)
Case # 10
What are the various criteria used in making a
diagnosis of SLE?
Malar rash
Discoid rash
Photosenstitivity
Oral ulcers (painless)
Arthritis, symmetrical
Serositis
Renal disease protein> 0.5 gm; cellular casts
Need 4 criteria to make a diagnosis.


Case # 10
SLE is a systemic disease. What organ systems
may be involved?
Kidney
Lung
Pleura
Pericardium
Cardiac valves
CNS
Hematopoietic system
Case # 10
What are the various hematologic
manifestatons of SLE?
Hemolytic anemia
Thrombocytopenia
Lymphopenia
Leukopenia
Case # 10 (continued)
Thick skin systemic sclerosis
CREST Syndrome:
Calcinosis
Raymauds changes
tricolor pattern white to blue to red
Esophageal dysmotility
Sclerodactyl
Telangiectasia
Case # 10
Final diagnosis:

SLE
File: case studies-musculo-skeletal - discussion