Immune Neuropathies: Axonal

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CHRONIC IMMUNE POLYNEUROPATHIES: AXONAL

Amyloidosis
Ataxic Sensory + GD1b antibodies
Collagen vascular diseases
Distal lower motor neuron syndromes
Distal sensory
Perineuritis
Sensory + NF-H antibody
Sulfatide antibody-related
Trigeminal sensory
TS-HDS antibody
Vasculitic neuropathies

Also see:
Acute motor axonal neuropathy
Sensory neuronopathies

Duchenne

Distal Motor Axonal Neuropathies: "Distal Lower Motor Neuron Syndromes"

Clinical Features
- Onset
  - Age: 16 to 62 years
  - Distribution: Initial symptoms usually in hands
- Weakness
  - Distal > Proximal
  - Asymmetric
  - Arms > Legs
  - Bulbar: Normal
- ± Fasciculations
- Sensory: Normal
- Tendon reflexes: Normal; Occasionally reduced or increased
- Time course: Slowly progressive (years)
Laboratory
- Electrophysiology
  - NCV
    - Axonal Loss (Asymmetric): Small CMAPs
    - Occasional signs of demyelination: Mild; No conduction block
    - Sensory: Normal
  - EMG: Denervation
    - Type: Acute & Chronic
    - Distribution: Distal; Not paraspinous
- Serum Autoantibodies
  - IgM vs GM1
  - IgG vs GM1: Occasional patient
  - IgM or IgG vs GalNAc-GD1a ¹: Also see
    - Acute neuropathy with IgM binding to GalNAc-GD1a
    - Demyelinating neuropathy with IgM binding to GalNAc-GD1a and GM2 gangliosides
- Serum M-Protein: Occasional
- CSF
  - Cells: None
  - Protein: Normal or Mildly elevated
Differential Diagnosis
- Multifocal motor neuropathy
- ALS with few upper motor neuron signs: Primary muscular atrophy (PMA)
- SMN^T or SMN^C deletions
- Distal SMA
- Acquired lower motor neuron disorders
Treatment:
- IVIg: Anti-GalNAc-GD1a antibody-associated syndromes
- Cyclophosphamide
  - Indications
  - Protocol
- ? Rituxan

Neuropathy with IgG or polyclonal IgM binding to Sulfatide

Clinical Features
- Sensory
  - Symmetric; Paraesthesias
  - Distal; Hands & feet
- Motor loss: Mild or absent
Electrophysiology
- Axonal loss
Serum Autoantibody: IgM or IgG vs Sulfatide
Serum M-Protein: Occasional
Treatment: Cyclophosphamide & Plasma exchange
- Polyneuropathy & IgM anti-sulfatide antibodies, and
- Gait disorder (disabling; GALOP Syndrome) or severe proximal sensory loss

NEUROPATHIES: VASCULITIC & CONNECTIVE TISSUE DISORDERS

Vasculitis: General features

Clinical features
Associated syndromes
Laboratory findings
Pathology
Treatment
Vessel change: Location; Size

From: M Al-Lozi

SLE vasculitis

Specific connective tissue syndromes

Behçet
Churg-Strauss
CREST
Cryoglobulinemia
Drugs
Giant cell arteritis
? GVHD
Infections

Peripheral Nerve Specific
Polyarteritis Nodosa
Rheumatoid Arthritis
Scleroderma
Sjögren's
Spanish toxic oil
Systemic lupus erythematosis
Wegener's

General Features of Vasculitis

Clinical Features: General

Epidemiology
- Age: 80% > 50 years
- Vasculitis: Male > Female 2:1
- Prognosis: Worse with Increased age
Several anatomical patterns of neuropathy
- Mononeuritis Multiplex
  - Onset
    - Abrupt: Most common
    - Slow progression: In elderly
  - Asymmetric
  - Motor & Sensory
  - Nerves commonly affected
    - Peroneal (Sciatic) nerve: Most common (90%)
    - Posterior tibial (40%)
    - Ulnar (35%)
    - Median (25%)
    - Radial
- Confluent Mononeuritis Multiplex
  - Distal; Asymmetric; Motor & Sensory Loss
  - Other asymmetry by symptoms or signs
- Distal ± Symmetric: In small vessel vasculopathy
- Plexopathy: Lumbosacral > Brachial
- ? Small fiber neuropathy
Pain: Common (50%); Burning Dysesthesias
Systemic features
- Fever; Weight loss; Arthralgias; Fatigue
- May be related to associated connective tissue disease

Specific connective tissue disorders associated with vasculitis

Behçet
Churg-Strauss
CREST
Cryoglobulinemia
Drugs
Giant cell arteritis
? GVHD
Infections

Peripheral Nerve Specific
Polyarteritis Nodosa
Rheumatoid Arthritis
Sjögren's
Spanish toxic oil
Systemic lupus erythematosis
Wegener's

Electrophysiology
- Multiple focal changes
- Axonal loss: Small amplitude CMAPs & SNAPs
- Conduction block: In acute phase (1st 1 to 2 weeks) only
Laboratory
- Sedimentation rate: Often elevated; Usually < 50 unless active systemic vasculitis
- CSF: Often normal
- Serum Autoantibodies
  - IgG vs Neutrophil Cytoplasmic Antigens
    - Wegener's Granulomatosis or Polyarteritis Nodosa
  - Antinuclear antibodies
- Serum M-Protein: Rare
Pathology
- Biopsy necessary for diagnosis: Indications & procedure
  - Asymmetric or disabling neuropathy
  - Biopsy both nerve & muscle
  - Perform total, not fascicular, nerve biopsy
- Pathological findings
  - Epineurial inflammation
    - Associated with vessels
    - Mononuclear cell types: T-cells > Macrophages
    - Polymorphonuclar leukocytes: Acute disease
    - Cell fragments
  - Vessel Pathology
    - Active: Necrosis of vessel wall; Inflammation
    - Size & location of vessel changes has some disease specificity
    - Chronic vasculitis
      - Luminal narrowing
      - Vessel recanalization
      - Focal calcification of walls
      - Increased number of epineurial vessels
  - Axonal loss
    - Wallerian degeneration
    - Patchy involvement: Differential fascicular loss of axons
  - Perineurium
    - Focal damage
    - Subperineurial edema
  - Hemosiderin: Old hemorrhage in nerve
Vasculitis: Treatment⁹
- General Outcome
  - Overall: Good in 72%
  - After relapse that requires additional treatment: Good (78%)
  - Death: 6%; Often with
    - No remission in 1st year
    - More severe disease
    - Cyclophosphamide treatment
- Corticosteroids
  - Prednisone: 1 mg/kg/day p.o.
  - Solumedrol: 1 gram/ day x 5 i.v.; Then 1 g weekly for 1 month & q.o. week for 2 months
- Cyclophosphamide
  - General
    - Often used in combination with corticosteroids
    - Reduces frequency of relapses (2%) compared to steroid treatment alone (20%)
    - 15% deaths in 1st year after treatment: May be related to severity of vasculitis
  - Doses
    - IV: 1 gram/M² monthly x 6, Or
    - Oral: 2mg/kg qd; More long term toxicity
  - Strongest indications: Patients with severe systemic features
    - Serum creatinine: Increased
    - Proteinuria
    - Cardiomyopathy
    - Gastrointestinal disease
    - Central nervous system signs
    - Severe Wegeners
- Methotrexate
  - Dose: 15 mg to 25 mg/week
  - Milder disease: May substitute for cyclophosphamide
  - Cyclophophamide intolerance
- Indomethacin
  - Dose: 100 mg/day
  - Persistent fever or high sedimentation rate
- Anti-viral therapy: Patients with vasculitis & Hepatitis B or C
- Aspirin: ? Use at onset of corticosteroid Rx to prevent vascular occlusion

Systemic connective tissue disorders & Vasculitis: Specific syndromes⁴

Behçet
Churg-Strauss
CREST
Cryoglobulinemia
Drugs
Giant cell arteritis
? GVHD
Infections

Peripheral Nerve Specific
Polyarteritis Nodosa
Rheumatoid Arthritis
Scleroderma
Sjögren's
Spanish toxic oil
Systemic lupus erythematosis
Wegener's

Rheumatoid Arthritis
- Neuropathy: Vasculitic
  - Epidemiology
    - 10% of all RA
    - 50% of RA with systemic vasculitis
    - Longstanding disease: ~ 15 years after onset of RA
  - Sensory-Motor or Sensory
  - Multifocal or asymmetric in 2/3
  - Prognosis: Poorer with low serum CH50 and C4 complement
  - Serum antibodies: Rheumatoid factor (97%); Cryoglobulinemia (13%)
  - Pathology
    - Necrotizing arteritis in muscle (86%) & nerve (64%)
    - Focal lesions at midhumeral & midfemoral levels
  - Prognosis: RA + Vasculitis
    - No treatment: 5 yr survival 10%
    - Immunosuppression: 5 yr survival 80%
- Sensory-Motor neuropathy
  - Onset: Late in disease course
  - Distal
  - Symmetric
  - Mild or Asymptomatic
- Compression neuropathy
  - Carpal tunnel syndrome: Increased frequency with RA, especially with digital flexor synovitis
  - Inflamed elbow synovium: Radial or Ulnar
  - Baker's cyst: Popliteal fossa (Peroneal or Posterior Tibial); Iliopsoas bursa (Femoral)
- Other systems
  - Articular erosions; Sjögren's; Nodules
  - Coronary & mesenteric artery occlusions
- Differential diagnosis of weakness in RA
- Treatment
  - Corticosteroids: Especially high dose intermittent
  - Cyclophosphamide: Refractory patients
  - Treat Rheumatoid arthritis: Adjunctive therapy
    - Infliximab
    - Methotrexate

Polyarteritis Nodosa (PAN; Systemic necrotizing vasculitis)

PAN: Diagnostic features vs other vasculitides¹¹

Positive predictive features
- Clinical: Mono- or Polyneuropathy
- Serum: Hepatitis B virus antigen or DNA
- Arteriographic anomalies
Negative predictive features
- Clinical
  - Asthma
  - ENT signs
  - Glomerulopathy
- Laboratory
  - ANCA (immunofluorescence)
  - Cryoglobulinemia

Epidemiology
- Male > Female: 1.6-2 times
- Onset age: 40 to 60 years
- Incidence: ~7/1,000,000/year
- Neuropathy
  - Present in ~25% at time of diagnosis
  - Occurs in ~50% to 75% during course of disease
Neuropathy
- Mononeuritis multiplex: Motor-sensory
  - Most common pattern of involvement (57%)
  - Radial, median, ulnar & sciatic (peroneal) most frequent
  - Occurs in with systemic features of PAN
  - Course: Step-wise or progressive; Over weeks to months
- Other patterns of neuropathy
  - Distal symmetric neuropathy (25%)
  - Cranial neuropathy: Oculomotor; Facial
  - Brachial plexopathy
  - Mononeuropathy
Pain: Myalgia (Normal CK); Testicular or Ovarian
CNS: Vasculitis may occur late in disease course

Systemic features

Systemic vasculitides
(PAN & Microscopic Polyangiitis)
Common features

Weight loss > 4 kg
Livido reticularis
Testicular discomfort
Myalgia, weakness or tenderness
Poly- or Mononeuropathy
Diastolic blood pressure >90 mm Hg
Renal dysfunction
- BUN > 40 mg%, or
- Creatinine > 1.5 mg%
Hepatitis B surface Ag or Ab
Arteriography
- Aneurysm or occlusion
- In visceral artery
Pathology: Cell infiltrates in artery
- Polymorpho- or mononuclear
- In arterial wall
- Small or medium size

General (60%): Edema; Weight loss; Fever; Arthralgia; Fatigue
Skin: Livido reticularis; Rash; Purpura; Ulcers
Renal dysfunction: 80%
- Increased BUN & Creatinine
- Hypertension
- Nephrotic proteinuria
GI: Bleeding; Infarction
Pulmonary: Asthma in ~10%
Cardiac: Juvenile forms
Associated infection: Hepatitis B (30%); Hepatitis C
Associated neoplasm: Hairy cell leukemia

Electrodiagnostic studies
- Axonal loss
  - Small CMAPs with relatively normal conduction velocities
  - Often Patchy & Asymmetric
  - Occasionally Distal & Symmetric
- Conduction block: With acute focal ischemic lesion; Present for ~ 1 week
Pathology: Diagnosis by tissue biopsy
- Necrotizing vasculitis of medium & small arterioles in epineurium
  - Vessel size: 100μm to 200 μm
  - Lesions are patchy & may need serial sectioins to detect
  - Entire nerve & muscle biopsy should be examined to increase chance of detection
- Patchy axonal loss
- Inflammation: Mononucler & Polymorphonuclear
Other diagnostic tests
- Angiography
- Hepatitis B & C
- pANCA
- Complement reduced: ~ 25% to 50%
- Cryoglobulins
Treatment
- Corticosteroids
- Cyclophosphamide in poorly responsive patients
Prognosis
- Untreated disease: High mortality
- After immunosuppressive treatment: Improvement in most over months to years

Churg-Strauss: Allergic granulomatosis & angiitis

Churg-Strauss: Diagnostic criteria*

Asthma
Livido reticularis
Neuropathy
Pulmonary infiltrates
Paranasal sinus disorder
Pathology: Extravascular eosinophils

* > 4 criteria
Specificity: > 99%
Sensitivity: 85%

Neuropathy (in 20% to 50%)
- Onset
  - Age: Mean 52 years
  - Painful distal dysesthesias: Legs > Arms
  - Edema in dysesthetic limb
  - After asthma; Before Visceral & Skin change
- Mononeuritis multiplex
  - Peroneal nerve (90%)
  - Other nerves: Tibial; Sural; Ulnar; Median
- Motor: Distal; Similar to sensory distribution
- Sensory: Limbs, but not Trunk
- Progression
  - To asymmetric neuropathy in limbs
  - Rapid: Over 2 to 4 weeks
- Occasional patients have symmetric neuropathy
CNS: Ischemic optic neuropathy
Systemic
- Fever; Fatigue; Arthralgias
- Pulmonary
  - Bronchial asthma: Precedes neuropathy by 1 to 30 years
  - Infiltrates
- Skin: Atopy
- Sinusitis: Paranasal
- Gastrointestinal
- Other: Renal (Uncommon); Hepatic
Disease association: ? Leukotriene receptor inhibitors
Prognosis
- Worse with
  - Renal involvement
  - Cardiomyopathy
  - CNS involvement
  - GI disorders
  - No immunosuppressive treatment
- Better with
  - Response to corticosteroids in 1st 4 weeks
  - Less systemic involvement
Lab
- Eosinophilia; Leukocytosis
- Increased serum LDH
- Hypoalbuminemia
- Acute phase reactants: Increased ESR & C-reactive protein (moderate)
- Immunoglobulin: High IgE (74%) & IgG (40%)
Serum antibodies
- p-ANCA (40% to 60%)
- Rheumatoid factor: (86%)
- ANA negative
Pathology
- Necrotizing vasculitis: Medium & small vessels; Epineurial
  - Found in nerve in 54%
  - Similar to PAN
- Inflammation
  - Infiltrates: CD8 + & CD4 + lymphocytes
  - Extravascular (eosinophilic) granulomas (40%)
  - Eosinophils: Extravascular
  - Rare CD20 + B-cells
- Sural nerve most common pathology (89%)
- Acute axonal loss
Treatment
- Corticosteroids
- Cyclophosphamide (Intravenous) in poorly responsive patients

Wegener's Granulomatosis⁶
- General
  - Onset: Mean ~ 50 years; Range 40 to 55 years
  - Frequency: 3 in 100,000
  - Male = Female
- Peripheral Neuropathy
  - Epidemiology of neuropathy in Wegener's
    - Frequency: Up to 44% of patients with Wegener's
    - Male (61%) > Female (39%)
    - More common in older patients: Mean 53 years vs 44 years in patients with no neuropathy
    - More severe disease: Renal, Skin or Cardiac involvement
    - ANCA: 2x Higher titers
  - Neuropathy Types
    - Symmetric: 24% of patients with Wegener's
    - Multiple mononeuropathies
      - Frequency: 20%
      - Progress to more disability than symmetric neuropathies
      - More response to immunosupprressive treatment
  - Onset
    - At or before systemic disease presentation: Some patients
    - During 1st 2 years of disease: 84%
    - Progression: Acute (45%) or Gradual (55%)
  - Weakness: Legs > Arms
  - Sensory involvement
    - Loss: Panmodal
    - Paresthesias
    - Pain: Burning
  - Tendon reflexes: Often reduced
  - Asymptomatic involvement detected by NCV: 20% of PN
- Cranial nerves (5%)
  - Optic; EOM; V; VII
  - Related to infiltration by granulomatous process
- CNS: 7%
- Systemic features
  - Renal (80%)
    - Glomerulonephritis
    - Active urinary sediment
    - Pathology: Focal segmental necrotizing glomerulonephritis
  - Pulmonary
    - Upper airway: Sinusitis, Epistaxis, Nasal septal perforation, Subglottic stenosis
    - Lung: Dyspnea, Hemoptysis, Wheezing, Cough
    - Abnormal chest X-ray & CT
  - Inflammation: Nasal; Oral
  - Associated neoplasm: Hodgkin's lymphoma
- Laboratory
  - Antibody
    - Antineutrophil cytoplasmic (ANCA)
      - c-ANCA (80%): Target antigen is Proteinase-3
      - p-ANCA (10%): Target antigen is Myeloperoxidase
  - Electophysiology
    - Axonal loss
    - EMG: Denervation
    - Rare demyelinating features (5%)
- Pathology
  - Small & Midsize vessel inflammation: Similar to PAN
  - Granulomas: Only occasionally found in nerve biopsy
  - ? Disease in symmetric neuropathy related to capillary pathology
  - Axonal loss
- Prognosis
  - No treatment: 5 yr survival 7%
  - Treatment induces remission in 90%
  - Some residual deficit common
- Treatment
  - Prednisone and Cyclophosphamide
  - Improvement common: Especially with mononeuritis multiplex
  - ANCA titers may guide treatment
  - Maintenance: Azathioprine; Methotrexate; Trimethoprim-sulfamethoxazole
Systemic Lupus Erythematosis

From: M Al-Lozi

SLE vasculitis
- Neuropathy: General
  - Frequency: 10%
  - Rarely initial manifestation of lupus
- Types of polyneuropathy
  - Multiple mononeuropathies: 2° to Vasculitis
  - Distal Symmetric Sensory-Motor⁵
    - Most common type
    - Usually predominantly sensory
    - Electrodiagnostic studies
      - Axonal loss
      - Progression
        
        Slow or none over years
        
        More in older patients
    - Pathology
      - Small vessel vasculopathy
      - Differential fascicular loss of axons
    - Treatment: Corticosteroids
  - Trigeminal neuropathy
    - Distribution
      - Usually 2 or more divisions affected
      - Unilateral or Bilateral
    - Sensory: Numbness & Pain
    - Motor: Normal
    - Treatment: Pain control
- ? Guillain-Barré & CIDP have increased frequency
- Most neurologic complications of Lupus are CNS
Peripheral Nerve Specific Vasculitis²
- Epidemiology: Females & Males
- Onset
  - Age: Mean 59 years; Range 22 to 70 years
  - Pain & Sensory loss
  - Progression: 3 months to 5 years
- Neuropathy
  - Sensory or Sensory-Motor
  - General patterns
    - Mononeuritis multiplex (13%)
    - Asymmetric polyneuropathy (85%)
    - Distal symmetric polyneuropathy (2%)
  - More slowly progressive than with systemic vasculitis
  - Pain: Nerve or Muscle
- General signs (50%): Fever; Weight loss
- Prognosis
  - Stepwise progression
  - 35% develop systemic vasculitis over 6 years
  - Long period between relapses (3.5 years)
    vs. initially systemic disorders (9 months)
  - 5 year survival: 85%
- Disease associations
  - Usually none
  - Diabetes
  - Occasional neoplasm²
- Laboratory
  - Sedimentation rate high: 18% to 65%
  - NCV: Axon loss, asymmetric
- Pathology: Necessary for diagnosis
  - Inflammation
    - CD4 & CD8 cells + Macropahages
    - Associated with small (30 to 100 μm) epineurial vessels
    - May also occur in small vessels in muscle
  - Subperineurial edema (30%)
  - Perineurial thickening (50%)
  - Axon loss: Patchy
  - Ig & C3 deposits in vessels with inflammation
- Treatment
  - Corticosteroids
  - Cyclophosphamide: Lowers long term disability when added to corticosteroid Rx
  - Azathioprine: Corticosteroid sparing agent
Scleroderma

Antibodies
Clinical
Myositis
Pathogenesis
Pathology
Types

Charcot
- Types
  - Localized scleroderma
    - Morphea: Plaques of skin fibrosis
    - Linear scleroderma: Bands of fibrosis; May be associated with facial hemiatrophy
    - En coup de sabre
  - Systemic sclerosis (Scleroderma)
    - Diffuse cutaneous scleroderma
      - Rapidly progressive
      - Widespread skin thickening
      - Similar syndromes 2° toxins: Silica; Vinyl chloride; Organic solvents; Eosinophilia myalgia
    - Limited cutaneous scleroderma
      - Slowly progressive
      - Skin changes confined to distal limbs & face
      - Types: Crest; Sine scleroderma (Visceral but no skin changes)
  - Raynaud's phenomenon
    - Primary
      - Multiple family members affected
      - Female predisposition
      - Teenage onset
    - Autoimmune
- Epidemiological features of systemic sclerosis
  - Peak onset: 30 to 50 years
  - Sex: Females > Males; Especially black females
- Clinical features of systemic sclerosis
  - Course: Rapidly progressive
  - Skin
    - Thick: Limbs ± Trunk
    - Shiny
    - Adherent
    - May impair mobility of muscles & joints
    - External link: DOIA Images
  - Nailfold abnormalities
  - Raynaud's phenomenon
  - Fatigue
  - GI
    - Esophageal: Dysmobility
    - Colon: Diarrhea or Constipation
  - Cardiac
    - Pericarditis
    - Myocardial fibrosis: Arrhythmias
  - Pulmonary
    - Parenchymal disease
    - Pulmonary hypertension
    - Restricted chest wall movement
  - Renal dysfunction: 2° Vascular intimal hyperplasia
  - Malignancies: Increased association
    - Treatment-associated
    - Scar cancer: In fibrotic lung tissue
- Neuropathies with systemic sclerosis: Rare
  - Trigeminal sensory neuropathy
  - Sensory-Motor neuropathy
    - Often Asymmetric & Distal
    - Distal paresthesias
    - Weakness: Distal; After disease progression
    - Pathology: Microangiopathy; Axonal loss
    - Treatment: Poor response
  - Entrapment neuropathies
    - Common
    - Especially median
- Myositis & Myopathy
- Autoantibodies in scleroderma⁸
  - Specific antibodies for scleroderma
    - Scl-70
    - Centromere
    - RNAP I/III
    - Fibrillarin
    - Th/To
  - Possibly related to disease pathogenesis
    - Endothelial cell
      - Induce vascular injury: Endothelial cell apoptosis
      - Clinical associations: Ischemic digital infarcts; Pulmonary arterial hypertension
    - Fibroblast
      - Induce fibroblast production of ICAM-1 & IL-6: Vascular damage & ECM production
      - Clinical associations: Limited scleroderma
    - Matrix metalloproteinase
      - Inhibit MMP-1 collagenase activity
      - Clinical associations: Diffuse scleroderma
    - Fibrillin-1
      - Induces instability of microfibrils: Extracellular membrane accumulation
      - Clinical associations: Choctaw American Indian & Japanese ethnic backgrounds
  - Correlation with phenotypes: Antinuclear & Antinucleolar
    - Topoisomerase-I
      - Staining pattern: Nucleolar/homogeneous
      - Specificity for scleroderma: 99% to 100%
      - Sensitivity for scleroderma: 20% to 43%
      - Clinical associations
        
        Diffuse cutaneous; Peripheral vascular; Pulmonary fibrosis; Cardiac; Malignancies
      - Fluctuate with disease activity
    - Centromere
      - Staining pattern: Centromere
      - Specificity for scleroderma: High
        
        CREST syndrome
        May occur in primary Raynaud's & other connective tissue disorders
      - Clinical associations
        
        Ischemic digital loss with limited cutaneous involvement
        
        Pulmonary hypertension without pulmonary fibrosis
        
        Renal involvement
    - Histone
      - Most commonly associated with drug-induced lupus
      - Prevalence in scleroderma: 29%
      - Clinical associations
        
        Severe pulmonary fibrosis
        
        Cardiac & Renal disease
        
        Poor prognostic indicator: Internal organ involvement & reduced survival
    - PM-Scl
      - Syndrome associations
        
        Myositis (5% to 8%)
        
        Scleroderma (3%)
        
        PM/scleroderma overlap (24%)
        
        Other
      - Clinical associations: Raynaud�s phenomenon; Arthritis; Pulmonary; Calcinosis
      - Good response to immunosuppressive therapy
      - Course: Benign
      - Antigenic target: Exosome
    - Th/To
      - Prevalence in scleroderma: 4% to 13%
      - Clinical associations
        
        Puffy fingers
        
        Small bowel disorders
        
        Hypothyroidism
        
        Poor survival
        
        Limited cutaneous disease
    - U3-small nucleolar ribonucleoprotein particle (U3-snoRNP)
      - Antigenic targets
        
        Fibrillarin protein complex: Most common
        
        Other: Mpp10
      - Sundrome: Diffuse cutaneous involvement (Low sensitivity)
      - Severe disease: Especially in African-Americans & men
      - More frequent cardiac, renal, or GI involvement
      - Isolated pulmonary hypertension
      - Mpp10: Esophageal & Lung involvement
    - U1-small nuclear ribonucleoprotein particle (U1-snRNP)
      - Syndrome association: Lupus overlap syndrome, MCTD
      - Clinical association: Raynaud�s phenomenon
    - RNA polymerase
      - Syndrome association: Diffuse cutaneous involvement
      - Clinical association: Renal crisis
    - B23
      - Syndrome association: Limited cutaneous disease
      - Clinical associations: Pulmonary arterial hypertension; Malignancies
- Pathology: 3 facets
  - Capillaries & Endothelial cells
    - Pathological features
      - May be early pathological feature
      - Malformation
      - Increased permeability
      - Basement membrane pathology
      - Rarefaction
      - Injury & Activation
    - Clinical association: Raynaud�s phenomenon
    - Laboratory testing
      - Increased serum levels of: von Willebrand factor; Endothelin
      - Increased numbers of circulating viable & dead endothelial cells
  - Cellular/Humoral Autoimmunity
    - Cells
      - Early: Perivascular monocytic/macrophage infiltrate
      - Later: Multiple inflammatory cell types
  - Fibrosis
    - Increased deposition of extracellular matrix components
    - Destruction of normal tissue architecture
    - Clinical association: Most tissue & organ dysfunction
- Pathogenesis: Tissue damage possibly related to several mediators
  - Transforming growth factor-β
  - Connective tissue growth factor,
  - platelet-derived growth factor
  - C�C family of chemokines
  - Endothelin-1 (ET-1)
    - Present early in lesioned tissues
    - Released from damaged or activated endothelial cells
    - Pro-fibrotic effects
    - Effects appear to be mediated via ETA and ETB receptor subtypes
  - VEGF: Levels increased in serum
- Differential diagnosis: See Nephrogenic Fibrosis
CREST
- Calcinosis; Raynaud's; Esophageal dysmotility; Sclerodactyly; Telangectasias
- Neuropathy: Vasculitic
  - Distal
  - Predominantly sensory
  - Multifocal & asymmetric
  - Indolent course
  - Pathology
    - Multifocal axon degeneration & loss
    - Inflammation & necrosis of epineurial arterioles
- Antibodies
  - Centromere
  - Fibrillarin
Giant Cell Arteritis
- Related to Polymyalgia rheumatica(PMR)
- Onset > 50 years of age
- Neuropathy
  - Some association with carpal tunnel syndrome & PMR
  - Occasional associations
    - Distal symmetric sensory-motor neuropathy
    - Ischemic mononeuropathy
    - Mononeuritis multiplex
Behçet
- Clinical
  - Oral: Aphthous ulcers
  - Genital ulcers
  - Ocular: Uveitis & Retinal vasculitis;m painless loss of vision
  - Skin: Papules & Pustules on skin of proximal limbs & trunk
  - Vascular: Venous occlusions; Arterial aneurysms
  - CNS (25%): Meningitis; Occasional brain vasculitis
- Neuropathy: Rare
  - Distribution: Symmetric neuropathy or Mononeuritis multiplex
  - Pathology: Axonal loss
Cryoglobulinemia
Drugs & Vasculitis: Amphetamine; Cocaine; Heroin; Ephedrine; Phenylpropanolamine
- Most drug-induced vasculitis affects skin 1st
- Amphetamine associated with early neuropathy
- Other drugs: Penicillin; Sulfonamide; Phenytoin; Allopurinol; Propylthiouracil
Infections & Vasculitis
- HIV
- Lyme
- Cytomegalovirus
- Parvovirus
- Hepatitis B > C > A

Perineuritis

Clinical features of neuropathy
- Age: 90% > 50 years
- Asymmetric
- Sensory & motor
Associated disorders
- Diabetes mellitus: > 50%
- CIDP
- Cryoglobulinemia
- Spanish toxic oil
- Weight loss
- Collagen vascular syndromes
- Sepsis
Pathology
- Thickening of perineurium focally around some fascicles
- Degeneration or loss of perineurial cells ± inflammation
Treatment: ? Immunosuppression

Sensory (± Ataxic) neuropathy with anti-GD1b (disialosyl) antibodies³

Epidemiology
- Male > Female
- Onset age: 39 to 76 years
Clinical (IgM)
Galβ1-3GalNAcβ1-4Galβ1-4Glcβ1-1'Ceramide 3 | Neu5Acα2-8Neu5Acα2
GD1b ganglioside
- Onset: Acute, Subacute or Chronic
- Sensory loss (100%)
  - Distal
  - Symmetric
  - Large & small fiber modalities
  - Legs & arms
- Paresthesias
- Tendon reflexes: Absent
- Strength
  - Normal in 50%
  - Weakness (50%): Mild; Distal
- Gait
  - Ataxic (Sensory)
  - + Romberg
  - Tandem relatively spared
    CANOMAD
    Syndrome
    Chronic
    Ataxic
    Neuropathy
    Ophthalmoplegia
    M-protein
    Agglutination
    Disialosyl antibodies
- Cranial nerves
  - Ophthalmoplegia (50% to 90%)
  - Trigeminal (50%): Perioral paresthesias
  - Facial (25%)
  - Bulbar (66%)
Course
- Usually slowly progressive over months to years
- Variants: Acute, Relapsing or Stepwise progressive sensory neuropathy
Antibodies
- IgM
  - M-protein: Often; κ > λ
  - Cross reactivity: Other gangliosides containing disialosyl groups
    - GD3; GD2; GT1b; GQ1b
    - NOT GM1; GM3; GD1a
  - Anti-Pr₂ activity
  - Cold agglutinins (50%)
  - Bind to: Dorsal root ganglion cells; Nerve terminals
  - Similar neuropathy after treatment with monoclonal anti-GD2 antibody
- IgG anti-GD1b antibody associations
  - Acute sensory neuropathy
  - Polyclonal antibody
- M-protein: 93%; κ or λ
Other lab
- Sedimentation rate: High
- CSF: Moderately high protein in some patients
- MRI: Occasional patient with white matter lesions
Nerve conductions
- Sensory axonal loss: Sensory potentials (SNAPs) Absent
- Motor: Normal or mildly reduced amplitude & conduction velocity
- Demyelination (50%)
  - Distal latencies: Mildly prolonged
  - NCV: Often normal; Occasionally slowed to 20 to 30 M/s
  - More prominent later in course
Pathology
- Peripheral nerve: Loss of large myelinated axons & Dorsal root ganglion cells
- 1 autopsy case with demyelination of nerve roots: Serum IgM binds to both GD1b & GD1a
Treatment: ? Cyclophosphamide; ? IVIg; ? Rituximab
Variant syndrome: Acute ataxic sensory neuropathy¹⁰
- Predisposing factor
  - Previous infection: C. jejuni
  - Clinical: Upper respiratory infection most common
- Clinical
  - Sensory
    - Paresthesias: Distal extremities
    - Sensory loss: Large > Small fiber modalities
    - Gait: Sensory ataxia; Romberg positive
  - Motor: Normal strength
  - Tendon reflexes: Absent or Reduced
- Course
  - Neuropathy onset: 1 to 3 weeks after infection
  - Monophasic
  - Complete recovery may occur over months
- Antibodies
  - Type: Polyclonal IgG vs GD1b
  - Serum may also bind to GQ1b or GT1a gangliosides
- Laboratory
  - CSF
    - Cells: None
    - Protein: Normal or High
  - NCV
    - SNAPS: Amplitude reduced; Velocity normal
    - CMAPs: Normal
- Differential diagnosis: Acute sensory neuropathy

Axonal sensory neuropathy with IgM binding to Trisulfated Heparin Disaccharide⁷

Epidemiology
- 5 patients described
  
  TS-HDS
- Onset age: 61 to 71 years
- Sex: 4 Female; 1 Male
Clinical
- Sensory loss (100%): Distal; Symmetric; All modalities except proprioception
- Pain (100%): Paresthetic; Occasional cramps
- Weakness (20%): Feet
- Tendon reflexes: Absent at ankles (100%)
- Progression: Slow over years
Antibodies
- Serum IgM target: Trisulfated heparin disaccharide (TS-HDS)
  - Structure: IdoA-2S GlcN-S-6S
  - Functions
    - Binds to fibroblast growth factor (FGF)-1
    - Modulates oligomerization of FGF-2 binding to FGF receptor
- Autoantibody types
  - Monoclonal κ class
  - Polyclonal
- Antibody correlations
  - Axonal neuropathy 72%
  - MAG neuropathy: 28%
- Antibody location: Serum
- M-protein detected by immunofixation: 20%; κ class
Electrodiagnostic testing
- Axonal loss: SNAP amplitude reduced or Abnormal quantitative sensory testing
- May be normal (20%)
Pathology
- Loss of unmyelinated axons
- IgM deposited around the outside of the wall of medium- and larger-sized vessels

Axonal sensory neuropathy with anti-neurofilament (200 kDa) antibodies

Clinical
- Age: > 60
- Sensory loss: All modalities
- Strength: Relatively preserved
Nerve conduction studies: Axonal loss
Antibodies
- Monoclonal IgM
- Neural Target: Neurofilament heavy chain
- Other cross-reactive antigens
  - Histone H2b: Common epitope PEPAKS (NF-H 663-668 & H2b 1-6)
  - Histone H1: Common epitope AKSPEKAK (NF-H 716-723 & H1 170-177)
Other syndrome with antineurofilament antibodies: Opsoclonus-Myoclonus syndromes

Immune axonal neuropathies: Other

Distal sensory neuropathy with systemic immune disorder

Connective tissue disorders
- Systemic lupus erythematosis (SLE) (10%)
- Rheumatoid arthritis (50% to 75%)
- Systemic sclerosis (14%)
- Sjögren's (15%)

Trigeminal sensory neuropathy

Clinical
- Facial numbness: Unilateral or bilateral
- Pain & paresthesias
- Corneal response: Reduced
Associated disorders: Systemic sclerosis; Other connective tissue diseases
Progression: Over 6 to 24 months; No remission
Treatment: Little response to immunosuppression

Amyloidosis

VASCULITIS: Nerve Location of vessel involvement
Epineurial arteriole	Epineurial small vessel	Endoneurial	Either
CREST Isolated PNS Giant cell Rheumatoid arthritis Malignancy (rare)	Peripheral nerve	Serum sickness Drug-induced Malignancy HIV-associated Paraprotein	Polyarteritis Churg-Strauss Overlap syndromes Wegener's SLE Sjögren's Cryoglobulinemia

VASCULITIS: Vessel size involved
Vessel size	1° Disease	2° Disease
Large arteries	Giant cell (Temporal) arteritis Takayasu's arteritis	Rheumatoid arteritis Syphilis
Medium arteries	Polyarteritis nodosa Kawasaki disease CNS angiitis	Infection: Hepatitis B
Small vessels & Medium arteries	Wegener's granulomatosis Churg-Strauss Microscopic polyangiitis	Rheumatoid arthritis & SLE Sjögren's Drugs & infections
Small vessels	Henoch-Schönlein purpura Essential mixed cryoglobulinemia Cutaneous leukoclastic angiitis Behçet Tumor-associated: Lymphoma; Hairy cell leukemia; Melanoma	Drugs Infection: Hepatitis B > C > A

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References
1. Muscle Nerve 2000;23:702-706, J Neuroimmunol 2001;119:114�123
2. Neurol Clin 1997:15:849-863, J Rheumatol 2005;32:769-772, J Rheumatol 2005;32:853-858
3. J Neuroimmunol 2001;112:181-187; Brain 2001;124:1968-1977
4. Muscle Nerve 2001;24:154-169
5. Acta Neurol Scand 2001;103:386-391
6. Arch Neurol 2001;58:1215-1221
7. Muscle Nerve 2003;27:188-195
8. Current Rheumatology Reports 2004;6:156�163
9. QJM 2007;100:41-51
10. Muscle Nerve 2007; Online September
11. Arthritis Rheum 2008;58:1528-1538

6/15/2009

CHRONIC IMMUNE POLYNEUROPATHIES: AXONAL

Distal Motor Axonal Neuropathies: "Distal Lower Motor Neuron Syndromes"

Neuropathy with IgG or polyclonal IgM binding to Sulfatide

NEUROPATHIES: VASCULITIC & CONNECTIVE TISSUE DISORDERS

Perineuritis

Sensory (± Ataxic) neuropathy with anti-GD1b (disialosyl) antibodies3

Axonal sensory neuropathy with IgM binding to Trisulfated Heparin Disaccharide7

Axonal sensory neuropathy with anti-neurofilament (200 kDa) antibodies

Immune axonal neuropathies: Other

Sensory (± Ataxic) neuropathy with anti-GD1b (disialosyl) antibodies³

Axonal sensory neuropathy with IgM binding to Trisulfated Heparin Disaccharide⁷