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
FGFR-3
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 (50%)
  - IgM vs NS6S (45%)
  - 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
- 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

Differential features
Clinical features
EGPA (Churg-Strauss)
GPA (Wegener)
Associated syndromes
Laboratory findings
ANCA
Pathology
Treatment
Vessel pathology
Location
Size

From: M Al-Lozi

SLE vasculitis

Vasculopathy: Connective tissue syndromes

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

MPA
Polyarteritis Nodosa
Rheumatoid Arthritis
Scleroderma
Sjögren's
Spanish toxic oil
Systemic lupus erythematosis
Wegener's

Vasculopathy: Nerve Specific
HIEM
NSVN

General Features of Vasculitis

Clinical Features: General
- Epidemiology
  - Age: 80% > 50 years
  - Vasculitis: Male > Female 2:1
  - Prognosis: Worse with Increased age
  - Genetic associations
    - Granulomatous Polyangiitis
      - HLA-DPB1 : Abnormal antigen presentation
      - PRTN3: Increased expression of PR3 on neutrophils surface
      - SERPINA1 : Reduced activity of α1-antitrypsin (Main inhibitor of PR3 activity)
      - PTPN22: Abnormal Treg function; Increased B cell & neutrophil function
      - CTLA4: Increased T-cell activity
    - Microscopic polyangiitis
      - HLA-DQ : MPA Abnormal antigen presentation
- Several anatomical patterns of neuropathy
  - Mononeuritis Multiplex
    - Onset
      - Abrupt: Most common
      - Slow progression: In elderly
    - Asymmetric
    - Axon loss: Motor & Sensory
    - Nerves commonly affected
      - Peroneal (Sciatic) nerve: Most common (90%)
      - Posterior tibial (40%)
      - Ulnar (35%)
      - Median (25%)
      - Radial
    - Pain: More common than in distal polyneuropathies
  - 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 with vasculitis or inflammatory vasculopathy
- Vasculitis pathology causing neuropathy: Associations ³⁰
  - More common with
    - Clinical
      - Course: Step-wise; Subacute (< 1 month)
      - Distribution: Asymmetric
      - Systemic disease association
      - Onset age: Younger for non-systemic vasculitis
    - Laboratory
      - Myeloperoxidase antibody (p-ANCA)
      - Rheumatoid factor
      - Cryoglobulins
      - ANA+
  - Less common with
    - Neuropathy: Symmetric; Pure motor
    - NCV: Normal or Demyelinating
    - CSF: Pleocytosis; Protein very high
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 (ANCA)
    - Wegener's Granulomatosis or Polyarteritis Nodosa
    - c-ANCA
    - p-ANCA
  - 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
- Vasculitis: Pathologic features
  - Vessels
    - Active: Fibrinoid Necrosis within vessel
      - Accumulation of fibrin at sites of vessel damage
      - Common with: ANCA associated vasculitis
    - Lumen
      - Fibrin deposits ("Fibrinoid Necrosis")
      - Neovascularization
      - Occlusion
      - Connective tissue (Intimal proliferation)
    - Wall damage
      - Fibril layer (VvG): Discontinuous or Absent
      - Smooth muscle layer (ATPase pH4.3; Smooth muscle actin): Interrupted
    - Vessel Pathology Locations
      - Arterioles ± Venules
      - Size & Location of vessel changes: Some disease specificity
    - Associated Cells
      - Acute lesion
        
        Location: Vessel walls & Surrounding connective tissue
        Cell Types
        
        Neutrophils & Other Leukocytes
        
        Leukocytoclasia: Fragmentation of leukocyte nuclei
        
        Histiocytes: Within & Around vessel walls
        Eosinophils: Some patients; EGPA
      - Chronic (Weeks) lesion
        
        Cell types: Histiocytes, Lymphocytes & Monocytes
      - Granulomatous
    - Surounding Connective tissue
      - Alkaline phosphatase +
      - Acid phosphatase +
      - Structure
        
        Disorganized
        
        Neovascularization
      - Hemosiderin deposits
    - Hemorrhagic Capillaritis: Some patients
    - Late (Chronic) vasculitis
      - Lumen narrowing
      - Occlusion
      - Recanalization & Neovascularization: Within & Surrounding Vessels
      - Epineurial vessels: Neovascularization
      - Focal calcification in walls
    - Immunostaining: IgM, IgG or C3 deposits on vessel walls ¹²
  - Connective tissue (Epineurial) cells
    - More near vessels
    - Mononuclear cell types: Histiocytes; Some with Lymphocyte foci
    - Polymorphonuclar leukocytes: Acute disease
    - Cell fragments
  - Axon loss
    - Active: Wallerian degeneration
    - Pattern: Patchy involvement
      - Differential fascicular loss of axons
      - Larger nerves (Sciatic/Tibial & Median): Central fascicular axon loss in proximal-middle portion
    - Distal > Proximal
  - Perineurium
    - Focal damage
    - Subperineurial edema: Vasculopathy
  - Hemosiderin: Old hemorrhage in nerve
Vasculitis: Treatment ⁹
- 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
- Rituximab
- 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 syndromes ⁴

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

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

Rheumatoid Arthritis: Neuropathy syndromes
- Vasculitic Neuropathy
  - Epidemiology
    - 10% of all RA
    - 50% of RA with systemic vasculitis
    - Longstanding disease: ~ 15 years after onset of RA
  - Clinical
    - Sensory-Motor or Sensory
    - Multifocal or Asymmetric in 2/3
    - Prognosis
      - Worse with: Low serum CH50 & C4 complement
      - RA + Vasculitis
        
        No treatment: 5 yr survival 10%
        Immunosuppression: 5 yr survival 80%
    - Treatment
      - Corticosteroids: Especially high dose intermittent
      - Cyclophosphamide: Refractory patients
      - Treat Rheumatoid arthritis: Adjunctive therapy
        
        Infliximab
        
        Methotrexate
  - Serum antibodies: Rheumatoid factor (97%); Cryoglobulinemia (13%)
  - Pathology
    - Necrotizing arteritis in muscle (86%) & nerve (64%)
    - Focal lesions at midhumeral & midfemoral levels
- 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

Polyarteritis Nodosa (PAN; Systemic Necrotizing Vasculitis)
- 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
  - Hereditary form: Pediatric onset
- 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
  - 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 multiple sections to detect
  - 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
- Vasculitis Variant: ADA2 deficiency ± PAN, Young onset (DADA2; VAIHS) ¹⁹
  ● Adenosine deaminase 2 (ADA2; CECR1) ; Chromosome 22q11.1; Recessive
  - Epidemiology
    - > 100 patients
    - Hot spots: Georgian Jews; Germans
  - Genetics
    - Mutations: Missense; Gly47Arg in Georgian Jews
    - Allelic disorder: Sneddon syndrome
  - ADA2 protein
    - Major extracellular adenosine deaminase
    - Catalyzes degradation of adenosine to inosine
    - Secreted by myeloid cells
    - Functions: Growth factor; Immunomodulation
    - Levels: May be biomarker of macrophage activation syndrome in juvenile arthritis ³¹
  - Clinical
    - General syndromes: Often overlap
      - Inflammatory/vascular
      - Immune dysregulatory
      - Hematologic
    - Onset age: Range 2 months to 59 years; Usual 1st & 2nd decade
    - Skin
      - Digital necrosis
      - Livido reticularis
      - Raynaud's
    - Neuromuscular (45%)
      - Polyneuropathy (40%)
        
        Vasculitis ³²
        
        Vessels involved: Epineurial small arteries
        
        Perivascular inflammation
        
        Axonal neuropathy
        
        Sensory + Motor
        
        NCV: Axon loss
        
        Previous history: Stroke
      - Muscle
        
        Myositis: Inflammation
        
        Locations: Perivascular; Endomysial
        
        Cells: Lymphocytes; Eosinophils
        
        MRI: T2 enhancement
        
        Atrophy
      - Cranial nerves: VII; VIII; Oculomotor; Vestibular
      - Pain: Myalgia; Arthralgia
    - CNS (20%)
      - Ischemic strokes: Often recurrent
      - Hemorrhage: Ventricular
      - Myelopathy
    - Systemic
      - Vasculopathy (70%)
        
        PAN-like syndromes
        
        Raynaud's
      - Hypertension, Renal
      - Gastrointestinal: Abdominal pain; Ischemia
      - Splenomegaly
      - Joints: Arthritis
      - Pulmonary: Frequent infections
      - Fever & Infections: Recurrent
      - Cardiomyopathy
    - Treatments
      - Anti-TNFα
      - Corticosteroids
      - Immunoglobulins
      - ADA2-enzyme replacement therapy: Fresh-frozen plasma (FFP)
    - Death: Often stroke-related
  - Laboratory
    - NCV: Axon loss
    - Pathology (Skin)
      - Arteries
        
        Type: Medium-sized (Similar to PAN)
        Inflammation
        
        Fibrinoid necrosis
        Endothelial cell damage
      - Leukocytoclastic vasculitis
    - Renal: Aneurysm
    - Hematologic
      - Hypogammaglobulinemia: Low IgA, IgG & IgM
      - Cytopenia
      - B-cell immunodeficiency: Adults < 200/μL
    - Inflammation markers
      - CRP: High; Especially with Hypogammaglobulinemia

PAN: Diagnostic features vs other vasculitides ¹¹

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

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

Eosinophilic Granulomatosis + Polyangiitis (EGPA)
- Nosology
  - Allergic Granulomatosis & Angiitis
  - Churg-Strauss
  - Variant syndrome: Eosinophilic vasculitis without asthma
- Epidemiology
  - Male = Female
  - Age of onset: Mean 52 years; Range 2nd to 7th decade
  - Association: HLA-DRB4
  - Males: More likely to develop neuropathy
  - Disease association: ? Leukotriene receptor inhibitors
- Clinical
  - Neuropathy (in 20% to 50%)
    - Onset of neuropathy
      - Painful distal dysesthesias: Legs > Arms
      - Edema in dysesthetic limb
      - After asthma; Before Visceral & Skin change
      - Presenting feature in 10% to 20%
    - Anatomic patterns of involvement
      - Mononeuritis multiplex
        
        Peroneal nerve (90%)
        Other nerves: Tibial; Sural; Ulnar; Median
      - Asymmetric neuropathy
      - Distal symmetric neuropathy
    - Motor loss: Distal; Similar to sensory distribution
    - Sensory loss: Limbs, but not Trunk
    - Progression
      - To asymmetric neuropathy in limbs
      - Rapid: Over 2 to 4 weeks
    - Occasional patients have symmetric neuropathy
  - CNS (10% to 20%): No consistent involvement
    - Ischemic optic neuropathy
    - Coma
    - Subarachnoid hemorrhage
    - Cranial nerve disorders: Rare
  - Systemic
    - Fever; Fatigue; Arthralgias
    - Pulmonary
      - Bronchial asthma
        
        Precedes neuropathy by 1 to 30 years
      - Infiltrates
    - Skin: Atopy
    - Sinusitis: Paranasal
    - Gastrointestinal
    - Renal: MPO-ANCA antibody positive
    - Hepatic
    - Cardiomyopathy
      - MPO-ANCA antibody negative
      - Eosinophil infiltrates
    - Hematologic: Anemia; Leukocytosis
  - 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
  - Treatment
    - Corticosteroids
    - Cyclophosphamide (Intravenous): Poorly responsive patients
    - Mepolizumab
- Lab
  - Eosinophilia (> 10%)
  - Serum LDH: High
  - Hypoalbuminemia
  - Acute phase reactants: Increased
    - ESR
    - C-reactive protein (moderate)
  - Immunoglobulins: High IgE (74%) & IgG (40%)
  - Serum antibodies
    - p-ANCA (MPO-ANCA) (40% to 60%): Associated with
      - Necrotizing vasculitis
      - Glomerulonephritis
    - Rheumatoid factor: (86%)
    - ANA negative
    - Sedimentation rate: High
  - Serum IL-5: High ²⁷
    - Frequency: 58%
    - Skin involvement: More frequent
    - MPO-ANCA: Less common with IL-5 high
    - Epineurial eosinophils: More common
  - Electrodiagnostic
    - Nerve conduction studies: Motor & Sensory axon loss
    - EMG: Denervation, Acute or Chronic
- Pathology ¹⁴
  - Necrotizing Vasculitis: Medium & Small Epineurial vessels;
    - Found in nerve in 54%
    - Vessels involved: Epineurial; Small (Mean = 90 mm)
    - Similar to PAN
    - MPO-ANCA antibodies: More common ¹³
      - Necrotizing vasculitis & Fibrinoid necrosis
  - Inflammation
    - Infiltrates: CD8 + & CD4 + lymphocytes
    - Granulomas (40%)
    - Eosinophils
      - Locations: Epineurium & Endoneurium
        
        MPO-ANCA antibodies: Absent
      - May be in granulomas
      - More common with serum IL-5 high
    - Rare CD20 + B-cells
  - Sural nerve most common pathology (89%)
  - Axon loss
    - Acute & Chronic
    - Patchy (Differential fascicular involvement)
  - Immunohistochemistry: IgE staining of nerve

Churg-Strauss: Diagnostic criteria*

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

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

Granulomatous Polyangiitis (Wegener's Granulomatosis) ⁶
- General
  - Onset: Mean ~ 50 years; Range 40 to 55 years
  - Frequency: 3 in 100,000
  - Male = Female
  - Associations
    - Staphylococcus aureus infection
    - HLA-DPB1*0401; HLA-DR4; HLA-DR13
    - Other genetic
- 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
    - Comparison to Churg-Strauss or MPA
      - Occurs later in disease course
      - Milder mononeuritis multiplex
  - 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; VIII; IX
  - Related to infiltration by granulomatous process
- CNS
  - Variable presentations
    - Frequency: 7% to 11%
    - Pachymeningitis: Hypertrophic
      - Headache: Chronic
      - Paraplegia
      - Cranial nerve paresis
      - CSF: Pleocytosis
    - Pituitary lesions
    - Cerebral vasculitis
    - Generalized: Seizure; Encephalopathy
    - Hemorrhage: Subarachnoid; Intracerebral
    - Onset: Presentation to 18 years after onset
  - Mechanisms
    - Spread of granulomatous process from ENT structures
    - Granulomatous intracerebral lesions
    - Vasculitis: May affect the cerebral or spinal cord vessels
- 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
  - Antibodies
    - Antineutrophil cytoplasmic (ANCA)
      - c-ANCA (PR3-ANCA) (80%): Proteinase-3 Target antigen
      - p-ANCA (10%): Myeloperoxidase Target antigen
  - CSF
    - Pressure: Mildly high
    - Cells: WBC high in 33%
    - Protein: Mildly high
  - Electrophysiology
    - 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; Rituximab

Systemic Lupus Erythematosis

SLE: General Neurologic
- Most frequent: Central NS disease
- Clinical syndromes: Seizures; Cerebrovascular
- Timing of CNS disease
  - Common early in disease
  - May be initial presentation
SLE: Nerve ³⁷
- Neuropathy: General
  - Frequency
    - General: 5% to 10%; Range 2% to 28%
    - Increases over 1st 10 years of disease
  - Rarely initial manifestation of lupus
- Multiple mononeuropathies
  - Usually 2° to Vasculitis ³⁸
- Distal Symmetric Sensory-Motor ⁵
  - Epidemiology
    - Common SLE PN type
  - Clinical
    - Sensory
      - Usually predominant
      - Loss: Distal; Symmetric
      - Pain
    - Autonomic: GI reflux; Constipation
    - Weakness: 40%
    - Treatment: Corticosteroids
  - Antibody association: Ro
  - Electrodiagnostic studies
    - Axon loss
    - Progression
      - Slow or none over years
      - More in older patients
  - Pathology patterns
- Small fiber neuropathies
  - Frequency: 17% of neuropathies in SLE
  - Onset age: Juvenile or Adult
  - Patterns
    - May be length, or non-length, dependent
    - Some are asymmetric
  - Treatment: Reports of pain improvement with corticosteroids
- Trigeminal neuropathy
  - Distribution
    - Usually 2 or more divisions affected
    - Unilateral or Bilateral
  - Sensory: Numbness & Pain
  - Motor: Normal
  - Treatment: Pain control
- Acute-onset neuropathy
  - Pain
  - Weakness: Diffuse
  - Tendon reflexes: Reduced in legs
  - NCV: Axon loss; Distal latency long
  - Course: Monophasic; May have relapses
  - Treatment: ? Corticosteroids
SLE: Muscle ³⁶
- Clinical myopathy: 9%
- Immune myopathy & Interstitial lung disease: Serum antibody associations
  - KL-6, Ro-52, Ku
- Muscle pathology
  - Inflammation
    - Frequency: 45%
    - Location: Perimysial, Endomysial & Perivascular
    - More in patients with perifascicular pathology
  - Muscle fiber necrosis (60%)
  - Fiber type changes
    - Type 2 atrophy 85%
    - Type 1 predominance 45%
  - Capillary pathology
SLE: Increased frequency of other autoimmune disorders
- Myasthenia gravis
- ? Guillain-Barré
- ? CIDP

From: M Al-Lozi

SLE vasculitis

Scleroderma (Systemic Sclerosis; SSc) ²⁵

Antibodies
Clinical
Myopathies
Neuropathy
Pathogenesis
Pathology
Types

Charcot
- Epidemiological features of systemic sclerosis
  - Peak onset: 30 to 50 years
  - Sex: Females > Males; Especially black females
- Susceptibility
  - Genetic
    - HLA: A23, B18, DR11
    - non-HLA: CD247, STAT4, IRF5, BANK1, ATG5, CSK
    - DNA demethylation: eNOS, CD40L, CD70
    - Klinefelter syndrome (47XXY; 47XXX) ³³
      - Associations: Scleroderma & Myositis; Sjögregn; SLE; Inclusion body myositis
  - Other
    - Vitamin D deficiency
- SSc Types
  - Localized scleroderma
    - Morphea: Plaques of skin fibrosis
    - Linear scleroderma: Bands of fibrosis; May be associated with facial hemiatrophy
    - En coup de sabre: Children > Adults; Face lesions; CNS involvement
  - Systemic sclerosis (Scleroderma): Subtypes
    - Diffuse cutaneous scleroderma (dcSSc)
      - Rapidly progressive: Trunk; Face; Extremities, Proximal & Distal
      - Widespread skin thickening
      - Other organs: Cardiovascular, Lungs, Renal, GI, CNS, PNS
      - Similar syndromes 2° toxins: Silica; Vinyl chloride; Organic solvents; Eosinophilia myalgia
    - Limited cutaneous scleroderma (lcSSc)
      - Slowly progressive
      - Skin changes: Distal limbs & Face; Raynaud early in course
      - Other organs: Esophagus; Lungs
      - Types: Crest; Sine scleroderma (Visceral but no skin changes)
      - 10 year survival: 90%
    - Systemic sclerosis sine scleroderma (5% of SSc)
      - Autoantibodies
      - Raynaud�s phenomenon
      - Lungs
      - No skin fibrosis
    - Undifferentiated connective tissue disease with features of scleroderma
  - Raynaud's phenomenon
    - Primary
      - Multiple family members affected
      - Female predisposition
      - Teenage onset
    - Autoimmune
- Systemic sclerosis: Clinical features
  - Course
    - Rapid progression
    - Mortality: Increased; 25% at 5 years; Related to pulmonary disease
  - Skin
    - Locations
      - Arms & Legs
      - Hands: Non-pitting edema
      - Fingers: Swollen
    - Thick: Limbs ± Trunk
    - Shiny
    - Adherent
    - Ulcerations: Over DIP or PIP joints due to trauma
    - May impair mobility of muscles & joints: Perioral tightening
    - Calcinosis cutis
    - Nailfold capillaroscopy: Dilated loops
    - External link: DOIA Images
  - Nailfold abnormalities
  - Raynaud's phenomenon (90% to 95%)
  - Fatigue
  - GI
    - Esophageal: Dysmobility, especially Lower
    - Colon: Diarrhea or Constipation
  - Cardiac
    - Pericarditis
    - Myocardial fibrosis: Arrhythmias
    - Cardiomyopathy, dilated: Mild to severe; Myocardial perfusion defects; Children
  - Pulmonary
    - Parenchymal disease
    - Pulmonary arterial hypertension
    - Restrictive
    - 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 ¹⁸
    - Trigeminal sensory neuropathy
    - Neuropathy: Sensory-Motor
      - Epidemiology
        
        More common in Afro-Americans & Males
        
        Limited cutaneous scleroderma
        
        Frequency: 28%; Unusual as isolated disorder; Some have other possible cause
      - Clinical
        
        Predominantly sensory
        Asymmetric
        Distal
        
        Paresthesias: Distal
        
        Weakness: Distal; After disease progression
        
        Treatment: Poor response
      - Associated disorder: Diabetes (27%)
      - Pathology: Microangiopathy; Axon loss
      - Autoantibody: U1 RNP (24%)
      - NCV
        
        Axon loss: Distal; SNAP & CMAP amplitudes small
    - Entrapment neuropathies
      - Common
      - Especially median
  - SSc: Myositis & Myopathy
    - Clinical: General
      - Frequency in SSc: 10% to 21%
      - Subtypes
      - Onset age: Adult or Childhood
      - Weakness
        
        Proximal: Often mild
        
        Onset: Mean = 6 years after SSc onset
        
        Dysphagia
        Paraspinous: Head drop; Bent spine
        Course: Often non-progressive
      - Myalgia
      - Associations ²²
        
        Age: Lower than average; 44 vs 51 years
        
        Male:Female ratio: Higher than average
        
        Klinefelter syndrome (47XXY; 47XXX) ³³
        SSc types
        
        Diffuse cutaneous > Limited cutaneous
        
        Myositis: SSc sine scleroderma
        
        Higher prevalence of
        
        Cardiac: Hydropericardium
        Pulmonary: Fibrosis & Hypertension
        Skin: Diffuse involvement; Pigmentation; Mechanic's hands
        Fingers: Contractures
        
        GI: Lower esophagal dysmotility
        
        Mortality: Increased
      - Treatment: Corticosteroids; Cyclosporine; Methotrexate
    - Laboratory
      - Antibodies ³⁹
        
        SSc-specific
        Other
        
        PM-Scl-75
        
        U1-RNP
        Ku
        
        Some patients have no associated serum autoantibodies
        ANA patterns: Myopathy ²⁴
        
        ANA+ Speckled
        
        Antibodies: RuvBL1/2, U4/U6RNP, U5RNP
        
        Clinical: SSc sine scleroderma
        
        ANA+ Nuclear dots
        
        ANA titers: 1:640 to 1:5,120
        Other Antibodies: Survival motor neuron (SMN)
        Clinical: SSc; Raynaud; Calcinosis (60%); Lower esophageal dysmotility; Infrequent ILD or Renal crisis
        
        Weakness: Proximal > Distal
        Serum CK: 1400 to 3600
        
        ANA Negative
        
        Clinical: Interstitial lung disease; Renal crises
        
        Laboratory: Abnormal SSc-type nailfold capillaroscopy
      - EMG: Myopathic
      - Serum CK: May be high
      - Muscle pathology: Varied patterns
        
        BCIM
        IMPP variant ¹⁰⁷
        
        Muscle pathology
        
        Perimysium: Widened
        
        Muscle fibers
        
        Little involvement
        
        Fiber sizes: Varied
        
        Clinical Associations
        
        Epidemiology: African American
        Skin SSc subtype: Diffuse
        Weakness: More
        
        Mortality: Increased
        Serum CK: Lower
        
        EMG: Less irritable
        Antibodies: Scl-70, U3 RNP
        
        Active myopathy ²³
        
        Muscle fibers
        
        Necrosis
        
        MHC1 upregulation
        
        Capillaries
        
        C_5b-9 deposits
        
        Numbers: Reduced
        Basal lamina: Thick
        
        Endothelial cell swelling
        
        Capillary pathology with Minimal myopathy ²⁹
        
        Capillaries
        
        Basement membranes: Thick & Reduplicated
        
        Endothelial cells: Activated
        
        Pericyte: Proliferation
        
        Alkaline phosphatase: + Stain
        
        Muscle fibers
        
        MHC1 upregulation: Common; Diffuse
        
        C_5b-9: Deposition on sarcolemma of some fibers
        
        Clinical associations
        
        Milder disease
        
        Limited cutaneous SSc
        Less pulmonary, skin or renal involvement
        
        Serum CK: High
        
        Inflammatory: CD4 lymphocytes; Few patients
- Scleroderma: Autoantibodies ⁸
  - ANA
    - Frequency: 94%; Range 85% to 99%
    - Staining patterns
      - Common: Homogeneous nucleolar
      - Other
  - Systemic sclerosis (Scleroderma): Specific antibodies ⁴¹
    - General
      - Usually only 1 per patient: Overlap unusual (2%) ⁴⁰
      - Disease correlations
    - Scl-70 (Topoisomerase I)
      - Frequency: 30%
      - Clinical: Diffuse Cutaneous SSc (dcSSc); Severe SSc; ILD; CREST
    - Centromere
      - Frequency: 20%-38%
      - Syndrome: Limited Cutaneous SSc (lcSSc) (50%)
      - Also Ro Ab: 50%
    - RNA polymerase III (RNAP I/III): 20% to 50%
      - Clinical: dcSSc; Rapid disease onset; Skin thickening; Renal crisis; Neoplasms increased
    - U3-snRNP (Fibrillarin (1.4%))
      - dcSSc
      - Onset age: Young
      - Organ involvement
      - Myopathy + Pulmonary arterial hypertension
    - Th/To
      - Clinical: Limited cutaneous SSc; Raynaud; ILD; Pulmonary arterial hypertension
      - Staining: Nucleolar
    - U1-snRNP (5%): lcSSc
    - hUBF (NOR90): lcSSc
    - BICD2: Organ complications
  - Additional associated antibodies
    - Myopathy
    - PM-Scl: Overlap syndromes
    - Ro-52 (TRIM21)(/-La): Overlap syndromes
    - Ro-60 (SS-A)
    - Ku
      - Frequency: 2% to 7% of SSc
      - Clinical: Synovitis, Joint contractures, Myositis, Less vascular
    - Mitochondrial
    - p25/23: Associated with Centromere
    - U11/U12 RNP
    - elF2B
    - Overlap syndromes: U1-RNP, PM-Scl, Synthetase, Ku
  - 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 (Scl-70)
      - Staining pattern: Nucleolar/homogeneous
      - Specificity for scleroderma: 99% to 100%
      - Sensitivity for scleroderma: 20% to 43%
      - Epidemiology: More frequently male
      - Clinical associations
        
        Diffuse cutaneous
        Digital ulcers
        Peripheral vascular
        Pulmonary fibrosis: Dyspnea; Lung restrictive defect
        Cardiac
        Malignancies
        
        Joint: Synovitis, Contractures
        Mouth
      - Fluctuate with disease activity
    - Centromere
      - Staining pattern: Centromere
      - Specificity for scleroderma: High
        
        CREST syndrome
        May occur in primary Raynaud's & other connective tissue disorders
      - Epidemiology
        
        Male: Less often
        
        Disease onset: Older
      - Clinical associations
        
        Ischemic digital loss with limited cutaneous involvement
        
        Pulmonary hypertension without pulmonary fibrosis
        
        Renal involvement
        
        General: Less involvement of several internal organs (Lung fibrosis, Cardiac, Musculosceletal, Mouth)
      - Antibody associations: Ro; Mitochondrial; p-25/23
    - 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
    - Fibrillarin
      - Epidemiology: Black patients; Onset age lower
      - Subtype: Diffuse
      - Musculoskeletal involvement: More
    - PM-Scl: Overlap
      - Frequency in SSc: 2% to 5%
      - Syndrome associations
        
        Myositis (5% to 8%)
        
        Scleroderma (3%)
        
        PM/scleroderma overlap (24%)
        
        Other
      - Clinical associations: Raynaud�s phenomenon; Arthritis; Pulmonary; Calcinosis
      - Laboratory: High CK; ESR normal
      - Low association: Esophagus; Internal organ involvement
      - Good response to immunosuppressive therapy
      - Course: Benign; Better survival than other SSc subgroups
      - 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)
    - RNA polymerase III
      - Frequency: 4% to 32%
      - Syndrome association: Diffuse cutaneous involvement
      - Clinical association: Renal crisis
      - Laboratory: CK elevation
    - Ku
      - Scleroderma overlap syndrome
      - Laboratory: CK high
    - B23
      - Syndrome association: Limited cutaneous disease
      - Clinical associations: Pulmonary arterial hypertension; Malignancies
    - P25/23
      - Sjögren
- Pathology: Several 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
    - Myopathies
      - Minimal myopathy + Capillary Pathology
      - Myopathy with Capillary pathology
  - 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
Microscopic Polyangiitis (MPA)
- Epidemiology
  - Male = Female
  - Onset age
    - Mean = Early 6th decade
    - Older than Churg-Strauss & Wegener's
- Clinical
  - Polyneuropathy (35%)
    - Patterns: Mononeuritis multiplex; Distal polyneuropathy
    - Less common than in Churg-Strauss & Wegener's
  - CNS (30%)
  - Systemic: Lung & Renal (Glomerulonephritis) most common
  - Causes of death
    - Diffuse alveolar hemorrhage
    - Infection
  - Treatments
    - Corticosteroids
    - Immunosuppressants
    - May be more difficult to treat than Churg-Strauss or Wegener's
- Laboratory
  - Antibody: MPO-ANCA (70%)
  - Leukocytosis
  - Sedimentation rate: High
- Nerve pathology ¹⁵
  - Axonal loss
    - Wallerian degeneration
    - Patchy involvement
      - Differential fascicular loss of axons
      - Larger nerves (Sciatic/Tibial & Median)
        
        Proximal-middle portion
        
        Central fascicular axon loss, and
        
        Wedge-shaped lesions
        
        Distal portion
        
        Diffuse axon loss
      - Spinal roots: Usually normal
  - Segmental demyelination
    - Proximal nerve segments: 8% to 20% of axons
    - Distal nerve segments: 0% to 8%
  - Vasculitis
CREST
- Nosology
  - Calcinosis; Raynaud's; Esophageal dysmotility; Sclerodactyly; Telangectasias
  - Systemic Sclerosis, Limited
- Neuropathy: Vasculitic
  - Distal
  - Predominantly sensory
  - Multifocal & asymmetric
  - Indolent course
  - Pathology
    - Multifocal axon degeneration & loss
    - Inflammation & necrosis of epineurial arterioles
- Myopathy: Capillary pathology
- Antibodies
  - Centromere
  - Fibrillarin
Giant Cell Arteritis
- Related to Polymyalgia rheumatica (PMR)
- General
  - Onset age: > 50 years
- Neuropathy
  - Some association with carpal tunnel syndrome & PMR
  - Occasional associations
    - Distal symmetric sensory-motor neuropathy
    - Ischemic mononeuropathy
    - Mononeuritis multiplex
- Pathology
  - Granulomatous arteritis
  - Locations
    - Aorta & major branches
    - Predilection for extracranial branches of carotid
    - Often involves temporal artery
Livedoid vasculopathy ¹⁷
- Clinical
  - Skin
    - Purpura
    - Livedo reticularis: Legs
    - Ulcerations: Painful
    - Scars: Atrophic, porcelain
  - Neuropathy: Occasional
    - Mononeuritis multiplex
  - Muscle: Clinically silent
  - Course: Recurrent; Chronic
- Pathology
  - Vessels
    - Intraluminal thrombosis
    - Endothelial cell hyperplasia
    - Sub-intimal hyaline degeneration
    - Inflammation: Perivascular, Not in wall
  - Nerve
    - Axon loss
    - Vessels
      - Epineurial: Perivascular lymphocytes
      - Endoneurial: Endotheial cell changes
  - Muscle: Perifascicular pathology
    - Capillary loss
    - Muscle fibers: Atrophy; Internal nuclei; Vacuoles
    - Endomysium: Macrophages; CD3 cells
    - MHC I: Up in few scattered muscle fibers
Behçet

From: R Bucelli
Neuro-Behçet (Flair MRI)
- Epidemiology: Most common regions
  - Middle East, Far East & Mediterranean basin
- Clinical
  - General
    - Recurrent inflammatory lesions
    - Locations
      - Mouth (Oral aphtae)
      - Genitalia (Ulcers)
      - Eyes (Uveitis)
  - Onset age: 3rd & 4th decades
  - Systemic
    - Ulcers
      - Oral: Aphthous
      - Genital
      - Intestinal
    - Ocular
      - Uveitis & Retinal vasculitis
      - Painless loss of vision
    - Skin
      - Papules & Pustules: Proximal limbs & Trunk
    - Joints: Knee arthritis
    - Vascular
      - Venous occlusions
      - Arterial aneurysms
  - CNS (25%)
    - Clinical
      - Onset: After 3 to 5 years of disease
      - Headache
      - Cerebral
        
        Hemiparesis & Pyramidal signs
        
        Encephalopathy & Behavioral changes
        
        Seizures
      - Brainstem syndrome
        
        Ophthalmoparesis
        
        Cranial neuropathy
        
        Cerebellar
        
        Pyramidal dysfunction
      - Myelopathy
      - Non-parenchymal syndromes
        
        Cerebral venous thrombosis
        
        Intracranial hypertension
        
        Acute meningeal syndrome
        
        Aneurysm: Intracranial or Extracranial
  - Neuropathy: Rare (3%)
    - Distribution
      - Symmetric, or
      - Mononeuritis multiplex
      - Legs > Arms
    - Pathology: Axon loss
  - Course: Chronic; Relapsing
  - Treatment
    - Brain disease: Corticosteroids often effective
    - Manage cerebral venous thrombosis
- Laboratory
  - Pathology: Vasculopathy
    - Perivascular inflammation
    - Systemic or CNS
  - Association with: HLA-B51
  - CSF
    - Abnormal in 75%: Especially with parenchymal inmvolvement
    - High: Cells, Protein, IL-6
  - Pathergy
Hyper-Eosinophilic Syndromes, Idiopathic
- Eosinophils
- Epidemiology
  - Onset age: 20 to 50 years
  - Male:Female = 9:1
- Genetic association
  - Fusion of FIP1L1 (Fip1-like1) gene to PDGFRA : Caused by Interstitial deletion
- Clinical
  - Definitions
    - Circulating eosinophils > 1,500/mm³ 2x ≥ 1 month apart
    - Tissue eosinophilia: Marked + Blood eosinophila above normal limits
  - Organ systems often involved
    - Heart (60%)
    - Lungs: Cough
    - Skin: Rash; Angioedema; Pruritis
    - Nervous system: CNS & PNS
      - CNS: Seizures, Stroke (Thromboembolic), Encephalopathy
      - PNS: Peripheral neuropathy, Mononeuritis multiplex
      - Muscle: Atrophy; Fatigue; Myalgia
    - Gastrointestinal
- Variant syndrome: Eosinophilic vasculitis ²⁶
  - Syndrome criteria
    - Circulation: Hypereosinophilia
    - Vasculitis
    - No: Asthma; ANCA antibody
  - Vasculitis: Single organ
    - Coronary
    - Temporal
    - Cerebral
    - Cutaneous
    - Peripheral nerve
    - Thromboangiitis obliteranse-like
    - Fever
    - Deep venous thrombosis
    - Non-asthma lung
  - Laboratory
    - CRP: Low (vs High in Eosinophilic granulomatosis with polyangiitis (EGPA)
    - Pathology
- 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

Vasculopathies: Nerve specific

Peripheral Nerve Specific Inflammatory Vasculopathy ²

Nosology: Non-Systemic Vasculopathic Neuropathy (NSVN)
Epidemiology: Females & Males
Clinical
- Onset
  - Age: Mean 49 to 63 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% to 78%)
    - Asymmetric polyneuropathy (18% to 85%)
    - Distal symmetric polyneuropathy (2%)
  - Nerves involved
    - Tibial (100%)
    - Fibular (100%)
    - Ulnar (50%)
    - Median (50%)
  - Pain (85% to 92%): Nerve or Muscle
  - Gait disorder: > 90%
- General signs (50%)
  - Fever (20%)
  - Weight loss (15%)
- Course & Prognosis
  - More slowly progressive than with systemic vasculitis
  - Stepwise progression: Some patients
  - 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
  - Diabetes (10% to 20%)
  - Neoplasm: Few ²
- Treatment
  - Corticosteroids
    - Some benefit: 70%
    - More benefit: Treatment early in disease course
    - Relapse: 33%
    - Dose: Prednisone > 1mg/kg/day, or IV Prednisolone
  - Cyclophosphamide
    - Lowers long term disability when added to corticosteroid Rx
  - Azathioprine: Corticosteroid sparing agent
Laboratory
- Sedimentation rate
  - High: 18% to 65%
  - Less commonly high vs. Systemic vasculitic neuropathy
  - CSF: No cells; Protein moderately high in 50%
- NCV: Axon loss, asymmetric
Pathology: Necessary for diagnosis
- Inflammation: Most patients
  - CD4 & CD8 cells + Macropahages
  - Small (30 to 100 μm) epineurial vessels: Perivascular
  - May also occur in small vessels in muscle
- Vessel wall damage (100%)
- Subperineurial edema (30%)
- Perineurial thickening (50%)
- Axon loss: Patchy
- Ig & C3 deposits in vessels with inflammation
- Also see: Disorders of small vessels

Vasculopathies affecting Nerve
	HIEM	NSVN	Vasculitis, Systemic
Onset	59 years Progressive	50 years Acute or Subacute	68 years Acute or Subacute
Course	Progressive Slow Months - Years	Stepwise (50%) Weeks - Months	Stepwise (50%) Weeks - Months
Diabetes	56%	Common	Uncommon
Frequency	Moderate	Uncommon	Uncommon
Asymmetry	+	+	+
Weakness (100%)	Distal Legs > Arms	Distal ± Proximal	Distal ± Proximal
Pain	Not prominent	Common	Varied
Treatment	Steroids	Steroids +	Steroids +
Serum Markers	ESR↑ 20%	ESR↑ 50%	ANA; p-ANCA RF; Cryoglobulin ESR↑ 100%
Endoneurial Vessel C_5b-9	Common	Uncommon	?
Epineurial Inflammation	Uncommon	Perivascular	Perivascular
Wallerian Degeneration	Mild	Common	Common

Humoral Immune Endoneurial Microvasculopathy (HIEM) ²⁸

Epidemiology
- 16 patients
- Male: Female = 3:1
- Diabetes: 56%
Clinical
- Onset age: Mean 59 years; Range 34 to 83 years
- Neuropathy syndrome: Motor + Sensory
  - Weakness
    - Distal
    - Asymmetric
    - Legs (100%) > Arms (44%)
    - Asymmetric
  - Sensory loss
    - Panmodal
    - Distal
    - Legs > Arms
    - Often severe
  - Tendon reflexes: Reduced at ankles or diffusely
  - Gait disorder
  - Pain: Not prominent
  - Course: Slow progression over years
  - Treatment
    - Solumedrol IV
      - Strength: Rapid improvement
      - Sensory loss: Less benefit
- Systemic features: Unusual
Laboratory
- NCV: Axon loss, motor & sensory
- Nerve pathology
  - Endoneurial microvessels: C_5b-9 staining
  - Axon loss: Patchy; Large > Small
  - Subperineurial edema: Some patients
  - Inflammation: Uncommon

Perineuritis

Clinical features of neuropathy
- Onset Age: 90% > 50 years
- Sensory loss
- Motor
  - Weakness: Distal; Asymmetric
- Treatment: ? Immunosuppression
Associated disorders
- Diabetes mellitus: > 50%
- CIDP
- Cryoglobulinemia
- Spanish toxic oil
- Lyme disease: B-cell perineurial inflammation
- Weight loss
- Collagen vascular syndromes
- Sepsis
Pathology
- Perineurium: Thickening or Damage focally around some fascicles
- Perineurial cells: Degeneration or loss of
- Inflammation: Histiocytic
- Vessels: Endoneurial & Epineurial pathology
- Axon loss: May be variable among fascicles

Sensory (± Ataxic) neuropathy with anti-GD1b & other Disialosyl antibodies ³

Nosology
- Chronic Ataxic Neuropathy with Disialosyl Antibodies (CANDA)
- CANOMAD
Epidemiology
- Male (75%) > Female
Clinical (IgM vs GD1b)
- Onset
  - Age: 30 to 76 years; Mean 55 years
  - Evolution: Acute, Subacute or Chronic
- Sensory loss (100%)
  - Distribution
    - Distal
    - Symmetric
    - Legs & Arms
  - Modalities: Large & Small fiber
  - Ataxia
- Paresthesias
- Tendon reflexes: Absent
- Strength
  - Normal in 50%
  - Weakness (50%): Mild; Distal
- Gait
  - Ataxic (Sensory)
  - + Romberg
  - Tandem relatively spared
- Cranial nerves
  - Ophthalmoplegia (50% to 90%)
  - Trigeminal (50%): Perioral paresthesias
  - Facial (25%)
  - Bulbar weakness (66%)
- Course
  - Usual: Slowly progression over months to years
  - Variants: Acute, Relapsing or Stepwise progressive sensory neuropathy
- Treatments: IVIg; Corticosteroids; Cyclophosphamide; Rituximab
Antibodies
- IgM
  - M-protein
    - Frequency: 50%
    - κ > λ
  - Cross reactivity: Gangliosides containing disialosyl groups
    - GD1b > GD3; GD2 > GT1b; GQ1b
    - NOT GM1; GM3; GD1a
  - Anti-Pr₂ activity
  - Cold agglutinins (50%)
  - Bind to: Dorsal root ganglion cells; Nerve terminals (in spindles)
  - Similar neuropathy after treatment with monoclonal anti-GD2 antibody
- IgG anti-GD1b antibody associations
  - Acute sensory neuropathy
  - Polyclonal antibody
- M-protein: 50% to 93%; κ or λ
Other lab
- Sedimentation rate: High
- CSF: Moderately high protein in 50% to 75%
- MRI: Occasional patient with white matter lesions
Nerve conductions
- Sensory axon 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 ³⁵
- Peripheral nerve: Loss of large myelinated axons & Dorsal root ganglion cells
- Paranodes: Macrophages
- Nodes of Ranvier: Wide; C3d binding
- 1 autopsy case with demyelination of nerve roots: Serum IgM binds to both GD1b & GD1a
Variant syndrome: Acute Ataxic Sensory Neuropathy ¹⁰
- Predisposing factors
  - Previous infection: C. jejuni
  - Clinical: Upper respiratory infection most common
- Onset: Paresthesias
- 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: Maximum ≤ 3 weeks
  - 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
  - MRI: Gadolinium enhancement of nerve rots
- Differential diagnosis: Acute sensory neuropathy

CANOMAD
Syndrome
Chronic
Ataxic
Neuropathy
Ophthalmoplegia
M-protein
Agglutination
Disialosyl antibodies

Galβ1-3GalNAcβ1-4Galβ1-4Glcβ1-1'Ceramide
                  3
                  |
 Neu5Acα2-8Neu5Acα2

GD1b ganglioside

Axonal Sensory Neuropathies with Serum IgM binding to Trisulfated Heparin Disaccharide (TS-HDS) ⁷

Epidemiology
- Frequency
  - Sensory neuropathies: 10% to 20%
  - Small fiber sensory neuropathies: 37%
  - Acute onset small fiber sensory neuropathies: 80% to 90%
- Sex: Female > Male
- TS-HDS: Most common neuropathy-related IgM MGUS antibody
TS-HDS
- Disaccharide
- Component of glycosylation of: Heparin & Heparan sulfate
- Hereditary Heparan sulfate-related neuropathy: NAGLU
Clinical
- Onset
  - Age: Mean 60 years; Range 7 to 83 years
  - Acute onset: More frequent than antibody negative patients
- Sensory loss (100%)
  - Distal predominant
  - Symmetric: 90%
  - Modalities
    - Small fiber (Pin): All
    - Vibration: Loss 57%; Absent at toes 17%
    - Proprioception: Spared
- Pain (66%)
  - Paresthesias & Myalgias
  - Distribution: Often not length dependent
  - Hands 40%: More common than in other sensory neuropathies
  - Cramps: Occasional
- Weakness (22%): Feet or Toes; More common with IgM M-protein
- Tendon reflexes: Absent at ankles (43%)
- Autonomic dysfunction ³⁴
- Progression
  - Slow over years
  - Duration at presentation: Mean = 5 years
- Diabetes: 12%; Less frequent than antibody negative controls
Antibodies
- Serum IgM target: Trisulfated heparin disaccharide (TS-HDS)
  - Structure: IdoA-2S GlcN-S-6S
  - Functions
    - Binds to fibroblast growth factor (FGF)-1
    - Modulates FGF-2 binding to FGF receptor
- Autoantibody types
  - Monoclonal: 86%; Usually κ class
  - Polyclonal: 14%
- Antibody: Clinical correlations
  - Common: Axonal neuropathy 85%
  - Small fiber neuropathies: Often non-length dependent
  - MAG Demyelinating neuropathy
    - 83% of anti-MAG antibodies cross react with TS-HDS
- Antibody location: Serum
- M-protein detected by immunofixation: 24%; κ class 92%
Electrodiagnostic testing
- Axon loss
  - SNAP amplitude, Sural: 55% reduced; 41% absent
  - Abnormal quantitative sensory testing
- Demyelinating features (Mild)
  - Frequency, general: 16%
  - IgM M-proteins: 50%
  - No M-proteins: 5%
- Normal (40%)
Pathology
- Axon loss
  - Unmyelinated & some myelinated axons
  - Skin biopsy: Axon loss is often non-length-dependent
- IgM deposits: Around the outside of wall of medium- & larger-sized vessels
- Capillaries
  - C_5b-9 complement depositis: Muscle & Nerve
  - Thickened walls: Endomysial capillaries

TS-HDS

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

IgG₄ Antibodies, Disease & Neuropathies

IgG₄ Antibodies
- < 5% of total IgG in normals
- Do not effectively activate the classical complement pathway
- Can undergo 'half-antibody exchange'
  - Results in recombined antibody molecules with two different binding specificities (F_ab subunits)
IgG₄ Autoantibodies
- Polyclonal
- Located in: Serum ± CSF
- Target antigens: Often surface membrane or extracellular proteins
- Disease-related antigens
  - Desmogleins: Pemphigus
  - Collagen VII: Epidermolysis bullosa acquisita
  - M-type phospholipase A2 receptor: Membranous glomerulonephritis
  - MuSK: Subtype of acquired myasthenia gravis
  - Lgi1: Encephalopathy + Neuropathy
  - Neurofascin: Demyelinating neuropathy + CNS or Tremor
  - Contactin-1: Demyelinating neuropathy + Ataxia
- Treatments: Corticosteroids; Rituximab
IgG₄ Disease
- Onset types
  - Tumefactive
    - Lesions in multiple organs
  - Allergic
    - Onset with: Atopy, Eczema, Asthma, Eosinophilia, Chronic sinusitis
- Multiorgan disorder
  - Pancreatitis
  - Hypophysis,
  - Lacrimal & Salivary glands
  - Eye: Orbital myositis; Infraorbital nerve enlargement
  - Thyroid
  - Bile ducts
  - Kidneys
  - Retroperitoneum
  - Skin: Sclerosis; Pigmentation
- Neuropathy ¹⁶
  - Epidemiology: 3 patients
  - Clinical: Multiple mononeuropathies or Polyneuropathy
    - Pain: Legs; Dysesthesias
    - Sensory loss: Legs; Asymmetric
    - Weakness: Distal > Proximal; Hands & Feet
    - Tendon reflexes: Reduced in legs > arms
    - Treatment: Prednisone
  - Electrodiagnostic: Axonal neuropathy
    - NCV: Normal or Mildly reduced
    - CMAP & SNAP amplitudes: Reduced in legs
    - Distal & F-wave latencies: Mildly long
  - Nerve pathology
    - Epineurium: Thickening
    - Abundant collagen fibers
    - IgG₄+ plasma cells: In epineurium & perineurium
    - Myelinated axon loss
- Neuropathy, Perineural: Focal
  - Intraorbital
  - Trigeminal
  - Paravertebral nerve
- Pathology: General
  - Tumefactive lesions
  - Fibrosis, extensive
  - Lymphoplasmacytic infiltrates: Contain IgG₄+ plasma cells & T-cells
- Serum IgG₄ levels: High

Plexin D1 (PLXND1) antibody (IgG2) with Neuropathic Pain ²⁰

Antibody subclass: IgG2
Tissue binding
- Small pain-related neurons & CNS Axon terminals (Lamina I & II): Contain Isolectin B4 & P2X3
- Axons in skin: PGP-9.5 & VIP (Parasympathetic) positive, Tyrosine hydroxylase negative
- PD1+ serums: Bind to dorsal root ganglion cells
Plexin D1 protein
- Expression: Vascular endothelial cells, Immunocytes, Muscle cells, Neurons
- Cell functions, Axon guidance; Apoptosis; Immune regulation with binding to semaphorins 3E & 4A
Clinical
- Females: 60%
- Frequencies
  - Small fiber neuropathy: 13%
  - Patients with neuropathic pain: 10%
  - Controls: 2%
- Onset age: 14 to 53 years; Often < 30 years
- Pain
  - Burning & Tingling
  - Thermal hyperalgesia
  - Legs ± Hands
  - Distal > Proximal
- May improve with immunotherapy
- Course: Chronic
- Associated systemic disorders
  - Atopy & Allergic
  - Collagen vascular disease
  - Multiple sclerosis-like syndromes

Amphiphysin antibody (IgG) with Neuropathies ²¹

Neuropathy patterns
- Polyradiculoneuropathy
- Sensory neuronopathy
- Autonomic: Gastroparesis
Clinical
- Epidemiology: Female 91%
- Onset
  - Age: Mean 65 years; Range 45 to 79 years
  - Before neoplasm: 76%
  - Course: Chronic or Subacute
- Pain
- Sensory loss
- Symmetric
- Associated Neoplasm: 90%; Breast 63%; Small cell lung 22%
- Associated CNS: 57%; Stiffperson; Myelopathy; Ataxia
- Treatment: 44% improved with corticosteroids or IVIg
- Death afteer 5 years: 29%
Laboratory
- NCV: Motor & Sensory Axon loss
- EMG: Denervation Diffuse in Trunk & Extremities
- Associated antibodies: Hu; CRMP5
- Nerve biopsy: Axon loss; Subperineurial edema
- CSF: High protein in 53%
- Antibody type: IgG

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 Wallerian degeneration	Polyarteritis Churg-Strauss Overlap syndromes Wegener's SLE Sjögren's Cryoglobulinemia

VASCULITIS & VASCULOPATHIES: 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 (MPA) Polyarteritis nodosa	Rheumatoid arthritis SLE Sjögren's Drugs Infections
Small vessels	Peripheral nerve: Vasculopathy Henoch-Schönlein purpura Essential mixed cryoglobulinemia Cutaneous leukoclastic angiitis Behçet Tumor-associated: Lymphoma; Hairy cell leukemia; Melanoma	Drugs Infections Hepatitis B > C > A
Microvessels	HIEM Ipilimumab	None

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