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
Associated syndromes
Laboratory findings
ANCA
Pathology
Treatment
Vessel pathology
Location
Size

From: M Al-Lozi

SLE vasculitis

Vasculopathy: Syndromes & Associations

Behçet
Churg-Strauss
CREST
Cryoglobulinemia
Drugs
EGPA (Churg-Strauss)
Giant cell arteritis
GPA (Wegener)
GVHD
Hereditary
ADA2
VEXAS

HIV
Infections
Livedoid vasculopathy
MPA
Peripheral Nerve Specific
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
- 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
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
  - Neuropathy features: Higher biopsy yield
    - Asymmetry
    - Weakness
    - Disabling
  - 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

Systemic connective tissue disorders & Vasculitis: Specific syndromes ⁴

Rheumatoid Arthritis: Neuropathy syndromes
- Vasculitic Neuropathy ⁴³
  - Epidemiology
    - 10% of all RA
    - 35% to 63% of RA with systemic vasculitis
    - Longstanding disease: ~ 15 years after onset of RA
  - Clinical
    - Onset: Acute or Subacute
    - Common pattern: Mononeuritis multiplex
    - Modalities: Sensory-Motor or Sensory
    - Multifocal or Asymmetric in 2/3
    - Nerves involved
      - Peroneal (90%)
      - Popliteal (50%)
      - Ulnar (35%)
      - Median (15%)
    - Prognosis
      - Worse with
        
        Cutaneous vasculitis
        
        Peripheral neuropathy
        
        Low serum CH50 & C4 complement
      - RA + Vasculitis: Course
        
        No treatment: 5 yr survival 10%
        Immunosuppression: 5 yr survival 80%
    - Systemic associations
      - Skin (65% to 88%)
      - Cardiac (33%)
      - Constitutional (70%)
    - Treatment
      - Corticosteroids: Especially high dose intermittent
      - Cyclophosphamide: Refractory patients
      - Treat Rheumatoid arthritis: Adjunctive therapy
        
        Infliximab
        
        Methotrexate
  - Laboratory
    - Serum antibodies
      - Rheumatoid factor (97%)
      - Anti-Citrullinated protein antibodies
      - ANA
      - Cryoglobulinemia (13%)
    - Pathology
      - 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)
- Early description: 1866 Kussmaul & Maier
- Epidemiology
  - Male > Female: 1.5x - 2x
  - Onset age: 40 to 60 years
  - Incidence: 1 - 7/1,000,000/year
  - Neuropathy
    - Present in ~25% at time of diagnosis
    - Occurs in ~50% to 75% during course of disease
  - Subgroups ⁵¹
    - Hereditary
      - ADA2: Pediatric onset
      - VEXAS: Vasculitis or Small vessel vasculitis
    - Acquired
      - Hepatitis-associated: B (30%; Few relapses) > C
      - Other infections: Human parvovirus B19, Epstein Barr virus
      - Malignancy-associated: Hairy cell leukaemia; Myelodysplasia; Solid cancer
      - Hyper-eosinophilic syndrome
      - Idiopathic
- 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 in 80%; T2 hyperintense lesions in muscle ⁴⁸
  - 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
  - Axon 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
  - 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

Neurologic
Nerve
Muscle
Antibodies
Medications

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: General Treatments
- 1st Line
  - Hydroxychloroquine: All SLE patients; 5 mg/kg
  - Corticosteroids (Prednisone)
    - No major organ damage: < 7.5 mg/day
    - Cerebritis, Nephritis, Thrombocytopenia: 40 to 60 mg/day
  - NSAID: Joint pain
- 2nd Line
  - Azathioprine: Nephritis, Severe SLE; 2 to 2.5 mg/kg/day
  - Methotrexate: 7.5 to 25 mg/week
- 3rd Line: Severe SLE or Nephritis
  - Cyclophosphamide
  - Mycophenylate mofetil
  - Rituximab
  - Anifrolumab
  - Belimumab
  - Voclosporin
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: ? Pain improved 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
    - Frequency in lupus: 3% to 9%
    - More common in: African-Americans
    - Onset: Before or after SLE onset
  - Increased frequency with myositis
- Laboratory
  - Immune myopathy: Serum antibody associations
    - KL-6
    - Ro-52 (75%): Active lupus
    - Ku
    - U1RNP (44%): Pulmonary hypertension; Raynaud"s
    - dsDNA
  - Serum CK: Often high
  - EMG: Myopathy ± Irritability
- Muscle pathology
  - Inflammation
    - Frequency: 45%
    - Location: Perimysial, Endomysial & Perivascular
    - More in patients with perifascicular pathology
  - Muscle fiber necrosis (60% to 80%)
  - 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
SLE: Systemic
- Onset age: Mean 25 to 30 years
- Arthralgia
- Fatigue
- Hematologic
- Skin
  - Photosensitivity
  - Raynaud's phenomenon
  - Malar rash
  - Alopecia
SLE: Autoantibodies ⁴⁵
- ANA
  - Frequency: 100%; Necessary for diagnosis
  - Patterns: Homogeneous; Speckled
- dsDNA
  - 70% of SLE
  - Levels related to disease activity: Especially lupus nephritis
- Sm
  - 30% of SLE
  - May relate to renal & CNS lupus
- U1snRNP
  - 13% of SLE
  - Musculoskeletal & Lung involvement
  - SLE specificity: IgM > IgG
- Ro52 (SSA)
- Histone H1: SLE disease activity
- Histone H2A-H2B: Drug-induce lupus
- β2-Glycoprotein: Thrombosis & CNS
- Ribosomal P protein
  - 15% of lupus
  - High specificty
- Phospholipid
  - 30% of lupus
  - Thrombosis & Hypertension
- N-methyl-D-aspartate receptor: CNS
- Cardiolipin: Thrombosis
- C1q: Higher in SLE nephritis

Systemic Lupus Erythematosus Diagnostic Evaluation (EULAR/ACR) ⁴²
Mandatory: ANA ≥ 1:80
Organ	Feature	Dx Points
Pulmonary	Effusion Pleural, or Pericardial	5
Cardiac	Pericarditis, Acute	6
Constitutional	Fever > 100.9°F	2
Mucosal	Alopecia, nonscarring Ulcers, Oral Lupus Rash Skin/Discoid, Subacute Skin, Acute	2 2 4 6
Skeletal	Joint Δ	6
CNS	Delerium Psychosis Seizure	2 3 6
Hematologic	Leukopenia Thrombocytopenia Hemolysis, Immune	3 4 4
Immune	Cardiolipin IgG Ab β2-Glycoprotein 1 Ab Lupus anticoagulant C3 or C4 low C3 + C4 low dsDNA or Sm Ab	2 2 2 3 4 6
Renal	Proteinuria/24 hr > 0.5g Renal bx Nephritis Lupus II or V Lupus III or IV	4 8 10
Systemic Lupus Erythematosus Dx + = Total points ≥ 10 + ANA ≥ 1:80

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; Sjögren; 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
      - Sarcopenia ⁵²
      - 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
        
        General: Varied tissue involvement
        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
      - ANA 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
    - SMN
    - 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)
      - General
        
        Epidemiology: More frequently male
        Levels: Fluctuate with disease activity
      - Staining pattern: Nucleolar/Homogeneous
      - Disease associations
        
        Systemic sclerosis
        
        Specificity for scleroderma: 99% to 100%
        
        Sensitivity for scleroderma: 20% to 43%
        
        Myopathy with Capillary Pathology
        
        SLE (26%): Correlates with Disease activity, Pulmonary hypertension, Nephritis
      - Clinical associations
        
        Diffuse cutaneous
        Digital ulcers
        Peripheral vascular
        Pulmonary fibrosis: Dyspnea; Lung restrictive defect
        Cardiac
        Malignancies
        
        Joint: Synovitis, Contractures
        Mouth
    - 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%
      - Syndrome: Limited cutaneous SSc
      - Clinical associations
        
        Puffy fingers
        
        Small bowel disorders
        
        Hypothyroidism
        
        Raynaud
        ILD
        Pulmonary arterial hypertension
        Poor survival
        
        Limited cutaneous disease
      - ANA Staining: Nucleolar
    - 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
  - General
    - Several patterns of tissue involvement
    - Muscle: Pathology patterns/syndromes
  - 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
  - Muscle fibers: Myopathy
    - 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

⁴⁶

Epidemiology
- Most common regions
  - Middle East, Far East & Mediterranean basin
- Sex
  - Male = Female
  - Most severe: Young males
- Onset ages
  - Post-puberty
  - Childhood
    - Higher frequency of Behçet in relatives
- Genetics: Associated with
  - HLA-B51
  - MICA polymorphism (GCT/AGC)
Clinical
- General: Inflammatory lesions, Recurrent
  - Painful
  - Locations
    - Mouth (Oral aphthae)
    - Genitalia (Ulcers)
    - Eyes (Uveitis)
- Onset age in adults: 3rd & 4th decades
- Systemic
  - Ulcers
    - Oral (98%)
      - Aphthous
      - Tongue, Dorsum & Side + Mucosa
    - Genital (75%): Aphthous
    - Intestinal
  - Ocular
    - Uveitis & Retinal vasculitis
    - Vision Loss: Painless
  - Skin (85%)
    - Papules & Pustules
    - Erythema nodosum
    - Locations: Proximal limbs & Trunk
  - Joints (50%)
    - Knee arthritis
    - Oligoarthropathy
  - Vascular (30%)
    - Venous thrombosis (Male > Female)
    - Arterial aneurysm (5%): Pulmonary
  - Course patterns
    - Monophasic (60%)
    - Relapsing (20%)
    - Progressive from onset
    - Relapse may lead to progressive disease
- CNS (25%)
  - Clinical
    - Onset: After 3 to 5 years of disease
    - Headache
    - Cerebral
      - Hemiparesis & Pyramidal signs
      - Encephalopathy & Behavioral Δ
      - Seizures
      - Cortical hypoperfusion
    - Brainstem syndrome: Most common
      - Ophthalmoparesis
      - Cranial neuropathy
      - Cerebellar
      - Pyramidal dysfunction
    - Myelopathy
    - Non-parenchymal syndromes
      - Cerebral venous sinus thrombosis
      - Intracranial hypertension
      - Acute meningeal syndrome
      - Aneurysm
        
        Intracranial or Extracranial
- Neuropathy: Rare (3%)
  - Distribution
    - Symmetric, or
    - Mononeuritis multiplex
    - Legs > Arms
  - Nerve Pathology
    - Axon loss: Varied
    - Artery & Vein damage
- Myositis
  - May occur at disease onset
  - Multifocal: Legs > Arms
  - Pain
  - Pathology: Perivascular inflammation
- Course: Chronic; Relapsing
- Treatment
  - Brain disease: Corticosteroids often effective
  - Cerebral venous thrombosis: Management
Laboratory
- Pathology: Venous disease
  - Perivascular inflammation
  - Systemic or CNS
  - Venous thrombosis
  - Activation of
    - Neutrophils
    - Helper Th-17 cell pathways
- Association with
  - HLA-B51: OR 5.9
  - Microbiome: Oropharynx & GI
- CSF
  - Abnormal in 75%
    - Especially with parenchymal involvement
  - High: Cells, Protein, IL-6
- Pathergy: Decreasing frequency

Diagnostic Criteria
Ocular lesions Apthosis Oral Genital Skin Δ Neurological Δ Vascular Δ Pathergy test +	2 2 2 1 1 1 1
Behçet Dx: Sum ≥ 4

From: R Bucelli

Neuro-Behçet (Flair MRI)

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 (90%)
    - Fibular (90%)
    - 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%
- Serum Neurofilament Light levels: Often high
- 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

Immune Vasculopathies affecting Nerve ^28, ⁵⁰
	HIEM	NSVN	Vasculitis, Systemic
Clinical
Onset	59 years Chronic- Progressive	50 years Subacute- Chronic	68 years Subacute- Acute
Course	Progressive Slow Months - Years	Stepwise (50%) Months	Stepwise (50%) Weeks
Diabetes	56%	25%	14%
Systemic Immune Disease	Uncommon	20% Sjögren	70%; EGPA, RA, PAN, GPA, MPA
Frequency	Moderate	Uncommon	Uncommon
Asymmetry	+	+	+
Weakness (100%)	Distal Legs > Arms	Distal ± Proximal	Distal > Proximal
Pain	Not prominent	Common	Common
Treatment	Steroids	Steroids +	Steroids +
Blood Tests
Immune Markers	ESR↑ 20%	ESR↑ 50%	ANA; p-ANCA RF; Cryoglobulin ESR↑ 100%
Serum NfL	Normal	High	Very High
Nerve Pathology
Endoneurial Vessel C_5b-9	Common	Uncommon	Uncommon
Epineurial Inflammation	Uncommon	Perivascular Vessels < 75μM Lymphocytes	Perivascular Vessels > 75μM Histiocytes
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
- Serum Neurofilament Light levels: Often normal
Differential diagnosis

Perineuritis ¹

Neuropathy: Clinical features
- Onset Age: 90% > 50 years; Range 18 to 75 tears
- Sensory
  - Loss: Pan-modal; Distal ± Trunk (35%)
  - Pain: > 90%
- Weakness
  - Frequency 80%
  - Distal predominant
  - Legs > Arms
  - Asymmetric
  - Multifocal
- Course: Progression over months
- Treatment: Immunosuppression; Corticosteroids
Associated disorders
- Diabetes mellitus: > 50%
- Immune
  - Collagen vascular syndromes
  - ICI treatment
  - Behçet: Perineurial damage
  - Sarcoid
  - CIDP
  - Cryoglobulinemia
- Toxic
  - Spanish toxic oil
  - Eosinophilia-Myalgia
- Infections
  - Lyme disease: B-cell perineurial inflammation
  - Leprosy
  - Borreliosis
  - Sepsis
- Neurolymphomatosis
- Weight loss
Pathology
- Perineurium
  - Thickening or Damage
  - Focally around some fascicles
- Perineurial cells: Degeneration or loss
- Inflammation: Histiocytes; T-lymphocytes
- Vessels: Endoneurial & Epineurial pathology
- Axon loss: May be varied among fascicles
Laboratory
- EMG & NCV: Axon loss
- CSF: Protein high

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: Sensory PN,Acute, Relapsing or Stepwise progressive
- Treatments: IVIg; Corticosteroids; Cyclophosphamide;
  Rituximab; Daratumumab (Anti-CD38) ⁴⁴
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
- Autopsy 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
Cold agglutinin disease
- Clinical
  - Acrocyanosis
  - Raynaud-like phenomena
  - Fatigue
  - May be associated with
    - IgM MGUS
    - Malignancies: Typically aggressive B-cell lymphoma
    - Infections: Mycoplasma pneumoniae, Epstein-Barr virus,
      Cytomegalovirus, SARS-CoV2
  - Treatments
    - Bendamustine + Rituximab
    - Sutimlimab
- Laboratory
  - RBCs
    - Agglutination of red blood cells
      - At temperatures < Normal core body temperature
    - Hemolytic anemia: Complement mediated
  - IgM
    - Type: IgMκ
    - Levels: Lower than other IgM MGUS
    - GD1b binding
  - Hemoglobin levels: Lower than other IgM MGUS
  - Occur in 50% of IgM MGUS vs GD1b
  - MYD88 mutations: Uncommon
  - Other genetics
    - Recurrent trisomies of chromosomes 3, 12, 18
    - Recurrent mutations in KMT2D, CARD11

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 ⁴⁹

IgG₄ Antibodies
- < 5% of total IgG in normals
- Can undergo 'half-antibody exchange'
  - Results in recombined antibody molecules with two different binding specificities (F_ab subunits)
- Disease mechanisms
  - Iinterfere with protein-protein interactions in cell adhesion or signal transduction pathways
  - No inflammatory-mediated tissue destruction
  - No activateion of classical complement pathway
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-155: Demyelinating neuropathy + CNS or Tremor
  - Contactin-1: Demyelinating neuropathy + Ataxia
  - CASPR2
  - IgLON5: Encephalitis with disordered sleep, cognition, gait, autonomic CNS
  - DPPX: Encephalitis
- 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
  - Course: Chronic
- May improve with immunotherapy ⁴⁷
- Associated systemic disorders
  - Atopy & Allergic
  - Collagen vascular disease
  - Multiple sclerosis-like syndromes
Laboratory
- Skin biopsy: Often normal
- NCV: Normal

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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3/18/2025

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

Systemic connective tissue disorders & Vasculitis: Specific syndromes 4

Vasculopathies: Nerve specific

Perineuritis 1

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

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