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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"



Neuropathy with IgG or polyclonal IgM binding to Sulfatide



NEUROPATHIES: VASCULITIC & CONNECTIVE TISSUE DISORDERS

Vasculitis: General 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
  NVSN

General Features of Vasculitis 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

  • 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
    • 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
    • Treatment
      • Corticosteroids
      • Cyclophosphamide in poorly responsive patients
    • Prognosis
      • Untreated disease: High mortality
      • After immunosuppressive treatment
        • Improvement in most over months to years
    • Variant: ADA2 deficiency ± PAN, Young onset (DADA2) 19
      Adenosine deaminase 2 (ADA2; CECR1) ; Chromosome 22q11.1; Recessive
      • Epidemiology: 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
      • Clinical
        • Onset age: Range 2 months to 59 years; Usual 1st & 2nd decade
        • Skin
          • Digital necrosis
          • Livido reticularis
          • Raynaud's
        • Pain: Myalgia; Arthralgia
        • Neuromuscular involvement (45%)
          • Polyneuropathy (40%)
          • Muscle: Myositis; Atrophy
        • CNS (20%)
          • Ischemic strokes: Often recurrent
          • Ventricular hemorrhage
          • Myelopathy
        • Systemic
          • Vasculopathy (70%): PAN-like syndromes
          • Hypertension, Renal
          • Gastrointestinal: Abdominal pain; Ischemia
          • Splenomegaly
          • Joints: Arthritis
          • Pulmonary: Frequent infections
          • Fever & Infections: Recurrent
        • Treatments
          • Anti-TNF alpha
          • Corticosteroids
          • Immunoglobulins
          • ADA2-enzyme replacement therapy: Fresh-frozen plasma (FFP)
        • Death: Often stroke-related
      • Laboratory
        • NCV: Axon loss
        • Pathology (Skin)
          • Arteries
            • 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
    • 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
        • 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%

Vasculopathies: Nerve specific



Perineuritis


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

  • Nosology
    • Chronic Ataxic Neuropathy with Disialosyl Antibodies (CANDA)
    • CANOMAD
  • Epidemiology
    • Male > Female
    • Onset age: 39 to 76 years
  • Clinical (IgM vs GD1b)
    • Onset: Acute, Subacute or Chronic
    • Sensory loss (100%)
      • Distribution
        • Distal
        • Symmetric
        • Legs & Arms
      • Modalities: Large & Small fiber
    • Paresthesias
    • Tendon reflexes: Absent
    • Strength
      • Normal in 50%
      • Weakness (50%): Mild; Distal
    • Gait
    • Cranial nerves
      • Ophthalmoplegia (50% to 90%)
      • Trigeminal (50%): Perioral paresthesias
      • Facial (25%)
      • Bulbar weakness (66%)
    • Course
      • Usually slowly progressive over months to years
      • Variants: Acute, Relapsing or Stepwise progressive sensory neuropathy
  • Antibodies
    • IgM
      • M-protein: Often; κ > λ
      • Cross reactivity: Other gangliosides containing disialosyl groups
        • GD3; GD2; GT1b; GQ1b
        • NOT GM1; GM3; GD1a
      • Anti-Pr2 activity
      • Cold agglutinins (50%)
      • Bind to: Dorsal root ganglion cells; Nerve terminals (in spindles)
      • Similar neuropathy after treatment with monoclonal anti-GD2 antibody
    • IgG anti-GD1b antibody associations
    • M-protein: 93%; κ or λ
  • Other lab
    • Sedimentation rate: High
    • CSF: Moderately high protein in some patients
    • MRI: Occasional patient with white matter lesions
  • Nerve conductions
    • Sensory axonal loss: Sensory potentials (SNAPs) Absent
    • Motor: Normal or mildly reduced amplitude & conduction velocity
    • Demyelination (50%)
      • Distal latencies: Mildly prolonged
      • NCV: Often normal; Occasionally slowed to 20 to 30 M/s
      • More prominent later in course
  • Pathology
    • Peripheral nerve: Loss of large myelinated axons & Dorsal root ganglion cells
    • 1 autopsy case with demyelination of nerve roots: Serum IgM binds to both GD1b & GD1a
  • Treatment: ? Cyclophosphamide; ? IVIg; ? Rituximab
  • Variant syndrome: Acute Ataxic Sensory 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
        • Improved sensation
        • Increased SNAP amplitudes
    • 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%)
    • 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
      • C5b-9 complement depositis: Muscle & Nerve
      • Thickened walls: Endomysial capillaries





TS-HDS

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


IgG4 Antibodies, Disease & Neuropathies


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


Amphiphysin antibody (IgG) with Neuropathies 21


Immune axonal neuropathies: Other

Distal sensory neuropathy with systemic immune disorder Trigeminal sensory neuropathy Amyloidosis



VASCULITIS: Nerve Location of vessel involvement
Epineurial arteriole Epineurial small vessel EndoneurialEither
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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References
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7/15/2021