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CHRONIC IMMUNE POLYNEUROPATHIES: AXONAL

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

Also see:
Acute motor axonal neuropathy
Sensory neuronopathies

Duchenne




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



Neuropathy with IgG or polyclonal IgM binding to Sulfatide



NEUROPATHIES: VASCULITIC & CONNECTIVE TISSUE DISORDERS

Vasculitis: General features
Clinical features
Associated syndromes
Laboratory findings
Pathology
Treatment
Vessel pathology
  Location
  Size

From: M Al-Lozi
SLE vasculitis
Specific connective tissue syndromes
Behçet
Churg-Strauss
CREST
Cryoglobulinemia 
Drugs
Giant cell arteritis 
? GVHD
Infections
MPA
Peripheral Nerve Specific
Polyarteritis Nodosa
Rheumatoid Arthritis
Scleroderma
Sjögren's
Spanish toxic oil
Systemic lupus erythematosis
Wegener's

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



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
      • Ataxic (Sensory)
      • + Romberg
      • Tandem relatively spared
    • 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 neuropathy with IgM binding to Trisulfated Heparin Disaccharide (TS-HDS) 7

  • Epidemiology
    • Frequency: 10% to 20% of sensory neuropathies
    • Sex: Female = Male
    • TS-HDS: Most common neuropathy-related IgM 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
    • 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 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 oligomerization of FGF-2 binding to FGF receptor
    • Autoantibody types
      • Monoclonal: 86%; Usually κ class
      • Polyclonal: 14%
    • Antibody correlations
    • Antibody location: Serum
    • M-protein detected by immunofixation: 24%; κ class 92%
  • Electrodiagnostic testing
    • Axonal loss
      • SNAP amplitude, Sural: 55% reduced; 41% absent
      • Abnormal quantitative sensory testing
    • Demyelinating features (Mild): 16%; 50% with IgM M-proteins; 5% without IgM M-proteins
    • Normal (40%)
  • Pathology
    • Axon loss
      • Unmyelinated & some myelinated axons
      • Skin biopsy: Often abnormal
    • 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


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: 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
Henoch-Schönlein purpura
Essential mixed cryoglobulinemia
Cutaneous leukoclastic angiitis
Behçet
Tumor-associated: Lymphoma;
    Hairy cell leukemia; Melanoma
Drugs
Infections
  Hepatitis B > C > A

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References
1. Muscle Nerve 2000;23:702-706, J Neuroimmunol 2001;119:114–123
2. Neurol Clin 1997:15:849-863,, J Rheumatol 2005;32:769-772,, J Rheumatol 2005;32:853-858, Journal Neurological Sciences 2006;241:31–37
3. J Neuroimmunol 2001;112:181-187; Brain 2001;124:1968-1977, Muscle Nerve 2014;49:629-635, J Neurol 2018 Apr 9
4. Muscle Nerve 2001;24:154-169
5. Acta Neurol Scand 2001;103:386-391, Biomed Res Int 2014;2014:524940
6. Arch Neurol 2001;58:1215-1221
7. Muscle Nerve 2003;27:188-195, Muscle Nerve 2011; Online November
8. Current Rheumatology Reports 2004;6:156–163, Arthritis Res Ther 2011;13:R172
9. QJM 2007;100:41-51
10. Muscle Nerve 2007; Online September
11. Arthritis Rheum 2008;58:1528-1538
12. Muscle Nerve. 2010 Apr 28
13. Mod Rheumatol 2010 Dec 29
14. Clin Neuropathol 2011;30:11-17
15. J Neuropathol Exp Neurol 2011;70:340-348
16. JAMA Neurol 2013; Feb 25
17. Neuropathol Appl Neurobiol 2015; Apr 14
18. Arthritis Care Res (Hoboken) 2015 Dec 14
19. Rheumatol Int 2017 May 17, Arthritis Rheumatol 2017;69:1689-1700

8/2/2017