---

Home, Search, Index, Links, Pathology, Molecules, Syndromes,
Muscle, NMJ, Nerve, Spinal, Ataxia, Antibody & Biopsy, Patient Info

---

Acute Immune Polyneuropathies

"Classic" Guillain-Barré   Associated disorders   Childhood GBS   Clinical features   Electrodiagnostic features   Epidemiology   Laboratory features   Morbidity   Pathology   Prognosis   Prodrome   Therapy Acute Immune Neuropathies   Autonomic   Motor (AMAN)   Sensory   Cranial nerve variants     Ataxia & Ophthalmoplegia     Bickerstaff     Facial diplegia     Miller Fisher Syndrome     Pharyngo-Cervico-Brachial   IgM vs GalNAc-GD1a   Pathology General topics   Acute immune neuropathies     Antibodies     Classification     Differential diagnosis     General Principles   GBS-like syndromes: Treatment

Georges Guillain

Ross & Bury 1893

Classification of Acute Immune Neuropathies

• Demyelinating (± 2° axonal loss)
  • Motor + Sensory
    • Classic Guillain-Barré
    • CIDP with acute onset: More prominent demyelination on NCV
  • Motor
• Axonal
  • Motor + Sensory (AMSAN)
    • GBS-like syndrome
    • Vasculitis
  • Motor: Associated with
    • Prodromal infection: Campylobacter jejuni; Haemophilus influenzae
    • Serum antibodies: IgG vs GM1, GM1b, GD1a or GalNAc-GD1a ganglioside
  • Sensory
  • Autonomic
• Cranial Nerve Syndromes: Associated with
  • Campylobacter jejuni prodrome
  • Serum IgG vs GQ1b ganglioside
  • Miller-Fisher
  • Facial diplegia
  • Bickerstaff's Brainstem encephalitis
  • Pharyngo-Cervico-Brachial
    
• Other GBS variants with autoantibodies
  • IgM vs GM2 gangliosides
  • IgM vs GalNAc-GD1a ganglioside

Acute immune neuropathies: General principles

• Epidemiology
  • Incidence
    • Europe & North America
      • 0·8–1·9 (median 1·1) cases/100,000 people per year
    • Age association
      • Childhood: 0.6/100,000 people per year
      • Elderly: 2.7/100,000 people per year
  • Males slightly > Females
• Common features
  • Prodromal illness
    • 50% of patients in 2 weeks prior to disease onset
      • Respiratory or GI
      • Strongest association: C. jejuni
    • GBS syndrome peak frequencies ²⁸
      • Correlate with hospitalizations for Pneumonia & influenza
      • No significant association with vaccinations
  • Progression
    • Average: 5 to 10 days
    • Spectrum: 2 to 28 days
  • Course
    • Usually monophasic
    • Rare relapses
  • Prognosis
    • Recovery in most
  • Cerebrospinal Fluid (CSF)
    • High protein (> 0.55g/L)
    • Few or no cells
• Variable features
  • Motor, Sensory, or Autonomic involvement
  • Tendon reflexes: More frequently preserved or increased with motor predominant syndromes
  • Demyelinating vs. Axonal Pathology
  • Degree of CNS involvement
  • Humoral vs. Cellular immunity
• Features suggesting another diagnosis
  • Sensory level: Spinal cord syndrome
  • Severe bladder or bowel dysfunction: Spinal cord syndrome
  • Marked asymmetry: Vasculitis
  • > 50 WBC/mm3
    • Infectious disorders: HIV; Lyme; Polio
  • Very slow nerve conduction velocities (< 32 M/s): CIDP
    • Relapses, or a chronic course, may be more likely
• Differential diagnosis of acute motor dysfunction
• Treatment of GBS-like syndromes: Plasma exchange vs IV Ig
  • Overall: No difference in efficacy
  • Indications for rapid treatment: 1st 2 weeks of disease
    • Bulbar disorders
    • Respiratory dysfunction
    • Inability to walk without assistance
  • Probably indicated: Milder weakness; Early in disease course
  • IV Ig: ? Primary therapy; 2 gm/kg total over 2 to 5 days
    • Slightly lower cost
    • Slightly fewer side effects
    • Easier to administer
    • Use in
      • Children
      • Rural settings with no access to plasma exchange
      • Syndromes with anti-glycolipid antibodies
        • Pure motor syndrome (IgG vs GM1)
        • Miller-Fisher syndrome (IgG vs GQ1b)
      • Patients with
        • Diarrhea prodrome
        • Infectious disorders (HIV)
        • Autonomic instability
        • Poor venous access
        • Relapses of weakness
  • Plasma Exchange: 4 or 5 treatments over 7 to 10 days
    • ? Fewer late relapses
    • No allergic reactions
    • Efficacy somewhat better documented
    • Use in
      • Adults with good venous access
      • Very recent onset of symptoms (1 to 3 days)
      • History of side effects with IV Ig
      • Pregnancy
        
      • Congestive heart failure
        
      • Renal insufficiency
        
      • IgA deficiency

"Classic" Guillain-Barré Syndrome

Autoantibodies Clinical features Electrodiagnostic Laboratory Morbidity Other features Pathology Prodrome Prognosis Therapy

English translation: By Bassam Malo MD

• Epidemiology
  • Incidence: 1 to 2/100,000/year
  • Male: Female = 1.25: 1
  • Peak ages: Bimodal
    • Children & Young adults
    • > 55 years
  • Zika infection: Colombia
  • Winter month peak: United States, Australia & Asia
  • Genetic risk factors ³⁸
    • Familial cases
    • Reported associations with occurrence, prognosis & severity of GBS
      • Conflicting results
      • FcγRIIa-H131 allele homozygosity (vs R131) ⁴
        • More common than in healthy controls
        • Higher risk for severe disease than other genotypes
        • Same allele protective against lupus nephritis
• GBS Prodrome
  • Upper respiratory: + CMV titers = 18%
    • Younger patients
    • More sensory loss & cranial nerve involvement
    • More severe disease
      • Respiratory insufficiency more common (65%)
      • Longer median time until independent locomotion
    • Antibodies
      • Higher Frequency of serum IgM vs GM2 ganglioside
      • Also see IgM vs GalNAc-GD1a ganglioside
  • Gastrointestinal: + Campylobacter jejuni titers = 28%
    • Motor predominant
    • More severe outcome
    • + Campylobacter titers in US GBS patients overestimate prevalence of infection
  • Mycoplasma pneumonia
    • Associated with antibodies to galactocerebroside (GalC)
    • Frequency: 5% of GBS patients in Japan
    • ? Associated with younger patients
    • Other associated disorders
  • Other infections
    • Epstein-Barr virus
    • HIV
    • Dengue fever: 6x risk
    • Zika virus
      • Frequency: 8x to 20x risk
      • More severe disease: More functional disability & respirator use
      • More EOM involvement
      • Prodrome features, common: Rash; Conjunctival hyperemia; Retro-ocular pain; Pruritis
      • GBS types: Demyelinating, AMAN, Transient polyneuritis
    • Chikungunya ³³
      • Epidemiology
        • Seasonal association
        • India: 16% of GBS
        • No statistical association in Mexico
      • GBS type: Demyelination in 75%
    • COVID-19
      • GBS frequency: Reduced ³⁴ or Increased ³⁶
    • Japanese encephalitis
    • ? Hepatitis A
    • Hospital diagnosed infections & antibiotic use
      • GBS frequency: OR 13.7x higher (4.3% vs 0.3%) in Denmark ³⁵
      • Time: More within 1 to 2 months of infection
      • Infection types: Lower respiratory, GI, Septicemia
  • Vaccinations
    • Tetanus toxoid; Influenza; ± Polio (oral)
    • Rabies
      • Vaccines: Myelin-containing (Semple); Suckling mouse brain
      • Usually > 10 years old
      • Some cases associated with sensitization to myelin basic protein
      • Occurs in clusters
  • Post-partum: 1^st 2 weeks with higher risk
  • Surgery
  • ? Graft vs Host disease
  • Drugs: Zimeldine
• Clinical features
  • Onset
    • Weakness: Most often symptomatic in legs
    • Pain: Low back & legs
    • Paresthesias: Distal
  • Weakness
    • Distribution: Proximal + Distal; Symmetric
    • Severity: Quadriplegia in 30%; Bedbound another 30%
    • Respiratory failure
      • Vital capacity < 1 liter: Observation in ICU necessary
      • ~33% of GBS require intubation
      • Indications for intubation
        • Vital capacity < 12 to 15 ml/kg: Especially with rapid decline
        • Negative inspiratory force (NIF) < 25 cm H₂O
        • Hypoxemia: Pa_O2 < 80 mm Hg
        • Difficulty with secretions
      • Time of onset: 7 days
      • Time on respirator: 50% < 3 weeks
      • Usually 2° to muscle weakness
      • Occasionallly related to aspiration
    • Cranial Nerves (70%)
      • VII
        • Symmetric: Occurs early in parallel with weakness
        • Asymmetric
          • Occurs later in disease course
          • Other weakness may be stable or improving
      • Extra-ocular: Overlap with Miller-Fisher
      • Tongue: Symmetric; Common (50%)
  • Sensory
    • Paraesthesias: Initial symptom in 50%; Eventually occur in 70% to 90%
    • Pain ²³
      • Prominent in 70%
      • Location: Extremities > Trunk
      • Timing: May occur with prodrome (35%), disease (65%) or sequelae (40%)
      • Associations
        • Neuropathy: In back, hips & legs at onset; Myalgias; Occasional radicular
        • Immobility: Myalgias
        • More severe disease
        • More prominent sensory involvement
        • Recovery phase: Distal; Legs > Hands; Dysesthesias
    • Loss
      • Distal; Symmetric
      • All modalities involved
  • Tendon reflex loss
    • Early in most (70%) but not all patients
    • Progressive reduction during 1st week
    • Distribution: Ankles most frequently lost; Biceps most frequently spared
    • Associations: Sensory loss; Weakest limbs; Distal
    • Spared reflexes all during disease course suggests another diagnosis
  • Autonomic dysfunction
    • Frequency: 60%
      • More common in more severe syndromes
    • Blood pressure
      • Transient hypertension or, less often, hypotension
      • Increased sensitivity to anti-hypertensive medications
    • Cardiac arrhythmias: Sinus tachycardia; Bradycardia
    • Bladder: Urinary retention; Sphincter symptoms in 10% to 15%
    • GI: Ileus
    • Test: Bilateral ocular pressure x 25 sec; Produces bradycardia (< 40 bpm)
    • Course
      • Usually improves in parallel with motor & sensory function
      • Rarely any long-term autonomic dysfunction
  • Progression
    • Nadir: Mean at 9 days
    • General definition: Progression for < 4 weeks
    • Treatment related fluctuations: More common with
      • Severe disease
      • Prominent sensory abnormalities
    • 1% to 20% have acute onset of CIDP vs GBS: May need repeat treatment; ? Steroid responsive
    • Causes of morbidity
      • Weakness
        • Respiratory failure
        • Pneumonia or sepsis
        • Dysphagia
        • Thromboembolism
        • Corneal exposure
      • Sensory
        • Pain: 2° neuropathy or immobility
      • Autonomic
        • Cardiac Arhythmias
        • Labile blood pressure
        • Hypersensitivity to cardiovascular medications
          
    • Prognostic factors
      • Mechanical ventilation needed ⁸
        • Rapid disease progression
        • Bulbar dysfunction
        • Facial weakness: Bilateral
        • Dysautonomia
        • Pulmonary function testing
          • Vital capacity < 20 ml/kg
          • Decrease from baseline > 30%: Vital capacity or Respiratory pressure
      • Residual disability greater
        • Clinical prognostic factors for residual disability
          • Increasing age (especially > 40 to 60)
          • Weakness
            • Severe at nadir
            • Need for ventilatory support
            • Rapid development
          • Complete areflexia in the acute stage
          • Diarrhea prodrome: Especially with Plasma exchange treatment
          • Lack of treatment with plasma exchange or IV Ig
          • Longer time to improvement
            • Initial improvement > 21 days
            • Disability present at 12 to 18 months
        • Laboratory prognostic factors for residual disability
          • Axon loss
            • Low compound motor action potential (CMAP) amplitudes
              < 20% of normal
            • ? Lack of demyelinating features
          • Serology
            • ? Serum IgG vs GM1 ganglioside
            • ? Preceding Campylobacter jejuni infection (past 4 weeks) or diarrhea
            • Recent CMV infection
          • Serum Albumin: Low ³¹
            • Respiratory weakness: More
            • Severe weakness at 1 and 6 months: More
            • Inability to walk: More
            • Albumin levels may be reduced after IVIg treatment
  • Death
    • Frequency: 3% to 10%
    • Causes: Pneumonia; Iatrogenic hypotension
    • Associations: Mechanical ventilation; ? Autonomic dysfunction
  • Associated Systemic Disorders
    • Infections: Prodromes
      • Viral
        • Cytomegalovirus (CMV)
        • Epstein-Barr virus (EBV) ± Hemophagocytic syndrome
        • HIV
        • Influenza
      • Bacterial
        • Campylobacter jejuni
        • Mycoplasma pneumoniae
        • Lyme
    • Lymphoma
    • Sarcoid
    • Porphyria
    • Hyponatremia
      • Mildly reduced Na⁺ in 7% to 26%
      • Severely reduced Na⁺ (SIADH) (105 to 120 mEq/L) may occur
      • No relation to degree of severity of GBS
    • Renal
      • Common: Mild transient proteinuria
      • Rare: Glomerulonephritis
    • Cardiac
      • Arhythmias: 10% to 75%
      • EKG changes: > 50%
    • Serum CK: High in 33%; Up to 4x normal
  • Treatment
    • Immunomodulation
      • Plasma Exchange or IV IgG
        • Definitely indicated
          • Patients with: Inability to walk
          • Timing: 1st 2 weeks of disease
          • Decision between IV IgG & PE: Depends on individual features of patient & disease
        • Probably indicated
          • Milder weakness
          • Early in disease course
        • Doses
          • Plasma Exchange: 5x over 8 to 10 days
          • IVIg: 2g/kg total over 2 to 5 days
        • Plasma Exchange vs IV IgG
          • Often provide similar degrees of benefit
          • Exception
            • Associated IgG vs GM1, GM1b, or GalNAc-GD1a gangliosides: IVIg more effective
        • 2nd treatment course: No additional benefit ⁴⁰
      • Not Corticosteroids
      • ?? Eculizumab ³²
        • Timing: Within 2–13 days of disease onset
        • Dose: 900 mg q week for 4 weeks with antibiotic prophylaxis
        • Concurent IvIg treatment
        • No benefit at 4 weeks
        • Possibly more improvement at later times (20 to 24 weeks) after treatment
    • Ventilatory support
    • Avoid anti-hypertensive medications
    • ? Sub-cutaneous heparin
      • No evidence of benefit with moderate or mild weakness
      • ? Lower Risk of thromboembolic events in intensive care with severe weakness
• Childhood GBS
  • Ages: Neonatal to Teens
  • Onset
    • Lower extremity ® Generalized weakness
    • Pain & Paresthesias (60%): Lower limbs or Back
  • Miller-Fisher syndrome: 1% of childhood AIDP
  • CNS signs: More frequent; At onset
    • Bladder dysfunction
    • Mental status changes & headache
    • Pain & meningismus (30%)
    • Ataxia: Gait
    • Occasional: Papilledema (< 5%)
    • Recovery
      • Often more rapid than adults
      • Disability at 1 year: Rarely full recovery
      • Residual disability (~30)%: Foot drop, Pes cavus, Tremor
• Nerve conduction studies in GBS: Demyelination ± Axonal loss
  

  M. Al-Lozi

  • Common early (< 1 week from onset) features ⁹
    • Reduced H reflex (97%)
    • SNAPs: Upper extremity (61%); Sural may be preserved
    • Reduced F-waves (84%)
  • Other electrodiagnostic features: Demyelination
    
    • Overall
      • Features less common in 1st 5 to 7 days of disease
      • Increased frequency when multiple nerves studied
    • Features of demyelination for more specific diagnosis
      • One abnormality in 2 different nerves
      • Nerves: Median & Ulnar or Peroneal
      • Specific features
        • Distal motor latency: > 150% upper limit of normal
        • Motor NCV: < 70% lower limit of normal (? CIDP)
        • F-wave latency: > 150% upper limit of normal
        • CMAP amplitude decay: > 10% to 30%
        • CMAP temporal dispersion
            > 300% upper limit of normal (Distal)
        • CMAP temporal dispersion
          • > 150% upper limit of normal
          • Distal: Proximal
  • Motor conduction block probably causes acute weakness
    • Locations
      • Proximal nerve roots
      • Along course of nerve
      • Distal near motor nerve terminals
  • Compound motor action potentials (CMAPs):
    • Often become progressively small
    • Small CMAPs may indicate
      • Axonal loss or distal conduction block
      • Poor prognostic sign
  • EMG: Fibrillations & Positive sharp waves
    • Onset: 2 to 4 weeks
    • Peak: 2 to 3 months
• Acute immune neuropathies: Humoral Immunity
  • IgM or IgG vs Tubulin: 7%
  • IgG vs GM1, GM1b or GalNAc-GD1a: Motor syndromes
    • United States: < 2%
    • Japan, China, Australia & ? Europe: 10% to 20%
  • IgM or IgG vs Heparan sulfate: 35%
  • IgG vs other glycolipids: 10% to 30%
  • IgM or IgG vs PMP-22: Probably testing artefact; Not specific for GBS
  • Tumor necrosis factor-α: High serum level correlates with demyelination
  • IgG or IgM vs molecules at nodes of Ranvier or paranodes (30%) ²⁷
    • Target molecules
      • Gliomedin (GLDN) : Demyelinating GBS
      • Neurofascin-186 : Axonal acute immune neuropathies
• GBS: Laboratory
  • CSF: Albumino-cytological dissociation
    • Protein
      • Early (1st 2 days): Usually (85%) normal
      • Later
        • High; 66% in 1st week; 82% in 2nd week
        • Highest with most slowing of NCV
    • Cells: Normal (~90%)
      • Usual (90%): Normal (< 10 cells/mm³)
      • May be high with associated disorder present
        • HIV
        • Lymphoma
        • Lyme
        • Sarcoid
    • Oligoclonal bands: 10% to 30%
  • Hematology: Only abnormal with associated infection or other disorder
  • Serum CK: Higher in patients with pain
  • ESR: Usually < 50 mm/hr
  • Mild proteinuria: 25%
  • Liver function test: Abnormal in 10%
  • WBC: Most commonly normal; > 20,000 only with associated infections
  • HLA types: Class II associations with AIDP in northern Chinese patients ¹⁴
    • General
      • Regions important in peptide binding and T cell recognition
      • Associated with other diseases with pathoimmunological basis
      • No class II associations found for AMAN
    • Susceptibility: DQβRLD^55–57/ED^70–71 & DRβE⁹V¹¹H¹³
    • Protection: DQβRPD^55–57 epitope
• Other: Books by GBS patients or relatives (PDF file)

Putnam 1909

Acute Motor (Axonal) Neuropathy (AMAN)

• Epidemiology
  • Geography
    • More common: Japan, China, Mexico & 3rd world countries
    • Rare: Most parts of United States
    • Occasional: Europe
  • Onset age: More common in children
  • Male = Female
  • Seasonal peaks
    • Mexico & China: July to September (Rainy season)
    • Japan: March for C jejuni + patients
• Prodrome
  • Gastrointestinal: Diarrhea
    • + Campylobacter jejuni titers in 67%
    • Campylobacter jejuni in GBS
      • Serotype associations
        • O-19 (HS:19) type
          • > 50% when Campylobacter culture positive
          • Risk of acute neuropathy: 1 in 158
          • 6x greater than after other Campylobacter infections
          • Common in China & Japan
          • Different isolates clonally related
            • Commonly bind cholera toxin
        • O-41 (HS:41): Over represented in South Africa & Mexico
        • Carbohydrate epitope associations: GD1a but not clearly GM1
      • Higher frequency of TNF-α polymorphism
      • Campylobacter jejuni cst-II polymorphisms: Neuropathic strains ¹⁸
        • cst-II: Gene encoding sialyltransferase
        • cst-II (Thr51)
          • More common than enteritic strains
          • Express GM1 (92%) & GD1a (91%) epitopes
          • Associated with related antibodies & Limb weakness
        • cst-II (Asn51)
          

          AMAN: After recovery Putnam 1909

          • 83% express GQ1b epitope
          • Associated with
            • Anti-GQ1b antibodies
            • Bulbar palsy
            • Ophthalmoparesis
  • Upper respiratory
    
    • Haemophilus influenzae infection ⁵
      • Geography: Japan
      • Frequency: 13%
      • Organism type: Non-typable; Contains GM1-like structure
      • Infection preceded disease by 4 to 12 days
      • Serum antibodies: IgG vs GM1 & GD1b ganglioside common (83%)
    • + CMV titers in 0%
  • Zika virus
  • ? Treatment with parenteral ganglioside mixture
    • Acute axonal motor syndromes reported
      • Onset 5 to 15 days after Rx
        
      • Associated serum IgG anti-GM1 antibodies
• Clinical ²⁰
  • Weakness
    • Distal: More severe than proximal
      • Finger extensors: May be selectively weak
      • Arms > Legs
    • Proximal: Mild weakness common (85%)
    • Symmetric: Usually
    • Cranial Nerves (6% to 25%)
      • Facial weakness: Occurs but less commonly than in AIDP
    • Respiratory failure
      • Uncommon
      • Less than in classic demyelinating GBS
  • Sensory
    • Normal by clinical & electrodiagnostic testing
    • Pain
      • More common in AMAN than AIDP
      • Locations: Back; Extremities
      • Myalgias
      • Onset: Often early in disease course
    • Paraesthesias/Dysesthesias: Some patients; More common in AIDP
  • Reflexes
    • Usual: Reduced in proportion to strength
    • Occasional: Preserved; Hyperreflexia in some ²⁶: Associated with
      • Milder disease
      • Serum IgG vs GM1, GM1b, GD1a or GalNAc-GD1a
  • Progression ¹⁷
    • Nadir: Mean at 6 to 12 days; May be as short as 2 days
    • Shorter course than demyelinating GBS
  • Treatment
    • IV Ig: Anecdotal evidence
    • Plasma Exchange: May be effective with Reversible Conduction Failure ⁴³
    • Not Corticosteroids
  • Recovery
    • Significant improvement in strength over 1 to 2 months
    • ? More rapid with
      • Haemophilus influenzae prodrome
      • Reversible Conduction Failure ⁴³
• Laboratory
  • Nerve conduction studies
    • Axon loss (CMAP amplitude ↓) >> Demyelination
    • May have: Prolonged distal latencies or Conduction block
      • Occurs: Early; 1st 2 weeks
      • Disappears: At later times
      • Less common than in AIDP
    • Reversible Conduction Failure (RCF) ⁴²
      • Features
        • Rapid recovery of: Conduction velocity & CMAP amplitudes
        • No evidence of temporal dispersion
      • More common with AMAN than AIDP
      • May suggest: More favorable prognosis; Less severe at 1 month
      • AIDP + RCF: Younger; Clinically more like AMAN
  • Serum Antibodies ²⁵
    • IgG vs GM1 ganglioside (40% to 50%)
      • IgG reactivity to both GM1 & GM1b gangliosides
        • More strongly associated syndromes
          • Distal motor
          • Rapidly progressive
        • Treatment response: IVIg, not plasma exchange
      • IgG subclass: Associated with prodrome & speed of recovery phase ¹⁶
        • IgG1
          • Preceding gastroenteritis
          • Campylobacter jejuni serology +
          • Slow recovery (> 1 month)
        • IgG3
          • Preceding respiratory infection
          • Rapid recovery within 1 month
      • Epidemiology
        • Common: Japan, China & 3rd world countries
        • Rare: Most GBS-like sydromes (AIDP) in US & Canada
      • Pathophysiology of IgG anti-GM1 antibodies ¹⁹
        • May bind to: Nodes of Ranvier & Paranode of axons
        • Induce binding of C3 complement
        • Nodes of Ranvier: Disrupts Na+ channel clusters
        • Paranode
          • Detachment of paranodal myelin terminal loops
          • Caspr: Absent or reduced
        • ? Anti-GM1 & other antibodies block nerve conduction
    • IgG vs GalNAc-GD1a: Similar to syndrome with IgG vs GM1 ganglioside
      • Campylobacter jejuni infection
      • Acute motor neuropathies
      • Distal predominant weakness & Sparing of the cranial nerves
      • Rapidly progressive, severe weakness
      • Poor recovery
    • Other antibodies in AMAN syndromes
      • IgM vs GM1 ganglioside (30%)
      • IgG vs GD1a ganglioside (12% to 60%)
        • May be 2° to IgG binding to GalNAc-GD1a contaminant in GD1a
        • May be associated with AMAN or AIDP
      • IgG vs GM1b (15%)
      • IgM vs GalNAc-GD1a ganglioside
    • Antibody associations: Other
      • More common with prodromal infections
        • Campylobacter jejuni
        • Haemophilus influenzae
      • Time course: Highest titers at disease onset; Fall over weeks ¹⁵
      • Geography: Uncommon in many areas of US
  • MRI: Ventral root enhancement

    Acute Motor Neuropathy
    From: R Bucelli MRI: Ventral root enhancement (Arrow)	From: R Bucelli MRI: Cauda equina enhancement (Arrow)

  • Pathology
    • Motor nerve terminal degeneration
    • Severe weakness: More proximal axonal damage
    • Ventral root: Axon loss
    • Macrophage invasion of motor nodal axolemma: Focal axon damage
    • Sensory nerves normal
• Variant syndrome: Acute Motor-Sensory Axonal Neuropathy (AMSAN)
  • Nosology: ? Severe form of AMAN
  • Clinical
    • Weakness: Severe; Distal & Proximal
    • Sensory loss
  • Laboratory
    • NCV: Axon loss; Sensory & Motor
    • Serum IgG vs GM1 ganglioside: Some patients
  • Pathology

Guillain-Barré-like syndrome with serum IgM binding to GalNAc-GD1a ganglioside ²

• Epidemiology
  • Japanese patients
  • Younger onset: Mean 3rd decade
  • ? Female > Male
• Clinical
  • Prodrome
    • GI: Campylobacter jejuni (75%)
    • Respiratory: Cytomegalovirus
  • Weakness: Mild; Proximal + Distal
  • Sensory: Paresthesias ± Loss (75%); More common with CMV prodrome
  • Cranial nerves: Facial weakness (27% to 80%); More common with CMV prodrome
  • Recovery: Good at 1 month; Better than with IgG or no antibodies
• Electrodiagnostic
  • Demyelination in many (38% to 64%)
  • Axonal loss uncommon
• Serum antibody
  • IgM vs GalNAc-GD1a ganglioside
  • Cross reactive with GM2 ganglioside: 100% with CMV prodrome; 50% with GI prodrome
  • Patients with GI prodrome commonly have other IgM antibodies as well: anti-GM1 & GD1b
  • Also see
    • Chronic demyelinating neuropathy with IgM binding to GalNAc-GD1a & GM2
    • Chronic motor neuropathy with IgG binding to GalNAc-GD1a
• Pathology

Miller Fisher Syndrome 6 Epidemiology Frequency Japan & Taiwan: 15% to 25% of GBS Europe & Thailand: 7% to 8% of GBS US: 1% to 2% of GBS Onset age: Mean 36 to 40 years; Range 13 to 78 years Seasonal: Higher frequencies in Fall-Winter or Spring Clinical prodrome Infection Respiratory: Most common Associated infections Campylobacter jejuni: 21%; Often serotype O-2 or O-10 Hemophilus influenzae: 7% 11 ? SARS-Cov-2 41 Male > Female Clinical Onset 7 days after infection Diplopia (Asymmetric) (80%) Myalgia & Paresthesias Vertigo & Ataxia General: Incomplete forms or Variants are common Eye External ophthalmoplegia (100%) Often earliest feature Symmetric or Asymmetric Pupillary dysfunction (42%): Mydriasis Ptosis (50% to 60%) Ataxia (100%): Dysmetria; Gait ataxia; Arms & Legs Areflexia (100%): By 1 week of disease; Range 4 to 45 days Sensory Distal & Facial paresthesias & dysesthesias (24%) Sensory loss: Minimal; Definite in 20% Weakness: 20% Autonomic: Bladder disorders 16% Other Cranial nerve disorders Oropharyngeal weakness (26%) Face weakness (30% to 50%) CNS associations Bickerstaff Hypersomnolence Progression Over days to weeks May progress to generalized weakness Recovery Onset: After 2 weeks to 2 months Long term: Many with no residual defects MFS-Cranial nerve variants: Often associated with IgG vs GQ1b or GT1b gangliosides GBS overlap: Ophthalmoplegia; Weakness; ± Ataxia Internal ophthalmoplegia: Dilated pupils; Light-near dissociation Acute external ophthalmoplegia: Complete or partial Acute ataxia: May progress to Weakness & GBS Visual impairment 7 Chronic ophthalmoplegia with serum IgG binding to GQ1b ganglioside 3 May be associated with vestibulopathy or demyelinating neuropathy Acute neuropathies with bulbar dysfunction: Pharyngo-cervical-brachial variants Bickerstaff brainstem encephalitis: Brainstem signs 13 Rule out: Neurosyphilis Laboratory CSF Protein: 20 to 60 mg/dl Cells: Few or None; 0 to 5/mm 3 Nerve conduction studies Sensory Axon loss SNAPs: Amplitude Reduced Motor Peripheral nerve: Normal or Reduced (35%) CMAP amplitudes Facial: Reduced CMAP amplitude F-waves: Prolonged; Dispersed; Absent H reflexes: Absent from soleus Serum antibodies IgG vs GQ1b (80%) IgG vs GT1a IgG staining of cerebellar molecular layer MRI Cranial nerve enhancement (gadolinium) may occur 12 Brainstem or Cerebellar lesions: Some patients Treatment: ? IVIg; ? Plasma exchange

MFS Serum IgG staining of cerebellar molecular layer

(Sub)Acute Sensory Neuropathies ²⁴

• Clinical
  • Antecedent illness: Flu or URI in some
  • Onset
    • Over Days to Weeks
    • Paresthesias & Pain
  • Sensory
    • Loss
      • Pansensory
      • Proximal + Distal
    • Paresthesias & Pain
  • Autonomic dysfunction: Mild
  • Motor: Normal; Occasional mild weakness
  • Tendon reflexes
    • Usually absent
    • Rare patients may have preserved tendon reflexes
      • ? Central branch of sensory neuron damaged rather than cell body
      • ? Preserved Ia afferents to motor neurons
  • Course
    • Monophasic
    • Prognosis: Often incomplete recovery
• Laboratory
  • Nerve conduction studies
    • Sensory potential amplitudes: Usually absent; May be reduced or normal
    • Conduction velocities: Relatively normal
    • Demyelinating features: Prolonged distal latencies in some patients
  • CSF: Protein high; No cells
  • Pathology
    • Nerve biopsy: Axonal loss; Mild inflammation
    • Autopsy: Lymphocytes in nerves & Dorsal roots
  • Epstein-Barr virus titers elevated in some patients ¹

Acute neuropathy: Bickerstaff brainstem encephalitis ¹³

• Epidemiology: Most reports from Japan
• Antecedent illness (92%): Most commonly upper respiratory infection
• Age: 3 to 91 years
• Onset: Diplopia or gait disorder most common
• Clinical: Brainstem signs
  • Reduced consciousness (74%): Drowsy, stupor or coma
  • Ataxia: Often trunk & limb
  • Eyes
    • Ophthalmoplegia, external (100%): Relatively symmetric
    • Pupil disorders (34%)
    • Ptosis (29%)
    • Nystagmus (27%)
  • Other cranial nerves
    • Facial diplegia (45%)
    • Bulbar weakness (34%)
  • Weakness: Flaccid tetraparesis (60%); Respiratory failure
  • Pyramidal signs
    • Tendon reflexes: Variable; Hyperreflexia to Absent
    • Plantar responses (40%): Extensor
  • Sensory loss
    • Small fiber (31%)
    • Large fiber (16%)
    • Hemisensory loss
  • Course
    • Monophasic
    • Often good prognosis: Complete remission in 51%; Death 4%
• Laboratory
  • Serum IgG binding to GQ1b ganglioside (66%)
  • Electrophysiology
    • Motor axon degeneration
    • Central involvement
  • MRI: CNS abnormalities
    • High intensity T2 signal
    • Locations: Brainstem, Thalamus, Cerebellum
  • CSF
    • Cells: Usually normal; Occasionally high WBCs (37%)
    • Protein: High in 59%; Higher in 2nd week than 1st
  • Pathology
    • Perivascular lymphocytic infitration
    • Edema
    • Glial nodules

Acute neuropathy: Pharyngo-Cervical-Brachial Variant ²¹

• Prodromal associations: Within 4 weeks of illness
  • Upper respiratory infection (70%)
  • Diarrhea or other GI (30%)
  • Infection: Campylobacter jejuni > Cytomegalovirus
• Clinical
  • Bulbar palsy
    • Dysphagia
  • Weakness
    • Neck
    • Arms: Proximal; Often initial symptom
    • Legs: Relatively preserved; Hip flexors most involved
    • Face: 50%
  • Sensation: Reduced or Normal
  • Tendon reflexes: Reduced, especially in arms
  • Cranial nerves
    • External ophthalmoplegia (50%)
  • Ataxia (40%)
  • Autonomic(20%): Especially heart rate & bladder dysfunction
  • Progression: 1 to 3 weeks
  • Overlap syndromes
    • GBS: 48%
    • Miller-Fisher (MFS)-like: 30%
    • None: Pure PCB in 13%
• Laboratory
  • CSF protein: High in some (42%)
  • NCV: Abnormal motor conduction or late responses
  • Antibody
    • IgG binding to GT1a or GM1b gangliosides without binding to GQ1b (65%)
    • IgG binding to GQ1b: Common with MFS overlap

Acute neuropathy: Bulbar Palsy Variant ²⁹

• Epidemiology: Asian patients
• Clinical
  • Onset age: 18 to 54 years
  • Bulbar: Weakness
  • Gait: Ataxia (82%)
  • Face palsy (55%)
  • Ophthalmoplegia (82%): Abducens or Complete
  • Strength: Normal
  • Tendon reflexes: Absent (90%)
  • Paresthesias (55%): Limbs
  • Dizziness (90%)
  • Course: Monophasic over weeks to 3 months
• Laboratory
  • NCV: Few patients with absent H-reflexes; Often normal
  • CSF protein: Usually normal
  • Antibody
    • IgG binding to GT1a (100%)
    • IgG binding to GQ1b (55%)

Acute Immune Neuropathies: Facial Diplegia Variant (BFP) ²²

• Epidemiology
  • Japanese & North American patients
• Prodrome
  • Infectious symptoms in previous 4 weeks
    • Frequency: 86%
    • URI or Fever most common
• Clinical
  • Onset
    • Age: 18 to 65 years
    • Limb numbness
  • Bifacial weakness
    • Progressive: Over weeks
    • Asymmetric: Often
  • Paresthesias
    • Most patients
    • Distal limbs
    • May persist for months
  • Strength: Normal or Mildly reduced
  • Tendon reflexes: Reduced or Absent
  • Other cranial nerves: Often normal
  • Course
    • Monophasic
    • Nadir at 4 weeks
    • Improvement over months
  • Differential diagnosis
• Laboratory
  • CSF: Albumino-cytologic dissociation
    • Protein: 51 to 256
    • Cells: 1 to 8
  • Nerve conduction studies
    • Demyelination (64%)
      • Evolve with disease course
      • Proximal or Distal
      • Distal latencies & F-waves: Prolonged
      • Recovery toward normal over months
  • CMV antibodies: 35%
  • Other possible infection: B. burgdorferi
  • IgM anti-GM2: 23%; Commonly with anti-cytomegalovirus IgM antibodies
  • No IgG antibodies

Acute Neuropathy: Sensory Polyradiculopathy ³⁷

• Epidemiology: 1 patient
• Clinical
  • Onset age: 19 years
  • Prodrome: Headache & Fever
  • Sensory loss
    • Arms & Legs
    • Distal to Upper arms & Thighs
    • Vibration & Proprioception
  • Ataxia: Limb & Gait
  • Areflexia
  • Motor & Cranial nerves: Normal
  • Course
    • Progression: Over 3 weeks
    • Recovery: Over 6 months
• Laboratory
  • NCS & EMG: Normal
  • SEP: Abnormal cervical & cortical respponses
  • CSF: Protein 94; 1 cell
  • Brain & spine MRI: Normal
  • Serum antibody: IgG vs Contactin-1