Acute Immune Polyneuropathies

Ismail Setyopranoto
Department of Neurology School of Medicine GMU

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 or GalNAc-GD1a ganglioside
 Sensory
 Autonomic
 Cranial Nerve Syndromes: Associated with
 Campylobacter jejuni prodrome
 Serum IgG vs GQ1b ganglioside
 Miller-Fisher
 Bickerstaff's Brainstem encephalitis
 Other GBS variants with autoantibodies
 IgM vs GM2 gangliosides
 IgM vs GalNAc-GD1a ganglioside

Acute immune neuropathies: General principles

Acute immune neuropathies have several features in common as well as those that vary and are
distinctive for a particular syndrome. Some features suggest a different diagnosis among the causes of
acute motor dysfunction. Principles regarding which treatment to use are somewhat subjective.

 Common features
 Prodrome
  50% of patients in 2 weeks prior to disease onset
 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
 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
 Epidemiology
 Incidence: 1 to 2/100,000/year
 Male: Female = 1.25: 1
 Peak ages: Young adults & > 55 years
  Genetic risk factor: FcRIIa-H131 http://www3.ncbi.nlm.nih.gov/htbin-
post/Omim/dispmim?146790http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?
146790allele homozygosity (vs R131)4
 More common than in healthy controls
 Higher risk for severe disease than other genotypes
 Same allele protective against lupus nephritis

 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: PaO2 < 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
 Prominent in 70%
 Associations
 Neuropathy: In back, hips & legs at onset; Myalgias; Occasional
radicular
 Immobility: Myalgias
 Recovery phase: Distal; Legs > Hands; Dysesthesias
 Loss
 Distal; Symmetric
 All modalities involved
 Tendon reflex loss
 Early in most (70%) but not all patients
 Progressive  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: Blood pressure; Cardiac arrhythmias; Urinary retention; Ileus
 Sphincter symptoms in 10% to 15%
 Test: Bilateral ocular pressure x 25 sec; Produces bradycardia (< 40 bpm)
 Progression
 Mean nadir at 9 days
 General definition: Progression for < 4 weeks
 1% have acute onset of CIDP vs GBS: May need repeat treatment; ? Steroid
responsive
 Death
 Frequency: 3% to 10%
 Causes: Pneumonia; Iatrogenic hypotension
 Associations: Mechanical ventilation; ? Autonomic dysfunction

 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
  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
 Other infections: Epstein-Barr virus; HIV; ? Hepatitis A; ? Mycoplasma
 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: 1st 2 weeks with  risk
 Surgery
 ? Graft vs Host disease
 Drugs: Zimeldine

 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: Demyelination ± Axonal loss

 Common early (< 1 week from onset) features9
 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

 Humoral Immunity
 IgM or IgG vs Tubulin: 10%
 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-: High serum level correlates with demyelination

 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%), unless associated disorder present
 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 : 10%
 WBC: Most commonly normal; > 20,000 only with associated infections

 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

 Associated Systemic Disorders

 Infections: Prodromes
 Viral
 Cytomegalovirus (CMV)
 Epstein-Barr virus (EBV) ± Hemophagocytic syndrome
 Human immunodeficiency
 Bacterial
 Campylobacter jejuni
 Mycoplasma pneumoniae
 Porphyria
 Hyponatremia
 Mild  Na+ in 7% to 26%
 Severe  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 : > 50%
 Serum CK: High in 33%; Up to 4x normal

 Prognostic factors
 Mechanical ventilation needed8
 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
 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

 Axonal 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
 Recent CMV infection

 Treatment
 Immunomodulation
 Plasma Exchange or IV IgG definitely indicated
 Patients with inability to walk
 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
  Plasma Exchange and IV IgG
 Often provide similar degrees of benefit
 Exception
 Associated IgG vs GM1, GM1b, or GalNAc-GD1a gangliosides:
IVIg more effective
 Not Corticosteroids
 Ventilatory support
 Avoid anti-hypertensive medications
 ? Sub-cutaneous heparin with immobility:  Risk of thromboembolic events
Acute Motor Neuropathy
 Geographic associations
 More common: Japan, China & 3rd world countries
 Rare: Most parts of United States
 Occasional: Europe
 Prodrome
 Gastrointestinal: Diarrhea
 + Campylobacter jejuni titers in 67%
 Campylobacter jejuni in GBS
 Serotype associations
 O-19
 > 50% when Campylobacter culture positive
 Risk of acute neuropathy: 1 in 158
 6x greater than after other Campylobacter infections
 O-41
 Genetic association: Higher frequency of TNF-
http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?
191160http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?
191160polymorphism http://www3.ncbi.nlm.nih.gov/htbin-
post/Omim/dispmim?139393http://www3.ncbi.nlm.nih.gov/htbin-
post/Omim/dispmim?139393
 Upper respiratory
 Haemophilus influenzae infection5
 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%
 ? Treatment with parenteral ganglioside mixture
 Acute axonal motor syndromes reported
 Onset 5 to 15 days after Rx
 Associated serum IgG anti-GM1 antibodies
 Clinical
 Weakness
 Distal > Proximal
 ± Symmetric
 Cranial Nerves (25%)
 ? Less respiratory failure vs classic GBS
 Sensory
 Normal by clinical & electrodiagnostic testing
 No paraesthesias
 Reflexes
 Reduced in proportion to strength
 Hyperreflexia may occur
 Progression
 Mean nadir at 6 days
 Recovery
 Significant improvement in strength over 1 to 2 months
 ? More rapid with Haemophilus influenzae prodrome
 Laboratory
 Nerve conduction studies: Axonal >> Demyelination
 Serum Antibodies
 IgG vs GM1 ganglioside (40% to 50%)
 Associated with IgG vs GM1b ganglioside
 Reactivity to both GM1 & GM1b gangliosides
 More strongly associated: Distal motor, rapidly progressive
syndromes
 Treatment response: IVIg, not plasma exchange
 IgM vs GM1 ganglioside (30%)
 ? IgG vs GD1a ganglioside (24% to 60%)
 May be 2° to IgM binding to GalNAc-GD1a contaminant in GD1a
 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
 More common with prodromal infections: Campylobacter jejuni; Haemophilus
influenzae
 Also see: IgM vs GalNAc-GD1a ganglioside
 Pathology
 ? Anti-GM1 & other antibodies block nerve conduction
 Motor nerve terminal degeneration
 Severe weakness: More proximal axonal damage
 Sensory nerves normal
 Treatment
 IV Ig
 Not Plasma Exchange or Corticosteroids

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

Miller Fisher Syndrome6

 Epidemiology in Japan
 Onset: Mean 40 years; Range 13 to 78 years
 Seasonal: Higher frequency in Spring (March to May)
 Clinical prodrome: Respiratory most common
 Frequency: 25% of GBS in Japan; 1% of GBS in US
 Associated infection: Campylobacter jejuni, often serotype O-2 or O-10
 Clinical
 Onset
 Diplopia (Asymmetric) (80%)
 Myalgia & Paresthesias
 Vertigo & Ataxia
 Eye
 External ophthalmoplegia (100%)
 Pupillary dysfunction (42%): Mydriasis
 Ptosis (58%)
 Ataxia (100%): Dysmetria; Gait ataxia; Arms & Legs
 Areflexia (100%): By 1 week of disease
 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%)
 Facial weakness (32%)
 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
 Variants
 GBS overlap: Ophthalmoplegia and weakness ± ataxia
 Internal ophthalmoplegia: Dilated pupils; Light-near dissociation
 Acute external ophthalmoplegia: Complete or partial
 Acute ataxia: May progress to weakness & GBS
 Bickerstaff brainstem encephalitis
 Visual impairment7
 Rule out: Neurosyphilis
 Chronic ophthalmoplegia with serum IgG binding to GQ1b ganglioside 3
 May be associated with vestibulopathy or demyelinating neuropathy
 CSF: Protein 20 to 60 mg/dl; Cells 0 to 5/mm 3
 Nerve conduction studies
 Sensory: Axonal loss
 Reduced action potential amplitude
 Motor: Normal
 F-waves: Prolonged; Dispersed; Absent
 Serum antibodies
 IgG vs GQ1b (80%)
 IgG staining of cerebellar molecular layer
 Treatment: ? IVIg; ? Plasma exchange

(Sub)Acute Sensory Neuropathy

 Clinical
 Onset
 Over Days to Weeks
 Paresthesias & Pain
 Pansensory loss
 Proximal + Distal
 Autonomic dysfunction: Mild
 Motor: Normal; Occasional mild weakness
  Prognosis: Often incomplete recovery
 Differential Diagnosis
 Paracarcinomatous (anti-Hu antibodies)
 Sjögren's (SSA or SSB antibodies)
 GD1b antibodies: Acute or Relapsing
 Toxic: Cis-platinum; Pyridoxine intoxication
 Laboratory
 Nerve conduction studies
 Sensory potential amplitudes: Usually absent; May be reduced or normal
 Conduction velocities: Relatively normal
 Nerve biopsy: Axonal loss; Mild inflammation
 Epstein-Barr virus titers elevated in some patients1

Patient information
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References
1. Muscle Nerve 1999;22:1607-1610
2. Brain 2000;123:116-124. J Neuroimmunol 2001;113:260-267
3. Neurology 2000;54:1000
4. Neurology 2000;54:1661-1665
5. Brain 2000;123:2171-2178
6. Neurology 2001;56:1104-1106
7. Acta Neurol Scand 2001;103:259-260
8. Arch Neurol 2001;58:893-898
9. Arch Neurol 2001;58:913-917

6/30/2001