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Guillain-Barr Syndrome and Other Immune-Mediated Neuropathies

Chapter 458 | Part 13: Neurologic Disorders · Part 13 – Neurologic Disorders · Chapter 458

Key Clinical Points

  1. GBS is an acute, frequently severe, and fulminant autoimmune polyradiculoneuropathy occurring at a rate of 10–20 cases per million annually.
  2. Approximately 70% of cases occur 1–3 weeks after an acute infectious process, most notably Campylobacter jejuni (20–30% of cases in North America, Europe, and Australia).
  3. Clinical hallmark: Rapidly evolving ascending paralysis with areflexia, absence of fever, and characteristic antecedent events.
  4. Diagnosis relies on the Brighton Collaboration criteria (Levels 1-3) requiring bilateral flaccid weakness, areflexia, monophasic course, and cytoalbuminologic dissociation.
  5. Treatment: High-dose IVIg (2 g/kg over 5 days) or Plasma Exchange (40–50 mL/kg, 4–6 times). Both are equally effective.
  6. Prognosis: ~85% achieve full functional recovery; mortality <5% in optimal settings, usually from pulmonary complications.
  7. Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) is distinguished by a chronic course (>8 weeks) and response to glucocorticoids.
  8. Miller Fisher Syndrome (MFS) is characterized by ophthalmoplegia, ataxia, and areflexia with anti-GQ1b antibodies (>90%).
  9. Acute Motor Axonal Neuropathy (AMAN) often follows C. jejuni infection and is associated with anti-GM1 or anti-GD1a antibodies.
  10. Red flags: Fever at onset, sensory levels, or early bladder dysfunction should prompt consideration of alternative diagnoses like spinal cord disease or myelitis.

DEFINITION & OVERVIEW

• Definition: Guillain-Barré syndrome (GBS) is an acute, frequently severe, and fulminant polyradiculoneuropathy that is autoimmune in nature. • Epidemiology: ◦ Incidence: 10–20 cases per million annually; ~5,000–6,000 cases/year in the United States. ◦ Demographics: Males at slightly higher risk than females; adults more frequently affected than children in Western countries. • Clinical Presentation: ◦ Rapidly evolving areflexic motor paralysis with or without sensory disturbance. ◦ Typical pattern: Ascending paralysis, often first noticed as "rubbery legs." ◦ Progression: Weakness typically evolves over hours to a few days. • Subtypes of GBS: ◦ AIDP (Acute inflammatory demyelinating polyneuropathy): Most common variant in the Western world; rapid recovery; anti-GM1 antibodies in <50% of cases. ◦ AMAN (Acute motor axonal neuropathy): Common in children and young adults; prevalent in China and Mexico; may be seasonal; rapid recovery; associated with anti-GD1a antibodies. ◦ AMSAN (Acute motor sensory axonal neuropathy): Mostly adults; uncommon; recovery slow, often incomplete; closely related to AMAN. ◦ MFS (Miller Fisher syndrome): ~5% of all cases; characterized by ophthalmoplegia, ataxia, and areflexia; strongly associated with anti-GQ1b antibodies (>90%). ◦ APCBN (Acute pharyngeal-cervicobrachial neuropathy): Localized form of AMAN or extensive form of MFS. ◦ Other variants: Bickerstaff's brainstem encephalitis (CNS variant), Acute ophthalmoparesis, and Acute ataxic neuropathy.

Table 458-1: Subtypes of Guill1ain-Barré Syndrome (GBS)

• AIDP: ◦ Features: Adults > children; 90% in Western world; rapid recovery; anti-GM1 <50%. ◦ Electrophysiology (EDx): Demyelinating. ◦ Pathology: First attack on Schwann cell surface; widespread myelin damage, macrophage activation, and lymphocytic infiltration; variable secondary axonal damage. • AMAN: ◦ Features: Children/young adults; China/Mexico; seasonal; rapid recovery; anti-GD1a antibodies. ◦ EDx: Axonal. ◦ Pathology: First attack at motor nodes of Ranvier; macrophage activation, few lymphocytes, frequent periaxonal macrophages; variable axonal damage. • AMSAN: ◦ Features: Mostly adults; uncommon; slow/incomplete recovery; closely related to AMAN. ◦ EDx: Axonal. ◦ Pathology: Same as AMAN, but also affects sensory nerves and roots; axonal damage usually severe. • MFS: ◦ Features: Adults/children; ophthalmoplegia, ataxia, areflexia; anti-GQ1b (>90%). ◦ EDx: Axonal or demyelinating. ◦ Pathology: Few cases examined; resembles AIDP.

EPIDEMIOLOGY

• Infectious Triggers (70% of cases): ◦ Occur 1–3 weeks after an acute infectious process, usually respiratory or gastrointestinal. ◦ Campylobacter jejuri: 20–30% of cases in North America, Europe, and Australia. ◦ Human Herpes Virus: ~20–30% (CMV, EB1). ◦ Other Pathogens: HIV, hepatitis E, Zika, Mycoplasma pneumoniae, SARS-CoV-2. • Vaccine Associations: ◦ Swine influenza vaccine (1976): Most notable example of risk. ◦ Influenza (1992–1994) & Seasonal: Risk <1 per million. ◦ H1N1: Slight increased risk. ◦ SARS-CoV-2: Increased risk with adenovirus vectors; no increase with mRNA vaccines. ◦ Meningococcal: No increased risk. ◦ Older Rabies (tissue-based): Risk in developing countries due to neural antigen exposure. • Associated Conditions: ◦ Lymphoma (including Hodgkin's), HIV-seropositive, SLE, Sjogren's syndrome, IBD, chronic hepatitis, amyloidosis, diabetes mellitus, neurosarcoidosis.

ETIOLOGY & PATHOPHYSIOLOGY

• Immune Mechanisms: ◦ T-cell mediated: AIDP is analogous to experimental allergic neuritis (EAN). ◦ Humoral: Autoantibodies against nonprotein determinants. ◦ Complement: Early step in AIDP; deposition on Schwann cell surface → myelin disintegration and macrophage recruitment. ◦ AMAN: Complement/IgG deposited at nodes of Ranvier along large motor axons. • Molecular Targets: ◦ Gangliosides: Primary targets are glycosphingolipids (e.g., GM1, GD1a, GQ1b). ◦ C. jejuri Cross-Reactivity: Surface glycolipids in C. jejuri cross-react with human gangliosides (GM1) concentrated in nerves. ◦ TLR4 Activation: Sialic acid from C. jejuri → TLR4 activation of dendritic cells → B-cell differentiation. • Conduction Block vs. Axonal Damage: ◦ AIDP: Conduction block (demyelinating) → rapid recovery as remyelination occurs; secondary axonal damage correlates with slower recovery. ◦ AMAN/AMSAN: Primary axonal pattern (low-amplitude CMAPs); often due to reversible conduction block from antibody binding to ion channel proteins at nodes and paranodes. • CSF Findings: ◦ Cytoalbuminologic Dissociation: Protein 1–10 g/L; White cells <50/μL. ◦ Timing: Often normal ≤48h; usually elevated by end of first week. ◦ Pleocytosis (10–100/μL): If sustained, suggests alternative diagnosis (viral myelitis, HIV, leukemia, sarcoidosis). • EDx Features: ◦ AIDP: Early features = prolonged F-waves, prolonged distal latencies, and reduced CMAP amplitudes. ◦ Later Findings: Slowing of conduction velocity, conduction block, and temporal dispersion. ◦ AMAN/AMSAN: Reduced CMAP (and SNAPs in AMSAN) without conduction slowing or prolonged distal latencies.

CLINICAL FEATURES

• Core Presentation: ◦ Rapidly evolving areflexic motor paralysis. ◦ Ascending pattern; often starts with "rubbery legs" (lower limbs > upper). ◦ Associated symptoms: Tingling dysesthesias, facial diparesis (50%), bulbar weakness (may mimic brainstem ischemia). • Pain: ◦ Common in early stages (~50%). ◦ Types: Neck/shoulder/back pain; deep aching pain; dysesthetic pain in extremities (self-limited, responds to analgesics). • Autonomic Involvement: ◦ Common even in mild cases. ◦ Manifestations: Loss of vasomotor control, blood pressure fluctuations, postural hypotension, cardiac dysrhythmias. • Critical Indicators: ◦ Bladder Dysfunction: Usually transient; if early or prominent → suspect spinal cord disease. ◦ Fever/Systemic Symptoms: Absent at onset; presence casts doubt on GBS diagnosis. ◦ Reflexes: Attenuate or disappear within first few days. • Progression: ◦ Plateau typically reached within 4 weeks of onset. ◦ Ventilation Risk Factors: Severe weakness on admission, rapid progression, facial/bulbar weakness in first week.

DIFFERENTIAL DIAGNOSIS

• Common Mimics: ◦ Acute myelopathies (look for back pain/sphincter issues). ◦ Diphtheria (oropharyngeal involvement). ◦ Lyme polyradiculitis, other tick-borne paralyses. ◦ Porphyria (abdominal pain, seizures). ◦ Vasculitic neuropathy (check ESR). ◦ Poliomyelitis & Acute flaccid myelitis (distinguished by CSF pleocytosis). ◦ Myasthenia Gravis/Botulism (Botulism: pupillary reaction lost early). ◦ Poisonings (organophosphates, thallium, arsenic). • Exclusion Criteria: ◦ Fever/Systemic Symptoms at onset → suggests infection. ◦ Early/Prominent Bladder Dysfunction or Sensory Level → suggests spinal cord disease. ◦ Sustained CSF Pleocytosis → suggests viral myelitis, HIV, leukemia, or sarcoidosis.

DIAGNOSTIC APPROACH

  1. Clinical Assessment: Identify hallmark features: Rapidly evolving ascending paralysis + areflexia + absence of fever + characteristic antecedent events.
  2. CSF Analysis: Perform lumbar puncture to check for cytoalbuminologic dissociation (Protein 1–10 g/L; White cells <50/μL). Note: If symptoms ≤48h, results may be normal; repeat if necessary by end of week 1.
  3. Electrophysiology (EDx): Evaluate for conduction block (AIDP) or reduced CMAP amplitudes (AMAN/AMSAN).
  4. AIDP: Early prolonged F-waves and distal latencies → later slowing and conduction block.
  5. AMAN/AMSAN: Reduced CMAP amplitude without conduction slowing.
  6. Antibody Testing: Identify specific gangliosides if needed (e.g., anti-GQ1b for MFS, anti-GM1/GD1a for AMAN).
  7. Brighton Criteria Application: Determine level of certainty based on clinical, CSF, and EDx findings.
  8. Level 1: Bilateral flaccid weakness + areflexia + monophasic (12h–28d) + EDx consistent + Cytoalbuminologic dissociation + No alternative diagnosis.
  9. Level 2: Bilateral flaccid weakness + areflexia + monophasic + CSF white cell count <50/μL (with or without protein elevation) OR if CSF not available, EDx consistent + No alternative diagnosis.
  10. Level 3: Bilateral flaccid weakness + areflexia + monophasic + No alternative diagnosis.

MANAGEMENT & TREATMENT

  1. Initial Stabilization: Monitor for respiratory failure and autonomic instability (fluctuating BP, dysrhythmias).
  2. Immunotherapy Selection: Select either IVIg or Plasma Exchange (both are equally effective).
  3. IVIg Protocol: Dosage: 2 g/kg administered over 5 days.
  4. Plasma Exchange Protocol: Volume: 40–50 mL/kg; Frequency: 4–6 times.
  5. Monitoring: Monitor for progression to plateau (usually within 4 weeks). Assess need for mechanical ventilation based on severity, speed of progression, and bulbar involvement.

PROGNOSIS & COMPLICATIONS

• Recovery: ◦ ~85% achieve full functional recovery. ◦ Slower/incomplete recovery in AMAN/AMSAN due to axonal damage. • Mortality: ◦ <5% in optimal settings; primarily from pulmonary complications. • Clinical Progression: ◦ Plateau typically reached within 4 weeks of onset; progression unlikely after this point.

SPECIAL CONSIDERATIONS

• CIDP (Chronic Inflammatory Demyelinating Polyneuropathy): ◦ Distinguished by chronic course (>8 weeks) and response to glucocorticoids. • Other Immune Neuropathies: ◦ CIDP-M: Associated with MGUS; target: various; IgG/IgA (monoclonal). ◦ Anti-MAG: Target: SGPG, SGLPG; IgM (monoclonal). ◦ Nodal/Paranodal: Target: CNTN1, NF155; IgG4. ◦ Multifocal Motor Neuropathy (MMN): Target: GM1, GD1a; IgM (polyclonal/monoclonal). ◦ Chronic Sensory Ataxic Neuropathy: Target: GD1b, GQ1b; IgM (monoclonal).

Table 458-2: Principal Antiglycolipid Antibodies

• AIDP: No clear patterns; IgG (polyclonal). ◦ AMAN: GM1 most common; GD1a, GM1, GM1b, GalNAc–GD1a (<50% for any); IgG (polyclonal). ◦ MFS: GQ1b (>90%); IgG (polyclonal). ◦ APCBN: GT1a (most); IgG (polyclonal).

KEY PEARLS & CLINICAL TRAPS

• The "Rule of Exclusion": If fever is present at onset or if there is a sensory level/early bladder dysfunction, the diagnosis is likely NOT GBS (think infection or spinal cord disease). ◦ CSF Timing: A normal CSF in the first 48 hours does not rule out GBS; protein usually rises by the end of the first week. ◦ Symmetry: GBS is typically a symmetric polyradiculoneuropathy; asymmetric presentation should raise suspicion for other conditions. ◦ Antibody Specificity: - Anti-GQ1b → MFS (90%). - Anti-GM1/GD1a → AMAN (common in China/Mexico). ◦ Treatment Equality: IVIg and Plasma Exchange are equally effective; choice may depend on logistics or specific clinical features.

Reference Tables

TABLE 458-1 Subtypes of Guillain-Barré Syndrome

Harrison's 22e, p.3617

SUBTYPE FEATURES ELECTRODIAGNOSIS PATHOLOGY
Acute inflammatory demyelinating
polyneuropathy (AIDP)		 Adults affected more than children; 90%
of cases in Western world; recovery rapid;
anti-GM1 antibodies (<50%)		 Demyelinating First attack on Schwann cell surface; widespread myelin
damage, macrophage activation, and lymphocytic
infiltration; variable secondary axonal damage
Children and young adults; prevalent
in China and Mexico; may be seasonal;
recovery rapid; anti-GD1a antibodies		 Axonal
Acute motor sensory axonal
neuropathy (AMSAN)		 Mostly adults; uncommon; recovery slow,
often incomplete; closely related to AMAN		 Axonal Same as AMAN, but also affects sensory nerves and
roots; axonal damage usually severe
Adults and children; ophthalmoplegia,
ataxia, and areflexia; anti-GQ1b antibodies
(90%)		 Axonal or demyelinating

TABLE 458-2 Principal Antiglycolipid Antibodies Implicated in Immune Neuropathies

Harrison's 22e, p.3619

CLINICAL
PRESENTATION		 ANTIBODY TARGET USUAL ISOTYPE
Acute Immune Neuropathies (Guillain-Barré Syndrome)
Acute inflammatory
demyelinating
polyneuropathy (AIDP)		 No clear patterns IgG (polyclonal)
GM1 most common
Acute motor axonal
neuropathy (AMAN)		 GD1a, GM1, GM1b,
GalNAc–GD1a (<50%
for any)		 IgG (polyclonal)
Miller Fisher syndrome
(MFS)		 GQ1b (>90%) IgG (polyclonal)
Acute pharyngeal
cervicobrachial
neuropathy (APCBN)		 GT1a (? most) IgG (polyclonal)
Chronic Immune Neuropathies
Rarely to P0, myelin P2
protein, or PMP22
Neural binding sites
SGPG, SGLPG (on MAG)
(50%)
Uncertain (50%)
Approximately 10% to
CNTN1 or NF155, less
often to NF140/186 and
Caspr1
GM1, GalNAc–GD1a,
others (25–50%)
GD1b, GQ1b, and other
b-series gangliosides

TABLE 458-3 Brighton Criteria for Diagnosis of Guillain-Barré Syndrome (GBS) and Miller Fisher Syndrome Clinical case…

Harrison's 22e, p.3621

Clinical case definitions for diagnosis of GBS
Level 1 of diagnostic certainty
Bilateral AND flaccid weakness of the limbs
AND
Decreased or absent deep tendon reflexes in weak limbs
AND
Monophasic illness pattern and interval between onset and nadir of weakness
between 12 h and 28 days and subsequent clinical plateau
AND
Electrophysiologic findings consistent with GBS
AND
Cytoalbuminologic dissociation (i.e., elevation of CSF protein level above laboratory
normal value AND CSF total white cell count <50 cells/μL)
AND
Absence of an identified alternative diagnosis for weakness
Level 2 of diagnostic certainty
Bilateral AND flaccid weakness of the limbs
AND
Decreased or absent deep tendon reflexes in weak limbs
AND
Monophasic illness pattern and interval between onset and nadir of weakness
between 12 h and 28 days and subsequent clinical plateau
AND
CSF total white cell count <50 cells/μL (with or without CSF protein elevation above
laboratory normal value)
OR
If CSF not collected or results not available, electrophysiologic studies consistent with
GBS
AND
Absence of identified alternative diagnosis for weakness
Level 3 of diagnostic certainty
Bilateral and flaccid weakness of the limbs
AND
Decreased or absent deep tendon reflexes in weak limbs
AND
Monophasic illness pattern and interval between onset and nadir of weakness
between 12 h and 28 days and subsequent clinical plateau
AND
Absence of identified alternative diagnosis for weakness
Clinical case definitions for diagnosis of Miller Fisher syndrome
Level 1 of diagnostic certainty
Bilateral ophthalmoparesis and bilateral reduced or absent tendon reflexes, and ataxia
AND		 Absence of limb weakness
AND
Monophasic illness pattern and interval between onset and nadir of
weakness between 12 h and 28 days and subsequent clinical plateau
AND
Cytoalbuminologic dissociation (i.e., elevation of cerebrospinal protein
above the laboratory normal and total CSF white cell count <50 cells/μL)
AND
Nerve conduction studies are normal, OR indicate involvement of sensory
nerves only
AND
No alterations in consciousness or corticospinal tract signs
AND
Absence of identified alternative diagnosis
Level 2 of diagnostic certainty
Bilateral ophthalmoparesis and bilateral reduced or absent tendon
reflexes and ataxia
AND
Absence of limb weakness
AND
Monophasic illness pattern and interval between onset and nadir of
weakness between 12 h and 28 days and subsequent clinical plateau
AND
CSF with a total white cell count <50 cells/μL) (with or without CSF protein
elevation above laboratory normal value)
OR
Nerve conduction studies are normal, OR indicate involvement of sensory
nerves only
AND
No alterations in consciousness or corticospinal tract signs
AND
Absence of identified alternative diagnosis
Level 3 of diagnostic certainty
Bilateral ophthalmoparesis and bilateral reduced or absent tendon
reflexes and ataxia
AND
Absence of limb weakness
AND
Monophasic illness pattern and interval between onset and nadir of
weakness between 12 h and 28 days and subsequent clinical plateau
AND
No alterations in consciousness or corticospinal tract signs
AND
Absence of identified alternative diagnosis