Guillain-Barré syndrome

Guillain-Barré syndrome (GBS) is an acute postinfectious polyneuropathy characterized by symmetric and ascending flaccid paralysis. In affected patients, cross‑reactive autoantibodies attack the host's own axonal antigens, resulting in inflammatory and demyelinating polyneuropathy. Albuminocytologic dissociation, characterized by elevated protein levels and normal cell counts in cerebrospinal fluid (CSF), is a hallmark finding of GBS. Additionally, muscle and nerve electrophysiology are used to diagnose demyelinating processes. Symptomatic and supportive treatment results in disease remission in about 70% of cases. In severe cases or patients who do not respond to treatment, intravenous immunoglobulin (IVIG) administration and/or plasmapheresis may be used. Potentially acute life-threatening complications such as respiratory insufficiency, pulmonary embolism, and/or cardiac arrest increase mortality. Although GBS is associated with a good prognosis overall, up to 20% of patients remain severely disabled and approximately 5% of cases are fatal, despite immunotherapy.

• Incidence ^[1]
  • ∼ 1 case per 100,000 individuals
  • Adults are affected more frequently than children.
• Sex: ♂ > ♀ (1.5:1) ^[2]

Epidemiological data refers to the US, unless otherwise specified.

• Overview
  • About ⅔ of GBS patients experience symptoms of an upper respiratory or gastrointestinal tract infection 1–4 weeks prior to onset of GBS. ^[1]
  • The causal connection between pathogens and GBS is still undetermined.
• Associated pathogens ^[1][3][4]
  • Campylobacter jejuni: campylobacter enteritis is the most common disease associated with GBS.
  • Cytomegalovirus: most common virus associated with GBS
  • HIV
  • Influenza
  • Zika virus
  • Epstein-Barr virus
  • SARS-CoV-2
  • Mycoplasma pneumoniae
• Vaccination
  • There have been reports of small increases in incidence after administration of certain vaccines. ^[5]
  • In the US, Guillain-Barré syndrome is listed as vaccination injury for the seasonal influenza vaccines.

• Postinfectious autoimmune reaction that generates cross-reactive antibodies (molecular mimicry)
• Infection triggers humoral response → formation of autoantibodies against gangliosides (e.g., GM1, GD1a) or other unknown antigens of peripheral Schwann cells → immune-mediated segmental demyelination → axonal degeneration of motor and sensory fibers in peripheral and cranial nerves (CN III–XII)

References:^[6]

Initial symptoms

• Back and limb pain
• Paresthesias affecting distal extremities

Advanced symptoms

• Ascending paralysis
  • Bilateral flaccid paralysis
  • Spreads from the lower to the upper limbs in a “stocking‑glove” distribution
• Landry paralysis: involvement of the respiratory muscles → respiratory failure
• Muscle reflexes
  • Reduced or absent
  • Commonly beginning in the lower limbs
• Paresthesias
  • Peripheral, symmetric
  • Usually affecting hands and feet
• Neuropathic pain: develops in about ⅔ of affected individuals
• Autonomic dysfunction
  • Cardiovascular
    • Arrhythmia
    • Blood pressure dysregulation: ↑ or ↓
  • Voiding dysfunction
  • Intestinal dysfunction
• Cranial nerve involvement
  • Facial diplegia due to frequent bilateral facial nerve involvement
  • Also affects glossopharyngeal nerve (IX) and vagal nerve (X)

GBS paralysis affects the muscles of respiration, possibly leading to death due to respiratory failure.

Overview

Chronic inflammatory demyelinating polyradiculopathy ^[8]

• Definition: a chronic polyneuropathy that affects the motor and sensory peripheral nerves and nerve roots
• Epidemiology
  • Most common in male individuals
  • Age of onset: 40–60 years
• Predisposing factors
  • Diabetes mellitus
  • HIV infection
  • Monoclonal gammopathies (e.g., MGUS)
  • Malignancies (e.g., hepatocellular carcinoma)
• Pathophysiology
  • Macrophages phagocyte myelin sheath → demyelination of peripheral nerves → remyelination by Schwann cells → onion bulb formation
  • Autoantibodies against nodal and paranodal proteins (e.g., neurofascin, contactin 1) → detachment of myelin sheath around the nodes of Ranvier → abnormal nerve conduction
• Clinical features: can be chronic-progressive or relapsing (progressive or remitting)
  • Typical CIDP (symmetric sensorimotor)
    • Symptom progression for > 8 weeks
    • Weakness: symmetric, proximal, and distal muscle involvement
    • Sensory involvement (e.g., paresthesias) of at least two limbs
    • Absent or decreased reflexes in all limbs
  • CIDP variants (previously known as atypical CIDP): can manifest with asymmetric symptoms and/or purely sensory or motor symptoms
  • Cranial nerves are rarely affected, automomic dysfunction is exceptional
• Diagnostics: based on clinical features and electrodiagnostic findings
  • Electroneurography: signs of demyelination (e.g., abnormal conduction in at least 2 motor and sensory nerves)
  • CNS analysis: albuminocytologic dissociation
  • Autoantibodies
    • Autoantibodies against nodal and paranodal proteins (specific to CIDP)
    • Anti‑GM1 ganglioside autoantibodies (can also be seen in other demyelinating polyneuropathies)
  • Further tests if diagnosis remains inconclusive: nerve ultrasound, nerve biopsy, and/or MRI of spinal nerve roots and plexus
• Treatment
  • First-line: intravenous immunoglobulin (IVIG) or corticosteroids
  • Second-line: plasmapheresis
  • Maintenance: IVIG, subcutaneous immunoglobulin, or corticosteroids
  • Refractory disease: immunomodulatory drugs (e.g., azathioprine, cyclophosphamide)

• Cerebrospinal fluid: albuminocytologic dissociation
  • ↑ Protein levels and normal white blood cell count in cerebrospinal fluid (CSF)
  • CSF cell counts higher than 50 cells per μl CSF indicate that GBS is unlikely
• Serological screening
  • To identify potential pathogens (e.g., Campylobacter jejuni)
  • Detection of antibodies directed against gangliosides (e.g., anti-GM1 antibodies)
• Electroneurography
  • ↓ Nerve conduction velocity (NCV) due to demyelination
  • ↑ F‑wave latency
• Electromyography
  • Signs of denervation: characteristic of axonal lesions
  • Pathologic spontaneous activity (unfavorable prognostic sign)
• ECG: autonomic cardiac dysregulation → impaired heart frequency variation

References:^[6]

• Supportive management
  • Monitor cardiac and respiratory function: in some cases, intensive care unit (ICU) treatment and intubation may be indicated
  • Prevent decubitus ulcer and/or thrombosis (esp. pulmonary embolism)
• Intravenous immunoglobulins ^[11]
• Plasmapheresis
  • In adults: equivalent outcome as IV immunoglobulins
  • In children: only recommended in children with rapidly progressing or severe disease

Although GBS is considered an autoimmune disease, glucocorticoids are not recommended for treatment. They have not shown to hasten recovery or affect the long-term outcome. The only exception is the CIDP variant of GBS.

• ∼ 70% of patients with GBS have a good prognosis ^[12]
  • Disease progression peaks 2–4 weeks after the onset of symptoms.
  • Symptoms then recede in reverse order of their development (i.e., the last symptoms to appear resolve first, as Schwann cells remyelinate peripheral nerve axons).
• 3–7% of patients with GBS die due to acute complications such as:
  • Respiratory paralysis (apnea)
  • Pulmonary infection/embolism
  • Cardiac dysfunction
• 6 months after onset, ∼ 20% of affected individuals are still unable to walk unaided.

Death can occur as many as > 30 days after onset of symptoms, during the recovery phase.