A. Epidemiology

1. Progressive acute peripheral polyneuropathy often following a viral illness
2. Rate currently ~1-2 per 100,000 persons
3. Increasing risk after age 40 (very rare below age 30)
4. Risk in persons >70 years is ~8 per 100,000
5. Approximately equal male to female incidence
6. Four Subtypes
   1. Acute inflammatory demyelinating polyradiculoneuropathy (AIDP)
   2. Acute motor axonal neuropathy (AMAN)
   3. Acute motor and sensory axonal neuropathy (AMSAN)
   4. Acute pandysautonomia

B. Etiology

1. All forms associated with various types of autoreactive T cells and/or antibodies
   1. AIDP likely due to myelin reactive T cells
   2. AMAN and AMSAN associated with antibodies to gangliosides (GM1 and GD1 most often)
   3. Acute pandysautonomia associated antibodies to gangliosides GQ1b and GT1a
2. Initial infection, then immune response, with cross reactivity to myelin in PNS
   1. Various viral agents
   2. Campylobacter infection
3. Lymphocytic and macrophage infiltration with macrophage mediated demyelination
   1. Both cellular and humoral immune systems are activated
   2. Circulating anti-ganglioside (GM1, GD1a, GD1b) and/or anti-glycolipid antibodies
   3. Activated macrophages invade peripheral myelin sheaths causing demyelination
4. Remyelination follows within weeks
5. Serologic evidence exists for previous Campylobacter jejuni infection in GBS [2,3]
   1. Cross-reactive immunity including (auto)-antibody production may be involved in GBS
   2. In addition, course of disease may be more severe in patients with C. jejuni infection
   3. Miller-Fisher Syndrome (MFS) is a variant of GBS caused by certain C. jejuni strains
   4. MFS is specifically associated with anti-GQ1b autoantibodies
   5. IVIg and Plasma Exchange, effective therapies, may block or remove autoantibodies
6. High rate of GBS following swine influenza vaccination in 1976
7. Very week association, if any, between GBS and standard influenza vaccination [4]
8. Concern over GBS association with measles vaccination is unfounded [5]

C. Symptoms

1. Weakness (90%) and areflexia (75-100%) are hallmarks of disease
2. Progressive polyneuropathy (days to weeks)
   1. Paresthesias are initial manifestation (75% of cases)
   2. This is followed by symmetric (bilateral), flaccid paralysis
   3. Begins distal, more often in feet (60%) than hands (20%)
   4. Facial (35-60%) and oropharyngeal (25-50%) muscle weekness occurs
3. Respiratory failure due to diaphragmatic paralysis
   1. Initial presentation ~10% of cases
   2. Overall, ~30% of cases
4. Symptoms Not Suggestive of GBS
   1. Sensory level or significant sensory loss
   2. Marked asymmetry of disease
   3. Severe or persistent bowel or bladder dysfunction
   4. Slow progression of disease
5. Prognosis
   1. Recovery begins 2-4 weeks after progression ceases
   2. Preceding C. jejuni infection associated with slower recovery, increased disability [3]
   3. ~70% of patients fully recover with no residua

D. Diagnostic Evaluation

1. Electrophysiologic Studies
   1. Abnormal in 95-99% of patients
   2. Show nerve but not muscle involvement
   3. Demyelination features and/or axonal damage are found
   4. Normal studies should prompt evaluation for other diagnosis
2. Normal CBC and Sedimentation Rate (ESR) in most patients
3. Cerebrospinal Fluid (CSF) Analysis
   1. Typical protein increase occurs 10-20 days into course
   2. Overall, ~90% of patients have CSF protein >55mg/dL
   3. Majority of patients have no CSF pleiocytosis
   4. CSF WBC >50/µL should prompt evaluation for other diagnosis
4. Raised serum anti-GM1 ganglioside antibodies
5. Bell's Palsy [12]
   1. Peripheral neuropathy of Cranial Nerve (CN) VII (Facial Nerve)
   2. Face pulled to one side
   3. Usually bilateral and symmetrical in GBS
   4. Common associations: herpes zoster, Guillian-Barre, various tumors, sarcoidosis
   5. Hyperacusis may also occur (paralysis of stapedius muscle)

E. Differential Diagnosis

1. CSF Pleiocytosis (>50 leukocytes/µL)
   1. Lyme Disease
   2. CSF Sarcoidosis
   3. Neoplasia
   4. HIV
   5. Other Meningitis and/or Encephalitis
2. Acute Disseminated Encephalomyelitis
   1. Occurs after infection with various viruses (Measles, Rubella, Chicken Pox, Polio)
   2. Associated with old rabies vaccine, papovavirus infections (JC Virus)
   3. Pathology: Lymphocytes in brain in CSF; Small disseminated foci of demyelination
3. JC Virus Infection
   1. Papovavirus
   2. Progressive Multifocal Leukoencephalopathy (PML)
   3. Also seen in immunocompromised individuals (HIV)
4. Defective Measles virus infection: Subacute Sclerosing Panencephalitis (SSPE)
5. Other Diseases
   1. Botulism
   2. Myasthenia Gravis
   3. Poliomyelitis
   4. Toxin Associated Neuropathy
   5. Abnormal Porphyrin metabolism
   6. Sensory neuropathy without weakness

F. Causes of Aucte Flaccid Paralysis (Panel 1; Ref [1])

1. Brainstem Stroke
2. Brainstem Encephalitis
3. Acute anterior poliomyelitis: poliovirus or other neurotropic virus
4. Acute myelopathy: mass lesion, acute transverse myelitis
5. Peripheral Neuropathy
   1. Guillain-Barre Syndrome
   2. Post-Rabies Vaccine Neuropathy
   3. Diphtheretic Neorpathy
   4. Heavy metals
   5. Other Toxin Associated Neuropathy
   6. Acute Intermittent Porphyria
   7. Vasculitic Neuropathy
   8. Critical illness neuropathy
   9. Lymphomatous neuropathy
6. Disorders of Neuromuscular Transmission
   1. Myasthenia gravis, Eaton-Lambert Syndrome
   2. Biological or industrial toxins
7. Muscle Disorders
   1. Hypokalemia
   2. Hypophosphatemia
   3. Inflammatory myopathy
   4. Acute rhabdomyolysis
   5. Trichinosis
   6. Periodic paralysis

G. Therapy

1. Intravenous immunoglobulin (IVIg) and plasma exchange similarly hasten recovery from GBS
2. Mechanical Ventilation
   1. Respiratory Failure
   2. Airway protection
   3. Secretion control
   4. Should be carried out prophylactically in any patient with marginal respiratory reserve
3. Intensive Care Monitoring
   1. Autonomic Dysfunction - labile blood pressure, especially hypotension
   2. Cardiac Arrhythmias - especially bradycardia, heart block, cardiac arrest
4. Intravenous Gamma Globulin (IVIg) [6]
   1. Treatment of choice for GBS
   2. Usual dose is 0.4gm/kg/day x 5 days - 2 weeks [3]
   3. Multiple, additional repeat doses may be effective in severe patients [7]
   4. No benefit to adding glucocorticoids to IVIg [8]
5. Plasma Exchange - 1.5X plasma volume qod or qd
6. Comparison of IVIg with Plasma Exchange [9,10]
   1. IVIg used initially is equivalent to plasma exchange at 4 weeks post-diagnosis
   2. Cost is similar
   3. IVIg is safer overall
   4. Main risk of IVIg is anaphylaxis in IgA deficient recipients
7. Glucocorticoids
   1. Methylprednisolone (Solumedrol®) 500mg IV qd x 5 days efficacy similar to placebo [11]
   2. When 500mg IV qd x 5 days added to IVIg standard therapy, no benefit over IVIg alone [8]
   3. No benefit to glucocorticoids
8. Physical Rehabilitation
9. Prognosis
   1. ~70-80% will recover without residua
   2. Remainder have mild to moderate persistent peripheral neuropathies
   3. Respiratory function returns in nearly all patients

References

1. Hughes RA and Comblath DR. 2205. Lancet. 366(9497):1653
2. Mishu B, Ilyas AA, Koski CL, et al. 1993. Ann Intern Med. 118(12):947
3. Rees JH, Soudain SE, Gregson NA, Hughes RAC. NEJM. 1995. 333(21):1374
4. Haber P, DeStefano F, Angulo FJ, et al. 2004. JAMA. 292(20):2478
5. da Silveira CM, Salisbury DM, de Quadros CA. 1997. Lancet. 349(9044):14
6. Dalakas MC. 1997. Ann Intern Med. 126(9):721
7. Farcas P, Avnun L, Frisher S, et al. 1997. Lancet. 350(9093):1747
8. Van Koningsveld R, Schimitz PIM, van der Meche FGA, et al. 2004. Lancet. 363(9404):192
9. Plasma Echange/Sandoglobulin GBS Trial Group. 1997. Lancet. 349:225
10. van der Meche FG and Schmitz PI. 1992. NEJM. 326(17):1123
11. Guillain-Barre Syndrome Steroid Trial Group. 1993. Lancet. 341:586
12. Gilden DH. 2004. NEJM. 351(13):1323