Guillain Barre Syndrome

Aka: Guillain Barre Syndrome, Guillain-Barre Syndrome, Landry-Guillain-Barre Syndrome, Guillain-Barre-Strohl Syndrome, Acute Inflammatory Demyelinating Polyradiculoneuropathy, Acute Motor Axonal Neuropathy, Acute Motor Sensory Axonal Neuropathy, Miller Fisher Syndrome, Bickerstaff Brainstem Encephalitis, Bickerstaff's Brainstem Encephalitis

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II. Definitions

  1. Guillain Barre Syndrome
    1. Acute Progressive, idiopathic immune polyradiculopathy
    2. Symmetrical weakness and loss of Deep Tendon Reflexes reaching maximal intensity within 4 weeks

III. Epidemiology

  1. Incidence
    1. Annual Incidence: 1-3 cases per 100,000
    2. Most common cause of Acute Flaccid Paralysis worldwide (including in children)
      1. Prior to Polio Vaccine, Polio was the most common cause
  2. Age
    1. May occur in any age group
    2. In children, most commonly affects age <5 years
    3. Most common over age 50 years and Incidence increases with advancing age
  3. Gender
    1. Male to female ratio: 3 to 2
    2. Almost all other Autoimmune Conditions are female predominant
      1. GBS is more common in women with Rheumatologic Disorders, Preeclampsia history or prior Blood Transfusions

IV. Background

  1. First identified pulverized myelin in affected patients in 1916 by Guillain, Barre and Strohl

V. Precautions

  1. Presentation may have subtle, non-specific findings early in the course
    1. Patients are initially well appearing
    2. Focal Paresthesias (esp. lower extremity)
    3. Perception of weakness without motor weakness on exam
    4. Deep Tendon Reflexes may initially be preserved, and may appear to be asymmetric
  2. Patients typically do not present with Dyspnea
    1. However, the highest morbidity and mortality is from Hypoventilatory Respiratory Failure
    2. Frequently monitor for significant respiratory weakness with Negative inspiratory pressure (NIF)

VI. Pathophysiology

  1. Inflammatory Neuropathy with cross reactivity between antibodies to infectious agents and neural Antigens
  2. Lipooligosaccharides in Bacterial cell wall resemble gangliosides
  3. Anti-ganglioside antibodies form in response to acute infections (e.g. Diarrhea with Campylobacter jejuni)

VII. Types: Most Common Subtypes

  1. Acute Inflammatory Demyelinating Polyradiculoneuropathy (AIDP)
    1. Most common subtype in the United States (90-95% of U.S. cases)
    2. Multifocal peripheral demyelination with slow remyelination
      1. Presents with progressive ascending Paresthesias, symmetrical weakness and hyporeflexia
      2. Symptoms start in legs in 90% of cases
      3. Associated back pain is common, while Leg Pain and Headache are uncommon
  2. Acute Motor Axonal Neuropathy (AMAN)
    1. Accounts for 5-10% of Guillain-Barre Syndrome cases in U.S.
      1. However, accounts for 30 to 60% of cases in China, Japan and South America
    2. Anti-ganglioside antibodies (GM1, GD1a, GalNAc-GD1a, GD1b) bind in peripheral Motor Nerve axons
    3. Most associated with Campylobacter jejuni infection (esp. younger patients, summer, China and Japan)
    4. Pure motor Neuropathy
      1. Acute motor weakness is followed by areflexia, Ataxia and oculomotor deficits
      2. Sensory predominant Axonal Neuropathy (AMSCAN, see below) may occur, but is rare
    5. No demyelination (contrast with AIDP)
    6. Nodes of Ranvier predominantly injured

VIII. Types: Uncommon to Rare Subtypes

  1. Miller Fisher Syndrome (3-5% of U.S. cases, but 25% of cases in Asia)
    1. Anti-ganglioside antibodies (GQ1b, GD3, GT1a)
    2. Bilateral Ophthalmoplegia, Ataxia and areflexia (2 of 3 present for diagnosis)
    3. Any Cranial Nerve may be affected, but predisposition to CN3, CN4 and CN6
    4. Facial or bulbar weakness (50% of cases)
    5. Trunk and extremity weakness (50% of cases)
    6. Rare in children
  2. Acute Motor Sensory Axonal Neuropathy (AMSCAN)
    1. Similar to AMAN subtype, but sensory Neuropathy predominates
    2. Pure sensory Axonal Neuropathy is rare
  3. Bickerstaff Brainstem Encephalitis (rare)
    1. Presents with Ataxia, encephalopathy and Ophthalmoplegia
    2. Median age of onset 35 years
    3. Rare in U.S. (more common in Asia)
  4. Descending Motor Weakness (rare)
    1. Motor weakness affects Cranial Nerves first, followed by arm and leg weakness
  5. Acute Panautonomic Neuropathy (rarest)
    1. Autonomic symptoms (cardiovascular and visual)
    2. Sensory loss (may be absent, with pure Autonomic Dysfunction)
    3. Slow, often incomplete recovery

IX. Risk Factors

  1. Idiopathic with no identified inciting event in up to one third of cases
  2. Acute infection
    1. Upper Respiratory Infection or Gastroenteritis (in prior 1 to 6 weeks) precedes GBS in 66-71% of cases
    2. Campylobacter jejuniGastroenteritis (most common)
      1. Guillain-Barre occurs in one in 1000 patient infected with Campylobacter jejuni
      2. C. jejuni Lipooligosaccharides resemble human peripheral membrane gangliosides
        1. Infection triggers autoimmune response against the peripheral membrane
    3. Cytomegalovirus (second most common)
    4. Epstein-Barr Virus (Mononucleosis)
      1. Associated with milder forms of Guillain-Barre
    5. Mycoplasma pneumoniae
    6. HaemophilusInfluenzae
    7. HIV Infection
    8. Herpes Simplex Virus
    9. Varicella Zoster Virus
    10. Vector-Borne Infections (Mosquito borne)
      1. West Nile Virus
      2. Zika Virus
  3. Vaccinations are associated with no significant increased risk
    1. H1N1 Influenza Vaccine was associated with a risk of 1-2 cases per 1 Million (esp. 1976 Influenza Vaccine)
      1. De Wals (2012) JAMA 308(2): 175-81 [PubMed]
    2. Covid19 Vaccine (associated with AIDP)
      1. Shao (2021) Emerg Infect Dis 27(12): 3175-8 [PubMed]
    3. Tetanus Vaccine and hepatitis Vaccines also have minimal increased risk
  4. Monoclonal Antibodies
    1. Rituximab
    2. Alemtuzumab
    3. Efalizumab

X. Course

  1. Symptoms may develop within hours to days
  2. Peak timing
    1. Peaks by 2 weeks in 50% of cases
    2. Peaks by 3 weeks in 80% of cases
    3. Peaks by 4 weeks in 100% of cases
  3. Respiratory Failure requiring Mechanical Ventilation (25% of hospitalized cases)
    1. Onset within 1-2 weeks of symptoms
  4. Mortality: 3 to 8%

XI. Symptoms

  1. Typically follows acute infectious illness
    1. Acute respiratory illness (fever, cough, Sore Throat)
    2. Acute gastrointestinal illness (Vomiting, Diarrhea)
      1. More likely to be associated with longer recovery and greater Disability (AMAN, AMSCAN subtypes)
  2. Progressive and ascending neurologic changes
    1. See signs below for more detailed description
    2. Tingling Paresthesias in distal extremities
    3. Proximal Muscle Weakness
  3. Myalgias (50% of cases)
    1. Deep, often severe aching pain in weak Muscles
    2. Worse with movement, and at night
    3. Distribution (most common sites)
      1. Shoulder
      2. Back
      3. Posterior thighs
  4. Autonomic Symptoms (70% of cases)
    1. Diarrhea (21%) or Constipation (22%)
    2. Urinary Retention

XII. Signs

  1. Progressive, symmetric neurologic symptoms
    1. Classically starts in distal extremities and ascends
      1. However lesions are random and patients may present first with Cranial Nerve deficit
    2. Progresses proximally over days to weeks (peaking by 2 to 4 weeks)
      1. Paresthesias (tingling) in distal extremities
      2. Proximal Muscle Weakness
        1. All limbs are ultimately affected at peak effects in 93% of cases
      3. Cranial Nerves may be affected
        1. Facial Muscles and eye movements may be affected (30-50% of cases)
        2. Ophthalmoplegia is rare except for in the Miller Fisher subtype
        3. Swallowing may be difficult
  2. Progressive, symmetric proximal Muscle Weakness
    1. Legs are affected more than arms (due to longer Neurons more apt to accumulate damage)
    2. Often onset in the legs and ascends to involve arms
    3. Observe patient standing and walking if possible
  3. Severe weakness (10-30% of cases)
    1. Quadriparesis
    2. Respiratory arrest requiring Ventilator support
    3. Bulbar failure (e.g. Dysphagia)
  4. Loss of Deep Tendon Reflexes (hyporeflexia)
    1. Onset within first few days
    2. Include DTR exam on every Neurologic Exam
    3. In combination with progressive symmetric motor weakness, hyporeflexia should raise GBS suspicion
  5. Variable sensory losses
    1. Most prevalent in AMSCAN subtype (rare)
  6. Autonomic Dysfunction
    1. Hyperhidrosis
    2. Postural Hypotension and Blood Pressure fluctuation
    3. Tachycardia
    4. Urinary Retention
    5. Gastrointestinal pseudo-obstruction
    6. Dysrhythmias

XIII. Labs

  1. Complete Blood Count
    1. Typically normal in GBS
  2. Comprehensive Metabolic Panel
    1. Typically normal in GBS
  3. Acute Phase Reactants (ESR, C-RP)
    1. Typically normal in GBS
  4. HIV Test (consider rapid Serology)
  5. Serum Vitamin B12
  6. Lumbar Puncture (see diagnostics below)
  7. Antibody Testing (e.g. Miller Fisher related antibodies, )

XIV. Imaging

  1. MRI Spine
    1. Evaluate for other causes (e.g. Transverse Myelitis, Compressive Neuropathy)

XV. Diagnostics

  1. Cerebrospinal fluid (CSF)
    1. Albuminocytologic dissociation
      1. CSF Protein increased without increase in CSF White Blood Cells
      2. Present only in 44 to 81% of cases early in disease (increases by second week)
      3. False Positives in older patients who may have unrelated increase in CSF Protein
    2. Increased CSF Protein >0.55 g/dl
      1. Increased by week 2 of symptoms in 90% of cases
    3. Normal CSF White Blood Cells Count (<50 cells/uL, some guidelines use cut-off of <10 cells/uL)
      1. If increased, then consider other diagnosis
      2. Differential diagnosis if CSF WBCs increased
        1. Lyme Disease
        2. Cancer
        3. Human Immunodeficiency Virus (HIV Infection)
        4. Sarcoid Meningitis
  2. Electromyogram (EMG)
    1. Slowing of Nerve Conduction to <60% of normal velocity within weeks of onset in 80% of cases
      1. Obtain after 10 to 14 days of symptoms
      2. Poorly diagnostic in first 4 days of symptoms (diagnostic in <30%)
    2. Specific findings
      1. Absent H reflex
      2. Low to absent sensory Action Potential amplitudes
      3. F Wave response prolonged
  3. Evaluate respiratory function in all suspected cases
    1. Pulmonary Function Testing
    2. Arterial Blood Gas
  4. Autonomic Dysfunction related Dysrhythmias are not uncommon
    1. Electrocardiogram on presentation
    2. Continuous telemetry monitoring

XVI. Diagnosis: Major Criteria

  1. Bilateral, relatively symmetric weakness or sensory deficit (typically with onset in legs)
  2. Decreased or absent Deep Tendon Reflexes
  3. Progressive and peaks within 4 weeks
  4. Not due to other cause (e.g. Acute HIV Infection, Wernicke Encephalopathy, Tickborne Illness)

XVII. Differential Diagnosis: General

  1. See Acute Motor Weakness Causes
  2. See Symmetric Peripheral Neuropathy
  3. See Peripheral Neuropathy
  4. See Acute Motor Weakness Causes
  5. See Drug-Induced Polyneuropathy
  6. Brainstem Conditions
    1. Cerebrovascular Accident
    2. Encephalitis
    3. Meningitis
  7. Spinal Conditions
    1. Cord Compression (e.g. central spinal stenosis)
    2. Myelopathy
    3. Poliomyelitis (esp. underimmunized, age <5 years old)
    4. Transverse Myelitis
  8. Muscular (and neuromuscular) Conditions
    1. Hypokalemia (includes periodic paralysis)
    2. Hypohosphatemia
    3. Myopathy
    4. Rhabdomyolysis
    5. Myasthenia Gravis
  9. Polyneuropathy conditions
    1. Arsenic
    2. Botulism
    3. Chronic inflammatory demyelinating Polyneuropathy
    4. Diabetic Neuropathy
    5. Diphtheria
    6. Lambert-Eaton Syndrome
    7. Lyme Disease
    8. HIV Infection (especially Acute Retroviral Syndrome)
    9. Wernicke Encephalopathy
    10. Lymphoma
    11. n-hexane (exposure with Inhalant Abuse)
    12. Paraneoplastic conditions
    13. Porphyria
    14. Sarcoidosis
    15. Tick Paralysis
    16. Uremia
    17. Vasculitis

XVIII. Differential Diagnosis: Findings Suggestive of Alternative Diagnosis

  1. Neurotoxic findings
    1. Porphyria
    2. Diphtheria
    3. Botulism
    4. Toxic Neuropathy
    5. Inhalant Abuse
    6. Occupational exposures
    7. Lead Poisoning
    8. Alcohol Abuse (e.g. Wernicke Encephalopathy, Vitamin B12 Deficiency)
  2. Exam and lab findings not suggestive of Guillain-Barre
    1. Pure sensory deficits (sensory-only GBS is rare)
    2. Significant asymmetric neurologic symptoms or findings
      1. By 4 weeks, findings are typically symmetric
    3. Well demarcated line of senory deficit
    4. Bowel or Bladder symptoms predominate
    5. CSF Leukocytosis (see diagnostics)
    6. Mental status changes (except Bickerstaff Brainstem Encephalitis)
    7. Findings worsening after 8 weeks
    8. Positive Babinski Reflex
    9. Clonus present

XIX. Management: Criteria for ICU admission (risk of Respiratory Failure)

  1. Pulmonary Function Test abnormalities with expected need for Mechanical Ventilation
    1. See Endotracheal Intubation indications below
    2. Forced Vital Capacity (FVC) <50% of predicted
      1. Intubation Indicated for FVC <20 ml/kg (or more than 30% drop from prior FVC)
    3. Negative inspiratory pressure (NIF) >-30 cm H2O
      1. Intubation Indicated for NIF >-20 to -30 cm H2O
  2. Poor Swallowing
  3. Ineffective cough
  4. Aspiration Pneumonia
  5. Autonomic Dysfunction
  6. Increased Respiratory Rate
  7. Dyspnea
  8. Severe Muscle Weakness
    1. Unable to lift elbows above bed or flex arms
    2. Unable to lift head above bed
    3. Unable to stand
  9. Other predictors of Respiratory Failure and Mechanical Ventilation
    1. Rapid progression of symptoms over <7 days
    2. Arm weakness
    3. Elevated Liver Function Tests
    4. Bulbar palsy

XX. Management: Indications for Endotracheal Intubation

  1. Endotracheal Intubation is required in up to 30% of GBS patients
  2. Consider when patient reports Dyspnea
  3. Forced Vital Capacity <20 ml/kg (or more than 30% drop from prior FVC)
    1. Some criteria differentiate with bulbar weakness
    2. Vital Capacity 15-18 ml/kg with bulbar weakness
    3. Vital Capacity <15 ml/kg without bulbar weakness
  4. Pressure measurement criteria
    1. Maximal expiratory pressure <40 cm H2O
    2. Maximal Inspiratory Pressure <20 to 30 cm H2O
      1. Negative inspiratory pressure (NIF) >-20 to -30 cm H2O

XXI. Management: Supportive care

  1. Admit all patients with suspected GBS (preferably to facility with neurology)
    1. Rapid clinical decompensation is not uncommon
  2. Monitor for Respiratory Failure (25%)
    1. Negative inspiratory pressure (NIF)
    2. Incentive Spirometry
    3. Control Secretions
  3. Monitor for autonomic failure
    1. Arrhythmias (EKG, continuous telemetry)
    2. Blood Pressure abnormalities
  4. Turn patient frequently (prevents Decubitus Ulcers)
  5. Subcutaneous Heparin (prevents Pulmonary Embolism)
  6. Fluid management (Observe for SIADH with low Sodium)
  7. Nutrition
  8. Monitor for infections (Urinary Tract Infection in 20%)
  9. Prevent exposure Keratitis
  10. Physical therapy reduces pain
    1. Gentle massage
    2. Range of motion
    3. Position changes
  11. Pain management (significant pain in affected Muscles)
    1. See physical therapy above
    2. NSAIDs
    3. Narcotics (use caution due to ileus)
    4. Carbamazepine (Tegretol)
    5. Gabapentin (Neurontin)
    6. Corticosteroids are no longer recommended
      1. Van Der Meche (1992) N Engl J Med 326:1123-9 [PubMed]
  12. Ventilatory management
    1. See Endotracheal Intubation
    2. Rapid Sequence Intubation
      1. As with other neuromuscular disorders, avoid Succinylcholine for paralysis
      2. Acetylcholinesterase receptors are upregulated with increased risk for Hyperkalemia
        1. Neuromuscular Blockade risks ventricular Arrhythmia
    3. Indicators to start weaning
      1. Vital Capacity > 15 ml/kg (if no lung disease)
    4. Weaning
      1. First: Change Ventilator to IMV
      2. Later: lower the Respiratory Rate

XXII. Management: Specific Treatment

  1. General
    1. Best efficacy if treatment given within first 2 weeks
      1. May administer up to 4 weeks from onset (esp. if unable to ambulate)
    2. Both plasma exchange and IV-Ig are equally effective (choose one)
    3. Corticosteroids are not recommended (contrast with Transverse Myelitis)
      1. No evidence of improved outcome
      2. Risk of delayed recovery, and worse longterm outcomes
  2. Plasma Exchange (Plasmapheresis)
    1. Protocol
      1. Number of exchanges depends on severity (up to five exchanges total)
        1. Mild Guillain-Barre: 2 exchanges
        2. Moderate to severe Guillain-Barre: 4-5 exchanges
      2. Perform one exchange every other day for 4 to 10 days (2-5 exchanges)
      3. Best outcomes if started within first 7 days from onset
    2. Special Indications
      1. Pregnancy
      2. Renal Insufficiency
      3. IgA deficient
      4. Has not been studied in children
  3. IV Immunoglobulin
    1. Easier management with fewer complications than plasma exchange
    2. Dose
      1. Standard: IV-Ig 400 mg/kg daily for 5-7 days
      2. Alternative: IV-Ig 2g/kg total with divided dosing over 2 days
    3. Special Indications
      1. Children
      2. Poor venous access
      3. Autonomic instability

XXIII. Prognosis

  1. Full recovery within 6-12 months in 75 to 85% of cases
    1. Children tend to have shorter courses with more rapid recovery and with typical complete recovery
    2. Recovery is typically complete by 12 months after onset (10 weeks on average)
  2. Neurologic sequelae in up to 15-20%
    1. Foot Drop
    2. Hand intrinsic Muscle Weakness
    3. Sensory Ataxia
    4. Unable to ambulate without assistance in 10-20% (6% in children)
  3. Median hospitalization duration: 7 days
  4. Relapse or recurrence rate <3-5%
    1. Relapse more common in women and children (typically after 7 years)
    2. Vaccination avoidance places the patient at greater risk than the risk of GBS recurrence
  5. Mortality rate <3-8% overall (regardless of age, including children)
    1. Mortality approaches 20% in some studies if Mechanical Ventilation required
    2. Highest mortality causes
      1. Ventilator Associated Pneumonia
      2. Autonomic Dysfunction (esp. Dysrhythmias resulting in Cardiac Arrest)
      3. Acute Respiratory Distress Syndrome
      4. Pulmonary Embolism
      5. Sepsis
  6. Predictors of poor prognosis or longterm Disability
    1. Age over 60 years
    2. Rapidly progressive, severe disease
    3. EMG showing axonal loss
    4. Prolonged Mechanical Ventilation >1 month
    5. Absence of motor response
    6. Inability to walk at 14 days
  7. Trigger conditions associated with worse outcomes
    1. Preceding Diarrheal illness (often Campylobacter jejuni)
    2. Cytomegalovirus infection

XXIV. Resources

  1. National Institute of Neurological Disorders and Stroke (NINDS)
    1. http://www.ninds.nih.gov/disorders/gbs/gbs.htm
  2. Guillain-Barre and Chronic Inflammatory Demyelinating Polyneuropathy Foundation International
    1. http://www.gbs-cidp.org/

XXV. References

  1. Della-Giustina (2024) Crit Dec Emerg Med 38(10): 27-34
  2. Gallagher in Marx (2002) Rosen's Emergency Med, p. 1510
  3. Lindquist and Stephanos in Swadron (2023) EM:Rap 37(3): 4-12
  4. Shields in Goetz (2003) Neurology, p. 1085-90
  5. Weinstock et al. in Herbert (2015) EM:Rap 15(1): 7
  6. Alshekhlee (2008) Neurology 70(18): 1608-13 [PubMed]
  7. Cornblath (2009) Ann Nuerol 66(5): 569-70 [PubMed]
  8. Joseph (2002) Adolesc Med 13:487-94 [PubMed]
  9. Newswanger (2004) Am Fam Physician 69(10):2405-10 [PubMed]
  10. van Doorn (2008) Lancet Neurol 7(10): 939-50 [PubMed]
  11. Walling (2013) Am Fam Physician 87(3): 191-7 [PubMed]

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