Guillain-Barre Syndrome - A True Story
 
Guillain-Barre Syndrome - A True Story
 
Guillain-Barre Syndrome - A True Story
 
Guillain-Barre Syndrome - A True Story
Exhaustive History
EXHAUSTIVE HISTORY
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Synonyms and related keywords: Guillain-Barré syndrome, GBS, acute inflammatory demyelinating polyneuropathy, AIDP, acute motor axonal neuropathy, AMAN, acute motor-sensory axonal neuropathy, AMSAN, Miller-Fisher syndrome, MFS, acute panautonomic neuropathy, pharyngeal-brachial-cervical variant, pure sensory variant, Campylobacter jejuni, acute placid paralysis.

Author: Andrew Miller, MD, Clinical Assistant Instructor, Departments of Emergency Medicine and Internal Medicine, State University of New York Downstate Medical Center, Kings County Hospital Center
Coauthor(s): Omar E Ali, MD, Staff Physician, Department of Internal Medicine, SUNY Downstate Medical Center, Brooklyn/Kings County Hospital Center; Richard Sinert, DO, Associate Professor of Emergency Medicine, Clinical Assistant Professor of Medicine, State University of New York College of Medicine; Consulting Staff, Department of Emergency Medicine, Kings County Hospital Center

Andrew Miller, MD, is a member of the following medical societies: American College of Physicians, American Medical Association, Islamic Medical Association of North America, and Medical Society of the State of New York

Editor(s): Edward A Michelson, MD, Program Director, Associate Professor, Department of Emergency Medicine, University Hospital Health Systems in Cleveland; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; J Stephen Huff, MD, Associate Professor of Emergency Medicine and Neurology, Department of Emergency Medicine, University of Virginia Health System; John Halamka, MD, Chief Information Officer, CareGroup Healthcare System, Assistant Professor of Medicine, Department of Emergency Medicine, Beth Israel Deaconess Medical Center; Assistant Professor of Medicine, Harvard Medical School; and Steven C Dronen, MD, FAAEM, Director of Emergency Services, Director of Chest Pain Center, Department of Emergency Medicine, Ft Sanders Sevier Medical Center.

Background: In 1859, Landry published a report on 10 patients with an ascending paralysis. This was followed by a report in 1916 written by 3 French physicians working in the Sixth Army camp during the First World War; they described 2 French soldiers with motor weakness, areflexia, and albuminocytological dissociation in the cerebrospinal fluid. In this report Guillain, Barré, and Strohl carefully recorded and interpreted the tendon reflexes of their patients and became the first to recognize the peripheral nature of the illness. Further cases were recognized, and the identified syndrome was later named Guillain-Barré syndrome (GBS). Historically, GBS was a single disorder; however, current practice divides the syndrome into several variant forms.

GBS is a heterogeneous grouping of immune-mediated processes generally characterized by motor, sensory, and autonomic dysfunction. In its classic form, GBS is an acute inflammatory demyelinating polyneuropathy characterized by progressive symmetric ascending muscle weakness, paralysis, and hyporeflexia with or without sensory or autonomic symptoms; however, variants involving the cranial nerves or pure motor involvement are not uncommon. In severe cases, muscle weakness may lead to respiratory failure, and labile autonomic dysfunction may complicate the use of vasoactive and sedative drugs.

Pathophysiology: Although the clinical syndrome classically presents as a rapidly progressive acute polyneuropathy, several pathologic and etiologic subtypes exist. Most patients with GBS exhibit absent or profoundly delayed conduction in action nerve fibers. This aberrant conduction results from demyelination of nerve cell axons. Peripheral nerves and spinal roots are the major sites of demyelination, but cranial nerves also may be involved.
GBS is believed to result from an autoimmune response, both humoral and cell mediated, to a recent infection or any of a long list of medical problems. Its relation to antecedent infections and the identification of various antiganglioside antibodies suggest that molecular mimicry may serve as a possible mechanism for the disease. The antibodies formed against gangliosidelike epitopes in the lipopolysaccharide layer of some infectious agents have been shown in both necropsy and animal models to cross-react with the ganglioside surface molecules of peripheral nerves. Symptoms generally coincide pathologically with various patterns of lymphocytic infiltration and macrophage-mediated demyelination, depending on the subtype in question. Recovery is typically associated with remyelination. In a subset of patients, GBS is associated primarily with myelin-sparing axonal damage resulting from a direct cellular immune attack on the axon itself.
The acute inflammatory demyelinating polyneuropathy (AIDP) subtype of GBS is by far the most commonly identified form in the United States. It is generally preceded by an antecedent bacterial or viral infection. Nearly 40% of patients are seropositive for Campylobacter jejuni. Lymphocytic infiltration and macrophage-mediated demyelination of the peripheral nerves are present. Symptoms generally resolve with remyelination.

The acute motor axonal neuropathy (AMAN) subtype is a purely motor subtype, which is more prevalent amongst pediatric age groups. Nearly 70-75% of patients are seropositive for Campylobacter. One third of these cases may actually be hyperreflexic. AMAN is generally characterized by a rapidly progressive weakness, ensuing respiratory failure, and good recovery.

Acute motor-sensory axonal neuropathy (AMSAN) is an acute severe illness similar to AMAN except that AMSAN also affects sensory nerves and roots. Patients are typically adults with both motor and sensory dysfunction, marked muscle wasting, and poor recovery. The hyperreflexia mechanism associated with AMAN is not known, but dysfunction of the inhibitory system via spinal interneurons may increase motor neuron excitability.

Miller-Fisher syndrome (MFS) is a rare variant that typically presents with the classic triad of ataxia, areflexia, and ophthalmoplegia. The ataxia tends to be out of proportion to the degree of sensory loss. Patients may also have mild limb weakness, ptosis, facial palsy, or bulbar palsy. Anti-GQ1b antibodies are prominent in this variant, and patients have reduced or absent sensory nerve action potentials and absent tibial H reflex. Recovery generally occurs within 1-3 months.

Acute panautonomic neuropathy is among the rarest of all variants and involves both the sympathetic and parasympathetic nervous systems. Cardiovascular involvement is common, and dysrhythmias are a significant source of mortality in this form of the disease. The patient may also experience sensory symptoms. Recovery is gradual and often incomplete.

Frequency:

  • In the US: The incidence is 1-3 per 100,000 inhabitants, making GBS the most common cause of acute flaccid paralysis in the United States.
  • Internationally: AMAN is a purely motor form that occurs mainly in northern China but is also more common in developing nations.

AIDP accounts for up to 90% of cases in Europe, North America, and the developed world.

Epidemiologic studies from Japan indicate that in this region a greater percentage of GBS cases are associated with antecedent C jejuni infections and a lesser number are related to antecedent cytomegalovirus infections when compared with their North American and European counterparts.

Mortality/Morbidity: Most patients (up to 85%) with GBS achieve a full and functional recovery within 6-12 months. Recovery is maximal by 18 months past onset.

  • Patients may have persistent weakness, areflexia, imbalance, or sensory loss. Approximately 7-15% of patients have permanent neurologic sequelae including bilateral footdrop, intrinsic hand muscle wasting, sensory ataxia, and dysesthesia.
  • The mortality rate varies but may be less than 5% in tertiary care centers with a team of medical professionals who are familiar with GBS management. Causes of death include adult respiratory distress syndrome, sepsis, pneumonia, pulmonary emboli, and cardiac arrest.
  • Despite intensive care, 3-8% of patients die.

Race: No racial preponderance exists.

Sex: The male-to-female ratio is 1.5:1. A Swedish epidemiologic study indicated that the incidence of GBS is lower during pregnancy and increases in the months immediately following delivery.

Age: GBS occurs at all ages, but a bimodal distribution with peaks in young adulthood (15-35 y) and in elderly persons (50-75 y) appears to exist. Rare cases have been noted in infants.

History: The typical GBS patient (likely AIDP) presents 2-4 weeks after a relatively benign respiratory or gastrointestinal illness complaining of dysesthesias of the fingers and lower extremity proximal muscle weakness. The weakness may progress over hours to days to involve the arms, truncal muscles, cranial nerves, and muscles of respiration. The illness progresses from days to weeks, with the mean time to the nadir of clinical function being 12 days and 98% of patients reaching a nadir by 4 weeks. A plateau phase of persistent, unchanging symptoms then ensues followed days later by gradual symptom improvement. The mean time to improvement and clinical recovery are 28 and 200 days, respectively.

  • Up to one third of patients require mechanical ventilation during the course of their illness. Causes for this include cranial nerve involvement affecting airway maintenance and respiratory muscle paralysis.
  • Motor dysfunction
    • Symmetric limb weakness typically begins as proximal lower extremity weakness and ascends to involve the upper extremities, truncal muscles, and head.
    • Inability to stand or walk despite reasonable strength, especially when ophthalmoparesis or impaired proprioception is present.
    • Respiratory muscle weakness with shortness of breath may be present.
    • Cranial nerve palsies (III-VII, IX-XII) may be present. Patients may present with facial weakness mimicking Bell palsy, dysphagia, dysarthria, ophthalmoplegia, and pupillary disturbances. The Miller-Fisher variant is unique in that this subtype begins with cranial nerve deficits.
    • Lack of deep tendon reflexes is a hallmark sign.
  • Sensory dysfunction
    • Paresthesia generally begins in the toes and fingertips and progresses upward but generally not extending beyond the wrists or ankles.
    • Pain is most severe in the shoulder girdle, back, buttocks, and thighs and may occur with even the slightest movements.
    • Loss of vibration, proprioception, touch, and pain distally may be present.
  • Autonomic dysfunction
    • Cardiovascular signs may include tachycardia, bradycardia, dysrhythmias, wide fluctuations in blood pressure, and postural hypotension.
    • Urinary retention due to urinary sphincter disturbances may be noted.
    • Constipation due to bowel paresis and gastric dysmotility may be present.
    • Facial flushing and venous pooling secondary to abnormal vasomotor tone may be present.
    • Hypersalivation
    • Anhydrosis
    • Tonic pupils
  • Papilledema secondary to elevated intracranial pressure is present in rare cases.

Physical:

  • Vital signs
    • Patients may have tachycardia or bradycardia, hypertension or hypotension, or hyperthermia or hypothermia.
    • Low oxygen saturation may be present with advanced respiratory muscle involvement.
  • Cranial nerves: Patients may present with facial weakness mimicking Bell palsy, dysphagia, dysarthria, ophthalmoplegia, and pupillary disturbances.
  • Dysreflexia
    • Patients with manifest weakness are invariably hyporeflexic or areflexic in the involved areas.
    • Respiratory symptoms
    • Poor inspiratory effort or diminished breath sounds
  • Motor
    • Symmetric limb weakness typically begins as proximal lower extremity weakness and ascends to involve the upper extremities, truncal muscles, and head.
    • Inability to stand or walk despite reasonable strength, especially when ophthalmoparesis or impaired proprioception is present.
    • Hypotonia
    • Wasting of limb muscles is not an acute finding.
  • Abdominal
    • Paucity or absence of bowel sounds suggests paralytic ileus.
    • Suprapubic tenderness or fullness may be suggestive of urinary retention.
  • Sensory: Patients may experience numbness, paresthesias, impaired proprioception, and pain.
  • Papilledema secondary to elevated intracranial pressure is present in rare cases.

Causes: GBS has been associated with antecedent bacterial and viral infections, administration of certain vaccinations, and other systemic illnesses. Case reports exist regarding numerous medications and procedures; however, whether any causal link exists is unclear.

  • Bacterial infections include C jejuni, Haemophilus influenzae, Mycoplasma pneumoniae, and Borrelia burgdorferi.
  • Viral infections include cytomegalovirus, Ebstein-Barr virus, and during seroconversion with the human immunodeficiency virus (HIV).
  • Vaccines
    • A study reviewing the cases of GBS during the 1992-1993 and 1993-1994 influenza seasons found an adjusted relative risk of 1.7 cases per 1 million influenza vaccinations.
    • Epidemiologic studies from Finland, southern California, and Latin America failed to validate an earlier retrospective study from Finland suggesting a cause-effect relationship between oral polio vaccination and GBS.
    • Data from 2 large-scale epidemiologic studies found that fewer cases of GBS occurred following administration of tetanus toxoid containing vaccinations than occurred in the baseline population.
    • Two epidemiologic studies failed to show any conclusive epidemiologic association between GBS and the hepatitis B vaccine.
    • A large Latin American study of more than 2000 children with GBS following a mass measles vaccination program in 1992 and 1993 failed to establish a statistically significant causal relationship between administration of the measles vaccine and GBS.
    • A recent report from the Centers for Disease Control and Prevention (CDC) suggests that an increased incidence of GBS may exist amongst recipients of the Menactra meningococcal conjugate vaccine.
    • Case reports exist regarding group A streptococci vaccines, the rabies vaccine, and the swine flu vaccine; however, conclusive statistically significant evidence is lacking.
  • Medications
    • A case-controlled study showed that patients with GBS had used antimotility drugs and penicillins more often and oral contraceptives less often. No definite cause-effect relationship has been established.
    • Case reports exist regarding streptokinase, isotretinoin, danazol, captopril, gold, heroin, and epidural anesthesia among others.
  • Anecdotal associations include systemic lupus erythematosus, sarcoidosis, lymphoma, surgery, renal transplantation, and snake bites.

CBRNE - Botulism
Cauda Equina Syndrome
Diphtheria
Encephalitis
Hyperkalemia
Hypokalemia
Hypophosphatemia
Meningitis
Myasthenia Gravis
Polymyositis
Spinal Cord Infections
Spinal Cord Injuries
Systemic Lupus Erythematosus
Tick-Borne Diseases, Lyme
Toxicity, Alcohols
Toxicity, Heavy Metals
Toxicity, Organophosphate and Carbamate

Other Problems to be Considered:
Basilar artery occlusion
Chronic inflammatory demyelinating polyneuropathy
Folate deficiency
Hereditary neuropathies
Neoplasia
Neurotoxic fish poisoning
Poliomyelitis
Porphyria
Sarcoid meningitis
Spinal cord compression
Spinal cord syndromes, particularly postinfection
Tick paralysis
Transverse myelitis
Vitamin B-12 deficiency

Lab Studies:

  • Diagnosis usually is made on clinical grounds. Laboratory studies are useful to rule out other diagnoses and to better assess functional status and prognosis.
  • Lumbar puncture and spinal fluid analysis
    • Elevated or rising protein levels on serial lumbar punctures and 10 or fewer mononuclear cells/mm3 strongly support the diagnosis.
    • Most, but not all, patients have an elevated CSF protein level (>400 mg/L), with no elevation in CSF cell counts.
    • Normal CSF protein level does not rule out GBS because the CSF protein level remains normal in 10% of patients and because any rise in the CSF protein level may not be observed until 1-2 weeks after the onset of weakness.
    • CSF pleocytosis is well recognized in HIV-associated GBS.
  • Biochemical screening
    • Biochemical screening includes electrolyte levels; liver function tests (LFTs); CPK level; erythrocyte sedimentation rate (ESR); antiganglioside antibodies; and antibodies to C jejuni, cytomegalovirus, Ebstein-Barr virus, herpes simplex virus (HSV), HIV, and M pneumoniae.
    • Syndrome of inappropriate antidiuretic hormone (SIADH) occurs in some patients with GBS.
    • LFT results are elevated in up to one third of patients.
    • CPK and ESR may be elevated with myopathies or systemic inflammatory conditions.
    • Patients with the Miller-Fisher variant may have anti-GQ1b antibodies.
    • Patients who have antibody subtype GM1 may have poorer prognoses.
  • Stool culture for C jejuni
  • Pregnancy test

Imaging Studies:

  • MRI
    • MRI is a sensitive but nonspecific test.
    • Spinal nerve root enhancement with gadolinium is a nonspecific feature seen in inflammatory conditions and is caused by disruption of the blood-nerve barrier.
    • Selective anterior nerve root enhancement appears to be strongly suggestive of GBS.
    • The cauda equine nerve roots are enhanced in 83% of patients.

Other Tests:

  • Forced vital capacity
    • Forced vital capacity (FVC) is very helpful in guiding disposition and therapy.
    • Patients with an FVC less than 15-20 mL/kg, maximum inspiratory pressure less than 30 cm H2O, or a maximum expiratory pressure less than 40 cm H2O generally progress to require prophylactic intubation and mechanical ventilation.
  • Nerve conduction studies
    • A delay in F waves is present, implying nerve root demyelination.
    • Nerve motor action potentials may be decreased. This is technically difficult to determine until the abnormality is severe.
    • Compound muscle action potential (CMAP) amplitude may be decreased.
    • Frequently, patients show evidence of conduction block or dispersion of responses at sites of natural nerve compression. The extent of decreased action potentials correlates with prognosis.
    • Prolonged distal latencies may be present.
    • Rarely neurophysiologic testing is normal in patients with GBS. This is believed to be due to the location of demyelinating lesions in proximal sites not amenable to study.
  • Muscle biopsy may help to distinguish GBS from a primary myopathy in unclear cases.
  • Many different abnormalities may be seen on ECG, including second-degree and third-degree atrioventricular (AV) block, T-wave abnormalities, ST depression, QRS widening, and a variety of rhythm disturbances.

Procedures:

  • Lumbar puncture and spinal fluid analysis

Prehospital Care:

  • ABCs, IV, oxygen, and assisted ventilation may be indicated.
  • Monitor for cardiac arrhythmias.
  • Transport expeditiously.

Emergency Department Care:

  • ABCs, IV, oxygen, and assisted ventilation may be indicated.
  • Intubation should be performed on patients who develop any degree of respiratory failure. Clinical indicators of the need for intubation include hypoxia, rapidly declining respiratory function, poor or weak cough, and suspected aspiration. Typically, intubation is indicated whenever the FVC is less than 15 mL/kg.
  • Patients who have, or are suspected of having, GBS should be monitored closely for changes in blood pressure, heart rate, and other arrhythmias.
    • Treatment rarely is needed for tachycardia.
    • Atropine is recommended for symptomatic bradycardia.
    • Because of the lability of dysautonomia, hypertension is best treated with short-acting agents, such as a short-acting beta-blocker or nitroprusside.
    • Hypotension of dysautonomia usually responds to intravenous fluids and supine positioning.
    • Temporary pacing may be required for patients with second-degree and third-degree heart block.

Consultations:

  • Consult a neurologist if any uncertainty exists as to the diagnosis.
  • Consult the ICU team for evaluation of need for admission to the unit.


Only plasma exchange therapy and intravenous immune serum globulin (IVIG) have proven effective. Both therapies have been shown to shorten recovery time by as much as 50%. The cost, difficulty, and efficacy of the 2 treatments are comparable.

Corticosteroids are ineffective as monotherapy. Limited evidence shows that oral corticosteroids significantly slow recovery from GBS. Substantial evidence shows that intravenous methylprednisolone alone does not produce significant benefit or harm. In combination with IVIG, intravenous methylprednisolone may hasten recovery but does not significantly affect the long-term outcome.

Immunoadsorption is an alternative that is still in the early stages of evaluation. A small prospective study showed no difference in outcome between patients treated with immunoadsorption and those treated with plasma exchange.

Interferon beta was not associated with significant clinical improvement compared with controls in a small randomized control trial.

Simple analgesics or nonsteroidal anti-inflammatory drugs may be tried but often do not provide adequate pain relief. Single small randomized controlled trials support the use of gabapentin or carbamazepine in the intensive care unit for the treatment of pain in the acute phase of GBS. Adjuvant therapy with tricyclic antidepressant medication, tramadol, gabapentin, carbamazepine, or mexiletine may aid in the long-term management of neuropathic pain.

Time to development of deep vein thrombosis (DVT) or pulmonary embolism (PE) varies from 4-67 days following symptom onset. DVT prophylaxis with gradient compression hose and subcutaneous low molecular weight heparin (LMWH) may cause a dramatic reduction in the incidence of venous thromboembolism, one of the major sequela of extremity paralysis.

True gradient compression stockings (30-40 mm Hg or higher) are highly elastic, providing a gradient of compression that is highest at the toes and gradually decreases to the level of the thigh. This reduces capacity venous volume by approximately 70% and increases the measured velocity of blood flow in the deep veins by a factor of 5 or more.

The ubiquitous white stockings known as antiembolic stockings or thromboembolic disease (TED) hose produce a maximum compression of 18 mm Hg and rarely are fitted in such a way as to provide adequate gradient compression. They have not been shown to be effective as prophylaxis against thromboembolism.

Drug Category: Blood product derivatives -- These agents are used to improve the clinical and immunologic aspects of the disease. They may decrease autoantibody production and increase solubilization and removal of immune complexes.

Drug Category: Fractionated low molecular weight heparins -- These agents are used in the prophylaxis of DVT. Fractionated LMWH first became available in the United States as enoxaparin (Lovenox). LMWH has been used widely in pregnancy, although clinical trials are not yet available to demonstrate that it is as safe as unfractionated heparin.

Reversible elevation of hepatic transaminase levels occurs occasionally. Heparin-associated thrombocytopenia has been observed with fractionated low molecular weight heparin.

Further Inpatient Care:

  • Admission to the ICU should be considered for all patients with labile dysautonomia, an FVC of less than 20 mL/kg, or severe bulbar palsy.
  • Any patients exhibiting clinical signs of respiratory compromise, in any degree, also should be admitted to an ICU.
  • The risk of sepsis and infection can be decreased by use of minimal sedation, frequent physiotherapy, and mechanical ventilation with positive end expiratory pressure where appropriate.
  • The risk of DVT and pulmonary embolus may be minimized by administration of heparin or a low molecular weight heparin and intermittent pneumatic compression devices.
  • The use of cardiac telemetry and pacing in the case of severe bradycardia may help to reduce the risk of cardiac morbidity and mortality.
  • Pain may be symptomatically improved by frequent passive limb movements, gentle massage, frequent position changes, and use of carbamazepine and gabapentin.
  • Narcotics should be used judiciously because patients may already be at risk for ileus.

Further Outpatient Care:

  • Physical therapy and occupational therapy may be beneficial in helping patients to regain their baseline functional status.

Transfer:

  • Transfer may be appropriate if a facility does not have the proper resources to care for patients who may require prolonged intubation or prolonged intensive care.

Complications:

  • With modern methods of respiratory management, most complications result from long-term paralysis. Possible complications include the following:
    • Persistent paralysis
    • Respiratory failure, mechanical ventilation
    • Hypotension or hypertension
    • Thromboembolism, pneumonia, skin breakdown
    • Cardiac arrhythmia
    • Ileus
    • Aspiration
    • Urinary retention
    • Psychiatric problems such as depression and anxiety

Prognosis:

  • Poor prognosis is associated with rapid progression of symptoms, advanced age, prolonged ventilation (>1 mo), and severe reduction of action potentials on neuromuscular testing.
  • Published reports indicate full recovery may be expected in 50-95% of cases.
  • Neurologic sequelae
    • Reported incidence of permanent neurologic sequelae ranges from 10-40%.
    • The worst-case scenario is tetraplegia within 24 hours with incomplete recovery after 18 months or longer.
    • The best-case scenario is mild difficulty walking, with recovery within weeks.
    • The usual scenario is peak weakness in 10-14 days with recovery in weeks to months. Average time on a ventilator (without treatment) is 50 days.
  • Mortality
    • Most is due to severe autonomic instability or from the complications of prolonged intubation and paralysis.
    • Mortality rates range from 5-10%.

Patient Education:

Medical/Legal Pitfalls:

  • Failure to anticipate dysrhythmias and autonomic instability
  • Failure to anticipate progressive respiratory failure
  • Failure to correctly diagnose GBS in patients with a variant form of the disease or in those with a normal CSF protein
  • Failure to provide adequate DVT prophylaxis in a patient that develops a DVT and/or pulmonary embolism.

Special Concerns:

  • The leading cause of death in elderly patients with GBS is arrhythmia.
  • Recurrence is rare but has been reported in 2-5% of patients.
  • Variants may present with pure motor dysfunction or acute dysautonomia.
  • The Miller-Fisher syndrome is a variant of GBS in which the initial symptoms include ataxia, ophthalmoplegia, and areflexia
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