Approach

Diagnosis is made by pattern recognition.[86] The classic presentation is a progressive symmetrical muscle weakness affecting lower extremities before upper extremities, and proximal muscles before distal muscles, accompanied by paraesthesias in the feet and hands.[87][88][11] The paralysis is typically flaccid with areflexia and progresses acutely over days, with around 80% of patients reaching a nadir by 2 weeks and 97% by 4 weeks.[89]

The progressive phase is followed by a plateau phase of persistent, unchanging symptoms lasting a variable duration before recovery begins. Mild dysautonomia occurs in approximately two-thirds of patients and causes sinus tachycardia, labile blood pressure, postural hypotension, urinary retention, ileus, and very rarely life-threatening cardiac arrhythmia.[90]

Initial tests include neurophysiological evaluation, lumbar puncture for cerebrospinal fluid (CSF) analysis, spirometry, and hepatic aminotransferases.

History

Two-thirds of patients have a history of influenza-like or respiratory illness or gastroenteritis in the 6 weeks before onset of neurological symptoms.[15][69] The most commonly presenting symptoms include a respiratory tract or gastrointestinal tract infection that has resolved by the time neurological symptoms begin, which is around 1 to 3 weeks (mean 11 days in several large studies) after the initial illness.[15]

Other reported anecdotal triggers include history of trauma, surgical procedures, immunisations, malignancy, and HIV infection.

GBS is more common in the older age groups and in males.[11]

Cases of GBS were reported following the outbreak of Zika virus in 2013.[43][44][20][45][21] Several other mosquito-borne viral infections such as dengue, chikungunya, and Japanese encephalitis have been linked to GBS.[46][47][48][49] GBS has been reported in patients with confirmed coronavirus disease 2019 (COVID-19) infection and after vaccination against COVID-19.[23][24][25][26]

Symptoms and signs: general

Paraesthesias in hands and feet frequently precede the onset of weakness.[11] These are usually mild and may extend proximally in the extremities. Most patients experience pain, which typically begins in the back and legs. It occurs at onset and during disease course.[91] Presence of back pain and paralysis is easily misinterpreted as cord compression, sometimes leading to unnecessary surgical intervention. Pain is a much more prominent symptom in children than in adults.[92]

Hyporeflexia or areflexia can be seen at the onset in both GBS and cord compression, but the presence of bowel or bladder dysfunction early on or the finding of a sensory level should alert the clinician to the prospect of acute myelopathy. Facial, oropharyngeal, and extraocular weakness may also occur. These cranial nerve deficits usually occur after trunk and limb involvement, but may precede them.[12]

Mild dysautonomia is common and results in sinus tachycardia, hypertension, and postural hypotension in approximately two-thirds of patients.[90] Other autonomic symptoms such as urinary retention and ileus can also occur.[93] Life-threatening cardiac arrhythmias are relatively rare.[11]

Around 20% to 30% of patients develop respiratory muscle weakness requiring mechanical ventilation.[11][94] In children, autonomic dysfunction may be an independent risk factor for mechanical ventilation.[92] Typical signs may include dyspnoea on exertion and shortness of breath, but respiratory muscle weakness can often be asymptomatic.

Symptoms and signs: acute inflammatory demyelinating polyradiculoneuropathy (AIDP)

Typical symptoms include acute polyradiculoneuropathy, causing progressive weakness of 2 or more limbs with reduced or absent tendon reflexes.[87] Time of onset is not more than 4 weeks, and alternative aetiologies should be absent.[87] Symptoms are predominantly proximal but may affect distal muscles. There may be motor, sensory, or mixed disturbances, with or without autonomic features. These usually follow an antecedent influenza-like illness, or respiratory or gastrointestinal infection.[51][95]

Symptoms and signs: acute motor axonal neuropathy (AMAN)

AMAN presents as acute weakness or paralysis without any sensory loss and with reduced or absent reflexes. Most cases are preceded by Campylobacter jejuni infection.[17][96] It is distinguished from AIDP by selective involvement of motor nerves, preservation of sensory fibres, and electrophysiology showing axonal features. AMAN has a more rapid progression and earlier lowest point than AIDP.[17][97]

Symptoms and signs: acute motor-sensory axonal neuropathy (AMSAN)

This is associated with sensory and motor deficits with axonal loss.[33][98] It often presents with fulminant paralysis and sensory loss with incomplete recovery.[64]

Symptoms and signs: Miller-Fisher syndrome (MFS)

This is characterised by impaired eye movements (ophthalmoplegia), abnormal coordination (ataxia), and loss of tendon reflexes (areflexia).[99] Occasionally ophthalmoplegia may be absent.[100] Patients with MFS may have bilateral tonic pupils.[101][102] Up to nearly half of patients with MFS have sluggish pupils and mydriasis.[103][102] Ptosis, and bulbar and facial palsy may occur.[103]

MFS does not cause limb or respiratory muscle weakness.[51] It is usually a self-limiting, benign condition.[103] The median period between neurological symptom onset and the disappearance of ataxia/ophthalmoplegia is between 32 and 88 days.[103]

Occasionally, an MFS-GBS overlap syndrome may give rise to limb weakness, which has a similar prognosis to that of GBS. Overlap syndromes, such as the pharyngeal-cervical-brachial variant of GBS or Bickerstaff's brainstem encephalitis, occur in 50% of patients with MFS within 7 days of disease onset.[104]

Symptoms and signs: Bickerstaff's brainstem encephalitis (BBE)

Clinical features are similar to those of MFS but also include altered consciousness (encephalopathy) or hyper-reflexia, or both.[6] BBE may be a separate clinical entity secondary to its clinical features of drowsiness, coma, hyper-reflexia, and extensor plantar responses.[105] Alternatively, it may also be a variant of MFS.[106][107] If the MFS triad presents with drowsiness and extensor plantar response, BBE is the likely underlying disease process.[108][109]

Symptoms and signs: pharyngeal-cervical-brachial

This presents with acute arm weakness, swallowing dysfunction, and facial weakness.[5]

Symptoms and signs: acute pandysautonomia

Presenting symptoms and signs include diarrhoea, vomiting, dizziness, abdominal pain, ileus, orthostatic hypotension, and urinary retention. GBS may be associated with bilateral tonic pupils and may involve both parasympathetic and sympathetic postganglionic neurons.[8] Other signs of dysautonomia, including fluctuating heart rate, decreased sweating, salivation, and lacrimation, may be present.[7]

Symptoms and signs: pure sensory

This presents with acute sensory loss, sensory ataxia, and areflexia, but no motor involvement.[9] It mostly affects the large sensory fibres, and may be associated with antibodies to GD1b.[9]

Investigations

If the diagnosis remains unclear despite clinical examination, anti-ganglioside antibodies, CSF analysis, and neurophysiological tests can be performed to differentiate subtypes.[108][110][111]

Neurophysiological evaluation

Nerve conduction studies are routinely performed and play an important role in diagnosis, subtype classification, and confirming that the disease is a peripheral neuropathy. A neurophysiological examination should be done as soon as possible.[88][112][113][12][11] At least 3 sensory nerves and 3 motor nerves with multisite stimulation F waves and bilateral tibial H reflexes need to be evaluated.[108] Early abnormalities typically include prolonged distal and F-wave latencies and reduced conduction velocities. H reflex is also prolonged or absent.[108] Evidence of demyelination is present in 85% of patients with early testing.[112]

Retrospective data indicate that a single neurophysiological examination may be diagnostically useful, provided that accurate neurophysiological criteria are employed.[114][115] Serial electrophysiology studies may be unhelpful.[115] However, a second examination (although not always practical) is recommended in patients showing no clear demyelinating features, low amplitude distal compound muscle action potentials, or conduction block without temporal dispersion.[116] Given the dynamic nature of the disease, a second study may be of benefit in determining the subtype of GBS.[116]

Cerebrospinal fluid analysis

CSF analysis is an important laboratory aid in excluding other infectious causes and should be performed early.[11] Elevated CSF protein with normal cell count (albuminocytological dissociation) is the classic finding. However, CSF protein may be normal during the first 2 weeks of the illness, and the extent of albuminocytological dissociation may vary in different populations and with different GBS variants.[5][89][11][117] Repeat lumbar puncture is warranted if the diagnosis remains in question. A retrospective study has suggested a correlation between the level of CSF protein elevation and the amount of electrophysiologically demonstrable demyelination.[118]

Cell counts are typically <5 cells/mm³. However, up to 15% of patients with GBS may have mild pleocytosis of 5 to 50 cells/mm³.[89] If CSF pleocytosis is present, further evaluation for HIV, Lyme disease, sarcoidosis, meningitis, or carcinomatous meningitis should be initiated.[108][109] These tests would include HIV enzyme-linked immunosorbent assay (ELISA), Lyme serology and Western blot, CSF Lyme antibody, CSF angiotensin-converting enzyme and a chest x-ray, CSF VDRL, CSF cytology and flow cytometry, CSF Gram stain, CSF culture, and CSF West Nile polymerase chain reaction. Further viral studies should be considered if immunosuppression is a concern.

Diagnostic lumbar puncture in adults: animated demonstration
Diagnostic lumbar puncture in adults: animated demonstration

How to perform a diagnostic lumbar puncture in adults. Includes a discussion of patient positioning, choice of needle, and measurement of opening and closing pressure.

Spirometry

Bedside spirometry should be performed every 6 hours initially. This will help triage the patient to the intensive care unit (ICU) or the regular ward. A forced vital capacity of <20mL/kg is an indication for ICU admission.[11]

Patients with bulbar dysfunction and high risk of aspiration should be intubated for airway protection and impending respiratory failure. Risk factors for progression to mechanical ventilation include rapid disease progression, bulbar dysfunction (odds ratio 17.5), bilateral facial nerve weakness, and dysautonomia.[125][126] Other risk factors include inability to lift head (odds ratio 5.0) or inability to cough (odds ratio 9.09).[127] Algorithms or tools that predict a patient's risk of respiratory failure at admission (e.g., the Erasmus GBS Respiratory Insufficiency Score [EGRIS]) may be more reliable than individual variables.[128][129][11] Pulse oximetry and arterial blood gases should not be relied on, as either hypoxia or hypercapnia is a late sign and patients will decompensate very quickly.

Serology and stool culture

An increase in titres for infectious agents, including cytomegalovirus, Epstein-Barr virus, Mycoplasma, Haemophilus influenzae, and C jejuni, may help in establishing aetiology for epidemiological purposes but is of limited clinical use. Some data suggest that positive serological markers for C jejuni are associated with worse prognostic outcome.[30][130]

Testing for C jejuni may be considered if there is an antecedent history of diarrhoea or if the patient has been in a region where AMAN is prevalent. Treatment with antibiotics may be indicated if there is persistent faecal excretion of the bacteria.

Anti-ganglioside antibodies

Measuring serum levels of anti-ganglioside antibodies has limited diagnostic value. A positive test result may be helpful in supporting a diagnosis, but a negative result does not rule out GBS.[11]

If clinical features suggest a less common variant, particularly MFS or the pharyngeal-cervical-brachial variant, testing for the anti-ganglioside antibodies anti-GQ1b and anti-GT1a, respectively, may have some diagnostic utility. Anti-GQ1b IgG antibodies are found in up to 90% of patients with MFS.[131] The evidence for clinical utility of other anti-ganglioside antibodies is less robust.[11]

Hepatic aminotransferases

Hepatic aminotransferases may be elevated during the first few days in patients with GBS, and often normalise by 1 to 2 weeks.[132] Presence of elevated liver enzymes also correlates with increased severity of disease and should be routinely tested and monitored.[133] If transaminases remain persistently elevated, evaluation for viral hepatitides should be considered.

Imaging

Spinal magnetic resonance imaging (MRI) may be useful when the diagnosis is unclear and electrophysiological abnormalities are equivocal. It can also be performed to exclude a disease process involving the spinal cord (i.e., epidural abscess, transverse myelitis, spinal stenosis, spinal cord stroke, or tumour). Brain MRI abnormalities are present in 30% of patients with BBE.[106]

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