Viruses targeting anterior horn cells or motor neurons

Certain viruses targeting anterior horn cells and motor neurones may cause acute flaccid paraparesis.29 Extensive necrotising myelopathy on MRI is associated with herpes simplex virus and West Nile virus. Poliomyelitis should be considered in unvaccinated individuals, especially those with recent travel to endemic regions.30 Most patients infected with polio remain asymptomatic, but 0.1%–1.0% develops paralysis. Typically, there is a prodromal flu-like illness, with fever, neck stiffness and significant myalgia. Rapidly progressive, often asymmetric paralysis, affecting proximal more than distal muscles, develops within 48 h in the absence of sensory deficit. CSF examination is usually lymphocytic.

Non-polio enterovirus, especially enterovirus 71, may cause acute flaccid paraparesis and there have been recent outbreaks in Australia and Cambodia.31 Typically, a 1–2 week prodromal illness of diarrhoea, lethargy, irritability and nuchal rigidity is followed by acute flaccid paraparesis and other neurological symptoms in up to 20% of individuals. The mortality is high.

Rabies virus may cause acute flaccid paraparesis 1–2 months after initial exposure.32 Early symptoms include behavioural changes and autonomic instability, followed by ascending paralysis associated with sphincter involvement and sensory disturbance.

Direct involvement of the spinal cord, nerve roots and peripheral nerves may occur in HIV or AIDS, but more often acute flaccid paraparesis is caused by the effects of opportunistic infections. These include cytomegalovirus, Epstein–Barr virus, varicella zoster virus and herpes simplex virus, which may also trigger acute motor axonal neuropathy.16 Cytomegalovirus and, less commonly, herpes simplex virus 2 or varicella zoster virus also cause polyradiculoneuropathy, especially if the patient is immunocompromised. Typically, there is ascending leg weakness, perineal paraesthesia, leg pain and variable bladder involvement. CSF usually shows increased polymorphs and protein with reduced glucose. Neurophysiologically, there is evidence of axonal neuropathy. Clinicians should also consider other infections, including syphilis, toxoplasmosis, giardiasis and tuberculosis.29 Patients with AIDS with cachexia may develop rapidly progressive weakness due to profound B12 deficiency.

Acute transverse myelitis

Acute transverse myelitis may cause acute flaccid paraparesis, usually with radiological evidence of spinal cord involvement. Initial spinal shock is followed by acute flaccid paraparesis associated with bladder disturbance and a sensory level. Often patients present with back pain. There are several infectious agents implicated, including—but not limited to—M. pneumoniae, herpes viruses, rabies virus, hepatitis A virus, enteric fever and parasitic infections (eg, schistosoma).28 ,29

Spinal cord injury

Spinal cord injury can usually be elicited from the history, and one should always ask about recent falls. Epidural abscess or haematoma may cause acute spinal cord compression and is usually associated with focal pain and can be shown radiologically. Anterior spinal artery occlusion may cause abrupt onset of acute flaccid paraparesis and should always be considered postoperatively if there has been cardiothoracic surgery requiring aortic clamping.

Acute peripheral neuropathies

In addition to GBS, clinicians should consider other causes of acute peripheral neuropathy. Acute-onset chronic inflammatory demyelinating polyradiculoneuropathy is difficult to distinguish from GBS, but can be diagnosed if there is deterioration after 8 weeks from onset or more than three further deteriorations during disease course.33 With the notable exception of diphtheritic neuropathy, which is demyelinating-type and discussed later, most other acute peripheral neuropathies are of axonal type. Numerous infectious agents can directly damage peripheral nerves (eg, HIV) and some have the additional ability to trigger GBS (eg, herpes simplex virus). Tick paralysis should be considered if endemic.34 A flu-like prodrome lasting 5–10 days may be followed by rapidly progressive symmetric ascending flaccid paralysis over 2–6 days. In Lyme disease,35 painful, often asymmetric polyradiculoneuropathy may occur several months after initial tick bite or after a characteristic erythema migrans rash. Isolated or bilateral facial weakness has also been reported. CSF shows raised lymphocytes and protein, and there is serological evidence of Lyme disease. Consumption of certain plants (eg, buckthorn)28 or intoxication with lead, arsenic36 or thallium have all caused a rapidly progressive polyneuropathy mimicking GBS. Raw puffer fish (fugu) is a Japanese delicacy, but if prepared incorrectly may result in tetrodotoxin poisoning and rapidly progressive paralysis within hours of consumption.37 Currently, there is no antidote and treatment is supportive. Porphyric neuropathy38 is rare but shares several clinical features with GBS, although usually more asymmetric. The onset can be acute and progression to nadir occurs in 4 weeks. CSF also shows albuminocytological dissociation, and nerve conduction studies show an axonal-type neuropathy. In half the cases, the weakness starts in the upper limbs and may therefore be confused with the pharyngeal-cervical-brachial variant. Invariably, patients report severe abdominal pain and show psychiatric symptoms or have seizures before developing porphyric neuropathy. The diagnosis relies upon showing urinary porphyrins under ultraviolet light or following exposure to oxygen.

Neuromuscular junction disorders

Autoimmune diseases (eg, myasthenia gravis or Lambert–Eaton myasthenic syndrome), exposure to certain toxins (eg, botulinum toxin), consumption of various plants (eg, hemlock) or indeed animal bites (eg, cobra or krait) result in neuromuscular dysfunction and, in some cases, rapidly progressive paralysis in the absence of sensory disturbance. In myasthenia gravis, there is usually also demonstrable muscle fatigability.

Neuromuscular weakness related to critical illness

Neurologists are frequently asked to assess patients on the intensive care unit who develop generalised weakness or are having difficulty weaning from mechanical ventilation. Although GBS may develop in this setting, neuromuscular weakness related to critical illness should always be considered first.39 Clinical assessment may be difficult as patients are often encephalopathic. Those receiving high-dose intravenous glucocorticoids (eg, for status asthmaticus) are at particular risk of developing critical illness myopathy, which typically affects proximal more than distal muscles and starts several days after treatment initiation. There is sometimes facial weakness although the ocular muscles are usually spared. The serum creatine kinase is raised and nerve conduction studies may show slight motor nerve abnormalities. Patients with severe sepsis may develop critical illness neuropathy, which has a worse prognosis. Weakness is often more distal and associated with sensory disturbance. Facial weakness is less common. The serum creatine kinase in these patients is usually normal and nerve conduction studies show a diffuse sensory motor axonal polyneuropathy.39 Many patients have both critical illness myopathy and neuropathy and these should be differentiated from cachectic myopathy, which may develop in patients following prolonged admission and is more slowly progressive. Prolonged use of neuromuscular blocking agents (eg, vecuronium bromide) also may lead to persistent weakness and failure to wean from the ventilator.

Muscle disorders

Acute myositis may develop following certain viral infections (eg, influenza A),40 and is associated with variable degree of rhabdomyolysis. Typically, weakness begins within 2 weeks of the start of flu-like symptoms. Patients often look unwell and report myalgia and fever. On examination, the muscles are tender to touch, while sensation is normal. Serum creatine kinase is greatly elevated (often >10 000 U/L) and liver transaminases are also deranged. Urine dipstick is positive for blood but there are no red blood cells on microscopy.

Acute hypokalaemic periodic paralysis may mimic GBS.41 Two-thirds of cases are due to the familial form, which is autosomal dominant, and typically affects Caucasians. The paralysis often follows a high carbohydrate meal or a prolonged period of exertion. Thyrotoxic periodic paralysis is more prevalent among Asian, Hispanic and Native American males, and may be triggered by excess endogenous or exogenous thyroid hormones.

Brainstem stroke

Posterior circulation or brainstem strokes produce a variety of well-described syndromes determined by specific vascular territories. Some patients, for example, those with vertebral artery dissection, may not have risk factors for stroke, but instead may report recent neck injury (eg, whiplash) and present with neck pain. Typically, brainstem strokes are unilateral (eg, lateral medullary syndrome) unless the basilar artery is affected, in which case the ischaemic lesion often localises to the mid-pons, where it extends from the paramedian pontine base to the tegmentum. In most patients, the symptoms are progressive and many report vertigo, nausea and headache, two or more weeks beforehand.43 Limb weakness is usually asymmetric and often unilateral at onset. Facial and bulbar weakness and lower limb ataxia are also common. Patients nearly always show eye signs: typically horizontal gaze paresis or internuclear ophthalmoplegia. Pontine lesions produce pinpoint pupils. Some patients have pseudobulbar lability. ‘Top of basilar’ strokes produce a different syndrome, with ischaemic lesions in the midbrain, thalami, temporal and occipital lobes. The underlying cause is usually embolic. Sensation and weakness often remain intact, but patients have problems with vertical gaze and convergence. The pupils are enlarged and react slowly or incompletely. Altered mentation, hallucinations and memory problems may develop, depending on the area of ischaemia.

Myasthenia gravis

Myasthenia gravis is characterised by fluctuating weakness in voluntary muscles, which is made worse by exertion and often precipitated by certain drugs (eg, β-blockers) or systemic illness (eg, sepsis).44 Careful history taking often shows that symptoms have been present for some time. The presentation is highly variable, but there are four subtypes: generalised 50%, ocular 13%, ocular and bulbar 17%, and ocular and limbs 20%. Commonly (85%), patients present with fluctuating ptosis or diplopia. Ptosis is often asymmetric and increases with prolonged upgaze and may resolve with the ‘ice-pack’ test. The pupils are normal. Ophthalmoparesis often fluctuates from one examination to the next, whereas in MFS or Bickerstaff's brainstem encephalitis, ophthalmoparesis is progressive. Lateral rectus palsy is most frequent and therefore patients often report horizontal diplopia. Facial weakness may also occur and weakness of eye closure (orbicularis oculi) may occur in isolation. Fifteen per cent of patients present with bulbar symptoms, which may be obvious or subtle; for example, with a history of frequent chest infections secondary to silent aspiration. Some patients present with head droop, which may occur in the pharyngeal-cervical-brachial variant of GBS. Similarly, in myasthenia gravis, limb weakness is also usually proximal and more obvious in the upper limbs. The diagnosis of myasthenia gravis is usually clinical but often supported by the presence of serum anti-acetylcholine receptor antibodies (85% in general myasthenia gravis, <50% ocular myasthenia) and showing decrement on low frequency (2–5 Hz) repetitive stimulation (75% generalised myasthenia gravis, <50% ocular myasthenia). Single-fibre electromyography is abnormal in >95% of patients but is non-specific. Anti-MuSK (muscle-specific kinase) antibodies occur in 40% of anti-acetylcholine receptor antibody-negative patients with myasthenia gravis; these characteristically present with facial, bulbar, neck, and respiratory muscle weakness with relative sparing of ocular muscles.

Diphtheritic neuropathy

Approximately 10% of patients with diphtheria develop neuropathy involving the cranial or peripheral nerves, which is demyelinating in nature and usually occurs within the first 2 months of infection. Fever is usually present and in the vast majority there is bulbar dysfunction early in disease course.45

Wernicke's encephalopathy

Wernicke's encephalopathy results from thiamine deficiency and is often associated with chronic alcoholism in the setting of poor nutrition or increased metabolic requirements (eg, systemic illness). Similar to Bickerstaff's brainstem encephalitis, patients typically present with differing degrees of encephalopathy, ocular dysfunction and ataxia.46 Rather than the hypersomnolence seen in Bickerstaff's brainstem encephalitis, patients are often profoundly disorientated and inattentive and appear indifferent to their surroundings. Gaze-evoked nystagmus is the most frequent ocular presentation. Although there may be ophthalmoparesis, especially in the horizontal plane, this is usually incomplete unless Wernicke's encephalopathy is very severe. Ptosis is rare, and the pupils are often sluggish or unreactive. Vestibular dysfunction without hearing loss is also common. Gait ataxia may be the first sign of Wernicke's encephalopathy and is often multifactorial in the alcoholic and, therefore, sometimes dismissed. Wernicke's encephalopathy is primarily a clinical diagnosis but supported by the presence of characteristic changes on MR brain imaging. These include symmetric T2-signal change around the third and fourth ventricles and the aqueduct and, in most cases, also the mamillary bodies. Laboratory demonstration of thiamine deficiency is not always needed for diagnosis, although thiamine status can be determined by measuring whole blood levels, which is more sensitive than measurement of serum levels or the plasma transketolase method. Parenteral thiamine must be given early and should not be delayed in suspected cases; it should be given before glucose to avoid deterioration.

Botulism

Intoxication with Clostridium botulinum toxin produces a pattern of weakness similar to MFS and the pharyngeal-cervical-brachial variant of GBS, and is increasingly seen in patients who inject black tar heroin. Interestingly, botulinum toxin type A, the most common cause of foodborne botulism, also binds to the gangliosides GQ1b and GT1a and may disrupt the same population of neurons.47 ,48 In addition to ptosis, ophthalmoplegia and faciobulbar weakness, the pupils are characteristically dilated and poorly reactive to light and accommodation. Descending paralysis in the absence of sensory disturbance may be complicated by respiratory failure, if severe. Some patients also develop autonomic symptoms, including dry mouth, postural hypotension and constipation. Foodborne botulism typically develops 12–72 h after ingesting contaminated food (eg, home-canned vegetables) and weakness may be preceded by nausea, vomiting and diarrhoea.49 Wound infections with C. botulinum spores, sometimes seen in drug users from contaminated supplies, and colonisation of the small intestine in newborns can also rarely occur. The diagnosis is confirmed with mouse bioassay, which involves intraperitoneal injection of the patient's serum, gastric secretions or stool into a mouse. The treatment is supportive and antitoxin should be administered early in suspected cases.

Rhombencephalitis

Brainstem encephalitis (rhombencephalitis) should be among the differential diagnosis in patients who develop rapidly progressive brainstem signs.50 When there is underlying infection, patients characteristically report headache, fever, nausea and vomiting, followed by brainstem, cerebellar and long tract signs. Respiratory depression and decreased consciousness are common and seizures may also occur. In some patients, meningeal symptoms are prominent and this narrows the differential further. Listeriosis is probably the most common cause, especially in the immunocompromised and among alcoholics or in healthy individuals who have consumed heavily contaminated food. It may also complicate the third trimester of pregnancy and lead to miscarriage. Its mortality is high and, therefore, ampicillin is often used empirically in patients at risk. Other infective causes depending on patients’ background should also be considered and include: tuberculosis, brucellosis, Lyme disease, herpes simplex virus, Epstein–Barr virus, JC virus, toxoplasmosis and cryptococcosis. A wide range of non-infective conditions may produce similar symptoms, although systemic illness, especially fever, are often less prominent.50 These include, but are not limited to: multiple sclerosis, sarcoidosis, Behçet's disease, systemic lupus erythematosus, lymphoma and paraneoplastic syndromes. Brainstem imaging is usually abnormal and there may be meningeal enhancement. CSF analysis, blood cultures and serological work-up are useful when abnormal or positive, but may be unrevealing, which can delay the final diagnosis.