INCIDENCE

Since the incidence of poliomyelitis has declined markedly due to mass immunisation programmes, GBS has become the major cause of rapid-onset flaccid paralysis in previously healthy people, with an incidence of approximately 1.7 per 100 000. Epidemics have occurred in large populations exposed to viral illness or immunisation.⁴ Immunosuppression and concurrent autoimmune disease may also be predisposing factors.⁵ The disorder is slightly commoner in males, and up to four times commoner in the elderly. No consistent seasonal or racial predilection has been demonstrated.

AETIOLOGY

Most recent evidence supports the proposition that GBS is caused by immunologically mediated nerve injury.⁶ Cell-mediated immunity, in particular, probably plays a significant role, and inflammatory cell infiltrates are often seen in association with demyelination, which is generally regarded as the primary pathologic process. Antibodies to a number of nervous system components have been demonstrated in GBS patients, with most interest in recent years focusing on antiganglioside antibodies.

Although the precise mechanism of sensitisation is not known, clinical associations suggest that antecedent viral infections or immunisations are commonly involved. Infective agents implicated include influenza A, parainfluenza, varicella-zoster, Epstein–Barr, chickenpox, mumps, human immunodeficiency virus (HIV),⁷ measles virus and Mycoplasma. Campylobacter jejuni gastroenteritis now appears to be the most common predisposing infection and may be associated with a more severe clinical course; 26–41% of GBS patients show evidence of recent C. jejuni infection.⁸ Cytomegalovirus infection accounts for a further 10–22% of cases.⁹ Immunisations against viral infections, tuberculosis, tetanus and typhoid have all preceded the development of GBS. Most of these associations are anecdotal and of doubtful aetiological significance, but 65% of patients present within a few weeks of minor respiratory (43%) or gastrointestinal (21%) illness.

PATHOGENESIS⁶

The peripheral nerves of patients who have died of GBS show infiltration of the endoneurium by mononuclear cells in a predominantly perivenular distribution. The inflammatory process may be distributed throughout the length of the nerves, but with more marked focal changes in the nerve roots, spinal nerves and major plexuses. Electron micrographs show macrophages actively stripping myelin from the bodies of Schwann cells and axons. In some cases, wallerian degeneration of axons is also seen, and failure of regeneration in these cases may correspond with a poor clinical outcome.

The underlying immune response is complex and poorly understood, but serum from GBS patients produces myelin damage in vitro when complement is present.¹⁰ Although antibodies to various glycolipids have been demonstrated in GBS, these are generally in low titre and can occasionally be seen in controls. Patients with recent C. jejuni infection have a high incidence of antibodies to the ganglioside GM1.⁸ Antibodies to GD1a and GQ1b gangliosides are associated with the rarer acute motor axonal neuropathy (AMAN) and acute motor sensory axonal neuropathy (AMSAN) variants (see below).¹¹ The basis of the effectiveness of plasma exchange and immunoglobulin therapy is likely to be blocking of demyelinating antibodies by several mechanisms.¹²

CLINICAL PRESENTATION

The majority of patients describe a minor illness in the 8 weeks prior to presentation, with a peak incidence 2 weeks beforehand. Approximately half the patients initially experience paraesthesiae, typically beginning in the hands and feet. One-quarter complain of motor weakness, and the remainder have both.¹³ Motor weakness proceeds to flaccid paralysis, which becomes the predominant complaint. Objective loss of power and reduction or loss of tendon reflexes usually commence distally and ascend, but a more haphazard spread may occur. Cranial nerves are involved in 45% of cases, most commonly the facial nerve, followed by the glossopharyngeal and vagus nerves. One-third of patients require ventilatory support.

In the Miller–Fisher syndrome, a variant of GBS,¹⁴ cranial nerve abnormalities predominate, with ataxia, areflexia and ophthalmoplegia as the main features. This is strongly associated with recent C. jejuni infection and with the presence of GQ1b antibodies.

Another subgroup of patients presents with a primarily axonal neuropathy – AMSAN. In these cases motor and sensory axons appear to be the primary targets of immune attack, rather than myelin. These patients have a more fulminant and severe course, and there is again a strong association with C. jejuni infection.

Sensory loss is generally mild, with paraesthesiae or loss of vibration and proprioception, but occasionally sensory loss, pain or hyperaesthesia can be prominent features. Autonomic dysfunction is common, and a major contributor to morbidity and mortality in ventilator-dependent cases.¹⁵ Orthostatic or persistent hypotension, paroxysmal hypertension and bradycardia are all described, as are fatal ventricular tachyarrhythmias. Sinus tachycardia is seen in 30% of cases. Paralytic ileus, urinary retention and abnormalities of sweating are also commonly seen.

DIFFERENTIAL DIAGNOSIS

Most of the important alternative diagnoses are listed as exclusion criteria in Table 49.2. In patients with prolonged illness, the possibility of chronic inflammatory demyelinating polyradiculopathy (CIDP) should be considered.¹⁶ In this condition, which is usually distinguished from GBS, preceding viral infection is uncommon, the onset is more insidious and the course is one of slow worsening or stepwise relapses. Corticosteroids and plasma exchange are possibly effective in this disorder, but adequate studies of immunosuppressive drugs have not been carried out.

Table 49.2 Diagnostic criteria for typical Guillain–Barré syndrome³

An intermediate subacute polyradiculopathy (SIDP) as well as a recurrent form of GBS are also described, and all of these variants may be part of the spectrum of a single condition. However, a purely motor axonal neuropathy (AMAN), which causes seasonal childhood epidemics mimicking classical GBS in China and elsewhere,¹⁷ appears to be a distinct entity. Once again, this is strongly associated with C. jejuni infection.

INVESTIGATIONS

In over 90% of patients, CSF protein is increased (greater than 0.4 g/l), within a week of onset of symptoms. The level does not correlate with the clinical findings. A pleocytosis with lymphocytes and monocytes in the CSF may be seen in a small proportion of patients, especially later in the disease. Nerve conduction studies typically demonstrate reduced conduction velocity and prolonged distal latencies,¹⁸ but there is no consensus on precise electrophysiological criteria for the various subtypes.¹¹ Severely reduced distal motor amplitude and a predominantly axonal pattern are associated with more severe disease and a guarded prognosis.

MANAGEMENT

The management of the patient with severe and protracted GBS provides a major challenge, as the prognosis is generally excellent if complications can be treated early or avoided. These complications may be life-threatening, affect any of the major organ systems or result in permanent disability, and can be prevented only by meticulous attention to detail.

SPECIFIC THERAPY

Plasma exchange (plasmapheresis) is of value in GBS. Two large controlled trials showed a reduction in patients requiring mechanical ventilation, reduced duration of mechanical ventilation for those who required it, reduced time to motor recovery and time to walking without assistance.¹⁹ Mortality, however, was not altered. Plasma exchange was most effective when carried out within 7 days of onset of symptoms. The plasma exchange schedules consisted of three to five exchanges of 1–2 plasma volumes each, over 1–2 weeks. Adverse events are common, and some relate to the disease itself. Fresh frozen plasma is reported to have more side-effects than albumin as the replacement fluid.

Immunoglobulin therapy was as effective as plasmapheresis²⁰ and previous concerns of higher recurrence rates are probably unfounded. Because of its ease of use, many authorities now advocate immunoglobulin as the treatment of choice. A dose of 0.4 g/kg body weight intravenously, daily for 5 days, was used in the most recent trials.

About 10% of patients relapse after initial treatment with either plasmapheresis or immunoglobulin; most respond well to a further course.

A recent Cochrane review confirms that low- or high-dose corticosteroids are of no value,²¹ and may even slow recovery. The combination of high-dose steroids with immunoglobulin may hasten recovery, but does not affect the long-term outcome.

SUPPORTIVE CARE

PROGNOSIS

The nadir of the disease is reached within 2–4 weeks, and gradual resolution follows over weeks to months. Of those who survive the acute illness, 70% are fully recovered within 1 year, and a further 20% are left with only minor limitation. Poor prognostic features include age over 60 years, rapid progression to quadriparesis in less than 7 days, the need for mechanical ventilation (except for children), and a preceding diarrhoeal illness. Even in patients ventilated for more than 2 months, gradual improvement may continue for 18 months to 2 years.²⁴ These severely affected patients require a protracted period of rehabilitation.

Death in up to 25% of GBS patients has been reported in those requiring intensive care.²⁵ Many of these deaths were due to potentially avoidable problems such as respiratory arrest, ventilator malfunction and intercurrent sepsis, and considerably better results have been achieved. A more representative estimate of the overall mortality is 5–8%.²⁶

CRITICAL-ILLNESS POLYNEUROPATHY

This acute, diffuse, mainly motor neuropathy is probably the commonest of these disorders. It usually presents in the recovery phase of a severe systemic illness with persistent quadriparetic weakness, hyporeflexia and difficulty in weaning from respiratory support. There appears to be a specific association with severe sepsis and MODS. Histological and electrophysiological features are consistent with axonal degeneration. The mortality in this group is high, presumably reflecting that of the underlying condition. However, among those who survive the acute illness, the outlook for recovery of function appears quite good, with 70% recovering completely over an average of 4–5 months.²⁹

CRITICAL-ILLNESS MYOPATHY

This disorder is linked with asthma and with the use of corticosteroids, NMBA and, less convincingly, aminoglycosides and β-adrenergic agonists. Reflexes are preserved except in severe cases, as is sensation. Elevated blood creatine phosphokinase (CPK) concentrations are often seen. A few patients have a more severe, fulminant form with very high CPK levels, frank rhabdomyolysis and, rarely, renal failure. Electrophysiological findings are somewhat variable, though muscle necrosis is usually apparent on histology. Although steroidal muscle relaxants (pancuronium or vecuronium)³⁰ have been particularly implicated, the disorder has also been seen with other types of NMBA. On the basis of two small case series, the outlook for functional recovery appears good.³⁰

DIFFERENTIAL DIAGNOSIS

The influence of drugs, metabolic abnormalities and hyperthermia should always be excluded when unexplained neuromuscular weakness appears in an intensive care patient. The possibility of a coincident illness such as the Eaton–Lambert syndrome, MG, vasculitis or GBS must also be carefully considered. Severe catabolism and disuse atrophy are common in many of these patients and can themselves result in significant weakness.

INCIDENCE

The incidence of MG is approximately 1 in 20 000 in the USA. There is no racial or geographic predilection. Although MG can occur at any age, it is very rare in the first 2 years of life, and the peak incidence is in young adult females. Overall, females are affected about twice as often as males. This sexual predilection decreases with increasing age, and there is a smaller, second incidence peak in elderly males.³¹

AETIOLOGY AND PATHOPHYSIOLOGY

In 75% of cases, there is histological evidence of thymic abnormality. Thymic hyperplasia is present in the majority of patients, but approximately 10% have a thymoma. The latter appears more common in the older age group. The precise role of the thymus is uncertain, but ACh receptors are present in the myoid cells of the normal thymus, and there is evidence that anti-ACh receptor antibody production is mediated by both B and T lymphocytes of thymic origin. Other organ-specific autoimmune disorders, most commonly thyroid disease,³² but also rheumatoid arthritis, lupus erythematosus and pernicious anaemia, are significantly associated with MG, and autoantibodies to other organs may be seen in MG patients without evidence of disease.

Children born to mothers with MG demonstrate transient weakness (‘neonatal MG’) in about 15% of cases. A number of congenital myasthenic syndromes exist, in which symptoms develop in infancy, without evidence of autoantibody production.³³ A familial tendency is more common in this group, and structural changes at the neuromuscular junction have been demonstrated.

The stimulus to autoantibody production is not known, but these can be detected in about 90% of patients with generalised myasthenia. They may interfere with neuromuscular transmission by competitively blocking receptor sites, by initiating immune-mediated destruction of receptors, or by binding to portions of the receptor molecule which are not part of the ACh receptor site, but which, nevertheless, are important in allowing ACh to bind.

CLINICAL PRESENTATION

Ptosis and diplopia are the most common initial symptoms, and in 20% of cases, the disorder remains confined to the eye muscles (ocular MG).³⁴ Bulbar muscle weakness is common and may result in nasal regurgitation, dysarthria and dysphagia. Limb and trunk weakness can occur with varying distribution, and is usually asymmetrical. Some patients complain of fatigue rather than weakness, and may be misdiagnosed as having psychiatric problems. However, weakness can be elicited by sustained effort of an involved muscle group, e.g. sustained upward gaze is often worse at the end of the day and improves with rest.

INVESTIGATIONS

Impairment of neuromuscular transmission may be confirmed by a positive edrophonium (Tensilon) test. However, this traditional test is waning in popularity as it has high sensitivity but rather poor specificity.³⁵ Atropine 0.6 mg is given intravenously to prevent muscarinic side-effects, and this is followed by 1 mg edrophonium. If there is no obvious improvement within 1–2 minutes, a further 5 mg may be given. Some authors recommend the use of a saline placebo injection, and the presence of a second doctor as a ‘blinded’ observer. Resuscitation facilities should be available, as profound weakness may ensue, especially in patients already receiving anticholinesterase drugs. Intramuscular neostigmine, 1–2 mg, may produce a positive response in 5–10% of patients who do not respond to edrophonium.

The presence of autoantibodies against ACh receptors is quite specific, but false positives may occur in patients with penicillamine-treated rheumatoid disease, other autoimmune diseases and in some first-degree relatives of myasthenic patients.³⁶ About 20% of patients are seronegative.

Electromyography shows characteristic changes in 90% of patients with generalised MG, and also in many patients with ocular symptoms only.

A syndrome of myasthenic weakness occurs in association with malignancy and other autoimmune diseases (Eaton–Lambert syndrome). Although fatigability is present, the pelvic and thigh muscles are predominantly affected, whereas ocular and bulbar involvement is rare. Tendon reflexes are reduced or absent, and there are specific eletromyographic changes.

MANAGEMENT

MYASTHENIC AND CHOLINERGIC CRISIS

Patients with known MG may undergo life-threatening episodes of acute deterioration affecting bulbar and respiratory function. These may occur spontaneously, or may follow intercurrent infection, pregnancy, surgery, the administration of various drugs (Table 49.4)⁴⁶ or attempts to reduce the level of immunosuppression. Such episodes, known as myasthenic crises, usually resolve over several weeks, but occasionally last months. The incidence of myasthenic crisis increases markedly with age.

Table 49.4 Drugs which may exacerbate myasthenia gravis

Rarely, a patient may deteriorate due to excessive dosage of anticholinesterase drugs (‘cholinergic crisis’). Abdominal cramps, diarrhoea, excessive pulmonary secretions, sweating, salivation and bradycardia may be present, but these can also occur in patients with myasthenic crisis on high doses of pyridostigmine. Though the two situations may be difficult to distinguish, myasthenic crisis is far more likely unless extremely large doses of pyridostigmine, at least 120 mg every 3 hours, have been administered.

A Tensilon test is now considered an unreliable method of distinguishing between these two possibilities, may be hazardous, and is generally not recommended.

Patients with myasthenic crisis should be admitted directly to the ICU, as there is a significant risk of pulmonary aspiration due to bulbar involvement, bacterial pneumonia due to stasis, acute respiratory failure or cardiorespiratory arrest. After initial stabilisation and resuscitation, every effort should be made to identify and correct reversible causes, especially respiratory infections and electrolyte disturbances.

Frequent estimations of vital capacity and maximum inspiratory force should be made and recorded. Tracheal intubation and mechanical ventilation should be considered in patients with significant bulbar involvement or clinical evidence of worsening respiratory failure. As with other neuromuscular disorders, deterioration of blood gases may occur late, and is an unreliable sign of progressive respiratory failure. Aggressive chest physiotherapy, urinary drainage and nasogastric feeding may be required. Hypokalaemia, hypocalcaemia and hypermagnesaemia should be avoided, as all may exacerbate muscle weakness.

If the patient’s clinical status cannot be rapidly improved by the adjustment of anticholinesterase dosage and aggressive treatment of intercurrent illness, high-dose corticosteroids and plasma exchange should be commenced simultaneously, and may produce some benefit within as little as 24 hours.⁴⁷

PERIOPERATIVE MANAGEMENT

MG patients often require intensive care in relation to surgery for intercurrent illness or, more often, thymectomy. Unstable patients should be admitted to hospital some days in advance for stabilisation. In severely affected patients, preoperative high-dose corticosteroids and/or plasma exchange may be used to improve the patient’s fitness for surgery. It may be prudent to omit premedication, and an anaesthetic technique which avoids the use of non-depolarising muscle relaxants is usually advocated, though vecuronium and atracurium are probably acceptable in reduced dosage.^48,49 Suxamethonium can be used safely in normal dosage.⁵⁰

Up to one-third of patients require continuing mechanical ventilation postoperatively following thymectomy. Predictive factors include a long preoperative duration of myasthenia, coexistent chronic respiratory disease, high anticholinesterase requirements (e.g. pyridostigmine > 750 mg/day), and a preoperative vital capacity of less than 2.9 litres.⁵¹ In those cases requiring mechanical ventilation, some authors advocate temporary cessation of anticholinesterase drugs to reduce respiratory secretions but in all other cases they should be continued, though dosage requirements must be reassessed carefully and repeatedly.

PATHOGENESIS

The disease affects both upper and lower motor neurones. The involvement of either can predominate early on, giving rise to several clinically recognisable subgroups (see Table 49.5). The cerebral cortex as well as the anterior horns of the spinal cord are involved, with shrinkage, degenerative pigmentation and, eventually, disappearance of the affected cells accompanied by gliosis of the lateral columns (‘lateral sclerosis’). As muscles are denervated, there is progressive atrophy of muscle fibres (‘amyotrophy’), but, remarkably, sensory neurones as well as those concerned with autonomic function, coordination and higher cerebral function are all spared. The precise cause remains unknown. Postulated pathogenetic causes include oxygen free radicals, viral or prion infection, excess excitatory neurotransmitters and growth factors, and immunological abnormalities.⁵³ Heavy-metal exposure has also been implicated. The only established clinical risk factors are age and family history.

CLINICAL PRESENTATION

The earliest symptoms are those of insidiously developing limb weakness, often asymmetrical, accompanied by obvious muscle wasting. This classically affects the small muscles of the hand and may be accompanied by fasciculation. As time passes, the disease becomes more generalised and more symmetrical, with a mixture of upper and lower motor neurone signs (i.e. spasticity and hyperreflexia in addition to gross wasting), eventually involving bulbar and respiratory muscles. Awareness and intellect were previously thought to be preserved, but it is now recognised that up to half the patients have evidence of cognitive dysfunction.⁵⁴ Death occurs in 50% of cases within 3–5 years, usually due to respiratory infection, aspiration or ventilatory failure from profound weakness. However, there is wide variability, and a few patients may survive for many years.

DIAGNOSIS

There are no specific investigations, and the diagnosis must be made on clinical grounds together with electromyogram (EMG) evidence of denervation in at least three limbs. Experienced neurologists correctly diagnose the condition with 95% accuracy.⁵⁵ The most important differential diagnosis is multifocal motor neuropathy. The distinction is of clinical importance, as the latter is amenable to treatment. Poliomyelitis can also result in a syndrome of progressive weakness, wasting and fasciculation, beginning many years after the initial illness (the post-polio syndrome), and leading occasionally to respiratory failure and death.⁵⁶

MANAGEMENT

Treatment is essentially symptomatic and supportive. No benefit has been shown with antioxidants, growth factors and immunosuppressants.⁵³ However, the centrally acting glutamate antagonist riluzole has been shown to slow slightly the progression of ALS.⁵⁷ Admission to ICU is sometimes requested when these patients present with an acute deterioration or intercurrent illness. The intensivist may be asked to assist with ambulatory or home respiratory support for gradually worsening chronic respiratory failure. Such cases present major ethical as well as clinical problems, but the provision of assisted ventilation can result in an improved quality of life, and possibly prolonged survival for carefully selected individuals.⁵⁸ Respiratory support may be given by facemask, nasal mask or, rarely, by tracheostomy using simple, compact ventilators. Some patients require only intermittent support, particularly at night or during periods of acute deterioration due to intercurrent illness. Long-term respiratory support outside the ICU is a major undertaking, requiring specific equipment and extensive liaison with the patient, the family and numerous specialised support services.

PERIODIC PARALYSIS⁵⁹

This term describes a group of rare primary disorders, mostly inherited as autosomal-dominant traits, producing episodic weakness. They must be distinguished from other causes of intermittent weakness, including electrolyte abnormalities, MG and transient ischaemic attacks. In the inherited disorders, the underlying abnormality is a defect of skeletal muscle ion channels. Symptoms begin early in life (before age 25), and follow rest or sleep rather than exertion. Alertness during attacks is completely preserved, and muscle strength between attacks is normal. Treatment is usually successful in preventing both the attacks and the chronic weakness, which can develop after many years in untreated patients.

The hypokalaemic form of periodic paralysis is predominantly inherited, but can also arise sporadically in association with thyrotoxicosis. Involvement of bulbar or respiratory muscles occurs rarely, as can cardiac arrhythmias. The degree of hypokalaemia during attacks is mild, but patients rapidly respond to potassium administration. Effective prophylaxis is conferred by acetazolamide, but not by oral potassium.

The hyperkalaemic form is milder, almost always inherited and virtually never requires intensive care. During attacks the serum potassium may be modestly elevated or normal. Patients respond to carbohydrate administration, and thiazide diuretics or acetazolamide provide effective prophylaxis.

BOTULISM⁶⁰

Botulism is a widespread but very uncommon potentially lethal disease caused by exotoxins produced by Clostridium botulinum – an anaerobic, spore-forming Gram-positive bacillus. The vast majority of botulism is food-borne and outbreaks are largely due to home-preserved vegetables (type A toxin), meat (type B) or fish (type E), but high-risk foods also include low-acid fruit and condiments. Signs and symptoms are caused by toxin produced in vitro and then ingested.

Wound botulism arises rarely, when wounds (typically open fractures) are contaminated by soil containing type A or B organisms. Intravenous drug abusers are an increasing source of this condition through infected injection sites.

Infantile botulism arises in infants under 6 months of age, and is due to the active production of toxin by organisms in the gut rather than the direct ingestion of toxin.

Hidden botulism describes the adult equivalent of infantile botulism, and is a rare complication of various gastrointestinal abnormalities.

Inadvertent botulism is the most recently described form, and occurs as a complication of the medical or cosmetic use of botulinum toxin.

Inhalational botulism is the form that would occur as a result of aerosolised toxin released in the context of bioterrorism.

In most cases, exogenously produced exotoxin is absorbed (primarily in the upper small intestine), and carried by the blood stream to cholinergic nerves at the neuromuscular junction, postganglionic parasympathetic nerve endings and autonomic ganglia, to which it irreversibly binds. The toxin enters the nerve endings to interfere with ACh release.

Most patients become ill about 3 days after ingestion of toxin, with gastrointestinal symptoms (nausea, vomiting, abdominal pain, diarrhoea or constipation), dryness of the eyes and mouth, dysphagia and generalised weakness, which progresses in a symmetrical, descending fashion, with ventilatory failure in severe cases. Cranial nerve dysfunction is manifested by ptosis and diplopia, facial weakness and impaired upper-airway reflexes.

The differential diagnosis includes food poisoning from other causes, MG and GBS. Botulism can be confirmed by the presence of toxin (either in the patient’s serum or stool, or in contaminated food) in about two-thirds of cases.

Treatment is mainly supportive, with airway protection and mechanical ventilation when required. Clearance of toxin from the bowel with enemas and cathartics has been advocated. Guanidine hydrochloride, which enhances the release of ACh from nerve terminals, has been reported to improve muscle strength, especially in ocular muscles, and may be useful in milder cases. Antibiotics have not been clearly shown to be useful. Equine antitoxins are available, but side-effects are common and their efficacy is limited. A human-derived antitoxin has been shown to be effective in infantile botulism,⁶¹ and the US Defense Department has a pentavalent antitioxin, which is not available for public use. In wound botulism, antibiotics (penicillin or metronidazole) and aggressive debridement are recommended.

Most patients begin to improve after a week or so, but hospitalisation is usually required for 1–3 months. The mortality is low (5–8%) with good supportive care, including mechanical ventilation. Mild weakness and constipation may persist for many months.