5 Toxic and environmental disorders

A huge range of toxins can affect the nervous system, most of which are rarely encountered clinically (Spencer and Schaumburg 2000). This chapter addresses those toxins, medical interventions, and environmental insults with common or noteworthy effects on the nervous system. The peripheral nervous system is particularly vulnerable to toxic effects of drugs, metals, and industrial and agricultural poisons; these manifestations are covered in Chapter 21. Overdosage with an enormous range of drugs and chemicals causes acute poisoning syndromes which affect multiple organ systems, including the nervous system. Such systemic poisonings are not covered below and the reader is referred to comprehensive toxicology reference texts (Dart 2004).

Acute alcohol intoxication adversely affects judgement, restraint, and co-ordination. In high dosage it starts to have general anaesthetic effects, but at lower dosage affects neurotransmitter systems including GABA-mediated inhibition, increasing opioid effects, and inhibiting glutamate neurotransmission. The behavioural effects contribute to the neurological injury caused by motor vehicle accidents and violent behaviour. Alcohol intoxication predisposes to the acquisition of sexually transmitted infections. In this regard the nervous system may be affected by HIV, herpes simplex virus type II, or syphilis. Pre-existing cerebral conditions such as subdural haematoma or infection dispose the sufferer to apparent intoxication after ingestion of lesser amounts of alcohol than usual. This phenomenon is known as ‘pathological drunkenness’.

Habitual heavy drinkers may become physically dependent upon ethanol: alcoholism. There is an inherited predisposition to alcoholism. This leads to a variety of neurological disorders described below. These result from the direct toxic effects of alcohol and its metabolites, or from secondary malnutrition, particularly of thiamine. Many alcoholic patients exhibit combinations of various alcohol-related neurological disorders. Prenatal exposure in alcoholic mothers can lead to a foetal alcohol syndrome with subsequent cognitive and behavioural impairments, and developmental abnormalities of brain structure, most notably microcephaly and dysgenesis of the corpus callosum (Sowell et al. 2001).

Withdrawal symptoms develop in established alcoholics who are starved of alcohol for more than a few hours. Withdrawal symptoms are particularly likely in those deprived of their usual access to alcohol by prostration due to acute infection, accidents, or surgical operations. The ‘shakes’, a generalized coarse tremor of the face, tongue, and hands, appears earliest and may be the only symptom in mild cases. Frank delirium tremens develops in more serious cases. These patients experience nausea and vomiting, terrifying visual hallucinations often of animals, acute confusion, agitation, tachycardia, sweating, and hyperpyrexia. Generalized tonic-clonic convulsions may occur. These symptoms are maximal about 36 h after alcohol withdrawal. The mortality of delirium tremens is considerable, and is particularly attributable to uncontrolled convulsions and to cardiac arrhythmias caused by autonomic nervous system dysfunction. On recognizing such symptoms, alcoholics usually resume drinking to suppress them. Medical treatment of delirium tremens consists of the administration of sedative drugs, such as 50 mg of Chlordiazepoxide orally every 6 h for 3 days, and benzodiazepines or chlormethiazole to control agitation and reduce the incidence of seizures (Thompson et al. 1975; Saitz and O’Malley 1997), beta-blockers, such as Atenolol to control autonomic manifestations (Kraus et al. 1985), and thiamine parenterally. Neuroleptic drugs are useful adjunctive therapy for troublesome hallucinations and agitation, but may provoke seizures. In addition, any associated infection, dehydration, or hypoglycaemia should be treated. Although delirium tremens is a self-limited disorder, which resolves spontaneously, the majority of patients resume their habit and are vulnerable to further attacks.

Alcoholics usually develop seizures either as a result of cerebral trauma or due to ethanol withdrawal. Occasionally acute alcohol intoxication provokes seizures within a few hours (Brennan and Lyttle 1987). Seizures due to cerebral trauma sustained during alcoholic binges constitute a diagnosis of epilepsy and should be treated with long-term anticonvulsant therapy. Alcohol withdrawal seizures are generally accompanied by other features of delirium tremens and should be investigated only if the seizures are focal, more than six in number, occur over a period exceeding 6 h, or are associated with protracted postictal confusion, evidence of cranial trauma, or focal neurological signs (Charness et al. 1989). Anticonvulsant drug therapy is not usually recommended for alcohol withdrawal seizures, either over the short- or the long-term (Simon 1988). Other associated features of alcohol withdrawal should be treated as outlined above. Benzodiazapine or chlormathiazole infusions are usually effective for recurrent withdrawal seizures or status epilepticus.

The role of prior alcohol consumption has been studied in an unselected population of patients presenting with their first ever seizure. Alcohol usage is a strong risk factor for a first seizure’s occurrence (Leone et al. 1997). Seizures are most frequent within 48 h of last drinking alcohol. However only half of all seizures occur within the conventional period for alcohol withdrawal symptoms, 6–48 h after the cessation of drinking (Ng et al. 1988). Chronic alcoholism alone is not a risk factor for a first symptomatic epileptic seizure (Leone et al. 2002).

Wernicke’s encephalopathy is a reversible cerebral disorder due to thiamine deficiency. In most patients with Wernicke’s encephalopathy, there is an underlying permanent disorder of memory known as Korsakoff’s psychosis. Because of the usual concurrence of these two disorders, they are often referred to jointly as the Wernicke–Korsakoff syndrome (Victor et al. 1989).

Wernicke’s encephalopathy is a reversible complication of thiamine deficiency in alcoholics, particularly those who are malnourished. Other causes of thiamine deficiency, such as starvation or gastro-intestinal disease, and protracted hyperemesis gravidarum, may also lead to Wernicke’s encephalopathy (Reuler et al. 1985). Neurological symptoms develop over hours or days and may be precipitated by a high carbohydrate intake. The typical clinical triad consists of encephalopathy, ataxia, and ophthalmoplegia. The encephalopathy produces somnolence and disorientation and eventually progresses to coma. Ataxia results from the combination of polyneuropathy and cerebellar dysfunction. Abnormal eye movements are crucial to the diagnosis of Wernicke’s encephalopathy in life. There may be bilateral lateral rectus palsies, nystagmus, or complex ophthalmoplegias and occasionally the pupils become small and unreactive. Patients may be hypothermic or hypotensive. Atypical presentations are common and post-mortem studies suggest that only 20 per cent of those reaching autopsy had been diagnosed in life (Harper et al. 1987). On suspicion of the diagnosis thiamine should be given intravenously and continued regularly thereafter: without treatment mortality approaches 20 per cent. The optimal thiamine dosage has not been established (Day et al. 2006); an initial dose of 100 mg is often used. The response to thiamine replacement is dramatically quick. Within 1–6 h, the ocular palsies begin to resolve and conscious level improves.

Underlying Korsakoff’s psychosis of variable severity is evident in most patients following thiamine treatment of their associated Wernicke’s encephalopathy. Patients exhibit retrograde amnesia, in which they are unable to recall previous information, and anterograde amnesia, in which they cannot register novel information. Confabulation may be present also. Useful recovery from Korsakoff’s psychosis occurs in less than a quarter despite adequate treatment of their associated Wernicke’s disease with thiamine. Mammillary body atrophy and neuronal loss from the dorsal medial thalamus, periaqueductal grey matter of the midbrain, vagal nuclei and cerebellar vermis are characteristic neuropathological features of Wernicke–Korsakoff disease (Victor et al. 1989). Mammillary body atrophy is particularly characteristic and may be demonstrated in life by MRI (Charness and DeLaPaz 1987).

Red cell transketolase enzyme activity is reduced in thiamine deficiency, or there can be an increased thiamine co-enzyme requirement in alcoholics (Heap et al. 2002). The slow availability of results of this enzyme assay precludes its use in diagnosing Wernicke–Korsakoff syndrome; treatment with thiamine should be started immediately once the disorder is suspected on clinical grounds. Some patients with Wernicke–Korsakoff disease have an inherited anomaly of the transketolase enzyme, affecting the binding of thiamine pyrophosphate (Blass and Gibson 1977).

Long-standing alcoholics may develop gait ataxia due to degeneration of cerebellar cortex Purkinje cells (Section 39.11.2). Although generally of gradual onset, alcoholic cerebellar ataxia may evolve relatively acutely, sometimes in the context of Wernicke’s encephalopathy. Early on demonstrable ataxia may be limited to the gait alone, but severely affected patients show ataxia if the legs or arms are tested individually. Dysarthria or nystagmus are unusual (Victor et al. 1959). In many patients, an alcoholic or thiamine deficiency peripheral neuropathy contributes to the ataxia. The incidence of cerebellar ataxia does not correlate with the extent of lifetime alcohol consumption (Estrin 1987) or with the occurrence of cerebellar atrophy on computed tomography of the brain (Hillbom et al. 1986). Quantitative histological studies show Purkinje cell loss from the cerebellum in alcoholics, which is particularly severe in those with additional Wernicke–Korsakoff syndrome (Phillips et al. 1987). These observations make it likely that cerebellar degeneration does not only result from the direct toxic effects of alcohol or its metabolites, but may also reflect some other factor, such as thiamine deficiency. Thiamine replacement and prolonged abstinence from alcohol should be recommended in all patients. Prolonged abstinence decreases the amplitude of body sway associated with alcoholic ataxia suggesting some capacity for the ataxia to improve (Diener et al. 1984).

Cognitive impairment is common in alcoholics. It usually reflects varying combinations of acute intoxication, Wernicke–Korsakoff syndrome, mild delirium tremens, depressive pseudo-dementia, pre-morbid cognitive impairments, previous cerebral trauma, and the diffuse alcoholic brain damage otherwise known as alcoholic dementia. Less frequently the cognitive impairment is due to subdural haematoma, metabolic encephalopathy, nicotinic acid deficiency, or Marchiafava–Bignami disease.

Whether diffuse alcoholic brain damage is an important and frequent cause of dementia in alcoholics (Lishman 1981) is questioned on the grounds that autopsy studies usually show evidence of inactive and chronic Wernicke–Korsakoff Disease (Victor 1994). Moderate regular alcohol consumption, particularly of wine, seems protective against subsequent onset of dementia (Ruitenberg et al. 2002; Truelsen et al. 2002). Generally it is assumed that alcoholic dementia involves generalized cognitive abnormalities, which distinguishes it from the selective amnesia of the Wernicke–Korsakoff syndrome. Neuropsychological studies show that alcoholic dementia predominantly affects problem solving abilities whereas it is memory which is selectively impaired in the Wernicke–Korsakoff syndrome (Carlen et al. 1981). Alcoholic patients with dementia display cortical shrinkage and ventricular dilatation on computed tomography of the brain (Carlen et al. 1981; Ron et al. 1982). Quantitative neuropathological studies show reduced numbers of neurons within the superior frontal cortex in such patients, despite preserved neuronal populations in the motor cortex (Harper et al. 1987). The cerebral volume loss, metabolic, and neuropsychological abnormalities of chronic alcoholism are partly reversible even during the early stages of abstinence, providing motivational feedback for some trying to cease their habit (Bartsch et al. 2007).

Alcoholics are particularly prone to central pontine myelinolysis, particularly if they are chronically hyponatraemic (Slager 1986). It can also occur in alcoholics with a normal serum sodium (McKee et al. 1988). The clinical picture typically develops an average of 6 days after correction of chronic hyponatraemia with intravenous fluids at rates exceeding 12 mmol/l of sodium per day. Accordingly, if intravenous therapy is deemed necessary, it is recommended that the serum sodium concentration should be increased by less than 8 mmol/l per day (Sterns et al. 1986).

Central pontine myelinolysis primarily affects the corticospinal tracts in the central brainstem (Section 37.6). It produces a symmetrical paraparesis or quadriparesis with extensor plantar responses. In some patients the bulbar and facial musculature is also paralysed. Gaze palsies occasionally occur. The full-blown state produces a locked-in syndrome in which the patient is incapable of any voluntary movements except vertical eye movements, yet consciousness is preserved. Many patients die, and the remainder suffer from substantial chronic disability. Worthwhile recovery from severe forms is rare, but does occur from milder forms of pontine myelinolysis. Autopsy studies show a characteristic large area of demyelination within the central pons; axons are spared (Wright et al. 1979). Computed tomography is relatively insensitive in detecting the large area of pontine demyelination, but magnetic resonance scanning demonstrates such lesions (Miller et al. 1988). MRI brainstem changes compatible with pontine myelinolysis are discovered in about 2 per cent of alcoholics, frequently without symptoms or signs (Uchino et al. 2003).

In this distinctive disorder, usually associated with underlying cirrhosis, demyelinating lesions develop in the corpus callosum. The disorder was originally noted in malnourished Italian red wine drinkers but is now known to occur also in other groups of alcoholics. Histologically, these lesions are similar to those in the brainstem in central pontine myelinolysis. Patients develop gait apraxia, dementia, spasticity, and dysarthria. Prior to introduction of MR scanning it was thought that most patients died, or survived for many years with severe dementia; recovery was rare. The demyelinating lesion in the corpus callosum and adjacent cerebral white matter is demonstrable by MRI. When based on MR diagnosis in vivo, Marchiafava–Bignami disease seems to vary between major and slight initial impairment of consciousness, with a corresponding severity of outcome, depending upon whether the corpus callosum is entirely, or only partially affected (Heinrich et al. 2004) and the nature of the signal change (Menegon et al. 2005).

Some have noted heavy alcohol intake to be a risk factor for ischaemic stroke, particularly in young males during or immediately following a bout of acute intoxication (Gill et al. 1986). Moderate chronic alcohol consumption is protective against the risk of ischaemic stroke in both men and women, irrespective of racial background (Reynolds et al. 2003; Elkind et al. 2006). By contrast, the risk of haemorrhagic stroke rises with alcohol consumption (Reynolds et al. 2003).

The peripheral neuropathies due to alcohol or disulfiram (Antabuse) are discussed in Section 21.19 and that due to thiamine deficiency associated with alcoholism, dry beriberi, in Section 21.22.2.

Alcoholic myopathy may develop chronically or acutely (Section 24.9.1). Episodes of acute deterioration frequently punctuate an insidious background myopathy. Chronic alcoholic myopathy is a relatively painless affliction predominately affecting proximal muscles. In many alcoholics mild myopathy is an incidental asymptomatic finding on examination. Established myopathy occurs in those chronic alcoholics with a cumulative lifetime consumption exceeding 13 kg ethanol per kg body weight. A standard measure of spirits, wine, or a half-pint of beer contains approximately 10 g of alcohol. Malnutrition or electrolyte imbalance are not thought to be important contributing factors (Urbano-Marquez et al. 1989). An associated cardiomyopathy is common. The serum creatine kinase levels are elevated in one-third of the patients. Muscle biopsies show varying degrees of necrosis and atrophy, particularly affecting type II fibres. Electromyography shows non-specific myopathic features; fibrillations occur in the more acute myopathies. Episodes of acute alcoholic muscle weakness due to rhabdomyolysis often follow bouts of massive alcohol ingestion and are associated with dark urine containing myoglobin. Abstinence leads to some improvement. Downhill progression occurs in persistent drinkers (Martin et al. 1985).

Consumption of doses of methylated spirits containing more than 30 g of methanol is often fatal. It can be an unnoticed substitute contaminating alcoholic drinks. Methanol causes a toxic confusional state. Misty vision, central scotomata, or blindness are associated with optic disc oedema and optic atrophy eventually develops (Sharpe et al. 1982). A Parkinsonian syndrome unresponsive to L-Dopa has been described and involves bilateral infarction of the frontal white matter and putamen (McLean et al. 1980). CT or MRI may show putaminal abnormalities. These permanent neurological complications, and death when it occurs, are thought to be due to the accumulation of formic acid. This metabolite of methanol forms within 12 h of ingestion and causes metabolic acidosis. Fomepizole intravenously, 15mg/kg loading dose followed by 10 mg/kg every 12 h according to whether the blood methanol level remains higher than 0.2 g/l should be administered to patients suspected of methanol poisoning (Mycyk and Leikin 2003). This drug inhibits hepatic alcohol dehydrogenase, thereby reducing formation of toxic metabolites, and is also effective for ethylene glycol poisoning, which can be difficult to differentiate from methanol poisoning. Early treatment with haemodialysis is indicated for mental or visual changes, metabolic acidosis, if the blood methanol level exceeds 0.5 g/l, or following ingestion of more than 30 g of methanol (Lancet 1983).

This section addresses the neurological consequences of recreational drug abuse. It does not cover the associated social, epidemiological, or psychiatric aspects. It should be noted that multiple drug abuse is common and may include alcohol; that underlying nutritional deficiency is common; that violent injuries are common in the drugs underworld; that pressure palsies of peripheral nerves may result from periods of stuporous immobility; and that intravenous drug abusers are prone to blood-borne infection, particularly with HIV.

Drug abuse should be considered in young adults developing the following neurological syndromes (Neiman et al. 2000):

Stroke. Both haemorrhagic and ischaemic stroke may occur within an hour of drug administration. Cardiovascular effects, embolization from intravascular infection or drug impurities, and rupture of aneurisms or arteriovenous malformations are the likely pathophysiological mechanisms. Most commonly implicated are cocaine, heroin, amphetamines, phenylcyclidine, and LSD.

Headache. Acute severe headache resembling migraine can follow administration of, or withdrawal from cocaine.

Seizures. These generally reflect acute intoxication, usually follow cocaine or amphetamine abuse and can present with status epilepticus. Withdrawal seizures occur from alcohol, barbiturates, or benzodiazepines.

Movement disorders. Various syndromes have been described including choreoathetosis, tremor, and akathisia with cocaine, so-called ‘crack dancing’, cocaine withdrawal dystonia, a constant choreiform ‘jerking sydrome’ with amphetamines, and compulsive repetitive behaviours during amphetamine psychosis, known as the ‘punding syndrome’.

Encephalopathy. Chronic abuse of cocaine, amphetamine derivatives, or organic solvents can cause diffuse cerebral damage with cognitive deterioration and mild psychiatric symptoms (Ernst et al. 2000). A progressive spongiform leukoencephalopathy can follow inhalation of heroin vapour, probably with impurities.

Cocaine is a currently fashionable central nervous system stimulant with vasoconstrictor effects used to induce pleasurable euphoria and hypersexuality. It is usually absorbed through the mucous membranes by sniffing or ‘snorting’, or by chewing. Highly purified free-base cocaine, ‘crack’, may be inhaled. Cocaine is occasionally used intravenously, usually in polydrug abusers. Overdosage sometimes follows rupture of cocaine-loaded condoms within body cavities in smugglers. The common neurological consequences of cocaine are seizures and strokes. Cerebrospinal fluid rhinorrhoea has followed protracted cocaine sniffing and poses the risk of meningitis (Sawicka and Trosser 1983). Cocaine may induce choreo-athetoid movements, so-called ‘crack dancing’ (Daras et al. 1994).

Seizures may follow acute intoxication with cocaine, generally occurring within 90 min of abuse (Pascual-Leone et al. 1990). Most such seizures are generalized but focal attacks do occur. The seizures are generally single and are particularly likely following the use of ‘crack’. Persistent neurological features and encephalographic or computed tomographic abnormalities are not subsequently evident. Cocaine provoked seizures are the reason for seeking medical attention in approximately 10 per cent of those with cocaine-induced medical problems. There is an increased frequency of seizures in pre-existing epileptics who abuse cocaine.

Cocaine abuse is a major risk factor for cerebrovascular disease in young adults. It is a potent vasoconstrictor and ischaemic and haemorrhagic strokes occur. Strokes may develop within minutes of ‘crack’ abuse and are frequently associated with headache. Intracerebral and subarachnoid haemorrhages may derive from pre-existing aneurysms or arteriovenous malformations and be provoked by hypertension during acute cocaine intoxication (Nolte et al. 1996). Cocaine-induced cerebral infarction may affect any arterial territory of the brain (Levine et al. 1990). Stroke syndromes affecting the thalamomesencephalic regions are noteworthy since they are otherwise uncommon (Rowley et al. 1989). The pathogenesis of cocaine-related cerebral infarction is uncertain but probably relates to its powerful vasoconstrictive properties. Although cerebral angiography may reveal narrowed segments and beading of arteries, it is probable that this reflects focal vasospasm rather than a true vasculitis (Aggarwal et al. 1996). Habitual cocaine abusers develop computed tomographic evidence of diffuse cerebral atrophy but it is not known whether there is associated dementia (Pascual-Leone et al. 1991).

Acute overdosage with heroin and other opiates may cause coma associated with pinpoint pupils. Acute ischaemic stroke has been noted either immediately, or within hours of injecting heroin (Caplan et al. 1982a). Heroin ‘mainlining’ may also cause bacterial endocarditis with the attendant risks of haemorrhage due to mycotic cerebral aneurysm and of blood-borne cerebral abscess. Seizures and choreiform movements have been noted soon after heroin administration but resolve spontaneously. Inhalation of poisoned heroin vapours, pyrolysate, has led to a spongiform leucoencephalopathy which initially causes apathy, bradyphrenia, motor restlessness, cerebellar ataxia, and pseudo-bulbar dysarthria; death may follow (Wolters et al. 1982). Aspergillosis of the cerebral ventricles (Morrow et al. 1983) and cerebral mucormycosis (Masucci et al. 1982) have occurred in heroin abusers. Lumbosacral and brachial plexus neuropathies have occurred in those injecting adulterant heroin mixtures. These plexus lesions are thought to represent hypersensitivity reactions and may respond to high-dose steroid therapy (Herdmann et al. 1988).

These central nervous system stimulants are generally consumed orally but can be inhaled or injected. Hypertension and tachycardia follow administration. Amphetamine psychosis with prominent paranoia usually occurs in chronic abusers. Acute neurological side-effects most commonly follow injection. Intracranial haemorrhage is signalled by sudden onset of headache within minutes of amphetamine administration. Both subarachnoid and intracerebral haemorrhage are well-recognized complications. Seizures, ischaemic strokes due to vasospasm, and intracranial infection all occur in intravenous amphetamine abusers (Caplan et al. 1982b). Methylphenidate, an amphetamine analogue, has been associated with exacerbation or the onset of Gilles de la Tourette syndrome (Golden 1977).

Ecstasy, MDMA or 3,4-Methylenedioxymethamphetamine, is an orally consumed amphetamine derivative popularly used at ‘rave’ dance parties to induce euphoria and a sense of familiarity. Sweating, tachycardia, and jaw grinding may accompany its use and hypertensive crises, paranoid psychosis, convulsions, stroke, systemic organ failure, and sudden death may occur (Henry 1992).

Carbon monoxide intoxication is a leading cause of death or brain damage due to poisoning. Accidental or suicidal exposure to vehicle exhaust fumes or coal gas leaks, fires, or paint removers may all be responsible. Carbon monoxide replaces the oxygen in haemoglobin with the formation of carboxyhaemoglobin, thus causing hypoxic brain damage. In fatal cases of carbon monoxide poisoning, there is multifocal neuronal loss particularly affecting the cerebral cortex, basal ganglia, and limbic system resembling that in anoxic encephalopathy. Prolonged or permanent neurological sequelae are usually seen only in patients rendered unconscious by the initial exposure. Such patients should be treated immediately with 100 per cent oxygen, and if promptly available, hyperbaric oxygen therapy. Hyperbaric oxygen therapy helps eliminate carboxyhaemoglobin and enhances the oxygen dissolved in plasma, but its practical role in treating carbon monoxide poisoning is uncertain. It should be considered when the carboxyhaemoglobin level exceeds 40 per cent in patients with significant neurological abnormalities within a few hours of the exposure (Dart 2004). Those patients who regain consciousness go through variable periods of restlessness, confusion, disorientation, and amnesia. Multifocal neurological abnormalities may appear and fluctuate considerably: agnosias, dyspraxias, dysphasias, dysgraphias, akinesias, rigidity, a Parkinsonian syndrome, deafness, epilepsy, incontinence, and involuntary movements (Garland and Pearce 1967; Lacey 1981; Klawans et al. 1982). Low-density lesions may be evident on brain computed tomography as early as 24 h after exposure, usually bilaterally in the globus pallidus. The presence of such lesions signals a poorer prognosis (Sawada et al. 1980). Some neurological recovery occurs in most patients. However, permanent neurological sequelae are common, particularly residual disturbances of gait and memory. An encephalopathy starting some weeks after the initial carbon monoxide exposure has been noted occasionally. This is due to delayed onset of demyelination in the cerebral hemispheres (Plum et al. 1962; Sawa et al. 1981).

Diffuse cerebral injury occurs in a variety of anoxic circumstances including temporary cardiorespiratory arrest, anaesthetic accidents, cardiopulmonary bypass operations, near-miss drownings, and attempted strangulation or suffocation. The clinical manifestations closely resemble those of carbon monoxide poisoning (Section 5.4.1). Cessation of oxygenated blood flow to the brain for more than 3–5 min is likely to cause long-term cerebral injury. Diffuse cerebral anoxic injury is unlikely if the patient has not been rendered unconscious by the initial insult. During the first 24 h following anoxia, a poor prognosis for independent daily functioning is signalled by absent pupillary light reflexes, disconjugate and disoriented eye movements, absent or extensor motor responses, and lack of response to commands (Levy et al. 1985). Gradual recovery occurs over weeks or months but is of variable extent. Severe anoxic-ischaemic insults may result in a permanent vegetative state in which there is no evidence of cognitive awareness despite recovery of brainstem responses (Dougherty et al. 1981). Focal cerebral lesions may occur in patients with pre-existing cerebral vascular disease. Persistent amnesia, Parkinsonism, movement disorders, or action myoclonus can all follow anoxic brain injury. Up to a fifth of children satisfactorily resuscitated from near-miss drownings have minor visuomotor impairments or subtle disparities between verbal and performance intelligence quotients; but hard neurological signs are rare (Pearn 1977). Post-mortem studies of hypoxic-ischaemic brain damage show relatively symmetric multifocal lesions affecting either the cerebral cortex or the cerebral white matter, and may involve the caudate nucleus or cerebellum (Dougherty et al. 1981).

Occasionally a secondary neurological deterioration occurs days or a few weeks after the initial cerebral anoxic-ischaemic insult. After a good initial recovery, such patients abruptly become irritable, apathetic, and confused and exhibit a shuffling gait with muscular rigidity (Plum et al. 1962). Autopsy studies show demyelination within the cerebral hemispheres.

Chronic repeated recreational inhalation of nitrous oxide can lead to sensorimotor polyneuropathy and a myelopathy, with abnormalities of visual evoked responses and sensory nerve action potentials. Improvement occurs with abstinence (Heyer et al. 1986). The neurological abnormalities resemble those seen in vitamin B₁₂ deficiency and it is of interest that normally non-toxic doses of nitrous oxide can produce neurological deterioration in patients with pre-existing vitamin B₁₂ deficiency (Holloway and Alberico 1990).

Ethylene oxide is used as an industrial chemical precursor and for sterilizing heat sensitive medical equipment. An encephalopathy manifesting with fatiguability, poor concentration, and impaired co-ordination, or a polyneuropathy, may result from prolonged exposure (Gross et al. 1979).

Paints and glues containing Toluene have been popular with solvent abusers because of their euphoric effects. Two-thirds of a group of chronic abusers showed cognitive, pyramidal tract, cerebellar, brainstem, or cranial nerve abnormalities (Hormes et al. 1986). Accidental massive exposure to Toluene di-isocyanate leads to immediate euphoria, ataxia, and impaired consciousness, with persistent memory, mood, and personality changes (Le Quesne et al. 1976).

This section addresses noteworthy or permanent neurological side effects of some drugs, and radiographic contrast agents. Many drugs produce mild temporary side effects such as giddiness, headache, or concentration difficulties; these are not covered in this section. Tardive dyskinesia (Section 40.9.2) and acute dystonic reactions (Section 40.4.13) due to neuroleptic drugs, and drug induced peripheral neuropathy (Section 21.19) are covered elsewhere.

Stroke is the commonest serious neurological consequence of oral contraceptive use. A three-fold increased incidence of ischaemic stroke is noted in women using oral contraceptives containing oestrogen (WHO 1996a), with a higher risk for pills containing ≥ 50 μg oestrogen. Hypertension, regular cigarette smoking and age over 35 years are important compounding risk factors for stroke in women using the pill. Haemorrhagic stroke is significantly increased in those pill-taking women aged over 35, with a history of hypertension and who smoke (WHO 1996b). Migraine is also a risk factor for ischaemic, but not haemorrhagic, stroke and this risk is increased in oral contraceptive users, particularly with oestrogen dosages of ≥ 50 μg or higher, and in those who also smoke or have high blood pressure (Chang et al. 1999). Cerebral venous sinus thrombosis is also attributable to oral contraceptive use (Atkinson et al. 1970).

Chorea may occur in patients taking oral contraceptives (Section 40.5.9). Carpal tunnel syndrome has been reported after oral contraceptive use (Sabour and Fadel 1970).

This life-threatening drug reaction produces fever accompanied by autonomic and extra-pyramidal abnormalities (Section 40.9.1). It is generally under-recognized and can produce permanent neurological abnormalities which may reflect a form of heat-stroke. It usually occurs in patients receiving neuroleptic drugs, acutely or chronically, either for psychiatric disorders, or as anti-emetics, or as premedication (Buckley and Hutchinson 1995). It has also been noted following cessation of dopaminergic therapy for Parkinson’s disease. Neuroleptic malignant syndrome usually develops subacutely over 1–3 days, even in those patients who have been taking neuroleptic drugs for a long time. A review of the clinical manifestations of a large number of cases shows that muscular rigidity and hyperthermia, sometimes greater than 41°C, are almost always present (Rosenberg and Green 1989). Other common features include mutism, tachycardia, tachypnoea, sweating, and hypertension. Tremor, mask-like facies, hyporeflexia, and obtundation are less common manifestations. The serum creatine phosphokinase level is elevated in three-quarters, often to extreme levels. Pneumonia and respiratory failure are the commonest life-threatening medical complications of the condition. Prompt recognition of the disorder and initiation of specific therapy greatly diminishes the chance of death, which occurs in up to 30 per cent of untreated patients. The offending causative drug should be stopped, and the patient rehydrated and treated with anti-pyuretics. Bromocriptine 5 mg orally or nasogastrically 4 times daily or Dantroline 2–3 mg per kg per day intravenously significantly reduces the recovery time (Rosenberg and Green 1989). Cerebellar degeneration has been described in a patient with a particularly hyperpyrexic form of neuroleptic malignant syndrome and it is proposed that such permanent neurological features may reflect heat-related nervous system injury (Lee et al. 1989).

The differential diagnostic considerations in a typical case include heatstroke, idiopathic lethal catatonia, malignant hyperthermia associated with anaesthesia, drug interactions with monoaminoxidase inhibitors, and a central anticholinergic syndrome which can be caused by the anticholinergic effects of several neuroleptic drugs.

Lithium carbonate is commonly used to treat bipolar affective disorders. It produces tremor in more than 50 per cent, generally mild in degree. This tremor resolves with reduction or cessation of lithium therapy. Overdosage with lithium can produce peripheral neuropathy (Section 21.19). Seventeen patients have been reported with persisting neurological deficits after lithium therapy, commonly female, often associated with toxic blood levels (Donaldson and Cuningham 1983). These permanent deficits include Parkinsonian syndromes with akinetic hypertonicity or cogwheel rigidity, tremors, drooling, dysarthria, mask-like facies, and a positive glabella tap sign. Less frequent permanent features include choreo-athetosis, corticospinal tract damage, oculogyric crises, opisthotonic attacks, ataxia, impaired ocular conjugation, myoclonus, and grand mal seizures. Downbeat nystagmus in the primary position can persist after cessation of lithium therapy (Williams et al. 1988). A subacute dementing syndrome associated with myoclonus has occasionally occurred and is associated with periodic complexes on EEG resembling Creutzfeldt–Jacob disease (Smith and Kocen 1988). Such patients recover after withdrawal of lithium.

A number of therapeutic agents used to treat cancer may induce encephalopathies (Verstappen et al. 2003). These should be distinguished from cerebral secondary deposits, malignant meningitis, opportunistic infections, metabolic disorders, and paraneoplastic neurological syndromes. Peripheral neuropathy may result from treatment with cisplatinum, misonidazol, taxol, or vincristine (Section 21.19). The spectre of neurological side effects is a frequent limiter of the safer upper dosage of antineoplastic drugs.

Methotrexate, intrathecally or intravenously, may cause three distinct encephalopathies (Glass et al. 1986). First, a slowly progressive intellectual loss and personality change, sometimes with seizures and ataxia may occur. This seems particularly common in children, especially if radiotherapy has also been given, and may have a delayed onset. Second, aseptic meningitis, sometimes with acute encephalopathy, may develop within hours of intrathecal methotrexate. Transverse myelopathy is a rare sequel of intrathecal methotrexate. Third, high-dose intravenous methotrexate therapy may cause transient focal neurological abnormalities. These usually develop about 7 days after the second or third administration of methotrexate (Glass et al. 1986). Such patients abruptly develop gaze palsies, hemiparesis, focal seizures, sensory deficits, or behavioural abnormalities. These may worsen for up to 3 days before slowly resolving completely; CT scans are normal.

Cytosine arabinocide, used intrathecally to treat leukaemia or lymphoma, can induce aseptic meningitis, myelopathy, or encephalopathy with seizures. Cerebellar dysfunction occurs with cumulative dosage, particularly in the elderly (Hwang et al. 1985).

5-Fluorouracil and Levamisole adjuvant therapy for 15–19 weeks for colonic adenocarcinoma has caused encephalopathy which progressively worsens over 2 or 3 weeks associated with MRI and biopsy evidence of central nervous system demyelination (Hook et al. 1992). Declining intellect, ataxia, or episodic loss of consciousness have occurred, with subsequent improvement, and the syndrome is most likely to represent 5-Fluorouracil toxicity. If 5-Fluorouracil clearance is delayed because of dihydropyrimidine dehydrogenase deficiency, a comatose encephalopathy may occur.

Ifosfamide can cause an acute encephalopathy with cerebellar and extrapyramidal signs, hallucinations, seizures, and coma. This comes on within a day of infusion, and usually recovers a few days later.

Interferon alpha can induce cognitive dysfunction of mild to moderate severity, often associated with a Parkinsonian syndrome, which is not reversible on stopping the drug (Meyers et al. 1991).

Arteriography. Neurological complications occur in 1–2 per cent of carotid or cerebral angiograms (Willinsky et al. 2003). Catheter-induced arterial embolization accounts for most cases of focal cerebral deficit or spinal cord damage and up to a third are left with permanent deficits. The direct toxic effects of angiographic contrast media include seizures, which occur most commonly in patients with an underlying disorder of the blood brain barrier. Spinal myoclonus may occur after selective spinal angiograms (Junck and Marshall 1983). Intravenous administration of contrast agents for computed tomography occasionally causes seizures, most commonly if the blood brain barrier is impaired due to an underlying tumour.

Myelography. Acute or chronic arachnoiditis has been associated with the use of oil-based myelographic contrast media such as iophendylate Pantopaque or iophenylundecylate Myodil (Keogh 1974; Jorgensen et al. 1975; Junck and Marshall 1983). The acute reactions usually involve meningismus associated with CSF pleocytosis and settle in a few days. Chronic reactions produce an adhesive arachnoiditis after an interval of some months or more. Chronic back pain and lumbar or sacral root symptoms occur. Patients may be more vulnerable to chronic arachnoiditis if they received myelograms and operations in close succession, making this a possible cause for the ‘failed back surgery syndrome’ (Jorgensen et al. 1975). MRI of the lumbar spine defines the changes of lumbar arachnoiditis. The most typical changes are clumping of nerve roots into small groups, and adhesion of the nerve roots to the dural tube. The treatment of chronic arachnoiditis is primarily symptomatic. Some recommend attempts to remove any residual contrast medium which is still mobile (Junck and Marshall 1983). Pantopaque and Myodil were generally replaced as myelographic contrast agents during the early 1980s by the water-based compound Metrizamide. Metrizamide could produce seizures or transient encephalopathy with confusion, hallucinations, asterixis, and myoclonus (Bertoni et al. 1981; Junck and Marshall 1983). Metrizamide has since been replaced by less toxic water-based myelographic contrast media such as iohexol. In turn, myelography itself is generally being replaced by non-invasive MR scanning.

Neurological complications follow about 1 in 10 000 epidural, intrathecal and caudal local anaesthetic blocking procedures (Puke et al. 1989). Often these neurological problems are not evident until persisting neurological symptoms or signs are noted 12 h or more after the last injection of anaesthetic, by which time the nerve block should have worn off.

Direct needle trauma to a cauda equina roots, or to the conus medullaris of the spinal cord, usually causes immediate neuralgic pain, often in a radicular distribution, often accompanied by sudden involuntary movements of a leg, and is sometimes followed by permanent neurological damage within the distribution of the affected nerve root (Hamandi et al. 2002). Spinal epidural haematoma is particularly likely in patients with pre-existing coagulation deficits and usually presents with low back pain associated with progressive leg paralysis over a few hours and loss of sphincter control; urgent scanning is required with a view to early neurosurgical decompression so as to try and prevent permanent neuro-logical damage. Spinal epidural abscess is a rare but potentially catastrophic complication, presenting with back pain, feet, and leg weakness; urgent MRI is required on suspicion of this disorder (Grewal et al. 2006).

Accidental puncture of the dura mater occurs during intended epidural anaesthesia in about 2–5 per cent of patients and the subsequent local anaesthetic infusion can lead to total intrathecal blockade with unconsciousness and cardiorespiratory failure; complete recovery is the rule with suitable intensive care. Presumed ischaemic lesions of the spinal cord or cauda equina occur, and may be particularly likely after accidental dural puncture and injection of local anaesthetic mixtures containing adrenaline. However, no pathogenetic mechanism is ever established in many cases of permanent neurological damage following epidural or spinal anaesthesia (Yuen et al. 1995). Headache in the upright position due to spinal fluid hypotension, and aseptic meningitis are other recognized transient complications of dural puncture during local anaesthesia.

Neurological disorders make a major contribution to the mortality and morbidity of organ transplantation, often developing many months or years later. A quarter of liver transplant recipients and 15 per cent of haematopoietic progenitor cell transplanted patients develop significant neurological disorders (Lewis and Howdle 2003; Denier et al. 2006; Saner et al. 2006). The range of neurological disorders is large, but particularly common disorders include stroke, cerebral lymphoma, intracranial infections, polyneuropathy, and side effects of immunosuppressant drugs. Graft-versus-host disease presents a particular problem after bone marrow transplantation, with malabsorption-induced metabolic encephalopathy and neuromuscular disorders prominent (Sostak et al. 2003).

The first diagnostic step requires the patients’ neurological syndrome to be categorized (see Table 5.1) (Donaghy 1999).

This may range from mild confusion or ataxia to deep coma, sometimes with headache, seizures, or meningeal irritation depending upon the underlying cause. Cyclosporine or tacrolimus toxicity usually appear within 3 months and may include tremors, seizures, or visual disturbances such as hallucinations or cortical blindness. Listeria meningoencephalitis usually develops more than a month after transplantation and often includes prominent features of brainstem dysfunction, such as abnormal eye movements or dysarthria. Cryptococcal meningitis is usually delayed at least 6 months after transplantation. A syndrome of rejection encephalopathy in young transplant recipients, which includes papilloedema, may reflect cumulative physiological and metabolic insults, including hypertension and electrolyte disorders, rather than representing a direct consequence of rejection. Cardiac or pulmonary transplant recipients may develop hypoxic-hypotensive encephalopathy perioperatively. Encephalopathy regularly occurs in the weeks following bone marrow or liver transplantation, although the pathogenesis often remains unclear. Patients require brain imaging to detect multiple mass lesions, such as multifocal lymphoma, masquerading as diffuse encephalopathy. If the brain scan is normal, spinal fluid examination will detect infections. As well as being itself a cause of encephalopathy, it should be noted that hyponatraemia may be a secondary feature of other neurological disorders, such as meningitis.

Hemiparesis, dysphasia, or homonymous hemianopia are usually due to ischaemic or haemorrhagic stroke, or primary cerebral lymphoma. Focal cerebral infection with Toxoplasma or Aspergillus may become evident as early as 2 weeks post-transplant whereas Nocardia brain abscess tends to present later than 3 months. Central pontine myelinolysis Is particularly likely in hepatic transplant recipients, particularly in the presence of blood sodium disorders (Winnock et al. 1993).

The risk of cerebral lymphoma in transplant recipients is estimated at 2 per cent, between 30 and 350 times higher than normal (Patchell 1988). The median interval from transplantation to clinical detection of primary cerebral lymphoma in transplant recipients is 9 months, with a range of 5.5–46 months (Hochberg and Miller 1988). The cerebral lymphoma is multifocal in a third and generally affects the cerebral hemispheres. High dose steroid therapy should be avoided prior to neurosurgical biopsy since dramatic tumour shrinkage can occur within a few days and confuse the histological picture. The treatment of cerebral lymphoma in transplant recipients should follow the usual lines (Section 27.8.3), although the prognosis appears to be poorer than in immunocompetent patients with lymphoma.

Stroke is a major cause of morbidity and mortality both early and late after transplantation. Cerebral ischaemic events occurred in nearly 10 per cent of 10-year survivors in the early days of renal transplantation, but the impression is that these are less frequent; now, high doses of steroid have been replaced by Cyclosporine for the prevention of graft rejection. Perioperative stroke is a particular risk in cardiac transplantation due to air or solid embolism, or cerebral hypoperfusion (Montero and Martinez 1986). Haemorrhagic stroke is a noteworthy problem in bone marrow and liver transplant recipients and can reflect underlying septicaemia, endocarditis, thrombocytopenia, or sickle cell disease (Patchell et al. 1985; Wijdicks et al. 1995).

A multiplicity of factors is generally responsible for convulsions in transplant recipients. Cyclosporine toxicity is a common cause, sometimes exacerbated by hypomagnaesaemia, particularly early after liver transplants (Kahan et al. 1987). Focal cerebral lesions such as lymphoma, infarction, or infection should be sought by scanning if convulsions develop after the immediate post-transplant period. If seizures persist in cyclosporine recipients, despite reducing the dosage if the blood level is high, the choice of an anticonvulsant drug is difficult. Phenytoin, carbamazepine, and phenobarbitone all induce hepatic enzymes which pose difficulties for achieving adequately immunosuppressive blood levels of Cyclosporine. Sodium valporate is the recommended anticonvulsant in patients simultaneously receiving Cyclosporine (Hillebrand et al. 1987).

Focal peripheral neuropathies may complicate transplant surgery (Donaghy 1999). Self-retaining retractors in the pelvis can cause femoral nerve palsies in renal transplant recipients. Diabetics undergoing renal transplantation are vulnerable to lumbosacral plexus lesions of presumed ischaemic cause. Phrenic nerve lesions can complicate lung transplantation and prolong ventilator dependence post-operatively. Various mononeuropathies complicate liver transplantation, especially brachial plexus injury due to arm malpositioning.

Acute polyneuropathies of Guillain–Barré type are usually seen in bone marrow or hepatic transplantation and can follow renal transplantation from a cytomegalovirus-infected donor. Chronic inflammatory demyelinating neuropathy can occur in the months following liver transplantation, sometimes after immunosuppression with tacrolimus, and shows the usual good response to steroids, plasma exchange, or intravenous immunoglobulin. Although Cyclosporine often produces tinglings in the fingers and toes, this is a ‘hyperexcitability’ phenomenon which does not reflect underlying polyneuropathy.

Myopathies occur in bone marrow or liver transplant recipients. Chronic graft-versus-host disease can cause polymyositis or myasthenia gravis. A recoverable quadriplegia can occur in liver transplant recipients; its cause is generally unknown although a few cases are due to rhabdomyolysis.

These immunosuppressive drugs are used widely because of their effectiveness in preventing rejection of organ transplants. Up to a quarter of patients experience neurological side-effects (Kahan et al. 1987; Walker and Brochstein 1988). Tremors are commonest, but seizures, dysaesthesia of the extremities, depression, sleepiness, ataxia, and visual hallucinations have all been reported (Kahan et al. 1987; Walker and Brochstein 1988; Steg and Garcia 1991). Occasionally patients with cyclosporin neurotoxicity are hypomagnesaemic (Thompson et al. 1984). Some others have toxic blood levels of cyclosporin or its metabolites. Symptoms generally resolve on reducing or stopping the drug but this should only be undertaken by those supervising the organ transplant for fear of precipitating graft rejection. Mild tremor or parasthesiae, the commonest complications, are often tolerated without reduction in drug dosage. If anti-convulsant therapy is needed for seizures, sodium valproate is recommended because of the risk that enzyme-induction by phenytoin, carbamezepine, or phenobarbitone will produce low cyclosporin blood levels (Walker and Brochstein 1988).

An acute encephalopathy with cortical blindness, mutism, or other focal deficits may occur, associated with cerebral white matter hypodensity on computed tomographic scan (Rubin and Kang 1987; Bianco et al. 2004). Vasogenic oedema is thought to be the cause. This leukoencephalopathy recovers after drug withdrawal, but sometimes recurs on reintroduction of cyclosporin (Walker and Brochstein 1988).

Tacrolimus provides an alternative immunosuppressant to cyclosporine, and is a useful alternative in case of neurological or other side effects. But Tacrolimus itself produces neurological side effects in up to 30 per cent; speech disturbance, seizures, tremor and ataxia, encephalopathy, nightmares, or agitation have been reported and usually resolve with dosage reduction (Wijdicks et al. 1994). A more serious leukoencephalopathy may occur, resembling that caused by cyclosporin, and presents with headache, vomiting, seizures, and visual disturbance (Small et al. 1996).

Please see also Section 21.19 for the peripheral neuropathies due to toxicity from gold, and Section 21.20 for neuropathies due to arsenic, lead, mercury, and thallium.

Aluminium has been implicated in the pathogenesis of Alzheimer’s disease. X-ray spectrometry shows aluminium accumulation in neuronal fibrillary tangles (Perl and Brody 1980). Increased brain aluminium has been associated with cerebral congophilic angiopathy when dementia developed some 15 years after exposure to high aluminium levels in drinking water (Exley and Esiri 2006). A geographical correlation has been noted between drinking water aluminium concentration and the incidence of dementia, as judged by computed tomography scanning requests (Martyn et al. 1989). Despite these findings, a causative relationship between ingested aluminium and Alzheimer’s disease is generally regarded as being conjectural.

Aluminium toxicity was responsible for the encephalopathy which used to occur in patients receiving long-term renal dialysis using aluminium-rich dialysis fluids. Such patients developed progressive dementia with noteworthy speech abnormalities, myoclonic jerkings, and epilepsy. They have increased aluminium levels in the cerebral cortex, bone, and blood (Alfrey et al. 1976). The incidence of dementia correlates closely both with the incidence of fracturing dialysis osteodystrophy and with the aluminium content of the water used in preparing the dialysis fluids (Parkinson et al. 1979). Over the last decade, reduction of the aluminium content in the diasylate has massively reduced the incidence of severe dialysis encephalopathy. However subtle alterations in psychomotor function can still be detected in dialysis patients with only mildly elevated serum aluminium levels (Altmann et al. 1989). This has led to the suspicion that dietary sources of aluminium, including gastrointestinal phosphate binders, may also lead to toxic aluminium accumulation in dialysis patients.

Encephalopathy has been noted in patients taking bismuth salts for chronic gastrointestinal disorders, particularly for the control of output from colostomies (Burns et al. 1974). Confusion, tremors, myoclonus, and a prominent gait abnormality develop. The blood bismuth level is raised. Recovery occurred when bismuth was withdrawn, sometimes with residual memory deficits.

Frank toxicity due to inorganic lead usually has followed ingestion of lead-containing paints by children or occupational exposure of adult metal workers. There are public health concerns about the degree to which lead from vehicle exhaust fumes and domestic water supply pipes can cause subtle developmental intellectual abnormalities. Chronic low level environmental exposure, as judged by bone deposition, is associated with reduced cognitive function (Shih et al. 2006). In adults, inorganic lead poisoning leads to a purely or predominantly motor peripheral neuropathy (Section 21.20.2). In children, inorganic lead poisoning causes a subacute encephalopathy with irritability or listlessness, sometimes associated with anaemia. This may be followed by clumsiness, seizures and evidence of elevated intracranial pressure with vomiting, headache and papilloedema (Lidsky and Schneider 2003). Childhood lead poisoning may be fatal and autopsy studies of the brain show exudative oedema and widespread patchy cerebral necrosis (Smith et al. 1960). Lead lines may be evident in X-rays of the epiphyseal plates of long bones. Mildly impaired cognitive and psychomotor development in children have been correlated with chronic low-level lead exposure as judged by blood and tooth lead contents (Fulton et al. 1987). Indeed intelligence quotient correlates inversely with blood lead level in children even below the 10 μg/dl level which has been defined as an elevated level (Canfield et al. 2003). Mild neuro-behavioural abnormalities associated with elevated childhood lead levels persist into young adulthood (Needleman et al. 1990).

Organic lead intoxication usually follows exposure to tetra-ethyl lead, the anti-knock compound of petroleum. Neurological disease has been reported in industrial workers in the petroleum industry (Cassells and Dodds 1946) and in recreational petroleum inhalers (Kaelan et al. 1986). The first symptoms consist of altered sleep patterns, dreams, irritability, and anorexia. Confusion or psychosis subsequently develop. In severe toxicity, myoclonic jerks, ataxia, and hallucinations are evident. Death may occur and autopsies characteristically show loss of neurones from Ammon’s horn in the hippocampus and of cerebellar Purkinje and granule cells. Former organolead workers show persisting atrophic brain abnormalities on MRI, which correlate with residual bone lead deposition (Stewart et al. 2006).

Manganese neurotoxicity has been reported in ore miners, particularly in Chile, and in steel workers and welders (Josephs et al. 2005) and in methcathinone abusers (Stepens et al 2008). Chronic manganese poisoning generally follows exposure for more than 1 year and produces a clinical picture intermediate between Parkinson’s and Wilson’s diseases (Cook et al. 1974; Huang et al. 1989). The initial symptoms consist of psychomotor excitement, somnolence, gait unsteadiness, slurred speech, and manipulatory difficulties. More chronic toxicity produces typical features of a notably low volume speech, oral tremors, dystonias, and neuro-psychiatric abnormalities which may progress even 10 years after ceasing exposure (Huang et al. 1998). There is a characteristic gait abnormality in which patients walk on the metatarsophalangeal joints in the talipes equinus position, a so-called ‘cock walk’ (Cook et al. 1974). During exposure, blood and hair manganese levels are elevated (Huang et al. 1989). MRI shows characteristically increased T1 signal intensity in the Globus pallidus (Jankovic 2005). Levels of manganese in tissues other than the brain slowly revert to normal after patients are removed from the exposure, with resolution of the MRI signal abnormality, although the neurological syndrome does not improve (Stepens et al 2008). Neuronal loss affects the globus pallidus predominantly, and the Lewy bodies characteristic of idiopathic Parkinsonism are not present (Jankovic 2005). Although minor neurological improvements have been noted following therapy after metal chelation therapy with eidetic acid, significantly prolonged benefit does not generally result (Cook et al. 1974). Indeed chronic asymptomatic manganese exposure in miners causes subtle movement disorders later in life, such as tremors (Hochberg et al. 1996). L-Dopa therapy may produce minor improvements in motor abnormality in some patients (Huang et al. 1989). Viewed overall, there is little evidence that either welding or manganese toxicity are relevant to the cause of idiopathic Parkinsonism (Jankovic 2005). The extrapyramidal syndrome known as acquired hepatocerebral degeneration, associated with hepatic cirrhosis, shows similar brain MRI features and elevated manganese levels (Burkhard et al. 2003). This MRI T1-signal hyperintensity is associated with a sevenfold increase in pallidal manganese content (Klos et al. 2006).

Two forms of mercury poisoning occur: exposure to inorganic or elemental forms occurs in the manufacture of mirrors and scientific instruments, whereas inorganic mercurial compounds may be consumed in foods such as fish, which have ingested them, or those such as grain, which have been treated with mercurial fungicide. The peripheral nervous system bears the main brunt of inorganic mercury toxicity (Section 21.20.3). Depression, tremor, emotional outbursts, and insomnia may also occur and chelation therapy may improve symptoms (Hargreaves et al. 1988). Methyl mercury poisoning produces paraesthesia in the limbs and mouth, gait ataxia, concentrically restricted visual fields or cortical visual loss, and intellectual loss which may persist until death (Davis et al. 1994). Mercury levels were increased in affected cortical areas showing neuronal loss and gliosis. There is no evidence that mercury amalgam in dental fillings, or the thimerosal preservative of vaccines produces either significant elevation of body mercury levels or are associated with neurodegenerative disease (Clarkson et al. 2003).

Triethyl tin and trimethyl tin toxicity have been associated with different syndromes of neurological disease; elemental or inorganic tin compounds are not neurotoxic. Over 200 patients were poisoned when triethyl tin contaminated the anti-bacterial drug stalinon (Alajouanine et al. 1958). The main clinical features were raised intracranial pressure, generalized seizures, and muscle weakness; 50 per cent of patients died. Autopsies showed intramyelinic oedema in the brain. Trimethyl tin poisoning has been reported less frequently, recently in six patients exposed to the vapour (Besser et al. 1987). Symptoms generally developed 3–5 days after exposure and consisted of deafness, cognitive impairment, behavioural abnormalities, seizures, ataxia, limb sensory disturbances, and hyperphagia. Death may occur and recovery may be incomplete in the more severely affected patients. Urinary organotin levels are elevated for 15–20 days after exposure. Attempts to reduce body tin levels using penicillamine were not thought to be clinically beneficial. Autopsy showed evidence of neuronal damage in the cerebellar Purkinje CCU layers and the amygdala.

Chronic peripheral neuropathies due to organophosphates and carbamates insecticides, to the organo-metal rodentocytes arsenic, thallium, and organic mercury, to the fumigant methylbromide, and the herbicide 2,4-D are covered in Section 21.21.

Organophosphorus insecticides are the leading cause of systemic poisoning due to agricultural chemicals. Human disease has been most frequently described following discrete episodes of intense exposure, such as tri-ortho-cresyl phosphate contamination of moonshine whisky in 1930s prohibition America ‘Jamaica ginger extract’ or of Moroccan cooking oil in the 1950s. Nowadays suicidal consumption is common in the developing world (Agarwal 1993) and accidental agricultural exposures are frequent, especially during crop spraying. The possible neurological effects of repeated low dose exposure have not been defined.

Three distinct phases of neurological illness may follow organophosphorus poisoning. The most common manifestation, which occurs within hours of exposure, consists of an acute cholinergic crisis with weakness, and autonomic and cerebral dysfunction. Occasionally, an intermediate paralytic syndrome develops after 1–4 days. Lastly, after a delay of 1 or 2 weeks, some patients develop a sensorimotor polyneuropathy which progresses over subsequent weeks (Section 21.21.9). It is uncommon for all three phases of organophosphate poisoning to occur in the same patient. There are more than 80 organophosphorus compounds in use with varying degrees of toxicity (Dart 2004).

Acute cholinergic phase. Organophosphates irreversibly phosphorylate acetyl-cholinesterase. This inactivates the enzyme causing build-up of acetylcholine at muscarinic, nicotinic, and central nervous system cholinergic synapses within 12 h of exposure. Muscarinic autonomic symptoms invariably occur: miosis, copious bronchosecretions, salivation and lacrimation, bronchoconstriction, bowel and bladder hyperactivity, bradycardia, and arrhythmias. Roughly half of patients also develop weakness due to depolarization block of neuromuscular transmission. In such patients, fasciculations precede the areflexia and weakness, particularly of proximal muscles. Various central nervous system manifestations may occur: impaired consciousness, agitation, tremors, confusion, ataxia, and convulsions. Respiratory failure is the usual mode of death in untreated patients and results from the combination of broncho-constriction and bronchosecretions, respiratory muscle weakness, and impaired central respiratory drive. Because of the clinical urgency posed by organophosphorus poisoning, decisions concerning specific treatment should be based upon the clinical features and history of possible exposure. A test dose of 1 mg atropine intravenously should confirm the diagnosis within 10 min by producing pupil dilation, tachycardia, confusion, and an ileus. The diagnosis may be confirmed retrospectively by measurement of the red blood cell cholinesterase activity which remains depressed for up to 2 months after intense exposure (Coye et al. 1987).

The immediate aim of therapy is to prevent death due to respiratory failure. Endotracheal incubation with suction and assisted ventilation may be necessary. Repeated large doses of atropine should be given parenterally to reduce secretions and bradycardia. Gastric lavage or activated charcoal administration help reduce further organophosphate absorption. Pralidoxime or obidoxime specifically reverse peripheral nervous system cholinesterase inactivation by organophosphorus compounds, by removing the phosphoryl group and should be administered as early as possible. The optimal initial and subsequent dosage of pralidoxime, and its actual clinical effectiveness remain uncertain from the limited human clinical trial evidence (Eddleston et al. 2002). Diazepam should be used to treat seizures. Prompt and adequate treatment of the cholinergic phase allows complete recovery in less than 2 weeks.

Carbamate insecticides can produce an acute cholinergic syndrome similar to that caused by organophosphorus compounds. However central nervous system effects are less, inactivation of cholinesterase is less complete and lasts for a shorter duration because the enzyme binding is reversible, and pralidoxime therapy may exacerbate the cholinergic excess.

An intermediate syndrome. This syndrome of muscle paralysis has been described which begins 1–4 days after organophosphorus poisoning, and is separate from the preceding cholinergic crisis (Senanayake and Karalliedde 1987). This delayed syndrome of muscle paralysis typically affects the neck, respiratory, cranial nerve, and proximal limb muscles and may require assisted ventilation. Repetitive nerve stimulation shows a myasthenia-like decrement (He et al. 1998). It lasts for less than 20 days. It has been described in patients who have already received pralidoxime for the preceding cholinergic phase of the poisoning. The pathogenesis of this delayed paralytic syndrome is not understood. The delayed respiratory failure of this intermediate syndrome may reflect peripheral neuromuscular disease, compared to the mixed central and peripheral contributions to respiratory failure in the early cholinergic phase (Eddleston et al. 2006).

Chronic neurotoxicity. A severe polyneuropathy can appear 1–3 weeks after exposure (Section 21.21.9). There is considerable interest currently in whether permanent central nervous system abnormalities follow organophosphate poisoning. A number of studies show relatively minor long-term impairment on neurobehavioural tests or altered sensory testing thresholds (Steenland et al. 1994). Whether chronic subclinical exposure can produce similar impairments has become a contested issue.

Carbon disulphide and carbon tetrachloride mixtures are extensively used in the grain industry for controlling insects. Abnormal finger tremor at 5–7 Hz has been noted in chronically exposed grain workers and some workers display Parkinsonian syndromes which also include rigidity and gait abnormalities (Chapman et al. 1991). Peripheral neuropathy due to carbon disulphide exposure is described in Section 21.21.2.

Strychnine is a plant extract present in some commercial rodenticides. Strychnine blocks inhibitory actions of the neurotransmitter glycine in the central nervous system. Symptoms usually occur within 1 h of poisoning with anxiety, extensor spasms, opisthotonos, and convulsions, usually with preservation of consciousness in the initial stages (O’Callaghan et al. 1982). In patients who survive, recovery occurs over a few days. In severely poisoned patients, therapy should include respiratory assistance using endotracheal incubation and neuromuscular blockade, and treatment of seizures with diazepam or barbiturates.

Convulsions may occur as an early feature of poisoning by this chlorinated hydrocarbon pesticide of the cyclodiene group. Small epidemics of poisoning have been reported from Pakistan in which patients, usually children, became ill suddenly within a few hours of consuming food presumed to be contaminated with Endrin (Rowley et al. 1987). Vomiting, headache, and muscle fasciculation were noted in some patients in addition to tonic-clonic convulsions. Seizures can be resistant to intravenous therapy with diazepam or phenobarbitone, and death may occur. Blood endrin levels may be elevated.

Two neurotoxic compounds are considered to have potential utility on the battlefield or by terrorists: cyanide gases and organophophates (Martin and Adams 2003).

Cyanides. Although intense exposure to cyanide gas rapidly causes death, lesser degrees of exposure will bring symptomatic patients to medical attention. Smoke from fires can produce cyanide poisoning. Cyanide blocks aerobic metabolism within the brain and other organs by preventing intracellular ATP synthesis due to blocking the electron transport chain. Accordingly, severe exposures cause unconsciousness, followed by respiratory depression and cardiac arrest within minutes. Less intense exposure causes a slower development of coma, preceded by headache, vertigo, nausea, seizures, and respiratory abnormalities (Martin and Adams 2003). The patient’s breath may smell of bitter almonds due to hydrogen cyanide being blown off from the lungs (Martin and Adams 2003). Lactic acidosis, with retention of oxygen in venous blood is characteristic. Apart from essential respiratory and circulatory support, the recommended therapy involves correcting the metabolic acidosis, and administering nitrites to induce the formation of methaemaglobin which acts to decoy the cyanate away from the body’s mitochondria. Survivors may develop a delayed Parkinsonian syndrome with MRI abnormalities of the basal ganglia, not dissimilar to carbon monoxide poisoning (Section 5.4.1).

Organophosphate nerve agents. Various organophosphates have been developed for inhalation on the battlefield, either immediately after delivery: Tabun or GA, Sarin or GB, Soman or GD, Cyclosarin or GF, or by delayed evaporation over more than a day, agent VX (Newmark 2004). Within minutes of exposure the characteristic symptoms of the initial cholinergic phase of organophosphate poisoning develop (Section 5.8.1). At-risk military personnel are routinely supplied with atropine and pralidoxime auto-injectors, and also benzodiazepine or midazolam injectors to counter the subsequent risk of seizures (Lee 2003; Newmark 2004).

This is considered together with chemical warfare because the most likely neurologically active agent, botulinum toxin, would also cause paralysis in the battlefield or terrorist setting. The clinical manifestations of botulinum toxin poisoning are considered in Section 24.10.5. Recognizing the clinical syndrome is the cornerstone of diagnosis: descending flaccid paralysis invariably starting in the bulbar musculature, with other cranial nerve and autonomic symptoms, including blurred vision and pupil dilatation (Donaghy 2006; Martin and Adams 2003). Terrorist attacks could employ oral ingestion or inhalation of one of the family of botulinum neurotoxins A–G which are the most poisonous substances known. Unlike the prompt onset of weakness following organophosphate poisoning, botulism generally produces neurological symptoms after a delay of 12–72 h. Survival depends upon respiratory support. Toxin may be detected retrospectively by bioassay of body fluids. Repetitive nerve stimulation at frequencies of 20–50 Hz produces an incremental electromyographic response similar to the Lambert Eaton syndrome. Antitoxin should be administered within the first 24 h if possible, or if weakness is continuing to progress. Most available antitoxins only cover a proportion of toxin subtypes, and carry the risk of hypersensitivity reactions.

Haemorrhagic meningitis may occur following bioterrorist attack with aerosolized anthrax spores. However, this generally follows the primary clinical presentation of anthrax with systemic and pulmonary illness (Donaghy 2006; Martin and Adams 2003).

A prominent intention of any bioterrorist attack would be the creation of panic amongst civilians, with mass sociogenic illness consequently disabling institutions. Panic and psychologically determined ‘me-too’ symptomatology would present the largest diagnostic and logistic challenges to neurologists in the case of a bioterrorist attack upon an institution or a random civilian population (Donaghy 2006).

The occurrence of radiation-induced damage to the brain and spinal cord depends upon the radiation dosage, the scheduling of fractionation, technical aspects of beam focusing, and different individual susceptibilities (Henson and Urich 1982). Because of these variations, it has proved hard to define ‘threshold dosages’ for the development of radiation-induced neurological injury. Accepted ‘safe’ dosage regimens are now in general use with the result that radiotherapy-induced injury to the nervous system is less common nowadays. The pathogenesis of nervous system injury involves prominent endothelial damage, and the resulting radiation-induced vasculopathy seems to be a common feature to the different syndromes discussed below. Initial interest that some such patients improve with anticoagulation has not been borne out by clinical experience (Glantz et al. 1994).

Various clinical syndromes of radiation-induced spinal cord damage occur. By analogy with animal studies, acute spinal cord damage might be expected within hours or days of inadvertently high dosages of irradiation. An early and benign form of spinal cord damage may develop within 6–18 weeks of treatment to fields that had included the cervical cord (Jones 1964). Paraesthesia may radiate through all four limbs and this syndrome usually resolves within 6 months. Lhermitte’s symptom of electric shock sensations in the limbs evoked by neck flexion is common in this benign myelopathy.

Delayed progressive radiation myelopathy may develop at any time from a few months to 6 years after radiotherapy (Godwin-Austen et al. 1975; Henson and Urich 1982). Patients experience progressive deterioration in the sensory, motor, and sphincteric functions of the spinal cord below the irradiated level. Sensory disturbance is the commonest initial symptom. Also, Lhermitte’s sign occasionally occurs early on in the progressive form of radiation myelopathy. Early on the signs may be referable to unilateral damage of the spinal cord with monoparesis or a Brown–Séquard syndrome. Ultimately signs of bilateral spinal cord damage develop. Progression over months or years leads to clinically complete loss of spinal cord function. Stabilization with incomplete spinal cord lesions can occur. The chief differential diagnosis is from spinal cord compression due to recurrence or metastasis of the underlying cancer. MRI of the spinal canal may be required to exclude spinal cord compression. Both these investigations may reveal diffuse spinal cord swelling in post-irradiation myelopathy. Many patients die from the effects of radiation-induced spinal cord disease. Pathological studies reveal necrosis of the spinal cord confined to the irradiated segments. White matter tracts are preferentially affected and the lesions may be patchy. Fibrinoid necrosis or hyaline fibrosis of associated blood vessels suggest a vascular basis for the spinal cord damage in some cases.

Estimating the tolerance of the spinal cord to radiation may provide more general guidance to ‘safe’ radiation doses to other parts of the nervous system. For palliative therapy the risk of radiation myelopathy increases with size of dose per radiation fraction, although smaller fractionation of the total dosage becomes less convenient in this clinical setting (Macbeth et al. 1996). Estimates of the risk of radiation myelopathy point to < 0.2 per cent if 45 Gy is given in fractions of ≤ 2 Gy. For fractional doses of 3 Gy or less, a 5 per cent incidence of radiation myelopathy occurs with a total dose of 57–61 Gy whilst there is a 50 per cent incidence with approximately 70 Gy (Schultheiss 1990).

Radiation-induced brain damage generally follows treatment of cerebral tumours, extracerebral head and neck tumours, or neuraxis irradiation in the treatment of leukaemia. Cerebral and carotid arteries may be damaged by irradiation and occlusive stroke may occur many years later. Angiography in such cases shows arterial narrowings within the previously irradiated field (Murros and Toole 1989). A follow-up of children irradiated for scalp ringworm shows an increased incidence of brain tumours 7–16 years later (Modan et al. 1974). Most of these radiation-induced tumours of the nervous system are not gliomas.

A transient encephalopathy may develop a few weeks after irradiation. This presents with drowsiness, clumsiness, and headache which resolve over subsequent months (Henson and Urich 1982). Bilateral low attenuation areas may be seen in the brain on MRI. Death has resulted from a brainstem form of this early delayed encephalopathy in which demyelination was noted at autopsy. A variant of early transient post-irradiation encephalopathy occurs in leukaemics receiving combined treatment with radiotherapy and chemotherapy. This is known as treatment encephalopathy (Section 5.5.4).

The more usual type of post-irradiation encephalopathy develops months or years after radiotherapy and progressively deteriorates. The onset of symptoms is commonest after an interval of 9 months to 2 years. It is particularly likely if standard brain tumour irradiation doses of 5000–7000 rad are administered in daily fractions exceeding 2 Gy (Martins et al. 1977). The focal neurological deficit in post-irradiation encephalopathy often parallels that of the underlying brain tumour to which radiotherapy had been originally directed. Progressive dysphasia, hemianopia, cognitive dysfunction, or hemiparesis may be features of radiation encephalopathy of the cerebral hemisphere. Focal or secondarily generalized seizures and features of raised intra-cranial pressure may occur (Henson and Urich 1982).

The diagnosis of post-irradiation encephalopathy is easy if such a neurological syndrome develops in a patient without a pre-existing brain tumour, who had received radiotherapy for an extra cerebral tumour of the head or neck. The diagnosis is usually difficult in patients who had received radiotherapy for an underlying brain tumour. Without further brain biopsy, the distinction from tumour regrowth often remains uncertain. MRI may show multifocal lesions with mass effect which contrast-enhance, sometimes in a ring pattern, within the field of previous radiotherapy, and the appearance of these waxes and wanes with time, unlike the steady growth of recurrent tumour (Peterson et al. 1995). Neuropathological studies show necrotic areas of brain which particularly involve white matter and associated fibrinoid necrosis, hyaline thickening, or thrombosis of vessels (Martins et al. 1977). Without treatment, radiation necrosis of the brain tends to worsen progressively, causing death. Occasionally it stabilizes spontaneously. Dexamethasone therapy may control symptoms (Martins et al. 1977). Surgical excision of the swollen area of necrotic brain can lead to permanent improvement (Rottenberg et al. 1977). Such surgical treatment is best confined to patients with cerebral necrosis following radiotherapy for extra-cerebral malignancies, and who are not going to be intolerably disabled by extirpation of the affected brain area.

Progressive visual failure from optic nerve and chiasm damage has followed external irradiation therapy for pituitary tumours and craniopharyngiomas (Atkinson et al. 1979). Such patients may also suffer radiation-induced hypothalamic damage. Any cranial nerve may be compromised as a delayed effect of radiotherapy. The hypoglossal nerve appears to be particularly susceptible following previous radiotherapy for tonsular, pharyngeal or supraglottic pharyngeal tumours and prominent bulbar palsy may develop (Shapiro et al. 1996).

Irradiation of the brachial or lumbosacral plexuses can lead to delayed onset of a slowly progressive plexopathy which needs to be differentiated from tumour recurrence by MRI. Unlike tumour infiltration, radiation plexopathy is usually painless, and the weakened muscles often show myokymia on electromyography (Section 22.4.3).

A predominantly motor disorder can affect the legs following irradiation of the lumbar spinal canal as part of treatment for testicular or other neoplasms. Weakness usually commences between 3 and 25 years after the radiotherapy. The radiotherapy doses exceed 40 Gy, which is above the current treatment recommendation of 35 Gy fractionated over 4 weeks for testicular tumours. The leg muscle involvement is often distal and asymmetrical and associated with areflexia. Despite the purely motor nature of this disorder early on, all patients develop mild sensory symptoms eventually, although sensory nerve action potentials remain normal. Half of them ultimately develop mild sphincter disorders, with lack of appreciation of bladder fullness, dribbling, or occasional incontinence (Bowen et al. 1996). In most patients the leg weakness slowly progresses, albeit with periods of stabilization for a year or more, and severe disability can result. With improved safety of radiotherapy schedules, and the substitution of chemotherapy for radio-therapy in treating testicular cancer, the incidence of this unusual disorder can be expected to lessen.

It was not known whether this disorder reflected irradiation damage to the cauda equina nerve roots, or alternatively to the motor neurones of the conus medullaris. However, a neuropathological autopsy study showed a radiation-induced vasculopathy of the proximal spinal roots within the cauda equina, whilst the spinal cord architecture and motor neuronal cell bodies are preserved (Fig. 5.1) (Bowen et al. 1996). MRI shows gadolinium enhancement of the cauda equina in some patients, but this is a relatively non-specific finding.

The differential diagnosis includes neural infiltration by recurrent neoplasm or radiation-induced nerve sheath tumours, for both of which pain, unilaterality, and predominantly proximal weakness are to be expected. Apart from the slow evolution, spinal fluid cytology excludes malignant meningitis. Myokymia may be noted on electromyography but does not serve to distinguish radiation-induced plexopathies from radiculopathies.

Heatstroke is defined as a state of acute onset in which the rectal temperature exceeds 40° C, accompanied by hypotension, tachy-cardia, and hyperventilation, with hot and yet dry skin, and with an associated neurological disturbance (Simon 1993; Yaqub 1987). It occurs in various circumstances including protracted exertions such as marathon running, in unacclimatized visitors to hot climates, in alcoholics, and in those with cardio-vascular disease particularly if elderly and exposed to a heat wave. Various drugs predispose to heatstroke including diuretics, phenothiazines, anti-Parkinsonian drugs, anti-cholinergics, beta-blockers, tricyclic-antidepressants, and amphetamines (Hart et al. 1982). Heat injury may cause some aspects of neurologic dysfunction in the neuroleptic malignant syndrome, particularly in those patients who develop residual neurological abnormalities (Section 5.5.2).

Altered consciousness is the main presenting neurological sign of heatstroke. The pupils are characteristically tightly constricted. Skin temperature may be substantially less than the rectal core temperature which should exceed 40° C. Patients in deep coma may lose brainstem and tendon reflexes and have a poor prognosis even if they receive prompt assisted ventilation and cooling (Yaqub 1987). Convulsions may occur, especially during cooling. The creatine phosphokinase level is elevated and a wide range of metabolic and electrolyte disturbances have been recorded, most notably raised liver enzyme levels or frank hepatic failure (Hart et al. 1982; Yaqub 1987).

Heatstroke constitutes a medical emergency and body cooling should be started immediately. The entire body surface should be exposed and wrapped in a continually moistened sheet in a cool room whilst evaporation is promoted by multiple fans (Yaqub et al. 1986). Such evaporative cooling should be continued until the rectal temperature reaches 38.5°C. A bad prognosis is signalled by an initial rectal temperature exceeding 42°C and failure to achieve cooling within 1 h. Death occurs in approximately 10 per cent of all patients with heatstroke (Yaqub et al. 1986). In the French heatwave of 2003, 60 per cent died of those requiring admission to intensive care. Early predictors of death included high body temperature, prolonged prothrombin times, and requirement for vasoactive drugs (Misset et al. 2006). Outcome was better if detected early and if treated in an intensive care unit with air conditioning. Permanent neurological abnormalities may persist after satisfactory cooling in a few patients. Cerebellar syndromes are commonest (Yaqub 1987) and spinal cord lesions with motor neuron loss also occur (Delgado et al. 1985).

Two forms of tissue injury result from extreme cold. Noteworthy peripheral nerve injury occurs in the trench and immersion foot syndromes which represent non-freezing cold injury resulting from prolonged immersion of the limbs in cold liquid mud in warfare trenches, or in cold waterlogged life rafts (Kennett and Gilliatt 1991). Freezing injury, or frostbite, produces a localized area of generalized tissue necrosis and peripheral nerve injury remains more or less confined to this area.

The clinical features of the trench and immersion foot syndromes are similar, although not identical. An affected limb becomes numb and clumsy. Pain and tingling are uncommon but calf cramps may occur. The skin passes through a hyperaemic red and oedematous phase before becoming ‘sickly yellow’ or mottled (Ungley et al. 1945). On removing the tight boots encasing oedematous feet and rewarming, the limb goes through a hyperaemic phase lasting up to 10 weeks. During this, signs of a predominantly sensory and autonomic neuropathy are present. Pain and heat sensations are impaired in a glove and stocking distribution and the limb is warm and dry. Over the long term, skin colour and temperature return to normal, sweating returns and may be excessive, and sensory and motor function returns towards normal. Chronic pain is reported by many patients, particularly a burning dysaesthesia in the region of the metatarsal heads exacerbated by walking (Blair et al. 1957). Hyperhidrosis or signs of distal sensorimotor neuropathy may persist. Histopathological studies show Wallerian degeneration in the early stages of cold immersion injury, particularly affecting inter-digital nerves.

Acute mountain sickness afflicts climbers who rapidly ascend to heights of at least 3000 m without intermediate periods of acclimatization. Symptoms develop a few hours or days after ascent. Headache, ataxia, cognitive impairment, and vomiting due to cerebral oedema may be accompanied by dyspnoea due to pulmonary oedema (Johnson et al. 1984). Headache is the commonest manifestation, in over 80 per cent, and often has characteristics of raised intracranial pressure (Silber et al. 2003). Various other neurological disorders are seen in climbers: transient ischaemic attacks, cerebral venous sinus thrombosis, syncope, and diplopia (Basnyat et al. 2004). Subtle aphasic errors and impaired verbal learning and memory may persist for at least a month after ascents to altitudes above 5000 m (Hornbein et al. 1989). Climbers with a history of repeated conquests of peaks exceeding 8500 m without using supplementary oxygen show long-term impairments of concentration and memory (Regard et al. 1989). Death may result from acute mountain sickness. Acetozolamide pre-treatment reduces the incidence of altitude sickness (Group BMRESMSS 1981). Rapid descent provides the definitive treatment for mountain sickness. However patients may benefit from dexamethasone if descent proves impractical (Levine et al. 1989).

Decompression sickness, or the ‘bends’, occurs in deep-sea divers returning to the surface without adequate decompression. It has also occurred in aviators ascending in unpressurized aircraft. At least 24 h should elapse between diving and going to altitude. Compressed air sickness was originally called caisson disease when it was noted following the introduction of high-pressure chambers for underwater work. The neurological illness is generally believed to result from the formation of intravascular gas bubbles, causing arteriolar or venular blockage. The commonest manifestation of acute decompression sickness is ‘limb-bends’ in which musculoskeletal pains flit from joint to joint. The ‘chokes’ refers to an acute respiratory decompression sickness which may occur after a latency of several hours. Neurological complications occur in roughly a quarter of patients, particularly if recompression has not been undertaken at the first sign of the ‘bends’. Neurological symptoms follow the ‘bends’ by 1–36 h. Spinal cord damage or ‘spinal bends’ is the commonest neurological manifestation (Kimbro et al. 1997). Minimal limb weakness or paraesthesia may progress to complete paraplegia or tetraplegia in less than 1 h. Minor degrees of spinal cord damage may be discovered at autopsy in medically fit divers dying for unrelated reasons or in divers who have made a full functional recovery from ‘spinal bends’ as a result of prompt recompression (Palmer et al. 1987). Occasionally there is evidence of brain involvement with visual blurring, diplopia, dysarthria, deafness, or cognitive disturbances. Migraine-like symptoms have been described in aviators after descent. Treatment of decompression sickness consists of immediate inhalation of a high concentration of oxygen, and immediate transport to a hyperbaric oxygen chamber for recompression. The nitrogen may be eliminated more quickly if recompression uses a helium–oxygen mixture rather than oxygen alone (Melamed et al. 1992).

The site of the neurological injury is mainly determined by the part of the body receiving the electric shock or lightning strike. The immediate consequences of electrical injury include the electrical tinglings familiar to all of us, and for more severe strikes, there may be temporary unconsciousness with retrograde amnesia, temporary tinnitus and deafness, complex visual disturbances, and temporary or permanent cardiorespiratory arrest. A wide variety of longer lasting or permanent neurological sequelae have been recorded following electrical injury: posthypoxic encephalopathy, intracranial haemorrhage, and cerebellar syndromes (Cherington 2003). These may be present from the time of the shock, or develop after delays of days, weeks, or even months. Immediate onset of transient paraplegia with sensory loss has followed lightning strikes, and may recover in less than 24 h. Permanent spastic quadriplegia with small hand muscle wasting has followed electric shock to the arm. The onset of quadriplegia may be delayed for some days after the electric shock, and sometimes eventually recovers partially some months later (Farrell and Starr 1968). Electric shocks or lightning strikes to the head can produce an immediate or delayed onset of hemiparesis, aphasia, or unilateral extra-pyramidal syndromes (Farrell and Starr 1968). Cerebral damage with delayed onset may reflect electrically induced damage to cerebral vessels. Persisting fatigue and concentration difficulties are reported in survivors of lightening strikes sufficient to render them unconscious (van Zomeren et al. 1998). Seizures or myoclonic jerks may occur as an immediate sequel of electrical injury. Peripheral nerve damage is usually restricted to the shocked limb. Permanent peripheral nerve damage occurs within the area of generalized tissue burn, most generally affecting the median or ulnar nerves in the hand but more extensive peripheral nerve damage may ensue (Hawkes and Thorpe 1992). Electrical muscle injury may produce substantial subfascial oedema and early fasciotomy may be required to prevent secondary peripheral nerve damage or distal ischaemia (DiVincenti et al. 1969).

A vast range of plants and fungi can produce systemic poisoning syndromes after ingestion which may include autonomic, neurological, or psychiatric features. These are too numerous for comprehensive discussion here and the reader is referred to detailed reference texts for further details (Dart 2004).

Progressive ascending polyneuropathy resembling Guillain–Barré syndrome has followed consumption of the poisonous Buckthorn shrub, Karwinskia humboldtiana, which grows in Mexico and Texas. Patients develop an areflexic quadriplegia, and may have weakness of respiratory and bulbar muscles. Sensory loss is relatively mild. Patients who survive recover completely over a matter of months. The spinal fluid protein content is typically normal in contrast to Guillain–Barré syndrome. Sural nerve biopsy shows acute segmental demyelination (Calderon-Gonzalez and Rizzi-Hernandez 1967). Supportive treatment should follow that outlined for Guillain–Barré syndrome (Section 21.10.1).

Water hemlock, or cicuta, contains the poison cicutoxin. The plant is sometimes accidentally consumed after misidentification as wild parsnip, artichoke, or potato. Different isoforms of cicutoxin have various ion channel blocking effects or block brain GABA receptors (Uwai et al. 2000). The symptoms of poisoning reflect cholinergic excess at muscarinic and disinhibition of central nervous system synapses. Abdominal pain, sweating, bronchosecretion, salivation, brachycardia, hypotension, and pupillary abnormalities are common early features. Convulsions are frequent and may lead to status epilepticus. Non-convulsive involuntary movements may occur causing trismus, opisthotomus, and hemiballismus. It is likely that cicutoxin has a direct toxic effect on muscles, causing tenderness and weakness of trunk and proximal limb muscles. Creatine phosphokinase levels are elevated and severe metabolic acidosis may occur. Infusions of thiopentone sodium control the abnormal muscle movements and seizures (Starreveld and Hope 1975). Infusions of atropine, and haemodialytic removal of the circulating toxin are recommended.

Acute ascending polyneuropathy has followed ingestion of Gloriosa superba, the glory lily, a tuber found in tropical Africa, Asia, and North America (Angunawela and Fernando 1971). Gloriosa contains colchicine which is known to cause a neuromyopathy when given for therapeutic purposes (Section 21.19.5). In massive overdose, colchicine may cause confusion and signs of cerebral oedema leading ultimately to brain death (Heaney et al. 1976).

The wide range of poisoning syndromes that may follow ingestion of different species of mushrooms include hepatorenal failure, gastroenteritis, parasympathomimetic syndromes due to muscarinic effects, and disulfiram-like ethanol sensitivity (Dart 2004). Primarily neurological and psychiatric syndromes follow poisoning with the hallucinogenic mushrooms, of which Psilocybin has been popular for recreational abuse. Patients may develop confusion, visual hallucinations, distorted perceptions, and ataxia, sometimes accompanied by signs of parasympathetic abnormalities. Symptoms usually develop within 90 min of ingestion and resolve within 4–12 h. Seizures or hyperthermia occasionally occur (McCormick et al. 1979). Sedation with benzodiazepines may be necessary. Gut decontamination should be considered within the first few hours of large overdoses, particularly in children. Major tranquillizers should be used sparingly if at all to control psychotic features because of their propensity to lower seizure thresholds. Self- injury may occur if the poisoning precipitates aggressive or suicidal behaviour. Disturbing psychiatric ‘flash-back’ symptoms may persist after the acute poisoning (Benjamin 1979).

Podophyllin is an antimitotic drug derived from the May Apple, of the genus Podophyllum, which has been used for topical treatment of warts. Human toxicity has followed excessive skin absorption or oral ingestion, including overdosage with herbal laxative tablets containing podophyllin (Dobb and Edis 1984; Filley et al. 1982). Confusion or impaired consciousness, hallucinations, and ataxia may all occur during the first week of toxicity. Evidence of an axonal degeneration sensorimotor peripheral neuropathy commences during the second week, although absent tendon reflexes may have been noted earlier. The neuropathy may worsen for up to 3 months before slowly improving (Filley et al. 1982; Dobb and Edis 1984).

Green or sprouting potatoes may contain glycoalkaloids, which causes illness 7–19 h after ingestion. Solanine poisoning from potatoes is uncommon if the green skins are not eaten and if the potato has been boiled thoroughly; baking does not detoxify solanine. Outbreaks of poisoning have occurred in institutions such as schools (McMillan and Thompson 1979). Solanine depresses human pseudocholinesterase activity. Vomiting, diarrhoea, and fever are the commonest symptoms. Some patients develop confusion, delirium, hallucinations, headaches, convulsions, paraesthesia, and muscle spasms. Recovery occurs over a few days but more persistent visual blurring or giddiness have been noted.

Poisons produced by organisms have survival benefit for those organisms either in terms of offence, such as the poison produced by snakes that enables them to immobilize their prey, or defence, such as the toxins produced by sea algae that discourage their consumption. Some biological toxins have highly specific effects upon nerve conduction or synaptic transmission and attract interest as molecular probes of excitable tissues. This section discusses human poisonings due to bungarotoxin and latrotoxin, both of which interfere with cholinergic neurotransmission, and tetrodotoxin, saxitoxin, brevitoxin, and ciguatoxin, all of which interfere with sodium channel function in excitable membranes.

Ciguatoxins occur in certain predatorial fish from tropical reefs in the Atlantic and Pacific: barracuda, red snapper, grouper, and amberjack. The toxin originates in dinoflagellate plankton of the Gambierdiscus genus which are ingested by small fish which, in turn, are themselves eaten by larger predators. Usually within 12 h of a meal, patients develop vomiting, diarrhoea, cramps or myalgias of distal muscles, paraesthesiae, and gait ataxia (Isbister and Kiernan 2005; Pearn 2001). Characteristically, the paraesthesiae start circumorally. The physical signs are of a sensory poly-neuropathy, often predominantly affecting small fibre functions. Life-threatening respiratory muscle paralysis occurs in severe cases. Symptoms generally undergo gradual resolution over approximately 1–2 weeks. There is no specific antidote. Although intravenous mannitol is generally accepted as treatment based on unblinded studies, it was not found effective by a double blind, randomized trial (Schnorf et al. 2002). Fatigue, arthralgias, or polymyositis have been reported as a sequel in some patients.

Tetrodotoxin reduces the excitability of nerve and muscle membranes by reducing their permeability to the inflow of sodium ions. Poisoning has usually followed ingestion of internal organs or skin of puffer fish, particularly in Japan and Australia, or occasionally after consumption of porcupine fish. It has also followed envenoming from the bite of the blue ringed octopus (Isbister and Kiernan 2005). Vomiting, dizziness, and a sensation of floating may occur. The initial neurological symptom is paraesthesia, often circumorally. Muscle twitching, generalized flaccid paralysis, repiratory muscle failure in severe cases, ataxia, and hypotension follow (Isbister et al. 2002). Neurophysiology shows axonal excitability to be diminished with conduction slowing, reduced compound muscle action potentials, and sensory action potentials. Detailed neurophysiological analysis showed the axonal membrane changes to be entirely consistent with the known biophysical effects of tetrodotoxin poisoning (Kiernan et al. 2005). There is no specific antidote to tetrodotoxin poisoning and treatment is supportive. It is unclear whether anticholinesterase drugs yield any benefit, despite anecdotal claims.

Paralytic shellfish poisoning: saxitoxin. Outbreaks of paralytic shellfish poisoning have followed consumption of crabs, mussels, and other shellfish obtained from waters where ‘red tides’ have been observed, usually in temperate zones. These ‘red tides’ are due to various toxic dinoflaggelate sea algae, principally of the genera Alexandrium, Pyrodinium, or Gymnodium. Some of these algae contain saxitoxin and are ingested and concentrated by shellfish. Also a blocker of axonal sodium channels, the biophysical and clinical effects of Saxitoxin closely resemble those of tetrodotoxin (Section 5.12.2) except for the hypotension (Isbister and Kiernan 2005; Lehane 2001). Outbreaks of poisoning have occurred in a wide variety of countries bordering on the Atlantic and Pacific oceans. Symptoms usually develop within an hour of the shellfish meal. Paraesthesiae are initially circumoral and later affect the limbs. In more severe cases there is progressive muscular paralysis leading to respiratory muscle failure. There are no specific antidotes to saxitoxin poisoning. Survivors generally recover within a week.

Neurotoxic shellfish poisoning: brevitoxin. The dinoflagellate alga Gymnodium brevis produces brevitoxin and is another cause of ‘red tides’ around the Atlantic coast of the southern USA and New Zealand. The alga is concentrated by shellfish and human disease follows within 3 h of their consumption (Sakamoto et al. 1987). Although the effect on sodium channels is similar to ciguatoxin (Section 5.12.1) there is an initial neuroexcitatory effect (Isbister and Kiernan 2005). Diarrhoea, abdominal pain, rectal burning pain, and circumoral paraesthesiae are the initial symptoms. Tingling later extends to the limbs and trunk. Vertigo, ataxia, and repeated seizures may all occur in severe poisonings. The poisoning is generally milder than paralytic shellfish poisoning due to saxitoxin, and no deaths have been notified.

Amnesic shellfish poisoning: domoic acid. An outbreak of toxic encephalopathy has followed ingestion of mussels contaminated with domoic acid derived from the algal genus Nitzschia, which is related to the excitatory transmitter substance glutamate. Patients developed gastrointestinal symptoms within 12 h of consumption. These were followed by various combinations of confusion, altered consciousness, short term memory loss, seizures, myoclonus, unsteadiness, weakness, fasciculations, alternating hemiparesis, and ophthalmoplegia (Perl et al. 1990). Many months later survivors displayed anterograde amnesia and evidence of a predominantly motor axonal peripheral neuropathy. Autopsy studies showed hippocampal damage in a pattern resembling that caused by excitotoxins (Teitelbaum et al. 1990).

Various neurotoxic polypeptides and phospholipases A₂ are present in the venoms of different snakes and are injected into the victim via fangs during a bite. Puncture marks may be visible on the skin. Spitting cobras can spray venom into their victim’s eyes without biting. Polypeptide neurotoxins act postsynaptically to block synaptic transmission at the neuromuscular junction. Phospholipases A₂ act presynaptically to deplete the motor nerve terminal of synaptic vesicles. A presynaptic form of blockade is suggested by lack of response to antivenoms or anticholinesterase (Goonetilleke and Harris 2002). Some snake venoms also contain other toxins causing severe bleeding disorders, rhabdomyolysis, renal failure, and hypovolaemic shock and pulmonary oedema due to increased capillary permeability.

Postsynaptic blockade. Krait, genus Bungarus, venoms contain bungarotoxins, including α-bungarotoxin which binds powerfully to postsynaptic acetylcholine receptors, thereby blocking neuromuscular transmission (Goonetilleke and Harris 2002) and β-bungarotoxin which acts presynaptically. Kraits are found in Southeast Asia, India, Indonesia, Taiwan, and China, and usually bite their sleeping victims at night (Warrell et al. 1983). Not all bites involve envenoming sufficient to result in paralysis. After the bite, the preparalytic phase usually lasts 1–3 h, but delays of up to 12 h have been recorded. Ptosis is usually the earliest sign of impending generalized muscular paralysis. Complete muscular paralysis may occur, with death from respiratory failure unless assisted ventilation is instituted promptly. Muscle fasciculations may be observed after mamba bites. Neither antivenom nor edrophonium show an impressive clinical effect in krait bite victims. With prompt ventilation and adequate supportive care, full recovery occurs within a few days.

Postsynaptic neuromuscular blockade occurs after cobra (Naja) envenoming, presenting a similar clinical picture to that of krait envenoming. A myasthenic decrement may be noted neurophysiologically after cobra envenomation, and positive Tensilon^®, edrophonium, test responses may occur. Unassisted respiratory function may be maintained by infusion of adequate doses of neostigmine (Watt et al. 1986).

African mamba bites not only produce severe blockade of neuromuscular transmission by activating presynaptic voltage-gated potassium channels, but also contain toxins blocking muscarinic acetylcholine receptors and inhibiting acetylcholinesterase (Goonetilleke and Harris 2002).

Presynaptic blockade. Russell’s viper, common in South Asia, produces a mixed clinical picture after envenoming. In parts of India and Sri Lanka the venom’s phospholipase A₂ presynaptic neurotoxins produce external ophthalmoplegia and ptosis, and rarely a descending paralysis resulting in respiratory failure, and limb paralysis. There is no response to Tensilon^®, edrophonium, suggesting that the neurotoxin inhibits presynaptic release of acetylcholine at the neuromuscular junction, rather than causing postsynaptic blockade. Generalized muscle tenderness and myoglobinuria indicate that the venom also causes rhabdomyolysis (Phillips et al. 1988). Generalized rhabdomyolysis is the most serious consequence of bites from a wide variety of other snakes, including sea snakes, the tropical rattlesnake in Brazil and some Australasian snakes: taipan, tiger snake, mulga snake, and small-eyed snake (Phillips et al. 1988). It is likely that the phospholipase A group of neurotoxins are responsible for both the presynaptic blockade of neuromuscular transmission and the myopathy. Acute renal failure may complicate the rhabdomyolysis.

The Australasian taipan’s venom contains Taipoxin, a phospholipase A₂, which acts on presynaptic nerve endings to abolish transmitter release with a latency of a few hours before the clinical onset of paralysis. Paralysis predominates in the cranial, trunk, and proximal limb muscles, and artificial ventilation may be necessary. Compound muscle action potential amplitudes are low, but repetitive stimulation produces a distinctive brief potentiation in amplitude followed by an enhanced decrement unaffected by edrophonium (Connolly et al. 1995).

Stroke. A number of snake venoms possess procoagulant, fibrinolytic anti-platelet and haemorrhagic metalloproteinase activity. This can cause haemorrhagic stroke. Ischaemic cerebral thrombosis is unusual except after envenoming by pit vipers from Martinique and St Lucia. The stroke onset is often delayed to more than 8 hrs following the snakebite, and contributes to the high risk of fatality (Mosquera et al. 2003).

Treating snakebites. Measures to delay toxin absorption should be undertaken immediately: immobilization of the affected limb and application of pressure bandages to reduce lymphatic drainage from the site. Analgesic treatment of the severe pain should avoid opiates, which enhance the potential for respiratory depression. The killed snake, or a description may allow species identification. Any signs of systemic envenoming should lead to emergency hospital admission. Antivenoms active against the identified snake, or known local species, should be administered with awareness of potential anaphylaxis. Anticholinesterase and any necessary respiratory support are required if neurotoxic signs emerge (Goonetilleke and Harris 2002).

These venoms are various mixtures of invertebrate nerve ion channel blockers, hyaluronidase, and phospholipases which immobilize invertebrate prey. Human sodium, calcium, and potassium channels are also affected (Goonetilleke and Harris 2002).

Spiders. Envenoming by black- and brown-widow spiders of the genus Latrodectus include toxins such as α-latrotoxin, which destroys motor nerve terminals, causing failure of neuromuscular transmission (Okamoto et al. 1971). Symptoms in humans also follow bites by funnel web, mouse, and banana spiders. Toxic spider bites are rare in humans but can arise from imported goods. The unlucky victims experience pain at the site of the envenoming, abdominal pain, and leg weakness. A prospective Australian study showed significant pain lasting more than a day in only 6 per cent, and severe neurotoxic effects to be very rare (Isbister and Gray 2002). Recently, it has been concluded that horse serum antivenom does not promote recovery and should be considered only in potentially life-threatening poisonings. The antivenom has the disadvantage of causing allergic reactions (Moss and Binder 1987).

Scorpions. Common in the tropics, the effects of scorpion stings are particularly attributable to their serotonin content, and the various nerve ion channel blockers, which often enhance nerve terminal neurotransmitter release (Goonetilleke and Harris 2002). Severe pain is characteristic at the sting site. Systemic release of neurotransmitters commonly produces autonomic symptoms such as colic and diarrhoea, sweating, priapism, hypertension, and cardiac arrhythmias. Secondary cardiopulmonary damage may result from this autonomic storm.

Ascending flaccid paralysis of the limbs, culminating in bulbar and respiratory muscle weakness follows prolonged attachment to the body in the early summer by various species of gravid female tick. This mainly occurs in Northwestern USA, but can occur elsewhere in North America, Australia, South Africa, and Southern Europe. About 40 tick species can cause paralysis. Tick paralysis of animals, particularly sheep, was once of economic importance to farmers. Children are particularly likely to be affected, and tick envenoming enters the differential diagnosis of the acutely weak child. The presence of an attached tick should be sought, usually to be found in the scalp or ear. Ascending paralysis usually occurs after the tick has been attached for 5 days or more. Areflexia and ptosis are frequent. Although paraesthesiae may occur, sensory loss is uncommon. Bulbar paralysis can develop within 2 days of the onset of weakness. Neurophysiological studies show reduced amplitude of compound muscle action potentials but only a moderate slowing of motor nerve conduction and no defect of neuromuscular transmission (Grattan-Smith et al. 1997; Vedanarayanan et al. 2002). The spinal fluid is usually normal. Clinical and electrophysiological improvement occurs within a few days of removing the tick, and recovery can be complete in less than a week. Guillain–Barré syndrome is the main differential diagnosis but the early clinical and electrophysiological features are not discriminating. Comprehensive search for a tick is critical to diagnosis in children developing ascending paralysis in endemic areas. This form of tick paralysis is due to a toxin and should not be confused with the polyradiculopathy caused by the Borrelia infection transmitted by tick bites which is known as Lyme disease or Bannwarth’s syndrome (Section 21.14.3).