Progress in NeurobiologyVol. 34, pp. 331 to 342, 1990 Printed in Great Britain. All rights reserved
0301-0082/90/$0.00 + 0.50 © 1990 Pergamon Press pie
DRUG-INDUCED NEUROLOGICAL DISORDERS WILLIAM DICKEY a n d JAMES I. MORROW
Department of Neurology, Royal Victoria Hospital, Belfast, BTI2 6BA U.K.
(Received 9 October 1989)
1. 2. 3. 4.
CONTENTS Introduction Coma Seizures Strokes 4.1. Hypotensive strokes 4.2. Thromboembolic strokes 4.3. Haemorrhagic strokes Headache 5.1. Vascular headaches 5.2. Headaches due to raised intracranial pressure Cranial nerve disorders 6.1. Disturbances of smell and taste 6.2. Disturbances of vision 6.3. Ocular movements 6.4. Disorders of hearing and balance Movement disorders 7.1. Parkinsonism 7.2. Involuntary movements 7.2.1. Tremor 7.2.2. Myoclonus 7.2.3. Chorea and athetosis 7.2.4. Tardive dyskinesia 7.2.5. Dystonias 7.2.6. Akathisia 7.2.7. Tics Neuromuscular disorders 8. I. Neuropathy 8.2. Myasthenia gravis 8.3. Myopathy 8.3.1. Rhabdomyolysis 8.3.2. Acute/subacute painful proximal myopathy 8.3.3. Subacute/chronic painless myopathy 8.4. Myotonia Specific drug-induced neurological syndromes 9.1. Malignant hyperpyrexia 9.2. Neuroleptic malignant syndrome 9.3. Reye's syndrome References
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Although some are clinically distinct syndromes, the majority are indistinguishable from those due to other causes. Failure to consider drugs as a possible aetiological factor may lead to delayed or inappropriate treatment with serious consequences. The most useful classification of drug reactions is that o f Rawlins and T h o m p s o n (1981). Type A reactions are exaggerated pharmacological actions, due to incorrect dosage or altered pharmacokinetics, which are often predictable and avoidable or easily reversed by dose adjustment. Type B are idiosyncratic, unpredictable and unrelated to drug dose or
1. I N T R O D U C T I O N Adverse effects of drugs on the nervous system form only a small proportion of all neurological disorders. O f 1500 neurological consultations at the Johns Hopkins Hospital, 14% of conditions were iatrogenic but only 1% of these were drug-related (Moses and Kaden, 1986). In a survey of neurological admissions to a district general hospital, 2% were drug-induced (Morrow and Patterson, 1987). However, drug-induced neurological disorders are almost certainly under-recognized and under-reported. 331
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pharmacology. Type B reactions by definition are more difficult to recognize or avoid and have therefore higher morbidity and mortality. The subject has been reviewed previously by Critchley (1979), Blain and Stewart-Wynne 0985), and Morrow and Routledge (1988).
2. COMA Drug-induced coma may arise in three ways. Most cases are due to drugs which act directly on the central nervous system, including benzodiazepines, antidepressants, barbiturates, phenothiazines and opiates. Rarely, drugs not normally considered to have significant neurological actions may cause coma in overdose, including propranolol (Helson and Duque, 1978) and chlorothiazide (Rongraff, 1959). Secondly, drugs may cause coma indirectly by interfering with cerebral metabolism. Examples include drug-induced hepatic and renal failure, hypoglycaemia due to insulin and sulphonylureas, and acidosis secondary to salicylates, biguanides and acetazolamide. Thirdly, coma may follow sudden changes in cerebral blood flow: drugs causing this are considered further in Section 4.1. Most drugs causing depression of the central nervous system affect vestibular and cerebellar as well as cerebral function. Thus, nystagmus, dysarthria and ataxia may be early features (Plum and Posner, 1982). In more severe cases, brainstem reflexes may be impaired. The oculocephalic and caloric responses tend to be depressed relatively early, while the pupillary and corneal reflexes are preserved until very deep coma supervenes (Cartlidge, 1981). Under these circumstances, particularly in barbiturate overdose, the criteria for brain death may be present, and drug overdose must be excluded before making such a diagnosis (Editorial, 1976). Although the clinical features of drug-induced coma are similar irrespective of cause, individual differences may aid identification. Generalized flaccidity with depressed tendon reflexes and flexor or equivocal plantar responses are usual but hyperreflexia with extensor plantars may be a feature of hypoglycaemia, drug-induced hepatic coma and tricyclic antidepressant overdose. Pin-point pupils, which remain reactive to light, are a well known feature of barbiturate poisoning. Drug-induced coma is usually dose-related but may occur at "normal" doses when drug metabolism is disturbed or the patient is elderly. Cimetidine may accumulate in renal failure and cause coma (McMillen et al., 1978). Ranitidine is probably safer, but can cause acute confusional episodes (Macdermott et al., 1987). Coma has also been associated with lignocaine in patients with severe liver impairment (Seldon and Sasahara, 1967). Phenytoin toxicity may be caused by drugs which inhibit its metabolism, including chloramphenicol, suthiame, isoniazid (particularly in patients with slow acetylator status), diazoxide, dicoumarol and disulfiram. Although sodium valproate often produces a transient fall in total plasma phenytoin levels, it may cause a significant rise in unbound phenytoin and has precipitated coma in epileptic patients (Sakellares et aL, 1979). Other examples of drug-induced c o m a may be
predicted from their pharmacokinetics. Significant absorption of topical drugs may occur through the skin if it is inflamed and a lipophilic vehicle is used. Coma has been reported due to topical salicylate in alcohol (Lindsay, 1968) and malathion in xylene (Ramu et al., 1973). The prognosis in drug-induced coma is usually good. Deaths are mostly due to complications including respiratory and circulatory failure, infection, hypothermia and arrhythmias. Supportive therapy is, therefore, the mainstay of treatment. However, naloxone, a narcotic antagonist is effective in reversing coma due to opiates, which are frequently contained in cough suppressants (codeine, pholcodeine and dextromethorphan) and antidiarrhoeals (diphenoxylate, morphine). A new competitive antagonist, flumazenil, is commercially available for the reversal of benzodiazepine sedation. Its role is not yet fully established.
3. SEIZURES Although a large number of drugs have been implicated in convulsions (Chadwick, 1981), drugrelated seizures are probablay rare. Of over 12,600 medical inpatients surveyed in the Boston Collaborative Drug Surveillance Program (1972), convulsions attributed to drugs occurred in only 0.13%. Druginduced seizures are commoner in epileptic patients and in those who have a low convulsive threshold for other reasons, but may also occur in apparently healthy people, and are clinically indistinguishable from those due to other causes. They are usually generalized tonic-clonic in type but partial seizures may occur in patients with pre-existing neurological disease. Drugs most frequently implicated readily cross the blood-brain barrier and have known CNS effects. They include antidepressants, neuroleptics, and anaesthetic agents. Tricyclic antidepressants may cause seizures (Houghton, 1971) and should be avoided where possible in epileptic patients. Although maprotiline and nomifensine are theoretically safer in these patients (Trimble, t978), the former in particular has been frequently reported as a cause of fits (Edwards et al., 1986). Phenothiazines are also frequently implicated, particularly in epileptics (Baldessarini, 1985); those with a piperazine (fluphenazine, trifluoperazine) as opposed to an aliphatic side-chain may be safer. Seizures may rarely be due to lithium (Demers et al., 1970). The most common cause of drug-related seizures is drug withdrawal or non-compliance, notably of benzodiazepines (Editorial, 1979) and antiepileptics, and tonic-clonic and partial seizures have followed sudden baclofen withdrawal (Terrance and Fromm, 1981). Recently, concern has been expressed concerning variations in drug formulation and hence bioavailability in generic anticonvulsant agents, and increased frequency of seizure due to changes in drug formulation has been reported (Tyrer et al., 1970; Sachdeo and Belendiuk, 1987). Flumazenil, a new competitive benzodiazepine antagonist, may precipitate acute benzodiazepine withdrawal in dependent patients or remove the
protective action of benzodiazepines in multiple overdose. It has been implicated in one case of status epilepticus (Burr and Sandham, 1989). Numerous anaesthetic agents, including halothane (Smith et al., 1966), ketamine (Thompson, 1972), enflurane (Wolf, 1981) and propofol (Committee on Safety of Medicines, 1989) have been implicated in seizures. The association of seizures with antibiotics is well established, and may be due to decreased gammaaminobutyric acid mediated inhibition (Snavely and Hodges, 1984). Penicillin may cause seizures if administered intrathecally or in high doses intravenously particularly if renal impairment is present. Seizures have also been reported with ampicillin therapy (Hodgman et al., 1984), carbenicillin (Whelton et aL, 1971) and cephalosporins (Snavely and Hodges, 1984), suggesting that the beta-lactam ring is responsible. Isoniazid intoxication may cause seizures which are unresponsive to anticonvulsant therapy but, like isoniazid neuropathy, respond to pyridoxine (Martin and DePadua, 1983). Radiographic contrast media given intrathecally may cause seizures. The risks appear to be less with the water-soluble contrast media now used, but reported seizure rates after myelography using one such agent, metrizamide, vary from 0 to 0.6% (Junck and Marshall, 1983). The risks are greater when the patient is tilted head-down and when cervical myetography or cisternography is performed; conversely, good hydration and nursing in an upright position after myelography reduce side-effects. Metrizamide competitively inhibits brain hexokinase, and may cause seizures by this means (Bertoni et al., 1981). Rapid increases in drug levels may trigger seizures. The rapid intravenous injection of lignocaine and theophylline may induce fits even though the measured plasma concentrations remain within therapeutic limits. Penicillamine may induce or worsen seizures in patients with Wilson's disease, but the risk is less if the initial dose is small and increased gradually (Meyboom, 1980). Finally, drugs may induce seizures by an indirect effect on cerebral metabolism. CNS depressants may induce cerebral hypoxia, insulin and sulphonylureas hypoglycaemia and hyponatraemia secondary to an inappropriate syndrome of anti-diuretic hormone secretion may follow treatment with carbamazepine, chlorpropamide, cyclophosphamide and vincristine. 4. STROKES
4.1. HYPOTENSIVESTROKES The role of antihypertensive medication, including diuretics, in causing strokes in the elderly is increasingly recognized. In a Dutch study, 7% of patient admitted to hospital with strokes or transient ischaemic attacks had had significant changes in antihypertensive or diuretic therapy over the previous 3 weeks (Jansen et aL, 1986). Although a significant fall in blood pressure was thought to be responsible, some patients also had evidence of haemoconcentration. Frusemide was particularly implicated. Of 26 patients developing stroke in hospital, four had symptoms after a fall in blood pressure due to
antihypertensive therapy (Kelly and Kovacs, 1986). Transient ischaemic attacks have also been reported with nitrates (Puvrin and Dunn, 1981) and nifedipine (Nobile-Orazio and Sterzi, 1981). 4.2. THROMBOEMBOLICSTROKES The available evidence is in favour of a link between some oestrogen-containing oral contraceptives and thromboembolic stroke. It is clear that preparations containing higher doses of oestrogen (50/~g or greater) carry a higher risk (Meade et al., 1980). The Oxford Family Planning Association community survey reported 13 strokes over 39,400 patient years' experience with preparations containing 50 #g or more of oestrogen, compared with none in 9,100 patient years' experience of low-dose preparations (Vessey et al., 1984). Older women (Bottiger and Westerholm, 1971) and smokers (Vessey et aL, 1984) are at significantly higher risk. Overall, however, the absolute risk remains small, and should fall with the more widespread use of low-dose oestrogen and progesterone-only pills. In fact, lower dose oestrogen regimens may actually be protective in some circumstances: oestrogen replacement therapy in postmenopausal women has been shown to reduce the risk of death due to stroke (Paganini-Hill et aL, 1988). This may be related to a fall in low density and rise in high density lipoprotein cholesterol concentrations (Wahl et al., 1983). Episodes of neurological disturbance, thought to reflect ischaemia, have been reported in patients receiving cytotoxic therapy for Hodgkin's disease (Feldman and Posner, 1986). 4.3. HAEMORRHAGICSTROKES Preliminary results reported by the Steering Committee of The Physicians' Health Study (1988), a placebo-controlled trial which assessed the impact of regular aspirin on mortality from cardiovascular disease, reported a significantly increased risk of moderate to severe or fatal haemorrhagic stroke in patients taking aspirin. However, the absolute incidence was low (0.1% over a mean 57 months followup compared with 0.05% for placebo). The risk of intracerebral haemorrhage during oral anticoagulant treatment has been assessed in a large retrospective study by Wintzen et al. (1984). In patients over the age of 50, the risk of haemorrhage was eleven times greater in patients on anticoagulants. Associated hypertension was a significant predisposing factor. Sub-arachnoid haemorrhage appears to be rare, but has been reported as a complication of lumbar puncture in patients on anticoagulants (Sadjapour, 1977). Steptokinase and other thrombolytic agents used in the early management of acute myocardial infarction theoretically predispose to intracerebral haemorrhage. However, one large prospective trial reported the incidence of in-hospital stroke as 1.1% for patients receiving streptokinase compared with 0.9% in controls (Rovelli et al., 1987). Of 477 patients receiving streptokinase in another study, 4 had cerebral haemorrhage (ISAM Study Group, 1986).
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The oral contraceptive pill has been associated with an increased risk of subarachnoid haemorrhage. One study reported a six-and-a-half-times risk in women taking the pill compared with non-users: in patients who were also smokers, the risk was twenty-two-fold (Petitti and Wingard, 1978). Other studies have reported a one-and-a-half- to two-fold increase in risk for haemorrhagic stroke (Vessey et al., 1984).
Drug-induced headaches may be caused by changes in vasomotor tone or in intracranial pressure. 5.1. VASCULARHEADACHES Vasodilator drugs frequently cause headache. Drugs commonly implicated include antianginal agents like nitrates and calcium antagonists (diltiazem is claimed to be less troublesome), peripheral vasodilators (oxpentifylline and cyclandelate) and antihypertensives (prazosin and hydrallazine). Bronchodilator preparations, including theophyllines and sympathomimetics, and nicotinic acid derivatives used in the treatment of hypercholesterolaemia also possess vasodilator activity. Headaches may also be caused by vasoconstrictor drugs (e.g. bromcriptine and dopamine) and by acute withdrawal of vasoactive compounds including caffeine, ergotamine, methysergide, clonidine and beta-blockers (Foster and Stewart-Wynne, 1981). Hypertensive crises with associated headaches may occur in patients taking monoamine oxidase inhibitors if indirect sympathetic agonists (ephedrine, tricyclic antidepressants, amphetamines) or food with a high tyramine content are taken in addition. Headache associated with non-steroidal antiinflammatory agents, most notably indomethacin, seems to be related to their salt- and water-retaining properties.
6. CRANIAL NERVE DISORDERS
6.1. DISTURBANCESOF SMELLAND TASTE Aminoglycosides (Kerekovic and Curkovic, 1971) and tyrothricin, an antibiotic used in throat lozenges (Kanof, 1970), have been reported to cause complete or partial anosmia. Vasoconstrictor nose drops and cocaine may also be responsible, and diltiazem has recently been implicated (Berman, 1985). Transient loss of taste sensation may occur during captopril therapy, particularly when thiazides or beta-blockers are administered concurrently (Vlasses and Ferguson, 1979), and in up to half of patients taking penicillamine. It has been suggested that this is due to a direct action on the taste receptors (Lyle, 1974): however, the lower incidence reported in patients with Wilson's disease has led to the suggestion that a penicillamine-induced copper or zinc deficiency may be responsible (Henkin and Bradley, 1970). Other drugs reported as causing alteration or loss of taste include carbimazole, clofibrate, lithium, griseofulvin, gold preparations, levodopa, ethambutol and aspirin. A metallic taste has been reported in association with metronidazole and biguanides (Diamond, 1981). 6.2. DISTURBANCESOF VISION
Drugs with actions on the parasympathetic nervous system, including anticholinergics, antidepressants and antihistamines, may affect the ciliary muscles and cause blurring of vision. Corneal opacities, usually reversible, may be caused by chlorpromazine, chloroquine, quinidine, amiodarone and indomethacin. Lens opacities have been reported in association with steroids, chlorpromazine, chlorambucil and busulphan. The commonest and most serious drug-induced retinopathy is caused by chloroquine (Bernstein, 1967), which has a high affinity for melanin and accumulates in the retinal pigment layer, where it inhibits protein synthesis. Chioroquine retinopathy is related to the total dose and duration of treatment: usually a dose of 250ms or less per day over a 12 month period is safe. It is initially reversible, but ultimately leads to progressive, irreversible damage. Quinine in toxic concentrations may also cause per5.2. HEADACHES DUE TO RAISED INTRACRANIAL manent retinopathy and blindness (Bacon et aL, PRESSURE 1988). Phenothiazines also cause a retinopathy on the A number of drugs have been implicated in basis of high affinity for retinal pigment. However, the development of benign intracranial hyper- the onset is more acute, occurring within days or tension, which typically presents with headache, weeks rather than months, and is nearly always visual disturbance and papilloedema in young reversible with drug withdawal (Cant, 1969). Piperfemales. Nalidixic acid (Editorial, 1970), and nitro- idine derivatives, such as thioridazine, are more toxic furantoin (Mushed, 1977) are associated. Concern than those with alkyl (e.g. chlorpromazine) or piperhas recently been expressed at increasing reports azine (e.g. prochlorperazine) substitutions. Indoof the condition occurring during the treatment of methacin may also cause a reversible retinopathy. acne with long term tetracyclines (Committee on Although cardiac glycoside toxicity most commonly Safety of Medicines, 1988). Withdrawal of corti- causes reversible disturbances in (red-green) colour costeroids in both oral (Neville and Wilson, 1970) vision, a retinopathy which may be irreversible can and topical (Roussounis, 1976) forms may be re- occur. Tamoxifen has been associated with retinosponsible. The condition may also be caused by pathy and cystoid macular oedema (Dukes, 1984). vitamin A toxicity (Morrice et aL, 1960), the oral Macular oedema has also been described in associacontraceptive pill (Davidson, 1971), danazol (Shah tion with nicotinic acid, and diuretics including ehlorthalidone, hydrochlorothiazide and acetazoet al., 1987), and amiodarone (Grogan and Narkun, lamide (Crombie, 198 l). 1987).
Bilateral macular degeneration has been described with tetracosactrin (Williamson and Dalakos, 1967). Oestrogens and oral contraceptives may cause retinal artery occlusion and retinal vein thrombosis (Lakowski and Morton, 1977). Retinal haemorrhages, which may result in scotomata, have been associated with non-steroidal anti-inflammatory preparations and sulphonamides. Optic neuritis, although rarely drug-induced, is particularly associated with the antituberculous drugs. Ethambutol is best documented, but isoniazid has also been implicated. Ethambutol-induced neuritis is dose-related and may be present with disturbance of colour vision or reduced visual acuity and progress to complete blindness. The elderly and patients with impaired renal function are at greater risk. The anti-diarrhoeal agent clioquinol, as Entero-Vioform, was responsible for a syndrome of optic neuropathy and subacute myelopathy (Nakae et al., 1973), which led to its withdrawal. Toxic amblyopia has been associated with ibuprofen (Williamson and Sturrock, 1976), sulphonylureas, salicylates, phenylbutazone, ergotamine and quinidine (Crews, 1962). Disulfiram, particularly in patients with high tobacco consumption, may cause optic neuritis, often after a delay of 2-30 months (Fastner, 1980). 6.3. OCULAR MOVEMENTS Drug-induced diplopia is most commonly due to weakening of fixation reflexes and reverses with stopping or reducing the dose of the offending drug. Some drugs do, however, cause extraocular muscle weakness. Ophthalmoplegia is the commonest presentation of penicillamine-related myasthenia gravis (see Section 8.2), and may occur in association with drug-induced raised intracranial pressure. It has also been reported in association with reserpine, cardiac glycosides, quinine, chloroquine, imipramine, monoamine oxidase inhibitors, diazepam, sulphonamides and vincristine. Barbiturates may cause an ophthalmoplegia combined with gaze palsies (Edis and Mastalgia, 1977). The opthalmoplegia described in association with phenytoin is thought to be neurogenic rather than due to a direct effect on muscles. Nystagmus may be secondary to drug-induced ataxia or ototoxicity but is frequently observed in patients taking therapeutic doses of anticonvulsants, benzodiazepines and antipsychotic drugs. 6.4. DISORDERS OF HEARING AND BALANCE Drugs may have direct effects on the vestibulocochlear apparatus or on central connections to the brainstem and cerebellum. The commonest and most serious is antibiotic ototoxicity. Two mechanisms are thought to be responsible, involving the inner ear fluids: immediate, reversible ionic changes and longer-term, irreversible changes due to alteration in protein synthesis. Streptomycin, gentamicin, netilmicin and tobramycin are predominantly vestibulotoxic, causing vertigo and ataxia, while cochlear damage is predominant with neomycin, kanamycin and amikacin. Ototoxicity may be caused by topical as well as parenteral aminoglycosides, and has been reported in association with topical gentamicin
(Keller and Bircher, 1980) and neomycin (Keller, 1984). Vancomycin, minocycline and erythromycin have also been implicated in ototoxicity. Chloramphenicol ear drops can cause hearing loss, but the relative contribution of the ethylene glycol vehicle which is often used is unclear. The mechanism of diuretic ototoxicity is similar but the changes may be reversed if detected early. All loop diuretics have been implicated but ethacrynic acid is most ototoxic, especially when large doses are given by rapid intravenous injection. The risk is greater if renal function is impaired, but ototoxicity has been reported in patients with normal renal function (Diamond, 1981). Thiazides have not been implicated but deafness can follow long-term acetazolamide therapy. As in the retina, chloroquine may accumulate in the melanin-containing cells of the stria vascularis, leading to changes in the endolymph and hair cell degeneration. Quinine and quinidine may also cause impairment of hearing, and ataxia may be caused by piperazine (Parsons, 1971). Non-steroidal anti-inflammatory drugs may cause dose-related tinnitus and deafness, which is usually reversible. Deafness has been reported following the use of salicylate ointment applied to the skin (Pearlman, 1966). Dose-related reversible tinnitus has been described in association with imipramine therapy (Racy and Ward-Racy, 1980). 7. MOVEMENT DISORDERS 7.1. PARKINSONISM
Drug-induced Parkinsonism may be under-recognized and under-reported. Fifty-one percent of new cases of Parkinsonism referred to a department of geriatric medicine were believed to be drug-induced (Stephen and Williamson, 1984), while in a community survey 18% of patients initially diagnosed as having idiopathic Parkinson's disease were subsequently thought to have the drug-induced syndrome (Mutch et aL, 1986). Clinically drug-induced Parkinsonism is indistinguishable from idiopathic Parkinson's disease. Although the classical 'pill-rolling' tremor and asymmetry of signs are said to be less common, this has been disputed (Stephen and Williamson, 1984). Coexisting dyskinesias may provide an indication of aetiology when a drug history is not available (Hardie and Lees, 1988). Many elderly patients who recover from Parkinsonism after the causative drug has been stopped subsequently develop an idiopathic form of the disease, suggesting that drugs unmask 'latent' Parkinson's disease. By far the most frequent causes of drug-induced Parkinsonism are the drugs which block dopamine receptors. Although the syndrome is best recognized in patients receiving antipsychotic agents, notably phenothiazines and butyrophenones, it is important to realise that drugs in this category may be given for non-psychiatric problems. Preparations containing prochlorperazine, trimeprazine, trifluoperazine, thioridazine or metoclopramide, prescribed for vague symptoms of dizziness or nausea or for night sedation may be easily overlooked as causes of Parkinsonism
W. DICKEYand J. 1. MORROW
(Pall and Williams, 1987). At conventional dosage levels, around half of patients developing Parkinsonism on major tranquillisers do so within one month of starting therapy and in 90% signs will be apparent within three months. The condition is dose-related and usually resolves with reduction in dosage or withdrawal of the drug. However, resolution may be slow or incomplete. Anticholinergic therapy increases the likelihood of tardive dyskinesia and ievodopa therapy may worsen the underlying psychiatric problem. One study reported few adverse effects of levodopa in patients with drug-induced Parkinsonism but therapeutic response was disappointing (Hardie and Lees, 1988). Methyldopa may be converted to a false neurotransmitter which causes drug-induced Parkinsonism, and reserpine acts by amine depletion. A reversible case of Parkinsonism has been reported in association with captopril therapy (Sandyk, 1985). Lithium has been associated with cogwheel rigidity, but no other features of Parkinsonism (Kane et al., 1978). 7.2. INVOLUNTARYMOVEMENTS 7.2.1. Tremor Apart from the resting tremor of drug-induced Parkinsonism, drugs may cause postural or intention tremors. Postural tremors are most commonly due to exaggeration of the normal physiological tremor, and may occur with sympathomimetic agents, thyroxine, tricyclic antidepressants and sodium valproate. Increased tremor may follow benzodiazepine and alcohol withdrawal. The postural tremor which occurs in association with lithium has features in common with benign familial ('essential') tremor. Patients affected may have a pre-existing or family history of tremor (Van Putten, 1978), and an inconsistent response to beta-blockers has been reported (Floru, 1977). The tremor may improve with a reduction in dosage. Intention tremor, with associated nystagmus and cerebellar ataxia, is a feature of anticonvulsant drugs at toxic levels. These drugs may also cause asterixis, a flapping tremor of the dorsiflexed hands with arms outstretched more commonly seen in liver failure, as may metoclopramide (Lu and Chu, 1988), and metrizamide (Bertoni et al., 1981). 7.2.2. Myoclonus Myoclonus, brief sharp muscle jerks, is often a feature of encephalopathy, which may be druginduced. Myoclonus may also be caused by antibiotics, particularly the penicillins, when used in high dosage or in patients with renal impairment. It has been reported in association with metoclopramide (Lu and Chu, 1988) and toxic levels of anticonvulsants (Chadwick et al., 1976). 7.2.3. Chorea and athetosis Drug-induced chorea, semi-purposeful irregular movements, is most commonly caused by anticonvulsants, particularly phenytoin (Chadwick et al., 1976) when it is usually a feature of toxicity and responds
to dose reduction. Chorea may also be caused by levodopa, when it usually affects the orofacial muscles and tongue but may spread to the limbs and trunk. Although it usually responds to dose reduction it may occur as part of the 'on/off' phenomenon, when it is more difficult to control. Reversible chorea has been reported in association with dopamine, anabolic steroids (Tilzey et al., 1981), benzhexol (Warne and Gubbay, 1979), amphetamines (Lundh and Turving, 1981), pemoline (Nausieda et al., 1981), and cimetidine (Kushner, 1982). Chorea associated with the oral contraceptive pill is thought to have a similar mechanism to chorea gravidarum, and resolves on discontinuing the drug (Bickerstaff, 1975). Athetoid movements do not appear to be drugrelated. 7.2.4. Tardive dyskinesia This choreiform disorder which usually affects the orofacial, masticatory and tongue muscles, but may spread to the limbs, is usually associated with longterm neuroleptic treatment. Metoclopramide has also been implicated (Kataria et al., 1978), and as for drug-induced Parkinsonism causative drugs may be prescribed for trivial symptoms of nausea or dizziness (Pall and Williams, 1987). The mechanism is thought to be denervation hypersensitivity caused by dopaminergic receptor blockade. It is more common in the elderly and a prevalence of 20% among patients receiving long-term neuroleptics has been reported (Marsden and Fahn, 1987). Unlike other druginduced extrapyramidal disorders, it develops late after the start of even withdrawal of medication, and responds poorly to treatment. It may become permanent, especially in older patients (Ramsay and Millard, 1986). In children it may develop after neuroleptics are stopped. The risk seems to be smaller if drugs are stopped gradually rather than abruptly (Polizos et al., 1973). Sulpiride and clozapine, two new neuroleptic agents with novel structures, are claimed not to induce dopamine receptor supersensitivity and to lack association with tardive dyskinesia (Mielke et al., 1977; Marder and Van Putten, 1988). 7.2.5. Dystonias Acute drug-induced dystonias, of which oculogyric crisis is the best recognized form, most commonly affect the eyes, mouth and face. They have been reported most commonly with phenothiazines, butyrophenones, tricyclic antidepressants and metoclopramide (Bateman et al., 1985). Dystonias reported in association with carbamazepine are usually dose-related (Chadwick et al., 1976) but idiosyncratic hemiballism and shivering dystonia have been described (Critchley and Phillips, 1988). Phenytoin (Chadwick et al., 1976) and propranolol in high dosage (Crawford, 1977) have also been implicated. The mechanism of drug-induced dystonias is thought to be enhanced dopamine release on hypersensitive postsynaptic receptors (Kolbe et al., 1981). Anticholinergic agents will abort attacks and the condition resolves slowly after drug withdrawal.
7.2.6. Akathisia Akathisia, or motor restlessness, is most commonly associated with levodopa therapy (Blain and StewartWynne, 1985) and with neuroleptics (Ayd, 1961). It can persist for several months after neuroleptic withdrawal (Weiner and Luby, 1983). It has been reported in association with oxazepam withdrawal (Mendelson, 1978). 7.2.7. Tics Simple tics have not been described in association with drugs. However, Giles de la Tourette syndrome which includes multiple motor tics, has been described in children in association with haloperidol withdrawal (Singer, 1981) and with CNS stimulants (Lowe et al., 1982).
8. NEUROMUSCULAR DISORDERS Drug-induced disorders of peripheral nerves and muscles have been extensively reviewed elsewhere (Argov and Mastalgia, 1979; Lane and Mastalgia, 1978) and, therefore, a brief synopsis only will be included here. 8.1.NEUROPATHY Peripheral neuropathy may be sensory or motor, and may be due to either axonal degeneration or segmental demyelination. Most drug-induced neuropathies are mixed sensorimotor, due to axonal degeneration, and are more likely to develop in the presence of systemic disease such as diabetes mellitus, alcoholism or vitamin deficiency. Drug-induced distal, sensorimotor neuropathy is most commonly due to antituberculous agents. Isoniazid inhibits vitamin B6 metabolism and causes a severe axonal neuropathy (Ochoa, 1970) which is reversible if recognized early and the drug withdrawn. Prophylactic administration of pyridoxine is recommended for patients particularly at risk, i.e. patients with poor nutrition or alcoholism. A neuropathy related to pyridoxine deficiency also occurs in association with ethionamide (Poole and Schneeweiss, 1961) and penicillamine. Ethambutol may rarely cause a sensorimotor neuropathy in addition to optic neuritis (Tugwell and James, 1972). Of other antibacterials, nitrofurantoin has been most frequently implicated. The risk of neuropathy, which may be irreversible, is greater in renal impairment, but one series reported neuropathy in up to 62% of patients with normal renal function (Lindholm, 1967). There have been several reports of sensory neuropathy associated with metronidazole (Ursing and Kamme, 1975; Bradley et aL, 1977). Of cardiovascular drugs, amiodarone may produce a mixed peripheral neuropathy. In contrast to other drug-induced neuropathies the aetiology is segmental demyelination, possibly through interference with glycolipid metabolism (Lustman and Monseu, 1974; Martinez-Arizala et al., 1983). Disopyramide may also cause a mild sensorimotor neuropathy (Dawkins and Gibson, 1978). A sensory neuropathy described
in association with hydrallazine (Perry, 1973), which is structurally related to isoniazid, seems to be on the basis of pyridoxine deficiency rather than related to the lupus syndrome also induced. Perhexiline, an older antianginal agent frequently associated with neuropathy, is no longer available in the U.K. Most cytotoxic drugs can cause a peripheral neuropathy and vincristine seems most troublesome in this respect. The neuropathy usually follows several months treatment and can be expected in virtually all patients on long-term treatment. Patients with lymphoma are particularly at risk (Editorial, 1973). It is generally reversible. Phenytoin, particularly in large doses, may cause a reversible sensorimotor neuropathy (Dobkin, 1977), as can amitriptyline (Leys et al., 1987), and clomipramine (Marley, 1987) in overdose. Pure motor neuropathies are less common, but have been reported with antimicrobials including sulphonamides, dapsone (Rapoport and Guss, 1972), nitrofuantoin and amphotericin B. The tricyclic antidepressants amitriptyline and imipramine, and cimetidine (Walls et al., 1980) have also been implicated. An ascending, predominantly motor, polyneuritis, similar to Guillain-Barr6 syndrome has been reported with gold therapy (Dick and Raman, 1982) and various vaccinations (Miller and Stanton, 1954; Ribera and Dutka, 1983). Mononeuritis multiplex has been reported following amphetamine abuse when it was thought to be due to drug-induced arteritis (Stafford et aL, 1975). Neuralgic amyotrophy has been reported following passive immunization with tetanus and diphtheria toxoid (Holliday and Bauer, 1983), and after penicillin injection. 8.2. MYASTHENIAGRAVIS In normal circumstances, there is a high safety reserve for neuromuscular transmission, and druginduced neuromuscular block is therefore rarely a problem. Where the reserve is compromised, however, in patients with latent myasthenia gravis or electrolyte disturbances, or following the administration of muscle relaxants during general anaesthesia, a drug-induced myasthenic syndrome may occur. Drugs known to significantly affect neuromuscular transmission in these circumstances include aminoglycosides, beta-blockers, membrane stabilising agents such as lignocaine, procainamide and quinidine, lithium and chloroquine. Patients may present with post-operative respiratory depression or with typical symptoms of myasthenia. Unless the patient has underlying myasthenia gravis, acetylcholine receptor antibodies are absent. Penicillamine-induced myasthenia gravis is an exception to this rule, and is also electrophysiologically and clinically identical to classical myasthenia. It follows therapy of 4 months to 5 years duration. It remits weeks or months after penicillamine withdrawal, with a concomitant fall in acetylcholine receptor antibodies. 8.3. MYOPATHY Several distinct clinical syndromes of drug-induced muscle disease have been described.
W. DICKEYand J. I. MORROW 8.3.1. Rhabdomyolysis
This is the most severe form, presenting with muscle pain, tenderness and swelling. The large muscle groups are most frequently affected. Serum creatine kinase (CK) levels are grossly elevated and myoglobinuria may be severe. Acute tubular necrosis secondary to high circulating myoglobin levels and hyperkalaemia may follow. It has been reported in association with abuse of alcohol, amphetamines, phencyclidine and alcohol, and more rarely with cytotoxic agents, amphotericin B, barbiturates and diazepam. There have been several reports of rhabdomyolysis complicating theophylline overdose (MacDonald and Jones, 1985; Rumpf et al., 1985). 8.3.2. Acute /subacute painful proximal myopathy Non-specific symptoms of muscle pain, tenderness, stiffness and cramps may occasionally indicate a drug-induced myopathy. Serum CK and electromyography may be abnormal. Three syndromes, clinically indistinguishable but with distinct histological abnormalities, may be defined. Necrotizing myopathy, Any drug causing rhabdomyolysis may also produce a necrotizing myopathy. It has also been reported in association with epsilon aminoeaproic acid (Lane et al., 1979), emetine, colchicine and clofibrate. Isolated reports have implicated salbutamol, terbutaline, danazol, amiodarone, bumetanide, lithium, propranolol (Forfar et al., 1979) and labetalol (Teicher et al., 1981). Although steroids usually cause a painless subacute or chronic myopathy, intravenous hydrocortisone has been reported to cause an acute necrotizing myopathy in asthmatic patients (MacFarlane and Rosenthal, 1977; Van Marle and Woods, 1980). In most cases the mechanism is unclear, but with aminocaproic acid intravascular coagulation resulting in ischaemia may be responsible. Inflammatory myositis. A polymyositis-like syndrome has been most frequently described in association with penicillamine (Fernandes et al., 1977). Myositis may also occur as part of a drug-induced lupus syndrome due to hydrallazine (usually in slow acetylators), phenytoin and procainamide (Fontiveros et al., 1980). Hypokalaemic myopathy. Severe hypokalaemia, due to diuretics, purgatives and amphoteracin B may cause a myopathy. Histological examination of muscle shows characteristic vacuolar changes. 8.3.3. Subacute /chronic painless myopathy This is the commonest form of drug-induced muscle disease, most commonly associated with steroid therapy. Many cases are overlooked because the myopathy is often subclinical (Yates, 1970) or because the symptoms are misinterpreted as representing progression of the disease being treated, such as polymyositis. Although any steroid may be responsible, fluorinated steroids such as triamcinolone are most commonly implicated. The muscle weakness is proximal and progressive, with marked wasting but preservation of tendon reflexes. Serum CK and myoglobin are normal and muscle biopsy reveals selective
type 2 muscle fibre atrophy. Chloroquine produces a myopathy clinically indistinguishable from that caused by steroids except that peripheral neuropathy may be associated. Muscle biopsy shows marked vacuolation particularly in type 1 fibres. A painless myopathy has also been described in association with rifampicin (Jenkins and Emerson, 1981). 8.4. MYOTONIA Myotonia, a failure of normal relaxation after voluntary contraction may be demonstrated experimentally for a number of drugs but in the clinical setting is rare. However, in patients with myotonic disorders, such as myotonia congenita or dystrophia myotonica, the condition may be unmasked or exacerbated by beta-blockers including pindolol and propranolol (Blessing and Walsh, 1977), barbiturates, fenoterol and depolarizing muscle relaxants (Mitchell et al., 1978). 9. SPECIFIC DRUG-INDUCED NEUROLOGICAL SYNDROMES 9,1. MALIGNANTHYPERPYREXIA
Malignant hyperpyrexia is a serious reaction to a number of anaesthetic agents. Predisposition is inherited in an autosomal dominant fashion. In many affected patients an overt or subclinical myopathy may be demonstrated, and an elevated serum CK detected pre-operatively. However, neither normal serum CK nor a history of previous uncomplicated anaesthesia guarantee absence of the disease, and muscle biopsy followed by in vitro studies of halothane induced muscle contraction (Ellis et al., 1972) may be required for definite diagnosis. Anaesthetic agents most frequently implicated are halothane and suxamethonium, but none has been demonstrated to be completely safe. The reaction usually starts during anaesthesia but may be delayed. Pyrexia, respiratory and metabolic acidosis, tachycardia, muscle rigidity and myoglobinuria are characteristic. Patients require general supportive measures, and dantrolene is beneficial both as emergency treatment and prophylactically. 9.2. NEUROLEPTICMALIGNANTSYNDROME This syndrome, first reported by Delay and Deniker (1968), is said to be rare, but is probably under-recognized. Two prospective studies of patients on neuroleptic therapy have reported incidences of 6 in 679 patients over 18 months (Keck et al., 1987) and t in 495 over 6 months (Friedman et al., 1988) respectively. Although classically due to neuroleptics, most commonly haloperidol and fluphenazine, a similar syndrome has been described in association with levodopa withdrawal (Friedman et al., 1985), and with the dopamine-depleting agent tetrabenazine (Burke et al., 1981). It has been reported in association with metoclopramide (Samie, 1987). The syndrome usually develops shortly after the onset of therapy. One case report described fever and coma within 45 min of exposure to trimeprazine (Moyes, 1973). However, it has occurred in patients
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