Clinical features, pathogenesis and management of drug-induced seizures.

Drug Experience

Drug Safety 5 (2): 109-151. 1990 0114-5916/90/0003-0109/$21.00/0 © ADIS Press Limited All rights reserved. MEDT03151a

Clinical Features, Pathogenesis and Management of Drug-Induced Seizures Gaetano Zaccara, Gian Carlo Muscas and Andrea Messori Department of Neurology, University of Florence, and Pharmaceutical Service, Careggi Hospital, Florence, Italy

Contents

Summary ................................................................................................................................... 110 I. Antidepressants and Lithium Salts ..................................................................................... 112 1.1 Tricyclic Antidepressants .............................................................................................. 112 1.2 Monoamine Oxidase Inhibitors .................................................................................... 114 1.3 Newer Antidepressant Drugs ........................................................................................ 114 1.4 Lithium Salts .................................................................................................................. 115 2. Antipsychotics ....................................................................................................................... 116 2.1 Phenothiazines ............................................................................................................... 116 2.2 Butyrophenones .............................................................................................................. 117 2.3 Therapy and Prevention of Antipsychotic-Induced Seizures ..................................... 117 3. Antihistamines (H I-Receptor Antagonists) ........................................................................ 118 4. Antiepileptic Drugs and Their Paradoxical Proconvulsant Activity ............................... 119 5. Central Nervous System Stimulants ................................................................................... 119 5.1 Cortical Stimulants ........................................................................................................ 119 5.2 Brain-Stem Stimulants ................................................................................................... 122 5.3 Spinal Stimulants ........................................................................................................... 123 5.4 Non-Prescription Stimulants ......................................................................................... 123 6. General Anaesthetics ............................................................................................................ 123 6.1 Inhalation Anaesthetics ................................................................................................. 123 6.2 Intravenous and Non-Narcotic Anaesthetics ............................................................... 124 7. Local Anaesthetics ................................................................................................................ 125 8. Antiarrhythmic Drugs .......................................................................................................... 127 9. Opioids and Other Narcotic Analgesics ............................................................................. 128 9.1 Pethidine (Meperidine) .................................................................................................. 128 9.2 Morphine ........................................................................................................................ 129 9.3 Dextropropoxyphene (Propoxyphene) .......................................................................... 129 9.4 Fentanyl and Sufentanil ................................................................................................ 129 9.5 Pentazocine ...................................., ................................................................................ 130 10. Non-Narcotic Analgesics and Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) ....... 130 10.1 Aspirin and Salicylates ................................................................................................ 130 10.2 Mefenamic Acid ......................................... .................................................................. 130 10.3 Other NSAIDs .............................................................................................................. 131 II. Antimicrobial Agents ......................................................................................................... 131 11.1 /3-Lactam Antibiotics ................................................................................................... 131 11.2 Other Antimicrobial Agents ........................................................................................ 133 11.3 Antituberculosis Drugs ................................................................................................ 133

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Drug Safety 5 (2) 1990

12. Antifungal Agents .......................................................... ................................. .. .................. 13. Antimalarial Drugs ...... ........................................................................ ...................... ......... 14. Antineoplastic Drugs ........................................................ ........................... ..... .................. 14. 1 Alkylating Agents .......................................................................... .. ............................. 14.2 Antimetabolites ................ ......... ................. ............. .. ................................................... 14.3 Vinca Alkaloids ............................................................................................................ 14.4 Other Antineoplastic Drugs .. ................................ .................... .............................. .... 15. Immunosuppressive Drugs ........................................ .. ...................................................... 16. Radiological Contrast Agents ............................................................................................ 16. 1 Agents for Intravascular Administration ................................................................... 16.2 Agents for Intrathecal Administration ...................................... .. ................ .. ............. 16.3 Treatment and Prevention .......................................................................................... 17. Vaccines ................................ .. ......... ............... .................... ..................... ........................... 18. Miscellaneous ........................................................................... ............................ ............... 19. Conclusions .............. .................................................................. .......................... .. .............

Summary

134 134 134 135 136 136 136 136 137 137 138 138 139 139 141

Many classes of pharmacological agents have been implicated in cases of drug-induced seizures. The list includes antidepressant drugs, lithium saIts, neuroleptics, antihistamines (H I-receptor antagonists), anticonvulsants, central nervous system stimulants, general and local anaesthetics, antiarrhythmic drugs, narcotic and non-narcotic analgesics, nonsteroidal anti-inflammatory drugs, antimicrobial agents, antifungal agents, antimalarial drugs, antineoplastic drugs, immunosuppressive drugs, radiological contrast agents and vaccines. For each of these classes of drugs, this article otTers a revision of the literature and emphasises in particular the frequency of the adverse reaction, its clinical presentation, its presumed epileptogenic mechanism and the therapeutic strategy for the management of drug-induced seizures. An attempt is also made to distinguish seizures induced by standard dosages from those provoked by accidental or self-induced intoxication. For some classes of drugs such as antidepressants, neuroleptics, central nervous system stimulants (e.g. theophylline, cocaine, amphetamines) and ~-Iactam antibiotics, seizures are a well recognised adverse reaction, and a large body of literature has been published discussing exhaustively the major aspects of the issue; sufficient data are available also for the other classes of pharmacological agents mentioned above. In contrast, several other drugs [e.g. allopurinol, digoxin, cimetidine, protirelin (thyrotrophin releasing hormone), bromocriptine, domperidone, insulin, fenformin, penicillamine, probenecid, verapamil, methyldopa] have not been studied thoroughly under this aspect, and the only source of information is the occasional case report. This review does not address the issue of seizures induced by drug withdrawal.

Numerous drugs are known to cause convulsions in various circumstances. To address this problem appropriately, a clear distinction must be made between situations in which this adverse effect is observed at therapeutic dosages and conditions in which seizures are part of the clinical picture of a poisoning. In seizures induced by therapeutic dosages, the pharmacological agent acts typically as a trigger factor, but almost invariably a number of pre-

existing conditions also contribute to the adverse reaction, conditions which are related either to the disease or to concurrent medication with other drugs. However, the particular association of the drug administration with these concomitant factors does not fully explain the occurrence of seizures, because only in a minority of cases does any association result in seizure. This observation leads to the conclusion that, in many cases, factors related to the individual patient are a major deter-

Drug-Induced Seizures

min ant affecting the occurrence of seizures. These factors are far from being clearly understood, but probably involve some form of predisposition to the seizure or an altered drug reactivity of some neurotransmitter system in the central nervous system (CNS). Drug poisoning can cause seizures through direct and indirect toxic effects on the CNS. A number of drugs implicated as epileptogenic agents have a direct neurotoxicity; for example, seizures mediated by a direct action on the CNS can be caused by several stimulants [e.g. pentetrazol (pentylenetetrazole), methylxanthines, cocaine] as well as by penicillin and other iJ-Iactam antibiotics. The poisoning can also provoke seizures indirectly through a variety of epileptogenic mechanisms. In general, indirect causes of seizures include hypoxia deriving from impaired ventilation, blockade of oxygen utilisation at cellular level (e.g. intoxications with carbon monoxide, cyanide, hydrogen sulphide), reduced oxygen transport capacity, cerebral oedema, hyperpyrexia, hypoglycaemia, hyponatraemia, and other metabolic disturbances such as alkalosis, acidosis or liver encephalopathy (Kulling & Persson 1986). Most of these conditions are known to increase the extracellular concentration of glutamate and of other excitotoxins, and this may be a general mechanism that induces seizures indirectly (Pellegrini-Giampietro et al. 1990). Drug poisoning can cause most of the conditions listed above, leading ultimately to seizures in a certain proportion of cases. For example, insulin and oral hypoglycaemic agents at high doses produce hypoglycaemia and neuroglycopenia, which can in turn provoke seizures (Jick et al. 1972). The antiarrhythmic agent disopyramide can induce severe hypoglycaemia and lactic acidosis, thus causing convulsions (Nappi et al. 1983). Similarly, hypocalcaemia provoked by prednisone, and dilutional hyponatraemia due to infusion of 5% dextrose in water, have been reported to cause seizures (Jick et al. 1972). Regardless of whether convulsions have been induced by therapeutic or toxic dosages, the proconvulsant action of several drugs has been thought to be related to some interference with neurotransmitter systems in the eNS. A great deal of data

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suggests that in different kinds of human epilepsies or different animal models of epilepsy, the stimulation or inhibition of the same neurotransmitter system can have convulsant, anticonvulsant or no effect (lobe & Laird 1987). As a result, the action of a given drug on a specific neurotransmitter system may be convulsant only in specifically predisposed subjects. For example, Marrosu and colleagues (1983) noted that apomorphine administration activated the EEG of patients with partial seizures; in contrast, the stimulation of dopaminergic receptors by apomorphine is known to prevent photically-induced seizures in patients with photosensitive epilepsy (Quesney et al. 1981). Amphetamine, which has the ability to increase dopaminergic transmission, decreases seizure activity and improves EEG patterns (Trimble 1977). Norepinephrine (noradrenaline) is thought to reduce the susceptibility to epileptogenic stimuli (Kresch et al. 1987), and the anticonvulsant effect of tricyclic antidepressants has in fact been attributed to their capability to enhance the concentration of this catecholamine (Kobayashi & Mori 1977). However, conflicting results have been reported in studies focused on the role of the noradrenergic system in various experimental models of epilepsy. For example, while noradrenergic agonists have the capacity to suppress seizure activity in the epilepsy-prone rat, noradrenergic increments may exacerbate seizures in other experimental models of epilepsy, e.g. epileptic mice or gerbil (Jobe & Laird 1987). Hence, one can speculate that, in humans, noradrenergic activation can also result in either an increase or a decrease in the seizure threshold. For serotonin (5-hydroxytryptamine, 5-HT) it is generally agreed that a decreased turnover of this monoamine in the CNS is often associated with epilepsy (Shaywitz et al. 1975). Chawick et al. (1975) noted that some patients with postanoxic intention myoclonus exhibited low 5-hydroxyindolacetic acid concentrations in lumbar cerebrospinal fluid, and these patients were shown to improve when treated with 5-hydroxytryptamine or clonazepam. However, some authors have postulated that myoclonic

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jerks induced by tricyclic antidepressants can be related to the capability of the drug to inhibit serotonin reuptake (Westheimer & Klawans 1974). An overwhelming body of observations shows that GABAergic agents protect against seizures, while agents blocking GABA-receptors have proconvulsant properties (Gale 1988). However, in some eNS regions implicated in the inhibition of seizures (e.g. the substantia nigra), GABAergic neurons often synapse on one another in series. This fact makes it difficult to predict the functional impact of a drug that modifies GABA transmission (Gale 1988). In fact, GABAergic cells may inhibit other GABAergic neurons so that disinhibition eventually occurs. Roberts and Ribak (1986) suggest that the abnormally high number of GABAergic neurons that are present in the genetically epilepsy-prone rat and in the epileptic gerbil are neuroanatomically arranged so that disinhibition occurs. These observations support the concept that in some circumstances a drug endowed with GABAagonistic properties can paradoxically exert a convulsant effect. In summary, present knowledge about the involvement of neurotransmitters in the genesis of epilepsy indicates that the role of a particular transmitter system can be different from one model of epilepsy to another. In drug-induced seizures, an individual predisposition which is dependent on I set of neurochemical factors remains the basic explanation for this adverse reaction, particularly when seizures develop after standard dosages of the drug. A systematic review of the pharmacological agents most often implicated in cases of druginduced seizures is given in the following sections.

1. Antidepressants and Lithium Salts Although antidepressants are a heterogeneous group in terms of chemical structure and biological activity, almost all of these drugs share some degree of convulsant activity. In this section, the antidepressants are divided into tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, the


so-called 'second generation' or newer antidepressant drugs and lithium salts. l.l Tricyclic Antidepressants

Shortly after the introduction in 1958 of imipramine (the first tricyclic antidepressant), seizures were noted in 3 patients following an overdose (Brooke & Weatherly 1959). Reports then began to appear of seizures occurring at normal therapeutic doses: imipramine (Feldman 1959), amitriptyline (Betts et al. 1968), desipramine (Lamont 1965) and clomipramine (chlorimipramine) [Marshall 1971] were shown to cause seizures at dosages varying from 50 to 400mg daily. In patients treated with imipramine or clomipramine, the reported incidence of fits was 0.7% for the former and slightly greater than 3% for the latter (Burley 1977). Almost all authors now agree that convulsions induced by tricyclic antidepressants represent a significant risk for predisposed patients, and that these drugs should be used very cautiously in such individuals (Betts et al. 1968; Dallos & Heathfield 1969). An attempt has been made to quantify the risk of tricyclic antidepressant-induced convulsions in patients with no known predisposing conditions treated with standard dosages of these drugs (Jick et al. 1983). For this purpose, 6829 patients who filled at least I prescription for a tricyclic antidepressant were retrospectively evaluated, and a total of 27 cases of drug-induced seizures were reviewed. Among these, only 5 cases were identified in whom seizures had probably been induced by antidepressants in the absence of any known predisposing medical condition. So seizures observed during treatment with these drugs in patients with no previous history of epilepsy and with no predisposing medical condition seem to be very infrequent, with an incidence of approximately 1/ 1000. Tricyclic antidepressant-induced seizures usually appear within a few days of starting the drug or changing to a higher dose (Betts et al. (968). A relationship has been postulated between the occurrence of seizures and both the number of different drugs prescribed and the rate at which they were introduced (Toone & Fenton 1977).


In animals, tricyclic antidepressants have been reported to increase or decrease seizure thresholds, depending on the dosage administered; thus, these drugs are similar in this aspect to phenothiazines. Low dosages of imipramine or amitriptyline were found to raise the maximal electroshock and pentetrazol seizure thresholds in mice (Sigg 1959; Vernier 1961). Further studies in different experimental models of epilepsy showed that imipramine has a biphasic effect since at low dosages the drug blocks the maximal electroshock seizures in mice, but induces clonic seizures at high dosages (Lange et al. 1976). Trimble and colleagues (1977) found that the intravenous administration of clomipramine or imipramine lowers the convulsive threshold in the photosensitive baboon Papio papio. The mechanism by which tricyclic antidepressants induce seizures is still unclear. The convulsant properties of these drugs have been ascribed to the inhibition of serotonin reuptake at the synaptic cleft. Increased concentrations of serotonin at striatal interneuron sites have been hypothesised to produce the myoclonic jerks (Westheimer & Klawans 1974). However, data from Trimble and colleagues (1977) suggest that an enhanced serotonin tone can protect against seizures. The effect of tricyclic antidepressants on the EEG in humans has been widely studied (Delay & Deniker 1959; Kiloh et al. 1961). These drugs simultaneously increase the amounts of slow and fast activity and reduce.Jhe frequency of ex rhythm (Fink 1968; ltil 1970, 1971). Most importantly, the administration of imipramine or amitriptyline to epileptic patients induces the appearance of (or increases) epileptic features in 50% of patients, thus showing an activating effect similar to that observed after administration of bemegride (Davison 1965; Kiloh et al. 1961). For this reason, tricyclic antidepressants, like phenothiazines, have been used in the diagnosis of epilepsy. Overdose with tricyclic antidepressants is relatively frequent and its management constitutes an important clinical problem. In England, tricylic antidepressants account for approximately 15% of deaths from suicidal drug overdose (Crome 1986). The main effects of tricyclic antidepressant poi-

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soning occur in 4 organ systems: (a) the peripheral autonomic system (anticholinergic effects); (b) the cardiovascular system; (c) the CNS; (d) the respiratory system. Coma, pyramidal signs, hallucinations, agitation and convulsions are the main symptoms due to the engagement of the CNS (Crome 1986). Among these, convulsions do not seem to be very frequent and have a reported incidence of only 4% (Noble & Matthew 1969; Starkey & Lawson 1980). However, convulsions are present in almost 13% of fatal cases (Crome & Newman 1979a). Death from tricyclic antidepressant poisoning is generally ascribed to cardiac and/ or respiratory failure (Crome 1986). Repeated convulsions are known to produce hyperpyrexia, hypoxia, hypoglycaemia, metabolic acidosis and hypokalaemia and, therefore, can dramatically worsen both respiratory and cardiac functions. Status epilepticus has been reported following poisoning by amitriptyline (Scharfetter 1965) and imipramine (Michon et al. 1959). No clear information is available comparing the relative toxicity of the different tricyclic antidepressants after overdose in humans. Amitriptyline-like drugs seem to be more likely to produce sedation and coma than imipramine-like drugs (Crome & Newman I 979b). In Crome and Newman's series, a high incidence of convulsions was found in patients taking an overdose of nortriptyline (22.2%), followed by imipramine (20.6%); there were no reports of convulsions with trimipramine, clomipramine and doxepin. In patients at high risk for tricyclic antidepressant-induced convulsions, the most dangerous antidepressants should be avoided in favour of drugs less implicated for this adverse effect (e.g. some of the newer antidepressants such as viloxazine or trazodone). If this is not possible, the simultaneous administration of an anticonvulsant has been advocated (Nguyen 1987); however, in view of the enzyme-inducing properties of the anticonvulsants, it should be borne in mind that the coadministration of these drugs with tricyclic antidepressants can preclude the achievement of adequate blood antidepressant concentrations with the usual dosages (Richens 1976). In addition, anti-


114

convulsants can increase the proportion of hydroxytricyclic antidepressant metabolites, which are pharmacologically active and perhaps toxic (Baldessarini et at. 1988). These observations constitute an important clinical problem, since depression is one of the commonest psychiatric problems affecting epileptic patients (Betts 1974). Concerning the general management of tricyclic antidepressant poisoning, 2 excellent reviews have recently been published (Crome 1986; Keon & Tierney 1988). In the treatment of convulsions, paraldehyde, phenobarbital, phenytoin and diazepam have all proven to be effective when administered either alone or in combination (Crome 1986). Phenytoin has been suggested to be the drug of choice because it also has antiarrhythmic properties (Price & PosteIthwaite 1974), even though it may also potentiate myocardial depression. Intravenous diazepam 5 to 20mg followed by phenytoin 15 to 20 mg/kg (not more than 50mg per minute) as a slow intravenous injection has been proposed by Keon and Tierney (1988). When convulsions are resistant to anticonvulsant drugs, neuromuscular paralysis and artificial ventilation are necessary. Physostigmine has been used to reverse coma and other CNS complications, including convulsions, induced by tricyclic antidepressant poisoning (Burks et al. 1974). Convulsions are, however, a recognised adverse effect of this agent (Newton 1975). 1.2 Monoamine Oxidase Inhibitors Convulsions are a possible symptom in patients intoxicated with monoamine oxidase (MAO) inhibitors, and have also been observed in the hypertensive crises associated with ingestion of tyramine-containing foods (Lieberman et al. 1985). The interaction between MAO-A inhibitors and tricyclic antidepressants can lead to a condition characterised by hyper-reflexia and clonus, ataxia and myoclonic leg movements, which has been defined by Insel et al. (1982) as 'serotonin syndrome' (by analogy to what is observed in the experimental animal after strong pharmacological activation

of serotoninergic pathways). In the most serious cases, hyperthermia, rigidity, convulsions and coma can be observed (White & Simpson 1981). With the exceptions outlined above, seizures do not seem to occur when MAO inhibitors are administered at therapeutic dosages (Henry & Martin 1987). A possible anticonvulsant action of these drugs has been suggested (Baldessarini 1989) but, on the other hand, common adverse effects of these drugs include muscle tension, hyper-reflexia and twitching, possibly progressing to myoclonic jerks. This last symptom does not seem to have an epileptic origin. It has been suggested (Lieberman et al. 1985) that the serotoninergic activation produced by the inhibition of MAO-A is responsible for this effect. In fact, several studies have demonstrated that serotonin increases a-motor neuron excitability (White & Neuman 1983). No reports have appeared in the literature of increased neuromuscular activity and myoclonic jerks caused by selegiline (deprenyl), a selective MAO-B inhibitor which does not interfere with serotonin metabolIsm. 1.3 Newer Antidepressant Drugs In recent years, a large number of new antidepressant drugs have become available. These substances are claimed to have lower epileptogenic effects than classic tricyclic antidepressants (Brion 1975; Edwards & G1en-Bott 1984; Pichot et al. 1975; Trimble 1978). However, subsequent studies showed that the incidence of convulsions with mianserin (Edwards & Glen-Bott 1983), bupropion (Peck et al. 1983) and maprotiline (Edwards 1979) was as great as that associated with the tricyclic antidepressants. Among these drugs, maprotiline (Edwards 1979) and amoxapine (Jabbari et al. 1.985) seem to have a particularly high risk factor. Maprotiline is thought to lead to a significant risk of seizures when the dose exceeds 225mg daily (Nguyen 1987). Interestingly, this drug was initially thought to have less epileptogenic effect than other available antidepressants, based on studies in animal models (Trimble 1978); however, in a subsequent retrospective study in hospitalised depressed patients, the risk of seizures induced by therapeutic

115


doses of maprotiline was found to be much higher (15.6%) than that calculated in patients treated with conventional tricyclic antidepressants (2.2%) [Bryan et al. 1983]. From a toxicological point of view, maprotiline is therefore similar to conventional antidepressants (Knudsen & Heath 1984) as confirmed by Crome and Newman's (l979b) study of intoxications with antidepressants, in which a very high incidence of convulsions (25%) was found in subjects taking an overdose of maprotiline. On the other hand, nomifensine (which has now been withdrawn from the market) seems to be devoid of epileptogenic properties, and has in fact been associated with only a single case of seizure (Gillman & Sandyk 1984). This drug has failed to produce any worsening of convulsions when administered to depressed epileptic patients (Trimble 1984). Viloxazine (Edwards & Glen-Bott 1984; Pichot et al. 1975) and the new anticonvulsant fluoxetine (which was released in 1988) have also been less frequently associated with seizures, although in a recent article the latter was reported to have caused a seizure episode (Weber 1989). Fluvoxamine, lofepramine and trazodone seem to have no convulsant properties (Henry & Martin 1987). Amoxapine appears to differ toxicologically from conventional tricyclic antidepressants. After an overdose, cardiotoxicity and anticholinergic effects are uncommon while coma and convulsions are the most frequent serious complications (Bishop & Kiltie 1983). Not only have seizures been reported in a very high percentage of intoxicated patients [36.4% according to Litovitz and Troutman (1983)], but they have also been reported to be severe and prolonged (Goldberg & Spector 1982). The lastnamed authors also reported observing permanent neurological damage, possibly caused by prolonged seizures. Renal failure, which is another complication of amoxapine intoxication (Bishop & Kiltie 1983), has been associated with rhabdomyolysis, which in turn seems to be caused by prolonged seizures (Pumariega et al. 1982). Limited data are available concerning fluoxetine, fluvoxamine and lofepramine overdosage, although these drugs are generally thought to be safer than conventional tricyclic antidepressants (Crome

& Ali 1986). Finally, seizures were not observed in 22 patients who ingested toxic dosages of trazodone (Henry et al. 1984); similarly, in a report referring to 100 cases of mianserin intoxication (Chand et al. 1981), seizures or deep coma were not observed in those patients (n = 54) who ingested the drug alone. The general management of poisoning with newer antidepressants has been thoroughly discussed in a recent review (Crome & Ali 1986). Concerning the specific treatment for seizures, those induced by amoxapine and maprotiline are often resistant to anticonvulsant drugs. In such cases, patients should be promptly anaesthetised and treated with muscle relaxants to avoid risks of brain damage, cardiotoxicity or renal failure (Crome & Ali 1986).

1.4 Lithium Salts There are conflicting reports regarding the association of lithium therapy with drug-induced convulsive disorders. Seizures have been reported in non-epileptic patients with plasma lithium concentrations in the therapeutic range (Baldessarini & Stephens 1970). More recently, the effect of lithium therapy on affective relapses and clinical seizure activity was evaluated in 8 bipolar patients with seizure disorders (Shukla et al. 1988); in these patients lithium therapy did not worsen the seizure frequency, nor were seizures induced in patients who were in disease remission. Interestingly, in a subgroup of patients, lithium also exerted an anticonvulsant effect in addition to its typical moodstabilising action. This finding is in keeping with previous observations (Kavellinis 1977). In conclusion, lithium salts at nontoxic serum concentrations can have both anticonvulsant and proconvulsant properties. Myoclonic jerks have been recently observed in 2 patients during combined tricyclic antidepressant and lithium treatments (Devanand et al. 1988). This adverse effect has been ascribed to enhancement of serotoninergic transmission. The effect of lithium salts on the EEG is essentially characterised by abnormal generalised slow-

116

ing and paroxysmal diffuse a activity (Henninger 1969), which can be observed in a high percentage of cases. These abnormalities are most likely to be seen when blood lithium concentrations are above the therapeutic range, but can paradoxically occur at moderate or even low concentrations of the drug (Struve 1987). Acute intoxication with lithium salts is always accompanied by striking EEG abnormalities such as diffuse slowing, paroxysmal abnormalities and triphasic waves (Spatz et al. 1978). Convulsions are frequently observed (Sansone & Ziegler 1985). The pathogenesis and the specific management of lithium poisoning have been recently reviewed by Amdisen (1988) and Simard et al. (1989).

2. Antipsychotics 2.1 Phenothiazines Within the first year of the introduction of chlorpromazine in clinical practice, a report of a seizure induced by this drug appeared in the literature (Anton-Stephens 1953). Subsequent studies showed that phenothiazines were able to produce convulsions even in patients with no previous history of epilepsy (Hil & Soldatos 1980; Jick et al. 1972; Kugler et al. 1979; Lomas et al. 1955). In a study on hospitalised psychiatric patients, Logothetis (1967) found that the incidence of spontaneous seizures was 1.2% among 859 patients under treatment with phenothiazines. The incidence increased to 9% among patients receiving large therapeutic doses of these agents, while only 0.5% of patients treated with low or moderate doses had seizures. Patients with organic brain diseases were at higher risk. Seizures were generally observed at the onset of therapy or after a sudden increase in the dose. Almost all the anti psychotics introduced in clinical practice are now known to induce seizures in some predisposed patients.. In this respect, the aliphatic phenothiazines (e.g~ chlorpromazine, promazine and triflupromazine) are thought to be at higher risk for this adverse effect than the phenothiazines bearing a piperazine or piperidine moiety (Itil & Soldatos 1980). In general, it has


been suggested (Itil & Soldatos 1980) that the more prominent the sedative properties of an individual antipsychotic, the higher its epileptic potential. For clozapine, which has been classified as an atypical antipsychotic (Bablenis et al. 1989), sporadic cases of patients who had seizures have been reported (Povlsen et al. 1985); most of these patients had taken doses larger than those prescribed (Simpson & Cooper 1978). A number of animal studies have been conducted to gain a better understanding of the mechanism by which antipsychotic drugs can induce seizures. It has been suggested (Morrell & Baker 1961) that subcortical pathways are mainly involved. The administration of chlorpromazine to guinea-pigs with cortical alumina-gel epileptogenic lesions induced seizures which were bilaterally symmetric and myoclonic; in contrast, focal seizures were observed in animals which did not receive this drug (Morrell & Baker 1961). The administration of chlorpromazine to Papio papio baboons (in which seizures can be induced as a response to flashing light) increased the susceptibility to the epileptogenic stimulus, particularly in the less sensitive animals. These observations support the concept that chlorpromazine enhances the susceptibility to generalised seizures. The biochemical basis of the epileptogenic effect of antipsychotics has been attributed to the dopamine-blocking properties of these drugs (Trimble 1977). Another interesting observation from in vivo experimental studies in animals is that these drugs have anticonvulsant or convulsant properties, depending on the dose administered. Chen et al. (1968) studied the epileptogenic effect of chlorpromazine using an extensor seizure threshold (the minimum current necessary to elicit clonic hindlimb extension) model in mice. A decrease in the threshold was observed at low doses, while higher doses increased it. Similar findings, indicating an epileptogenic effect of chlorpromazine at low doses, had been obtained previously using another experimental model of epilepsy, the minimal electroshock seizure threshold in mice (Tedeschi et al. 1958).

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Studies with in vitro models confirm that chlorpromazine, and perhaps other antipsychotic drugs, have dose-related convulsant properties. Oliver et al. (1977) evaluated the effects of chlorpromazine, thioridazine, fluphenazine and haloperidol on potassium- and penicillin-induced interictal spike activity (in isolated perfused guinea-pig hippocampal slices) using drug concentrations representing a typical range of therapeutic serum concentrations. Chlorpromazine and thioridazine were found to produce inverted V-shape dose-response curves with a maximum epileptogenic effect (increase of neuronal firing) at concentrations less than the typical therapeutic levels. The implication of these ob~ servations is that patients would be at increased risk at the beginning of the therapy or upon drug withdrawal. Several studies have been conducted on the EEG changes induced by phenothiazines. These drugs increase the a activity with a slight shift to the lower range; they also enhance the amount of slow activity and the general amplitude of background rhythms, which also display a lower variability in all frequencies. The percentage time of {3 frequencies is decreased (Itil 1971; Terzian 1952). In a recent report (Small et al. 1987), a quantitative analysis of EEG measured in schizophrenic patients before and after administration of various an tipsychotics showed that the most striking alterations were induced by clozapine, followed by chlorpromazine, and that the least prominent alterations were seen with haloperidol. Enhancement of various EEG abnormalities (Jorgensen & Wulff 1958) and the appearance of generalised paroxysmal discharges (Logothetis 1967) have also been observed during antipsychotic therapy. Previously, the administration of low dosages of chlorpromazine or other neuroleptic drugs had been proposed as an EEG activating agent for diagnostic purposes (Stewart 1957; Friedlander 1959), but the use of this application has subsequently declined. Overdosage with antipsychotic drugs may lead to sedation and coma. In milder cases, patients can be agitated and confused (Lang & Moore 1961).

Involuntary extrapyramidal movements and seizures can be prominent but fatalities are rare. 2.2 Butyrophenones Haloperidol has been reported to possess little epileptogenic effect both in humans and in animals (Remick & Fine 1979) although the drug is considered more epileptogenic than piperazine derivatives (Itil & Soldatos 1980; Kline & Angst 1978). One case of psychomotor status-like episodes under treatment with haloperidol has been reported by Kaminer and Munitz (1984). EEG changes induced by haloperidol are similar to those observed after chlorpromazine, but less marked (Small et al. 1987). In animal models of epilepsy, dose-related convulsant and anticonvulsant effects similar to those displayed by phenothiazines have been observed (Chen et al. 1968). In the previously cited in vitro method for determining the relative epileptogenic potency of various psychoactive drugs, haloperidol produced a dose-related increase in neuronal discharges at concentrations up to 100 /-Lg/L. Higher concentrations produced no further increase in the response (Oliver et al. 1977). 2.3 Therapy and Prevention of Antipsychotic-Induced Seizures When a decision to start a treatment with antipsychotics is taken, those patients who have symptoms or a history of organic brain disease or epilepsy should be managed cautiously. Agents with a high seizure potential (e.g. chlorpromazine, promazine, perphenazine) should be avoided in favour of drugs with fewer convulsant properties; the dose should always be increased slowly (Lipka & Lathers 1987). Itil and Soldatos (1980) have given specific recommendations for patients in whom abnormal EEG findings are observed during psychotropic drug treatment (fig. I). A special problem is the treatment of epileptic patients on anticonvulsant therapy. In these cases, the possibility of pharmacokinetic interactions should also be carefully considered. Haidukewych and Rodin


118

I

Epileptiform EEG dunng psychotropIc drug treatment

I

~,

J

l

, Abnormal

~,

I I

"

I

Search for clinical findings:

I history re-evaluation and neurological examination I

, Seizures present

~

1. Further neurological workup 2. Reconsider diagnOSIS and treatment 3. Gradually discontinue epileptogenic drug use and substitute with a less epileptogenic agent. If possible 4. Weigh the therapeutiC pnorilles

I ~ I l I

L

I

Normal

No seizures

,

1. Treatment can be continued 2. Avoid dose changes 3. Avoid condilions lowering convulsive threshold 4. Record follow-up EEGs 5. PeriodiC neurological examination 6. Administer antlepileptic as adjunct. prophylactically 7 Substitute With a less epileptogenic drug If EEG detenorates

Fig. 1. Recommendations for patients showing abnormal EEG findings during psychotropic drug treatment. From !til and Soldatos (1980), with permission.

(1985) have recently observed that blood phenytoin concentrations can be reduced by more than 40% when phenothiazines are administered concurrently. A further reduction can be observed after increasing the dose of phenothiazines, while the discontinuation of the neuroleptic can lead to phenytoin intoxication. Similar but less evident changes have been observed for phenobarbital.

3. Antihistamines (HI-Receptor Antagonists) Antihistamines exert a depressant effect on the CNS, but a variety of stimulant effects (such as restlessness, nervousness and insomnia) can also be seen with conventional dosages of these drugs (Schuller & Turkewitz 1986). Overdoses of di-

phenhydramine can be characterised by jittery movements, seizures, tremors, arrhythmia, acidosis and hypotension (Hestand & Teske 1977; Krenzelok et al. 1982). An anticholinergic syndrome occurs frequently (Olson et al. 1987). The toxic effects of antihistamine drugs in overdosed patients include a combination of central excitation and depression. Children have a special susceptibility to the convulsive properties of these drugs, and particularly of those compounds that produce stimulating effects (Magera et al. 1981). In adults, convulsions are uncommon and the depressant effects are often severe. In the series reported by Wyngaarden & Seevers (1951), 5 of 8 fatalities in children under 2 years of age were accompanied by convulsions; nonfatal cases presented with convulsions in 5 of 7 children and in


3 of 11 adults. The latent period after drug ingestion can be very short and convulsions can begin after one-half to 2 hours, preceded by signs of cerebral depression or irritation. Since seizures are a sign of severe toxicity from antihistamines, concern has been expressed about the use of this class of drugs in epileptics. For example, cases of activation of epileptogenic foci in patients with focal lesions of the cerebral cortex have been reported with pyribenzamine (King & Weeks 1965); several antihistamines have also been shown to alter a normal EEG. Ethylenediamines (e.g. tripelennamine) and ethanolamines (e.g. diphenhydramine) have the greatest epileptogenic potential (Schuller & Turkewitz 1986).

4. Antiepileptic Drugs and Their Paradoxical Proconvulsant Activity Antiepileptic drugs can provoke seizures in rare cases. This adverse effect can be due to metabolic actions unrelated to the mechanism of action of the drug in the CNS (Zaccara et al. 1983), but in other cases some relationship can be suspected between the convulsant effect of the drug and its mechanism. A proconvulsant action of antiepileptic drugs can stem from the use of inappropriate anticonvulsant therapy. For example, it has long been known (Levy & Fenichel 1965) that phenytoin may aggravate absence seizures; similarly, oxazolidinediones (although effective in controlling absence seizures) can precipitate generalised convulsions (Lennox & Lennox 1960). More interestingly, increased seizure activity can also occur when antiepileptic drugs are used appropriately. Tassinari and colleagues (1972) and, more recently, Bittencourt and Richens (1981) reported a paradoxical effect of intravenous benzodiazepines, producing status epilepticus in children with the Lennox-Gastaut syndrome. According to the latter authors, the decreased level of consciousness induced by benzodiazepines and other CNS depressants could be the cause of this paradoxical effect. Many reports have revealed that carbamazepine can aggravate tonicclonic seizures (Lerman 1986; Snead & Hosey 1985).

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5. Central Nervous System Stimulants This group consists of a variety of drugs that share the ability to produce widespread dosedependent excitation leading ultimately to convulsions. CNS stimulants have been classified on the basis of their presumed major action at different levels of the neuraxis and their mechanism of action. Thus, the methylxanthines, cocaine, amphetamine, methamphetamine, ephedrine, mephentermine, methylphenidate, phenmetrazine and pipradol are defined as cortical stimulants; pentetrazol, picrotoxin and bemegride are brain-stem stimulants; strychnine is a typical spinal stimulant [see Faingold (1987) for review]. 5.1 Cortical Stimulants 5.1.1 Theophylline Theophylline preparations have been increasingly used over the past few years, particularly after the development of slow-release formulations. This increase has been paralleled by an increase in the number of theophylline intoxications, which present with a variety of symptoms affecting the gastrointestinal, cardiovascular and central nervous systems (Gaudreault & Guay 1986). The severity of symptoms may vary from mild gastrointestinal upset to serious neurological manifestations, including seizures. The latter are recognised to be associated with a bad prognosis, because the mortality rate is increased when convulsions develop and also the frequency of neurological sequelae becomes significantly higher. Seizures induced by theophylline intoxication are usually generalised, but can occasionally be focal. The mechanism by which methylxanthines stimulate the CNS is related to the blockade of adenosine receptors (Gaudreault & Guay 1986; Jensen et al. 1984; Persson & Erjefalt 1982). A diminution of the cerebral blood flow with resultant cellular hypoxia also contributes to the neurological toxicity (Oberdoster et al. 1975) and is thought to derive from the blockade of the vasodilating action of adenosine type 2 receptors (Edvinsson & Fredholm 1983). As indicated by Gaudreault and Guay (1986),

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no clear correlation between theophylline concentrations in serum and CNS has been demonstrated. However, following 1 large single dose, seizures have invariably been observed in patients in whom serum theophylline concentrations exceeded 100 mg/L. On the other hand, patients on long term treatment with the drug have experienced seizures at concentrations ranging from 8.6 to > 100 mg/ L. This difference between an acute overdose and a state of chronic intoxication is clinically important. A number of factors (previous history of seizures, encephalitis, cerebral vascular insufficiency, other brain anomalies and alcohol withdrawal) have been identified as predisposing patients on long term treatment to the development of theophylline-induced convulsions. In general, the treatment of theophylline overdosage consists in the prevention of absorption, the enhancement of its elimination and the provision of supportive care. These topics have been recently addressed in a review by Gaudreault and Guay (\ 986). Concerning the treatment of seizures, an important goal of the clinician is to stop them as rapidly as possible because a correlation has been found between the morbidity and mortality rate of theophylline intoxications and the duration of seizures. In animal studies, phenobarbital 10 mg/kg has been shown to possess the highest anticonvulsant efficacy against theophylline-induced seizures. Diazepam 10 mg/kg and phenytoin 30 mg/kg were less efficacious (Stone & Javid 1980; Walker 1981), and the latter drug exhibited in some cases the paradoxical effect of decreasing the seizure threshold instead of increasing it (Stone & Javid 1980). In humans, seizures induced by theophylline are frequently refractory: as emphasised by Gaudreault and Guay (\ 986), among the 78 cases of theophylline-induced seizures reported in the literature, more than 90% received no benefit from standard anticonvulsant treatments with diazepam (alone or in combination with phenobarbital) or phenytoin. The efficacy of phenobarbital, when used alone, has not been specifically evaluated. The treatment recommendations proposed by Gaudreault and Guay (1986) suggest that diaze-


pam (5 to 20mg intravenously at a low infusion rate within 5 to 20 minutes) should be given first. If convulsions do not stop rapidly, or if they recur, phenobarbital 15 mg/kg should be administered intravenously. If seizures do not stop within 20 minutes, the treatment strategy should be switched to the administration of thiopental. A loading dose of 3 to 5 mg/kg followed by infusion of 2 to 4 mg/ kg/h is usually efficacious. 5.1.2 Cocaine Cocaine was the first local anaesthetic, and rapidly gained popularity in ophthalmology and dentistry. Convulsions were among the earliest known adverse effects (Freud 1974; Pullay 1922). Cocaine and amphetamine augment the effects of catecholamine neurotransmitters, probably by blocking (or prolonging) reuptake at the synaptic junction and leaving an excess of these transmitters that restimulates receptors. Cocaine also has a local anaesthetic effect. In animal studies, repeated high doses of cocaine produce a convulsive response classified as pharmacological kindling. Comparison studies between amphetamine, cocaine and lidocaine (lignocaine) in seizure-kindled paradigms have shown that the effects of cocaine on the electrical activity of the brain are similar to those of lidocaine (Russel & Stripling 1985). The studies of Catravas et al. (1978) and Catravas and Waters (1981) in dogs suggest that seizures are a major determinant of lethality for cocaine poisoning. Cocaine infusion elicited prolonged generalised seizures that progressed to lactic acidosis and hyperthermia before death. Similar experiments by Fekete and Borsy (1971) and Antelman et al. (1981) indicate that pretreatment with diazepam or high dose chlorpromazine prevented the seizures and death, as did neuromuscular blockade with pancuronium. Diazepam also counteracted the sympathomimetic action of cocaine on the heart, and death was prevented if the animals were maintained in a hypothermic state; the treatment of acidosis alone had no effect. Propranolol blocked the positive inotropic and chronotropic actions of cocaine but did not affect lethality when given alone.


Seizures can be primary, because cocaine lowers the seizure threshold (Castellani et al. 1983; Cohen 1984; Jonsson et al. 1983). In humans, cocaine-induced hyperpyrexia and cardiac arrhythmias can play an important role in the induction of seizures (Cregler & Mark 1986; Jonsson et al. 1983; Quandt et al. 1988). The clinical features of cocaine poisoning consist of agitation, paranoia, visual hallucinations, hyperthermia, hypertension and tachycardia; these symptoms rapidly progress to generalised seizures and cardiopulmonary arrest. Sudden death from recreational ingestion of cocaine may be preceded by delirium, hyperpyrexia and convulsions (Fishbain & Wetli 1981; Lathers et al. 1988b; Wetli and Wright 1979). One patient intoxicated with cocaine exhibited combined metabolic and respiratory acidosis from seizures: both hypo ventilation and acidosis potentiate the effects of catecholamine on the heart (Lathers et al. 1988a) and can therefore contribute to cocaine-induced arrhythmias. An autopsy study has been performed by Mittleman and Wetli (1984) on 36 deaths attributable to cocaine use alone: in 13 of these cases the patient was observed to have a seizure before death. The incidence of acute neurological symptoms with cocaine abuse was noted in· a retrospective chart review of 989 patients with complications related to cocaine abuse (Lowenstein et al. 1987). Seizures occurred in 29 of a total of 150 patients who experienced predominant neurological problems, and were observed both in first-time users and in long term addicts. The interval between the most recent cocaine use and the seizure ranged from a few minutes (usually after intravenous injection) to 12 hours. Seizures were generally tonic-clonic, and 2 patients presented with status epilepticus. Recent reports (Merriam et al. 1988) have emphasised that the differential diagnosis of cocaineinduced behavioural disorders should include prolonged partial complex status epilepticus precipitated by cocaine abuse. Cocaine can be administered intranasally or injected subcutaneously, intramuscularly or intravenously. It can also been taken by oral, vaginal, sublingual, or rectal routes and it can be smoked

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(Cregler & Mark 1986). Multiple seizures following the rupture of cocaine-filled condoms in 'body packers' have been associated with high blood concentrations of 2.0 to 5.2 mg/L (Bettinger 1980; Suarez et al. 1977). The route and the speed of administration seem to be important factors in cocaine toxicity. Myers and Earnest (1984) have reported 3 cases of generalised tonic-clonic seizure shortly after injecting cocaine. Intravenous use results in a rapid rise in blood drug concentration and intense euphoria. A lower intravenous dose may produce the same effect as a higher dose by the nasal route (Resnick et al. 1977). 'Street' cocaine alone, which is assumed to be water-soluble hydrochloride salt, can actually be adulterated by a number of substances including local anaesthetics, antihistamines and sympathomimetics (Mittleman & Wetli 1984; Quandt et al. 1988). Schwartz et al. (1988) postulated that the admixture of cocaine and phencyclidine (or alcohol) can be expected to produce seizures even more frequently. The currently accepted management of adrenergic cocaine crisis involves the judicious use of propranolol (Gay 1981, 1982; Ramoska & Sacchetti 1985). Labetalol, which possesses both a- and (j-blocking capabilities, has been proposed as an alternative; the establishment of a-blockade counters the cocaine-induced vasoconstriction and hypertension, while the (j-blockade decreases the tachyarrhythmias (Gay & Luperka 1988). In a series of animal studies by Trouve and Nahas (1986), the cocaine-antagonistic effects of nitrendipine, a Ca++ modulator, were evaluated. In addition to its cardioprotective properties, nitrendipine exerted a central activity which prevented motor tremors, convulsion and seizures. Lathers et al. (I 988b) stated that nitrendipine could in future become the drug of choice for treatment of cocaine intoxication. The management of a patient with cocaineinduced seizure is empirical at present, and should be based on presentation symptoms. All patients should have a thorough evaluation to rule out other neurological problems either pre-existing or co-

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caine-induced, such as subarachnoid or intracerebral haemorrhage and ischaemic stroke (Bates 1988; Chasnoff et al. 1986; Cregler & Mark 1986; Mody et al. 1988; Rowbotham 1988). If no cause of the single seizure other than drug use is found, and no other neurological or cardiac event appears, no long term treatment other than drug abstinence is required. If the patient presents a second seizure, diazepam can be administered to counteract it. If status epilepticus develops, phenobarbital loading (Lowenstein et al. 1988) and pentobarbital anaesthesia can be used (Rowbotham 1988). It is essential to keep the body temperature as near normal as possible, and to correct the acidosis which can increase the risk of seizures. 5.1.3 Amphetamine Amphetamine-induced seizures are very rare among users of low doses but can occur in high dose 'binge' users. Convulsions, as a complication of amphetamine use, were first described by the Report of the Council on Pharmacy and Chemistry (Editorial 1937). Amphetamine poisoning can produce central widespread stimulation, diaphoresis, tachycardia, hypertension, hyperhydrosis, hyperthermia, auditory or visual hallucinations and psychosis that usually gives way to fatigue and mental depression which may be followed by convulsions and coma (Espelin & Done 1968; Litovitz 1983; Quandt 1988). In the management of amphetamine poisoning, it is mandatory to control seizures when present, but it is also important to anticipate the possibility of hyperthermia secondary to prolonged muscular hyperactivity and increased metabolic activity. Severe hyperthermia may itself cause seizures and is often complicated by rhabdomyolysis and myoglobinuric renal failure (Olson & Benowitz 1984). Unlike cocaine, amphetamine has no central convulsive effects in low doses (Nausieda 1979; Stevens et al. 1969). The drug protects young chicks against maximal electroshock seizure, and this activity has been attributed to dopamine release, since it was potentiated by FLA-63 (a dopamine (j-hydroxylase inhibitor) and antagonised by pimozide (Osuide et al. 1983).


Pharmacological evidence supports a role of dopaminergic neurotransmission in epilepsy: in fact, drugs that deplete brain monoamines, such as reserpine, result in an increase of seizure susceptibility and, in addition, neuroleptics with dopamine receptor blocking properties result in EEG evidence of seizure activity and worsen the EEG pattern. In contrast, amphetamine increases dopaminergic transmission, decreases seizure activity and improves EEG (Kobayashi & Mori 1977; Lamprecht 1977; Trimble 1977). Warte et al. (1988) showed that, in a model of genetic petit mal-like seizures of a strain of Wistar rats, mixed dopaminergic D1/D2 agonists (e.g. levodopa, apomorphine, amphetamine and nomifensine) gave dosedependent reductions of the duration of spike and wave discharges. Mixed D,/D2 antagonists (e.g. haloperidol, flupenthixol and pimozide) caused a dose-dependent increase of duration of spike and wave discharges. The authors also tested D2 and D, agonists and antagonists in this model and suggested that both activities were necessary for influencing spike and wave discharges. Based on these considerations, the use of amphetamines was proposed as a comedication of some epileptic disorders (Lennox & Lennox 1960). However, the Physician's Desk Reference (1984) states that methylphenidate, an amphetamine-like compound, may lower the convulsive threshold in patients with prior history of seizures or EEG abnormalities. Some clinical experiences in children with epilepsy and attention-deficit disorder contradict this hypothesis and suggest that the drug does not lower the seizure threshold when used at therapeutic doses (from 0.33 mg/kg/dose to 0.63 mg/ kg/day) [McBride et al. 1986].

5.2 Brain-Stem Stimulants Pentetrazol and picrotoxin act as brain-stem stimulants: the former produces direct excitation and the latter blocks the inhibitory actions of GABA [for review see Faingold (1987)]. These drugs were used in the 1950s to induce convulsions in psychotic patients for therapeutic purposes (Dolenz 1967). Other drugs that act as respiratory stimulants (e.g. doxapram) are now used in anaesthetic practice to counteract the excessive sedation and

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ventilatory depression induced by barbiturates or diazepam; while possessing epileptogenic potential, doxapram is nonetheless effective and safe in reversal of drug-induced sedation and, when used at conventional doses, it does not carry a significant risk of drug-induced convulsions (Allen & Gough 1983; Calverley et al. 1983). 5.3 Spinal Stimulants Strychnine acts by blocking the inhibitory action of glycine at postsynaptic receptors in several CNS locations, particularly in the spinal cord (Curtis et al. 1971; for review see Faingold 1987). Myoclonic movements, trismus, rigidity, opisthotonus, risus sardonicus and generalised convulsions are recognised features of strychnine poisoning (Dittrich et al. 1984). Intravenous diazepam is the drug of choice for the treatment of convulsions. 5.4 Non-Prescription Stimulants Many different non-prescription tablets and capsules are widely distributed as safe and powerful stimulants. The stimulants contain (alone or in combination) the same basic ingredients: caffeine 100 to 200mg, phenylpropanolamine 25 to 50mg and ephedrine 25mg. Although phenylpropanolamine, as a diet-aid or nasal decongestant, and ephedrine, as a bronchodilator, are both available in non-prescription preparations, the incidence of abuse and toxicity has remained relatively low. Phenylpropanolamine is known to cause headache, insomnia, nervousness and hypertension (Appelt 1979). Howrie and Wolfson (1983) reported that a 13-year old patient experienced 2 generalised seizure episodes preceded by headache, nausea and hypertension after ingesting phenylpropanolamine 150mg following a 2-week treatment with 75mg daily. Phenylpropanolamine-induced seizures are probably mediated by the hypertension caused by the drug. Although the case report described by Howrie refers to a dosage exceeding the manufacturer's recommendations, hypertension associated with seizures has also been observed with usual

dosages of phenylpropranolamine (Deocampo 1979; Mueller & Solow 1982). The management of acute toxicity from nonprescription stimulants has been reviewed by Sawyer et al. (1982), and involves establishing respiration, initiating emesis, administering activated charcoal and cathartics, and monitoring blood pressure, ECG, fluid intake and urinary output. Intravenous diazepam is the drug of choice for the treatment of convulsions.

6. General Anaesthetics Seizure activity under anaesthesia is an uncommon phenomenon and has been observed following anaesthesia with enflurane, isoflurane and intravenous anaesthetics; halothane has virtually never been implicated. The possible aetiologies include epilepsy, local anaesthetic overdose, accidental intravascular injection of a drug, idiosyncratic reactions, hyperventilation syndrome, cerebrovascular accidents, hypoglycaemic reactions, oxygen toxicity and vasodepressor syndrome. 6.1 Inhalation Anaesthetics 6.1.1 Enflurane Enflurane is the anaesthetic most widely recognised as having epileptogenic properties (Quail 1989). The drug has been shown to produce generalised seizures which may be evoked by a variety of sensory stimuli (Botty et al. 1968; Joas et al. 1971; Linde et al. 1970; Mori 1973). Studies have reported on the nature (Moorthy et al. 1980) and the origin (Meyers & Shapiro 1978) of this epileptogenic effect. Enflurane anaesthesia is associated with high amplitude spikes and periods of electrical silence on the EEG (Julien & Kavan 1972). The hyperexcitability originates in the limbic system with subsequent spread to other areas (Darimont & Jenkins 1977), and is potentiated by increasing concentrations of enflurane and by hypocapnia (Bart et al. 1971). Small doses of thiopentone, methohexitone or diazepam can enhance the seizure activity (Darimont & Jenkins 1977; Furgang & Sohn 1977; Schettini & Wilder 1974). The concom-

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itant use of nitrous oxide can have an anticonvulsant action on the epileptogenic property of enflurane, but rebound hyperexcitability can occur when nitrous oxide is withdrawn (Stevens et al. 1983). Nitrous oxide-associated convulsions have also been reported (Steen & Michenfelder 1979). Frank motor seizures have been observed with enflurane, often during recovery from anaesthesia (Rosen & Sioderberg 1975). Several reports have described convulsions in non-epileptic subjects during recovery from enflurane anaesthesia (Allan 1984: Jenkins & Milne 1984; Yazji & Seed 1984). Julien and Kavan (1972) have shown that in cats there is a prolonged period of abnormal EEG activity of up to 16 days following enflurane anaesthesia: curiously, the EEG can be initially normal from 2 to 24 hours after exposure. Even in humans, the EEG changes can persist for many days after exposure (Burchiel et al. 1977; Kruczek et al. 1980): indeed, 2 cases of delayed convulsions have occurred 6 and 8 days postoperatively after enflurane anaesthesia (Ohm et al. 1975). Localised myoclonic jerks at 48 hours after anaesthesia have also been reported in patients with no previous history of epilepsy (Grant 1986). It has been suggested that when the enflurane concentration is low [less than 1.5 minimum alveolar concentration (MAC), i.e. about 2.5%] and hypocapnia is avoided, the occurrence of seizures can be minimised (Michenfelder & Cucchiara 1974). Opitz and Oberwetter (1979) have been able to give enflurane safely to epileptic patients and in a recent review Quail (1989) states that enflurane should not be contraindicated in patients with a history of cerebral convulsive disorders, provided that its concentration is kept low and normocapnia is ensured. However, in the epileptic patients studied by Yamashiro et al. (1985), enflurane induced paroxysmal discharges in the EEG during normocapnia and at concentrations commonly considered not to be epileptogenic. No conclusive recommendations are, therefore, available on this issue. Enflurane is also used for activating epileptogenic foci during epilepsy surgery (Ito et al. 1988).


6.1.2 Isoflurane Seizure activity during general anaesthesia with isoflurane in patients with no previous history of neurological disorders has been reported by Hymes (1985) and Harrison (1986). Myoclonic seizures developed in Hymes's patient 2 hours after induction, while still receiving isoflurane, and progressed to a generalised seizure involving the musculature of the extremities, abdomen, trunk and face. After this episode, the patient continued to have sustained myoclonus in all the extremities and his seizure-like activity persisted in the recovery period when the patient was awake. The proposed role of isoflurane as the aetiological agent has been questioned by Keats (1985) on the basis that the patient had received multiple drugs including diazepam, morphine, glycopyrrolate, fentanyl, d-tubocurarine, thiopental, succinylcholine, nitrous oxide, oxygen and isoflurane. Harrison's patient developed myoclonus in the recovery period (90 minutes after induction); the patient received only thiopental, nitrous oxide, oxygen and isoflurane. In both cases described by these authors, myoclonic movements of the extremity were increased by stimulation, and the patients had normal laboratory values and unchanged vital signs. 6.2 Intravenous and Non-Narcotic Anaesthetics An increasing interest in intravenous anaesthetic techniques has resulted from the availability of more efficacious agents. Their seizure potential in the general population is negligible, but like enflurane and isoflurane, some of these agents have been used in epilepsy surgery to activate epileptogenic foci. 6.2.1 Ketamine While an increase in seizure incidence has been reported to follow ketamine anaesthesia (Steen & Michenfelder 1979; Corssen et at. 1974), Celesia et al. (1974) and Madsen et al. (1974) have administered this agent to epileptic patients for anaesthesia without observing any significant seizure effects. However, in epileptic patients receiving


ketamine anaesthesia, behavioural changes and tonic and tonic-clonic motor activity have been observed; depth electrode recordings have found isolated subcortical seizure activity originating in limbic and thalamic areas (Ferrier-Allado et al. 1973). There is no evidence that this seizure activity affects cortical regions, or that clinical seizures are likely to occur (Myslobodsky et al. 1981). Severe myoclonus has followed ketamine anaesthesia in infants with myoclonic encephalopathy, and has been attributed to subcortical activation which may not be seen in surface EEG recordings (Burrows & Seeman 1982). 6.2.2 Etomidate Since its introduction in clinical practice, etomidate has been reported to cause involuntary myoclonic movements during induction and maintenance of anaesthesia (Laughlin & Newberg 1985; Tasch 1985; McIntosh et al. 1979). The myoclonus produced after administration of etomidate may be quite dramatic, and at times may simulate tonic seizure (Ghonein & Yamada 1977). These involuntary movements have not been correlated with any epileptogenic activity of the drug, which is on the contrary known to possess potent anticonvulsant properties in animals (Ashton & Wauguier 1979; Ashton 1983). There is no definite neuropharmacological explanation for this seizure-like activity of etomidate, which is, however, thought to result from a disinhibition of subcortical activity rather than from a specific epileptogenic effect of the compound (Kugler et al. 1977). Etomidate has been reported to enhance the epileptogenic activity in patients with refractory epilepsy (Gancher et al. 1984; Krieger et al. 1985). Such activation of epileptogenic activity during the induction of anaesthesia is an effect that seems to be paradoxical, but is not unique to etomidate (see also methohexital, below). 6.2.3 Methohexital Methohexital, another ultrashort-acting drug, enhances epileptogenic activity in patients with focal seizures and is in fact used to help localise epileptogenic foci during seizure surgery (Musella et

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al. 1971). In a study by Wyler et al. (1987) the drug proved to possess safe and reliable capabilities to activate epileptogenic foci during acute electrocorticography.

7. Local Anaesthetics Lidocaine and other local anaesthetics have convulsant effects at high doses and anticonvulsant action at low doses; indeed, lidocaine can even be effective to treat convulsive status epilepticus (Hellstrom-Westas et al. 1988; Lemmen et al. 1978; Pascual et al. 1988; Taverner & Bain 1958). Seizures are a frequent and hazardous toxic effect of local anaesthetic overdosage, and in most cases occur when the injection is made accidentally into a blood vessel. Brief convulsions may occur after standard doses of intravenous bupivacaine or may follow the injection of small doses in the head or neck (Reynolds 1987). For example, convulsions have been reported following local injection ofbupivacaine 7.5mg for stellate ganglion blockade (Korevaar et al. 1979). Also, the interscalene block with a bupivacaine 25% test dose (2ml followed by 5ml and 1: 200,000 epinephrine) in an epileptic patient has been associated with Jacksonian fit and Todd's ,paralysis; 150 minutes later, a grand mal seizure occurred (Collier & Engelking 1984). The authors hypothesised a toxic reaction to intravascular injection of bupivacaine. In the report by Coates et al. (1983),4 of 100 patients undergoing regional hip block with bupivacaine developed convulsions. An extremely rich venous plexus that surrounds the quadratus femuris muscle, and rapid absorption of local anaesthetic solution, may explain the high risk of seizures. Other acute reactions to local anaesthetic agents include myoclonus following spinal anaesthesia. This has been reported by Fox et al. (1979), with tetracaine in combination with epinephrine, and by Nadkarni and Tondare (1982), with lidocaine in combination with epinephrine. The latter authors hypothesised that the concomitant action of local anaesthetic and epinephrine caused ischaemia in the spinal cord, with resultant transient and localised seizure-like spinal activity.

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eNS toxIcity of local anaesthetics depends largely upon the membrane-stabilising effect of the drug, and for this reason the intravenous lethal dose (LDso) bears a direct relationship to the potency of the drug in nerve conduction block (Reynolds 1987). A clear exception to this rule is cocaine, the toxicity of which stems not only from membrane stabilisation, but also from interference on aminergic reuptake. The plasma concentrations of local anaesthetics measured in association with mild toxicity and convulsions vary widely, partly because they can change very rapidly following a bolus entry into the circulation. For example, seizures following a dose of bupivacaine 4.8 mg/kg have been associated with a measured plasma concentration of only 1.1 mg/L (Hassel strom & Mogensen 1984), while there has been an absence of fits in association with concentrations as high as 6 mg/L, albeit in anaesthetised patients (Neil & Watson 1984). There is agreement, however, that the cumulative toxicity of local anaesthetic agents depends directly on the concentration achieved in the plasma. Following infusion, a plasma bupivacaine concentration of 1.6 mg/L is associated with mild toxic symptoms (Reynolds 1971); according to another report (Editorial 1989), eNS depression, stimulation or seizure can occur with plasma lidocaine concentrations above 5 mg/L. Factors affecting plasma concentrations and thus toxicity include the site and rate of injection, concentration and total dose administered, use of a vasoconstrictor, rate of distribution, degree of ionisation, degree .of plasma and tissue binding, age, weight and rate of metabolism and excretion (Reynolds 1987). In agreement with these considerations, the incidence, duration .and severity of systemic reactions encountered with the clinical use oflocal anaesthetic agents have been much less with rapidly hydrolysable agents than with those that are hydrolysed only slowly, or not at all, by plasma esterases (Foldes et a1. 1960). Neonates may metabolise bupivacaine, mepivacaine and etidocaine more slowly than adults (Reynolds 1984), but in contrast tend to exhibit lower total plasma concentrations because of reduced protein binding.


Symptoms in neonates occur in the same order as in adults, namely: convulsions, hypotension, respiratory arrest, circulatory collapse (Morishima et al. 1983). Seizures resulting from the cumulative toxicity of local anaesthetics may give rise to concern, particularly during continuous extradural blockade and during lidocaine infusion in intensive care (Reynolds 1987). Adverse effects from oral viscous lidocaine therapy are rare, although some authors have reported cases of cumulative toxicity of viscous lidocaine in infants, leading to seizures (Rothstein et al. 1982). Giannelly et al. (1967) have suggested that lidocaine-induced toxic effects (e.g. eNS depression and convulsions) can be avoided if the dose is kept below 55 ~g/kg/min (4 mg/min in a 70kg patient) and blood concentrations are below 5 mg/L; conversely, these effects are very likely to occur if the dose exceeds 75 ~g/kg/min and the blood concentration is above 9 mg/L. In this series, 3 patients experienced eNS toxicity with blood levels of 22.8, 10.9 and 6.8 mgfL, respectively. All were stuporous, and focal seizures developed in 2. Another patient had a tonic-clonic seizure after receiving two IOOmg boluses within 15 minutes. However, he had had 2 seizures associated with ventricular fibrillation before lidocaine infusion was begun, and a third grand mal seizure after the infusion when the circulation was functioning normally. Lidocaine is 70% eliminated by the liver to produce the primary metabolite monoethylglycinexylidide (MEGX), which can contribute to its toxicity (Karang et al. 1978). Both the metabolite and parent drug have been found to accumulate in high concentrations in congestive cardiac failure, and lidocaine-induced toxicity can be seen at low drug concentrations if MEGX concentrations are elevated (Davison et al. 1982; Halkin et al. 1975). Acidosis increases the amount of unbound active drug, thus augmenting its toxicity (Burney et al. 1978). In addition, hypoxia and hypercapnia can increase cerebral flow, carrying more lidocaine to the brain. Hence, correcting the respiratory acidosis and reducing the cerebral blood flow can both

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be important to control the seizure actIvity lflduced by the drug (Edgren et al. 1986). The management of acute lidocaine intoxication is aimed mainly at supportive care. In adults, toxicity often results in severely depressed cardiac function, and the consequent hypoxia and acidosis can facilitate seizures. Drug interactions can also potentiate the toxicity of lidocaine in intensive care: for example, hepatic blood flow, and therefore lidocaine clearance, can be reduced by cimetidine (Feely et al. 1982) and propranolol (Ochs et al. 1980), and so lidocaine toxicity during an antiarrhythmic infusion can be potentiated by the coadministration of these drugs. Albright (1979) postulated that the new anaesthetic agents (bupivacaine, etidocaine) can produce almost simultaneously both seizures and cardiovascular collapse, without antecedent hypoxia, if a standard dose is administered inadvertently by the intravenous route. Conversely, Moore et al. (1982) have reported 2 cases of severe hypoxia and acidosis occurring prior to or concomitantly with convulsions, and proposed that any delay in the proper treatment of associated hypoxia and acidosis can trigger cardiac arrest (Moore 1980; Moore et al. 1980). Animal work has suggested that diazepam might be better than barbiturates in the treatment oflocal anaesthetic-induced convulsions (Scott 1981). However, both agents, but particularly thiopentone, will seriously exacerbate circulatory and respiratory depression. Since severe hypoxia, hypercapnia and lactic acidosis occur concomitantly with local anaesthetic-induced convulsions (Moore et al. 1982), treatment with intravascular suxamethonium (succinylcholine) 80 to 100mg and simultaneous ventilation by bag and mask using 100% oxygen is the immediate treatment of choice to stop convulsions rapidly; this treatment should be preferred to diazepam or thiopentone (Moore & Bonica 1985; Moore & Bridenbaugh 1985). The advantages of suxamethonium are that it rapidly and consistently stops convulsions (and thus lactic acid production), permits ventilation and does not depress the myocardium, as do thiopental and all local anaesthetics. It has, however, been argued that

suxamethonium might cause hyperkalaemia and thus exacerbate lidocaine cardiotoxicity (Moore & Bridenbaugh 1983) while having no effect on cortical electric seizure activity (Reynolds 1987).

8. Antiarrhythmic Drugs Seizures have frequently been reported with the use of antiarrhythmic agents (Editorial 1989; Jick et al. 1972; Olson et al. 1987; Russel et al. 1983; Schwartz et al. 1981). Lidocaine toxicity has already been discussed. Mexiletine and tocainide possess electrophysiological properties similar to those of lidocaine, and both can induce central toxicity and convulsions (Editorial 1989; Schwartz et al. 1981). In particular, therapy with intravenous mexiletine has been associated with adverse effects affecting the CNS such as tremors, nystagmus, blurred vision, dizziness, drowsiness, confusional states, ataxia, dysarthria, insomnia, nausea, tinnitus and seizures (Campbell et al. 1977). Schuster et al. (1987) showed that, in dogs, tocainide at therapeutic serum concentrations can lower the threshold of seizures induced by lidocaine. These findings have important implications for clinical care because they suggest that lidocaine should be used cautiously and in reduced dosage in patients already treated with tocainide or with other oral lidocaine analogues. Ajmaline, a reserpine derivative, shows doserelated neurological adverse effects that can produce eye-twitching, convulsions and respiratory depression (Beermann et al. 1971). Severe hypoglycaemia induced by disopyramide has probably caused seizures in a patient, reported by Nappi et al. (1983). Johnson et al. (1978) reported grand mal convulsions following disopyramide, and attributed this adverse reaction to its anticholinergic effect; however, blood glucose was not measured. Cases of convulsions and coma related to quinidine overdosage have been reported by Kerr et al. (1971) and Thomson (1956). Clinically, quinine poisoning is seen either in self-poisoning or accidentally as a result of the adulteration of 'street drugs'; use of quinine in excessive doses in the hope


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of achieving abortion has also been reported. Seizures are a sign of massive overdosage with quinine derivatives, and may occur before coma and respiratory depression; convulsions are usually shortlived but, if they persist, intravenous diazepam can control them (Bateman & Dyson 1986). Seizures have been reported after overdosage with propranolol. Weinstein (1984) reviewed a series of reported cases of ~-blocker overdose, the majority of which involved propranolol. Bradycardia (92%) and hypotension (77%) were found to be the most common symptoms; seizures occurred in 58% of patients. In the series reviewed by Frishman et al. (1984), depression of consciousness correlated closely with depression of blood pressure, irrespective of the ~-blocker involved. In contrast, the incidence of convulsions was not apparently related to depression of blood pressure, and was not a common feature with drugs other than propranolol. Propranolol and related drugs can reduce or completely suppress convulsions induced by electroshock, pentetrazole and strychnine (Madan & Barar 1974; Yeah & Wolf 1968). Tkatchenko et al. (1987) studied the influence of ~-blockers on epileptiform activity of the rabbit hippocampus, and found that the i1-adrenergic blocking agents caused faster and more intense activity of the epileptogenic focus in comparison with control animals, but the number of seizures decreased by 25%. It is unclear how propranolol can induce seizures at very high dosages, but a nonspecific action on centrally located neurons, related to its membrane-stabilising effects, is probably involved, as well as the high lipophilicity of the drug and its ability to penetrate into cerebral tissues (Buiumsohn et al. 1979). Convulsions have also been reported following massive metoprolol overdosage (Wallin & Hulting 1983). The management of acute poisoning due to ~-adrenoreceptor antagonists has been recently reviewed in the Journal by Critchley and Ungar (1989).

9. Opioids and Other Narcotic Analgesics When administered centrally, both morphine and the related endogenous opioid peptides (e.g. ~-endorphin, [Met5]enkephalin and

[Leu5]enkephalin) can evoke an epileptiform activity in the EEG (Henriksen et al. 1978; Teitelbaum et al. 1976; Tortella et al. 1978; Urca et al. 1977). There is some evidence that these epileptiform discharges are mediated by specific opioid receptors; this activity is in fact antagonised by opiate antagonists such as naloxone (Henriksen et al. 1978; Tortella et al. 1978), and a tolerance to these EEG peptide-induced seizures develops after repeated intraventricular injections (Tortella et al. 1979). In rats, the seizure activity evoked by opioids is thought to be mediated by ~-receptors in the hippocampus (Lee et al. 1988) and, in humans, these receptors are increased in patients with temporal lobe epilepsy (Frost et al. 1988). Morphine has also an anticonvulsant effect in experimental models (Nowack et al. 1987). 9.1 Pethidine (Meperidine) While the opioids can produce EEG-proven seizures in animals (de Castro et al. 1979), the doses required are many times greater than those used in anaesthesia or analgesia. This does not hold, however, for pethidine. Pethidine is metabolised to norpethidine, which is about half as active as the parent compound in terms of analgesic potency but twice as active as a convulsant. Accumulation ofnorpethidine can typically be seen after prolonged administration of pethidine, especially in the presence of renal impairment (Kaiko et al. 1983). Jitteriness, tremors, myoclonus and convulsions occur in progression proportional to the plasma concentration of the metabolite (Goetting & Thirman 1985). EEG changes of slow wave activity and epileptiform discharges are commonly seen, but these resolve after the norpethidine has been excreted, unless an underlying cause for seizures persists (Kaiko et al. 1983). Norpethidine side effects develop at plasma concentrations around 0.8 mg/L. The pharmacokinetics of pethidine influence its cerebral toxicity. The drug undergoes extensive firstpass metabolism when given orally (Mather & Tucker 1976); hence, an oral dose produces a higher ratio of metabolite/drug concentrations than the

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same dose given parenterally (Stambaugh et al. 1976). Naloxone does not reverse norpethidine toxicity and can, on the contrary, exacerbate the condition by antagonising the anticonvulsant effect of pethidine (Armstrong & Bersten 1986; Kaiko et al. 1983). Monoamine oxidase (MAO) inhibitors can interact with pethidine, giving an idiosyncratic reaction involving CNS excitation, hypertension, tachycardia, pyrexia, rigidity and convulsions (Duthie & Nimmo 1987); the combination of MAOinhibitors with pethidine should therefore be avoided. This interaction has not been reported with morphine in humans, but has been seen with pethidine, morphine and pentazocine in mice (Rogers & Thornton 1969).

Acute dextropropoxyphene overdosage in cases of self-poisoning is often associated with ingestion of other drugs, usually hypnotic, sedative or psychotropic agents. Dextropropoxyphene hydrochloride is commonly associated in the tablet with paracetamol (acetaminophen) [dextropropoxyphene 32.5mg and paracetamol 325mg as in 'Distalgesic', 'Dista' and 'Digesic']. Presenting features of dextropropoxyphene overdosage may include status epilepticus in about 10% of symptomatic cases (Young & Lawson 1980); this condition requires immediate intravenous administration of diazepam and assisted ventilation, if needed, before the patient is treated with naloxone (Young 1983). 9.4 Fentanyl and Sufentanil

9.2 Morphine Morphine can induce seizures at high doses in neonates and infants (Koren et al. 1985). An incomplete blood-brain barrier allows greater penetration of the drug into CNS receptor sites, thus increasing toxicity, as demonstrated in rats by Kupferberg and Way (1963). In adults, seizures are probably only a theoretical complication of intraspinal administration of morphine or other opioids (Cousins & Mather 1984), and the cases reported are in fact very rare. Landow (1985) described the occurrence of a focal seizure which was probably correlated with a high-pressure intrathecal injection in a patient with cancer. Borgeat et al. (1988) reported the case of an epileptic woman who developed a generalised tonic-clonic seizure 6 hours after the administration of morphine 3mg into the extradural space. 9.3 Dextropropoxyphene (Propoxyphene) Dextropropoxyphene, a narcotic agent chemically similar to methadone, is biotransformed to a potentially toxic metabolite (norpropoxyphene). Dextropropoxyphene and the metabolite can accumulate after repetitive dosing or overdose, leading in some cases to convulsions (Inturrisi 1989; Young 1983).

Recent case reports, unaccompanied by EEG recordings, of fentanyl- or sufentanil-induced seizures in patients have generated much discussion and concern (Brian & Seifen 1987; Katz et al. 1988; Rao et al. 1982; Safwat & Daniel 1983; Sebel & Bovill 1983); seizures have in fact been associated with both low and high doses of these opioid agents. Murkin et al. (1984) found that a very high peak plasma fentanyl concentration, and moderately high but sustained fentanyl concentrations, were not associated in humans with EEG signs of seizure activity or cortical excitation. Scott and Sarnquist (1985) described seizure-like movements with no signs of cortical seizure activity on the EEG. Katz et al. (1988) observed a patient in whom seizurelike activity was elicited by sufentanil and by fentanyl on 2 separate occasions: during the second episode, EEG recordings revealed no unusual CNS activity. Fentanyl produces subcortical seizures in rats, and the subcortical region of the brain has been identified as the focus of fentanyl-induced seizure activity. A hypermetabolic state in the structures of the limbic system was observed in rats during drug-induced epileptoid activity, coupled with significant reduction of glucose utilisation in the remainder of the brain (Tommasino et al. 1984). It is a matter for speculation whether or not the


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tonic-clonic movements described in these patients were true seizures. Somatic muscle rigidity has been proposed as an explanation for these phenomena, because studies using large doses of fentanyl failed to reveal any EEG activation (Murkin et al. 1984; Sebel et al. 1981). In some cases the successful use of small doses of nondepolarising muscle relaxants to control such seizures has led to the conclusion that these phenomena can represent an exaggerated form of narcotic-induced muscle rigidity (Benthuysen & Stanley 1985). Another possibility is that this reaction is a form of myoclonus secondary to narcotic-induced depression of inhibitory neurons; however, if the significant number of cases in which this seizure-like activity has been linked to fentanyl or sufentanil administration are taken into account, an unknown, idiosyncratic mechanism for this reaction should be ruled out (Katz et al. 1988; Scott & Sarnquist 1985; Sebel & Bovill 1983). 9.S Pentazocine Seizures have been reported following intravenous administration of pentazocine 30 mg/kg for anaesthesia (Jackson et al. 1971). Conclusive data on the frequency of this adverse reaction are, however, lacking.

10. Non-Narcotic Analgesics and Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) 10.1 Aspirin and Salicylates Aspirin is the drug most commonly taken in overdosage by children less than S years of age. It is also frequently implicated in many suicide attempts in adults. A unique feature of aspirin intoxication is that it inhibits gastric emptying, thus prolonging the drug absorption over a period of up to 24 hours after ingestion. Methylsalicylate is another common cause of salicylate intoxication; it can be absorbed through the skin as well as orally. A Sml dose of methylsalicylate is as toxic as 6 to 7g of aspirin (Brenner & Simon 1982). The toxic effects of aspirin are almost entirely mediated by salicylic acid, formed by hydrolysis of

the drug. Salicylate uncouples oxidative phosphorylation from electron transport; as a result, heat production is increased. Tissue glycolysis and the peripheral demand for glucose are also increased, inasmuch as adenosine triphosphate is not being generated. The consequence is a depletion of the body stores of glucose. In clinical terms, patients with salicylate intoxication typically present with tachypnoea and neurological abnormalities including confusion, agitation, tinnitus, hyperactivity, slurred speech, hallucination and seizures. An anion-gap type metabolic acidosis is frequently associated with the respiratory alkalosis. Seizures present most often as generalised convulsions, although focal seizures have also been observed in rare cases. The seizures are believed to result from the depletion of brain glucose, even though blood glucose frequently remains normal. The symptoms of salicylate intoxication in elderly patients can mimic other diseases, and so diagnosis can be delayed or even missed completely. Reduced liver blood flow and metabolism in the elderly impair the biotransformation of aspirin, predisposing these patients to salicylate intoxication. The nonlinear pharmacokinetics of salicylates also contribute to this effect (Vivian & Goldberg 1982). The general guidelines for the management of salicylate intoxication have been reviewed by Brenner and Simon (1982) and by Vivian and Goldberg (1982). For treatment of salicylateinduced convulsions (should they occur) intravenous diazepam is considered the drug of choice, while short-acting barbiturates are the second-line agents (Rumack 1981; Temple 1978). Seizures can, however, be prevented by instituting a comprehensive therapeutic programme such as those outlined in the 2 reviews mentioned above. 10.2 Mefenamic Acid Mefenamic acid has analgesic and anti-inflammatory actions. An overdose of the drug can cause convulsions (Young 1979), which are extremely resistant to intravenous diazepam. The drug is rap-


idly absorbed after oral administration and has a very short half-life (about 2 hours); this is why convulsions after an overdose are most likely to occur during the first few hours following ingestion of the drug. Shipton and Muller (1985) described the case of an 18-year-old girl who ingested 90 capsules of mefenamic acid 250mg and manifested generalised tonic-clonic convulsions approximately I hour later. Following admission to hospital, the patient received intravenous diazepam 80mg, which was virtually ineffective. The plasma concentration of the drug was 103 mg/L. Seizures were controlled only after intubation by administration of etomidate 20mg plus pancuronium. Standard therapeutic measures were also applied (gastric aspiration via nasogastric tube and administration of activated charcoal 30g plus sodium sulfate 40g). By the following day the patient had regained full consciousness and movement, and her subsequent recovery was uneventful. A similar case has been described by Balali-Mood et al. (1981) in which mefenamic acid reached an even higher plasma concentration (211 mg/L) and convulsions were not controlled by intravenous diazepam 60mg. Therapeutic dosages of mefenamic acid seem to be very unlikely to cause seizures (Young 1979); however, the possibility that mefenamic acid poisoning may be responsible for a previously well patient presenting with status epilepticus should be borne in mind. Some authors (Reynolds 1982) recommend that the drug should be avoided in subjects with a history of epilepsy. 10.3 Other NSAIDs Most of the other NSAIDs (e.g. ibuprofen and indomethacin) seem to be devoid of a significant seizure potential.

11. Antimicrobial Agents ll.l (j-Lactam Antibiotics Penicillin has the ability to produce focal seizures by topical application in vivo and in vitro, and for this reason the drug has been employed exten-

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sively in epilepsy research. The mechanisms implicated in the epileptogenic activity of penicillin involve blockade of the action of GABA. In vitro studies suggest that penicillin selectively blocks GABA-mediated postsynaptic inhibition in mouse spinal cord neurons in culture; the drug has in fact been shown to block the changes in chloride conductance in response to GABA in crab muscle, and the release of GABA from cortical slices (Faingold 1987). In humans, (j-Iactam antibiotics are known to cause convulsions, but the frequency of this adverse effect is thought to be less than I % (Mouton 1980; Norrby 1986a; Perry 1984; Snavely & Hodges 1984). In general, the presence of CNS abnormalities, renal impairment or the administration of an excessive dosage have been recognised as the principal risk factors influencing the occurrence of seizures (Mouton 1980). However, studies specifically aimed at calculating statistically the relative risk associated with the use of individual (j-Iactam antibiotics, or with the presence of individual clinical conditions, are lacking - probably because of the difficulty of collecting well matched data from the very large and representative population of patients needed for this kind of epidemiological research (Norrby 1986a). The problem of reliably estimating the incidence of seizures caused by the use of ~-Iactam antibiotics is complex, because the underlying disease (as well as several other disease-related factors) also contributes to the risk of seizures. Predisposing factors include 'background' CNS abnormalities [such as stroke (Shin ton et al. 1987), past history of convulsions (Annegers et al. 1986), or head trauma (Annegers et al..I980)], infections caused by particular bacterial strains (Calandra et al. 1988), cardiopulmonary arrest (Snyder et al. 1980), electrolyte abnormalities (Ammoff & Simon 1980; Messing & Simon 1986), alcohol (Gross et al. 1974) and certain procedures or conditions such as burns (McManus et al. 1974) or hyperbaric oxygenation (Chadwick 1983). In addition, the concurrent administration of drugs that are potentially epileptogenic is particularly frequent in patients receiving ~-lactam antibiotics, and

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this fact further complicates the statistical evaluations. In the case of the penicillins, the incidence of drug-induced seizures was calculated to be 0.3% in a survey of 1293 patients (Jick et al. 1972), a figure which was similar to that subsequently reported by Porter and J ick (1977). However, a variety of statistical problems are unavoidable in these epidemiological studies (Norrby 1986a), and so the possibility cannot be excluded that the 'true' incidence can differ significantly from the values reported thus far. Two studies by Lerner et al. (1967) and Wright and Wilcowske (1983) indicate that the presence of decreased renal function is by far the most significant predisposing factor. It can be concluded that penicillin-induced seizures are a well recognised problem occurring with a low but significant frequency, and that this adverse reaction is observed almost exclusively in patients treated with excessively high doses in relation to their renal function. Cephalosporins have a similar seizure potential, and in animal studies at least 2 drugs of this group (e.g. cefalothin and cefaloridine) have been shown to induce seizures after intracerebral injection (Gerald et al. 1973; O'Brien & McLaurin 1968). The neurotoxicity of cephalosporins in humans has been recently reviewed by Norrby (1987), who reappraised 12 cases of CNS toxicity induced by systemic administration. All patients had impaired renal function, and in all cases the measurement of the drug concentration in serum and/or CSF confirmed that excessively high doses had been given. Overall, the data indicate that the cephalosporins, when given at appropriate dosages by systemic route, have a very low neurotoxic potential (or none at all) and that seizures result almost invariably from an overdose. For example, Shah et al. (1988) found no cases of cefotaxime-induced seizures in a series of 602 consecutive patients treated with this drug. Even the injection of cephalosporins into the CSF seems to entail a low risk of seizures, as confirmed by the fact that cephalosporins are often administered intraventricularly with no noticeable CNS effects. Cefalothin is the most commonly used


cephalosporin for intraventricular treatment, but cefuroxime has been given by this route with no signs of toxicity (including I patient who mistakenly received 750mg instead of 75mg) [Norrby 1987]. Convulsions following intralumbar administration of cefaloridine have, however, been described in a neonate with meningitis (Yoshioka et al. 1975). In conclusion, present knowledge suggests that cephalosporins can very rarely induce seizures (Bechtel et al. 1980; Norrby 1986b; Tse et al. 1986) and that the incidence of this adverse reaction is probably lower than that observed with penicillins. Imipenem/cilastatin seems to possess a particular potential to induce seizures. The incidence of drug-induced seizures was reported to be 0.4% by the manufacturer (Package insert. 'Primaxin' - imipenem/cilastatin sodium. Merck Sharp & Dohme, West Point, PA; November 1985), but other sources have reported higher values of incidence: 1.5% (Calandra et al. 1988) and 7.5% (Tse et al. 1987). It remains unclear, however, whether the slightly higher seizure potential of imipenem/cilastatin, compared with other ,B-Iactam antibiotics, is related to the drug itself, or merely reflects the higher risk of seizures occurring in the clinically compromised patients treated with this drug. The 3 cases described by Tse et al. (1987) were all elderly women, 2 of whom had decreased renal function. Similarly, the 2 cases reported by Brotherton and Kelber p 984) were also associated with decreased renal function. CNS toxicity in patients treated with imipenem/cilastatin is thought to be caused by the accumulation of an open-Iactam metabolite of imipenem, whereas cilastatin seems to have no role. According to Tse et al. (1987), this open-lactam metabolite is formed during ,B-Iactam cleavage of imipenem and has a seizure potential similar to that of cefazolin. In clinical practice, the risk of imipenem-induced seizures is likely to be higher in patients with decreased renal function in whom there is no individualisation of dosage; a concurrent medication with drugs that lower the seizure threshold enhances the risk. Clissold et al. (1987) have observed that patients with convulsions were


generally elderly and had concomitant predisposing factors, such as prior history of seizure activity, underlying eNS disease, previous head injury or alcoholism. Renal function is known to be decreased in the elderly, but it is difficult to quantify to what extent the decreased renal clearance of imipenem can contribute to the adverse reaction in comparison with the other predisposing factors. Seizures induced by imipenem/cilastatin have generally been treated with intravenous diazepam alone or in association with intravenous phenytoin. The efficacy of this treatment seems to be satisfactory, particularly when associated with discontinuation of imipenem or reduction of its dosage. Phenobarbital is probably less efficacious, although this drug has been used in only a few cases. 11.2 Other Antimicrobial Agents The aminoglycosides have virtually never been implicated in cases of drug-induced seizures. This class of antibiotics seems to be devoid of significant neurological side effects, apart from the wellknown ototoxicity and the ability to induce neuromuscular blockade (Glauser & Neftel 1988). However, neuromuscular irritability and seizure activity have been observed, very rarely, as a result of the hypomagnesaemia and hypocalcaemia induced by gentamicin (Bar et al. 1975; Patel & Savage 1979). Tetracyclines and macrolide antibiotics also possess virtually no seizure potential. On the other hand, the quinolones can cause seizures. Several reports (Fraser & Harrower 1977; Stamey et al. 1969) indicate that nalidixic acid can induce convulsions, which are in some cases associated with a marked hyperglycaemia; these toxicities have generally resulted from an overdose or have involved patients with a history of seizures. The newer 4-fluoroquinolones (e.g. ciprofloxacin) also have a certain seizure potential, which can be related to their GABA-inhibitory action; the incidence of this adverse reaction is low (less than 1%), but cases have been described after conventional dosages of these drugs (Editorial 1988). Cases of convulsions during metronidazole

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therapy have been reported by Kusumi et al. (1980), but this association remains elusive. 11.3 Antituberculosis Drugs Many antituberculosis drugs can cause neurological manifestations, and this subject has been reviewed recently by Holdiness (1987). Isoniazid is the drug most widely studied under this aspect, and its epileptogenic potential seems to result from its inhibitory action of glutamic acid decarboxylase, the enzyme responsible for the synthesis of GABA. An overdose of isoniazid is very likely to cause seizures, but therapeutic dosages can also have this effect: convulsions have in fact been reported in 1 to 3% of tuberculosis patients receiving isoniazid 14 mg/kg/day twice weekly (Devadatta 1965). The ingestion of 6 to 30g of isoniazid can be fatal (Brown 1972; Mitchell et al. 1976; Sievres & Herrier 1975) and is accompanied by the presence of metabolic acidosis and seizures. The management of isoniazid overdosage relies essentially on the control of these 2 major signs of toxicity (Holdiness 1987). Wason et al. (1981) reported a series of 5 cases of seizures induced by isoniazid overdose in which the administration of pyridoxine, in amounts equivalent to the ingested isoniazid dose, produced a reduction in the seizure activity and in the metabolic acidosis associated with the convulsive state. Recently, Spalding and Buss (1986) described a case of toxic overdose of 3 antituberculosis drugs in a 21-year-old female patient who was admitted to hospital because of seizures a few hours after ingestion of isoniazid 7.5g, rifampicin 15g and ethambutol 20g. Two seizures occurred lasting I to 2 minutes, after which intractable convulsions developed with loss of consciousness and full extension of all four extremities. A marked reduction in bicarbonate (5 mmol/ L) was observed. Intravenous phenytoin 1.5g was ineffective, and seizures were controlled only by intubation and intravenous administration of diazepam IOmg followed by pancuronium 2mg. Therapy was also directed at reversing the condition of metabolic acidosis. Dialysis was instituted and continued for 4 hours in combination with the administration of pyridoxine 7g. Another dose of pyridoxine 4g was given following the discontinuation of dialysis. While convulsions resisted the in-

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itial treatment with phenytoin, they did not recur after the treatment with dialysis plus pyridoxine. These data indicate that isoniazid-induced seizures are not controlled by intravenous phenytoin, and that high-dose pyridoxine is probably the treatment of choice. Finally, it should be stressed that seizures associated with ingestion of isoniazid have almost invariably been observed after an acute overdose of the drug. Standard dosage regimens of isoniazid have a very low seizure potential in healthy subjects (Girling 1982), although the elderly demonstrate a slightly increased susceptibility to isoniazid-induced seizures, and this serious side effect has sporadically been observed under treatment with standard dosages of the drug (Mahler 1987). The ingestion of an overdose of ethambutol has been associated with neuropathy and mental confusion, but no seizures or deaths have occurred (Ducobu et al. 1982; Holdiness 1987). Rifampicin has caused only a mild transaminase elevation after ingestion of a dose of 12g (Newton & Forrest 1975), but death has occurred after an overdose of 60g (Broadwell et al. 1978). The rare occurrence of convulsions after severe poisoning has been reported by Holdiness (1987). Cycloserine has been reported to lower the seizure threshold, particularly after ingestion of alcohol; for this reason the drug is contraindicated in patients with a history of seizure disorders (Holdiness 1987). Vanasin et al. (1972) have described 1 patient who received conventional dosages of viomycin and developed electrolyte abnormalities leading to mental confusion and grand mal seizures. Holdiness' review (1987) also mentions rare cases of petit mal seizures after thioacetazone, and of convulsions after ethionamide.

12. Antifungal Agents Grand mal seizures have rarely occurred in subjects treated with amphotericin-B or miconazole (Benson & Nahata 1988), but the relationship between this adverse reaction and the drug administration has remained uncertain.


13. Antimalarial Drugs Prophylactic antimalarial drugs at standard dosages can induce convulsions in healthy subjects, and more frequently in subjects with a history of epilepsy. Four case reports recently presented by Fish and Espir (1988) are representative of this therapeutic problem. In 2 of these patients (one previously healthy, the other with a history of absence seizures), tonic-clonic convulsions developed under treatment with chloroquine sulfate, dapsone and pyrimethamine; both patients showed an EEG with brief generalised spike and wave activity of 3Hz; no seizures recurred after discontinuation of antimalarial drugs and initiation of antiepileptic treatment (carbamazepine or valproic acid). The third patient, who had a long history of complex partial seizures (well controlled by carbamazepine), manifested a prolonged tonic-clonic convulsion after taking chloroquine sulfate 400mg. The fourth patient, previously healthy, presented with tonicclonic seizures after beginning prophylactic antimalarial therapy with chloroquine, sulfadoxine, and pyramethamine; following the discontinuation of these drugs, the patient remained seizure-free without antiepileptic treatment. Other reports indicate that an acute overdose with chloroquine (Kiel 1964) or pyramethamine (Grisham 1962) can cause convulsions. The mechanism of seizures induced by antimalarial drugs is uncertain.

14. Antineoplastic Drugs It is well known that antineoplastic agents can very occasionally cause convulsions, although ·the aetiology of this adverse reaction remains obscure (Thalayasingam 1985). While a large number of case reports have been described in the literature, only a few studies have addressed the problem systematically; hence, the present information does not permit provision of a precise estimate of the frequency with which seizures induced by these agents can occur. Nonetheless, this frequency is likely to be less than 1% considering that, for example, studies on patient series as large as 238 cases (Love et


al. 1989) have shown no cases of seizures induced by cancer chemotherapy. Another indication that seizures are not a primary side effect of antineoplastic drugs is that reviews specifically addressing the management of cytotoxic drug overdose (Thomas et al. 1988) do not mention seizures induced by these agents. One major problem in evaluating seizures caused by cytotoxic agents is that the patients who experience convulsions are frequently treated with combination chemotherapy [e.g. the case report by Thalayasingam (1985)]; obviously, this makes it difficult to attribute the aetiology of the seizure to a specific drug among those administered. The administration of prophylactic anticonvulsants during chemotherapy (e.g. phenytoin 100 mg/ day) has been proposed, but the problem remains controversial (Hugh-Jones & Shaw 1985; Thalayasingam 1985) because no agreement has been reached on which chemotherapeutic protocols require such prophylaxis. 14.1 Alkylating Agents All alkylating agents probably possess a slight but definite seizure potential. However, seizures associated with these agents have been reported more frequently for a relatively small subgroup, particularly chlorambucil and busulphan. It remains unclear whether these substances possess a more marked epileptogenic activity than the other alkylating agents or if they are simply more widely available due to the fact that the diseases they cure (e.g. chronic leukaemias) are relatively common and require a long term treatment lasting several years. The frequent reports of children intoxicated accidentally with chlorambucil probably has this latter explanation. Chlorambucil has well known epileptogenic properties; for example, the drug has been used in rats to reproduce the EEG pattern of petit mal epilepsy (Mirsky et al. 1966; Pinel & Chorover 1972). In humans, chlorambucil has been reported to induce seizures frequently after episodes of acute intoxication (Eack & Bennett 1977), particularly in children (Byrne et al. 1981; Green & Naiman 1968;

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Wolfson & Olney 1957). A low seizure potential is maintained, however, even when the drug is administered in the usual dosages. In the reported cases of chlorambucil poisoning in children (Byrne et al. 1981; Green & Naiman 1968; Wolfson & Olney 1957), the neurological symptoms were fairly well correlated with the dose ingested; current information suggests that doses of 1.5 mg/kg of the drug or less are likely to cause only hyperactivity and jerky movements, but 5 mg/kg or more is almost invariably associated with generalised tonicclonic seizures. For example, Byrne et al. (1981) observed myoclonic seizures after an acute overdose of chlorambucil in a 3Ih-year-old girl, while Wolfson and Olney (1957) have described a 2-yearold boy who developed generalised tonic-clonic seizures after ingestion of 5 mg/kg of the drug. When administered in standard dosages, chlorambucil has caused seizures (Williams et al. 1978) in 7 of 91 children treated for renal disease, but 2 of these subjects had a history of myoclonic seizures. The seizures generally occurred between the sixth and ninetieth days of treatment. In a subsequent study by the same group (Williams et al. 1980), 2 of 65 cases with idiopathic nephrotic syndrome of childhood were reported to experience focal seizures after treatment with chlorambucil. Busulphan also has a certain seizure potential. Martell et al. (1987) have described I case of myoclonic epilepsy associated with high dose busulphan. Marcus and Goldman (1984) reported 2 cases, one of generalised tonic-clonic convulsions and the other of muscle twitching with unconsciousness, in patients receiving high dose busulphan (4 mg/kg/day orally for 4 days) before bone marrow autograft; on the basis of this experience, these authors have recommended the use of prophylactic anticonvulsants in association with high dose busulphan therapy. On the other hand, HughJones and Shaw (1985) found no cases of convulsions in a series of 41 children receiving high dose busulphan, and have therefore questioned the need for such prophylaxis. Drug-induced seizures have occasionally been reported following the administration of mechlorethamine (Bethlenfalvay & Bergin 1972; Sullivan

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et al. 1982). Conversely, cyclophosphamide has not been reported as causing convulsions. 14.2 Antimetabolites Acute reactions associated with high dose methotrexate have frequently been observed and include somnolence, fatigue, confusion, disorientation, increased intracranial pressure and seizures (Allen & Rosen 1978; Bleyer 1981; Kay et al. 1972). Seizures can occur during a bolus infusion or can manifest as a delayed reaction. Encephalopathy has been reported in 7 children treated for acute leukaemia with prolonged methotrexate therapy; 2 of these children developed seizures (Kay et al. 1972). Encephalopathy appears to be more common in patients who have been treated with methotrexate and cranial radiation therapy (Bleyer 1981). Rudnick et al. (1979) reported somnolence, headache, confusion and a single case of seizures after high-dose therapy with cytarabine. Eden et al. (1978) reported 2 cases of seizures after intrathecal therapy with cytarabine; both patients had a history of intrathecal methotrexate therapy and cranial irradiation, and I patient also had hyponatraemia. Fluorouracil seems to be devoid of significant convulsant properties. Azathioprine is discussed in section 15. 14.3 Vinca Alkaloids Vincristine is a known neurotoxin, and its neurotoxicity is a dose-limiting factor in the clinical utility of the drug (Legha 1986). Although various forms of neuropathy are frequently caused by vincristine, CNS toxicity is not a prominent feature in the general frame of the side effects induced by the drug. The lack of serious eNS toxicity may be partly due to a lack of significant penetration into the eNS, as demonstrated by the low concentrations generally found in the CSF (Weiss et al. 1974). One of the manifestations of CNS effects of vincristine is an excessive release of antidiuretic hormone resulting in hyponatraemia, which can be severe and can cause mental confusion and seiz-


ures. However, seizures have occasionally been observed in children treated with vincristine even in the absence ofhyponatraemia (Johnson et al. 1973; Sandler et al. 1969). In patients who have received accidental drug overdoses a more severe eNS toxicity occurs, with delirium progressing to unconsciousness, seizures , and death (Kaufman et al. 1976). Toxicity is often fatal after inadvertent administration of vincristine by the intrathecal route; in such cases seizures can also be common (Legha 1986). 14.4 Other Antineoplastic Drugs Seizures have occasionally been reported during cisplatin therapy (Bruckner et al. 1977; Rossof et al. 1979; With shaw et al. 1979). Berman and Mann (1980) described I patient who developed seizures and transient cortical blindness within 12 hours after administration of cisplatin, vinblastine and bleomycin. Seizures have also been reported in patients receiving carmustine (Burger et al. 1981) and asparaginase (Land et al. 1972), but no such adverse reactions have been observed after administration of bleomycin or anthracycline antibiotics (e.g. daunorubicin and doxorubicin).

15. Immunosuppressive Drugs The neurological side effects of cyclosporin have an estimated incidence of about 10% (Atkinson et al. 1985) and include cerebellar disorders, neuropathies, visual hallucinations, seizures and other manifestations (Scott & Higenbottam 1988). Seizures have an incidence ofless than I % in heart and heart-lung transplants, but the figure can be higher in recipients of bone marrow transplantation (approximately 3%). They appear to be more common in young subjects and occur typically in the immediate postoperative period. The relationship between seizures and cyclosporin concentration is elusive, inasmuch as this adverse reaction has been reported with both toxic and nontoxic concentrations of the drug (Scott & Higenbottam 1988). Cyclosporin-induced seizures are probably


caused by direct tissue damage similar to that involving the kidney. Both the brain and the kidney contain high concentrations of the cytosolic-binding protein cyciophillin, suggesting that the drug can be taken up more readily into the cells of these tissues (Scott & Higenbottam 1988). In patients with cyciosporin-induced neurotoxicity, EEGs usually demonstrate diffuse slowing, consistent with a metabolic or encephalitic process; less frequently, focal spike, slow wave complexes and diffuse 0 wave slowing in the right occipital region have been reported. Focal slowing or epileptiform activity are very rare (Scott & Higenbottam 1988). Glucocorticoids have occasionally been implicated in cases of drug-induced seizures. Some patients have been described in whom pulse therapy with high dose intravenous methylprednisolone (e.g. Ig over 15 minutes) elicited generalised seizures; typically, these have manifested with a delay of 24 to 68 hours after dosing (Cerilli & Miller 1972; Stubbs & Morrell 1973; Suchman et al. 1983). While seizures associated with high-dose methylprednisolone are rare, acute CNS symptoms (lethargy, confusion, jitteriness, insomnia, euphoria) are more common, thus confirming the neuroexcitatory potential of this form of therapy. The occurrence of seizures is more frequent in patients treated with a combination of cyciosporin and high dose methylprednisolone (Boogaerts et al. 1982; Durant et al. 1982). Azathioprine can also induce seizures, although the incidence of this side effect is very low. One case has been reported of a patient who manifested seizures, facial oedema and papilloedema due to this drug (Lockskin & Kagen 1972).

16. Radiological Contrast Agents The administration of radiological contrast agents is usually associated with a variety of neurological adverse effects, and seizures are one of the most common complications (Junck & Marshall 1983). Their incidence can vary depending on a number of factors, which are in part correlated

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with the different routes of administration and with the different compounds used. 16.1 Agents for Intravascular Administration

The agents employed intravascularly for studies such as angiography, urography and computer tomography are usually sodium or methylgiucamine salts oftriiodinated derivatives of benzoic acid (e.g. diatrizoate, iothalamate, metrizoate). The incidence of seizures following arteriography was reported to be about 0.2 to 0.4% (Junck & Marshall 1983), but they seem to occur much more frequently in patients with brain tumours (Olivecrona 1977). After intravenous administration, the incidence of seizures in the general population has been reported to be as low as 0.01% (Witten et al. 1973); however, even in the latter study, seizures were very often observed in patients with focal brain lesions. Following contrast agent administration for computer tomography, seizures have been reported in 6 to 19% of patients with brain metastases (LoZito 1977; Scott 1980) and were, in general, focal motor or secondarily generalised. Brain irradiation, antineoplastic therapy or previous seizure history, usually due to the tumour, predispose the patients to the risk of radiological contrast agent-associated seizures (Pagani et al. 1983, 1984). The epileptogenic effect of radiological contrast agents seems to result from a direct action of these substances on the cerebral cortex. Experiments with rat hippocampus slice preparations have demonstrated that concentrations of water-soluble radiological contrast agents similar to or less than those achieved in brain extracellular fluid after cerebral arteriography when the blood-brain barrier is open or defective had epileptogenic effec~s demonstrated by repetitive action potentials arising from an early prolonged depolarisation (Bryan & Hershkowitz 1984). However, radiological contrast agents usually cross the intact blood-brain barrier only in very small quantities (Newhouse & Murphy 1981); for this reason they are safe in the vast majority of patients. When a disease process disrupts the blood-brain barrier, these agents can more readily enter the brain; probably for this rea-

138

son, seizures following administration of contrast agents for computer tomography scan is frequent in patients with brain tumours (Pagani et al. 1984) or brain metastases (Pagani et al. 1983) and is in fact thought to be related to damage to the bloodbrain barrier. A prophylactic treatment is generally indicated under these circumstances. It has also been suggested that radiological contrast agents themselves, in high concentrations, can damage the blood-brain barrier and can thus facilitate their own entry into the brain (J unck & Marshall 1983). This seems to be due, at least in part, to their hypertonicity. Such a mechanism can playa role in seizures associated with cerebral arteriography when the contrast medium reaches the brain in high concentrations. Finally, spinal cord injury is a possible complication of aortography, particularly selective spinal cord arteriography. In this case, spinal myoclonus is often the first manifestation of toxicity, and seems to be due to a direct toxic effect of radiological contrast agents on the spinal cord (Junck & Marshall 1983). 16.2 Agents for Intrathecal Administration Metrizamide and, more recently, iopamidol are non ionic water-soluble agents, which are now widely used for myelography, cisternography and ventriculography. Although they are certainly less toxic than previous oily agents (iophendylate), these substances display a variety of adverse effects on the eNS (Junck & Marshall 1983). Generalised tonic-clonic seizures, focal seizures (Amundsen 1977; Nickel & Salem 1977), complex partial status epilepticus (Russel et al. 1980), epilepsia partialis continua (Shiozawa et al. 1981), absence status (Vollmer et al. 1985) have all occurred following metrizamide myelograms. The incidence of seizures estimated from a large series of patients ranges from 0.6% (Amundsen 1977) to 0.02% (Dugstad & Eldevik 1977). In prospective studies, a transient increase of slow activity and, less often, the appearance of paroxysmal activity on the EEG have been observed in 10 to 35% of patients (Ropper et al. 1979).


Iopamidol, which is a newer nonionic water-soluble medium, seems to be less toxic than metrizamide. However, recent reports indicate that this substance can also induce convulsions (Levey et al. 1988) and EEG abnormalities with a frequency as high as 23%; these abnormalities ar~ similar to those observed after metrizamide (Macpherson et al. 1983). Finally, it has recently been demonstrated that focal collection of intracranial iophendylate after lumbar myelograms can cause a chronic focal seizure disorder even after several years (Pascuzzi et al. 1988). 16.3 Treatment and Prevention Specific antiepileptic treatment is necessary only in those cases in which seizures are repeated or a condition of convulsive or nonconvulsive status epilepticus has occurred. In cases at higher risk for seizures following radiological contrast agent administration for computer tomography (e.g. patients with brain metastases or glioma), prophylactic treatment has been suggested (Pagani et al. 1983, 1984). Diazepam prophylaxis (5mg intravenously prior to administration of the contrast agent) has been shown to reduce the incidence of seizures in patients with metastases (from 15 to 3%) or glioma (from 16 to 2%) [Pagani et al. 1983, 1984). In these patients, long term anti epileptic treatment with phenytoin does not prevent seizures. On the other hand, oral phenytoin (unlike intravenous diazepam) is effective against seizures induced by administration of contrast agents in the subarachnoid space (de Vane et al. 1986). To prevent seizures induced by radiological contrast agents, it should be borne in mind that metrizamide slowly diffuses rostrally in a semi-sitting patient, and its diffusion is more rapid if the patient is kept in a horizontal position or tilted down. This substance has been found in the posterior fossa after 6 hours and over the convexities, where it exerted its epileptogenic effect, after 24 hours (Hindmarsh 1975). For this reason, most adverse effects of metrizamide myelography reach


a peak several hours after administration. As a routine measure, the patient should therefore be kept in a semi-upright position; prophylactic treatment is useful, particularly if the patient is tilted down for thoracic or cervical myelography or cisternography. The administration of oral phenytoin in 3 doses (6 mg/kg on the evening prior to the procedure, 6 mg/kg on the following morning, 200mg after the procedure) has been proposed (de Vane et al. 1986). In this way, therapeutic blood concentrations of the drug are maintained over the whole period at risk.

17. Vaccines From a review of yellow cards (Bem et al. 1988), vaccines have proved to be the commonest reported cause of convulsions induced by drugs. For example, among 162 reports of drug-induced seizures, 41 concerned vaccines, compared with only 14 cases related to tricyclic antidepressants. Despite this striking evidence of a convulsant effect of vaccines, very few reports deal with vaccine-induced convulsions. To the present authors' knowledge, only 1 other study [by Hirtz et al. (1983)] has addressed this problem specifically, showing that vaccination was the suspected cause of seizures in 1.4% of children who experienced convulsions during the first 7 years of life. Pertussis vaccine, which is commonly administered with diphtheria and tetanus vaccine (DTP), is probably the most often implicated among those recommended and routinely used. Common minor effects are seen in about one-half of infants and children who receive the vaccine. However, the incidence of serious toxicity (impaired consciousness, convulsions, hypotonic-hyporesponsive episodes, etc.), and in rare cases encephalitis, is very low. It has been calculated that the risk of an induced seizure within 48 hours of vaccination is 1 in 1750 (Cody et al. 1981). Almost all episodes manifest as febrile convulsions, but nonfebrile seizures have also been observed. In 1986, the report of the Committee on Infectious Diseases of the American Academy of Pediatrics recommended that children who have had a

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major reaction to a previous vaccination, or children with progressive neurological disorders or a personal history of convulsions (Zimmerman et al. 1987), should be excluded from pertussis vaccination. According to the recommendations of the Immunization Practices Advisory Committee (ACIP), a history of convulsions in immediate family members is not a contraindication for pertussis vaccination. However, since it has been calculated that these children have a 3.2-fold risk for neurological events (febrile convulsions), the prophylactic use of antipyretics has been recommended (paracetamol at a dose of 15 mg/kg at the time of DTP vaccination and again 4 hours later) [Editorial 1987]. Untoward reactions associated with measles vaccine include fever of 39°C or higher in 5 to 15% of recipients. Encephalitis has been reported with a frequency of approximately 1 in 1 million vaccinations (Bart et al. 1987). For this reason, children with brain disorders, convulsions or a history of idiopathic epilepsy in first-degree relatives are at risk for febrile convulsions. To reduce the adverse effects of this vaccination, concomitant administration of immunoglobulin has been recommended in children at risk for convulsions (Lingam et al. 1986). With this procedure, adverse effects are greatly reduced and an effective immunisation is obtained. Many other vaccines (diphtheria and tetanus toxoids, rabies, cholera, hepatitis B, influenza, rubeola and Haemophilus injluenzae type B polysaccharide vaccines) are known to produce fever in some cases (Bart et al. 1987). For this reason, in predisposed children, a febrile convulsion may be observed. Parents of children at risk for a febrile convulsion should be informed of their children's increased risk of seizures following vaccination, and should be told to adopt adequate measures to interrupt the convulsions should they appear. The pathogenesis and management of vaccine-induced encephalitis are" beyond the scope of this review.

18. Miscellaneous Drugs other than those discussed above have occasionally been implicated as a cause of seizures. A list of such drugs includes: allopurinol (Weiss et


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Assess cardiorespiratory function Insert oral airway. administer oxygen 30% Insert Indwelling Intravenous catheter Monitor respiration. blood pressure. body temperature. ECG and EEG

~,

First-line drugs Intravenous diazepam no faster than 2 mg/min to a total of 20mg and intravenous phenytoin no faster than 50 mgjmin to a total of 18 mg/kg: if hypotension develops. slow down infusion rate If seizures persist

~

Have intubation and ventilatory support immediately available Either

Or

Intravenous phenobarbital 16 mg/kg no faster than 100 mg/mln

Intravenous diazepam 100mg m dextrose 5% 500ml no faster than 40 ml/h If seizures persist

Start mfusion With glucose 10%: control hyperpyrexia If necessary

Possible alternatives if anaesthesiologist is not Immediately available: Intravenous paraldehyde 0.05 to 0.1 ml/kg diluted 4% In normal saline Intravenous lidocaine (lignocaine) 1-2 mgjkg: if effective. administer additional 50-100mg in dextrose 5% 250ml no faster than 2 mg/kgjh If seizures persist

~.----J Fig. 2. General algorithm for the treatment of status epilepticus.

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al. 1978), digoxin (Kerr et al. 1982), cimetidine (Schentag 1980), thyrotrophin releasing hormone (Maeda & Tanimoto 1981), bromocriptine (Editorial 1984), domperidone (Weaving et al. 1984), insulin (Jick et al. 1972), fenformin (Jick et al. 1972), penicillamine (Chalmers et al. 1982), probenecid (McKinney et al. 1951), verapamil (Passal & Crespin 1984) and methyldopa (Feldman et al. 1967).

19. Conclusions When a seizure occurs, the possibility that it has been induced by a drug should always be borne in mind; in this context, this review has therefore been aimed mainly at describing the clinical aspects of this adverse reaction and at providing information about its frequency. Whatever the aetiological agent, seizures should always be regarded as a serious symptom. If not promptly treated, they can in fact contribute heavily to a worsening of the prognosis of intoxicated patients; for example, in tricyclic antidepressant poisoning untreated seizures can provoke metabolic and electrolyte disturbances and hypoxia that unfavourably affects myocardial function and eventually cause malignant arrhythmias and cardiac arrest (Crome 1986). It is, therefore, also important to emphasise the therapeutic aspects of the management of drug-induced seizures, even though this problem is not always discussed adequately in papers describing these adverse reactions. Specific measures of treatment, when available from the literature, have been presented above. In the absence of specific therapeutic directions, discontinuation of the drug and use of standard anticonvulsant treatments are warranted. Particular attention should be paid when seizures are repeated leading to the condition called status epilepticus. Convulsive status epilepticus is a life-threatening condition demanding immediate and effective treatment to prevent permanent brain damage or death; it is well known that the longer a tonic-clonic status epilepticus continues, the more difficult it is to control and the higher the incidence of mortality and morbidity (Treiman & Delgado-

Escueta 1983). Status epilepticus can be induced by pharmacological agents such as some antidepressants (e.g. amoxapine), theophylline and lidocaine. In general, when specific therapeutic indications are lacking, intravenous benzodiazepines are the first-line drugs for controlling drug-induced seizures. Careful monitoring of blood pressure, respiration and ECG is also recommended, since cases of respiratory depression and hypotension have occasionally been described. If convulsive status epilepticus is not promptly interrupted, intravenous phenytoin is usually indicated. General anaesthesia and artificial respiration with neuromuscular blockade are needed to control refractory cases: previously published reviews which have specifically addressed this therapeutic problem are those by Bleck (1983) and Delgado-Escueta and Bajorek (1982). Figure 2 illustrates a general algorithm for the treatment of status epilepticus. Drug withdrawal has frequently been implicated as a cause of seizures, but a discussion of this problem is beyond the function of this review.

Acknowledgements The authors are indebted to Professor Flavio Moroni of the Department of Preclinical and Clinical Pharmacology, University of Florence, for his critical review of the manuscript. This work has been supported in part by funds from the Ministero della Pubblica Istruzione and from the Regione Toscana.

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Authors' address: Dr G. Zaccara, Department of Neurology, University of Florence, viale Morgagni 85, 50134 Florence, Italy.

XIV International Congress of the European Association of Poison Control Centres Date: 25-29 September 1990 Venue: Milan, Italy For further information, please contact: Prof. M. Bozza-Marrubini Congress Studio Via Cappuccio. 19 20123 Milan ITALY

Seizures in sleep: clinical spectrum, diagnostic features, and management.

Drug-induced cholestasis: pathogenesis and clinical features.

Melanoma of the oral cavity: pathogenesis, dermoscopy, clinical features, staging and management.

Basal cell carcinoma: pathogenesis, epidemiology, clinical features, diagnosis, histopathology, and management.

Non-Alcoholic Steatohepatitis: Pathogenesis and Clinical Management.

Clinical Features And Management Of Snake Bite.

Clinical Features and Management of Blast Injuries.

Nonalcoholic Fatty Liver Disease: Clinical Features and Pathogenesis.

MFN2-related neuropathies: Clinical features, molecular pathogenesis and therapeutic perspectives.

Intracranial aneurysms in sickle-cell anemia: clinical features and pathogenesis.

[Delayed-type cutaneous drug reactions. Pathogenesis, clinical features and histology].

Danon disease: clinical features, evaluation, and management.

Orbital osteoma: clinical features and management options.

Progress in pathogenesis and management of clinical intraamniotic infection.

Clinical features and management of adverse effects of quinolone antibacterials.

Management of neonatal seizures.

Clinical Features and Management of a Median Cleft Lip.

Etiology, clinical features and management of acute recurrent pancreatitis.

The clinical features and management of pituitary apoplexy.

Clinical features and patient management of Lujo hemorrhagic fever.

Clinical features and endovascular management of iliac artery fibromuscular dysplasia.

Clinical features, diagnostic criteria, and management of Coffin-Siris syndrome.

Current and evolving features in the clinical management of haemophilia.

Pyridoxine-dependent seizures: report of a case with atypical clinical features and abnormal MRI scans.