Clinical manifestations

Presentation and course

	• No characteristic clinical features differentiate drug-induced seizures from idiopathic epileptic seizures.
	• Drug-induced seizures are usually self-limiting and do not recur if the offending medication is discontinued.

Central nervous system toxicity caused by drug exposure is a common reason for presentation to the emergency department. Manifestations include psychoses, various levels of impairment of consciousness, and seizures (31). No characteristic clinical features differentiate drug-induced seizures from idiopathic epileptic seizures. Generalized seizures with focal features are common, whereas simple partial seizures are rare (25). Generalized seizures usually present with loss of consciousness, convulsions, tongue biting, and incontinence of urine. There is usually no preceding aura or focal disturbance and no residual neurologic deficit. Severe attacks may lead to status epilepticus, which is drug-induced in 10% of cases.

Prognosis and complications

Drug-induced seizures are usually self-limiting and do not recur if the offending medication is discontinued. Complications may occur in status epilepticus, particularly in association with drug poisoning. Factors associated with complications of drug-related seizures include stimulant exposure, suicide attempt, initial hypotension, and admission acidosis or hyperglycemia (35).

Biological basis

	• The main cause of drug-induced seizures is drugs acting directly on the brain.
	• The effects of drugs on the brain can be indirect via other systems.
	• Predisposing factors may enhance onset of drug-induced seizures.

Etiology and pathogenesis

Drugs associated with seizures are shown in Table 1.

Table 1. Drugs Associated with Seizures

Therapeutic categories
	• Anesthetics: local and general • Antidepressants: tricyclics, monoamine oxidase inhibitors, serotonin reuptake inhibitors • Antipsychotics: butyrophenones, phenothiazines*, clozapine*, lithium, zotepine • Antiseizure medications • Antihistaminics • Antimalarial drugs • Antimicrobial agents*: antibiotics (eg, carbapenem), antifungal drugs, antitubercular, antihelmintic agents • Antineoplastic agents: alkylating agents, antimetabolites, vinca alkaloids* • CNS stimulants*: theophylline, caffeine, cocaine, amphetamines, methylphenidate • Cytokines as therapeutic agents: eg, interferon-alpha-2b, interleukins • Diuretics: eg, acetazolamide • Immunosuppressive drugs: glucocorticoids, cyclosporin, azathioprine, OKT3 • Nonsteroidal anti-inflammatory drugs: aspirin, indomethacin, mefenamic acid • Opioids and other narcotic analgesics: morphine, meperidine*, tramadol • Proton pump inhibitors: eg, omeprazole • Radiologic contrast agents*: intravascular and intrathecal • Vaccines*
Miscellaneous drugs
	• Acyclovir • Alcohol • Allopurinol* • Aminophylline* • Aspartame • Atropine sulfate • Baclofen • Beta-blockers • Bromocriptine • Bupropion • Camphor • Chloral hydrate • Desmopressin • Digoxin • Domperidone • Donepezil • Drug abuse • Erythropoietin • Famotidine • Flumazenil* • Fluorescein • Ganciclovir • Hyperbaric oxygen • Insulin* • Iodine • Isotretinoin • Levodopa • Melatonin • Methyldopa • Naftidrofuryl • Nicotine • Nonsteroidal antiinflammatory drugs • Ondansetron • Papaverine delivered directly into cerebral arteries • Sulprostone • Terbutaline • Thyroxine • Tranexamic acid • Vardenafil
*Frequently reported Updated from (14).

Drugs may produce seizures by several mechanisms, as shown in Table 2.

Table 2. Mechanisms by Which Drugs Produce Seizures

Direct effects on the central nervous system
	• Disturbances of cerebral energy metabolism
		- stimulation of the CNS - neurotransmitter disturbances - chronic changes in alpha-2 receptors - cerebral cortical irritation - toxic effects on neurons
Indirect effects
	• Cerebral blood flow disturbances • Cerebral hypoxia • Cerebral hyperoxia with oxidative stress • Secondary to non-neurologic drug reactions:
		- cardiac rhythm disturbances - electrolyte disturbances, eg, hyponatremia, hypomagnesemia - metabolic disturbances, eg, hypoglycemia - fever
Overdosage of drugs affecting the CNS Sedative drug withdrawal Drug interactions
	• Interference with the effect of antiseizure medications • Concomitant use of two drugs where one drug raises the concentration of other • Drug known to induce epileptic seizures

Risk factors that predispose to drug-induced seizures can be patient related or drug related, as shown in Table 3.

Table 3. Risk Factors That Predispose to Drug-Induced Seizures

Patient-related factors
	• Family history of epilepsy or previous seizures • Patients with CNS disorders without a history of previous seizures: brain tumors, stroke, AIDS encephalopathy • Breach of blood-brain barrier such as occurs in head injury and meningitis • Psychiatric disorders: major depressive disorder • Patients at extremes of age: the elderly and infants • Systemic diseases affecting drug metabolism and excretion, particularly those affecting renal and hepatic functions • Drug-induced nonconvulsive status epilepticus has been reported in children who are chronically ill with leukemia (08) • High fever
Drug-related factors
	• Multiple medications: drug interactions • Use of drugs known to induce seizures • Factors affecting CNS levels of drugs: lipid solubility, protein binding transport by endogenous systems • Serum levels of drugs: dose, frequency, and route of administration • Overdosage • Withdrawal
Drug-induced status epilepticus is more likely to occur due to the following drugs:
	• Antiseizure medications with sodium channel or GABA-ergic properties if used inadvertently in generalized epilepsies. Tiagabine is more likely to trigger nonconvulsive status epilepticus. • Antibiotics such as cephalosporins and quinolones • Immunotherapies • Chemotherapies • Overdoses of antidepressants or other psychotropic medications

Among various categories of drugs, psychotropic drugs like antidepressants, antipsychotics, and mood stabilizers have a well-recognized potential to induce seizures. The pathomechanism of drug-induced seizures according to the category of drugs are as follows:

Anesthetics. Convulsions are a prominent feature of the neurologic adverse effects of anesthetic agents. Seizures have been reported following repeated spinal injections of tetracaine, a local anesthetic. Seizures may occur in patients receiving propofol. Lidocaine used as a local anesthetic can induce seizures in patients with a history of epilepsy.

Antibiotics. Beta-lactam antibiotics are known to cause potent convulsant activity in humans. Penicillin produces focal seizures by topical application in vitro and in vivo and has been used to produce models for epilepsy research. The most commonly accepted mechanisms underlying the development of antibiotic-induced seizures include direct and indirect gamma-aminobutyric acid (GABA) antagonism, inhibition of GABA synthesis, and glutaminergic N-methyl-D-aspartate (NMDA) receptor agonistic activity (36). Inhibition of the inhibitory pathway leads to increased neuronal excitability and lowered seizure threshold. The administration of antibiotics, together with antiseizure drugs, may also lead to enhanced seizure risk due to drug interactions, which predisposes to alterations in drug metabolism and therapeutic efficacy.

Cephalosporins and carbapenems might also induce convulsions through the inhibition of GABA receptor binding when they accumulate in the central nervous system. Central nervous system toxicity in patients treated with imipenem-cilastatin is caused by the accumulation of an open lactam metabolite of imipenem, whereas cilastatin appears to have no role. Central nervous system lesions, history of head injury and stroke, seizure disorders, high doses, multiorgan failure, and elderly patients with renal insufficiency are strong risk factors. Ciprofloxacin-induced seizures may occur in healthy patients. An analysis of 511 serious central nervous system adverse reactions of cephalosporins recorded in the French Pharmacovigilance Database from 1987 to 2017 included encephalopathy in 30.3%, convulsions in 5.1%, myoclonia in 9.4%, and status epilepticus in 9.2% (19).

Antidepressants. Antidepressants can have both anticonvulsive and convulsive actions; the former occur at lower doses and the latter at higher doses or higher blood levels. Tricyclic antidepressants are associated with a higher incidence of seizures than selective serotonin reuptake blockers. The following mechanisms have been considered according to the class of the drug:

	• For selective serotonin reuptake inhibitors, the risk is generally considered to be low if no predisposing factor is seen. A case of paroxetine-induced epileptic negative myoclonus has been reported with a bilateral parieto-occipital EEG pattern, and inhibition of the primary motor cortex by hyperexcitability of the primary somatosensory cortex output was offered as an explanation of the EEG-clinical correlation (06).
	• Monoamine oxidase inhibitors decrease the reuptake of monoamines, increase the brain monoamine levels, and decrease the threshold for seizures. Drugs reported to have an epileptic potential in increasing order are desipramine, nortriptyline, trimipramine, imipramine, clomipramine, and amitriptyline.
	• Seizure threshold increases with dopaminergic agents, whereas dopamine-blocking drugs (antipsychotics and antidepressants) enhance seizures.
	• The noradrenergic system can suppress or induce seizures. Seizures do not usually occur with therapeutic doses of monoamine oxidase inhibitors. At low doses, imipramine acts as an anticonvulsant, but at high doses, it can be epileptogenic by inhibiting the presynaptic reuptake of norepinephrine.
	• Alpha-adrenoreceptors downregulate with chronic tricyclic administration and may be a mechanism for seizure exacerbation.
	• Antidepressants also block the seizure-inhibiting effects of GABA by antagonizing the GABA receptor.
	• Antidepressants are potent inhibitors of chloride influx into the neurons, whereas anticonvulsant agents such as diazepam enhance it.
	• Interactions of antidepressants may produce seizures. The interaction of monoamine oxidase inhibitors with tricyclic antidepressants may produce serotonin syndrome. This may be accompanied by seizures in most serious cases.

The role of serotonin in the etiology of antidepressant-induced seizures is not clear. Enhancement of serotonin activity both increases the risk of seizures and protects against them in different animal models. Although serotonin is thought to be involved in several myoclonic seizure states, the relationship of these to other forms of epilepsy remains unclear.

Drugs can produce EEG changes without the occurrence of a seizure. Increase of slow waves and fast activity, such as that following the use of imipramine, is considered more epileptogenic. Nonconvulsive status epilepticus has also been reported during antidepressant therapy. Seizures are part of the neurologic picture following tricyclic antidepressant overdose. Seizures can occur in neonates following withdrawal from maternal clomipramine.

In evaluating seizures in association with antidepressants, the peculiar antagonism between epilepsy and depression should be taken into consideration. Seizures in patients with depression improve the depression, and electroconvulsive therapy is still being used as a treatment for depression.

Intentional ingestion of antidepressants, particularly bupropion, is the most common cause of drug-induced seizures in children and adolescents presenting for emergency care (09).

Some of the conclusions of a comprehensive systematic review of publications on epileptic seizures under antidepressant drug treatment includes the following (34):

	• Evidence for moderate risk was ranked from the highest to the lowest in the following order: clomipramine, quetiapine, amitriptyline, venlafaxine, citalopram, sertraline, trazodone, mirtazapine, paroxetine, bupropion, and escitalopram.
	• The risk is negligible for fluoxetine and duloxetine.
	• Antidepressant treatment is rather safe in terms of risk of seizures and can also be generally recommended in the treatment of patients with epilepsy.

Antihistamines. In a study from South Korea, drugs were found to be the most common provocation factor for acute symptomatic seizures, and the most common causative drug was an antihistamine (17). Considering that antihistamines are widely used as over-the-counter drugs around the world, they should be considered a possible cause of new-onset seizures.

Antineoplastic agents. Seizures are a recognized complication of antineoplastic agents.

Antipsychotics. Almost all antipsychotics in use are known to induce seizures in some predisposed patients. Seizures associated with antipsychotic medications occur in about 1% of patients. Incident seizures are more frequent in those taking risperidone and multiple antipsychotics.

The potential of antipsychotic drugs to induce seizures may be related to effects on various neurotransmitter systems. Those agents with greater histaminic, adrenergic, and serotonergic affinity are associated with more reports of seizures than those with less affinity. Risk factors for antipsychotic-induced seizures are as follows:

	• History of epilepsy
	• Electroconvulsive therapy
	• Abnormal EEG. Some antipsychotic medications (eg, clozapine) are associated with EEG abnormalities and have been shown to increase the risk of having a seizure, but seizures may also occur with antipsychotics such as quetiapine that do not produce EEG abnormalities.
	• History of drug-induced seizures
	• Neurodegenerative disorders such as Alzheimer disease
	• Head injury
	• Previous psychosurgery
	• Insulin shock therapy
	• Large doses of antipsychotics
	• Antipsychotics with sedative effects
	• Polypharmacy: two or more antipsychotics
	• Sudden changes in the doses of antipsychotic medications

The pathophysiologic of the seizure-inducing effects of some antipsychotics are as follows:

Phenothiazines. The biochemical basis of the seizures induced by phenothiazines is inhibition of GABAergic neural transmission. Enhancement of various EEG abnormalities has been noted during antipsychotic therapy. Chlorpromazine and thioridazine have been found to produce inverted U-shaped, dose-response curves with a maximum epileptogenic effect at concentrations lower than therapeutic levels. Such patients are at increased risk of seizures at the beginning of therapy and on withdrawal. Seizures can also occur with overdosage of these drugs.

Clozapine. Clozapine lowers the seizure threshold in patients, and the propensity to cause seizures is dose related.

Olanzapine. Myoclonic status induced by this olanzapine are like those with clozapine.

Zotepine. This drug has a high affinity for the 5-HT1 binding sites in the cerebral cortex. This property is considered to induce seizures.

Antiseizure medications. Antiseizure medications have been reported to aggravate seizures in specific patients. Those at greatest risk of experiencing antiseizure medication-related seizure exacerbation are children with epileptic encephalopathies, patients with high frequency of seizures or several types of seizures, and patients on polytherapy. Seizures may also be caused by antiseizure medications. Various explanations of this paradoxical effect are as follows:

	• An incorrect choice of drugs in the treatment of epilepsy.
	• A decrease in the blood level of a previously effective antiseizure medication.
	• "Paradoxical intoxication" has been described in patients treated with phenytoin or carbamazepine in whom the seizure frequency increases as the blood levels of antiseizure medications rise to a supra-therapeutic range.
	• A progressive neurologic condition with an increase in the frequency of seizures.
	• Loss of efficacy of a previously effective antiseizure medication.
	• Overdosage effect of antiseizure medications leading to neurotoxicity.
	• Interactions of antiepileptic drugs with other drugs leading to rise or fall of antiseizure medication serum levels.
	• Adverse effect caused specifically by the antiseizure medications.
	• Seizures due to electrolyte disturbances produced by antiseizure medications. For example, hyponatremia can be produced by carbamazepine.
	• Reduced bioavailability of the antiseizure medication.
	• Withdrawal of antiseizure medications. Increase in seizure frequency in patients with epilepsy during withdrawal from barbiturate therapy is well known. In patients with focal seizures, increase in seizure frequency is seen when blood phenobarbital levels fall below 20 mg/L. Epilepsy patients withdrawn rapidly from carbamazepine experience significantly more seizures than those withdrawn slowly over several days.
	• Patients with focal seizures may experience an increase in seizure frequency when a new antiseizure medication is added to their therapy. It may represent spontaneous fluctuations, not necessarily a drug effect.
	• Mutations in epilepsy-related genes.

Examples of seizures caused by antiseizure medications include the following:

Carbamazepine. Children with mixed seizure disorders, particularly those with generalized slow spike-and-wave discharges on EEG, become worse on carbamazepine. Carbamazepine has also been reported to cause myoclonic, atonic, and absence seizures. Mutation h1u-1962 T > G in the SCN1A gene, the most clinically relevant epilepsy gene, was identified in a patient with focal epilepsy and febrile seizures, which was aggravated by oxcarbazepine (12).

High doses of carbamazepine can lead to exacerbation of seizures without any other evidence of neurotoxicity. Status epilepticus has been reported following carbamazepine overdose.

Oxcarbazepine. This is chemically related to carbamazepine and can exacerbate myoclonic and absence seizures in idiopathic generalized epilepsy.

Benzodiazepines. These drugs can produce status epilepticus when injected intravenously in children with Lennox-Gastaut syndrome. Another explanation of these seizures is that they are due to the vehicle propylene glycol in the injection.

Phenytoin. This drug can aggravate absence seizures. Photosensitive focal seizures can be aggravated by phenytoin. Seizures are an occasional manifestation of phenytoin toxicity.

Valproic acid. Valproic acid is associated with a paradoxical enhancement of seizures and interictal EEG manifestations. Seizures may be the result of encephalopathy induced by valproic acid in patients with focal seizures. Valproic acid can occasionally provoke aggravation of absence seizures in patients with absence epilepsy without inducing encephalopathy. Valproic acid can occasionally induce status epilepticus.

Vigabatrin. This drug is rarely associated with the aggravation of seizures, mostly in patients with therapy-resistant generalized seizures. Status epilepticus has been reported to occur during vigabatrin treatment.

Lamotrigine. Evidence indicates that lamotrigine is inappropriate in severe myoclonic epilepsy and may aggravate it.

Antimalarials. Prophylactic antimalarial drugs at standard doses can induce convulsions in healthy subjects and more frequently in those with a history of epilepsy. Mefloquine has been reported to be associated with seizures. The mechanism of seizures induced by antimalarial drugs is uncertain. Chloroquine inhibits glutamate dehydrogenase activity and could reduce the concentration of inhibitory neurotransmitter GABA.

Antituberculosis drugs. The epileptogenic effect of isoniazid seems to result from its inhibitory effect on glutamic acid decarboxylase, the enzyme responsible for synthesis of GABA.

Beta-blockers. When administered in therapeutic doses, these have an anticonvulsant effect, but seizures have been reported in patients with beta-blocker overdosage. Possible mechanisms of seizures induced by beta-blockers are as follows:

• Marked bradycardia that may be induced by these agents. • Severe hypoglycemia is a known adverse effect of beta-blockers. • A nonspecific effect on centrally located neurons, related to its membrane stabilizing effects. • High lipophilicity of the drug and its ability to penetrate into the tissues.

Central nervous system stimulants. This group contains drugs that share the ability to produce dose-related excitation of the central nervous system leading to convulsions. The stimulation may be at cortical, brainstem, or spinal levels. Examples of cortical stimulants are caffeine, cocaine, theophylline, amphetamine, ephedrine, and methylphenidate.

Caffeine. It has an intrinsic convulsant activity because of its adenosine receptor antagonizing properties. Animal studies have shown changes in the activity of norepinephrine, dopamine, and serotonin. The drug also acts directly on the cerebral arterial musculature to cause vasoconstriction and a decrease in cerebral blood flow. Intravenous caffeine given before electroconvulsive therapy can prolong seizure duration but does not reduce the seizure threshold.

Cocaine. This was the first local anesthetic, and convulsions are among its earliest known adverse effects. Cocaine augments the effects of catecholamine neurotransmitters, probably by blocking reuptake of these transmitters that restimulate receptors. Repeated high doses of cocaine produce a convulsive response in animal studies, and seizure-kindled paradigms have shown that effects of cocaine on the electrical activity of the brain are like those of lidocaine.

Methylphenidate. Some clinical evidence shows that methylphenidate may lower the convulsive threshold. There are reports of seizures associated with the use of methylphenidate during the first month of treatment, but four large observational studies have shown that it may be safely used in children and adolescents, even those with a history of epilepsy (01). Safe concomitant use of anticonvulsants and methylphenidate has not been established. If seizures occur, the drug should be discontinued. The risk of potential triggers of seizure during the first month of treatment with methylphenidate needs to be reexamined in future studies.

Theophylline. Like other xanthines, theophylline is a powerful central nervous system stimulant. Seizures are a known complication of theophylline toxicity and may occur within therapeutic levels. Status epilepticus has been reported in asthmatic children with serum theophylline levels within therapeutic range. The precise mechanism of theophylline-induced seizures is not known but may involve its action on adenosine and 5'-nucleotidase. Usually, clinical or EEG evidence of focal seizure activity is seen in the absence of focal central nervous system disease. Various risk factors for serious outcome in theophylline-induced seizures are:

	• Advanced age.
	• History of previous seizures.
	• Neurologic disease: encephalitis, cerebrovascular insufficiency.
	• Low serum albumin levels that allow an increase in the absolute free theophylline concentration because theophylline is 55% to 65% protein bound.
	• Severe chronic obstructive pulmonary disease.

Cytokines. Several cytokines are used as therapeutic agents. Findings from both the clinical literature and from in vivo and in vitro laboratory studies suggest that cytokines can increase seizure susceptibility and may be involved in epileptogenesis (11).

Nicotine. The only therapeutic use of nicotine is as transdermal patches for smoking cessation. There are no reported human cases of seizures due to nicotine abuse or overdose. However, experimental studies have been carried out in rodents to clarify the mechanisms underlying nicotine-induced seizures. In one study, administration of 4 mg/kg of nicotine produced motor excitement and elicited seizures, which were effectively blocked with an alfa7 nACh (neuronal acetylcholine) antagonist (13). Furthermore, Fos expression analysis revealed that the convulsive dose of nicotine region-activated neurons in the amygdala, and electric lesioning of the amygdala inhibited nicotine seizure generation. Results of this study suggest that nicotine induces seizures by activating amygdala neurons, mainly via alfa7 nACh receptors. Early in 2019, the FDA announced that it had received 35 reports of seizures in those smoking e-cigarettes, and they are being investigated. It may not be nicotine alone; other chemicals used in propelling the vapors have toxic effects as well.

Nonsteroidal antiinflammatory drugs. Seizures have also been reported, mostly after overdose ingestions, but even therapeutic doses have occasionally been associated with seizures (02).

Aspirin. The toxic effects of aspirin are almost entirely mediated by the salicylic acid that is formed by hydrolysis of the drug. Salicylate uncouples oxidative phosphorylation from electron transport and leads to depletion of body stores of glucose. Seizures are part of the clinical picture of patients with salicylate intoxication and are believed to be due to a depletion of brain glucose.

Thyroxine. Thyroid hormones lower the seizure threshold in humans and cause seizures in patients with Graves disease. Thyroxine can exacerbate absence seizures in juvenile myoclonic epilepsy.

Immunosuppressant drugs. Leukoencephalopathy is a known complication of immunosuppressant drugs used to counteract transplant rejection. Seizures are a manifestation of leukoencephalopathy.

Interferon-alpha. Generalized seizures occur in 1% to 4% of patients during interferon-alpha therapy. Possible mechanism is exposure of the cerebral cortex to interferon-alpha, possibly through a breach of the blood-brain barrier.

Opioid analgesics. Endogenous opioid peptides can evoke epileptiform activity on EEG in experimental animals, and evidence exists that these epileptiform discharges are mediated by specific opioid receptors and that this activity can be antagonized by opioid antagonists such as naloxone.

Morphine. Morphine can induce seizures in high doses in neonates and infants. This may be due to an immature blood-brain barrier allowing a greater penetration of the drug into the central nervous system. In adults, seizures are a rare occurrence after intraspinal administration of morphine or other opioids. Seizures following intravenous morphine have been attributed to the sodium bisulfite preservative contained in the morphine.

Meperidine (Pethidine). Pethidine is metabolized to norpethidine, which has half the analgesic potency of the parent compound but is twice as active as a convulsant. There are several reports of seizures associated with its use either intramuscularly or intravenously. The risk of seizures increases when meperidine is administered via a patient-controlled analgesia pump. Other risk factors for meperidine-induced seizures include the following:

	• History of seizures.
	• Renal impairment leading to prolongation of elimination of norpethidine and, therefore, greater accumulation. Patients with sickle cell crisis are more prone to develop seizures after intramuscular pethidine because of renal function impairment.
	• High meperidine doses (ie, daily doses exceeding 25 mg/kg).
	• Coadministration of hepatic enzyme-inducing medications.
	• Concomitant use of monoamine oxidase inhibitors, as they interact with pethidine, giving an idiosyncratic reaction involving central nervous system excitation and seizures.
	• Naloxone does not reverse norpethidine toxicity and can, on the contrary, exacerbate the seizures by antagonizing the anticonvulsant effect of pethidine.

Tranexamic acid. This is an antifibrinolytic agent used for reducing the risk of blood loss and transfusion in patients undergoing cardiac surgery. A metaanalysis of clinical trials on patients showed that the odds ratio of seizure is 5.39 in patients with tranexamic acid exposure versus patients with nontranexamic acid exposure (24). The incidence rate of tranexamic acid-associated seizures is dose-related. In a post hoc analysis of patients who received tranexamic acid while undergoing coronary-artery surgery, those who had one or more postoperative seizures were more likely than those who did not have any seizures to have a stroke (28).

Hyperbaric oxygen (HBO). Inhalation of 100% oxygen, at pressures higher than atmospheric, is like drug therapy. Seizures are rare and no more than a chance occurrence during hyperbaric oxygen sessions at pressures between 1.5 and 2.5 ATA (atmospheres absolute) even in patients with a history of epilepsy; in patients with cerebral ischemia, hyperbaric oxygen may abort seizures (15). However, seizures are well known as a toxic effect of hyperbaric oxygen when pressures over 2.5 ATA are used. Carbamazepine and vigabatrin are effective in preventing hyperbaric oxygen-induced convulsions in patients under high ATA hyperbaric oxygen. An experimental study has tested the effect of various antiseizure medications on seizure onset in hyperoxia at 5 ATA and showed that Na+-channel antagonists, carbamazepine and lamotrigine, more than tripled seizure latency compared to controls, leading to the inference that Na+-channel function and GABA neurotransmission may be critical targets in the pathophysiology of CNS O2 toxicity (07). Because these are essential components of neuronal excitation and inhibition, they provide an insight into molecular mechanisms of seizure disorders due to other causes. Induction of oxidative stress by hyperbaric oxygen is also an etiological factor in clinical epilepsies.

Intravascular contrast agents. The agents employed intravenously for studies such as angiography, urography, and computer tomography are usually sodium or methylglucamine salts of tri-iodinated derivatives of benzoic acid. The epileptogenic effect of radiologic contrast media seems to result from direct action of these substances on the cerebral cortex. The neurotoxicity of the contrast agents is probably related to disruption of the blood-brain barrier, disturbances in neuronal membranes, or both. Because these agents can cross the intact blood-brain barrier only in small quantities, they are safe in most cases. However, disruption of the blood-brain barrier by brain pathology makes the patients more susceptible to seizures. Seizures have been reported occasionally following intravenous contrast injection in patients undergoing CT scan for brain tumors.

A large volume of contrast material during coronary angiography can lead to retention of contrast material in the cerebral cortex and deep nuclei with a tendency for seizures until the contrast material is cleared out.

Agents for intrathecal administration. Metrizamide and iopamidol are nonionic water-soluble agents used for myelography, cisternography, and ventriculography. A variety of seizures have been reported following metrizamide myelography. Metrizamide competitively inhibits brain hexokinase and may cause seizures by this means. Iopamidol myelography is associated with risk of seizures in nonepileptic patients and can cause status epilepticus in epileptic patients.

Drug withdrawal seizures. Seizures are also known to occur during withdrawal from diazepam. Diazepam withdrawal has been stressed as a cause of seizures because of the ubiquitous use of this drug. Many anxiolytic drugs produce their effect by enhancing brain GABA transmission. During long-term exposure to anxiolytics, the effectiveness is reduced as brain GABA synapses show adaptive changes. Abrupt cessation of anxiolytic treatment may, therefore, lead to an acute reduction in GABA function, thus, leading to seizures.

Drugs inducing hypomagnesemia. Several categories of drugs, such as diuretics, proton pump inhibitors, antimicrobials, and anticancer drugs, may cause hypomagnesemia, potentially leading to seizures (20).

Vaccines. Postvaccine encephalomyelitis is a known complication of vaccination, and seizures are one of the manifestations. Pertussis vaccine (commonly administered with diphtheria and tetanus vaccine) is probably the most often implicated among those recommended and routinely used. It has been recommended that children who have had a major reaction to a previous vaccination, progressive neurologic disorders, or a history of convulsions should not be given pertussis vaccination. Children at risk for febrile convulsions should not be given vaccines known to produce fever.

Epidemiology

There are few studies of the prevalence of drug-induced convulsions. In a series of 32,812 patients studied in the Boston Collaborative Drug Surveillance Program (30), drug-associated convulsions occurred in 26 persons (0.08%). In a study on pediatric patients, nearly 5% of consultations by a toxicologist presented with drug-induced seizures (09). The majority of these were teenagers between 13 and 18 years of age, and the most common cause was intentional ingestion of antidepressants.

The frequency of occurrence of seizures in association with certain drugs is available. For newer antidepressants (eg, bupropion, mirtazapine, etc.), the risk of seizures with selective serotonin reuptake inhibitors is very low and risk with tricyclic antidepressants at effective therapeutic doses is somewhat higher. Seizures have been reported to occur more commonly with clozapine than with conventional antipsychotics.

Observations on 1754 patients treated with imipenem-cilastin in phase III dose-ranging studies revealed a 0.9% incidence of seizures related to this therapy.

Convulsions have been observed in 1% to 3% of patients on isoniazid therapy.

The incidence of seizures following arteriography has been reported to be about 0.2% to 0.4%. The incidence of seizures following metrizamide myelography, estimated from a large series of patients, ranges from 0.6% to 0.02%.

It is difficult to determine the incidence from clinical trials because most trials are carried out on a relatively small number of patients. To detect a single case of drug-induced seizure with an incidence of 1:1000 per year, about 3000 patients would have to be studied for the 1-year period.

According to various reports, 5% to 9% of all status epilepticus cases are drug induced. The latest such report specifies a slightly higher number of 12% in adults (05).

Prevention

• Drugs known to induce seizures should be used cautiously.

Knowledge of the drugs known to induce seizures is important, and these drugs should be avoided or given cautiously to epileptic patients or to those with risk factors for seizures, such as infants with high fever.

During development, the liability of a drug for inducing seizures is usually not tested until a later stage when toxicity studies are done on experimental animals. Functional evaluation assays using human-induced pluripotent stem cell (hiPSC)–derived neurons as well as astrocytes and using multielectrode arrays to determine in vivo convulsive firing enhancement can predict the convulsion toxicity of new drugs (29). Effects of drugs on microelectrode array recordings from cultured rat neurons have been shown to correlate with EEG on anesthetized rats exposed to the same drugs (18). Furthermore, combination of these data with concomitant gene expression enabled identification of several potential molecular targets that might explain the drug-induced seizures occurring in both rats and humans. These in vitro tests have potential for clinical applications to predict drug-induced seizures.

Seizures as adverse effects of drugs are discovered during clinical trials or when the drug is already in clinical use, and it is too late to modify the chemistry of the drug. A vector machine modeling method has been used to develop a prediction model of seizure liability of drugs; this method could be used in the seizure risk assessment at the early stage of drug discovery (39).

Appropriate dose monitoring should be undertaken in patients receiving a combination of imipenem-cilastatin, as this is associated with seizures in 2% to 4% of patients. Limitation of dose to 50 mg/kg per day in patients with normal renal function and to 20 mg/kg per day to those with impairment of renal function has been shown to reduce the frequency of seizures to less than 1%. When dosed appropriately, imipenem-cilastatin may be used to treat serious infections in critically ill patients with central nervous system disorders or injury with minimal seizure risk, but safety data are lacking for meningitis, and cautious use is recommended.

Various guidelines to reduce the risk of seizures with clozapine are as follows:

	• An EEG should be obtained prior to raising the dose above 600 mg per day.
	• Clozapine should be administered with caution to patients with a history of seizures or head injury.
	• In patients with a history of previous clozapine-induced seizures, an anticonvulsant should be combined with clozapine. Valproic acid is the anticonvulsant of choice. Topiramate can also be used. Alternatively, the dose should be reduced to half of that at which the seizure occurred.
	• On initiation of clozapine therapy, the dose should be raised slowly along with monitoring of blood levels.
	• The use of comedications that increase the risk of seizures when combined with clozapine should be avoided.

In patients who are at high risk for seizures, such as those with brain metastases, the use of intravenous diazepam has been suggested as a prophylactic measure prior to injection of contrast agent for computer tomography.

The use of a gradual withdrawal schedule of benzodiazepines may reduce the probability of a seizure, but no controlled studies have been done to verify this.

Multielectrode array systems are useful for evaluating seizure risk of drugs in development because they can noninvasively measure the electrophysiological activities of neural networks in cultures of human-induced pluripotential stem cell-derived neurons (32).

Differential diagnosis

Confusing conditions

Some of the confusing conditions are:

• Spontaneous seizures • Seizures of unknown origin • Epileptic seizures • Stimulant drug abuse

Drug-induced seizures need to be sorted out the same way as any other form of epileptic seizure. In epileptic patients, differentiation from spontaneous seizures is based on the course of the disorder. Possible seizure-inducing effects of antiseizure medications should be considered if seizure frequency increases on introduction of a new drug, is associated with an increase of dose, or occurs despite continued treatment with previous antiseizure medications. Suspicion of association with an antiseizure medication can be verified by discontinuation of the drug followed by improvement of seizures and aggravation of seizures on reintroduction of the drug.

The features of the stimulant-induced seizures are distinct and enable differentiation of seizures induced by cocaine and those induced by amphetamine. The duration of convulsive activity is shortest for cocaine but longest for amphetamine. Cocaine-related seizures are effectively prevented by phenytoin, whereas amphetamine-induced seizures are refractory to phenytoin.

Associated or underlying disorders

These are conditions listed as patient-related predisposing factors in Table 3 such as:

• Family history of epilepsy or previous seizures • Previous brain lesion such as a tumor even without history of seizures • Fever

Diagnostic workup

• In addition to routine laboratory and drug level measurements in blood, the investigations are similar to those used for first onset seizure, eg, EEG and brain imaging.

It is important to have a detailed history of previous seizures and all drugs taken by the patient before the seizure. Routine blood counts and a biochemistry screen should be done, and attention should be paid to detect any abnormalities associated with adverse effects of drugs that may be associated with seizures, ie, hypoglycemia, hyponatremia, and hyperammonemia. Blood levels of the suspected drugs may be measured where relevant.

An EEG examination is essential, particularly in patients with epilepsy who have an aggravation of seizures on antiseizure medications. However, the significance of the EEG abnormalities and seizure risk is not established.

One retrospective investigation of the value of head CT with drug-induced seizures identified that about half of the patients had an alcohol-induced seizure and 1 of the 64 patients had an abnormal head CT scan without an alcohol-related seizure (23). A cohort of 396 patients with nontraumatic etiology that presented to an emergency department were retrospectively analyzed (33). The risk factors for an abnormal CT head were age greater than 61, loss of consciousness, or focal neurologic deficit. Mutations or variations in noncoding regions that may affect SCN1A gene expression should be checked in patients with antiseizure medication-induced seizure exacerbation.

Management

	• As a preventive measure, patients being considered for antidepressant treatment should be screened for predisposition to seizures.
	• Benzodiazepines are generally accepted as the first-line anticonvulsant therapy for drug-induced seizures.

As a preventive measure, patients being considered for antidepressant treatment should be screened for predisposition to seizures. If predisposition is detected, antidepressants should be administered cautiously with slow titration and avoidance of overdose.

Most drug-induced seizures are self-limiting and do not result in severe sequelae. About 15% may present as status epilepticus, and this has potential for morbidity. The treatment of drug-induced seizures is usually like that of seizures due to other causes, although drug-induced seizures are more difficult to control. Drug-induced seizures are frequently toxic-metabolic in nature, and because they lack a focal brain lesion, they may be less responsive to conventional antiseizure medications such as phenytoin.

Benzodiazepines are generally accepted as the first-line anticonvulsant therapy for drug-induced seizures, and if they fail to halt seizures promptly, second-line drugs include barbiturates and propofol, but not phenytoin (03). Phenytoin is not recommended due to animal studies suggesting a risk of harm when used to treat seizures induced by lidocaine, theophylline, or tricyclic antidepressants. A retrospective study has shown that levetiracetam can be safely used as a second-line agent for control of drug-induced seizures and prevention of seizure recurrence (21). A prospective trial had a small number of patients with drug-induced status resistant to benzodiazepines, and used levetiracetam, fosphenytoin, and valproate (05). Numbers are too small to say more than these agents may be safe.

A neurologic consultation is expected in cases where the seizure is not clearly related to the drug or where the offending drug needs to be continued for medical reasons. Loss of seizure control in a patient stabilized on antiseizure medications is an indication to check the patient's calcium status. Drug-induced hypocalcemia can be treated with vitamin D and calcium supplementation.

Special problems according to the drug involved are mentioned here:

Paraldehyde, phenobarbital, phenytoin, and diazepam have all proven to be effective in the management of convulsions due to tricyclic antidepressant poisoning when administered either alone or in combination.

When a first seizure occurs in a patient on clozapine therapy, dosage of the drug should be reduced, or an alternative antipsychotic agent be employed. If a second seizure occurs, an anticonvulsant drug should be started (38). Valproic acid is the anticonvulsant of choice for the treatment of clozapine-induced seizures. Other antiepileptic drugs such as phenytoin, carbamazepine, and phenobarbital cause hepatic enzyme induction, lower the blood levels of clozapine, and should be avoided. One patient who had recurrent seizures whenever clozapine was reintroduced was managed by addition of valproic acid to clozapine and remained seizure free (10).

Convulsions due to isoniazid intoxication are unresponsive to anticonvulsant therapy alone but respond to addition of pyridoxine. An adequate amount of pyridoxine is required to correct gamma-aminobutyric acid deficiency due to isoniazid toxicity and can be combined with benzodiazepines for a possible synergistic effect in terminating seizures (27).

Use of propranolol is recommended for the management of adrenergic cocaine crisis. An alternative is labetalol, as it possesses both alpha-blocking (to counter the cocaine-induced vasoconstriction and hypertension) and beta-blocking capabilities (to decrease the tachyarrhythmias). Diazepam can be administered to control the seizures, and phenobarbital loading is used if status epilepticus develops.

Theophylline-associated seizures are usually refractory to diazepam as theophylline is known to antagonize the effects of benzodiazepines. Prompt use of barbiturates is recommended when diazepam is not effective in controlling theophylline-associated seizures. Phenobarbital 15 mg/kg should be given intravenously. Some cases may require general anesthesia to control seizures. Hemodialysis may be required to lower blood levels of the drug.

If seizures do not stop within 20 minutes, a loading dose of thiopental 3 to 5 mg/kg should be followed by an infusion of 2 to 4 mg/kg per hour.

Intravenous diazepam is the drug of choice for the management of salicylate-induced convulsions. Short-acting barbiturates are the second-line agents.

Intravenous benzodiazepines are effective for acute management of bupropion-induced seizures and may require supplementation with barbiturates or propofol.

Oral phenytoin is more effective than diazepam against seizures induced by administration of contrast agents in the subarachnoid space and should be given prophylactically starting the day before the procedure to achieve therapeutic blood levels.

Carbamazepine has been used successfully for the treatment of benzodiazepine withdrawal. In addition to controlling seizures, it reduces other withdrawal symptoms, such as hypersensitivity to sensory stimuli and depersonalization.

Management of drug-induced status epilepticus. In addition to eliminating the potential trigger, an approach should be the same as for status epilepticus in any other circumstances. Phenytoin is used as the first-line treatment with the exception that phenobarbitone is recommended as a second-line treatment if drug toxicity is suspected, as the risk of cardiovascular complications may be exacerbated by phenytoin (04).

Special points to be noted regarding management of seizures due to overdoses of drugs include the following:

	• In the case of overdose of tricyclic antidepressants, acidemia due to seizures makes the cardiotoxicity more severe.
	• If paralyzing agents are used, EEG monitoring should be used to monitor ongoing electrical seizure activity.
	• Seizures due to drug-induced hypoglycemia should be recognized and treated quickly to avoid neurologic sequelae.
	• Seizures induced by isoniazid usually respond quickly to the administration of pyridoxine.
	• Seizures related to the overdosage of anticholinergic agents may respond to physostigmine, if standard anticonvulsants are ineffective.
	• Seizures in patients taking lithium or salicylates may indicate toxic concentrations of these drugs in the brain. This may require hemodialysis.
	• Intravenous diazepam is the most frequently used drug for the control of drug-induced seizures, and it can be given rectally if intravenous access is not available.
	• Carbapenem-associated seizures are best managed with benzodiazepines. Combination with valproic acid should be avoided because drug interaction results in clinically significant declines in valproic acid serum concentrations (26).

Special considerations

Pregnancy

Apart from usual complications of seizures during pregnancy, a drug-induced seizure may indicate possible neurotoxic effect on the fetus if the drug in question accesses the fetal brain.

Older antiseizure medications such as phenobarbital and phenytoin have been shown to induce neuronal apoptosis in developing white matter of rat models in the first week of the postnatal period, whereas lamotrigine, carbamazepine, and levetiracetam did not show this effect (16). Whether antiseizure medications used for the management of seizures in infants with intraventricular hemorrhage or hypoxic-ischemic encephalopathy will alter outcomes in the presence of underlying brain damage remains to be investigated. It may be prudent to avoid the use of phenobarbital and phenytoin in infants with seizures due to brain damage.

Bupropion, an antidepressant, enters maternal milk with a potential risk of seizures in breastfeeding infants.

Anesthesia

See the articles on neurologic complications of general anesthesia and neurologic complications of local anesthesia.