Drug class
Drugs
Analgesics
Meperidinea, opioids, tramadol
Anesthetics
General anesthetics
Enflurane, isoflurane, sevoflurane
Intravenous anesthetics
Propofol, ketamine
Local anesthetics
Lidocaine, bupivacaine, procaine
Antibiotics
Beta-lactams
Penicillins, cephalosporinsb (all generations), carbapenems
Fluoroquinolones
Ciprofloxacin, levofloxacin
Antituberculosis
Isoniazida
Nitroimidazole
Metronidazole
Antimalarials
Chloroquine, mefloquine
Antidepressants
Tricyclic antidepressants
Imipraminea, clomipramine, amoxapine, amitriptyline
Maprotiline (tetracyclic antidepressant)
Maprotiline
Bupropion
Bupropion
Selective serotonin reuptake inhibitors
Fluoxetine, sertraline, paroxetine
Lithium
Lithium
Typical antipsychotics
Chlorpromazine, haloperidol, trifluoperazine, pimozide, fluphenazine
Atypical antipsychotics
Clozapinea, olanzapine, risperidone
Antiepileptic drugs (AEDs)
Benzodiazepines, carbamazepine, tiagabine, vigabatrin, lamotrigine, levetiracetamb
Antihistamines
Diphenhydramine, desloratadine
Antineoplastic agents
Alkylating agents
Ifosfamideb, cisplatin, chlorambucil
Antimetabolites
Cytarabine
Vinca alkaloid
Vincristine
Beta-blockers
Propranolol
CNS stimulants
Cocaine, theophyllinea, caffeine, methylphenidate, MDMA, other amphetamines
Contrast
Intravenous
Iodinated contrast
Intrathecal
Metrizamide, iopamidol
Immunosuppressants
Cyclosporine, interferon alpha, methotrexate
NSAIDs
Aspirin, mefenamic acid
Miscellaneous
Allopurinol, cimetidine, thyrotropin-releasing hormone, bromocriptine, methyldopa, verapamil, insulin
Antidepressants
Antidepressants can have anticonvulsant and proconvulsant properties depending on their effects on neurotransmitters. Higher levels of monoamines such as dopamine, noradrenaline, adrenaline, and serotonin can reduce the seizure threshold. As such monoamine oxidase inhibitors will decrease the seizure threshold. Dopaminergic chemicals will increase the seizure threshold, whereas dopamine receptor blocking agents, such as antipsychotics, will decrease the threshold. The noradrenergic system can both suppress and induce seizures, and its effect appears to be dose dependent, especially with tricyclic antidepressants, which can block presynaptic norepinephrine reuptake. There is also evidence that antidepressants may block the GABA receptor, another mechanism for decreasing seizure threshold. Furthermore, long-term use of antidepressants can downregulate α-adrenergic receptors resulting in a delayed exacerbation of seizures. The role of serotonin in seizure exacerbation is controversial with animal models showing both proconvulsant and anticonvulsant properties [10]. In general, selective serotonin reuptake inhibitors (SSRIs) are considered to carry a lower risk of seizures than tricyclic or tetracyclic antidepressants [6].
Bupropion
Bupropion is a monocyclic antidepressant and indicated for smoking cessation. The incidence of seizures has been reported to be 0.2–0.4 % [10]. At least half of these patients had predisposing risk factors for epilepsy. There appears to be a dose-dependent increase for the risk of seizures, especially over 450 mg per day. The seizures also seem to occur within 6 weeks of starting the medication. Long-acting forms of bupropion (IR and ER) have resulted in seizures, usually with overdose, with reported incidence of 21 %. Treatment with clonazepam has been suggested as efficacious in treating bupropion-induced seizures [11].
Tetracyclic Antidepressants
Maprotiline and amoxapine are tetracyclic antidepressants introduced in the early 1980s. Maprotiline was reported to cause seizures in 0.4 % of the manufacturer’s clinical trial of 6100 patients. It has a strong lipophilic affinity and high brain concentrations that block the presynaptic uptake of norepinephrine. Unlike tricyclic antidepressants, the pro-convulsive effects of maprotiline appear to be more immediate, usually within 1 week of starting the medication [10]. Amoxapine intoxication is associated with an incidence of seizures as high as 36 % with some suggestion of severe, prolonged seizures [12].
Tricyclic Antidepressants (TCAs)
TCAs are traditionally prescribed for the treatment of depression and other mood disorders but currently have a broader scope of use in peripheral neuropathy and headaches. Animal studies and in vitro studies show that tricyclic antidepressants have convulsive and anticonvulsant properties due to an increase in biogenic amines such as norepinephrine and serotonin [10]. Since imipramine was first introduced to the market in 1958, tricyclic antidepressants have been known to cause seizures. In the early clinical trials for imipramine, the rate of seizures was 4 %. Other studies, of which only one was prospective, showed an incidence of seizures of 1–2 % [1, 10]. In cases of TCA overdose, generalized tonic-clonic seizures have been reported in 4 % of cases [12]. Traditional first-line treatment with benzodiazepine, phenytoin, or phenobarbital has been reported to be effective in these cases. Electroencephalograms performed on patients taking tricyclic antidepressants have shown activation or aggravation of abnormal waveforms in patients with a known history of epilepsy or who had preexisting abnormal EEGs. They were not shown to generate new abnormal EEG activity [6].
Selective Serotonin Reuptake Inhibitors (SSRIs)
SSRIs are generally considered to have a lower risk of seizures among antidepressants and may even have anticonvulsant properties. However, case reports and small case series of seizures associated with the use of fluoxetine, sertraline, and paroxetine have been reported. The risk associated with SSRIs is considered to be about 0.2 % [6]. The use of fluoxetine in combination with tricyclic antidepressants and bupropion has been known to also cause seizures [2].
Antipsychotics
Approximately 1 % of all patients on antipsychotic drugs will have seizures related to drug use. Risk factors predisposing patients to have seizures while on antipsychotic drugs include a history of epilepsy, electroconvulsive therapy, history of a brain lesion from trauma, tumor or previous surgery, treatment with two or more antipsychotic agents, or a large dose of antipsychotic medications [2]. Chlorpromazine and clozapine have a higher incidence of causing seizures and changes on EEG. Haloperidol, fluphenazine, pimozide, and trifluoperazine have a lower seizure potential among the antipsychotic drugs. The newer generation antipsychotics, such as olanzapine and risperidone, have had reports of drug-induced seizures in the literature but are generally considered to be less epileptogenic [6].
Clozapine
Clozapine is a dibenzodiazepine derivative with a high affinity for the D4 receptor and a low affinity for the D2 receptor. It is used in the treatment for refractory schizophrenia. During clinical trials, 2.8 % of 1418 patients had seizures with a 10 % cumulative risk after 10 years of treatment [13, 14]. Doses greater than 600 mg/day are associated with the highest rate of seizures. It is estimated that the incidence of seizures at a dose of 600–900 mg/day is 5 %, for 300–599 mg/day the risk is 3–4 %, and for doses less than 300 mg/day, the risk is 1–2 % [13, 15]. Seizure types including generalized tonic-clonic seizures, myoclonic seizures, and 3 Hz status epilepticus have been described in the literature. In a series of 5629 patients exposed to clozapine, 1.3 % had generalized tonic-clonic seizures and 33.8 % of these patients had recurrent seizures. The average number of days from the start of treatment to developing seizures was 42. Patients who were successfully weaned from their total dosage had no recurrence of their seizures [13].
There appears to be affinity of the drug for the temporal regions and these are where the EEG changes are usually found. Another mechanism that has been proposed includes kindling models in the hippocampi [15]. In a series of 12 patients who underwent EEG recording, eight showed interictal epileptiform abnormalities. Two of these patients did not experience clinical seizures [16]. In another retrospective study of 283 patients who had EEGs performed prior to, during and after treatment with clozapine, 61.5 % showed abnormalities [17]. However, these findings were not predicative of clinical seizures. The application of EEG screening prior to the use of clozapine has not been established and is controversial [15].
Among the psychiatric community, the general trend for treatment of clozapine-induced seizures is to first attempt to reduce the dose. If the seizure is recurrent or if the patient is refractory to reduction of the clozapine, then an AED may be considered. Valproic acid appears to be the antiepileptic drug of choice as drug-inducing AEDs such as phenytoin, phenobarbital, and carbamazepine lower the levels of clozapine. Furthermore, carbamazepine in conjunction with clozapine has a higher risk of bone marrow suppression. Other treatment options include lamotrigine, gabapentin, and topiramate [2, 15].
Lithium
Phenothiazines
The aliphatic phenothiazines which include chlorpromazine, promazine, and triflupromazine have a much higher risk of seizures then the piperazine phenothiazines (fluphenazine, prochlorperazine, perphenazine) [12]. In a 4-year prospective study following 859 psychiatric patients on chlorpromazine without risk factors for epilepsy, 1.2 % developed seizures. Those receiving doses greater than 1000 mg/day had a seizure incidence of 9 %, whereas doses less than 1000 mg per day had a seizure incidence of 0.5 % [6, 12, 20]. In comparison to the phenothiazines, other classes of antipsychotics including haloperidol, pimozide, quetiapine, olanzapine, and risperidone are considered to have lower epileptogenic potential [6, 12].
Antiepileptic Drugs (AEDs)
Antiepileptic drugs can also cause a paradoxical increase or exacerbation of seizures. Risk factors for this include young children with epileptic encephalopathies, patients on polytherapy, or patients with multiple seizure or seizure types. There may be multiple causes of AEDs inducing seizures. Drug-drug interactions can lead to an increase or decrease in the serum level of other drugs. Incorrect selection of the AED may worsen a particular type of epilepsy syndrome. A classic example of this is the use of carbamazepine in a patient with primary generalized epilepsy which can exacerbate seizures or induce new seizure types including typical and atypical absence, atonic, tonic, myoclonic seizures and absence status epilepticus. Toxic levels or overdose of certain AEDs can cause a paradoxical worsening of seizures as can be seen with phenytoin or carbamazepine. Electrolyte abnormalities as a secondary effect of some drugs can lead to seizures such as carbamazepine or oxcarbazepine causing hyponatremia. A sudden cessation or rapid withdrawal of medication may cause drug-induced seizures such as can be seen with benzodiazepines or barbiturates. Changes in the absorption or bioavailability of the active metabolite may cause seizures. An example is worsening seizures in a pregnant woman taking lamotrigine or levetiracetam due to increased relative clearances.
Benzodiazepines
The most common cause of benzodiazepine-inducing seizures is rapid withdrawal. However, the use of benzodiazepines may precipitate tonic seizures or status. Case reports and case series of children with Lennox-Gastaut syndrome given intravenous benzodiazepines causing absence status or tonic status epilepticus have been reported. The EEGs in these five patients showed numerous slow spike-waves, which peaked concomitantly with serum levels of the benzodiazepines [21, 22].
Carbamazepine
Carbamazepine is well recognized to worsen or induce seizure activity in primary generalized epilepsies. EEGs in these cases have shown an increase of generalized spike-wave discharges. Myoclonic status has been reported in a case of Angelman syndrome. Worsening atypical absence and tonic seizures in patients with benign epilepsy with centro-temporal spikes (BECTS) have also been reported after carbamazepine use. Case reports have also been published on carbamazepine causing status epilepticus, which was reversible by lowering the dose [2, 23].
Lamotrigine
The use of lamotrigine in myoclonic epilepsies is well known to aggravate myoclonus. Myoclonic status induced by lamotrigine in a child with Lennox-Gastaut syndrome has been reported. Worsening of absence seizures in BECTS has also been reported [22].
Levetiracetam
Levetiracetam has also been shown to induce or worsen seizures in patients. In a series of 70 adults and 44 children with refractory epilepsy, levetiracetam was used as adjunctive treatment. In the adult group, 18 % of patients had an increase in their seizure frequency and three adults had status epilepticus within 4 weeks of starting levetiracetam. In the children subgroup, 43 % had an increase in seizure frequency at a dose greater than 30 mg/kg/day [24].
Tiagabine
Multiple case reports have been reported of tiagabine causing absence status in idiopathic generalized epilepsies as well as focal NCSE. These cases of status were generally in patients taking over 40 mg/day. However, a case of tiagabine with a dose as low as 20 mg/day may also result in focal status [25]. The pathophysiology is theorized to be due to higher doses blocking GABA reuptake and depleting intercellular GABA [22, 25].
Valproic Acid
A case of valproic acid inducing tonic status has been reported in the literature in a patient with mild cognitive impairment [26]. Focal NCSE has been reported secondary to hyperammonemic encephalopathy due to valproic acid 4 days after initiation of treatment [27]. Multiple case reports on the carbapenem class of antibiotics inducing seizures in patients on valproic acid treatment with and without a history of epilepsy have also been published. Drops in VPA concentrations can be as high as 58 % after initiation of carbapenems [28].
Vigabatrin
Vigabatrin can aggravate absence seizures in patients with childhood absence epilepsy. It can also induce myoclonic seizures and status in myoclonic epilepsies [22].
Antibiotics
Since the advent of penicillin, antibiotics in the class of beta-lactams and fluoroquinolones have been reported to induce seizures by lowering the seizure threshold [29]. Risk factors for seizures induced from antibiotics include renal insufficiency, age greater than 50 years, high doses or serum levels, and alterations of the blood-brain barrier (tumor, stroke, cardiopulmonary bypass surgery) [7]. Seizure types can include tonic-clonic seizures as well as nonconvulsive seizures or status epilepticus [7]. In general, patients who have antibiotic-induced seizures do not require chronic AED treatment, and if they do, then short-term treatment can be considered.
In a retrospective review of 112 consecutive patients, who were diagnosed with status epilepticus, 10 % were attributed to antibiotic usage. These patients had comorbidities including hepatic failure (41.7 %), renal failure (50 %), and abnormal brain lesions diagnosed on MRI (77.8 %). The most common antibiotics in these cases were cephalosporins and fluoroquinolones, sometimes used in combination [30].
Beyond the direct effects of antibiotics on the central nervous system as described below, antibiotics may also induce seizures by altering serum levels of AEDs. For example, carbapenems can reduce levels of valproic acid as much as 66 % as published in a case report. Chloramphenicol can increase the levels of phenytoin and clarithromycin. Erythromycin and isoniazid (INH) may increase carbamazepine levels. As such, recommendations are to monitor levels of AEDs prior to starting antibiotics [7].
Carbapenems
Carbapenems are a class of beta-lactam antibiotics with broad-spectrum coverage and are used commonly in the setting of hospital-acquired infections. Imipenem/cilastatin has been reported to cause seizures in up to 20 % of patients who have renal dysfunction and an organic brain lesion [7]. Like fluoroquinolones and β-lactams, the epileptogenicity of the carbapenems is thought to be due to the binding of GABA receptors. Various prospective trials for imipenem suggested seizure rates of 0.2–0.9 % due to the drug itself. With other confounding factors such as the use of multiple antibiotics, a history of seizures or continued seizures despite stopping the carbapenem, the incidence was closer to 3 % [10]. In a meta-analysis looking at carbapenems and seizures, carbapenems were more epileptogenic than competitor antibiotics (odds ratio of 1.87, 95 % confidence interval 1.35–2.59). Imipenem was specifically more epileptogenic and this was a dose-dependent effect. Patients receiving ≤ 2 g/day had a risk difference (RD) of three patients per 1000 with seizure, whereas patients receiving > 2 g/day had an additional eight patients per 1000 with seizure. The meta-analysis showed no significant difference in seizure risk between imipenem and meropenem, even though meropenem is considered less epileptogenic of the two [30, 31].
Cephalosporins
Cephalosporins are used for surgical prophylaxis and for the treatment of pneumonia, strep throat, staphylococcal infections, sexually transmitted diseases (STDs), and urinary tract infections. Seizures have been reported with each generation of cephalosporins. The cephalosporins act as GABA inhibitors and may increase glutamate levels [29]. Increased risk of seizures is associated with reduced creatinine clearance and organic brain lesions. The third- and fourth-generation cephalosporins (e.g., ceftazidime and cefepime, respectively) seem to have a higher incidence of seizures [10, 29, 32].
The onset of seizures is generally 3–21 days after starting treatment. Cefepime in particular has been reported to cause NCSE in the setting of an elderly patient recovering from renal failure [29, 33]. Furthermore, cefepime has also been reported to cause cortical myoclonus. EEGs in cefepime-associated seizures may frequently show generalized discharges that are often of triphasic morphology. These have been interpreted as NCSE [32]. As mentioned in the introduction, these cases are often challenging to distinguish between true NCSE and encephalopathy.
Fluoroquinolones
Fluoroquinolones are used to treat urinary and respiratory tract infections, STDs, and gastrointestinal and soft tissue infections. Many case reports of seizures induced from ofloxacin, ciprofloxacin, norfloxacin, and alatrofloxacin have been reported. Fluoroquinolones bind to GABA receptors in the brain and possibly act as an agonist on the NMDA receptor causing CNS activation [10]. The incidence of seizures with fluoroquinolones is estimated to be 0.1–0.5 %. Ciprofloxacin is estimated to induce more seizures than levofloxacin (0.5 % vs. 0.1 %, respectively) [7].
Isoniazid
Isoniazid is used in the treatment of tuberculosis. Intoxication with ingestion of over 35–40 mg/kg generally produces a syndrome of seizures, metabolic acidosis, respiratory depression, and coma roughly 30–120 min after ingestion [34]. INH is thought to produce seizures by depleting pyridoxine, a required cofactor for the production of GABA by glutamic acid decarboxylase. Case reports of status epilepticus with overdoses have been reported. However, therapeutic doses of 14 mg/kg/day twice a week produce seizures in 1–3 % of patients [12]. Treatment with IV pyridoxine can be used to terminate seizures [34, 35]. In severe cases of renal failure, dialysis may be considered as well.
Metronidazole
Metronidazole is used to treat gastrointestinal, skin, vaginal, joint, and respiratory infections. A case report of a patient with treatment of the drug resulting in NCSE and death has been reported [36]. In a systematic review of the literature, of 64 patients with metronidazole-induced neurological toxicity, 15 % had seizures [37]. Prolonged use is thought to lead to a higher risk of seizures [7, 36]. In general, cessation of the antibiotic is associated with improved prognosis.
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