In animals opioids are associated with electroencephalogram (EEG) proven seizure activity; however, the dose required to replicate this in the clinical setting is far greater that what is administered with either analgesia or anesthesia. On the other hand, focal neuroexcitation on the EEG occasionally occurs in humans after large doses of fentanyl, alfentanil, sufentanil, and remifentanil [29–32]. In animal studies midazolam, naloxone, and phenytoin have been shown to prevent seizure activity on the EEG where seizure activity was induced by large doses of fentanyl [33]. All strong mu agonists can cause myoclonus after an IV bolus with some of the more rapid-onset agents more likely the culprits [34]. However, the relationship between myoclonus or rigidity, subcortical seizure activity and cortical seizures is unclear. The postulated neuronal mechanisms of seizure induction include opioid induced disinhibition of GABAergic interneurons and inhibition of hyperpolarization-activated potassium currents [35, 36]. It is important to note that epidural and intrathecal administration of opioids has also been linked to seizure activity [37–39]. The most common reason for seizures due to opioids is linked to opioid withdrawal and use of agents with a higher risk for causing seizures (meperidine and tramadol).

Meperidine is metabolized via N-demethylation to an active metabolite normeperidine, which is then renally excreted. Accumulation of this metabolite is associated with seizure activity and patients with renal impairment or receiving large doses are at risk [40, 41]. Oral administration of meperidine will result in increased concentrations of normeperidine due to extensive first-pass metabolism, thus having increased risk for seizures at therapeutic dosing [42]. The elimination half-life is approximately five times as long as the parent compound (3–6 h versus 15–40 h), thus the toxic metabolite can quickly accumulate . Typically normeperidine toxicity develops at concentrations greater than 0.8 mg/dL. EEG changes associated with normeperidine include slow wave activity and epileptiform discharges that will resolve once normeperidine is eliminated [43]. Normeperidine induced seizures often begin after the onset of other clinical sequelae such as delirium, tremors, or myoclonus. Seizures that develop are usually generalized tonic-clonic. Naloxone does not reverse the toxicity and could exacerbate the seizure activity. Treatment includes supportive measures and withdrawal of meperidine. Treatment with traditional antiepileptic drugs (AEDs) should be avoided as they have been shown to accelerate the conversion of meperidine to normeperidine potentially worsening the seizures [44]. Return to baseline neurologic functioning is dependent upon removal of the parent compound and the toxic metabolite so it would not be anticipated until a few days after meperidine discontinuation.

Morphine can induce seizures at high doses in neonates with immature blood-brain barriers but has never been shown to be associated with seizures in adults [45]. There have been some reports of seizure activity with fentanyl, alfentanil, and sufentanil [46–50], which have not been confirmed with EEG findings of seizure activity [51, 52]. Surface EEG recordings are characterized by high-voltage slow delta waves following administration of these agents [44]. It has been postulated that the tonic-clonic movements originally reported is somatic muscle rigidity or subcortical seizure activity and not true seizure activity.

Tramadol is a weak mu-receptor agonist with other pharmacological properties including inhibition of serotonin and norepinephrine reuptake. Tramadol has been reported to cause seizures following overdose and also with therapeutic dosing (primarily with chronic dosing) [53]. The lowest dose associated with seizures was 200 mg with the seizure occurring within 6 h of administration [54]. The incidence of seizures following overdose has been reported to be around 8% and the risk of a recurrent seizure is low (7%) [55–57]. Subsequently during the second year the agent was on the market a warning letter was issued by the Food and Drug Administration to all healthcare practitioners based upon the increased number of reports of seizures they had received. In most of the cases, patients were receiving other agents that were known to increase the risk of seizures and many were overdoses [58]. In a post-marketing surveillance case-controlled study in over 10,000 patients the risk of seizures with tramadol was similar to other analgesic agents [59]. The use of naloxone and risk of inducing a seizure in tramadol poisonings is controversial with some studies showing improvement in brain waves [60], others showing increased clonic seizures [61], and others showing no benefit [62]. Tapentadol is an orally active, central synthetic analgesic that acts via the mu-opioid receptor and inhibition of norepinephrine reuptake. The seizure rate of tapentadol reported to the National Poison Data System is 1.8% which was less than that associated with tramadol (13.7%) [63].

Seizures can also be the result of opioid withdrawal. Interestingly, Wijdicks and Sharbrough [15] attributed one-third of new-onset seizures in the critically ill patients in their cohort to opioid withdrawal. In this cohort, all patients who experienced new-onset seizures received at least 7 days of repeated intramuscular injections. Seizures related to drug withdrawal typically occur 2–4 days after last ingestion depending on the pharmacokinetic profile of the offending agent. Gradual tapering of agents that are associated with drug withdrawal, including opioids, is optimal in preventing seizures.

Salicylate toxicity primarily mediated through salicylic acid clinically presents with neurologic abnormalities including seizures. Most seizures are generalized and related to the depletion of brain glucose and increased CNS oxygen consumption even with normal blood glucose. First-line treatment for salicylate induced seizures is benzodiazepines followed by barbiturates as second-line agents. Since seizure is the most important symptom of severe salicylate toxicity other treatment should include gastrointestinal decontamination, urine alkalinization, and hemodialysis [19].

Seizure activity associated with general anesthetic agents is largely thought to be an uncommon event. Nonetheless seizure activity has been reported with both volatile and nonvolatile agents. These agents are commonly used in the operating or procedure rooms and rarely in the ICUs. Therefore, their potential epileptogenic effects may be encountered in critically ill patients only in cases of immediate post-op transfer to an ICU bed without passing through the recovery room.

The most widely reported volatile anesthetic agent associated with seizures is enflurane [64]. This agent produces high amplitude spikes and periods of electrical silence on the EEG with the hyperexcitability originating in the limbic system and then spreading to other areas [65]. Most seizures reportedly occur during recovery from anesthesia [66, 67]. Interestingly, delayed seizures have also been reported up to eight postoperative days even with an initial normal EEG [68–70]. The occurrence of seizures can be minimized by using lower concentrations (less than 1.5 minimum alveolar concentration) and avoiding hypocapnia [71]. However others have reported seizure activity with enflurane even with normocapnia in patients with seizure disorders [72]. No specific recommendations are available regarding the use of these agents. With the availability of other volatile agents, however, that have less seizure risk, it is best to avoid enflurane in patients with a pre-existing seizure disorder or is at risk of seizures.

There have also been a couple reports of isoflurane-associated seizures [73, 74]. In these reports, myoclonic seizures occurred 2 h after induction and progressed to generalized seizures with sustained myoclonus during recovery. However the bulk of information in humans suggests that isoflurane has anticonvulsant properties [75, 76].

Sevoflurane has a reported incidence of seizures up to 12% in clinical trials conducted in children, healthy adults, and elective gynecological surgery [77–83]. Most of the seizures were reported within 90 min of sevoflurane administration and epileptiform EEG activity was seen in over 70% of the cases. A case report also described seizure activity with emergence from sevoflurane anesthesia [82]. When compared to isoflurane, sevoflurane has stronger epileptogenic property. Recently postulated risk factors for epileptiform activity include high alveolar sevoflurane concentration (greater than 2.0 MAC), more rapid anesthetic induction, hyperventilation, history of epilepsy, and female gender [84]. The concomitant use of nitrous oxide, benzodiazepine, or opioid seems to counteract the epileptogenic property of sevoflurane [81, 85]. The postulated mechanism is via NMDA receptor activation, similar to that observed with enflurane, since both agents have a similar molecular structure with seven fluoride atoms [86].

The seizure potential of the nonvolatile agents appears to be negligible. Some of the agents have been used intraoperatively, however, to activate epileptogenic foci during epilepsy surgery. There have been some reports of seizures associated with ketamine anesthesia [87, 88], although EEG recordings have not revealed seizure activity in patients without a seizure disorder. However, it is well described that ketamine can activate epileptogenic foci, primarily subcortical seizure activity originating in the thalamic and limbic areas , in patients with a known seizure disorder [89, 90]. There is no evidence of seizure activity in cortical regions. Ketamine does possess anticonvulsant properties and has received attention as an intervention for patients with refractory status epilepticus [91].

During induction and maintenance of anesthesia, etomidate is associated with involuntary myoclonic movements, which may simulate a tonic seizure but not correlated with any epileptogenic activity [92, 93]. It is also possible that this represents subcortical seizure activity [44]. In patients with a history of seizure disorders, surface EEG recordings have documented proconvulsant activity of etomidate at lower concentrations [94, 95]. Further studies are necessary to further evaluate the proconvulsant nature of these agents.

There have been several types of CNS reactions to propofol including twitching, hypertonia, myoclonus, and seizure activity [96]. Propofol has been used in the treatment of status epilepticus; however, there are some reports correlating propofol to seizure activity in patients without a seizure disorder history [97]. The seizure activity described in these reports primarily occurred during induction and emergence of anesthesia with induction doses of 0.5–5.2 mg/kg with 34% of the patients having associated EEG abnormal tracings [97]. The Committee on the Safety of Medicines in the United Kingdom estimated the seizure incidence as 1 in 47,000 [98]. However it is uncertain if the reports are simply “abnormal movements” or seizure activity since there is very little EEG epileptiform activity reported.

Local anesthetics are known to be associated with both neurotoxicity and cardiotoxicity, especially following overdose in patients with and without a seizure disorder. The most commonly cited local anesthetic agents associated with seizures are lidocaine and bupivacaine.

Lidocaine can be administered to critically ill patients by a variety of different dosing routes, including topical, subcutaneous, intravenous, and intraspinal/epidural and seizures (clonic and tonic/clonic) following each route of administration has been reported. The greatest risk for neurotoxicity is following intravenous administration and when the drug is inadvertently injected directly into the blood vessel. Lidocaine is metabolized to monoethylglycinexylidide (MEGX), which can also contribute to its toxicity by lowering the seizure threshold [99]. The risk of seizures is correlated to serum concentration with seizures commonly reported with lidocaine concentrations of 8–12 mg/dL. Seizures are usually short lived ranging from a few seconds to a few minutes. At concentrations between 0.5 and 5 mg/dL, lidocaine can suppress the clinical and EEG manifestations of seizures in experimental models and has been used to treat status epilepticus in the clinical setting [100, 101]. There are several factors that can affect serum concentrations of local anesthetics including site and rate of injection, concentration, total dose administered, use of a concomitant vasoconstrictor, degree of ionization, degree of plasma and tissue binding, age, weight, and rate of metabolism and excretion [102]. Bupivacaine is similar to lidocaine in epileptogenic potential. This agent is approximately 7 times more potent than lidocaine so toxicity can develop at doses as low as 2–3 mg/kg [103].

Patients who are at the greatest risk for local anesthetic induced seizures are those with a history of renal or hepatic failure, older age, congestive heart failure, and/or septic shock [20]. In addition toxicity has been reported as a result of drug interactions with cimetidine and propranolol [104, 105]. Clinicians should utilize the lowest effective dose, follow serum concentrations, and avoid long-term infusions. Treatment for seizures associated with local anesthetics should include benzodiazepines and supportive care.

Seizure activity has been most commonly described with the penicillin class dating back to 1945 where myoclonic twitching was described in a toddler following intraventricular administration of benzylpenicillin [114]. Since that time, beta-lactams have been associated with neurotoxicity to varying degrees. Penicillin consistently produces seizures via any route of administration, although more common after intrathecal administration [115, 116]. The most frequently reported seizure types are myoclonus and generalized tonic-clonic seizures occurring 23 to 72 h after initiation of antibiotic therapy [117, 118]. Risk factors for seizures are those associated with increasing CNS concentrations and include older age, infants, renal impairment, history of meningitis, past history of central nervous system abnormality, administration of intraventricular antibiotics, continuous infusion administration, and history of seizures [119]. Penicillin brain toxicity is also due to a decrease in active transport out of CNS, when co-administered with other drugs, including anesthetics and probenecid, leading to an accumulation in the CNS at a higher concentration than in the blood [120]. Neurotoxicity has not been shown to correlate to CSF or serum concentrations of the antibiotic while brain tissue concentration is a better indicator [120]. The convulsive activity following semisynthetic penicillins has been described; however, their proconvulsant potency is lower than what is observed for benzylpenicillin [121].

Cephalosporins have a similar risk of inducing seizures in experimental models yet in clinical practice cephalosporins rarely produce seizures unless given in high doses or in patients with renal impairment [122]. In a recent systematic review of cephalosporin-induced neurotoxicity more than 10% of the cases evaluated reported overt seizures and similar proportion had EEG-confirmed nonconvulsive status epilepticus [123]. Essentially, all generations of cephalosporins are reported to cause seizures, but approximately 50% of reported cases have renal insufficiency and/or elderly patients with pre-existing neurological disease [123]. There have been several reports of nonconvulsive status epilepticus in patients with renal dysfunction who were being treated with cefepime [124, 125]. Naeije et al. [126] evaluated patients with normal renal function who underwent continuous EEG monitoring and also received cefepime or meropenem. They found that 1.25% of patients who were receiving cefepime with normal renal function showed epileptiform discharges compared to 0.19% of those patients receiving meropenem. If one considers, however, those patients with concomitant to the administration of the antibiotic EEG testing, the percentages are quite different: 23.7% of those with cefepime infusion had continuous epileptiform discharges versus 3.75% of those with meropenem [126]. This study suggests that cefepime may be an independent risk factor for periodic epileptiform discharges so clinicians should be cognizant of this potential. Most patients develop seizure 1–5 days after starting the agent. Treatment of beta-lactam associated seizures includes benzodiazepines and barbiturates.

Carbapenems are synthetic beta-lactam agents that are typically used for treating serious infections in hospitalized patients. The postulated mechanism of seizure induction is via binding to the GABAA receptor [127]. The traditional carbapenem, imipenem/cilastatin, has been associated with seizures at lower concentrations than other antibiotic agents and has a reported incidence of seizures ranging from 1.8–6% [120, 127]. Experimental studies suggest that imipenem is 10 times more neurotoxic than benzylpenicillin [128]. The toxicity associated with imipenem is due to accumulation of an open lactam metabolite of imipenem with cilastatin having no role alone in increasing seizure risk. Risk factors for seizures associated with imipenem include high dose, renal impairment, elderly, pre-existing neurologic abnormality , and Pseudomonas aeruginosa infection [129]. Seizures typically occur within 3–7 days of treatment initiation and are generalized or focal [129, 130]. The average daily dose of imipenem-cilastatin in those patients who experienced seizures ranged between 13 mg/kg to 4 g of imipenem [130]. As with other beta-lactam agents the treatment of choice for seizure activity is removal of the agent and administration of benzodiazepines. Phenytoin and other sodium channel blockers should be avoided. The newer carbapenems (e.g., meropenem) have a lower affinity for GABA_A receptor and have a reduced incidence of seizures (0.8%) [131]. Patients whose medical course is complicated by hydrocephalus show a marked decrease in the elimination rate of meropenem from the CSF as compared to that from the serum [127].

Fluoroquinolone agents are associated with seizures in animals; however in the clinical setting, seizures are rare and generally associated with overdoses or in patients who are susceptible to seizures [132]. The mechanism of seizures is similar to that of beta-lactams. Receptor binding affinity is likely secondary to the similarities between the chemical structures of GABA and the antibiotics [133]. The incidence of CNS toxicity of fluoroquinolones was originally thought to be associated with lipophilicity of the agent although that theory has since been disproven [132]. There does appear to be varying degrees of binding to the GABA receptor, which may result in inhibiting or displacing GABA from the receptors. Animal studies also suggest that these agents have an agonist effect on the glutamate receptor NMDA [134]. The most epileptogenic agent is trovafloxacin followed by enoxacin, moxifloxacin, ciprofloxacin, ofloxacin, and gatifloxacin, which is equivalent in epileptogenicity to levofloxacin [132, 135]. The estimated incidence in humans of seizure activity is 1% or less [136]. The seizures that have been described include tonic-clonic and generalized myoclonic activity occurring anywhere from 8 h to 12 days after initiation of therapy, although seizures have been reported up to a week following discontinuation of therapy [109, 137, 138]. Additionally seizures have been reported when fluoroquinolones are co-administered with theophylline and nonsteroidal anti-inflammatory drugs [20].

Isoniazid (INH) remains one of the most common agents for drug-induced seizures in the USA[13]. INH has a 1–3% risk for development of seizures. The epileptogenic potential results from INH being metabolized to hydrazines, resulting in a pyridoxine (vitamin B6) deficiency via inhibition of pyridoxine phosphokinase (the enzyme transforming pyridoxine to pyridoxal phosphate). Pyridoxal phosphate (activated B6) is required by glutamic acid decarboxylase to convert glutamic acid to GABA thus leading to decreased levels of GABA [139]. Mortality associated with INH is reported as high as 19%, particularly after ingestion of 10–15 g of INH [139]. An overdose of INH is very frequently associated with seizures, although therapeutic doses have also been linked to seizure activity primarily in elderly patients [140, 141]. Serum INH concentrations greater than 10 mg/L on presentation, greater than 3.2 mg/L 2 h after ingestions or greater than 0.2 mg/L 6 h after ingestion are associated with severe toxicity [142]. Seizures associated with INH may occur without warning usually 1–3 h after ingestion, frequently as generalized tonic-clonic seizures, which are prolonged and difficult to treat [143]. Other symptoms that accompany seizures include coma and metabolic acidosis. Phenytoin is ineffective in treating seizures associated with INH. Benzodiazepines are considered first-line agents; however, patients may be refractory since the agents require the presence of GABA for their therapeutic effects. Therefore, primary treatment includes intravenous administration of pyridoxine in amounts equivalent to ingested INH dose (1 g IV pyridoxine for each gram of INH ingested [144, 145]. If unknown quantities are ingested, then the dose of pyridoxine should be 5 g IV. This dose may be repeated on five to 20 min intervals until control of seizures has been obtained [20, 120]. A low threshold should be used for pyridoxine administration in the setting of INH toxicity. One study reported the absence of adverse effects with pyridoxine doses of up to 357 mg/kg [145].

Isoniazid remains less likely than other antibiotics to cause seizures within the hospital or the ICU, as most cases of INH-induced seizure result from acute, accidental, or intentional overdose. In this case, the presence of an unexplained anion-gap metabolic acidosis with high lactate level in the presence of no seizures or after a brief seizure should alert the intensivist for the possibility of INH overdose. Damaging neurologic sequelae have resulted from exposures as low as 20 mg/kg [120]. This is striking, as the recommended dosage for children requiring therapy runs from 10–15 mg/kg [120]. Clear understanding of dosage regimens must be carefully communicated, not only to the health care team, but also to patients or parents of patients on INH.

Experimental evidence and scattered case reports suggest that metronidazole has proconvulsant activity [146–149]. The mechanism of action by which metronidazole induces epileptogenicity is largely unknown [120]. It is known that seizures seem to develop approximately seven to 10 days following the initiation of high dose therapy (5–6 g/day) in susceptible patients [120]. Patients witnessed to have seizures on metronidazole therapy were also afflicted with metastatic cancers (metronidazole was used as a radiation sensitizer) and were also treated with other medications with known pro-convulsant actions (for example, phenothiazines, cefamandole, ciprofloxacin, and theophylline) [120]. Based on these rare human reports and some limited evidence from animal experiments, metronidazole use should be considered safe, if not used in high doses or in combination with other epileptogenic drugs.