Seizures and General Medical Disorders

Use of Antiseizure Medications in Renal Disease

The treatment of seizures in renal failure requires both the correction of metabolic abnormalities and the use of ASMs. Several points regarding ASMs in renal impairment are important to remember. First, newer third- and fourth-generation ASMs tend to be cleared renally and should be used cautiously in patients with renal impairment or failure. If used, these newer ASMs usually require dose adjustments in the setting of reduced renal function. Conversely, earlier first- and second-generation ASMs do not usually require dose adjustments for renal function. However, uremic molecules may downregulate the expression of cytochrome P-450 enzymes, thereby decreasing hepatic metabolism and increasing the risks of drug toxicities for these earlier first- and second-generation ASMs that are hepatically metabolized ( Table 57-1 ).

Second, many ASMs bind extensively to serum albumin ( Table 57-1 ). Patients with chronic renal disease are hypoalbuminemic, so protein binding is decreased; a larger amount of free drug is therefore available to exert a pharmacologic effect. Uremic molecules may also bind to plasma proteins, displacing drugs. For these reasons, the free serum level—where available—should guide therapy.

Third, some ASMs are cleared by dialysis. As molecular size decreases, solubility increases such that the fraction removed increases. Conversely, as protein binding increases and the volume of distribution decreases, the fraction removed declines. Highly lipophilic ASMs with large volume and tissue distribution are less available for removal by dialysis. This volume is independent of renal clearance, and usually is not modified in renal impairment ( Table 57-1 ). For this reason, ASMs that are cleared significantly by hemodialysis should be taken after the dialysis session or supplemental doses should be prescribed.

There are few data or systematic reviews on the use of third- and fourth-generation ASMs in renal failure, including patients on dialysis. Data for the pharmacokinetics of individual ASMs and recommended dosing adjustments for newer ASMs are summarized in Tables 57-1 and 57-2 , respectively.

Antiseizure Medications and Hepatic Injury

Gabapentin, vigabatrin, and levetiracetam are the only ASMs not hepatically metabolized. Certain ASMs, including selected newer agents, undergo extensive hepatic metabolism ( Table 57-1 ), but unless hepatic dysfunction is severe its effects on their pharmacokinetics are difficult to predict. Barbiturates, and benzodiazepines, as well as other central nervous system (CNS) depressants, may unmask hepatic encephalopathy in patients with compensated liver disease, and are relatively contraindicated. Valproic acid is potentially hepatotoxic and should be used with care in patients with pre-existing liver disease. The free fraction of highly protein-bound ASMs may increase due to hypoalbuminemia, and (as for renal impairment) the free serum level—where available—should guide therapy.

In persons without hepatic disease, ASMs may cause drug-induced hepatic injury. In most cases, these reactions are reversible by stopping the ASM but, occasionally, acute hepatic failure may necessitate transplantation. ASMs (as a class) were the third most-common cause (phenytoin, n =10; valproic acid, n =10) of acute drug-induced liver failure requiring liver transplantation in the United States between 1990 and 2002 ( n =270).

Overall, the incidence of clinically important hepatotoxicity seems less for third- and fourth-generation ASMs than for older ASMs, but cases of severe hepatotoxicity have been reported for newer ASMs, including lamotrigine, levetiracetam, gabapentin, pregabalin, and oxcarbazepine. Felbamate specifically has been associated with multiple cases of aplastic anemia and acute liver failure, and has a “black box warning” label that restricts its use.

Two types of hepatic injury by ASMs are described. First, ASMs may induce one of several systemic immune-mediated drug hypersensitivity syndromes that may cause hepatic injury and are potentially life-threatening. These syndromes are characterized by fever, rash, and increased serum levels of aminotransferases several weeks after starting an ASM. The risk for these hypersensitivity reactions is highest for first- and second-generation ASMs, and is estimated to be 1 to 10 per 10,000 for phenytoin, carbamazepine, and phenobarbital, but also for lamotrigine (third-generation). For carbamazepine specifically, the HLA-B*15:02 allele is strongly associated with Stevens–Johnson syndrome/toxic epidermal necrolysis in Southeast Asia. For this reason, the U.S. Food and Drug Administration (FDA)–approved drug label for carbamazepine now recommends testing for HLA-B*15:02 for all patients with ancestry in populations having an increased frequency of HLA-B*15:02 , prior to initiating carbamazepine therapy.

Second, first- and second-generation ASMs may cause hepatic injury as a direct effect of hepatic metabolism, and not as a systemic hypersensitivity syndrome. This is a concern specifically for felbamate and (especially in children) valproic acid. For valproic acid, the risk for hepatic injury in young children less than 2 years old and on multiple ASMs is as high as 1 in 800, and the drug is relatively contraindicated in this population. In adults and children, hyperammonemia may be seen with normal liver function tests in the majority of persons on valproic acid, usually with no associated clinical symptoms. Topiramate may increase this risk of hyperammonemic encephalopathy and hepatic injury from valproic acid.

Cannabidiols (CBD) derived from Cannabis sativa have become very popular in recent years for a variety of conditions, particularly pain. In June 2018, the first CBD-based drug, Epidiolex, was approved by the FDA for treatment of selected severe epilepsy syndromes (Dravet and Lennox–Gastaut syndromes). In the trials on which approval was based, CBD was associated with elevated serum levels of aminotransferases. Except for Epidiolex, CBD products are not regulated and the risks for hepatic injury are unclear.

Use of Antiseizure Medications in Cardiac Disease

Cardiovascular disease and epilepsy may co-exist, especially in the elderly, persons with congenital cardiac disease, and persons with alcohol and polysubstance use. This complicates treatment of acute seizures and status epilepticus. Intravenous benzodiazepines may cause hypotension in medically ill or elderly patients. Rapid intravenous administration of phenytoin may cause sinus arrest and hypotension; fosphenytoin, a water-soluble prodrug of phenytoin that does not require propylene glycol as a diluent, is generally preferred for treating status epilepticus as its infusion rate is faster and there is a lesser risk of arrhythmia than with phenytoin. In these patient populations, valproic acid, levetiracetam, or lacosamide are preferred if fosphenytoin is not available.

Various cardiac arrhythmias have been described in persons with epilepsy, including ictal asystole (usually self-limiting), postictal asystole (not self-limiting), ventricular tachycardia/ventricular fibrillation, bradycardia, and atrioventricular block. In some epilepsies, these abnormalities may reflect genetic ion channel mutations expressed in the brain as well as in the heart, and may in part explain the increased risk for sudden unexplained death in epilepsy (SUDEP). The most recognized example of this is Dravet syndrome, a severe epilepsy syndrome with high premature mortality, caused by an SCN1A mutation. Biomarkers associated with the risk of sudden cardiac death (e.g., decreased heart rate variability) have been found in patients with this syndrome. In mutant SCN1A knock-out mice, postictal bradycardia and seizure-triggered ventricular fibrillation have been recorded before a death resembling SUDEP.

ASMs that affect sodium channels may influence cardiac excitability and conduction, but clinically relevant arrhythmias are usually related to ASM overdose. Long-term ASM use has been associated only rarely with significant cardiovascular complications. A prolonged PR interval is seen in patients on lacosamide and carbamazepine. Symptomatic arrhythmias have been reported in patients receiving lacosamide and carbamazepine in therapeutic dosages, but underlying cardiac abnormalities or the use of multiple sodium channel-blocking ASMs usually (but not always) have been present. Shortening of the QT interval is seen in patients on rufinamide. Routine electrocardiograms should be considered in all patients started on these ASMs and in all patients with pre-existing cardiac arrhythmias.

Anticonvulsant agents may also interact with certain cardiac medications. The concomitant use of phenytoin and quinidine may increase ectopy in patients with ventricular arrhythmias. The metabolism of quinidine, digoxin, lidocaine, and mexiletine may be increased by phenytoin and phenobarbital because of induction of hepatic microsomal enzymes. Amiodarone increases phenytoin levels, and calcium-channel blocking agents, such as verapamil, may increase serum carbamazepine concentrations. For these reasons, serum ASM levels and cardiovascular function should be followed closely when either antiseizure or cardiac medications are introduced or altered.

Nonconvulsive Seizures and Status Epilepticus

Acute symptomatic seizures in patients who are critically ill are detected typically on continuous EEG monitoring, may have subtle or no clinical signs, and are probably under-recognized. The published incidence of seizures in critically ill patients is highly variable but is nonetheless impressive, ranging from 8 percent to as high as 48 percent in various studies. The possibility of nonconvulsive seizures and status epilepticus should be suspected in any critically ill patient with altered mental status of unknown cause. Subtle motor activity, such as rhythmic twitching of the fingers or eye movements, should raise suspicion of seizure activity in this setting. Diagnosis depends on the EEG findings. Prompt recognition and treatment are essential because delay is associated with a poor outcome.

Continuous EEG monitoring of brain function in critically ill patients usually includes simultaneous video recording and quantitative analysis of EEG trends ( Fig. 57-1 ). The guideline recommendation of the American Clinical Neurophysiology Society for recording for at least 24 to 48 hours using continuous EEG enables the identification of 80 to 95 percent of patients with nonconvulsive seizures. Monitoring should be initiated as soon as possible when nonconvulsive seizures are suspected, and is required in newly admitted critically ill patients with altered mental status and observed seizures.

Treatment of Seizures in Critically Ill Patients

When evaluating the causes of seizures in critically ill patients, various metabolic derangements must be considered; if detected, therapy is directed at their correction. The electrolyte abnormalities contributing most frequently to seizures are reviewed in a later section. Reversible causes, such as medications (or acute withdrawal of them, including anticonvulsants, benzodiazepines, and barbiturates) and substance abuse are important ( Table 57-3 ).

When ASM treatment is necessary, the increased potential for complex drug interactions in patients receiving numerous other medications and the possibility of altered pharmacokinetics (e.g., due to renal or hepatic impairment) and of adverse systemic effects must be considered. For example, in hypoalbuminemic patients, it may be necessary to monitor free drug levels when using a first- or second-generation ASM (e.g., phenytoin) that exhibits significant serum protein binding. Many first- or second-generation ASMs that are inhibitors or inducers of certain metabolic enzymes may also affect the serum concentration of other medications taken concurrently.

Ideally, ASMs should initially be administered parenterally as loading doses to attain therapeutic serum concentrations, especially in patients with gastrointestinal dysfunction, so limiting the selection of ASMs to those with intravenous formulations.

The use of continuous renal replacement therapy (CRRT) in critically ill patients complicates the use of the third- and fourth-generation ASMs, as most of these are cleared renally. There are as yet no data available for ASM dosing in patients on CRRT. For this reason, ASMs with readily measured serum levels are preferred to guide dosing in patients on CRRT. In general, an ASM that is eliminated renally or affected by dialysis will be removed using CRRT, but the degree of removal will depend largely on the replacement parameters and the specific ASM.

The use of extracorporeal membrane oxygenation (ECMO) is also increasing in critically ill patients, but as for CRRT, no data are available for evaluating specific ASM dosing. The biggest impact of ECMO on drug dosing lies in the propensity for the ECMO circuit to sequester drugs, resulting in a larger than expected volume of distribution. This phenomenon may decrease over time with continued dosing due to saturation of binding sites. In general, medications with higher volumes of distribution/lipophilicity and higher protein binding tend to be sequestered more. Patients on ECMO frequently receive concomitant CRRT, further complicating dosing. For these reasons, ASMs that have readily available serum levels are strongly preferred.

Seizures Caused by Anoxic-Ischemic Encephalopathy

A high proportion of patients who have been resuscitated after a cardiac arrest go on to develop seizures due to global anoxic-ischemic cerebral injury. Seizures typically commence within 24 hours of cardiopulmonary arrest and may consist of generalized tonic-clonic, tonic, myoclonic, or partial seizures, as well as tonic-clonic or myoclonic status epilepticus. Electrographic status epilepticus with restricted clinical manifestations (usually limited to extraocular or facial muscles) is also well described after cardiopulmonary arrest, occurring in 12 to 22 percent of patients, but may be difficult to recognize.

Published guidelines have emphasized the importance of neurocritical care for patients with brain injury after cardiac arrest, including EEG monitoring for the detection and treatment of seizures. Certain EEG patterns are associated with poor outcome. Thus, generalized background suppression to 20 µV, a burst-suppression pattern with generalized epileptiform activity, or generalized periodic complexes on a flat background are strongly but not invariably associated with poor outcome.

The occurrence of focal seizures or even of generalized tonic-clonic status epilepticus does not determine the eventual clinical outcome of patients in postanoxic coma. By contrast, myoclonic status epilepticus (defined as spontaneous, repetitive, unrelenting, generalized multifocal myoclonus in comatose patients) seems invariably associated with poor outcome and may well represent a marker of severe anoxic-ischemic brain injury. Although hypothermia has antiseizure effects, seizures in resuscitated patients after cardiac arrest may occur during therapeutic hypothermia and, in many patients with nonconvulsive status epilepticus, seizures first appear on EEG during therapeutic hypothermia.

The available evidence does not support the use of prophylactic ASMs in these patients. The same ASMs used for the treatment of status epilepticus from other causes may be considered for seizures and status epilepticus after cardiac arrest, but bearing in mind the potential cardiac effects of selected ASMs reviewed earlier. The neurologic complications of anoxic-ischemic encephalopathy are reviewed in detail in Chapter 9 .