KeywordsSeizures, epilepsy, uremia, hepatic failure, critical illness, porphyria, transplant recipients, connective tissue diseases, HIV infection, diabetes, hypoglycemia, thyroid disease, sodium, magnesium, alcohol, cocaine, medication-induced seizures, trauma
Seizures commonly arise as a symptom of neurologic dysfunction in various general medical disorders. The occurrence of epileptic seizures in medically ill patients often carries significant implications regarding the treatment and prognosis of the primary disease. In addition, the treatment of epilepsy due to primary disturbances of central nervous system (CNS) function, or of seizures caused by general medical disorders, may be complicated or influenced by factors associated with systemic disease. The occurrence and management of seizures in common medical conditions that may either produce acute or recurrent seizures, or exacerbate an existing epilepsy syndrome, are discussed in this chapter. Attention is also directed at certain uncommon medical diseases in which seizures are a relatively frequent complication, and at the treatment of preexisting epilepsy in patients with medical conditions that might complicate management. Selected therapeutic agents and recreational drugs that may cause seizures are reviewed.
Some general points are worthy of emphasis. First, in persons with epilepsy, seizures often occur in the context of medical illness. Second, “acute symptomatic seizures” do not necessitate a diagnosis of epilepsy. This term was introduced in the 1970s to differentiate seizures occurring in the context of an acute illness from epileptic seizures and is defined as “a clinical seizure occurring at the time of a systemic insult or in close temporal association with a documented brain insult.” This term, then, includes seizures due to disorders that may be reversible (e.g., alcohol intoxication) as well as seizures occurring in the acute phase after an irreversible brain injury (e.g., stroke) that may subsequently lead to development of epileptic seizures. Different neurophysiologic mechanisms are probably responsible for acute symptomatic seizures and later unprovoked (epileptic) seizures, despite the fact that both may relate to the same injury. Conceptual advances in understanding this process of epileptogenesis are outside the scope of this chapter and are reviewed elsewhere. Finally, acute symptomatic seizures in comatose or critically ill patients may have subtle or no clinical manifestations and may be detected by electroencephalography (EEG), as discussed in a later section.
Seizures are common in acute uremia, typically developing between 7 and 10 days after the onset of renal failure, while the patient is anuric or oliguric. Generalized convulsive seizures are most common; partial seizures or even epilepsia partialis continua may also occur. Seizures are relatively unusual in chronic renal insufficiency, occurring in less than 10 percent of cases and usually only when a significant encephalopathy is present or at a preterminal stage. Generalized tonic-clonic seizures are the most common seizure type, but partial and myoclonic seizures also may be seen. Treatment requires the correction of metabolic abnormalities and renal failure, and antiseizure medications. Status epilepticus occurs rarely and acute management is the same as when it occurs in other contexts. Phenytoin, valproic acid, and phenobarbital are all effective for seizures in renal failure. Newer antiepileptic drugs (AEDs) should be used cautiously in patients with renal impairment, given their extensive renal clearance.
Risk factors for acute symptomatic seizures in renal failure include hypertensive encephalopathy, metabolic disturbances, and altered renal clearance of proconvulsant medications such as penicillin. Hypocalcemia and hypomagnesemia may be seen in renal disease, and seizures in this context present an increased risk of convulsive status epilepticus.
Dialysis also increases the risk of generalized convulsive seizures, usually during the end of or the first several hours after a hemodialysis session (termed dialysis disequilibrium syndrome ). Fluid shifts may be responsible, leading to cerebral edema from increased brain osmolality in the uremic state. Improved dialysis techniques have reduced the incidence of seizures. The dialysis encephalopathy syndrome of myoclonus, asterixis, a distinctive speech disorder, psychiatric disturbances, and seizures due to increased aluminum levels in the brain has largely disappeared in response to removing aluminum from the dialysate.
Prominent myoclonus that may or may not be epileptic occurs in renal failure. Cephalosporins, levetiracetam, amlodipine, and verapamil, diltiazem, and nifedipine may induce acute myoclonic jerking without convulsive seizures. Metformin in the presence of end-stage renal disease and pregabalin may also induce myoclonus in patients receiving hemodialysis. Valproate may be especially helpful for myoclonic seizures.
Use of Antiepileptic Drugs in Renal Disease
Several points require emphasis. First, loading doses for AEDs are determined by their respective volumes of distribution; AEDs with large volumes are lipophilic, and less available for dialysis. This volume is independent of renal clearance and usually is not modified in renal impairment.
Second, protein binding of drugs is affected in renal disease. The fraction of drug that is protein bound does not exert any pharmacologic effect, and many AEDs 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.
|Volume of Distribution ( V d L/kg) (0.6= V d for H 2 O)||Renal Elimination||Hepatic Metabolism||Molecular Weight (Hemodialysis More Effective If Low)|
|First- and Second-Generation AEDs|
|Minimal or no protein binding||Ethosuximide * |
|0.6 to 0.7 |
0.4 to 1.0
|Moderate protein binding||Phenobarbital||0.5 to 1.0||Minimal||High||232|
|High protein binding||Benzodiazepines, including clobazam||1.4 to 1.8 (CLZ), 1.1 to 3.4 (DZP), 1.3 (LZP)||Minimal||High||300 (CLZ), 284 (DZP), 321 (LZP)|
|Carbamazepine||0.8 to 2.0||Minimal||High||236|
|Phenytoin||0.5 to 1.0||Minimal||High||252|
|Valproic acid||0.14 to 0.23||Minimal||High||144|
|Third- and Fourth-Generation AEDs|
|Minimal or no protein binding||Eslicarbazepine||Minimal||High||296|
|Felbamate||0.7 to 1.0||Moderate||Moderate||238|
|Gabapentin *||0.8 to 1.8||High||None||171|
|Topiramate||0.6 to 0.8||Moderate||Moderate||339|
|Moderate protein binding||Lamotrigine||0.9 to 1.3||Minimal||High||256|
|Zonisamide||0.8 to 1.6||Minimal||Moderate||212|
|High protein binding||Ezogabine||2 to 3||High||High||303|
Third, uremic molecules downregulate the expression of cytochrome P450 enzymes, so decreasing hepatic metabolism and increasing drug half-life and the risk of drug toxicity for AEDs that are hepatically metabolized ( Table 57-1 ).
Fourth, depending on the dialysis technique and the AED, some drugs are cleared by dialysis. As protein binding increases and the volume of distribution increases, the fraction removed declines ( Table 57-1 ). The advent of dialysis membranes with larger surface areas and pore size enables more drugs to be dialyzed than previously. For example, post-dialysis seizures resulted from decreased serum levels of phenytoin after the introduction of improved dialysis membranes. For this reason, AEDs that are cleared significantly by hemodialysis should be taken after the dialysis session or supplemental doses prescribed.
Fifth, newer AEDs tend to be rapidly and completely absorbed when given orally, have linear kinetics, and fewer drug–drug interactions. Renal clearance is important for the newer AEDs, which usually require dose adjustments in the setting of reduced renal function.
There are few data or systematic reviews on the use of AEDs in renal failure, including patients on dialysis. Data for the pharmacokinetics of individual AEDs and recommended dosing adjustments for newer antiepileptic medicines are summarized in Tables 57-1 and 57-2 , respectively.
|GFR 60–90 ml/min||GFR 30–60 ml/min||GFR 15–30 ml/min||GFR≤15 ml/min||Hemodialysis|
|Third- and Fourth-Generation AEDs|
|Gabapentin||300–1200 mg t.i.d.||200–700 mg b.i.d.||200–700 mg/day||100–300 mg/day||Plus 125–350 mg after HD|
|Levetiracetam||500–1000 mg b.i.d.||250–750 mg b.i.d.||250–500 mg b.i.d.||500–1000 mg/day||Plus 250–500 mg after HD|
|Topiramate||50% decrease for≤70 ml/min||50% decrease||50% decrease||Plus 50–100 mg after HD|
|Zonisamide||100–400 mg/day||100–400 mg/day|
|Oxcarbazepine||300–600 mg b.i.d.||300–600 mg b.i.d.||300 mg/day (starting dose)|
|Vigabatrin||25% decrease||50% decrease||75% decrease|
|Rufinamide||None||None||None||Plus 30% of dose after HD|
|Lacosamide||None||None||300 mg/day||Plus≤50% replacement dose|
|Ezogabine||None||50–200 mg t.i.d.||50–200 mg t.i.d.|
|Eslicarbazepine||None||400–600 mg/day||400–600 mg/day|
|Pregabalin||None||50% decrease||25–150 mg/day||25–75 mg/day||Plus 25–150 mg after HD|
* The product monograph for Lamictal XR recommends reduced maintenance doses in patients with significant renal impairment, and caution in patients with severe renal impairment. Lamotrigine pharmacokinetics were essentially unchanged in a study comparing 10 subjects with renal failure (estimated creatine clearance of 10 to 25 ml/min) to that of 11 healthy subjects. (Wootton R, Soul-Lawton J, Rolan PE, et al: Comparison of the pharmacokinetics of lamotrigine in patients with chronic renal failure and healthy volunteers. Br J Clin Pharmacol 43:23, 1997.)
Seizures are relatively uncommon in patients with acute hepatic encephalopathy, at least when seizures related to alcohol withdrawal are excluded. Either focal or generalized seizures may occur, usually in severe hepatic encephalopathy. Treatment involves management of the hepatic dysfunction and hepatic encephalopathy. Anticonvulsant therapy often is not required except when an underlying cause of epilepsy (e.g., prior cerebral trauma) is present.
Chronic liver disease does not usually cause convulsions. The occurrence of seizures in alcoholics with hepatic cirrhosis is usually related to prior trauma, intracranial hemorrhage, or alcohol withdrawal. Seizures are common in Reye syndrome and rare in Wilson disease. Convulsions in patients with acute hepatic necrosis are frequently associated with severe hypoglycemia.
Gabapentin, vigabatrin and levetiracetam are the only AEDs not hepatically metabolized. Certain AEDs, including selected newer agents, undergo extensive hepatic metabolism ( Table 57-1 ) but unless hepatic dysfunction is severe, the effect of hepatic dysfunction on anticonvulsant pharmacokinetics is difficult to predict. The free fraction of highly protein-bound AEDs may increase due to hypoalbuminemia, and serum free drug levels should be followed (if available). Lamotrigine metabolism is reduced in patients with significant liver disease, necessitating a decrease in dosage. Dosage reduction is required also in patients with unconjugated hyperbilirubinemia (Gilbert syndrome). Barbiturates, benzodiazepines, and other sedatives or CNS depressant drugs 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—if at all—in patients with established liver disease.
Drug-induced liver injury by first- and second-generation AEDs seems independent of dose (except in children younger than 2 years, taking valproic acid). In most cases, these reactions are reversible by stopping the AED. Infrequently, acute hepatic failure may necessitate transplantation. AEDs (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). Two types of injury are described.
First, an immune-mediated hypersensitivity syndrome characterized by fever, rash, and hepatic involvement may occur several weeks after starting an AED. A prime example of this reaction is the acute hepatic injury caused by phenytoin, and in perhaps 30 percent of persons with acute hepatic injury on carbamazepine. The risk of hypersensitivity reactions is 1 to 10 per 10,000 for phenytoin, carbamazepine, phenobarbital, and lamotrigine; the risk probably is similar for zonisamide, based on its class (sulfonamide).
Second, AEDs may cause a hepatocellular injury pattern as a direct effect of hepatic metabolism, and not as a hypersensitivity syndrome. This is exemplified by the hepatic injury induced by valproic acid (and, frequently, carbamazepine). Presentation is with fatigue, nausea, vomiting, and weakness; the combination of high serum aminotransferases and jaundice, if present, predicts a mortality of 10 to 50 percent in these patients. The incidence of hepatic injury on valproic acid is very high, perhaps 1 in 800 for children less than 2 years old, and the drug is relatively contraindicated in this population.
Hyperammonemia may occur with normal liver function tests in the majority of persons on valproic acid, with no associated clinical symptoms. This seems unrelated to the dose (except in children less than 2 years old). Topiramate may increase the risk of hyperammonemic encephalopathy and hepatic injury from valproic acid. For felbamate, concern for acute hepatic failure (as well as aplastic anemia) has limited the use of this AED; frequent monitoring of hepatic function is required, although the usefulness of this is not clear.
Cardiac disease may lead to seizures from cardioembolic stroke and focal ischemia or from global cerebral ischemia after cardiac arrest. Seizures may also infrequently complicate coronary bypass surgery.
Cardiovascular disease and epilepsy may coexist, especially in the elderly, persons with congenital cardiac disease, and persons with alcohol or polysubstance use. This complicates treatment of acute seizures and status epilepticus. Intravenous benzodiazepines may cause hypotension in medically ill or elderly patients. Phenytoin and fosphenytoin may cause hypotension or cardiac arrhythmias with intravenous infusions. 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. If fosphenytoin is not available, valproic acid, levetiracetam, or lacosamide are alternatives in these patient populations.
AEDs that affect sodium channels may influence cardiac excitability and conduction, but long-term AED use has been associated only rarely with significant cardiovascular complications. 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 multiple sodium-channel AEDs usually (but not always) have been present. Shortening of the QT interval is seen in patients on rufinamide. Routine electrocardiograms should probably be obtained in all patients started on these AEDs and in all patients with preexisting cardiac disease. Epilepsy patients as a group have lower heart-rate variability than normal—this is a marker of impaired vagal activity and predicts arrhythmias and mortality in cardiac patients. This may be relevant to the phenomenon of sudden unexplained death in epilepsy (SUDEP); if correct, the effect of AEDs on these measures may be important, but this has not yet been demonstrated.
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 AED levels and cardiovascular function should be followed closely when either antiepileptic or cardiac medications are introduced or altered.
Seizures in Critically Ill Patients
Seizures are among the most common neurologic complications of severe medical illnesses treated in the ICU. In one study, neurologic complications occurred in 217 (12.3%) of a total of 1,758 patients admitted to an ICU with a non-neurologic primary diagnosis. Seizures occurred in 61 cases (28.1%) and were the most frequent neurologic complication after metabolic encephalopathy. Seizures most commonly resulted from vascular lesions, but infection, metabolic derangement, mass lesion, hypoxia, and a variety of other causes were found. Approximately two-thirds of patients experienced focal-onset seizures, and the remainder had seizures of presumed generalized onset. Status epilepticus occurred in six cases, two of which were refractory and required management by pentobarbital-induced coma. Neurologic complications were associated with increased mortality rates and longer lengths of stay in the ICU and hospital.
More aggressive AED therapy of discrete seizures is often warranted, given the increased risk of seizure-related complications, in patients who are already compromised by severe illness such as multiorgan system failure. However, anticonvulsants are ineffective in controlling seizures caused by various metabolic derangements such as severe hypoglycemia or hyperglycemia, hyponatremia, and hypocalcemia. In these instances, therapy should be directed at correcting the underlying metabolic abnormality. When AED treatment is necessary, the increased potential for complex drug interactions in patients receiving numerous other medications, altered pharmacokinetics due to factors such as renal or hepatic impairment, and adverse systemic effects must be considered. For example, in the hypoalbuminemic patient, it may be necessary to monitor free anticonvulsant drug levels when using an AED, such as phenytoin, that exhibits significant serum protein binding. Treatment may also be further complicated by the requirement for parenteral administration in patients with gastrointestinal dysfunction.
Nonconvulsive Status Epilepticus
Nonconvulsive seizures and nonconvulsive (i.e., absence or complex partial) status epilepticus may occur in critically ill patients. Although its incidence is not known, nonconvulsive status epilepticus is probably under-recognized based on studies of patients in neurologic ICUs using continuous EEG monitoring. This condition should be suspected in any critically ill patient with altered mental status of unknown cause. Subtle motor activity, such as rhythmic twitching of fingers or eye movements, should raise suspicion of seizure activity in this setting. Diagnosis depends on prolonged EEG recordings. Quantitative EEG techniques have been helpful to detect electrographic seizures in these patients in context with other changes on the EEG ( Fig. 57-1 ). Prompt recognition and treatment are essential because delay is associated with a poor outcome.
Seizures Caused by Anoxic-Ischemic Encephalopathy
Seizures resulting from global anoxic-ischemic cerebral damage occur acutely after resuscitation from cardiopulmonary arrest in 15 to 44 percent of survivors. They 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 myoclonus status epilepticus. Electrographic status epilepticus with restricted clinical manifestations (usually limited solely to extraocular or facial muscles) is also well described after cardiopulmonary arrest, but may be difficult to recognize.
The occurrence of seizures or even generalized tonic-clonic status epilepticus does not influence the eventual clinical outcome of patients in postanoxic coma. However, myoclonic status epilepticus, that is, continuous myoclonus for at least 30 minutes with or without other seizure types, does suggest a poor prognosis after global cerebral hypoxic-ischemic insult. It may begin at any time within approximately 5 days after cardiopulmonary arrest, most often within 24 hours Generalized myoclonus may be synchronous or asynchronous, but sometimes involves the facial muscles predominantly. The EEG typically reveals generalized spike-wave or polyspike-wave bursts on an abnormal background or a burst-suppression pattern; a diffuse unreactive alpha-frequency pattern is sometimes found. Neuropathologic examination shows diffuse anoxic-ischemic damage involving cerebral cortex, hippocampus, cerebellar Purkinje cells, thalamus, basal ganglia, and, to a lesser extent, the brainstem and spinal cord.
Myoclonus status epilepticus is poorly responsive to anticonvulsant therapy and may well represent a marker of severe anoxic-ischemic brain injury that rarely permits survival. Treatment decisions in these settings should be individualized based on the clinical examination and neurophysiologic studies.
Connective Tissue Diseases
The connective tissue diseases are discussed in detail in Chapter 50 . Of these, systemic lupus erythematosus (SLE) probably has the highest incidence of neurologic or psychiatric manifestations. Among these, seizures are the most frequent neuropsychiatric manifestation, both at time of diagnosis and during disease flares, seen in 40 to 85 percent of persons with SLE. The prevalence of epilepsy in the SLE population is also increased, variably reported in larger series to be from 3 to 29 percent.
Generalized convulsive seizures are the most common seizure type and may reflect direct brain involvement or may be due to a hypertensive or metabolic encephalopathy, especially in the context of lupus nephritis and uremia or as a complication of immunosuppressive therapy. Focal seizures and status epilepticus are relatively rare. Occasionally, seizures or other neuropsychiatric manifestations are the initial features of SLE, and systemic manifestations may not develop for many years. Neuropsychiatric manifestations imply a poorer prognosis for SLE than otherwise, but the presence of seizures or psychosis without other neurologic features or significant renal disease does not reduce survival.
Various antibodies have been implicated in the pathogenesis of neuropsychiatric SLE. Of these, antiphospholipid antibodies are important as these can lead to arterial or venous thrombosis and also may have a direct neuromodulatory effect. The frequency of seizures and epilepsy may correlate with the presence of these antibodies, although this is not clear. Cerebral microinfarcts and, less often, subarachnoid and intracerebral hemorrhages are found on pathologic examination and may relate to an immunologically mediated vasculopathy.
Treatment of CNS lupus is discussed in Chapter 50 . The treatment of an isolated seizure during an SLE flare does not necessarily require anticonvulsant therapy. However, AEDs are frequently started for a limited time (e.g., 3 months) while immunosuppression is used to treat the SLE flare. Although a drug-induced lupus may occur with various AEDs (including phenytoin, carbamazepine, valproic acid, and lamotrigine), there is no evidence that AEDs exacerbate idiopathic SLE, and anticonvulsant treatment should not be withheld from patients with SLE when it is required for seizure control.
Cerebral vasculopathy from other causes may lead to seizures. Antiphospholipid antibody syndrome may be seen without SLE. In Sjögren or Behçet syndrome, convulsions may be associated with a disease flare. Seizures rarely are described due to cerebral involvement in rheumatoid arthritis, scleroderma, or mixed connective tissue disease. The one exception to this is linear scleroderma with hemifacial atrophy of the face, or Parry–Romberg syndrome, in which intractable epilepsy can be part of the spectrum of disease.