Seizures commonly occur in the setting of general medical disorders, and their occurrence may then have significant implications regarding the prognosis and treatment of the primary disease. In addition, the treatment of seizures—whether secondary to some general medical disorder or the manifestation of a primary disturbance of central nervous system (CNS) function—may be complicated or influenced by nonneurologic factors. This chapter discusses these varying aspects.

Seizures occur in about one third of patients with acute or chronic renal failure. The seizures that occur in acute uremia tend to be associated with a severe encephalopathy, usually occurring between 7 and 10 days after the onset of renal failure and during its anuric or oliguric stages.^21,200 They are commonly generalized tonic–clonic seizures and are often multiple. Partial seizures also occur, and epilepsia partialis continua has been described.¹⁵⁸ When recurrent seizures or single partial seizures occur in uremic patients, however, investigations should be undertaken to exclude an underlying structural lesion.

The uremic convulsions complicating chronic renal failure are most likely to occur with advanced disease and develop especially in patients with a significant encephalopathy or who are preterminal.^21,158 Fewer than 10% of patients with chronic renal insufficiency now experience convulsions.^157,200 The decline in the incidence of seizures may reflect more aggressive treatment of renal failure and its various complications, such as hypertensive encephalopathy, abnormalities of fluid and electrolyte balance, and altered metabolism of proconvulsant medications such as penicillin.^21,158,200

The convulsions associated with chronic renal failure are typically generalized tonic–clonic seizures; partial motor and generalized myoclonic seizures occur less often.^21,158 Treatment involves correction of renal failure and associated metabolic abnormalities, but it may also necessitate anticonvulsant treatment, especially when no specific cause of the convulsions is evident.^21,157 Phenytoin is commonly used, but other agents, such as phenobarbital and valproic acid, are also effective.^12,21,158 Status epilepticus, a rare complication of chronic renal failure, is managed as when it occurs from other causes.¹⁵⁸

Treatment of renal failure may itself lead to seizures. Generalized convulsions sometimes occur during the late stages of hemodialysis or several hours after a session in patients with the dialysis disequilibrium syndrome.¹⁵⁷ They may relate to fluid shifts associated with the hemodialysis and resulting in cerebral edema.⁵⁹ With improved dialysis techniques, seizures are now a less common occurrence.^59,157

Dialysis encephalopathy is characterized by a distinctive speech abnormality, psychiatric and cognitive disturbances, asterixis, myoclonus, gait ataxia, and seizures. It often has a fatal outcome. Clinical dysfunction is preceded by electroencephalographic (EEG) abnormalities, especially paroxysmal bursts of frontally predominant high-voltage delta or spike-and-wave activity.^86,143 The syndrome, which generally develops after treatment by dialysis for several years, may relate to increased aluminum levels in the brain.¹⁰ The origin of the aluminum may be the water in the dialysate, phosphate-binding compounds that are ingested, or both. Treatment of the dialysate to remove aluminum has reduced the incidence of the disorder.^{10,59,143,157} Seizures, usually of the generalized tonic–clonic variety, occur in almost two thirds of patients with dialysis encephalopathy and are especially likely during or immediately after dialysis. Myoclonic, simple partial, and complex partial seizures are less common.²¹ Convulsions usually respond initially to diazepam, phenytoin, or carbamazepine but become harder to control as the disease progresses.^21,143,185

The use of anticonvulsants in patients with preexisting renal disease is sometimes problematic. Uremia complicates anticonvulsant therapy because of altered protein binding and renal excretion of drugs; dialysis may also result in removal of anticonvulsant agents from the circulation. The situation is exemplified by phenytoin. This anticonvulsant is normally 90% protein bound, but in advanced renal failure, protein binding of phenytoin declines by as much as 20%, resulting in a greater volume of distribution and lower serum concentrations.^12,142 Nevertheless, the benefit of a given dose is maintained because the proportion of unbound (active) phenytoin increases. Consequently, in advanced renal disease, the optimal therapeutic range of phenytoin in the blood decreases from 10 to 20 μg/mL to approximately 5 to 10 μg/mL.¹⁰⁷ Therapy is best monitored in uremic patients by measurement of free phenytoin levels; the therapeutic range is 1 to 2 μg/mL. The total daily dose need not be reduced because phenytoin is unlikely to accumulate unless hepatic function is impaired. Because the half-life of phenytoin may diminish in uremia,¹¹² it may be appropriate to divide the daily dose rather than to take it all at one time.¹² Phenytoin is not removed to any significant extent by dialysis, and, therefore, the daily dose does not require adjustment.¹⁰⁷

Valproic acid is especially helpful for myoclonic and generalized tonic–clonic seizures in uremic patients.¹² In renal insufficiency, plasma protein binding decreases, but the free fraction remains constant.¹⁰⁷ Careful clinical and laboratory monitoring is important when patients have severe renal failure. Dialysis does not necessitate additional doses.

Plasma phenobarbital levels are unaffected by uremia. The drug may accumulate,¹⁰⁷ however, and lower maintenance doses are used when it is given on a long-term basis to patients with severe renal failure.¹² Because it is 40% to 60% protein bound, phenobarbital may be partially removed by hemodialysis; some patients therefore require supplemental doses after dialysis.¹⁰⁷ Primidone and its metabolites may also accumulate and lead to toxicity in patients with renal failure.¹² Serum carbamazepine levels are unchanged by uremia, and doses do not need adjustment.¹⁰⁷ Ethosuximide levels are significantly reduced by hemodialysis, and supplementation may therefore be necessary.¹⁰⁷

Many of the newer antiepileptic drugs show decreased clearance when renal function is impaired. These agents include felbamate,⁶⁸ gabapentin,²⁰ topiramate,¹⁰⁴ levetiracetam,⁴⁵ vigabatrin,⁷⁵ pregabalin,¹⁶ and oxcarbazepine and its active metabolite monohydroxycarbazepine.¹⁶⁸ Gabapentin and pregabalin are excreted almost exclusively by the kidney with negligible metabolism,^16,20,156 and these drugs should be used with extreme caution and at reduced doses in patients with renal insufficiency. Topiramate also is eliminated mainly in the urine, although the percentage decreases somewhat in the presence of hepatic enzyme–inducing medications^11,104; doses must be reduced in patients with kidney disease as with gabapentin and pregabalin. In patients on hemodialysis, supplemental doses of levetiracetam, typically 250 to 500 mg, are required.⁴⁵ Topiramate¹⁰⁴ and pregabalin¹⁵⁶ concentrations also decrease significantly after hemodialysis, and additional doses may be required. Gabapentin should be administered as a single 200- to 300-mg dose after each dialysis session.

Zonisamide is 40% to 50% protein bound and undergoes both hepatic metabolism and renal clearance.^11,110 Dose reduction may be necessary in patients with moderate or severe renal insufficiency. Protein binding may be lower in patients undergoing hemodialysis, and about 50% is removed during each dialysis session; however, supplemental doses often are not required if zonisamide is administered as a single daily dose after dialysis sessions, given the markedly reduced clearance in end-stage renal disease.⁸⁷ Tiagabine and lamotrigine pharmacokinetics appear largely to be unaltered even when renal function is severely impaired, and dose adjustment is usually unnecessary.^30,210 Occasionally, the half-life of lamotrigine is prolonged with severe renal insufficiency, however, and its elimination is more rapid in patients undergoing hemodialysis.⁵⁶

Although early reports suggested that convulsions occurred in up to one third of patients with acute hepatic encephalopathy, Plum and Posner¹⁵² found a smaller incidence and attributed many of the seizures in earlier reports to alcohol withdrawal rather than liver disease. Seizures may be generalized or partial and typically occur in stage III hepatic encephalopathy.¹⁶⁷ Treatment is directed at the underlying hepatic disorder and at relieving the hepatic encephalopathy with protein restriction and agents such as lactulose. Anticonvulsant therapy may not be required unless there is an underlying cause for the seizures, such as intracranial hemorrhage.

Chronic liver disease rarely causes seizures.¹¹⁶ Seizures that occur in alcoholics with hepatic cirrhosis usually result from previous trauma, intracranial hemorrhage, or alcohol withdrawal. Seizures are common in Reye syndrome¹⁵¹ and infrequent in Wilson disease.¹⁶⁷ When convulsions occur in patients with acute hepatic necrosis, they frequently relate to severe hypoglycemia.

Many anticonvulsant agents are metabolized by the liver and may cause hepatic toxicity. This is discussed elsewhere in this book and is not considered further here.

The effect of hepatic disease on anticonvulsant pharmacokinetics is usually clinically insignificant until the liver disease is advanced. The management of anticonvulsant drug regimens in patients with liver disease may be problematic. There is reduced protein binding of phenytoin and valproic acid, correlating with levels of serum albumin and bilirubin.^12,107 However, clearance is usually unaltered, and toxicity from drug accumulation is unlikely unless the liver disease is severe. In this latter circumstance, reduction in dose of phenytoin and valproic acid may be necessary, depending on serum drug concentrations. Free serum levels should be monitored closely. The hepatotoxicity of valproic acid mandates that it be used with caution in patients with preexisting liver disease.¹²

Hepatic encephalopathy may be precipitated by phenobarbital, benzodiazepines, and other sedatives in patients with otherwise compensated liver disease.¹⁵¹ These agents, therefore, are best avoided or used very cautiously in patients with hepatic dysfunction; daily doses may have to be reduced to avoid their accumulation as a result of decreased hepatic metabolism.¹⁰⁷ The slightly decreased protein binding of carbamazepine that occurs in patients with liver disease is clinically insignificant, and serum carbamazepine concentrations are unaltered.¹²

Liver dysfunction alters the clearance of some newer antiepileptic agents. The elimination of lamotrigine decreases in the setting of significant hepatic insufficiency, and dose reduction therefore may be necessary.¹²³ Lamotrigine clearance also decreases by about one third in patients with Gilbert syndrome, or unconjugated hyperbilirubinemia, requiring the use of lower doses of the drug.¹⁵⁴ Tiagabine undergoes extensive hepatic metabolism, and its clearance is reduced by hepatic dysfunction; the dose should be lowered or the dosing interval increased in this situation.¹⁰⁶ The elimination of topiramate¹⁰⁴ and levetiracetam⁴⁵ is reduced only modestly with liver impairment, and the effect is usually clinically insignificant in the absence of concurrent renal dysfunction. Gabapentin¹¹ and pregabalin¹⁶ undergo only minimal hepatic metabolism, and dose reductions are unnecessary in patients with hepatic insufficiency but preserved kidney function. Liver disease may increase the risk of felbamate-induced hepatic failure, and this medication should not be used in patients with liver disease under most circumstances.

The hepatic porphyrias are characterized by a partial defect in the heme biosynthetic pathway in the liver. The three autosomal-dominant forms with neurologic manifestations are acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria. In acute intermittent porphyria, there is a partial deficiency of porphobilinogen deaminase, and this leads to the buildup of δ-aminolevulinic acid and porphobilinogen, which are excreted in the urine. Hereditary coproporphyria is caused by a partial deficiency of coproporphyrinogen oxidase, and variegate porphyria by a partial deficiency of protoporphyrinogen oxidase.

The neurologic features of these disorders are similar and include peripheral neuropathy, autonomic dysfunction, and behavioral disturbances. Seizures occur in 10% to 20% of patients with acute intermittent porphyria and may be its presenting feature.⁹³ They may be partial or generalized.^22,170 Status epilepticus may occur but is rare.¹⁷⁰ Cerebral dysfunction in porphyria may relate to γ-aminobutyric acid (GABA) receptor binding by δ-aminolevulinic acid,^14,136 which causes seizures when infused directly into rat brain.⁹³ In addition, defects in hepatic heme synthesis can affect levels of neurotransmitter substrates, such as tryptophan, in the CNS.⁹³ Patients with acute porphyric attacks may also have seizures as a result of fluid and electrolyte disturbances, usually from excessive vomiting and inappropriate secretion of antidiuretic hormone. Moreover, idiopathic or symptomatic epilepsy may coexist with porphyria,^{64,81,105,118,192} so that anticonvulsant treatment may be required in both acute and chronic settings.

Unfortunately, many antiepileptic agents have been implicated in exacerbating hepatic porphyria by stimulating hepatic δ-aminolevulinic acid synthase activity in humans, in animal models, or in assays in vitro. The anticonvulsants implicated include phenobarbital, phenytoin, primidone, carbamazepine, valproic acid, succinimides, oxazolidones, and benzodiazepines.^{22,64,81,105,118,130,160,161,170,176,192} The positions
of clonazepam and paraldehyde remain unclear,^119,133 but bromides and magnesium sulfate do not have this enzyme-stimulating effect and their safe use in porphyria has been reported.^{22,118,161,176,192} In vitro or animal studies of some of the newer antiepileptic agents, including lamotrigine, felbamate, topiramate, and tiagabine, suggest that they may exacerbate hepatic porphyrias^76,99; one case report supports this idea for lamotrigine, which was implicated in inducing a porphyric attack that led to multiorgan system failure.⁷¹ Other new agents, such as gabapentin, pregabalin, and levetiracetam, do not induce the relevant hepatic enzymes and may offer additional therapeutic options, as discussed later.

Seizures occurring during acute attacks of porphyria are managed by treating the underlying porphyrinogenic metabolic defect. This includes intravenous administration of a 10% dextrose solution, infusions of hematin or heme-arginate,⁹³ and correction of associated metabolic abnormalities such as hyponatremia. If seizures persist, magnesium sulfate, given as an intravenous infusion to maintain serum magnesium concentrations between 2.5 and 7.5 mEq/L, may be helpful.^170,176 Others prefer paraldehyde or intravenous benzodiazepines,¹⁶¹ but this remains controversial.¹⁷⁶ More recently, successful treatment of seizures or status epilepticus in patients with hepatic porphyria has been reported with gabapentin^98,194,213 or levetiracetam,^149,212 although the numbers of cases are small.

Choices for long-term antiepileptic drug therapy in the setting of hepatic porphyria are likely to expand, given the availability of newer antiepileptic drugs without hepatic enzyme–inducing properties. In the past, bromides were commonly recommended despite their toxicity and narrow therapeutic index^{22,64,118,161,176}; when using bromides, serum concentrations should be maintained <90 mg/dL.¹⁷⁶ Many reports suggest that low-dose clonazepam is safe for the long-term treatment of patients with hepatic porphyria.^{22,64,105,176,192} The current agent of choice, however, is probably gabapentin or levetiracetam,^{98,149,194,212,213} although clinical experience is limited. Pregabalin is not an enzyme-inducing agent and may eventually be a useful alternative. A single case report described the safe and effective use of oxcarbazepine in a patient with porphyria cutanea tarda,⁶² but this safety profile may not extend to hepatic porphyrias because oxcarbazepine has some hepatic enzyme–inducing properties. Regardless of the treatment choice, levels of urinary δ-aminolevulinic acid and porphobilinogen should be followed closely during therapy.

When seizures occur in patients with connective tissue diseases, it is generally because of a cerebral vasculitis or vasculopathy (Chapter 266). Both systemic and isolated CNS vasculitides may lead to seizures, sometimes accompanied by focal or diffuse cerebral abnormalities. Patients with Sjögren or Behçet syndrome occasionally have convulsions during a flareup of disease activity. Seizures reflecting cerebral involvement are rare in rheumatoid arthritis, scleroderma, and mixed connective tissue disease.^37,133,135 In many connective tissue diseases, seizures result from the effects of the disease on other organs, such as the kidneys, or from complications of therapy, especially with immunosuppressive agents, which predispose to CNS infections.

The connective tissue disease having the highest incidence of seizures and other neurologic manifestations is systemic lupus erythematosus (SLE). Seizures and behavioral abnormalities are probably the most common neurologic symptoms of lupus.^61,178 The incidence of seizures in SLE has ranged in different series from 10% to 54%.^{27,61,178,208} Generalized convulsions are especially common, but simple partial, complex partial, absence, and akinetic seizures also occur, as may status epilepticus.²⁷ Seizures may be the initial feature of SLE, sometimes preceding systemic manifestations by several years.¹⁹⁸

Pathologic examination in patients with SLE and seizures typically reveals cerebral microinfarcts and, less frequently, subarachnoid and intracerebral hemorrhages that have been attributed to an immunologically mediated vasculopathy.⁷⁷ Convulsions may also result from infections related to immunosuppressive therapy, uremia from lupus nephritis, or hypertensive encephalopathy and sometimes occur as a terminal event.^61,208 Evaluation must therefore include brain imaging, CSF examination, and investigation for metabolic abnormalities and systemic disease activity.

The treatment of seizures in patients with SLE depends on their etiology. Convulsions resulting from an exacerbation of cerebral lupus are frequently isolated, self-limited events for which anticonvulsant therapy is unnecessary; if several seizures occur over a period exceeding 48 hours, anticonvulsant medication is prescribed for a limited interval (e.g., 3 months) depending on the response to treatment of the underlying SLE. In cases of severe cerebral lupus associated with recurrent seizures, immunosuppression with corticosteroids, cyclophosphamide, or azathioprine may be required.²⁷ The occurrence of seizures or psychosis without other neurologic features or significant renal disease does not affect the prognosis for survival adversely.²⁷

Many anticonvulsants, especially hydantoins, trimethadione, and ethosuximide, are known to cause drug-induced SLE.^78,206 There are also reports of an SLE-like syndrome associated with primidone,²⁰⁶ carbamazepine, valproic acid,^3,19,48 and lamotrigine.¹⁷² Symptoms typically occur many months after commencement of anticonvulsant therapy and clear days to weeks after its discontinuation, although they sometimes persist for months. Unlike idiopathic SLE, complement levels are usually normal, and antibodies to native DNA are rarely present.²⁰⁶ There is no evidence that the implicated antiepileptics exacerbate idiopathic SLE,⁸⁵ and appropriate therapy should not be withheld from patients with seizures caused by SLE or with coexistent epilepsy and lupus.

Seizures caused by focal or global cerebral ischemia may occur in patients with cardiac disease (see also Chapter 275). Focal ischemia usually results from cardiogenic embolism, and global cerebral ischemia from cardiac arrest. Convulsive or myoclonic seizures are common after cardiac arrest, and clinical or electrographic status epilepticus is also well described.

Heart disease and epilepsy often coexist in the elderly, and this may pose therapeutic dilemmas. Thus, although intravenous phenytoin and benzodiazepines are important in the acute management of convulsions and status epilepticus, this approach must be used especially carefully in patients with cardiac disease because of the risk of inducing hypotension and cardiac arrhythmias. This risk depends on the rate of drug delivery, advanced age, and severity of underlying cardiovascular disease⁴⁴ and has been related to toxicity of the diluent, propylene glycol, a direct cardiotoxic effect of phenytoin, or both.^36,46 In patients at high risk, intravenous phenytoin should be infused at a rate of 25 mg/min rather than 50 mg/min, with continuous electrocardiographic monitoring and frequent blood pressure measurements.^36,46 Hypotension or an arrhythmia generally resolves with temporary discontinuation of the infusion; when restarted, the infusion rate may require reduction to 10 mg/min or less. Intravenous fosphenytoin appears to have the same therapeutic profile as intravenous phenytoin but with fewer cardiovascular effects.¹⁵⁵

Long-term anticonvulsant therapy is rarely associated with significant cardiovascular complications. Symptomatic arrhythmias have developed, however, in association with plasma levels of carbamazepine in the optimal therapeutic range, usually in patients with underlying cardiac disturbances.^15,94 It seems appropriate, therefore, to obtain routine electrocardiograms in patients with known cardiac disease who are receiving either carbamazepine or phenytoin on a long-term basis. Any disturbance of consciousness in such patients may relate to a cardiac arrhythmia as well as to seizures, and investigations should be undertaken with this in mind.

The interaction of anticonvulsant and cardiac medications may complicate the management of epilepsy in patients with heart disease. Concurrent use of phenytoin and quinidine sometimes increases ectopy in patients with a history of ventricular arrhythmias.²⁰¹ Phenytoin and phenobarbital may increase the metabolism of quinidine, digoxin, lidocaine, and mexiletine through induction of hepatic microsomal enzymes.^46,201 Amiodarone may increase serum phenytoin levels,¹²⁶ and calcium channel blockers may increase serum carbamazepine concentrations.⁴⁶ It is therefore necessary to measure serum levels of anticonvulsant drugs frequently and to monitor cardiovascular function when introducing or adjusting antiepileptic or cardiac medications.

Seizures are frequent in transplant recipients, who may be put at risk by the nature of their underlying illness, prior treatments, perioperative metabolic abnormalities, and postoperative complications such as cerebral ischemia. Following the transplantation procedure, seizures may relate to immunosuppression, drugs, and rejection. The incidence of seizures after transplant procedures depends on the type and method of transplantation and the patient population under study (Table 1). Children are generally at greater risk than adults for posttransplant seizures.^{2,66,91,125,129}

The etiology of seizures in transplant recipients is frequently multifactorial. Immunosuppressive agents, especially cyclosporine, may themselves cause seizures. Neurologic complications occur in up to 25% of patients receiving cyclosporine; in addition to seizures, tremor, ataxia, leukoencephalopathy, cortical blindness, neuropathy, quadriparesis, and dysesthesias are well described.²⁰⁴ O’Sullivan¹⁴⁶ reported cyclosporine-induced seizures in 1.5% of kidney recipients and 5.5% of bone marrow recipients. Others have suggested higher rates, particularly in liver recipients^40,69 and in children.^66,91

Cyclosporine-induced seizures occur regardless of whether serum levels are within or exceed the therapeutic range and have been attributed to a cyclosporine metabolite.³⁴ Metabolic and systemic abnormalities and other therapeutic agents may potentiate cyclosporine-related seizures. These various factors include concomitant methylprednisolone therapy,^23,49 hypertension,⁸⁹ hypomagnesemia,^2,69,196 hypocholestero- lemia,⁴⁰ microangiopathic hemolytic anemia,^65,159 and, after renal transplantation, aluminum overload.¹⁴¹ In many patients with suspected cyclosporine-induced seizures, however, none of these additional abnormalities is present.