Seizures and General Medical Disorders

CHAPTER

Seizures and General Medical Disorders

57

SIMON M. GLYNN n JACK M. PARENT n MICHAEL J. AMINOFF

RENAL FAILURE  Use of Antiepileptic Drugs in Renal Disease  HEPATIC DISEASE  CARDIAC DISEASE  SEIZURES IN CRITICALLY ILL PATIENTS  General Considerations  Nonconvulsive Status Epilepticus  Seizures Caused by Anoxic-Ischemic Encephalopathy  CONNECTIVE TISSUE DISEASES  INFLAMMATORY AND AUTOIMMUNE DISEASES  HEPATIC PORPHYRIAS  SEIZURES IN TRANSPLANT RECIPIENTS  HUMAN IMMUNODEFICIENCY VIRUS INFECTION AND SEIZURES 

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.

Aminoff’s Neurology and General Medicine, Fifth Edition. © 2014 Elsevier Inc. All rights reserved.

SEIZURES ASSOCIATED WITH SYSTEMIC CANCER  ENDOCRINE OR METABOLIC DISORDERS  Disorders of Glucose Metabolism  Thyroid Disease  Disorders of Sodium Homeostasis  Calcium and Magnesium Imbalance  SEIZURES RELATED TO ALCOHOL, MEDICATIONS, AND RECREATIONAL DRUG USE  Alcohol  Cocaine and other Recreational Drugs  Medications  Antidepressant Drugs  Antipsychotics and Lithium  Antibiotics  Other Agents  CEREBRAL TRAUMA, SEIZURES, AND EPILEPSY 

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.”1 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

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outside the scope of this chapter and are reviewed elsewhere.2,3 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.

RENAL FAILURE 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.4 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.4 Generalized tonic-clonic seizures are the most common seizure type, but partial and myoclonic seizures also may be seen.4 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.5 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,6 levetiracetam,7 amlodipine,8 and verapamil, diltiazem, and nifedipine may induce acute myoclonic jerking without convulsive seizures. Metformin in the presence of end-stage renal disease9 and pregabalin10 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.11 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.11 For these reasons, the free serum level— where available—should guide therapy. Third, uremic molecules downregulate the expression of cytochrome P450 enzymes, so decreasing hepatic metabolism and increasing drug halflife and the risk of drug toxicity for AEDs that are hepatically metabolized (Table 57-1).12,13 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).11 The advent of dialysis membranes with larger surface areas and pore size enables more drugs to be dialyzed than previously.12,13 For example, post-dialysis seizures resulted from decreased serum levels of phenytoin after the introduction of improved dialysis membranes.14 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

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TABLE 57-1 ■ Selected Pharmacokinetics of Antiepileptic Drugs Volume of Distribution (Vd L/kg) (0.6 = Vd for H2O)

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

Minimal

High

141

Primidone

0.4 to 1.0

Minimal

High

218

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

Minimal

High

296

Third- and Fourth-Generation AEDs Minimal or no protein binding

Moderate protein binding

High protein binding

Eslicarbazepine Felbamate

0.7 to 1.0

Moderate

Moderate

238

Gabapentin*

0.8 to 1.8

High

None

171

Lacosamide

0.6

Minimal

Moderate

250

Levetiracetam*

0.7

Moderate

None

170

Pregabalin*

0.5

High

Minimal

159

Rufinamide

0.7

Minimal

High

238

Topiramate

0.6 to 0.8

Moderate

Moderate

339

Vigabatrin*

1.1

High

None

129

Lamotrigine

0.9 to 1.3

Minimal

High

256

Oxcarbazepine†

0.7

Minimal

High

252

Zonisamide

0.8 to 1.6

Minimal

Moderate

212

Ezogabine

2 to 3

High

High

303

Stiripentol‡

–

Minimal

High

234

Tiagabine

–

Minimal

High

412

*

Is not protein bound. The active metabolite 10-OH-carbamazepine is 40% bound (minimal–moderate). ‡ Approved in Europe for SMEI (Dravet syndrome). CLZ, clobazam; DZP, diazepam; LZP, lorazepam. Data from: Israni RK, Kasbekar N, Haynes K. et al: Use of antiepileptic drugs in patients with kidney disease. Semin Dial 19:408, 2006; Diaz A, Deliz B, Benbadis SR: The use of newer antiepileptic drugs in patients with renal failure. Expert Rev Neurother 12:99, 2012; Johannessen Landmark C, Patsalos PN: Drug interactions involving the new second- and third-generation antiepileptic drugs. Expert Rev Neurother 10:119, 2010; and individual product monographs in Micromedex Healthcare Series (Internet database). Thomson Reuters (Healthcare) Inc, Greenwood Village, CO (updated periodically). †

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.11,15 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.

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AMINOFF’S NEUROLOGY AND GENERAL MEDICINE TABLE 57-2 ■ Dose Adjustments for Selected Newer AEDs in Renal Disease AED dose 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

Zonisamide

100–400 mg/day

100–400 mg/day

Oxcarbazepine

300–600 mg b.i.d.

300–600 mg b.i.d.

Felbamate

None

50% decrease

Lamotrigine*

None

None

None

None

Tiagabine

None

None

None

None

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

Clobazam

None

None

None

Pregabalin

None

50% decrease

25–150 mg/day

Plus 50–100 mg after HD

300 mg/day (starting dose)

None

None 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.) Blanks indicate inadequate data; individual AEDs should be used with caution or avoided in these circumstances. “None” indicates no change in dose is recommended. HD, hemodialysis; b.i.d., 2 times daily; t.i.d., 3 times daily. Data from: Israni RK, Kasbekar N, Haynes K. et al: Use of antiepileptic drugs in patients with kidney disease. Semin Dial 19:408, 2006; Diaz A, Deliz B, Benbadis SR: The use of newer antiepileptic drugs in patients with renal failure. Expert Rev Neurother 12:99, 2012; and individual product monographs in the Micromedex Healthcare Series (Internet database). Thomson Reuters (Healthcare) Inc, Greenwood Village, CO (updated periodically).

HEPATIC DISEASE 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.16 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

Seizures and General Medical Disorders

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.17 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.18 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 secondgeneration 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).19 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.20 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).21 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).20 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.20 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.

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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.22

CARDIAC DISEASE 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.23 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 watersoluble 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.24 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 sodiumchannel AEDs usually (but not always) have been present.25,26 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 pre­ existing cardiac disease. Epilepsy patients as a group have lower heart-rate variability than normal—this is a marker of impaired vagal activity and predicts

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arrhythmias and mortality in cardiac patients.27,28 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.28 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 General Considerations 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.29 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 multi­ organ 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.30 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.31,32 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.32

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.33 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

Seizures and General Medical Disorders A

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B

Figure 57-1  A, Quantitative EEG. EEG for 1 hour in a young man intubated for respiratory failure with symptomatic generalized epilepsy and subtle tonic seizures. The upper two panels use a proprietary algorithm to calculate the probability of seizures over time (Persyst seizure detection, Persyst Corporation, San Diego, CA). The lower two panels show time along the x-axis, frequency on the y-axis (0–25 Hz) and EEG on a color scale. Most power is in the delta range for most of the tracing. There is an asymmetry in faster frequencies, increased over the left hemisphere. Intermittent bursts of power in higher frequencies represent brief electrographic seizures, with subtle or no clinical correlate on video. B, EEG recorded using an average reference and corresponding to arrow in A.

described after cardiopulmonary arrest, but may be difficult to recognize.34 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 hypoxicischemic 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.33 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.35 The prevalence of epilepsy in the

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SLE population is also increased, variably reported in larger series to be from 3 to 29 percent.36,37 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.38 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.39 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.40 The frequency of seizures and epilepsy may correlate with the presence of these antibodies, although this is not clear.41,42 Cerebral microinfarcts and, less often, subarachnoid and intracerebral hemorrhages are found on pathologic examination and may relate to an immunologically mediated vasculopathy.43 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.44

TABLE 57-3 ■ Antigens for Autoantibodies Associated With Seizures Intracellular Antigens ANNA-1, CRMP5, GAD65, Ma2 Extracellular (Cell Surface or Synapse) Antigens AMPA receptor, GABA(B) receptor, ganglionic AChR, NMDA receptor, VGKC complex (Caspr2; Lgi1) AChR, acetylcholine receptor; ANNA-1, antineuronal nuclear antibody-type 1; Caspr2, contactin-associated protein-like 2; CRMP5, collapsin response-mediator protein 5; GABA(B), γ-aminobutyric acid subtype B; GAD65, glutamic acid decarboxylase 65; Lgi1, leucine-rich glioma inactivated 1; NMDA, N-methyl-daspartate; VGKC, voltage-gated potassium channel antibody.

INFLAMMATORY AND AUTOIMMUNE DISEASES Systemic autoimmune diseases with neurologic manifestations including seizures may occur in the context of systemic cancer or immune-mediated medical illnesses, including thyroid disease and inflammatory bowel disease. Limbic encephalitis is the prototype for neurologic presentations of autoimmune disease. Clinical features include impaired short-term memory, hallucinations, and sleep disturbance; patients are anxious, irritable, or paranoid. Partial and secondarily generalized seizures are seen in nearly all cases, and often do not respond to AEDs. Diagnosis is by autoantibodies to intracellular antigens, or extracellular (cell surface) antigens involved in synaptic transmission (Table 57-3). Paraneoplastic etiologies for limbic encephalitis must be excluded. These syndromes are discussed in detail in Chapter 27. Hashimoto encephalopathy is a relapsing encephalopathy occurring in association with Hashimoto thyroiditis, with high titers of antithyroid peroxidase antibodies (anti-TPO), antithyroid microsomal antibodies, and antithyroglobulin antibodies. Thyroid hormone levels are usually decreased (hypothyroid), but 30 percent of persons may be euthyroid or hyperthyroid. Seizures occur in the majority of these patients. Many patients respond to intravenous methylprednisolone (termed steroid-responsive encephalopathy associated with autoimmune thyroiditis, or SREAT).45 AEDs are required for acute seizures; seizures tend to remit as the encephalopathy improves. The disorder is discussed in detail in Chapter 18. Inflammatory bowel diseases, including ulcerative colitis and Crohn disease, are chronic relapsing

Seizures and General Medical Disorders

inflammatory diseases of the gut. Both conditions are associated with neurologic and systemic complications, possibly including an increased incidence of epilepsy, but this is not quite clear.46 The epidemiologic association of celiac disease with epilepsy is clearer, seen in between 3.5 and 5.5 percent of patients with celiac disease.47,48 Occasionally, seizures are the first presentation of multiple sclerosis.49 On balance the incidence in multiple sclerosis is quite low, varying in different series from no change from baseline risk of seizures50 to 7.8 percent.51 Focal seizures as well as generalized convulsive seizures may occur. Onethird of seizures occur in the context of an acute flare of the disease, and occasionally present as focal status epilepticus.52 Seizures usually stop with disease remission. The reason for the occurrence of seizures (a cortical disturbance) in demyelinating disease is not clear, but specialized magnetic resonance imaging sequences do demonstrate intracortical lesions in patients with seizures.53

HEPATIC PORPHYRIAS Porphyrias are caused by deficiencies in enzymes of the heme biosynthetic pathway that lead to the accumulation of heme precursors (porphyrins). The inherited conditions are classified into the acute porphyrias (hepatic porphyrias) and cutaneous (erythropoetic) porphyrias, reflecting the location of the accumulation of porphyrins. Three of the acute porphyrias may present with epilepsy and neuropsychiatric symptoms: acute intermittent porphyria (AIP), hereditary coproporphyria, and variegate porphyria. Acute intermittent porphyria is the commonest hepatic porphyria, and the one most frequently associated with seizures and epilepsy. The clinical features of variegate porphyria are identical to AIP, except for cutaneous photosensitivity seen in 30 percent. Persons are asymptomatic until exposed to circumstances that demonstrate the deficiency, including infection, hormonal cycles, diet, or medications. Symptoms are due to an acute neuropathy and evolve over hours or days. These include abdominal pain, nausea, vomiting, weakness, and severe neuropathic pain. Laboratory studies demonstrate increased δ-aminolevulinic acid (ALA) and porphobilinogen in the urine. Encephalopathy, coma, or seizures are seen in 5 to 20 percent of persons during acute attacks, and

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may be the presenting feature in AIP.54 Seizures may be partial or generalized convulsive seizures55,56 and, rarely, status epilepticus.56 These seizures may reflect a direct neurologic effect of ALA binding to GABA receptors.56 Defects in hepatic heme synthesis may also alter brain levels of neurotransmitters.57 Seizures may also be symptomatic of metabolic disturbances from excessive vomiting or inappropriate antidiuretic hormone secretion. All the enzyme-inducing antiepileptic drugs, valproic acid, and benzodiazepines may exacerbate or precipitate attacks by stimulating hepatic ALA synthase activity, and these drugs should be avoided.55,56,58 Experimental studies suggest that lamotrigine, felbamate, topiramate, or tiagabine use will exacerbate hepatic porphyrias.59,60 These studies are supported clinically in the case of lamotrigine.61 Gabapentin, pregabalin and levetiracetam are probably safe, and gabapentin62 and levetiracetam63 have been used successfully for acute seizures and status epilepticus. The use of intravenous benzodiazepines seems relatively safe but this is debated.58 If seizures are medically refractory, magnesium sulfate may be infused intravenously to keep serum magnesium concentrations between 2.5 and 7.5 mmol/L.56 Long-term pharmacotherapy of recurrent seizures in patients with hepatic porphyria is difficult. Clonazepam may be safe in the chronic treatment of patients with hepatic porphyria58 despite evidence that clonazepam is porphyrinogenic.55 The preferred AED is probably gabapentin, pregabalin, or levetiracetam.62,63 Urine ALA and porphobilinogen levels must be monitored closely during therapy.

SEIZURES IN TRANSPLANT RECIPIENTS The neurologic complications of organ transplantation are summarized in Chapter  45. Transplant recipients are at high risk of seizures that may relate to their underlying illness, irradiation or chemotherapy, and perioperative metabolic abnormalities or complications such as cerebral ischemia. After surgery, the effects of immunosuppression, therapeutic agents, and rejection are also important causes. The approximate percentage incidence of seizures varies depending on the transplanted organ (Chapter 45). Children in general appear to be at greater risk than adults of post-transplantation seizures.64,65 Immunosuppressive agents, especially cyclosporine, have been associated with seizures. Such seizures may occur with serum levels of cyclosporine

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within or exceeding the therapeutic range and may relate to a cyclosporine metabolite.66 Various metabolic and systemic abnormalities, as well as other therapeutic agents, have been reported to potentiate them. These factors include concomitant methylprednisolone therapy, hypertension, hypomagnesemia, hypocholesterolemia, microangiopathic hemolytic anemia,67,68 and (after renal transplantation) aluminum overload. Other immunosuppressive agents may also cause post-transplantation seizures. Tacrolimus (FK506) has neurologic complications similar to cyclosporine, including seizures and encephalopathy,69,70 and the antirejection agent muromonabCD3 (OKT3) can cause seizures as part of a cytokine encephalopathy.71 Sirolimus (rapamycin), one of the newer immunosuppressive agents, did not cause seizures or other neurotoxicity in at least one series consisting of kidney and liver transplant recipients.72 In bone marrow recipients, busulfan, either alone or in combination with cyclophosphamide, may cause seizures.73 Seizures may also result from CNS infections or relate to noninfectious structural and metabolic abnormalities that require specific treatment. Cerebral ischemia or hemorrhage, hyponatremia with central pontine myelinolysis, hyperosmolar states, hypoglycemia, delayed malignancy related to prior treatment, or multiorgan system failure may be responsible. Finally, transplant rejection may lead to an encephalopathy syndrome that includes seizures, sometimes as the first manifestation of rejection.74 The treatment of seizures in transplant recipients may be difficult. When seizures are self-limited and caused by correctable abnormalities that are not recurrent, anticonvulsant therapy is not required. Prolonged seizures or those placing the patient at high risk of complications should be controlled with intravenous benzodiazepines. Long-term anticonvulsant therapy is required for recurrent seizures. An antiseizure agent is selected, bearing in mind the type of transplantation procedure undergone by the patient and the immunosuppressive drugs in use. Valproic acid is best avoided in liver recipients because of its potential hepatotoxicity; low-dose levetiracetam (500 mg twice daily) is a reasonable alternative, although experience is limited.75,76 Carbamazepine should not be used in bone marrow recipients because it may cause myelosuppression. Bone marrow engraftment occurs 2 to 6 weeks after transplantation, and phenytoin, phenobarbital and

valproic acid are best avoided over this period in favor of a newer agent. The enzyme-inducing AEDs may have an effect on immunosuppressive agents metabolized by the liver. Thus, the clearance of cyclosporine and corticosteroids is increased by phenobarbital, phenytoin, and carbamazepine,77 necessitating increased dosages of corticosteroids by 25 to 30 percent and of cyclosporine depending on serum cyclosporine levels. The use of valproic acid avoids such pharmacokinetic interactions. Oxcarbazepine add-on therapy led to decreased serum cyclosporine and sodium concentrations in a single report involving a renal transplant patient, but the abnormalities reversed with reduction in the dose of oxcarbazepine.78 Levetiracetam does not appear to influence immunosuppressive drug levels, has been used successfully in liver transplant recipients, and therefore may be a good initial choice for AED therapy in the overall transplant population. The lack of hepatic enzyme– inducing activity of pregabalin and gabapentin suggests that they also may be useful in this context.

HUMAN IMMUNODEFICIENCY VIRUS INFECTION AND SEIZURES Seizures occur in perhaps 10 percent of persons infected with human immunodeficiency virus (HIV).79 They may occur at any stage of HIV infection or acquired immunodeficiency syndrome (AIDS) and are sometimes the presenting symptom of HIV infection.79 Involvement of the nervous system is present at autopsy in 85 percent of persons with HIV infection.80 The introduction of combination antiretroviral treatment (cART) using protease inhibitors has reduced brain involvement by opportunistic infections in these autopsy series, but also corresponds to an increase in HIV encephalopathy from 34 to 60 percent, perhaps reflecting the dramatic improvement of survival in HIV infection.80 Variants of HIV encephalitis with intense perivascular inflammation have also emerged, presumably due to an exaggerated response from a newly reconstituted immune system.80 In nearly half of the patients with HIV/AIDS seen for seizures, no cause except HIV infection is found and in these persons direct cerebral HIV infection seems the correct explanation.79 Other important CNS disorders that may be responsible and are associated with HIV/AIDS include CNS toxoplasmosis,

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cryptococcal meningitis, neurotuberculosis, progressive multifocal leukoencephalopathy, and CNS lymphoma. Systemic illness, drug or alcohol use (especially cocaine), and even antiretroviral agents are also important causes of symptomatic seizures.81 A detailed diagnostic evaluation is therefore required when HIV-infected patients experience the new onset of seizures. The risk of subsequent seizures following a first seizure is relatively high in HIV-infected persons, and for this reason AEDs are usually started following a first seizure.79 Monotherapy with one of the newer antiepileptic agents that do not induce hepatic enzymes is preferable as first-line therapy. On balance, the older enzyme-inducing antiepileptic agents are best avoided in patients with HIV/ AIDS, because of concerns about hypoalbuminemia, hypergammaglobulinemia (which may predispose to AED hypersensitivity reactions), and potential drug–drug interactions.82 For example, phenytoin interacts with protease inhibitors, affecting viral load, and may cause intoxication in patients treated concurrently with fluconazole, commonly prescribed in AIDS patients.83

SEIZURES ASSOCIATED WITH SYSTEMIC CANCER Seizures are an important complication of systemic cancer. The number of persons who develop seizures varies by series and seizure type, from 12 to 35 percent.84 Seizures are a more common neurologic complication of systemic cancer in children and were the second most common reason for pediatric neurology referrals (18 percent of referrals) in one series, compared to only 5 percent in adults.85 Different potential etiologies must be considered when seizures occur in patients with cancer. First, seizures may be due to direct brain effects including parenchymal metastasis in 10 to 20 percent of persons with systemic cancer.86 These lesions deafferent the adjacent cortex and may alter the immediate microenvironment by distortion, ischemia, or hemorrhage. All of these factors contribute to epileptogenesis in the adjacent cortical tissue and subsequent seizures that arise in these circumstances. Metastases are especially frequent for melanoma, lung, breast, renal cell, gastrointestinal, and germ cell tumors, as well as when leptomeningeal seeding occurs by malignant tumor cells (carcinomatous meningitis).87

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Second, seizures may be symptomatic of an associated diagnosis or condition occurring in systemic cancers. For example, they may result from cerebrovascular events due to hypercoagulable states or nonbacterial thrombotic endocarditis associated with cancer. CNS infections, including fungal or parasitic abscesses, may result from immunosuppression after chemotherapy and produce seizures. Convulsions are an uncommon complication of chemotherapy, but may be seen with etoposide, l-asparaginase, alkylating agents such as chlorambucil or busulfan, immunotherapies, methotrexate, and cytosine arabinoside.87 Other causes include cancer-induced metabolic disturbances, paraneoplastic encephalitis, and drugs used to treat cancer complications, such as pain medications or antibiotics. Guidelines for the treatment of patients with single metastatic lesions recommend surgery (if possible) followed by whole-brain radiation therapy.88 In patients not presenting with seizures, AEDs may be given perioperatively for 7 days and then discontinued.89 Phenytoin is frequently used in this circumstance, although patients receiving wholebrain cranial irradiation have an increased risk of Stevens–Johnson syndrome, and levetiracetam is preferred for this reason. AEDs are not indicated for persons with metastatic disease who have not had seizures. Once a seizure has occurred, AEDs are recommended. There are no recommendations for the type of AED, dose, or length of therapy.88 Chemotherapeutic agents used to treat systemic cancers complicate the selection of an AED. Drug interactions may occur. For example, corticosteroids are indicated for patients with symptoms secondary to elevated intracranial pressure. Phenobarbital and phenytoin shorten the half-life of corticosteroids, and increased or decreased serum concentrations of phenytoin have been described in patients receiving corticosteroids.90 A second concern is that many chemotherapeutic agents undergo hepatic metabolism or induce or interfere with hepatic enzymes. Consequently, AEDs that induce hepatic enzymes or are metabolized hepatically may lower the effectiveness of cancer chemotherapy, interfere with seizure control, or induce anticonvulsant toxicity.91 Because of the potential for drug–drug interactions, AEDs that do not induce hepatic enzymes, including levetiracetam, gabapentin, pregabalin, or lacosamide, are preferred in individuals undergoing cancer chemotherapy.

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ENDOCRINE OR METABOLIC DISORDERS Disorders of Glucose Metabolism Both focal motor and generalized seizures may occur in patients with hypoglycemia; seizure flurries or convulsive status epilepticus may also occur. Other neurologic abnormalities include depressed level of consciousness, behavioral changes, tremor, and hemiparesis. These deficits correlate poorly with level of hypoglycemia, although in symptomatic patients levels are usually below 40 mg/dl. Hypoglycemia must be considered as a possible cause in any patient with seizures; it is treated by intravenous administration of dextrose and correction of any other metabolic abnormalities. Patients usually do well but are best hospitalized for observation because hypoglycemia may recur hours after initial treatment. Seizures are relatively common in nonketotic hyperglycemia and may be of any type. Partial motor seizures or epilepsia partialis continua may be the presenting feature. The range of glucose elevation is broad and may be associated with only mild elevation of serum osmolarity. Seizures are refractory to AEDs but respond to correction of hyperglycemia with insulin and intravenous fluid replacement. Associated focal neurologic abnormalities are usually transient, and recovery is typically complete if treatment is initiated before coma occurs. Anticonvulsant therapy is not required for seizures related to nonketotic hyperglycemia. Phenytoin must specifically be avoided because it can exacerbate hyperglycemia by inhibiting insulin release.

Thyroid Disease Seizures are not uncommon in hypothyroidism, are usually generalized, and remit with treatment of the hypothyroidism. Anticonvulsant drugs, such as phenytoin and carbamazepine, may reduce serum thyroxine and triiodothyronine measurements because of competition for serum-binding proteins; however, patients remain clinically euthyroid because free thyroxine and triiodothyronine fractions are increased.92 Seizures are uncommon in thyrotoxicosis, but hyperthyroidism or excess thyroxine may occasionally cause seizures or exacerbate preexisting epilepsy. Both partial and generalized seizures may occur in hyperthyroid patients and in those receiving thyroxine for hypothyroidism. In addition,

worsening of both partial and generalized epilepsies may occur with increased thyroxine levels.93 When seizures occur in the setting of thyrotoxicosis, the hyperthyroid state should be corrected; anticonvulsants usually are not required except occasionally in the acute setting.

Disorders of Sodium Homeostasis A full account of the neurologic manifestations is provided in Chapter  17. Hyponatremic encephalopathy relates to an osmotic imbalance between the extracellular fluid and brain cells, and the effects of a compensatory loss of intracellular cations. Neurologic symptoms reflect the rate of development of hyponatremia rather than absolute serum sodium levels, and chronic hyponatremia is surprisingly well tolerated. Seizures are usually seen in the context of acute hyponatremia with concentrations less than 115 mEq/L, but seizures may occur at higher levels if the decrease is very rapid.94 Children are at high risk of cerebral edema in hyponatremia.95 Both partial and generalized seizures may occur. Seizures require treatment using intravenous hypertonic (3%) saline. This should be given at a controlled rate so that increases in serum sodium concentration do not exceed 1 mmol/L (1 mEq/L) per hour; treatment can be stopped once the patient is asymptomatic. The correction should not exceed 12 mmol/L (12 mEq/L) over the first 24 hours and 25 mmol/L (25 mEq/L) in the initial 48 hours.96,97 More rapid correction of hyponatremia may cause osmotic demyelination (previously termed pontine and extrapontine myelinolysis), as well as seizures.98 Hypernatremia indicates a relative deficit of body water related to body sodium content. As a consequence, water shifts from the intracellular to extracellular compartment. If severe (>160 mEq/L), this causes an encephalopathy. The aim of treatment is to replace body water. Partial or generalized seizures may occur, especially during rehydration. Cautious correction of hypernatremia with halfisotonic saline may lower the risk of convulsions during treatment.97

Calcium and Magnesium Imbalance The causes and clinical features of hypocalcemia are reviewed in Chapter 17. Altered sensorium and

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seizures are common neurologic manifestations of hypocalcemia. Hypocalcemic seizures are usually generalized, but partial seizures occur in 20 percent of patients and may include motor or sensory phenomenology. Between 30 and 70 percent of patients with hypoparathyroidism experience seizures, often accompanied by an altered sensorium and tetany, although tetany is occasionally absent. Treatment of hypocalcemic seizures involves correction of serum calcium levels and treatment of any underlying cause. Multifocal and generalized seizures may also be provoked by hypomagnesemia, especially when the serum magnesium concentration decreases below 0.8 mEq/L (see Chapter 17). Convulsions in such circumstances are treated with magnesium salts administered by slow intravenous bolus after the adequacy of renal function has been determined; calcium gluconate should be available to counteract transient hypermagnesemia. Hypercalcemia infrequently causes seizures. Seizures are not seen in hypermagnesemia.

SEIZURES RELATED TO ALCOHOL, MEDICATIONS, AND RECREATIONAL DRUG USE Alcohol Seizures are a common consequence of alcohol abuse, as discussed in Chapter  33. Alcohol potentiates the activity of GABAA receptors, and alcohol dependence seems to result in a compensatory downregulation of these receptors. As a consequence, when alcohol and its effect on the GABAA receptors are withdrawn, there is decreased neuronal inhibition and seizures.99 Alcohol-related seizures are usually self-limited generalized convulsions that occur within 48 hours after stopping alcohol, often accompanied by other signs and symptoms of alcohol withdrawal. Seizures may be isolated or occur in flurries and are usually due to acutely declining ethanol levels in long-standing heavy drinkers.100 Convulsive status epilepticus may result uncommonly from alcohol withdrawal.101 The brain substrates responsible for these seizures are largely in the brainstem, and perhaps for this reason AEDs effective for generalized epilepsies seem to be helpful.99 In the United States, benzodiazepines are preferred to treat alcohol withdrawal and to prevent seizures.

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Patients with seizures solely in the setting of alcohol or drug abuse do not, by definition, have epilepsy. Because seizures are self-limited, long-term AED therapy is not indicated. However, approximately 2 to 4 percent of patients with alcoholrelated seizures have preexisting epilepsy.100 These patients should be advised against chronic alcohol use or binge drinking.102

Cocaine and other Recreational Drugs Seizures may be induced by acute intoxication with recreational drugs, especially cocaine103 and other stimulants, or, less frequently, may appear as a withdrawal phenomenon. Seizures are typically isolated convulsions that are self-limited and do not require acute or long-term treatment with AEDs. Between 2 and 8 percent of patients presenting with cocaine toxicity exhibit seizures, usually an isolated generalized convulsive seizure.103 This risk is highest with rapid administration (intravenous or inhaled crack cocaine) and may reflect a direct CNS stimulant effect through blockage of neurotransmitter reuptake at dopaminergic and noradrenergic nerve terminals, perhaps a kindling effect with chronic use, cerebrovascular or systemic effects, or a terminal event in massive cocaine overdose.100,103 Seizures are infrequent in intoxication with other recreational drugs. Amphetamine is an uncommon cause of generalized convulsions, which occur more commonly after intravenous use and administration of high doses. Seizures are also uncommon with phencyclidine. Heroin use has been associated with convulsions, although this may relate to anoxia and chemical adulterants rather than to a convulsant effect of heroin itself.104 Complications of intravenous drug abuse that may cause seizures, including infectious endocarditis and HIV infection, should be sought in patients with convulsions associated with the use of heroin or other intravenous drugs. Marijuana is often used concurrently with heroin and other recreational drugs but seems independently to lower the risk of a first seizure.104

Medications Antidepressant Drugs The most commonly implicated drugs in causing seizures are the tricyclic antidepressants (TCAs) and bupropion. The relative risk of TCAs at usual

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therapeutic doses is actually quite low, but on overdose TCAs may cause seizures due to their effect on GABAA receptors, decreasing inhibition. Compared to other drugs, overdose with TCAs is also associated with high mortality.105 Bupropion is a monocyclic inhibitor of dopamine and has a clear dose-related risk of seizures, with a seizure incidence of 0.4 percent at doses of 450 mg/day or less, increasing to 2.2 percent at doses exceeding 450 mg/day.106 Conversely, the selective serotonin reuptake inhibitors (SSRIs) appear to have low epileptogenic potential even in overdose, with no seizures in a series of 234 cases of fluoxetine overdose.107 The seizure risk with SSRIs is generally quoted as 0.2 percent, based on premarketing data for sertraline.108 Importantly, antidepressants as a class may actually reduce the risk of seizures compared to placebo,109 consistent with the observation that low levels of pre/post-serotonergic transmission in depressed persons may be a risk factor for seizures.110

Antipsychotics and Lithium Clozapine, an atypical antipsychotic, demonstrates a clear dose-related risk of seizures of 0.9 percent for doses less than 600 mg/day and 1.5 percent for higher doses,111 and has the highest seizure risk of all the antipsychotic medications.109 An increased risk of seizures has also been reported with olanzapine and quetiapine, but the other atypical antipsychotics (ziprasidone, aripiprazole, and risperidone) as a group do not seem to be associated with an increased incidence of seizures.109 Seizures with lithium intoxication are common when levels exceed 3.0 mEq/L although seizures have been reported in patients on lithium at therapeutic levels.109

Antibiotics Seizures have been reported for penicillins, cephalosporins, carbapanems (β-lactam antibiotics), and fluoroquinolones. They are believed to be due to direct or indirect binding to GABAA receptors.112 Of these antibiotics, the risk is highest for imipenem, from 0.2 to 0.9 percent, although acute seizures were seen in one series in 11 of 200 patients on imipenem.113,114 Risk is increased in the very young or very old and with renal insufficiency, focal neurologic deficits, and severity of illness, and when given intravenously or intrathecally.112

Other Agents Tramadol is a weak μ-opioid receptor agonist that also induces serotonin release and inhibits the reuptake of norepinephrine. Seizures have been reported with tramadol at therapeutic doses, but are very frequent at supratherapeutic levels, occurring in 14 percent of overdoses in one series.115,116 Isoniazid is a common cause of drug-induced seizures, particularly in intentional overdose, believed to be due to inhibition of pyridoxine (vitamin B6) metabolism that is required to synthesize GABA.117 For this reason, isoniazid-induced seizures may be refractory to AEDs and should be treated with intravenous pyridoxine.112 Seizures may result from certain antiasthmatic medications and especially theophylline. This is most likely due to the inhibition of phosphodiesterase, which may reduce adenosine-mediated CNS inhibition.118 Status epilepticus may be seen in acute overdose; it does not respond to AEDs and requires hemodialysis or hemoperfusion therapy.118,119 Theophylline is best avoided in persons with epilepsy for these reasons. Seizures have been reported with the anesthetic agents propofol, sevolfurane, and lidocaine.113 Propofol, which acts on the GABAA receptors and is used in the treatment of refractory status epilepticus, has also been associated with seizures during induction or recovery from anesthesia.120 Seizures can occur in the setting of abruptly stopping benzodiazepines and barbiturates, and also baclofen, which may cause nonconvulsive status epilepticus.121

CEREBRAL TRAUMA, SEIZURES, AND EPILEPSY Traumatic brain injuries (TBI) are an important cause of seizures and epilepsy, especially in young adults, and may also worsen seizures in persons with preexisting epilepsy.122,123 Post-traumatic seizures may present across the spectrum of simple to complex seizures, including generalized and secondarily generalized seizures and (infrequently) status epilepticus. Seizures caused by TBI are classified as immediate (at the moment of injury, or within minutes), early (within the first 7 days), and late (beyond the first week after injury).124 The incidence of immediate seizures following TBI is 1 to 4 percent125,126; they are usually generalized convulsions and do not imply that the patient will develop epilepsy.127

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Early seizures developing more than 1 hour after injury do present an increased risk of posttraumatic epilepsy. These seizures are symptomatic for the physics of the initial brain injury including shearing injury to fiber tracts and blood vessels, bleeding, and brain swelling.128 The incidence for early seizures (within the first 7 days) is 2 to 9 percent, depending on the severity of the brain injury. Most early seizures are generalized convulsions; for late post-traumatic seizures, seizure types are more variable.129 The latency from the initial brain injury to a first unprovoked seizure can be up to several years.124 Approximately 80 percent of individuals with posttraumatic epilepsy experience their first seizure within the first 12 months after injury and more than 90 percent do so before the end of the second year.130 However, the risk still is increased more than 10 years after the traumatic event.131 The presence of early seizures is the most important risk factor for the development of late seizures and epilepsy, and the incidence of late seizures in persons with early seizures is high, from 25 to 75 percent.132,133 Other risk factors include open or penetrating brain injury, focal lesions (hematoma, contusion) or neurologic signs, and prolonged coma or amnesia.134,135 The precise mechanisms of epileptogenesis that leads to late seizures are poorly understood. Secondary epileptogenesis may also occur—the initial epileptogenic focus causes the emergence of a second distant and perhaps ultimately independent seizure focus in the hippocampal formation, especially in children.136 The EEG is disappointing as a predictor of the risk of development of post-traumatic epilepsy, as many patients who eventually develop post-traumatic epilepsy have normal recordings early after injury.135 Magnetic resonance imaging of the brain is the imaging modality of choice, and has shown some promise for improving prediction of post-traumatic seizure risk.137 Treatment of early-onset seizures is imperative, as they may lead to secondary brain damage as a result of increased metabolic demand, raised intracranial pressure, and excess neurotransmitter release. However, although AEDs decrease early seizures, prospective clinical trials have failed to demonstrate that preventing early seizures using AEDs affects mortality, morbidity, or the development of late epilepsy.138 These include randomized or quasi-randomized monotherapy studies using

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phenytoin, phenobarbital, carbamazepine, and valproic acid.139–141 Glucocorticoids also appear to have no benefit in preventing the development of seizures after traumatic brain injury.142

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