Seizures Associated with Nonneurologic Medical Conditions
Stephan Eisenschenk
Robin L. Gilmore
Seizures frequently arise during the course of medical illnesses that do not primarily affect the central nervous system (CNS). The truism that appropriate treatment depends on correct diagnosis emphasizes the importance of the differential diagnosis. A patient’s history, including a review of medications and physical examination should be informed by a consideration of the seizures as a symptom of CNS dysfunction. The urgency to pursue a diagnosis is related to the time of presentation following the seizure. The evaluation of a patient presenting 24 hours after a single seizure is paced by other manifestations of CNS dysfunction. In a neurologically intact patient without progressive symptoms, quick (within days), but not emergent (within hours), evaluation may be appropriate. Within the first 24 hours, vital signs, level of consciousness, and focality on examination determine urgency. The need for emergent neuroimaging studies and lumbar puncture depends on the likelihood of intracranial lesion, CNS or systemic infection, a patient’s metabolic state, and the possibility of intoxication. In a patient who presents more than 1 week after an initial seizure, recurrent attacks establish the diagnosis of epilepsy.
Several factors predispose a patient to seizures, including (a) changes in blood-brain barrier permeability as a result of infection, hypoxia, dysautoregulation of cerebral blood flow, or microdeposition of hemorrhage or edema secondary to vascular endothelial damage; (b) alteration of neuronal excitability by exogenous or endogenous substances, such as excitatory and inhibitory neurotransmitters; (c) inability of glial cells to regulate the neuronal extracellular environment; (d) electrolyte imbalances; (e) hypoxia-ischemia; and (f) direct and remote effects of neoplasm (1). Some patients without epilepsy may be genetically prone to seizures secondary to systemic factors.
Understanding the interaction of other organ systems is necessary for the appropriate management of seizures. In patients with hepatic or renal dysfunction, changes in pharmacokinetics induced by metabolic dysfunction alter treatment with antiepileptic drugs (AEDs). In cases of hepatic dysfunction, plasma concentrations must be correlated with serum albumin and protein levels and, if possible, free (unbound) levels. Patients with hepatic and renal failure may have normal serum and albumin levels, but altered protein binding, resulting in elevated concentrations of free drug (2).
METABOLIC DISORDERS
Metabolic disorders, although often suspected during outpatient evaluation of new-onset seizures, are found in <10% of patients and usually involve glucose metabolism (3). In the hospital setting, disorders of electrolytes and fluid balance predominate. Encephalopathies may be associated with electrolyte disturbances, hypocalcemia, hypercalcemia, hypoglycemia, hypothyroidism, thyrotoxic storm, adverse effects of drugs, organ failure, and many other conditions.
Hyponatremia
Because electrolyte disturbances are usually secondary processes, effective management of associated seizures begins with identification and treatment of the primary disorder in conjunction with cautious correction of the
electrolyte disturbance. Hyponatremia, defined as a serum sodium level lower than 115 mEq/L, is one of the most frequently reported metabolic abnormalities, affecting 2.5% of hospitalized patients (4). Neurologic symptoms occur often in patients with acute hyponatremia (5,6), and convulsions in this setting have a mortality rate estimated to exceed 50% (7). Correction to levels higher than 120 mEq/L is essential; however, the rate of correction is controversial. Rapid correction of hyponatremia is associated with central pontine myelinolysis, manifested as pseudobulbar palsy and spastic quadriparesis (8). Originally described in patients with alcoholism and malnutrition, the condition was later observed in dehydrated patients undergoing rehydration (9) and in one small study (10) was accompanied in each patient by a recent rapid increase in serum sodium levels. Pathologic features include symmetrical, noninflammatory demyelination in the basis pontis, with relative neuronal and axonal sparing. In animal models of central pontine myelinolysis, rapid correction of sustained vasopressin-induced hyponatremia with hypertonic saline was followed by demyelination (11). Some authorities consider a correction of more than 12 mEq/L per day to be unnecessarily aggressive (10).
electrolyte disturbance. Hyponatremia, defined as a serum sodium level lower than 115 mEq/L, is one of the most frequently reported metabolic abnormalities, affecting 2.5% of hospitalized patients (4). Neurologic symptoms occur often in patients with acute hyponatremia (5,6), and convulsions in this setting have a mortality rate estimated to exceed 50% (7). Correction to levels higher than 120 mEq/L is essential; however, the rate of correction is controversial. Rapid correction of hyponatremia is associated with central pontine myelinolysis, manifested as pseudobulbar palsy and spastic quadriparesis (8). Originally described in patients with alcoholism and malnutrition, the condition was later observed in dehydrated patients undergoing rehydration (9) and in one small study (10) was accompanied in each patient by a recent rapid increase in serum sodium levels. Pathologic features include symmetrical, noninflammatory demyelination in the basis pontis, with relative neuronal and axonal sparing. In animal models of central pontine myelinolysis, rapid correction of sustained vasopressin-induced hyponatremia with hypertonic saline was followed by demyelination (11). Some authorities consider a correction of more than 12 mEq/L per day to be unnecessarily aggressive (10).
Levels of serum sodium are most commonly reduced as a result of either sodium depletion, water “intoxication,” or both (7); these are examples of hypoosmolar hyponatremia. Hyponatremia with normal osmolality is rare, but may accompany hyperlipidemia or hyperproteinemia. Hyperosmolar hyponatremia occurs in such hyperosmolar states as hyperglycemia and is discussed later in this chapter. Hypoosmolar hyponatremia may occur with normal extracellular fluid volume, hypovolemia, or hypervolemia (12). Hypoosmolar hyponatremia with hypovolemia may follow renal (diuretic use, Addison disease) or extrarenal (vomiting, diarrhea, or “third spacing”) loss. The syndrome of inappropriate antidiuretic hormone secretion, hypothyroidism, and some psychotropic agents may lead to hypoosmolar hyponatremia with normal volume. Hypoosmolar hyponatremia with hypervolemia, frequently seen with clinical edema, occurs in patients with cardiac failure, nephrotic syndrome, and acute or chronic renal failure. The therapeutic implications of these conditions are significant, because appropriate treatment for normovolemic or hypervolemic hyperosmolar hyponatremia is water restriction. Hypovolemic hyponatremia is managed by replacement of water and sodium (12).
Finally, hyponatremia is sometimes considered to be an iatrogenic effect of prescribed medications, including diuretics and serotonin reuptake inhibitors (13). Hyponatremia can also be a complication of abuse of illicit substances, such as 3,4-methylenedioxymethamphetamine (MDMA, or “Ecstasy”) (14,15).
Hypocalcemia
Although seizures resulting from severe hypocalcemia (<6 mg/dL) are relatively uncommon, they occur in approximately 25% of patients who present as medical emergencies (16). Severe, acute hypocalcemia most often follows thyroid or parathyroid surgery. Late-onset hypocalcemia with seizures may appear years after extensive thyroid surgery (17); the condition is believed to be rare and is not well understood. Hypocalcemia frequently complicates renal failure and acute pancreatitis (7), and may also occur along with vitamin D deficiency and renal tubular acidosis. Nutritional rickets is still reported, although rarely in the United States, occasionally with hypocalcemic seizures (18). Tetany is the most common neuromuscular accompaniment of hypocalcemia (19). Manifesting as spontaneous, irregular, repetitive action potentials that originate in peripheral nerves, tetany is sometimes confused with seizure activity. Latent tetany may be unmasked by hyperventilation or regional ischemia (Trousseau test). In the average adult, an intravenous (IV) bolus of 15 mL of 10% calcium gluconate solution (a calcium concentration of 9 mg/mL) administered slowly, along with cardiac monitoring, followed by infusion of the equivalent of 10 mL per hour of the same solution, should relieve seizures (20).
Hypomagnesemia
Hypomagnesemia is associated with seizures, but usually only at levels lower than 0.8 mEq/L (21). Because a related hypocalcemia may be produced by a decrease in, or end-organ resistance to, circulating levels of parathyroid hormone, magnesium levels should be measured in the patient with hypocalcemia who does not respond to calcium supplementation. Convulsions are treated with intramuscular injections of 50% magnesium sulfate every 6 hours. Because transient hypermagnesemia may induce respiratory muscle paralysis (21), IV injections of calcium gluconate should be administered concurrently.
Hypophosphatemia
Profound hypophosphatemia may accompany alcohol withdrawal, diabetic ketoacidosis, long-term intake of phosphate-binding antacids, recovery from extensive burns, hyperalimentation, and severe respiratory alkalosis. A sequence of symptoms consistent with metabolic encephalopathy involves irritability, apprehension, muscle weakness, numbness, paresthesias, dysarthria, confusion, obtundation, convulsive seizures, and coma (22). Generalized tonic-clonic seizures have been noted at phosphate levels lower than 1 mg/dL, and affected patients may not respond to AED therapy (23).
Disturbances of Glucose Metabolism
Hypoglycemia and nonketotic hyperglycemia may be associated with focal seizures; such seizures do not occur with ketotic hyperglycemia, however, probably because of the anticonvulsant action of the ketosis (24). Ketosis also
involves intracellular acidosis with enhanced activity of glutamic acid decarboxylase, which leads to an increase in τ-aminobutyric acid and a corresponding increase in seizure threshold.
involves intracellular acidosis with enhanced activity of glutamic acid decarboxylase, which leads to an increase in τ-aminobutyric acid and a corresponding increase in seizure threshold.
Nonketotic hyperglycemia, with or without hyperosmolarity, may produce seizures and in animal models increases seizure frequency through brain dehydration, provided a cortical lesion is present (25). Focal motor seizures and epilepsia partialis continua, well-known complications of nonketotic hyperglycemia, occur in approximately 20% of patients (26).
Rarely, patients with focal seizures associated with nonketotic hyperglycemia may have reflex- or posture-induced epilepsy provoked by active or passive movement of an extremity (27,28) and usually have nonreflex seizures as well, related perhaps to an underlying focal cerebral ischemia. Such seizures are refractory to conventional anticonvulsant treatment. In fact, phenytoin may further increase the serum glucose level by inhibiting insulin release (29). Thus, correction of the underlying metabolic disturbance is of utmost importance.
Hypoglycemia is particularly seizure provoking and is most frequently related to insulin or oral hypoglycemic agents, although occasionally the etiology may not be obvious. Another common cause is the use of drugs that interact with oral hypoglycemic agents (30). Islet cell dysmaturation syndrome, characterized by islet cell hyperplasia, pancreatic adenomatosis, and nesidioblastosis, is associated with infantile hyperinsulinemic hypoglycemia. Bjerke and coworkers (31) reported on 11 infants with this condition, 8 of whom presented with hypoglycemic seizures. Five infants had preoperative neurologic impairment. All showed improvement postoperatively, but only one infant had normal findings on neurologic examination. Early diagnosis is a decisive factor in averting long-term complications; treatment entails resection of the pancreas.
Hypoparathyroidism
Seizures occur in 30% to 70% of patients with hypoparathyroidism, usually along with tetany and hypocalcemia. They may be generalized tonic-clonic, focal motor, or, less frequently, atypical absence and akinetic seizures. Restoration of normal calcium levels is necessary. Because AEDs may partially suppress seizures, as well as tetany and the Trousseau sign, hypocalcemia must be considered.
Thyroid Disorders
Hyperthyroidism is associated only rarely with seizures, although generalized and focal seizures have occurred in 10% of patients with thyrotoxicosis (32). Typically, thyrotoxicosis may be associated with nervousness, diaphoresis, heat intolerance, palpitations, tremor, and fatigue. Hashimoto thyroiditis often coexists with other autoimmune disorders (33), such as Hashimoto encephalopathy, a steroid-responsive relapsing condition (34) that produces seizures even in euthyroid patients (35).
Adrenal Disorders
Seizures are uncommon with adrenal insufficiency but may occur in patients with pheochromocytoma (38). More commonly, a pheochromocytoma-induced hypertensive crisis may trigger a hypertensive encephalopathy, characterized by altered mental status, focal neurologic signs and symptoms, and/or seizures. Other neurologic complications include stroke caused by cerebral infarction or an embolic event secondary to a mural thrombus from a dilated cardiomyopathy. Intracerebral hemorrhage may also occur because of uncontrolled hypertension. Additional symptoms are tremor, nausea, anxiety, sense of impending doom, epigastric pain, flank pain, constipation or diarrhea, and weight loss. These spells may last minutes to an hour. Blood pressure is almost always markedly elevated during the episode.
Uremia
A change in mental status is the hallmark of uremic encephalopathy, which also involves simultaneous neural depression (obtundation) and neural excitation (twitching, myoclonus, generalized seizures). Epileptic seizures occur in up to one-fourth of patients with uremia, and the reasons are quite varied.
Phenytoin is the AED usually administered to nontransplanted patients with uremia (see “Transplantation and Seizures”). Critical changes in the pharmacokinetics of AEDs include (a) increased volume of distribution, producing lowered plasma drug levels; (b) decreased protein binding, creating higher free-drug levels; and (c) increased hepatic enzyme oxygenation, yielding increased plasma elimination (2). Because patients with uremia have plasma protein-binding abnormalities and because phenytoin is highly plasma bound, drug administration is different from that in nonuremic patients. In one study, a 2-mg/kg IV dose produced a level of 1.4 μg/mL in patients with uremia, compared with 2.9 μg/mL in control patients (39). In nonuremic patients, up to 10% of phenytoin is not protein bound, whereas in uremic patients, as much as 75% may not be protein bound. Thus, free phenytoin levels (between 1 and 2 μg/mL) should be used instead of total phenytoin levels to assess therapeutic efficacy (40). With gabapentin, which is eliminated solely via renal excretion, the usual total dose should be reduced equivalently to the reduction in creatinine clearance (41).
The treatment of renal failure may also lead to dialysis dysequilibrium, characterized by headache, nausea, and
irritability, which may progress to seizures, coma, and death attributable to the entry of free water into the brain, with resultant edema. Dialysis dementia, caused by the toxic effects of aluminum, is now rare. Renal transplant recipients may experience cerebrovascular disease, opportunistic infections, or malignant neoplasms, particularly primary lymphoma of the brain.
irritability, which may progress to seizures, coma, and death attributable to the entry of free water into the brain, with resultant edema. Dialysis dementia, caused by the toxic effects of aluminum, is now rare. Renal transplant recipients may experience cerebrovascular disease, opportunistic infections, or malignant neoplasms, particularly primary lymphoma of the brain.
In uremic patients with renal insufficiency, adverse reactions to antibiotics are a common cause of seizures (42). Patients may have focal motor or generalized seizures, or myoclonus. In uremia, reduced protein binding increases the free fraction of highly protein-bound drugs in serum (and therefore in the CNS). Raised concentrations of neurotoxic agents, such as cephalosporins, may increase seizure susceptibility, which may be enhanced further by the altered blood-brain barrier.
The hemodialysis patient represents a special challenge because of decreased concentrations of dialyzable AEDs. Plasma protein binding determines how effectively a drug can be dialyzed. The more protein bound a drug, the less dialyzable it is (43). Hence, levels of a drug such as phenobarbital (40% to 60% protein bound) will decrease during dialysis more than will levels of valproic acid (80% to 95% bound). One way, albeit cumbersome, to avoid “losing” an agent is to dialyze against a dialysate containing the drug. Another option, if seizures occur near the time of dialysis, is to use a highly protein-bound drug, such as valproic acid. For special considerations in the kidney transplant patient, see “Transplantation and Seizures.”
Inborn Errors of Metabolism
Metabolic errors, either inborn or acquired, occur most often in early childhood. Phenylketonuria is the most common of several aminoacidopathies that may be associated with infantile spasms, and myoclonic or tonic-clonic seizures occur in one-fourth of these patients (44). Evidence of hypsarrhythmia may be seen on the electroencephalogram (EEG), but a high proportion of patients have abnormal EEGs without seizures.
Although hereditary fructose intolerance does not usually involve neurologic impairment, as does untreated phenylketonuria, a small number of children experience seizures that are sometimes related to prolonged hypoglycemia (45).
Because excess ammonia is excreted as urea, disorders of the urea cycle, such as hyperammonemia, may be associated with symptoms ranging from coma and seizures to mild, nonspecific aberrations in neurologic function (44).
Various storage diseases result from abnormal accumulation of normal substrates and their catabolic products within lysosomes. The absence or inefficiency of lysosomal enzymes in such conditions as sphingolipidoses, mucopolysaccharidoses, mucolipidoses, glycogen storage diseases, and glycoproteinoses may give rise to seizures (44).
Purine syndromes and hyperuricemia are not usually associated with seizure disorders unless mental retardation or dementia coexists. Allopurinol is an important adjunctive treatment in some patients.
Porphyria
The disorders of heme biosynthesis are classified into two groups: erythropoietic and hepatic. Seizures and other neurologic manifestations occur only in the hepatic group, which comprises acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria (46). Seizures affect approximately 15% of patients, usually during an acute attack (47) often precipitated by an iatrogenically introduced offending agent. The generalized (occasionally focal) seizures may begin up to 28 days after exposure to the agent. The epileptogenesis mechanism is not well understood. Some authors have suggested that δ-aminolevulinic acid and porphobilinogen, both structurally similar to the neurotransmitters glutamate and γ-aminobutyric acid (GABA), are toxic to the nervous system, although clinical evidence refutes this contention (46).
A cornerstone of treatment is the provision of a major portion of daily caloric requirements by carbohydrates to lower porphyrin excretion. Glucose prevents induction of hepatic δ-aminolevulinic acid synthetase in symptomatic patients, as does IV hematin. Porphyrogenic drugs, such as phenytoin, barbiturates, carbamazepine, succinimides, and oxazolidinediones, should be avoided. Drugs are considered unsafe if they induce experimental porphyria in animals. Using chick-embryo hepatocyte culture, Reynolds and Miska (47) found that carbamazepine, clonazepam, and valproate increased porphyrin to levels comparable with those achieved with phenobarbital and phenytoin. Bromides are recommended for the long-term management (48) and diazepam, paraldehyde, and IV magnesium sulfate therapy for the acute treatment of seizures (49). Serum bromide levels should be maintained between 60 and 90 μg/dL. Many side effects and a long half-life make bromides difficult to use. Bromides are excreted by the kidney, and paraldehyde is excreted unchanged by the lungs (the remainder by the liver). Larson and colleagues (50) reported on one patient with intractable epilepsy who was safely managed with low-dose clonazepam and a high-carbohydrate diet after phenytoin and carbamazepine use had independently precipitated attacks. In two separate studies, gabapentin controlled complex partial and secondarily generalized seizures in patients with porphyria (51,52). Because gabapentin is excreted unmetabolized by the kidneys, it does not induce hepatic microsomal enzymes (53) and should not worsen hepatic cellular dysfunction. Vigabatrin, which also does not induce hepatic metabolism, may be a useful antiseizure medication in patients with porphyria. Table 38.1 lists agents that are safe and unsafe to use in patients with porphyria (54).
TABLE 38.1 SAFE AND UNSAFE AGENTS IN PATIENTS WITH PORPHYRIA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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OXYGEN DEPRIVATION
Perinatal Anoxia and Hypoxia
In utero, during delivery, or in the neonatal period, significant anoxia can extensively damage the CNS, leading to chronic, usually secondarily generalized, epilepsy most commonly associated with mental retardation or other neurologic impairment. Neonatal seizures carry a risk for increased mortality, probably from the underlying brain disease rather than from the seizures themselves (55).
In the neonatal period, subtle, frequently refractory seizures may occur, as well as tonic, focal clonic, myoclonic seizures and multifocal clonic jerks. Not all paroxysmal events are seizures, however; some are brainstem release phenomena. Continuous video-electroencephalographic monitoring has made the diagnosis of these disorders more accurate and has led to improved treatment, including the avoidance of inappropriate AED use.
Because the initial insult usually occurs in utero, ventilation, cerebral perfusion, and adequate glucose levels must be maintained as preventive measures. Vigorous AED treatment is recommended because of the potential for additional brain injury, but opinions vary as to the degree of vigor to be applied. Arguments for aggressive therapy have been based on the realization that seizures may compromise ventilation and increase systemic blood pressure and cerebral perfusion, leading to hemorrhagic infarction, intraventricular hemorrhage, or both (56,57). Seizures may also result in cellular starvation through exhaustion of cerebral glucose and high-energy phosphate compounds. Experimental studies demonstrate that seizures decrease brain protein levels, DNA, RNA, and cell content. Treatment of anoxic seizures in the newborn is reviewed in Chapter 32.
As the infant matures, the seizure type changes. Infantile spasms and hypsarrhythmia may occur in patients 2 to 12 months of age.
Adult Anoxia and Hypoxia
In adults, anoxic or posthypoxic seizures are residuals of cardiac arrest, respiratory failure, anesthetic misadventure, carbon monoxide poisoning, or near-drowning. Precipitating cardiac sources typically are related to embolic stroke, 13% of which involve seizures (58) or hypoperfusion or hyperperfusion of the cerebral cortex (2). Approximately 0.5% of patients who have undergone coronary bypass surgery experience seizures without evidence of focal CNS injury (59). In patients with respiratory disorder, acute hypercapnia may lower seizure threshold, whereas chronic stable hypoxia and hypercapnia rarely cause seizures. Subacute bacterial endocarditis can lead to septic emboli and intracranial mycotic aneurysms, which can produce seizures either from focal ischemia or from rupture and subarachnoid hemorrhage. Syncopal myoclonus and convulsive syncope may result from transient hypoxia.
Seizures may involve only minimal facial or axial movement (60), although nonconvulsive status epilepticus typically signifies a poor prognosis (61,62). Myoclonic status epilepticus or generalized myoclonic seizures that occur repetitively for 30 minutes are usually refractory to medical treatment (63). Concern has been raised that myoclonic status epilepticus may produce progressive neurologic injury in comatose patients resuscitated from cardiac arrest (63). When postanoxic myoclonic status epilepticus is associated with cranial areflexia, eye opening at the onset of myoclonic jerks, and EEG patterns indicating poor prognosis, the outlook for neurologic recovery is grim (64).
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