Antiepileptic Drugs, 5th Edition

Phenytoin and Other Hydantoins

63

Adverse Effects

Joseph Bruni MD, FRCP(C)

Associate Professor, Department of Medicine, University of Toronto; and Consultant Neurologist, Department of Medicine, St. Michael's Hospital, Toronto, Ontario, Canada

PHENYTOIN

Toxicity

The toxicity of antiepileptic drugs can be a limiting factor in the long-term management of the patient with epilepsy. The physician should be aware of the potential acute, idiosyncratic, chronic, and teratogenic side effects of these agents.

Central nervous system (CNS) toxicity is usually dose related; however, significant toxicity and adverse effects may involve other systems: hematopoietic, gastrointestinal, immune, endocrine, skeletal, and skin. The intravenous administration of phenytoin may also precipitate cardiac arrhythmias.

Since its introduction in 1938, phenytoin has remained one of the most widely used antiepileptic drugs, and because of its widespread use, a large literature on the adverse effects of phenytoin has accumulated. This summary is based on reviews in previous editions of this book (1, 2, 3) as well as on several other reviews (4, 5, 6, 7, 8).

Acute Toxicity

Acute toxicity from antiepileptic drugs is usually the result of overdosage and is less often secondary to an allergic or idiosyncratic reaction. The CNS signs of acute toxicity can usually be predicted on the basis of drug dose-weight or drug dose-plasma concentration relationships. This toxicity occurs as a result of direct drug action on receptor sites as therapeutic concentrations are exceeded. The cerebellovestibular, pyramidal, and higher integrative functions may be involved separately or in various combinations with phenytoin therapy. Initially, cerebellovestibular dysfunction (nystagmus, ataxia, incoordination, dysarthria, and hand tremor) may be observed. As toxicity increases, higher cortical functions (judgment, concentration, behavior, speech, and mood) are altered. With more severe toxicity, pyramidal and extrapyramidal signs of dystonic posturing, asterixis, athetoid and choreiform movements, and (rarely) myoclonic jerks develop. Epileptic seizures may be exacerbated. With prolonged toxicity, autonomic dysfunction and altered level of consciousness may occur. Phenytoin intoxication is not always easy to recognize clinically, and antiepileptic drug plasma level monitoring can be invaluable in detecting subtle toxicity.

Cerebellar Syndrome

Cerebellovestibular dysfunction with nystagmus and ataxia is well recognized as a manifestation of acute phenytoin toxicity, and it is usually dose related (9). Often, one sees a stepwise effect of nystagmus, ataxia, and mental changes, but this is not universally so. Some patients may demonstrate only one of the symptoms or signs. Neurologically handicapped patients and patients receiving polytherapy generally experience adverse effects at lower plasma concentrations, and a wide interindividual difference exists regarding what plasma concentrations will be associated with toxicity.

Prolonged treatment with phenytoin, especially at high doses, may lead to irreversible cerebellar deficits, and the distinction between reversible cerebellar syndrome and chronic ataxia may be difficult to make on clinical grounds (10). Cerebellar degeneration has been attributed to large doses of phenytoin or prolonged phenytoin therapy (9,11,12). Dam (13) noted Purkinje cell degeneration and astrocytic changes in patients receiving long-term phenytoin therapy. The relative contribution of phenytoin toxicity and repeated episodes of seizures is not uniformly agreed on, however, although phenytoin-related cerebellar degeneration has been reported in nonepileptic patients (14) and after acute intoxication (15). Considering the number of patients treated with prolonged phenytoin therapy, clinically significant permanent cerebellar deficits are uncommon. The long-term effects of high phenytoin levels in patients who do not demonstrate clinical signs of toxicity are unknown.

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Extrapyramidal and Pyramidal Signs

Anticonvulsant-induced dyskinesia, chorea, ballismus, and dystonia are clinically similar to those conditions induced by neuroleptic drugs (16). The dyskinetic movements may involve the extremities, trunk, and face and generally occur early in the course of therapy. The dyskinesias are more frequently observed with high phenytoin concentrations, but some patients may demonstrate similar adventitious movements with concentrations that generally are within the usually accepted therapeutic range. With reduction in the phenytoin dosage, these symptoms often improve.

Spasticity and transient hemiparesis have been observed with high phenytoin concentrations (17,18). Choreoathetosis is an uncommonly observed movement disorder (19). Anterior horn cell dysfunction resulting in muscle fasciculations was observed in one patient (20). Occasionally, a parkinsonian syndrome or aggravation of Parkinson's disease can occur. These are isolated case reports, and their relationship with antiepileptic drug therapy is not definitely established. Considering the large number of patients treated with phenytoin, these are extremely rare occurrences.

Acute Encephalopathy

It is well recognized that phenytoin can cause encephalopathy that can exacerbate seizures (21,22). This usually occurs in association with a high phenytoin concentration and may lead to stupor and coma. Dyskinetic movements may be observed concurrently, and ophthalmoplegia may be observed (23).

A syndrome of chronic phenytoin encephalopathy characterized by the insidious deterioration of intellect and behavior with or without seizure exacerbation, mild cerebrospinal fluid pleocytosis, and moderate increase in protein has also been observed. This encephalopathy is more common in children, and preexisting brain damage may be a risk factor (24).

Allergic and Idiosyncratic Reactions

Phenytoin hypersensitivity reactions are well documented. Idiosyncratic drug reactions are rare but are potentially serious. Idiosyncratic reactions generally occur early in the course of therapy and represent genetically determined abnormal responses to drugs. Skin rashes, mostly morbilliform, represent the most frequently observed reactions. Less frequently, exfoliative dermatitis with systemic symptoms or toxic epidermal necrolysis (Lyell's syndrome) may be observed. These conditions are potentially lethal. Cutaneous vasculitis, a lupuslike syndrome, lichenoid eruptions, and purpuric rashes are less frequently observed manifestations (25). Less common reactions include pancytopenia, thrombocytopenia, erythema multiforme, pseudolymphoma, interstitial nephritis, myositis, polyarteritis nodosa, disseminated intravascular coagulation, and red cell aplasia (2,7,26,27). With intravenous phenytoin, extravasation of the drug into interstitial tissues can cause limb ischemia and skin necrosis. Rarely, hepatic necrosis, with a 25% mortality rate, can occur (28). Mild elevation of hepatic enzymes may be seen in 10% to 15% of patients.

Lymphadenopathy may be associated with systemic symptoms such as fever, rash, arthralgias, and hepatosplenomegaly. Most frequently, this is a benign condition and is reversible with discontinuation of phenytoin therapy, but it may be confused with Hodgkin's lymphoma. This syndrome may be secondary to decreased immunologic surveillance, and depressed cellular and humoral immunity may be found in phenytoin-treated patients. Immunoglobulin A (IgA) production is reduced, and IgG and IgM production may be altered (29).

Chronic Toxicity

Chronic toxicity of phenytoin may involve the following systems or may cause certain deficiency states: neurologic toxicity, connective tissue and dermatologic effects, endocrine disturbances and metabolic effects, hematologic effects and deficiency states, and immunologic effects.

Neurologic Toxicity

Peripheral Neuropathy.

Although electrophysiologic abnormalities are common in patients maintained on longterm phenytoin therapy, clinically significant neuropathy is rare. In one report, lower limb areflexia was observed in 15% of patients after ≥5 years of treatment (30). In >50% of those tested, nerve conduction velocities were slow. Transient dysfunction associated with acute toxicity and high phenytoin levels may also occur.

Although phenytoin has been implicated in the neuropathy after long-term therapy, many patients reported that they were concurrently receiving other antiepileptic drugs. Folate deficiency and vitamin B12 deficiency are not significant factors. Whether phenytoin monotherapy results in neuropathy after prolonged use is uncertain. One study (31) failed to show evidence of neuropathy in patients treated with phenytoin for <5 years.

Disturbances of Higher Cortical Functions.

Cognitive and behavioral side effects of antiepileptic drugs have received wide attention (24,32, 33, 34, 35). The barbiturate drugs have the greatest importance. However, other antiepileptic drugs such as phenytoin may impair motor speed, concentration, and memory. These disturbances appear to be dose related (33,36). Meador et al. (34) assessed the neuropsychological effects of phenytoin and carbamazepine in 21 healthy adults with various cognitive measures and found that the differences in cognitive effects of carbamazepine and phenytoin were not clinically significant. Both drugs, however, impaired subjects on certain tests as compared with non-drug-related conditions. Dodrill and Troupin (33) also found no significant differences between phenytoin

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and carbamazepine when adjustments were made for serum plasma levels. Most studies support the absence of a clinically significant effect in most patients, although subtle defects may be identified on formal neuropsychological evaluations.

Connective Tissue Effects

Thickening of subcutaneous tissue, enlargement of lips and nose, coarsening of facial features, and subcutaneous fibrous deposits are often recognized in epileptic patients who receive long-term phenytoin therapy. The term hydantoin facies has been used to describe these features, which are common in institutionalized patients (37). These changes may be related to long-term therapy with multiple drugs and high phenytoin levels. Dermatologic changes of hirsutism, acne, and hyperpigmentation may also contribute to the characteristic facies.

There appears to be an association between Dupuytren's contracture and antiepileptic drug therapy, most frequently phenobarbital. Phenytoin may increase the risk of this condition by its influence on collagen synthesis and fibroblast proliferation (38).

Gingival hyperplasia may occur in ≤50% of patients receiving phenytoin therapy. This disorder is more frequently observed in children and in institutionalized patients. Poor oral hygiene (39) and a deficiency in saliva IgA may play a role (40). Genetic factors and high phenytoin concentrations may also be contributory. Gingival hyperplasia usually becomes apparent in the first few months of therapy. Alveolar bone loss is not increased (1). Pulmonary fibrosis secondary to phenytoin-induced pulmonary toxicity rarely has been described, and investigators have suggested that it may represent an immune-complex injury (41).

Endocrine Disturbances and Metabolic Effects

At least four endocrine systems and processes are targets for antiepileptic drug effects: bone metabolism, thyroid gland, pancreatic β cells, and the pituitary-adrenal-gonadal axis. Such effects are found by laboratory tests, but occasionally they result in clinical changes.

Metabolic Bone Disease.

Although biochemical abnormalities such as elevated alkaline phosphatase, reduced serum calcium, and decreased serum 2-hydroxycholecalciferol are seen in many patients, clinically significant metabolic bone disease with osteomalacia and rickets is uncommon. It is more prominent in institutionalized patients and in patients receiving multiple drug therapy. Dietary factors and the amount of sunlight exposure may be contributory factors. In a bone biopsy study (42), osteomalacia was found in 53% of patients along with evidence of increased bone resorption (secondary hyperparathyroidism). In another bone biopsy study (43), bone mineral mass was decreased in 44%, but no clinical evidence of metabolic bone disease was found in any of the patients.

Metabolic bone disease may be secondary to decreased intestinal absorption of calcium, altered hepatic vitamin D hydroxylation, and inhibition of parathyroid hormoneinduced release of calcium from bone. Metabolic bone disease may lead to fractures, postural changes, and muscle weakness, including a specific myopathy. In populations at risk, long-term treatment with vitamin D should be considered in patients with elevated serum alkaline phosphatase and decreases in serum 25-hydroxycholecalciferol or bone mineral mass.

Thyroid Function.

The decline of serum protein iodine sometimes induced by phenytoin is related to changes in protein binding of the thyroid hormones and increased clearance (44). Uptake of triiodothyronine and radioactive iodine by red blood cells is not altered, and most patients are clinically euthyroid. Triiodothyronine and thyroid-stimulating hormone levels are usually normal. The symptoms of phenytoin toxicity may mimic those of hypothyroidism.

Pancreatic β Cells.

Most patients receiving long-term phenytoin therapy have normal carbohydrate metabolism, but insulin secretion may be impaired in some patients, especially those with prediabetes or diabetes. This effect may be manifested by an abnormal glucose tolerance test, and acute phenytoin intoxication may be associated with high blood glucose levels. Experimentally, phenytoin can cause hyperglycemia (45).

Pituitary-Adrenal-Gonadal Axis.

Phenytoin can influence the pituitary-adrenal-gonadal axis. Short-term administration of large doses may initially increase circulating adrenocorticotropic hormone and cortisol levels. Longterm administration may lead to a shift in steroid metabolism, with an increase in urinary exertion of 6-hydroxycortisol. Phenytoin administration can result in erroneous results on metyrapone and 2-mg dexamethasone suppression tests (46). Phenytoin may also depress the release of antidiuretic hormone.

Testosterone and estradiol metabolism may also be enhanced by phenytoin. Long-term therapy may be associated with elevated plasma concentrations of sex hormone-binding globulin in male and female patients (47). The effect on sexual function of increased testosterone binding to the excess globulin and lower free testosterone levels is uncertain. In male rats, phenytoin treatment for 2 months did not affect fertility (48).

In men with epilepsy, a higher incidence of hyposexuality and sperm abnormalities has been observed (49,50). This may be as a result of altered pituitary hormones, or it may be a direct result of an effect on the testes. In epileptic patients, phenytoin has been reported to stimulate secretion of luteinizing hormone, follicle-stimulating hormone, and prolactin.

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Hematologic Effects and Deficiency States

The effects of phenytoin on the hematopoietic system can be classified under neonatal coagulation defects, bone marrow suppression, and folate deficiency.

Neonatal Coagulation Defects.

Neonatal coagulation defects have been associated with both phenytoin and phenobarbital (51). Although coagulation disturbances are common, clinical hemorrhage that may become apparent in the first 24 hours is uncommon. Bleeding is caused by a deficiency of vitamin K-dependent clotting factors (II, VII, IX, X). Vitamin K administered to the mother before delivery and to the infant at delivery will prevent this coagulopathy.

Bone Marrow Suppression.

Agranulocytosis, pancytopenia, neutropenia, leukopenia, thrombocytopenia, and aplastic anemia occur very rarely with phenytoin use (52). Selective red cell aplasia has been reported with phenytoin, and this may be secondary to inhibition of the incorporation of uridine into normoblasts (53). Mild leukopenia is commonly observed in patients treated with standard antiepileptic drugs. This generally does not require discontinuation of therapy.

Megaloblastic Anemia and Folate Deficiency.

Folate deficiency is common in patients with epilepsy who receive long-term treatment. The incidence varies from 27% to 41% (7). The clinical significance is uncertain, except in the case of the megaloblastic anemia induced by phenytoin, which is unassociated with vitamin B12 deficiency. This anemia always responds to folate therapy. Folic acid deficiency can be confirmed by low red cell and serum folate levels.

Although megaloblastic anemia is rare, mild macrocytosis can be observed in ≤50% of patients. Other indicators of folate deficiency include decreased folate concentrations in cerebrospinal fluid, marrow megaloblastosis, decreased serum lactic dehydrogenase, and hypersegmentation of peripheral neutrophils. Theoretically, widespread CNS damage, such as Purkinje cell loss, chronic encephalopathy and other neuropsychiatric symptoms, and peripheral neuropathy, could result from severe folic acid deficiency. Such changes, however, have not been commonly reported.

The mechanism by which phenytoin produces folate deficiency is not clear, although several mechanisms are possible. Folate absorption (54,55), folate coenzyme metabolism, and tissue use of folate (53) may be altered. Investigators have suggested a possible relationship between the antifolate effects of antiepileptic drugs and seizure control, although the major mechanisms of action of the standard drugs are not related to folate.

Immunologic Effects

Some phenytoin-treated patients have depressed cellular and humoral immunity (56). The reduced production of IgA in some patients has been confirmed (29,57,58). It has been suggested that IgA deficiency is more likely to develop in phenytoin-treated patients possessing the HLA-A2 histocompatibility antigen (59). Antinuclear antibodies and lymphocytotoxins of the IgM class have been found in epileptic patients receiving phenytoin (60). These findings may have importance in the genesis of an altered immune state in epileptic patients receiving phenytoin.

Teratogenicity

The incidence of congenital anomalies and major malformations in children born of epileptic mothers is about three times that in children of nonepileptic mothers. The role of antiepileptic drugs, nutritional factors, and genetic factors has to be considered. Most epileptic patients receive multiple drug therapy, and interpretation of potential individual drug teratogenesis is difficult. A higher incidence of anomalies has been found in infants born to mothers receiving multiple drugs than in those born to mothers receiving monotherapy. Teratogenesis in pregnancy has been reviewed (61, 62, 63, 64, 65).

Malformation and abnormalities described with an increase incidence include cleft lip and palate, cardiac defects, skeletal and CNS defects, hypospadias, intestinal atresia, and hypoplastic phalanges and nails. A fetal hydantoin syndrome was described by Hanson and Smith (66), but whether a true anticonvulsant drug syndrome exists has been questioned. This syndrome has been reported to be associated with cranial anomalies, limb anomalies, and growth and mental deficiency; however, the significance of the dysmorphic features remains unclear. In a prospective study of 121 children, none had the fetal hydantoin syndrome, and the only dysmorphic features attributable to hydantoin exposure were hypertelorism and digital hypoplasia (67). Several studies on the incidence and types of major and minor anomalies have been reported (68, 69, 70).

The pharmacologic mechanisms of teratogenesis are poorly understood, and the precise molecular mechanisms are unknown. Folate deficiency, altered oxidative metabolism, and chromosomal abnormalities may be contributing factors (71, 72, 73). Certain drug combinations may carry a greater risk because of changes in enzymatic metabolism with inhibition or induction of enzymes (74). Consensus guidelines for the management of the pregnant woman with epilepsy have been developed (75, 76, 77).

Summary

Many decades of clinical use of phenytoin have allowed extensive experience with adverse effects. Acute and excessive dose effects are most frequent, and they are characterized by cerebellovestibular signs and symptoms. With increasing dose, cognitive and sedative effects are observed. Acute idiosyncratic systemic toxicity is characterized by a rash, which occasionally may be quite serious and may involve many organs.

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Chronic neurologic effects include gingival hyperplasia, hirsutism, and coarsening of the facies. Other systemic dysfunction is uncommon. Neuropathy and cerebellar degeneration may occur with long-term use. Despite the extensive number of adverse effects reported, most patients receiving the drug have little or no toxicity.

ETHOTOIN

Ethotoin is a drug approved by the United States Food and Drug Administration for the treatment of complex partial and tonic-clonic seizures, although it is uncommonly used. Adverse effects include allergic skin reactions, gastrointestinal side effects, sedation, and lymphadenopathy. These adverse effects are uncommon (78). With toxic doses, a cerebellar ataxic syndrome can occur. Hallucinations, memory impairment, and aggression have also been described. Gingival hyperplasia has not been observed (78). Congenital malformations have been reported (79,80).

MEPHENYTOIN

Mephenytoin is uncommonly used in the treatment of partial and tonic-clinic seizures because of its greater incidence of serious toxicity. Gingival hyperplasia, hirsutism, gastrointestinal side effects, and ataxia are less common than with phenytoin. Drowsiness, serious allergic reactions, hepatitis, and hematologic toxicity are more common than with phenytoin (81). Patients with deficiency in the hydroxylation of (S)-mephenytoin may be predisposed to greater toxicity because of drug accumulation. Approximately 4% of white persons and 20% of Japanese persons are poor hydroxylators and are particularly prone to mephenytoin toxicity (82).

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