Antiepileptic Drugs, 5th Edition

Succinimides

69

Adverse Effects

Tracy A. Glauser MD

Division of Neurology, Children's Hospital Medical Center, Cincinnati, Ohio

The first anticonvulsants to demonstrate efficacy against absence seizures, trimethadione and its analog paramethadione, were introduced in the 1940s but displayed significant toxicity (1, 2, 3, 4). These toxicity issues spurred the discovery and testing in the 1950s of the succinimide family of anticonvulsants (ethosuximide, methsuximide, and phensuximide), in the hope of finding more effective, safer, and better-tolerated anticonvulsants for patients with absence seizures (4,5). Among the succinimide family, ethosuximide has the greatest efficacy against absence seizures with the least toxicity and has been considered as possible first-line therapy for absence seizures since its introduction in 1958 (4,6,7). Methsuximide and phensuximide are used as later treatment options because they exhibit less favorable efficacy and side effects profiles compared with ethosuximide.

The adverse event profile of the succinimide class of anticonvulsants can be separated into four categories: (a) most commonly observed adverse effects; (b) less common, but clinically relevant adverse effects; (c) potentially life-threatening adverse effects; and (d) manifestations of overdose. As with most drugs (8,9), the most commonly observed adverse effects of drugs of the succinimide class are usually predictable, dose dependent, and host independent, and they resolve with dose reduction. The less common but clinically relevant adverse effects may result from multiple mechanisms, including (a) dose-dependent side effects, (b) effects of long-term therapy, effects of the cumulative dose, and (c) delayed effects (e.g., teratogenicity and carcinogenicity) that are host dependent but not necessarily dose dependent (8,9). The potentially life-threatening adverse events, frequently called idiosyncratic drug reactions, cannot be predicted based on the known pharmacologic effect of the drug. These side effects do not demonstrate a simple dose-response relationship, they are host dependent, and they can be serious and life-threatening (10). Preclinical animal toxicology testing may not detect these reactions, and often these reactions cannot be reproduced in animal models (8,9). Although rare, the symptoms of succinimide (especially methsuximide) overdose are important to recognize so appropriate therapy can be initiated as soon as possible.

MOST COMMONLY OBSERVED ADVERSE EFFECTS

Ethosuximide

During the first 8 years after ethosuximide's release, the results of 12 large clinical trials (each involving >50 patients) were published, detailing the spectrum of ethosuximide's adverse effects. Browne summarized these studies and found that the overall incidence of ethosuximiderelated adverse effects ranged from 26% to 46% (Table 69.1) (11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23). In half of these large trials, ≥37% of the subjects experienced adverse effects (11).

The most common ethosuximide concentration-dependent adverse effects involve the gastrointestinal system. These gastrointestinal symptoms include nausea (the most common), abdominal discomfort, anorexia, vomiting, and diarrhea (5,7,24, 25, 26, 27). Symptoms usually occur at the onset of therapy, they affect 20% to 33% of children, are they considered mild and resolve promptly to dose reduction (24, 25, 26, 27). In some patients, the adverse effect is transient, and no dose reduction is needed, whereas for other patients, dividing the total daily dosage and administering the smaller doses at mealtime is another technique to lessen the symptoms (6,11). Gastrointestinal symptoms are seldom severe enough to cause discontinuation of ethosuximide (11).

Central nervous system-related adverse events, such as drowsiness, are the second most common form of ethosuximide concentration-dependent adverse events (11). Similar to the gastrointestinal side effects, drowsiness usually occurs at the onset of therapy and resolves promptly when the ethosuximide dose is reduced (6,24,25,27).

Additional commonly observed central nervous system-related adverse events include dizziness, hiccups, lethargy, fatigue, ataxia, insomnia, and behavior changes (e.g., aggression, euphoria, irritability, hyperactivity) (7,27). Nervousness is reported in 12% of children (7,27). A direct

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relationship between ethosuximide therapy and reported behavioral changes is not certain because poor methodology (e.g., the lack of reliable methods for objectively measuring behavior changes, the confounding variable of polypharmacy, and the lack of serum antiepileptic drug concentrations) make analysis of existing reports difficult at best (24,25).

Approximately 14% of children taking ethosuximide develop headaches. In contrast to the other central nervous system side effects described earlier, these headaches do not appear to be concentration dependent, they may not respond to dose reduction, and they may be persistent (6,24,25,27,28).

Assessing ethosuximide's effects on cognition is difficult because few trials have examined the issue in a controlled fashion accounting for confounding variables such as plasma concentrations, underlying mental retardation, concomitant antiepileptic drug use, or seizure type. Memory, speech, and emotional disturbances were noted on psychometric testing in 25 children receiving ethosuximide for various seizure types in one early report (29). Confounding these results are multiple methodologic issues including the finding that all the patients were also taking barbiturates, 60% of the cohort had intelligence quotient (IQ) scores <83, no ethosuximide plasma concentrations were measured, and no matched control group was used (29). In contrast, ethosuximide therapy resulted in a significant improvement in verbal and full-scale IQ scores without change in motor performance or personality test scores in a cohort of children without epilepsy but with learning disorders and 14 and six per second positive spikes on the electroencephalogram (30). Similarly, psychometric performance improved significantly over 8 weeks of ethosuximide therapy in 17 of 37 (46%) children with absence seizures in a well-designed study by Browne et al. (31). This improvement was significantly different compared with a control group of patients tested in the same fashion over the same interval (31). Only 25% of the study group had IQ scores <83, and only 32% were taking other antiepileptic drugs (31).

Methsuximide

Although methsuximide's adverse effect profile is qualitatively similar to that of ethosuximide, overall its adverse effects occur with higher incidence, have greater severity, and persist long than ethosuximide's (6,7,11,32). Browne noted that drowsiness and gastrointestinal symptoms (e.g., nausea, vomiting, anorexia, constipation, diarrhea, and abdominal pain) were the most commonly reported side effects in eight large methsuximide clinical trials performed from 1957 to 1977 (Table 69.1) (11,33, 34, 35, 36, 37, 38, 39, 40).

In comparison with ethosuximide, methsuximide's adverse effects were less likely to resolve spontaneously without a dosage adjustment and were more likely to lead to the need to discontinue the medication (11,32). Multiple authors propose that some of the central nervous system symptoms (e.g., drowsiness, ataxia, irritability) observed during methsuximide therapy could be related to a pharmacokinetic interaction between methsuximide and other anticonvulsants such as phenobarbital and phenytoin, rather a direct effect of methsuximide (11,32,34,41).

Commonly noted methsuximide-associated central nervous system adverse effects include dizziness, ataxia, confusion, somnolence, lethargy, irritability, hiccups, personality change, fearfulness, irritability, photophobia, nervousness, and headaches. Methsuximide therapy has also been associated with vertigo, diplopia, blurred vision, increased seizures, inattention, dysarthria, incoordination, slurred speech, and adventitious movements (7,34,35,42, 43, 44, 45, 46). In one study, two patients experienced psychic changes, including “depression, withdrawal, weepiness and impulsive behavior” (43).

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Phensuximide

The most common adverse effects noted with phensuximide usage involve gastrointestinal symptoms (nausea and vomiting) and central nervous system symptoms (drowsiness and dizziness) (11). Other commonly noted phensuximide-associated central nervous system adverse effects include headaches and hiccups (45). The actual rate of these adverse effects is unknown; some authors propose the incidence to be at least the rate of other succinimides (11,47). High doses of phensuximide can produce a dreamlike state, unlike with other succinimides (11,47). Long-term phensuximide use has been reported to be associated with urinary frequency, burning, hematuria, proteinuria, hemorrhagic cystitis, and mild nephrotoxicity (45,47, 48, 49).

LESS COMMON, BUT CLINICALLY RELEVANT ADVERSE EFFECTS

Ethosuximide

Episodes of psychotic behavior (anxiety, depression, visual hallucinations, auditory hallucinations, and intermittent impairment of consciousness) have been noted in patients taking ethosuximide (12,14,24,50,51). Risk factors for this adverse effect include age (young adults in their teens or twenties) and a history of mental illness (6,11,24). Reported acute psychotic episodes appeared after ethosuximide-induced seizure control with associated electroencephalographic improvement; the episodes resolved when ethosuximide was stopped and the seizures returned, a finding illustrating the phenomenon of forced normalization (6,24). Psychotic symptoms have recurred when ethosuximide therapy is resumed in patients with previous ethosuximide-related psychotic episodes (24). This forced normalization reaction is not dose dependent and, among all antiabsence antiepileptic drugs, occurs with highest frequency with ethosuximide (6,52). This type of side effect seldom occurs in young children with no previous history of psychiatric disease who are receiving ethosuximide for typical absence seizures (11).

Most studies find no evidence of ethosuximide-associated seizure exacerbation (16,21,23,24,31,53). There are scattered reports of exacerbation of myoclonic and absence seizures and transformation of absence into grand mal seizures in patients receiving ethosuximide (24,54,55). Dreifuss considered that the appearance of grand mal seizures is simply a consequence of the high incidence of generalized tonic-clonic seizures in patients with absences seizures coupled with ethosuximide's lack of efficacy against generalized tonic-clonic seizures (24).

In early studies, the incidence of ethosuximide-related granulocytopenia ranged from 0% to 7% (11). Dreifuss considered this symptom to be probable dose-dependent granulocytopenia that often resolved with dose reduction without requiring termination of ethosuximide therapy (24,25). It is critical to distinguish between this probable dose-dependent adverse event and ethosuximide-associated idiosyncratic bone marrow depression (see later). Careful clinical and laboratory monitoring is essential in making this decision. Ethosuximide therapy is not reported to cause hepatotoxicity or serious endocrine adverse effects (11). Ethosuximide can precipitate an attack of acute intermittent porphyria (27,56).

Long-term cumulative dose ethosuximide side effects are infrequent. Extrapyramidal reactions (e.g., severe bradykinesia, akathisias, dyskinesias, and parkinsonian syndrome) have been reported after several years of ethosuximide treatment (15,57).

In mice, ethosuximide exhibits considerably less teratogenic effect than carbamazepine, phenytoin, phenobarbital, or primidone (58). However, in one report of 10 women with epilepsy who were taking ethosuximide, two of 13 newborns had major malformations (bilateral clefting, hare lip), and the cohort had a higher rate of minor abnormalities compared with a pair-matched control group of newborns of women without epilepsy (59). The mothers of these two seriously affected newborns were taking ethosuximide in combination with phenobarbital in one mother and primidone in the other mother (59). In another small series, one of five infants born to a mother taking ethosuximide was malformed (60). Little information is available about the overall risks maternal ethosuximide use poses to the fetus (24). Data are currently insufficient to assess the teratogenic effect of ethosuximide accurately in humans.

Methsuximide

Restless legs syndrome was described in two patients taking methsuximide and phenytoin (61). Methsuximide can precipitate an attack of acute intermittent porphyria (56,62). Periorbital edema, proteinuria, microscopic hematuria, and hyperemia have been seen (32). One article proposed that methsuximide therapy caused or aggravated irreversible cerebellar damage in two patients (63).

Phensuximide

Phensuximide can precipitate an attack of acute intermittent porphyria (56).

POTENTIALLY LIFE-THREATENING ADVERSE EFFECTS

Overview

Idiosyncratic drug reactions are unpredictable, at times dose-independent, host-dependent reactions that cannot be predicted based on the known pharmacologic effect of the drug, and they can be serious and life-threatening (8,9). In

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general, the skin is the most commonly affected site, followed by the formed elements of the blood and the liver and, to a lesser extent, the nervous system and kidneys (8,64). These reactions can be very organ specific, or they may present with generalized nonspecific symptoms, such as lymphadenopathy, arthralgias, eosinophilia, and fever (8,65). Idiosyncratic reactions are proposed to result from toxic metabolites that either directly or indirectly (by way of an immunologic response or free radical mediated process) cause injury (10).

Ethosuximide

Ethosuximide has been associated (to varying degrees) with many different idiosyncratic reactions (24,25,27,66), including allergic dermatitis, rash, erythema multiforme, Stevens-Johnson syndrome (67), systemic lupus erythematosus (68, 69, 70), a lupuslike syndrome (24,71, 72, 73), blood dyscrasias (aplastic anemia, agranulocytosis) (17,22,31,53, 74, 75, 76,77, 78, 79), dyskinesia (80,81), akathisia (80), autoimmune thyroiditis (82), and diminished renal allograft survival (83).

The mild cutaneous reactions, allergic dermatitis and rash, are the most common ethosuximide-associated idiosyncratic reaction. These reactions frequently resolve with withdrawal of ethosuximide, but some patients may require steroid therapy. Patients developing Stevens-Johnson syndrome, a potentially life-threatening condition, require more aggressive therapy in the hospital.

The symptoms of the lupuslike syndrome are described as “fever, malar rash, arthritis, lymphadenopathy, and, on occasion, pleural effusions, myocarditis, and pericarditis” (24). After ethosuximide discontinuation, patients with the lupuslike syndrome usually fully recover, but recovery may be prolonged (24).

The manifestations of ethosuximide-associated blood dyscrasias range from thrombocytopenia to pancytopenia and aplastic anemia (17,22,31,53,74, 75, 76, 77, 78). Between 1958 and 1994, only eight cases of ethosuximide-associated aplastic anemia were reported, with an onset 6 weeks to 8 months after ethosuximide was initiated (77). Six patients were receiving polypharmacy, and five were taking either phenytoin or ethotoin in combination with ethosuximide (77). Despite therapy, five of the eight patients died (17,22, 31,53,74,75, 76, 77, 78).

There is no evidence that laboratory monitoring of blood counts during ethosuximide therapy anticipates ethosuximide's idiosyncratic hematologic reactions. Patients need to be educated to watch for fever, sore throat, and cutaneous or other hemorrhages and to alert their physician immediately if these symptoms occur (24). However, one recommendation for blood monitoring has been “that periodic blood counts be performed at no greater than monthly intervals for the duration of treatment with ethosuximide and that the dosage be reduced or the drug discontinued should the total white-blood-cell count fall below 3,500 or the proportion of granulocytes below 25% of the total white-blood-cell count” (24).

Methsuximide

Similar to ethosuximide, methsuximide therapy has been associated with various idiosyncratic reactions including rashes and hypersensitivity reactions (11). Some reports describe patients who experienced cross-sensitivity between phenytoin and methsuximide; these patients had a history of a hypersensitivity reaction to phenytoin and then developed a hypersensitivity reaction to methsuximide (84,85). Other idiosyncratic reactions have included isolated cases of Stevens-Johnson syndrome, two cases of transient nonfatal leukopenia, a single case of fatal pancytopenia, a single case of fatal aplastic anemia, and one patient with reversible osteomalacia (11,45,86). Methsuximide therapy is not associated with hepatotoxicity (11).

Phensuximide

Phensuximide is associated with a higher rate of idiosyncratic reactions than other succinimides (11). These reactions include fever, rash, erythema multiforme, leukopenia, and renal damage manifested by proteinuria, microscopic hematuria, and granular casts (11,47). There is one report of megaloblastic anemia in a patient taking phensuximide and phenobarbital (87).

MANIFESTATIONS AND MANAGEMENT OF OVERDOSE

Manifestations of Overdose

The manifestations of acute ethosuximide overdose include nausea, vomiting, and symptoms of central nervous system depression including stupor and coma leading to respiratory depression. At least five cases of methsuximide overdose have been reported; four patients survived without sequelae, and one died after an overdose of methsuximide and primidone (88, 89, 90, 91, 92). The major symptoms associated with methsuximide overdose are stupor and coma, although respiratory depression, central neurogenic hyperventilation, increased or decreased reflexes, coffee ground emesis, second-degree heart block, and myoclonus have also been reported (32,93).

Development of stupor and coma after methsuximide overdose may occur in a monophasic or biphasic fashion. The biphasic course can present with initial ataxia, dizziness, loss of consciousness, or stupor, followed by a period of improved alertness or arousal, then followed by a lapse into a coma within 24 hours (90,92,93). Three proposed explanations for the biphasic course include (a) methsuximide's conversion into the N-desmethylmethsuximide (normethsuximide) metabolite with subsequent accumulation,

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(b) methsuximide's interference with the metabolism of other antiepileptic medications (32), and (c) delayed absorption (45). There have not been any published reports of phensuximide overdose (45).

Management of Overdose

The management of a succinimide overdose involves life-support measures, symptomatic treatment, procedures to decrease drug absorption, and procedures to enhance drug elimination. Life-support measures involve initial and immediate evaluation and stabilization of the patient's airway, breathing, and circulation. Symptomatic treatment involves the subsequent care for each of the patient's overdose symptoms as they occur. No specific antidote exists for a succinimide overdose.

Three potentially useful methods to decrease drug absorption after any overdose include the following: induction of emesis, use of activated charcoal, and use of gastric lavage. Because succinimide overdose can rapidly lead to significant alteration of consciousness, induction of emesis is not recommended (93). In conscious patients who are able to protect their airway, administration of activated charcoal as an aqueous slurry may reduce absorption; effectiveness is greatest if it is given within 1 hour of succinimide overdose (93). If emesis or rapid deterioration of consciousness occurs or is impending, only personnel skilled in airway management should administer activated charcoal to minimize the potential for aspiration. Contraindications for the use of activated charcoal include a patient with an unprotected airway or a situation in which the therapy increases the risk or severity of aspiration (94). The recommended dose of activated charcoal is 1 g/kg of weight for infants ≤1 year old, 25 to 50 g in children between 1 and 12 years old, and 25 to 100 g in adults. The optimal dose has not been established (94).

Gastric lavage with a large-bore orogastric tube may be considered if a potentially life-threatening amount of succinimide has been ingested and the procedure can be performed within 1 hour of the ingestion (95). Because of the risk of significant morbidity associated with the procedure, gastric lavage should not be employed routinely in the management of patients after an overdose of succinimides (95).

Four potentially useful methods to decrease absorption after a drug overdose include hemodialysis, hemoperfusion, exchange transfusion, and forced diuresis. Hemodialysis may be useful in the treatment of ethosuximide overdose, based on an observed extraction efficiency of 61% to 100% in one study of four patients with chronic renal disease who were supported by hemodialysis and who received a single dose of 500 mg of ethosuximide 4 hours before dialysis. In this study, the elimination half-life of ethosuximide was reduced by dialysis to an average of 3.5 hours (96).

Hemoperfusion with a cellulose-activated charcoal hemoperfusion column led to rapid improvement in one patient after a methsuximide overdose through rapid clearance of methsuximide's primary metabolite, N-desmethylmethsuximide (88). Both exchange transfusion and forced diuresis have little use in the treatment of succinimide overdose because succinimides have low protein binding, and little of the parent succinimide compound is excreted unchanged in the urine.

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