Antiepileptic Drugs, 5th Edition

Valproic Acid

89

Adverse Effects

Pierre Genton MD^*

Philippe Gelisse MD^**

* Neurologist, Center of Saint Paul, Merseilles, France

** Chief of Clinic, Laboratory of Experimental Medicine, Institute of Biology; and Chief of Clinic, Epilepsy Unit, Gui de Chauliac Hospital, Montpellier, France

Valproate (VPA), which was first marketed in France over 30 years ago, and in North America over 20 years ago, has become one of the leading drugs for the treatment of various forms of epilepsy. It was recently approved in other indications, including mood disorders and migraine. Patient-years of treatment are numbered in millions and are steadily increasing; VPA now is probably the antiepileptic drug (AED) with the best-investigated array of adverse effects (AEs), some frequent, sometimes predictable and mostly benign, others rare and potentially severe. AEs of VPA have been extensively collected, studied, and reported; over 2,000 peer-reviewed papers have been published on this topic, with a new interest triggered by the new indications, especially in psychiatry. There remains much controversy over the prevalence, severity, and clinical significance of most of these AEs, as well as over their mechanisms. This reflects in part unresolved questions pertaining to the multiple mechanisms of action of VPA, and to its complex metabolic pathways. A specific, genetically determined sensitivity may play a major part in the occurrence of many of these AEs.

The successful career of VPA has been punctuated by three major “scares.” The first concern was raised in the 1970s after observations of acute liver toxicity. The second serious concern was raised in the early 1980s and focused on the occurrence of major malformations (e.g., spina bifida) in children born to mothers treated with VPA. A third problem came to the foreground in the 1990s with regard to the risk of reproductive disorders [specifically, of polycystic ovary syndrome (PCOS)] in girls and young women treated with VPA. At the onset of the 21st century; these concerns can be put into perspective, but need to be discussed in detail.

Using a clinician's perspective, we review the acute and chronic dose-related AEs, the allergic and idiosyncratic AEs, the risks involved in reproduction and pregnancy, and some special situations, including the coprescription of VPA with some of the newer AEDs. The AEs of VPA are considered globally here, but the availability of several presentations of VPA, including chemical variants (valproic acid, valproate salts, divalproex sodium, valpromide) and a solution for intravenous (i.v.) use, also may raise some specific questions. The issue of paradoxical aggravation of epilepsy by AEDs also is worth considering. This review thus adds a significant amount of recent data to the extensive review written by F. Dreifuss in the previous edition of this volume (52).

GLOBAL TOLERABILITY PROFILE

Clinical trials easily detect the common, dose-related AEs that are seen most often during the early days or weeks of treatment, especially during uptitration The most recent studies were performed in patients treated for psychiatric disorders or for migraine; very few recent studies have evaluated valproate in the context of epilepsy, either in comparison with placebo or with other AEDs.

Divalproex sodium has been used as adjunctive therapy for complex partial seizures in patients who were not adequately controlled with either carbamazepine (CBZ) or phenytoin monotherapy (Abbott Laboratories, data on file). The adverse events occurring significantly more often with divalproate versus placebo (>5% of patients) were nausea, asthenia, somnolence, vomiting, tremor, abdominal pain, and anorexia (Table 89.1). Table 89.2 reports the most common AEs in a trial comparing high-dose (mean valproic acid level = 123 µg/mL) versus low-dose (mean valproic acid level = 71 µg/mL) divalproex sodium monotherapy in patients with refractory complex partial seizures (16). The main AEs related to high-dose therapy were asthenia, nausea, diarrhea, vomiting, tremor, somnolence, alopecia, and thrombocytopenia. Headache was the only adverse event that occurred with a higher incidence in the low-dose group. The probability of thrombocytopenia increased significantly at total trough valproic acid plasma concentrations >110 µg/mL in women and >135 µg/mL in men. In this trial, 27% of patients receiving approximately 50 mg/kg/day on average had at least one platelet count value ≤75 × 10⁹/L. Approximately half of these patients discontinued treatment, with return of platelet counts to normal. In the remaining patients, platelet counts normalized with continued treatment (Abbott Laboratories, data on file).Table 89.3 compares the global incidence of AEs and of withdrawal from study in head-to-head comparisons between VPA and other AEDs.

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TABLE 89.1. ADVERSE EVENTS REPORTED BY ≥5% OF PATIENTS TREATED WITH DIVALPROEX SODIUM DURING PLACEBO-CONTROLLED TRIAL OF ADJUNCTIVE THERAPY FOR COMPLEX PARTIAL SEIZURESa

Body System/Event Divalproex Sodium (n = 77) Placebo (n = 70) Body as a whole Headache 31% 21% Asthenia 27% 7% Fever 6% 4% Gastrointestinal system Nausea 48% 14% Vomiting 27% 7% Abdominal pain 23% 6% Diarrhea 13% 6% Anorexia 12% 0 Dyspepsia 8% 4% Constipation 5% 1% Nervous system Somnolence 27% 11% Tremor 25% 6% Dizziness 25% 13% Diplopia 16% 9% Amblyopia/blurred vision 12% 9% Ataxia 8% 1% Nystagmus 8% 1% Emotional lability 6% 4% Mental slowing 6% 0 Amnesia 5% 1% Respiratory system Flu syndrome 12% 9% Infection 12% 6% Bronchitis 5% 1% Rhinitis 5% 4% Other Alopecia 6% 1% Weight loss 6% 0 aThe dosage of divalproex sodium was increased gradually over 8 weeks. At the maintenance period, the mean daily dose and serum valproic acid concentration were respectively, 31.4 mg/kg/day and 59.1 µg/mL. Data from Abbott Laboratories.

TABLE 89.2. ADVERSE EVENTS DURING DIVALPROEX SODIUM MONOTHERAPY IN PARTIAL EPILEPSIES, IN A TRIAL COMPARING HIGH- AND LOW-DOSE GROUPS

Divalproex Sodium, High-dose, 80-150 µg/mL (n = 96) Divalproex Sodium, Low-dose, 25-50 µg/mL (n = 47) Tremor 61% 6% Thrombocytopenia 31% 0% Alopecia 28% 4% Diarrhea 21% 4% Asthenia 17% 0% Vomiting 17% 0% Headache 16% 32% Weight gain 15% 4% Anorexia 15% 0% Exit rate from adverse events 32% 2% Adapted from Beydoun A, Sackellares JC, Shu V, and the Depakote Monotherapy for Partial Seizures Study Group. Safety and efficacy of divalproex sodium monotherapy in partial epilepsy: a doubleblind, concentration-response designed clinical test. Neurology 1997;48:182-188, with permission.

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TABLE 89.3. INCIDENCE OF SIDE EFFECTS AND RATE OF WITHDRAWAL RESULTING FROM SIDE EFFECTS IN RANDOMIZED CONTROLLED TRIALS COMPARING MONOTHERAPY IN ADULTS WITH NEWLY DIAGNOSED EPILEPSY

Reference Duration (mo) Valproate Carbamazepine Phenytoin Richens et al., 1994 (141) 36 Number of patients n = 149 n = 151 Average dose 924 mg/day 516 mg/day Withdrawal rate 5% (first 6 mo) 15% (first 6 mo) 5% (between 6 and 36 mo) 5% (between 6 and 36 mo) Incidence of side effects 49.4% (at 36 mo) 48.9% (at 36 mo) Heller et al., 1995 (77) 30 Number of patients n = 61 n = 61 n = 63 Average dose NS NS NS Withdrawal rate 5% 11% 3% Incidence of side effects NS NS NS Callaghan et al., 1985 (28) 14-18a Number of patients n = 64 n = 59 n = 58 Average dose 15.6 mg/kg/day 10.9 mg/kg/day 5.4 mg/kg/day Withdrawal rateb 14% 14% 9% Incidence of side effects 10.9% 8.5% 10.3% Turnbull et al., 1985 (164) 24 Number of patients n = 70 n = 70 Average dose NS NS Withdrawal rate 23% 23% Incidence of side effects NS NS NS, not stated in published trial data. a Median follow-up for patients with partial and generalized seizures was 14 and 15 months, respectively, for carbamazepine, 18 and 24 months, respectively, for phenytoin, and 24 and 24 months, respectively, for valproate. b Withdrawal resulting from all causes. Adapted from Heaney DC, Shorvon SD, Sander JW. An economic appraisal of carbamazepine, lamotrigine, phenytoin and valproate as initial treatment in adults with newly diagnosed epilepsy. Epilepsia 1998;39[Suppl 3]:S19-S25, with permission.

From these data, a global tolerability profile of VPA as it is used in clinical practice becomes apparent. These findings, however, must be discussed in detail.

DOSE-RELATED ADVERSE EFFECTS

Overdosage

Toxic doses are greater than 3 g in adults and 50 mg/kg in children. The main risks of overdosage are calm hypotonic coma, convulsions, and respiratory depression at very high doses (17). Doses less than 100 mg/kg are associated with minor toxicity. Profound coma usually occurs only at doses greater than 200 mg/kg; otherwise, the presence ofcoingestants should be suspected. Overdosage with VPA may result in gastrointestinal disturbances, drowsiness, mental confusion, and encephalopathy. At high doses, heart block, hypotension, hypophosphatemia, deep coma, cerebral edema, muscular hypotonia, hyporeflexia, myosis, respiratory depression, convulsions, and metabolic disorders (metabolic acidosis, hypernatremia, hypoglycemia, hyperammonemia) can arise. Reversible methemoglobinemia also has been reported (113). Fatalities have been described (15,35,94) but are rare. Mortensen et al. (120) reported the case of 20-year-old woman who was comatose for several days after intoxication with 75 g VPA (peak serum VPA of a 2,120 µ/mL 8.5 hours after drug intake) and who recovered. Treatment must be symptomatic and supportive, with particular attention to the maintenance of adequate urinary output. Gastric lavage and activated charcoal should be performed as soon as possible. Because the drug is rapidly absorbed, gastric lavage may be of limited value excepted for delayed-release formulations. Multiple dosing of activated charcoal may be effective. In overdosage, the fraction of drug not bound to protein is high, and in severe intoxication with coma, hemodialysis or hemoperfusion may be beneficial (96,120,156). Naloxone has been reported to reverse the central nervous system-depressant effects of VPA overdosage (2,118). L-Carnitine (100 mg/kg loading dose, then 250 mg every 8 hours for 4 days, or 150 to 500 mg/kg/day, up to 3 g/day) may be useful to prevent hepatic dysfunction after VPA overdose (44,84,122).

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Acute Dose-Related Adverse Effects

Gastrointestinal

Nausea with or without vomiting and gastrointestinal distress are common AEs, often noted at the initiation of VPA therapy, in up to 25% of patients. Their incidence is maximal with the oral solutions, and has been markedly decreased by the availability of enteric-coated and controlled release preparations. Tolerance to these symptoms usually develops within weeks, but in many cases it is necessary to recommend drug intake during or after meals, and a slowing of uptitration (49). Their persistence beyond the initial period of treatment or their occurrence during longterm treatment should raise specific concerns about metabolic, hepatic, or pancreatic complications.

Tremor

Although patients exhibit a specific sensitivity to this AE, tremor clearly is a dose-related symptom that is associated with high blood levels of VPA (97). It usually appears as fast, low-amplitude tremor resembling adrenergic tremor, or it resembles essential tremor; it rarely appears as asterixis (21), which is mostly a symptom of hepatopathy with or without hyperammonemia in VPA-treated patients. VPA-induced tremor always responds to dose reduction, but propranolol may be useful in some patients (97).

Encephalopathy and Coma

Acute encephalopathy or coma may occur early in the course of VPA treatment with or without evident metabolic changes such as hyperammonemia and low carnitine (see later), with or without interactions with other AEDs, especially phenobarbital (146), and without overdosage (171). This makes its categorization as a dose-related AE uncertain. However, many such cases cannot be fully explained by coexisting metabolic disturbances, and their pathogenesis remains unclear. They are characterized by marked alterations of the electroencephalogram (EEG), mostly in the form of continuous slow waves, and are rapidly reversible on discontinuation of VPA. In clinical practice, this complication should be rapidly diagnosed using the EEG, overdosage and major metabolic changes quickly evaluated, and VPA discontinued.

Chronic Dose-Related Adverse Effects

Weight Gain

In clinical practice, weight gain is significantly associated with VPA (47). It may be particularly difficult to control in younger patients and in patients with mental handicap. Girls are particularly at risk (127), as are persons with normal or below-normal baseline weight (38): In the latter study, 70% of patients on VPA monotherapy gained at least 4 kg. Patients tend to report increased appetite, and to increase both the number and the size of daily food intakes. Several mechanisms have been proposed that may be based on a genetic predisposition to obesity, and weight gain may be associated with decreased β-oxidation of fatty acids (23), increased insulin and insulin/glucose ratios (42), and increased leptin and insulin levels (169). A direct central effect on hunger or satiety is not excluded. Carnitine levels do not seem to play a significant part (42). However, weight gain may occur owing to other factors, and the causal role of VPA in the genesis of weight gain in children receiving VPA has been challenged recently (53). In a randomized trial comparing VPA with CBZ in 260 children aged 4 to 15 years with newly diagnosed epilepsy, it was shown that there was no statistical difference in weight increase between the two groups, and that three-fourths of subjects who gained weight on VPA continued to do so if they were switched to CBZ. Weight gain and related metabolic disturbances may play a major part in the genesis of reproductive disorders in women (see later), and also may lead to social problems. Patients therefore should be warned about this risk, and dietary measures should be proposed whenever necessary.

Hair Changes

Some patients may report thinning of hair, alopecia (95), change of hair color, or regrowth of curly hair. Such changes have been seen with many psychotropic drugs (116), and their incidence has not been established. These changes usually are benign and transient, and may remit even under continuing therapy. There is no explanation for this phenomenon, which may be related to hypothyroidism in a minority of cases. The therapeutic value of vitamin or mineral supplements has not been documented, although most patients receive such treatment in case of hair changes induced by VPA.

Cognitive and Other Chronic Central Nervous System-Related Side Effects

The negative effects of VPA on cognition usually are considered minimal (162). A study compared the effects of newly prescribed VPA (low-dose and high-dose) and CBZ on motor speed and coordination, memory, concentration, and mental flexibility (137). There were no significant differences compared with pretreatment levels at 6 and 12 months. However, subtle cognitive dysfunctions may be present, especially in children who receive high doses of VPA, and should be monitored (106). If present, cognitive AEs are nonspecific and quickly and completely reversible after withdrawal (62). There are some rare cases of severe cognitive disturbances. In a 21-year-old man with a 3-year history of dementia, dementia was reversed within 2

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months on discontinuation of VPA (185). In another case report, an 11-year-old girl with normal intelligence experienced marked mental deterioration after 2 years and 6 months of continuing VPA treatment (72). There were no metabolic changes, and magnetic resonance imaging (MRI) findings mimicked diffuse brain atrophy; both MRI changes and cognitive dysfunctions disappeared within 4 months after drug reduction and discontinuation. A similar case of reversible cognitive dysfunction was reported in a patient in whom cognitive decline and “pseudoatrophy” of the brain appeared within 2 weeks of initiation of VPA (153). Reversible pseudoatrophy also may be associated with parkinsonism (149), but the latter may occur in an isolated manner, or in association with cognitive decline (10); it remits within weeks after discontinuation of VPA (129). Reversible hearing loss was reported but not confirmed by other observations (9).

Endocrine (Excluding Reproduction) and Metabolic Changes

Subclinical peripheral hypothyroidism (i. e., elevated serum levels of thyroid-stimulating hormone) has been reported in children (56,181). These changes were reversed in selected cases after discontinuation of VPA, and never were associated with overt thyroid dysfunction. Coadministration of VPA with enzyme-inducing AEDs may cause a decrease in serum levels of the thyroid hormones triiodothyronine and thyroxine (86). The occurrence of a dose-related inappropriate secretion of antidiuretic hormone-like syndrome has been reported in a patient on VPA who also had nephritis (22). Subclinical hyperglycemia and hyperglycinemia also have been reported (91). An unfavorable lipid profile has been associated with the use of VPA in women who gained weight and in whom polycystic ovaries also developed (89), and the metabolic changes were partially reversed after substitution of VPA by lamotrigine (LTG), with an increase in the high-density lipoprotein cholesterol/total cholesterol ratio.

However, the major metabolic changes associated with VPA concern hyperammonemia and the metabolism of carnitine. Hyperammonemia appears to occur in as much as 50% of patients treated with VPA, especially in polytherapy, and is a subclinical change in most cases, without signs of hepatic dysfunction (5,124,158,184). Serum valproic acid levels above 100 µg/mL and age younger than 2 years may be risk factors for development of hyperammonemia (5). It also may appear in the form of marked encephalopathy with or without coma, and in association with overt liver toxicity. It is clearly enhanced in the presence of polytherapy with hepatic cytochrome P450 (CYP) inducers (182). Hyperammonemia has been ascribed to increased renal production of ammonia, to inhibition of nitrogen elimination due to inhibition of urea synthesis, or to a combination of these factors (80). Hyperammonemia also might be secondary to increased glycine and propionic acid concentrations (39). Similarly, lowered carnitine levels have been reported in patients receiving VPA (125), but whether these changes are clinically significant remains debatable. Carnitine deficiency has been related to the occurrence of malignant, fatal cerebral edema without liver dysfunction in a young woman (161). In many instances, the occurrence of encephalopathy related to hyperammonemia and carnitine deficiency has been ascribed to a preexisting, unrecognized metabolic defect such as ornithine transcarbamylase deficiency (81,82,128,159). Carnitine deficiency may predispose to the occurrence of otherwise unexplained coma (160). Hence, carnitine supplementation, which is highly recommended in the presence of liver toxicity, also may be useful as a preventive measure in some cases (115). However, otherwise healthy children treated with VPA apparently do not exhibit carnitine deficiency, and supplementation therefore may not be necessary (138) except in those who are exposed to low-carnitine diets because of associated handicaps (79).

Other Uncommon Chronic Adverse Effects

Diffuse peripheral edema may be associated with longstanding VPA therapy (26,57). This occurs without associated liver toxicity, and the mechanisms are unknown. Gingival hyperplasia, which is a very common AE of phenytoin, has been ascribed to VPA in a 9-year-old girl who had not been treated with other AEDs (6,8). VPA has also been reported to provoke an increase in sister-chromatid exchange and in chromosomal abnormalities in peripheral lymphocytes in patients on VPA monotherapy who were compared with age-matched control subjects (83); such acquired changes also were found after short-term, 6-month VPA treatment, and in lymphocytes of control subjects exposed in vitro to VPA. However, these interesting findings have not been duplicated. Facilitation of bone fractures also has been reported in children on longterm VPA treatment, without any speculation on possible mechanisms (132). Renal toxicity, in the form of Fanconi's syndrome, was reported in two children (104). Both recovered normal proximal tubular function within 4 months of discontinuing VPA therapy.

ALLERGIC AND IDIOSYNCRATIC SIDE EFFECTS

Allergic Reactions

Because of the simple, nonaromatic structure of VPA, allergic reactions are uncommon, and less frequent than with other AEDs (24). In a retrospective study, there were 8 serious adverse skin reactions in 8,888 new phenytoin users, 6 in 9,768 new CBZ users, and none in 1,504 new VPA users (157). As with other AEDs, skin reactions develop early in

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the course of VPA treatment. A 28-year old woman who had a generalized skin eruption associated with marked eosinophilia and altered liver function was reported (134); the responsibility of VPA was confirmed by a positive patch test. A case of Stevens-Johnson syndrome was ascribed to VPA in another case report (163). Two cases of systematic lupus erythematosus possibly induced by VPA have been reported (20), but the causal relationship was unclear because one of these patients clearly had other predisposing factors. A case of acute, near-fatal multiorgan system failure that probably was of allergic origin also has been reported (135).

Blood Dyscrasias

Blood dyscrasias due to AEDs are rare, although all classic agents have been implicated in their occurrence (19). Thrombocytopenia and inhibition of platelet aggregation are the most common hematologic abnormalities associated with VPA (111). VPA may reduce the activity of the arachidonate cascade in platelets and inhibit the cyclooxygenase pathway and synthesis of the platelet aggregator thromboxane (98). Thrombocytopenia can be tolerated as long as the platelet count is stable in the range of 100,000/mm³ and there are no signs of an increased bleeding tendency, the risk of which is low (3,170). Thrombocytopenia with a platelet count below 80,000/mm³ requires close monitoring. This condition is correlated with both dosage and serum concentration of VPA (69), and responds to dosage reduction or discontinuation of the drug. Occasionally, severe bleeding, hematoma, epistaxis, and petechiae have been observed (111). May and Sunder (115a) reported that 33% of 60 patients receiving long-term VPA monotherapy (mean, 14.6 years) exhibited at least one prominent hematologic abnormality (i.e., thrombocytopenia, macrocytosis, leukopenia, and anemia). The incidence was 55% in the subset of patients whose VPA plasma concentrations exceeded 100 mg/L. However, these abnormalities were not severe enough to discontinue therapy and always responded to small decrements in VPA therapy. Neutropenia, macrocytosis, bone marrow suppression leading to aplastic anemia or peripheral cytopenia affecting one or more cell lines, myelodysplasia, and a clinical picture resembling acute promyelocytic leukemia are extremely rare but all have been associated with VPA therapy [review in Acharya and Bussel (1)] (63,172). Valproic acid also may be associated with abnormal coagulation factors such as low fibrinogen levels (14, 75,114) and acquired von Willebrand's disease type I. Kreuz et al. (103) investigated bleeding disorders in a group of children receiving VPA and observed a reduction in fibrinogen concentration and platelet count, and a significant decrease in factor VII complex. The effect of VPA on bleeding time and coagulation factors can lead to hemorrhage. It is recommended that a complete blood count, thrombocyte count, and coagulation parameters be performed before initiation of treatment, after initiation, and before elective surgery. However, a surgical series has shown no increase in bleeding complications or blood loss in patients who underwent cortical surgery (6).

Hepatotoxicity

A minor increase in serum aminotransferases is common. It is observed in 30% to 50% of patients (154), appears to be dose related, is transient, and is observed more commonly during initial therapy and in patients comedicated with phenobarbital or phenytoin (73). When this increase remains moderate (lower than two or three times baseline values), asymptomatic, and without any abnormal changes in other liver function test results, the treatment may be continued. More rarely, results of other liver tests, such as alkaline phosphatase, lactate dehydrogenase, and bilirubin, may be increased. Occasionally, γ-glutamyl transferase activity may be slightly increased (70). If the level is higher than expected, alcoholism or hepatitis may be suspected.

VPA has been linked to serious hepatotoxicity. It is a rare, typically idiosyncratic side effect. In a retrospective study of patients treated between 1978 and 1984, the overall incidence was approximately 1 in 10,000 cases (50). Children younger than 2 years of age appear to be at higher risk, particularly those receiving multiple AEDs, those with genetic disorders of metabolism, and those with mental retardation or organic brain disease. The overall risk of fatal hepatic dysfunction was approximately 1/500 in children younger than 2 years of age receiving VPA in polytherapy. The risk declined with age, with a rate of 1/12,000 if receiving polytherapy and 1/37,000 in monotherapy (51). From 1987 through 1993, over 1 million patients were newly treated with VPA. Fatal hepatotoxicity was observed in 29 patients (25). This apparent decrease in fatal liver toxicity appears to be due to changes in prescribing patterns and to physician awareness of highrisk factors for hepatic failure. Adult patients are considered to have a lower risk than children. However, they can be affected as well. König et al. (102) conducted a thorough review of the medical literature and identified 26 cases of adult fatalities published since 1980: The age range was from 17 to 62 years, 3 had received VPA in monotherapy, and 23 in combination. Twelve (46%) had no significant underlying disease. Thus, VPA should be used with extreme caution in higher-risk groups and should be avoided in patients with preexisting hepatotoxicity and inborn errors of metabolism such as carnitine deficiency. Such disorders, however, may be subclinical, as was the case in a fatal hepatopathy of a child after 4 months of VPA treatment; fibroblast culture showed the presence of a medium-chain acyl-CoA dehydrogenase deficiency (52,101,126). Dreifuss (52) and König et al. (101) provided guidelines to minimize the risk of serous VPArelated hepatotoxicity, which are summarized in Table 89.4.

Severe hepatotoxic effects of VPA typically occur during the first 6 months of treatment, but can occur later (100). A

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baseline liver evaluation usually is recommended before starting therapy and at regular intervals thereafter. However, hepatic failure may occur after repeatedly normal measurements of liver enzymes. Laboratory tests have a poor predictive value for serious hepatotoxicity. In most cases, changes in laboratory values were preceded by clinical signs such as vomiting, anorexia, lethargy, facial edema, weakness, abdominal pain, and sudden and inexplicable increases in seizure frequency, especially in the presence of febrile disorders. Thus, clinical symptoms appear to be more reliable indicators of hepatotoxicity. The histologic findings in VPA hepatotoxiciry differ from those observed with other AEDs such as CBZ, phenytoin, and phenobarbital, where liver damage is associated with inflammatory changes. The typical liver histology of VPA toxicity includes microvesicular steatosis, cellular ballooning, and single- or multiple-cell necrosis (102). The histologic features resemble those found in Jamaican vomiting sickness and Reye's syndrome. Young et al. (180) reported a case described as a fatal Reye's-like syndrome. The pathogenesis of hepatotoxicity remains unclear, and different theories have been proposed. A breakdown of β-oxidation is considered to be the main mechanism of VPA-related hepatotoxiciry (102). The 4-ene metabolite may be play a role in hepatotoxicity by inhibiting enzymes involved in β-oxidation (40). This metabolite depends on CYP, which may explain in part the higher risk of liver toxicity in cotherapy with enzyme-inducing AEDs (52). However, the CYP3A4 isoform usually associated with induction by anticonvulsants is not responsible for the enhanced 4-ene-VPA formation that occurs during polytherapy; instead, enhanced 4-ene-VPA formationin vivo likely results from induction of CYP2A6 or CYP2C9 (147). Triggs et al. (160) also hypothesized that VPA may sequester coenzyme A, which leads to impairment of β-oxidation enzymes. Metabolic defects, polytherapy, or infections probably contribute by depleting intracellular coenzyme A (100). VPA therapy often is associated with decreased carnitine levels (125,166). L-Carnitine is an essential cofactor in the β-oxidation of fatty acids (138). It was suggested that the carnitine deficiency induced by VPA leads to impairment of mitochondrial β-oxidation enzymes. Neurologic handicap, age younger than 2 years, or multiple AEDs are risk factors for carnitine deficiency (138). L-Carnitine supplementation helps restore β-oxidation. Carnitine supplementation clearly is indicated in case of hepatotoxicity, overdosage, and other acute metabolic events associated with carnitine deficiency (i.v. carnitine 150 to 500 mg/kg/day, up to 3 g/day) (44).

TABLE 89.4. RECOMMENDATIONS TO MINIMIZE THE RISKS OF VALPROATE-INDUCED HEPATIC TOXICITY

1. Avoid the use of valproate in patients with preexisting liver disease and/or elevated baseline liver and/or pancreatic enzymes at least three times the normal upper limit and/or significant coagulopathies. 2. Avoid the use of valproate in patients with a personal or a family history of metabolic diseases implying β-oxidation, mitochondrial and peroxisomal functions, or unclear liver diseases with or without previous toxicity of valproate. 3. Specially careful monitoring should be provided when valproate is given in children aged less than 2 years, in association with enzyme-inducing drugs and in patients with mental retardation of unexplained origin, neurometabolic diseases or hereditary metabolic disorders. Administration of valproate in these situations should be done only after careful evaluation of the risk/benefit ratio. 4. Liver enzymes, amylase, platelets, bilirubin, and prothrombin time should be assessed prior to initiation of valproate in all patients, and reassessed after 1 month. They should then be reassessed only in the presence of significant clinical symptoms and (concerning coagulation parameters) prior to surgical procedures. 5. If possible, use valproate only in monotherapy under the age of 3 years, and at the lowest possible dosage in all. 6. Patients and parents should be advised to report immediately vomiting, anorexia, headache, edema, jaundice, or seizure breakthrough, especially after a febrile illness and/or other symptoms suggestive of possible hepatic dysfunction. 7. Administration of salicylates should be done cautiously, and high doses of salicylates should be avoided. Adapted from Dreifuss FE, Langer DH, Moline KA, et al. Valproic acid hepatic fatalities: II. US experience since 1984. Neurology 1989;39:201-207; and König SA, Elger CE, Vassella F, et al. Empfehlungen zu Blutuntersuchungen und klinischer Überwachung zur Früherkennung des Valporat-associierten Leberversagens. Nervenarzt 1998;69:835-840, with permission.

Pancreatitis

Potentially fatal acute hemorrhagic pancreatitis has been reported (4,11,18,27,29,58,130,174,177). Reexposure to VPA after recovery may lead to recurrence of pancreatitis. This complication is rare, with an incidence estimated at 1/40,000 (101). In their survey of 39 cases identified from personal files, literature, and a survey of physicians with a special interest in treatment of epilepsy, Asconapé et al. (11) noted that 14.5% of the 366 physicians who participated in the survey had seen at least 1 case. Acute pancreatitis may occur at any age, but is more common in patients younger than 20 years of age, in polytherapy, and in patients with chronic encephalopathy (58). Patients on hemodialysis, particularly children, may represent a group at greater risk (60). It can appear at any stage of treatment, although nearly half of the cases occur during the first 3 months, and 70% during the first year, secondary either to a recent dosage increase or to initiation of treatment. Most patients in whom acute pancreatitis develops have serum VPA levels within the therapeutic range. Abdominal pain, nausea, vomiting, or anorexia are the initial symptoms, and prompt medical attention should be sought if they appear while on VPA therapy. In patients treated with VPA who experience severe abdominal pain, amylase or lipase levels should be systematically performed before a surgical decision. Wyllie et al. (177) reported two patients who underwent

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exploratory laparotomy before diagnosis of pancreatitis. Complications include pseudocyst, pericardial effusion, laparotomy wound infection, and coagulopathy. If pancreatitis is diagnosed, VPA should be discontinued and pancreatitis may be rapidly reversed. The mortality rate has been estimated at 21% (18). The prognosis is worse in patients with associated liver failure (18). Systematic measurement of amylase levels is not recommended because mild, transient, and asymptomatic elevations are not uncommon, and at least one case of pancreatitis has been reported in which the plasma amylase level was normal but the other pancreatic enzymes (lipase, elastase, trypsin) were elevated (130).

REPRODUCTION

Puberty

Pubertal arrest has been reported to occur during VPA therapy (37), but a prospective study of eight boys and four girls treated with VPA and followed throughout puberty failed to detect any significant clinical or biologic change (36,112). Recently, the focus has been shifted to the occurrence of hyperandrogenism in peripubertal girls on VPA (165): compared with a control population, testosterone levels exceeding the mean plus two standard deviations were seen in 38% of prepubertal, 36% of pubertal, and 57% of postpubertal girls. However, there were no definite clinical consequences of these changes, although the authors suggest that they might be related to development of polycystic ovaries in later life. Such changes might be at least partially related to weight gain in the population treated with VPA.

Polycystic Ovaries and Polycystic Ovary Syndrome

Studies have focused on the occurrence of polycystic ovaries (PCO) and PCOS in women treated with VPA. In a retrospective study (87), 238 women with epilepsy (9 treated with VPA, 120 with CBZ, 12 with a combination of these, and 62 with other AEDs, whereas 15 were untreated) and 51 healthy control subjects were compared. Menstrual disturbances were present in 45% of the VPA group, 19% of the CBZ group, 25% of the combination group, 13% of the group receiving other drugs, 0% of the untreated group, and 16% of control group. Vaginal ultrasonographic examination was performed in all patients with menstrual disturbances and in some of the others, as well as in the control subjects. Ultrasonography revealed PCO in 43%, 22%, 50%, and 11%, respectively, in the four treatment groups and in 5% in the regularly menstruating control subjects; elevated serum testosterone levels occurred in 17%, 0%, 38%, and 0% of patients, respectively, in the four treatment groups. Eighty percent of women treated with VPA before the age of 20 years had PCO or elevated testosterone; this compared with 27% of women treated with other AEDs. The mechanism involved was suggested to be related to hyperinsulinism and lowered insulin-like growth factorbinding protein 1 (88,89). These ovarian, hormonal, and metabolic changes were partly reversed after substitution of VPA with LTG. More recent studies, however, have questioned the reproducibility of these findings.

In a study of 65 women with epilepsy, including 21 women treated with VPA, 21 with phenobarbital, and 23 with CBZ, and 20 healthy control subjects, there was no difference in hirsutism score, ovary volume, or in the prevalence of PCO, although the VPA group had higher body weight and body mass index (123). Herzog, although acknowledging the possibility of increased incidence of PCO, pointed to the increased incidence of menstrual disorders and possibly PCO in women with epilepsy, and suggested that enzyme-inducing AEDs might protect against the effects of hyperandrogenism by increasing the level of sex hormone binding globulin (78). In a review on PCO, PCOS, and anticonvulsant therapy, it was stressed that many factors were involved in this very common disorder, and that the prevalence of VPA-induced changes was not as high as suggested by the aforementioned studies (68). In practice, there are limited data suggesting that VPA increases the incidence of reproductive disorders in young women, but clinicians should be aware of this possibility and monitor patients accordingly, with special attention given to the occurrence of weight gain (32,68). There are, however, no data that contraindicate the use of VPA in young women with epilepsy (12).

Male Reproduction

No major effects of VPA have been reported on male sexual and reproductive function. Follicle-stimulating hormone levels were shown to be slightly increased in men on VPA (65), whereas levels of other sex hormones (pituitary, adrenal, and gonadal) were unchanged (61,85). A recent comparison of monotherapies with VPA, CBZ, and oxcarbazepine showed that VPA increases the serum concentrations of androgens, whereas CBZ decreases their free fractions (139). The clinical significance of these findings is unclear. However, treatment with VPA has been associated with abnormal sperm mobility and count. In a 32-year-old man, a low sperm count of 50,000/mL was improved to >16 million with subsequent fertility after a switch from VPA to felbamate (179). Indeed, long-term treatment with VPA and with other AEDs [i.e., CBZ and phenytoin (but not phenobarbital)] has been associated with lower sperm mobility (34), but others failed to find any such abnormality with VPA (155).

Teratogenicity

The first case of spina bifida related to fetal exposure to VPA were seen in France approximately 20 years ago (143),

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where nine cases were reported in infants born to mothers who had received VPA during pregnancy. There had been isolated reports before this impressive series (41,71), and further cases afterward (64,108). These findings were confirmed by prospective studies (48), and later studies (both prospective and retrospective) showed that the incidence of neural tube defects is approximately of 1% to 20% in children born to mothers treated with VPA, which is approximately the risk of recurrence of neural tube defects in case of previous occurrence in a sibling. In a multicenter survey, the prevalence of neural tube defects was 2.5% in offspring of mothers treated with VPA monotherapy during the first trimester of pregnancy, which compared with 0.35% when other AEDs were used, and 0% in nonepileptic control subjects (109). The risk appears to be related to dose and peak VIA blood levels, but does not depend on seizure frequency during pregnancy (110). Additional risk factors include family history of neural tube defects, and association with CBZ.

A fetal VPA syndrome has been described that is characterized by minor craniofacial abnormalities with possible subsequent developmental delay, with or without occurrence of major organ malformations (46). Congenital defects associated with exposure to VPA include lung hypoplasia (three cases, including two siblings) (93), abnormal pulmonary artery origin (117), autism (175), other types of developmental delays (119), and limb deficiencies (131,144), especially bilateral radial hypoplasia (99). Although exposure to the AED is thought to play the predominant role in the incidence of malformations, other factors, such as genetic predisposition, appear to play a major role (30). Prevention of major malformation associated with intrauterine exposure to VPA is based:

In case of a planned pregnancy, on the use of alternative treatments or on a reappraisal of the necessity of VPA

Whenever VPA treatment appears unavoidable, on the lowest possible dosage and on fragmentation of intake (or use of controlled-release forms) to avoid high peak plasma VPA concentrations

Prophylactic administration of folic acid is recommended (121), although its effectiveness in preventing VPA-induced neural tube defects is unproven. Diagnostic ultrasonography (18th to 20th week of gestation) is indicated whenever there has been exposure to VIA in early pregnancy and pregnancy termination is an option. Amniocentesis at week 15 to 16 for the determination of α-fetoprotein also may be considered, but its use has declined after advances in ultrasonography (including specialized applications such as transvaginal ultrasonography).

Pregnancy and Lactation

The course of pregnancy usually is not affected by VPA (178). Specific problems such as bleeding, toxemia, preterm delivery, spontaneous abortion, intrauterine growth retardation, or mortality may be increased in women with epilepsy, but have not been associated specifically with VPA. However, a study of pregnancy outcome in women on VPA monotherapy showed a higher rate of infant distress at birth and of low Apgar scores compared with control subjects (92). Other mechanisms of toxicity may occur during pregnancy: A fatal case of liver toxicity has been reported in infants exposed during gestation (107). Newborns may experience withdrawal symptoms and hypoglycemia (54). Because only 3% to 5% of VPA diffuses in maternal milk, breast-feeding is not contraindicated. However, an infantile case of thrombocytopenic purpura that remitted after cessation of breast-feeding was reported recently (150).

DRUG COMBINATIONS

Because of a clear potentiation of their respective anticonvulsant activities, VPA and LTG are now increasingly used in combination for the treatment of resistant forms of generalized and focal epilepsies. This combination, however, poses several problems of tolerability that are due mostly to pharmacokinetic interactions (i.e., to the marked increase in half-life and plasma levels of LTG in the presence of VPA). Most AEs attributed to LTG (i.e., dizziness, headache, insomnia) are increased by this combination, and tremor may occur at comparatively low plasma levels values of VPA. However, the increased risk of LTG-induced skin rash and of more severe forms of cutaneous allergy after the addition of LTG in patients already receiving VPA represents the major risk, and titration of LTG should be particularly slow in this situation, with increments as small as 5 mg/day at intervals of 2 weeks in children, and 25 mg in adults (59). A lupus anticoagulant developed in a 5-year old boy, which eventually disappeared after discontinuation of VPA (55). Disseminated intravascular coagulation and multiorgan dysfunction, including rhabdomyolysis, was reported in two other children (33).

Although the combination of VPA and CBZ also is useful, it produces significant interactions. VPA decreases the clearance of CBZ-10,11-epoxide (CBZ-E) and increases CBZ-E blood levels (142), sometimes resulting in the appearance of CBZ-related AEs (dizziness, ataxia, diplopia, fatigue) that may be wrongly ascribed to VPA. The amide derivative of VPA, valpromide, is a much stronger inhibitor of CBZ-E metabolism, and CBZ-E-related side effects are seen much more commonly when valpromide is combined with CBZ (136).

The combination of VPA with topiramate (TPM) may be useful, and pharmacokinetic interactions do not pose specific problems (145). However, this combination occasionally has been associated with a hyperammonemic encephalopathy with mental confusion and slowing of the EEG (74), which clearly is related to the combination

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because its clinical, EEG, and biologic symptoms and signs remit after dose reduction or discontinuation of either VPA or TPM.

Pharmacokinetic interactions may have accounted for the occurrence of status epilepticus in a patient who received clomipramine in addition to VPA: Serum clomipramine concentrations were markedly elevated (43). Hepatic encephalopathy was precipitated by the addition of clozapine in a patient treated with VPA (176). A case of catatonia, which recurred after rechallenge with VPA and remitted definitively after withdrawal of VPA, occurred in a patient treated for schizoaffective disorder with risperidone and sertraline, and might represent a very uncommon interaction (105).

SPECIFIC ADVERSE EFFECTS ACCORDING TO PRESENTATION AND ADMINISTRATION ROUTE

Except for the aforementioned interactions between valpromide and CBZ-E, there are very few indications that chemical variants of VPA may produce different AEs. Divalproex sodium may be marginally better tolerated than VPA with regard to gastrointestinal side-effects, especially anorexia, nausea, and dyspepsia, and patients are less likely to stop medication because of AEs (183). Diarrhea has been ascribed to the excipient of a VPA solution (i.e., to glycerin and sorbitol) rather than to the drug itself because it resolved with another VPA preparation (167). Although most patients now receive either enteric-coated or controlled-release preparations of VPA, which were marketed with the aim of decreasing dose-related, acute AEs, an increasing number of generic preparations of VPA now are used around the world. Change to generic forms has caused gastrointestinal AEs to appear (148).

TABLE 89.5. ADVERSE EVENTS REPORTED BY AT LEAST 0.5% OF PATIENTS AFTER INTRAVENOUS VALPROATEa

Type of Event Percentage of Patients (%) Any event 17 Body as a whole Headache 2.4 Injection site inflammation 0.9 Injections site reaction 2.4 Injection site pain 0.9 Pain (unspecified) 0.6 Digestive system Abdominal pain 0.6 Diarrhea 0.6 Nausea with or without vomiting 2.8 Vomiting alone 1.6 Nervous system Dizziness Taste perversion 1.3 Hiccup 0.6 Somnolence 1.9 Tremor 0.6 aThis study includes 318 patients (22 children and 296 adults). Adapted from Devinsky O, Leppik I, Willmore U, et al. Safety of intravenous valproate. Ann Neurol 1995;38:670-674, with permission.

Intravenous VPA has been evaluated in clinical trials involving 318 patients with epilepsy, given at doses of 50 to 1,500 mg (45) (Table 89.5). The mean rate of infusion studied was 6.3 mg/min (range, 0.8 to 25 mg/min). Nausea, headache, and injection site reactions were the AEs most often reported, but their incidence was very low. There are, however, numerous, often contradictory reports on the tolerability of i.v. VPA. In 21 patients who received 24 infusions of VPA, there were no AEs on blood pressure and ECG parameters, and local reactions were seen only twice (168). In another study, however, reactions at peripheral injection sites occurred in 21 % of patients (versus 30% of patients receiving i.v. phenytoin) (7). Other AEs have been reported in isolated cases or very small series of patients—significant hypotension (173), pathologic laughter (90), and metabolic acidosis (140).

PARADOXICAL AGGRAVATION OF SEIZURES

Aggravation of epilepsy due to AED therapy may have several causes, among which a specific adverse pharmacodynamic effect of the drug on a specific seizure type is the most troublesome (66). This type of aggravation occurs without overdosage, encephalopathy, or other metabolic side effects. Many AEDs can produce this type of aggravation, resulting in increased seizure frequency and occurrence of new seizure types (13,67,133). Among currently prescribed AEDs, VPA stands out with a very low potential for seizure exacerbation. There are only very isolated reports mentioning this possibility: somnolence and increased spike-and-wave activity in a patient with hypothalamic hamartoma when VPA was added to CBZ and phenobarbital (151); and induction of tonic status epilepticus in a patient when VPA was added to phenobarbital (31). In both cases, pharmacodynamic interactions may help explain this apparent aggravating effect, which may not be due to a direct effect of VPA. A further case report described the reversing effect of flumazenil on impairment of consciousness considered to be due to VPA-induced nonconvulsive status epilepticus (152); however, these authors apparently mistake slow-wave stupor, which was probably a marker of VPA-induced encephalopathy, for nonconvulsive status. Exacerbation of seizure in the context of VPA-induced hepatotoxicity, encephalopathy, or metabolic disturbances is described earlier in this chapter.

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CONCLUSION

As an established anticonvulsant, with expanding indications in various fields of neurology and psychiatry, VPA has fared well. If the success of a given drug is a measure of its usefulness and tolerability, it appears that VPA has withstood the test of time. Although its common, benign, dose-related undesired side effects usually are easily managed, its comparatively long history has been marked by a succession of more severe, well advertised, and intensively scrutinized AEs. The possibility of their occurrence in patients treated for epilepsy should be kept in mind by practitioners, who also should be aware of their true incidence and clinical signification. Honest and comprehensive information should be given to patients who are treated with VPA for epilepsy, and preventive measures should be taken whenever possible to limit the extent and severity of AEs. In daily clinical practice, weight gain probably is the most troublesome AE, but aggravation of epilepsy by VPA is not an issue. Hepatic and pancreatic toxicity, teratogenicity, and reproductive dysfunctions are rare but significant problems. Abnormal laboratory values are not always associated with clinically significant problems. Overall, however, benefit/cost and benefit/risk ratios still appear to be quite favorable for the continuing and even increasing use of VPA in the treatment of epilepsy.

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