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Myoclonic atonic/astatic epilepsy (MAE), first described well by Doose1 (pronounced dough sah: ), is a generalized electroclinical syndrome with early onset characterized by myoclonic, atonic/astatic, generalized tonic-clonic, and absence seizures (but not tonic seizures) in association with generalized spike-wave (GSW) discharges. Thought to have a genetic component that has proven to be complicated,2 MAE sometimes occurs in children who have otherwise been developing normally and has variable outcome. MAE is typically treated with antiseizure medications that are used for generalized epilepsy syndromes, with perhaps a best response to valproate, felbamate, or the ketogenic diet.3,4

Until 1993, six antiepileptic drugs (phenytoin, phenobarbital, primidone, ethosuximide, carbamazepine, and valproate) accounted for the overwhelming majority of prescriptions written for the treatment of epilepsy. Among those, only valproate was truly a broad-spectrum drug, with some or good efficacy against all seizure types. Since 1993, felbamate, gabapentin, lamotrigine, topiramate, tiagabine, oxcarbazepine, levetiracetam, zonisamide, and pregabalin were approved in the United States for the treatment of epilepsy. All were initially tested and approved as add-on treatment of partial-onset seizures, with or without secondary generalization. The era that began in 1993 was characterized not only by a new generation of antiepileptic drugs, but also by controlled trials in specific epileptic syndromes and in seizure types other than partial onset. From these trials, a gradually expanding pattern of a broader antiepileptic efficacy spectrum has emerged for several of the newer drugs, although some of them still retain a narrow spectrum, such as gabapentin, tiagabine, oxcarbazepine, and pregabalin (table). View this table: Table Current FDA-approved indications of newer antiepileptic drugs The Lennox-Gastaut syndrome is a generalized epilepsy that is notoriously refractory to treatment. In a trial reported in 1993, felbamate was the first drug ever to be submitted to a controlled trial in this syndrome, and it was found to be superior to placebo, in particular against the most debilitating drop attacks.1 Following this lead, subsequent similar placebo-controlled trials in this syndrome demonstrated the efficacy of lamotrigine2 and then topiramate.3 Another generalized seizure type, absence seizures, was shown in a controlled trial to respond to lamotrigine.4 Generalized tonic-clonic seizures (GTCS) are …

Some patients with acute hereditary porphyrias have seizures and require anticonvulsant therapy, but many anticonvulsants induce exacerbations of the hepatic porphyrias. Recently, several new anticonvulsants have become available. Among these are gabapentin, vigabatrin, felbamate, lamotrigine, and tiagabine. Little is known about their potential for induction of porphyric attacks. We used a cell culture model of primary chicken embryo liver cells, which maintain intact heme synthesis and regulation, to study the effects of these new anticonvulsants on porphyrin accumulation. Treatment of the cells with deferoxamine (250 microM) led to a partial block in heme synthesis, simulating the conditions encountered in human beings with porphyria. Concomitant exposure of these cells to phenobarbital (2 mM) strongly induced accumulation of porphyrins, serving as a positive control in this model. Cells were treated for 20 hours with increasing doses (3.2 to 1,000 microM) of the newer anticonvulsants, with or without deferoxamine. For most of these anticonvulsants 5 to 100 microM is representative of the concentrations achieved in humans with therapeutic doses. Porphyrins were measured spectrofluorometrically as uro-, copro-, and protoporphyrins. Results were confirmed by high-pressure liquid chromatography. Neither vigabatrin nor gabapentin treatment, with or without deferoxamine, led to any increase in porphyrin accumulation. Similar doses of felbamate (with deferoxamine) led to a marked increase in (mainly proto-) porphyrin levels, qualitatively and quantitatively almost identical to the accumulation produced by phenobarbital. Lamotrigine or tiagabine (with deferoxamine) caused similar porphyrin accumulation. Tiagabine treatment up to 100 microM (with deferoxamine) also resulted in very high levels of predominantly proto-porphyrin. In contrast to the other anticonvulsants tested, tiagabine without deferoxamine led to mild porphyrin accumulation. In the presence of deferoxamine, phenobarbital, felbamate, lamotrigine, or tiagabine, but not gabapentin or vigabatrin, increased levels of the mRNA of ALA synthase, the first and rate-controlling enzyme of porphyrin synthesis. Such enzyme induction is a sine qua non for acute porphyric attacks. We conclude that neither vigabatrin nor gabapentin is porphyrogenic, whereas felbamate, lamotrigine, and, especially, tiagabine lead to much accumulation of porphyrins. The latter three anticonvulsants, therefore, may precipitate or exacerbate acute porphyric attacks in humans. We recommend use of vigabatrin or gabapentin, but not felbamate, lamotrigine, or tiagabine, in patients with acute porphyria and seizures.

Article abstract-Since the emergence of the specialty, neurologists have worked with a rather restricted list of relatively inexpensive pharmacologic agents. This is rapidly changing with the development of new agents for the treatment of migraine, multiple sclerosis, Parkinson's disease, Alzheimer's disease, and epilepsy, accelerated in part by designation of the 1990s as the "Decade of the Brain". Exciting as these developments are, they are very costly when applied to the large number of patients who may benefit, perhaps exceeding $6.4 billion. Since this cost exceeds the $1.5 billion income of all practicing neurologists, it enhances the value of the neurologic consultation, which can provide more accurate diagnosis and more expertly directed therapy. Our relationships with the drug manufacturers are changing as our prescribing habits become a more likely determinant of profits.NEUROLOGY 1995;45: 569-572

Approximately 30% of patients with epilepsy are medically refractory despite multiple antiepileptic drug (AED) trials due to continued seizures or intolerable side effects. Novel AEDs and other therapies are needed that are more effective with improved tolerability. New treatments and new insights into management of comorbidities are discussed, with a focus on adult patients with epilepsy. The Food and Drug Administration (FDA) recently approved 3 new AEDs, and a fourth AED may be near approval. Lacosamide (LCS) is approved by the FDA for adjunctive treatment for partial-onset seizures. It has novel mechanisms of action, enhancing the slow inactivation of voltage-gated sodium channels and binding collapsing response mediator protein 2. LCS has a low potential for drug–drug interactions, is renally excreted, and is dosed twice daily. It does not affect plasma concentrations of concomitant AEDs. The most common adverse effects were dizziness, headache, diplopia, nausea, and vomiting, which were mild or moderate. Small increases in the PR interval were observed, but were not of clinical consequence. In a recent randomized, double-blinded, placebo-controlled trial of adjunctive treatment with LCS for medically refractory partial-onset seizures at doses of 400 to 600 mg daily, median reductions in seizure frequency were 37.3% for the 400 mg/day and 37.8% for the 600 mg/day groups. For secondarily generalized tonic-clonic seizures, median reductions in seizure frequency were more robust at 59.4% for the 400 mg/day group and 93.0% for the 600 mg/day groups. In addition, 8% of the patients in the 600 mg/day group became seizure-free.1 Rufinamide (RUF) is FDA-approved for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS). This new AED adds to the AEDs already used for LGS including valproic acid, lamotrigine, felbamate, and topiramate. Its mechanism of action includes limiting the excessive firing of sodium-dependent action potentials, but RUF also exhibits a broad …

Objective: To determine rates of cross-sensitivity of rash among commonly used antiepileptic drugs (AEDs) in patients with epilepsy. Methods: The incidence of AED-related rash was determined in 1875 outpatients (≥12 years), taking carbamazepine (CBZ), clobazam (CLB), felbamate (FBM), gabapentin (GBP), levetiracetam (LEV), lamotrigine (LTG), oxcarbazepine (OXC), phenobarbital (PB), phenytoin (PHT), primidone (PRM), tiagabine (TGB), topiramate (TPM), vigabatrin (VGB), valproic acid (VPA), or zonisamide (ZNS). We compared rates of rash for each AED in patients with vs those without a rash to 1) another specific AED; 2) any other AED; 3) any two other AEDs; and 4) any non-epilepsy medication. Results: A total of 14.3% (269/1,875) of patients had a rash attributed to at least one AED; 2.8% had a rash to two or more AEDs. Of patients who had a rash to CBZ and were also prescribed PHT (n = 59), 57.6% had a rash to PHT (abbreviated as CBZ → PHT: 57.6%); of patients who had a rash to PHT and were also prescribed CBZ (n = 81), rate of rash was 42% (i.e., PHT → CBZ: 42%). Other results: CBZ → LTG: 20% (n = 50); LTG → CBZ: 26.3% (n = 38); CBZ → OXC: 33% (n = 15); OXC → CBZ: 71.4% (n = 7); CBZ → PB: 26.7% (n = 30); PB → CBZ: 66.7% (n = 12); LTG → PHT: 38.9% (n = 36); PHT → LTG: 18.9% (n = 74); PB → PHT: 53.3% (n = 15); PHT → PB: 19.5% (n = 41); OXC → LTG: 37.5% (n = 8); LTG → OXC: 20% (n = 15). There was evidence of specific cross-sensitivity between CBZ and PHT, and between CBZ and PB. Conclusion: Cross-sensitivity rates between certain antiepileptic drugs (AEDs) are high, especially when involving carbamazepine and phenytoin. Specific cross-sensitivity rates provided here may be useful for AED selection and counseling in individual patients.

The adverse effect profiles of new drugs are often incomplete at the time of approval.1,2 Rare or idiosyncratic reactions, as well as mutagenic or teratogenic effects, may only become evident with widespread use. These reactions may be identified through reports from clinicians to the manufacturer or to the US Food and Drug Administration (FDA) or through postmarketing clinical trials and database searches.1,3 One of the most striking examples occurred with felbamate. It entered the market in 1993 after having been studied in fewer than 5,000 adults. Shortly after introduction, the FDA began to receive reports of felbamate-associated aplastic anemia. In August 1994, a black box warning was added to the product labeling. In October 1994, the black box was modified to include a warning for hepatotoxicity. With an estimated incidence of 1 in 8,000 for aplastic anemia and 1 in 10,000 for hepatotoxicity, it is understandable that these reactions were not identified in small-scale premarketing clinical trials.4 Felbamate was the first of eight antiepileptic drugs (AEDs) approved by the FDA from 1993 to 2000. For many patients, these AEDs provide a major improvement over traditional agents. However, as the experience with felbamate has shown, knowledge of their adverse effects at the time of approval was limited. To examine …

There is no evidence that oral contraceptives (OCs) increase seizure activity, and OC use in the setting of antiepileptic drug (AED) treatment provides pregnancy prevention at among the highest rates of any available contraceptive method. One concern, however, is the increased risk for OC failure with the use of cytochrome P450 3A4 enzyme-inducing AEDs, such as phenobarbital, carbamazepine, phenytoin, felbamate, topiramate, and oxcarbazepine. Felbamate induces metabolism of only the progestogenic component, whereas topiramate induces metabolism of only the estrogenic component. There is preliminary evidence that lamotrigine induces the metabolism of a progestin, levonorgestrel. It is unclear whether the estrogenic or the progestogenic component is more clinically important in preventing pregnancy. To ensure maximal pregnancy prevention, it is therefore recommended that women taking enzyme-inducing AEDs should receive OCs containing at least 50 mug of ethinyl estradiol and that low-dose formulations in general should not be used. AEDs that do not induce cytochrome P450 3A4 enzymes, including valproic acid, gabapentin, levetiracetam, tiagabine, vigabatrin, zonisamide, and pregabalin, do not interact with OCs. There are no concerns regarding the treatment of seizures or increased pregnancy risk with the use of OCs and these non-enzyme-inducing AEDs. Lamotrigine levels, however, are reduced by 50% in the setting of OC use. Therefore, women with epilepsy taking lamotrigine need to be monitored carefully for seizures when OCs are started and for toxicity when OCs are discontinued. Dose adjustment to maintain clinical stability may be necessary in these settings. The placebo or pill-free week of the OC regimen may also be a period when clinical toxicity can occur. Even with the considerations discussed in this review, OCs are a reasonable contraceptive option for women with epilepsy taking AEDs.

During the past decade, eight new antiepileptic medications (AEDs), including felbamate (FBM), gabapentin (GBP), lamotrigine (LTG), levetiracetam (LEV), oxcarbazepine (OXC), tiagabine (TGB), topiramate (TPM), and zonisamide (ZNS), have been approved in the United States. In multicenter controlled clinical trials, each of these new AEDs has demonstrated efficacy as adjunctive therapy in adults with refractory partial seizures,1-18⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓ and some have shown efficacy as monotherapy in adults with partial seizures.19-27⇓⇓⇓⇓⇓⇓⇓⇓ Although large amounts of data have emerged from these trials, the challenge for clinicians who treat adults with epilepsy has been to integrate these data into their clinical practices. Clinicians who treat children with epilepsy have faced greater obstacles. Only a handful of multicenter controlled clinical trials involving the newer AEDs have been conducted in children with epilepsy. In addition, these studies have focused on answering regulatory questions rather than addressing routine clinical issues. However, it is possible to extract practical and clinically useful information from these multicenter trials by systematically examining specific aspects of the efficacy, safety, and serum concentration trial data. An important factor in evaluating clinical trial data is to determine whether the study’s efficacy data demonstrate the potential usefulness of an AED for children with epilepsy. Direct application of adult clinical trial data to children has many potential hazards. There are a variety of differences between pediatric and adult epilepsy, including age-related seizure types and epilepsy syndromes, etiologic differences in partial seizures between adults and children, and a higher frequency of localization-related epilepsy syndromes in children.28 Therefore, only data from pediatric studies are included in this analysis. The design of the clinical trial is the critical factor determining the potential …

Taste disorders can occur during different pharmacologic treatments.1,2⇓ Among antiepileptic drugs (AED), carbamazepine (CBZ), felbamate (FBM), and phenytoin (PHT) have been reported to induce taste abnormalities. IV fosphenytoin and valproic acid (VPA) have occasionally been associated with dysgeusia. To our knowledge, taste abnormalities related to lamotrigine (LTG) have never been recorded. We describe three patients with drug-resistant partial epilepsy who had dysgeusia during treatment with LTG. A 65-year-old man with frontal lobe epilepsy since childhood added LTG treatment, up to 100 mg/d, to his stable phenobarbitone (PB) (25 mg/d), CBZ (1200 mg/d), and VPA (1500 mg/d) polytherapy. One year later, as seizures improved, the patient reduced VPA treatment to 900 mg/d, and gradually (over 3 months) withdrew CBZ. Twenty days after complete CBZ withdrawal, the patient started to complain of severe dysgeusia, characterized by a marked bitter taste and hypersalivation, which interfered with eating and caused …

Background/justification. Epilepsy is a common condition, affecting up to 1% of the population. Until recently, there were only a handful of effective medications to treat this condition, many of which produced unwanted side effects or were capable of producing serious adverse events in some people. Despite these drawbacks, from 1978, when valproate was introduced, until 1993, no new therapies emerged. In 1993, felbamate was approved by the Food and Drug Administration (FDA). At that time, it represented a significant advance for many patients with inadequately controlled seizures or with significant side effects for whom no options had been available. The substantial need for a new agent was evidenced by the fact that within 1 year, felbamate had been prescribed for 126,000 patients with epilepsy.1 Many of these patients experienced complete seizure control for the first time. Others found that felbamate, which does not have the central nervous system depressant effect of many other agents, provided significant improvements in quality of life. In September 1994 the FDA issued a “dear doctor” letter, warning of a higher than expected incidence of aplastic anemia and hepatic failure among patients receiving felbamate.2 In all, 33 US cases of aplastic anemia occurred between January and October of 1994. Eighteen patients experienced hepatic failure.3 This prompted most physicians to remove most or all of their patients from felbamate therapy. Of the original cohort, only 12,000 remained on felbamate. A similar number have continued to the present. Of interest, no new cases of aplastic anemia have been reported in patients who remained on felbamate, or among the smaller cohort who have initiated therapy since that time. Some have argued that the initial high incidence of serious adverse events may have overestimated the magnitude of the problem, as many of the affected patients had other …

Optimal treatment of epilepsy in adults requires a tailored approach that weighs the efficacy of individual drugs in the specific diagnosis against the patient9s risks for adverse events. Partial seizures, which are the most common seizure type in adults, can be effectively controlled by virtually all the standard and newer antiepileptic drugs (AEDs). For the generalized epilepsies, valproate remains the drug of choice. Data continue to accumulate regarding use of the newer agents. Overall, many of the newer AEDs may offer a better tolerability than the standard agents because of more favorable pharmacokinetic characteristics and lack of interactions with drugs other than AEDs. Serious adverse events have been associated with felbamate and lamotrigine, however, and more experience is needed with many of the other newer AEDs to better define their safety profiles. Monotherapy should be the goal when AED treatment is instituted for the adult with epilepsy. Dosage modification on the basis of seizure control and toxicity should be implemented, as well as single-drug trials with alternative AEDs, before resorting to polytherapy. With the introduction of several promising newer AEDs, safe and effective seizure control may become a reality for an increasing number of adults with epilepsy.

Although no new antiepileptic drugs (AEDs) were approved by the Food and Drug Administration (FDA) between 1978 and 1993, there were over 20,000 compounds tested in animals and many were brought to clinical trials. Many proved to be ineffective or too toxic, but five drugs and one device have now been approved: felbamate, 1993; gabapentin, 1993; lamotrigine (LTG), 1994; topiramate, 1996; tiagabine, 1997; and vagus nerve stimulator, 1997. The first double-blind study that showed the efficacy of felbamate began in 1982.1 This study, sponsored by the attention deficit disorder (ADD) program of the Epilepsy Branch of the National Institutes of Health (NIH), was followed by a number of industry-sponsored trials. These included pediatric studies and monotherapy trials before submission to the FDA.2,3 Felbamate was approved for use as adjunctive and monotherapy in adults and Lennox-Gastaut in children. Felbamate studies had begun earlier than those for gabapentin and LTG, and the industry sponsors of the latter decided to submit for approval as adjunctive agents initially and then expand the approved indications to monotherapy. Monotherapy studies for these have been completed, and in this issue, the results of the US monotherapy trial for LTG are reported.4 Monotherapy studies using an active control model have been done in Europe comparing LTG, carbamazepine (CBZ), and phenytoin (PHT), and have shown that LTG is as effective as monotherapy with the standard AEDs.5 However, there are theoretical problems with active-control studies, and the FDA does not accept these study designs for monotherapy approval.6 Important issues, however, make approval of placebo-controlled outpatient studies unethical. To obtain monotherapy approval, many of the new AEDs have used a low-dose active control design.7-9 These studies have compared what is generally considered to be a "suboptimal" dose of valproate (VPA) with the new AED. Although …

In the course of a large retrospective evaluation of our experiences with the new antiepileptic agent felbamate aimed at defining the therapeutic range of this drug and other clinical pharmacokinetic issues, we found a pharmacokinetic interaction with another new agent, gabapentin. Although the larger study is being submitted for publication, the fact that no previous interactions with gabapentin have hitherto been described prompts this short report. ### Methods and Results. The complete study reports 104 observations of clinical efficacy, doses, serum levels, graded side effects, and weights in patients taking felbamate as monotherapy or with one or two associated antiepileptic drugs. Clearances were calculated …

Until 10 years ago the initial selection of anticonvulsant drug treatment was relatively straightforward. Partial seizures with or without secondary generalization were typically treated with phenytoin or carbamazepine. Phenobarbital was a second choice because of its sedating side effects. Valproate, which obtained a formal indication for partial seizure treatment in 1996, was sometimes used as a first- or second-line agent. Primarily generalized epilepsy, with either absence or myoclonic seizures or generalized tonic–clonic attacks with 3-per-second spike–wave discharges on the EEG, was typically treated with valproate. For pure absence, ethosuximide was an alternative choice, especially for young children. In the past 10 years, eight new agents for the treatment of epilepsy have been introduced to the United States market, and an additional agent, vigabatrin, has been available in Canada and Europe. Although there are subtle differences in the formal indications for each of these agents approved by the FDA and by European licensing authorities, all of them have demonstrated efficacy as adjunctive treatment of partial seizures with or without secondary generalization. Oxcarbazepine and felbamate have been approved as initial monotherapy (although felbamate is not currently used as first-line treatment), and lamotrigine has been approved for conversion to monotherapy. By contrast, none of the new agents has a formal indication for the treatment of absence and other forms of primarily generalized epilepsy, although topiramate is indicated for the treatment of generalized tonic–clonic seizures. Although FDA-approved indications are generally based on evidence obtained from randomized double-blind trials and typically guide the initial use of new therapeutic agents, they …

To the Editor: I read with interest the article by Kerrick et al [1] concerning two cases of involuntary movement, one with choreoathetosis and the other with an acute dystonic reaction. …

Felbamate is a newly available antiepileptic agent useful as monotherapy and adjunctive therapy in adults with partial seizures and in children with Lennox-Gastaut syndrome [1]. Although dose-dependent cerebellar dysfunction is common with other anticonvulsants, this has occurred with felbamate only in add-on trials in which the dysfunction was plausibly linked to increases in the level of the primary anticonvulsant [2]. We report a case of felbamate intoxication associated with ataxia, downbeat nystagmus, and behavioral changes. Case report. A 44-year-old man was admitted to the hospital on May 11, 1994, because of unsteady gait and falling. He had a history of left frontotemporal contusion in July 1993, with subsequent development of complex partial seizures. Phenytoin was prescribed for his seizure disorder; he was subsequently admitted twice for episodes of phenytoin toxicity with ataxia and agitated behavior. The psychiatric consultant felt that these were part of a pattern of behavior consistent with …

Article abstract-A 53-year-old woman began taking felbamate for uncontrolled complex partial seizures. Four months later, she developed fatigue and ecchymotic skin lesions. Laboratory studies revealed very severe aplastic anemia. There have been an additional nine reported cases of aplastic anemia in the setting of felbamate treatment. The association between felbamate and aplastic anemia has resulted in a joint recommendation by the US Food and Drug Administration and the manufacturer of felbamate, Carter-Wallace, Inc., for the immediate withdrawal of patients from treatment with felbamate.NEUROLOGY 1995;45: 456-460

Article abstract-Two children developed involuntary movements while taking felbamate as an adjunct to their antiepileptic regimen. One exhibited choreoathetosis and the other an acute dystonic reaction. In both children the symptoms resolved with no recurrence after felbamate discontinuance.NEUROLOGY 1995;45: 185-187

Objective: We conducted indirect comparisons of the relative efficacies of clobazam, felbamate, lamotrigine, topiramate, and rufinamide as adjunctive treatments for patients with Lennox-Gastaut syndrome (LGS). Background It is not feasible to make direct comparisons of treatments for LGS without head-to-head studies. Design/Methods: We compared Phase III clobazam results in LGS 1 with RCT results of approved adjunctive LGS therapies from a 2009 Cochrane Review. 2 One of two lamotrigine studies in the Cochrane Review was not included, since randomization methodology for the published study was unclear. Since all 5 studies in our analysis, including the clobazam trial, employed these drugs with adjunctive therapy vs. placebo plus adjunctive therapy, we used traditional, pair-wise indirect comparisons to evaluate clobazam vs. the other drugs. As trial outcomes were not identical, we transformed primary endpoints into effect sizes (using Cohen9s d ). Typical interpretations of Cohen9s d results are: d d d d , large change. Results: High-dosage clobazam (1.0 mg/kg/day) had the greatest effect size, followed by medium-dosage clobazam (0.5 mg/kg/day), and rufinamide. According to Cohen9s d interpretation, effect size (0.80) for high-dosage clobazam was important. Medium-dosage clobazam and rufinamide had d -values >0.50, indicating a moderate clinical effect vs. placebo. Comparisons of numbers of total and drop or tonic-clonic seizures also supported the greater effect of high-dosage clobazam. Because of the few studies in the analysis, however, no results achieved statistical significance. Conclusions: High- and medium-dosage clobazam was estimated to be more efficacious than other LGS treatments. Our analysis relied on published data and could not draw on direct head-to-head data of clobazam with alternatives. Further comparative research is ongoing to assess the usefulness of clobazam for LGS. 1 Ng YT, et al. Neurology . 2011;77:1473–81. 2 Hancock EC, et al. Cochrane Database Syst Rev . 2009;8:CD003277. Supported by: Lundbeck SAS. Disclosure: Dr. Cramer has received personal compensation for activities with Bial, Eisai Inc., Sepracor, and UCB Pharma. Dr. Sabin has received personal compensation for activities with Lundbeck SAS as an employee. Dr. Gani has received personal compensation for activities with Lundbeck Research USA, Inc. an employee. Dr. Francois has received personal compensation for activities with Lundbeck Research USA, Inc.

We report a 3-year-old boy with the neurocutaneous combination of unilateral alopecia, ipsilateral hemimegalencephaly, and intractable seizures. He was born with an asymmetric hair pattern consisting of absent patches of hair, a small left eyebrow, and less eyelashes on the left eye; he had normal development until age 17 months, when he experienced right focal seizures with fever. Two months later, fever triggered new seizures characterized by flurries of head and body flexion and adduction of the right arm. He had left hand preference and language regression. EEG manifested left hemihypsarrhythmia, and MRI showed left hemimegalencephaly with marked enlargement of the temporal lobe with ventriculomegaly. Seizures were refractory to treatment with phenobarbital, adrenocorticotropic hormone, pyridoxine, sodium valproate, clonazepam, carbamazepine, phenytoin, and felbamate. This may represent a previously undescribed neurocutaneous syndrome.

After 1977, no new antiepileptic drugs (AEDs) were available until felbamate was approved in 1993. Since then, three more new AEDs have been approved for use in the United States: gabapentin, lamotrigine, and topiramate. These new medications have greatly improved the medical treatment of epilepsy. Gabapentin is indicated for the treatment of partial and secondarily generalized seizures in adults. It has proven to be a safe, well-tolerated medication and is also beneficial in treating pain syndromes. Lamotrigine and topiramate are approved for partial and secondarily generalized seizures in adults, and, both likely have a broader spectrum of action, with efficacy against primary generalized seizures and seizures that occur with Lennox-Gastaut syndrome. Both must be slowly titrated due to their potential side effects, lamotrigine to avoid rash and topiramate to avoid cognitive impairment. Serious rash from lamotrigine occurs at a higher rate in children than in adults.

Felbamate, a novel dicarbamate anticonvulsant that blocks the glycine site of the N-methyl-D-aspartate receptor and protects the hippocampal slice from hypoxic damage, shows remarkably low toxicity in animals and in humans. Since most treatment of human cerebral ischemia will have to be delivered after the insult, we investigated the neuroprotective potency of post hoc felbamate in rat pups with bilateral carotid ligations exposed to an atmosphere of 6.5% O2 for 1 hour. Brain temperature was unaffected by surgery, hypoxia, or felbamate. Neuroprotection was greatest at 300 mg/kg, less effective at 200 and 400 mg/kg, and ineffective at 100 mg/kg. Post hoc felbamate (300 mg/kg) reduced the volume of infarction from 67% ± 7% of neocortex in unmedicated rats to 32% ± 8%, 51% ± 12%, 38% ± 19%, and 53% ± 10% when given 0, 1, 2, and 4 hours after hypoxic exposure, respectively. By 6 hours, post hoc protection was no longer significant. Delayed neuronal necrosis in hippocampal granule cells was reduced from 156 ± 33 neurons to 12 ± 7 (0 hour, p < 0.01) and 37 ± 17 (1 hour, p < 0.05). These effects were obtained at plasma concentrations (60 to 120 mg/ml) that have occasionally been reached without serious toxicity in human anticonvulsant trials. These data suggest that, in this animal model, felbamate given after a hypoxic-ischemic insult is effective in reducing cerebral infarction and extremely effective in preventing delayed neuronal necrosis, but that the window of opportunity for post hoc treatment is only 1 to 4 hours.

We evaluated felbamate (FBM) monotherapy in 111 patients with uncontrolled partial-onset seizures in a multicenter, double-blind, parallel-group trial. During the 56-day baseline period, patients had at least eight partial-onset seizures and received one standard antiepileptic drug (AED) at a therapeutic level; a second AED was allowed if at a subtherapeutic level. Patients received either FBM 3,600 mg/d or valproate (VPA) 15 mg/kg/d. The baseline AED at therapeutic levels was discontinued by one-third decrements on study days 1, 14, and 28 and the sub-therapeutic AED, if any, was discontinued completely on study day 1. Study endpoints were completion of 112 study days or fulfilling one or more escape criteria. Criteria for escape relative to baseline were (1) twofold increase in monthly seizure frequency, (2) twofold increase in highest 2-day seizure frequency, (3) single generalized tonic-clonic seizure (GTC) if none occurred during baseline, or (4) significant prolongation of GTCs. The primary efficacy variable was the number of patients in each treatment group who met escape criteria. Thirty-seven patients on VPA and 18 on FBM met escape criteria (p0.001). Even when we considered FBM dropouts to have fulfilled escape criteria and VPA dropouts to have completed the 112-day trial, the treatment difference remained statistically significant (p = 0.039) in favor of FBM. Adverse experiences with FBM were all mild or moderate in severity. The frequency of adverse experiences was much lower during monotherapy. FBM monotherapy was effective in the treatment of partial-onset seizures with or without secondarily generalized seizures and demonstrated a favorable safety profile.

Frequent side effects vagus nerve stimulation (VNS) include hoarseness, cough, and throat pain. Although the vagus nerve physiologically regulates gastrointestinal motility, changes in bowel movement frequency are not included as side effects of VNS. We report a patient who developed chronic diarrhea associated with VNS. A 35-year-old man had complex partial seizures since age 14, occurring up to six times per month. Multiple medications including phenytoin, carbamazepine, gabapentin, felbamate, and topiramate did not control the seizures. Intracranial EEG monitoring demonstrated both right and left temporal origin seizures, excluding the patient from consideration for resective surgery and leading to referral for VNS. After an uncomplicated VNS implantation, the stimulator was set at 0.25 mA/30 Hz/500 ms/30-s on/5-min off/magnet 0.50 mA. The patient was discharged the following day with only a sore throat. One week later, he reported two seizures and an increase in bowel movements. At that time, the stimulator intensity …

To the Editor: An important Practice Advisory was recently published in both Neurology 1 and Epilepsia .2 As an influential “guidelines” paper emanating from leading professional associations, this type of paper is often referenced and used to make clinical decisions. The methodology refers to 54 articles: one class I, one class II, and 44 class III. However, on closer scrutiny, some of these “articles” are abstracts. In fact, most “articles” cited to support the efficacy of felbamate in generalized epilepsy are actually abstracts of data presented at the American Epilepsy Society meetings of 1991 and 1992. Abstracts of meeting presentations are certainly an important …

To the Editor: I read with interest the article by Zahn et al.,1 which reviews women’s health and epilepsy. The section on contraception deserves comment. The authors note no interaction between felbamate or tiagabine with hormonal contraception. This may be incorrect. Whereas felbamate is an overall hepatic P450 enzyme inhibitor and would not be expected to decrease hormonal efficacy, it is an inducer of the isoenzyme P4503A4. This isoenzyme is responsible for metabolism of progestins and estrogens. Felbamate may adversely affect contraceptive efficacy.2 Tiagabine is also metabolized by the isoenzyme P4503A. Information on its interaction with low dose birth control is limited. At doses of tiagabine 8 mg/day in healthy volunteers, no interaction was noted, although breakthrough bleeding did occur.3 An interaction may be expected with more typical treatment doses. # {#article-title-2} To the Editor: Antiepileptic drugs (AED) have been known to cause bone mass loss for many years, yet anticonvulsant-induced osteoporosis remains unrecognized by the vast majority of the medical community. It is unfortunate that the recent Report of the Quality Standards Subcommittee (QSS) of the American Academy of Neurology on management issues for women with …

Thirty-six cases of hepatic toxicity associated with felbamate therapy have been collected by the Food and Drug Administration. Five patients died. We describe a case of massive acute hepatic necrosis and death within 40 days of initiation of felbamate therapy for a generalized tonic-clonic seizure disorder. We describe the clinical and histopathologic features.

We studied the efficacy and safety of felbamate, an investigational antiepileptic drug, in a unique, double-blind, placebo-controlled trial. Sixty-four patients with refractory partial-onset seizures who completed a routine evaluation for epilepsy surgery met seizure frequency entry criteria. Each patient received felbamate or placebo in addition to the anticonvulsant regimen present at the conclusion of the presurgical evaluation. The treatment phase consisted of an 8-day inpatient period and a 21-day outpatient period. The efficacy variable was time to fourth seizure. The difference in time to fourth seizure was statistically significant (p = 0.028) in favor of felbamate. Eighty-eight percent of the patients in the placebo group had a fourth seizure during the treatment phase compared with 46% of the patients in the felbamate group (p = 0.001). Adverse experiences with felbamate were generally mild or moderate in severity. This trial demonstrated the ability of felbamate to quickly and safely reduce the occurrence of frequent partial-onset seizures and maintain effective seizure control following reductions in the dosages of standard antiepileptic drugs.

Felbamate (2-phenyl-1,3-propanediol dicarbamate) has a favorable preclinical profile in animal models of epilepsy. We present the results of a double-blind, randomized, placebo-controlled clinical trial in patients with partial seizures. Criteria for entry included a requirement for four or more partial seizures per month despite concomitant therapeutic blood levels of phenytoin and carbamazepine. Fifty-six patients (mean age, 31.4 years; 32 men, 24 women) completed the trial. The mean seizure frequencies for the 8-week periods analyzed were felbamate = 34.9, placebo = 40.2. Felbamate was statistically superior to placebo in seizure reduction, percent seizure reduction, and truncated percent seizure reduction. The mean felbamate dosage was 2,300 mg/d. Plasma felbamate concentrations ranged from 18.4 to 51.9 mg/l, mean = 32.5 mg/l. Adverse experiences during felbamate therapy were minor and consisted primarily of nausea and CNS effects. This trial indicates that felbamate is safe and effective in the treatment of comedicated patients with severely refractory epilepsy.