Clorazepate therapy for intractable epilepsy

Thirty-one epileptic patients with seizures refractory to conventional anticonvulsants were treated by adding clorazepate dipotassium to their regimen. Twelve cases showed improvement in seizure frequency, three of whom attained a seizure free state. Response to clorazepate was not related to the type of epilepsy, but patients with secondary generalized epilepsy tended to be less responsive than those with partial epilepsy. Among the various seizure types, generalized tonic-clonic seizures and simple partial seizures showed, although not significant, a tendency to be more responsive to clorazepate therapy than other seizure types, including complex partial seizures, atypical absence, atonic seizures, and tonic seizures. Drowsiness was the main adverse effect, of which 14 patients complained. Six patients were withdrawn from clorazepate because of drowsiness, but in the remaining 8 patients, this side effect disappeared within a week. The appearance of adverse effect was not related to the dose of clorazepate given. Clorazepate may be an effective secondary anticonvulsant in the treatment of intractable epilepsy.     

Conversion to valproate monotheraphy in nonretarded adults with primary Generalized tonic-clonic seizures

Studies have demonstrated improved seizure control with fewer side effects when multidrug regimens are converted to valproate monotherapy. We studied 71 nonretarded adults, a group often unwilling to risk changes, with primary generalized tonic-clonic seizures. Their antiepileptic treatment was changed from treatment with one or more antiepileptic medicines to valproate monotherapy because of uncontrolled seizures or unacceptable side effects of the original regimen; 77% were successfully converted. Of those, 71% became seizure-free or had a >50% reduction in seizure frequency. The most frequent side effects of valproate were tremor, weight gain, and initial gastrointestinal irritation. Side effects were usually mild and interfered with the patient's quality of life less than those that prompted treatment conversion (sedation, gingival hypertrophy, cognitive dysfunction). One case of Reyes-like syndrome developed, but the patient recovered fully after valproate was discontinued. We concluded that conversion to valproate monotherapy is safe and effective for most treatment-resistant adults with primary generalized tonic-clonic seizures.     

Monotherapy with Valproate in Primary Generalized Epilepsies

Summary: Sodium valproate enteric-coated tablets were administered as monotherapy to 118 patients (median age, 19 years) with primary generalized epilepsies. More than half (56%) of these patients were transferred from prior drug therapy, most of them because of inadequate seizure control, and some because of adverse effects. Seventy-one percent of the patients experienced tonic-clonic seizures, either alone or in combination with other types of seizures, principally absences. Mean duration of follow-up was 18 months (median, 17 months; range, 1–68 months). At a mean daily dosage of <20 mg/kg, 83% of the patients became seizure-free. Therapy was equally effective against tonic-clonic seizures, absences, and myoclonic seizures. Tonic-clonic seizures were suppressed in 85% of cases (89% when patient had only one seizure type), absences in 82% (95% when patient had only one seizure type), and myoclonic seizures in 82%. Paroxysmal activity was present in 88% of the electroencephalogram (EEG) records before valproate monotherapy, and in 32.4% at the study's end. These results were achieved with generally mild and mostly transient side effects; side effects were reported by 16% of patients during the first month, and 2% at the last follow-up. No hematologic or hepatic toxicity was observed. The lag time between attaining steady-state serum concentrations and achieving maximal clinical improvement suggests that sodium valproate monotherapy should be given an adequate trial to ensure that patients derive the greatest possible benefit before adding or switching to another drug.     

Antiepileptic effect and serum levels of clorazepate on children with refractory seizures

Clorazepate dipotassium is rapidly decarboxylated to yield desmethyl diazepam. The antiepileptic effect of clorazepate was studied in 29 epileptic children with refractory seizures. Their ages were ranged from one year 9 months to 20 years (mean 11 years 6 months). Serum clorazepate levels were also determined in 16 patients. The mean initial dose was 0.91 mg/kg/day, and the dose was increased up to 3 mg/kg/day. Within several days after initiation of clorazepate therapy, a decrease in seizure frequency was seen in patients in whom clorazepate was effective. Excellent results (decrease in seizure frequency by more than 80%) were obtained in 7 patients (24.1%), a moderate improvement with a 50 to 80% decrease was seen in 7 patients (24.1%), and a partial improvement with less than 50% decrease was seen in 7 patients (24.1%). No benefit was seen in 8 patients (27.7%). Serum clorazepate levels in patients with excellent results were 31 to 77 ng/ml (mean 55 ng/ml), those in patients with a moderate improvement were 130 to 225 ng/ml (mean 163 ng/ml), and those in patients with a partial improvement were 142 to 518 ng/ml (mean 273 ng/ml). Serum clorazepate levels in patients with no benefit were 34 to 97 ng/ml (mean 56 ng/ml). There was no direct relationship between serum clorazepate levels and clinical response. The results of this study indicate the efficacy of clorazepate for epileptic children with refractory seizures.     

Intravenous levetiracetam in children with epilepsy

Intravenous levetiracetam recently became available for use in patients aged >16 years. There are few data about its safety and efficacy in children. We retrospectively analyzed data from children treated with intravenous levetiracetam. Ten patients (6 female, 4 male), aged 3 weeks to 19 years, were treated with intravenous levetiracetam at a mean dose of 50.5 mg/kg/day for a mean duration of 4.9 days. Four patients received intravenous levetiracetam for acute repetitive seizures/status epilepticus, and three as replacement for oral levetiracetam because administration of oral levetiracetam was temporarily infeasible. One patient each received intravenous levetiracetam for seizure prophylaxis during brain biopsy, as maintenance treatment after acute seizures, and as substitute for sodium valproate. Three of four patients with acute repetitive seizures/status epilepticus became seizure-free; the fourth patient had a partial reduction in seizure frequency. All three patients who received intravenous levetiracetam as substitute for oral levetiracetam tolerated the switch well. The other three patients were seizure-free on intravenous levetiracetam. No serious adverse effects were observed, and all patients completed treatment with intravenous levetiracetam for the intended period. Intravenous levetiracetam may be effective in various clinical situations requiring intravenous administration of an antiepileptic drug.     

Epilepsy and antiepileptic drug therapy in juvenile neuronal ceroid lipofuscinosis

PURPOSE: To survey the characteristics of epilepsy in patients with juvenile neuronal ceroid lipofuscinosis (JNCL) and determine the antiepileptic drug (AED) treatment most suitable for these patients. METHODS: The study included 60 patients with JNCL; their mean age was 16.5 years (range 5-33). The age at onset of epilepsy, type of seizures, effect of the first AED on seizures, and the current seizure frequency and AED therapy were studied. The side effects of the AEDs were also clarified. RESULTS: Fifty of the 60 patients had epilepsy. Patients' first epileptic seizure occurred at a mean age of 10.0 years (range 5-16), the most common type being generalized seizures. As the first AED tried, valproate (VPA) and lamotrigine (LTG) appeared equally effective, with 80% of the patients responding to these AEDs. During the study year, the median seizure frequency was four seizures a year (range 0-120), and 72% of the patients had good or satisfactory seizure control (0-6 seizures a year). In the different AED therapy groups, the proportion of patients with good or satisfactory seizure control ranged from 25% to 100%. LTG in monotherapy or in combination with clonazepam (CZP) was superior to other AEDs or combinations, but VPA also seemed effective. Adverse effects leading to the discontinuation of an AED were observed in 25% of the patients, most frequently in patients receiving phenobarbital (PB). No patient receiving LTG had to discontinue the drug due to adverse effects. CONCLUSION: Epilepsy in JNCL can usually be successfully treated with the current AEDs. In Finnish patients with JNCL, treatment is based on LTG, or, secondarily, VPA. In combination therapy, CZP seems a valuable add-on AED.     

Selection of drugs for the treatment of epilepsy

Antiepileptic drug selection is based on efficacy for specific seizure types and epileptic syndromes. For idiopathic generalized epilepsies with absence, tonic-clonic, and myoclonic seizures, the drug of choice is valproate. Secondary generalized epilepsies with tonic, atonic, and other seizure types are difficult to treat with any single drug or combination of drugs. The drugs of choice for absence seizures are ethosuximide and valproate. For control of tonic-clonic seizures, any of the other major antiepileptic drugs can be effective. If valproate cannot be used, carbamazepine, phenobarbital, phenytoin, or primidone is effective, but ethosuximide or a benzodiazepine needs to be added to control associated absence or myoclonic seizures. The drugs of first choice for partial epilepsies with partial and secondarily tonic-clonic seizures are carbamazepine and phenytoin. Increasing evidence suggests that valproate may be a third alternative. Phenobarbital and primidone are second choice selections because of side effects. A combination of two of these five major antiepileptic drugs may be necessary for inadequately controlled patients. Other epilepsy syndromes such as neonatal and infantile epilepsies, febrile epilepsy, and alcoholic epilepsy require specific drug treatment. For all these seizure types and epilepsy syndromes, treatment ultimately must be selected to provide maximal efficacy and minimal adverse effect for each individual patient.     

Amantadine hydrochloride for refractory generalized epilepsy in adults

Amantadine hydrochloride has been shown in several open studies to benefit children with refractory generalized epilepsy. We used amantadine as adjunctive therapy in 10 adolescents and adults with generalized tonic-clonic, myoclonic, or absence seizures refractory to therapeutic levels of valproate, carbamazepine, phenytoin, and benzodiazepines. Seven patients were men and 3 were women aged 18-29 years, and 8 of 10 patients were mentally retarded. All patients had generalized epileptiform paroxysms on EEG, with generalized or absence seizure recorded in 9. Five patients had both absence and tonic-clonic seizures, and 2 had all three seizure types. Amantadine was added to the existing regimens in weekly increments to 400 mg/day. Two patients had greater than 90 per cent seizure reduction, both with vomiting and somnolence. Two patients had seizure reduction between 50 and 90 per cent, 1 with anorexia and sleepiness. Three patients had no change in seizures, and 3 had worse tonic-clonic seizures. Amantadine may have some antiepileptic efficacy of unknown mechanism, but it may worsen generalized tonic-clonic seizures and is likely to be of limited value in adults.     

Gabapentin as add-on therapy in children with refractory partial seizures: a 24-week, multicentre, open-label study

The efficacy and safety of gabapentin as add-on therapy for refractory partial seizures in 237 children, aged 3 to 12 years were evaluated over a 6-month period. All children received gabapentin at 24 to 70 mg/kg/day. Efficacy variables included the percent change in seizure frequency and the responder rate (defined as those patients who showed >50% reduction in seizure frequency). For all partial seizures, the median percent change in seizure frequency was -34% and the overall responder rate was 34%. Simple partial seizures showed a median reduction of -53%; complex partial seizures, -38%; and secondarily generalized tonic-clonic seizures, -35%. Thirteen patients (5%) withdrew during the 6-month period because of adverse events. Concurrent antiepileptic medication remained unchanged in 185 patients (78%), was decreased in 27 (11%), and increased in 25 (11%) patients. This 6-month follow-up study has demonstrated that gabapentin was well tolerated and appeared to show a sustained efficacy in a large population of children with refractory partial and secondarily generalized tonic-clonic seizures.     

左乙拉西坦单药或添加治疗癫痫的临床观察

目的观察左乙拉西坦单药和添加治疗癫痫的临床疗效和不良反应。方法对91例门诊癫痫患者进行左乙拉西坦开放性治疗;其中少儿组54例,成人组37例;简单部分性发作(SPS)19例,复杂部分性发作(CPS)20例,全面性强直阵挛性发作(GTCS)32例,继发性全面性强直阵挛性发作(sGTCS)20例;采用单药治疗66例,添加治疗25例。左乙拉西坦起始剂量即为治疗剂量,儿童为10 mg/(kg.d),成人为0.5～3.0 g/d;治疗6个月时根据发作频率自身对照评价疗效,观察不良反应。结果治疗6个月时本组癫痫控制率为52.7%(48例),总有效率为75.8%;少儿组控制率和总有效率分别为64.8%及90.7%,明显高于成人组(35.1%,54.1%;均P<0.01);单药治疗组分别为62.1%及81.8%,明显高于添加治疗组(28.0%,60.0%;均P<0.01);SPS、CPS和GTCS的控制率分别为68.4%和55.0%及53.1%,明显高于sGTCS(35.0%,均P<0.01);SPS控制率明显高于GTCS(P<0.05)。本组不良反应发生率为16.5%,多较轻微,2例因明显脱发而换药。结论左乙拉西坦对多种类型的癫痫发作具有较好的疗效,对儿童及单药治疗的患者疗效更好;儿童及成人患者均有较好的耐受性。     

Lamotrigine and valproate: efficacy of co-administration in a pediatric population

This study aimed to assess the risks and benefits of the co-administration of lamotrigine and valproate in a pediatric population with refractory epilepsy. Twenty-eight children who received lamotrigine and valproate during co-medication were evaluated. Outcome measurements were established according to efficacy in seizure control, adverse effects, and tolerability. Treatment was considered effective when >50% frequency reduction was obtained. Adverse effects were also analyzed and in patients who presented them the mode of administration was compared with those who did not to verify the importance of this factor. Association of lamotrigine and valproate was considered effective in 64.3% of all patients, regardless of the seizure type. Seizure-free status was obtained in six patients. Drop attacks and secondary generalized tonic-clonic seizures were reduced in five patients, who remained under treatment despite less than the satisfactory (<50%) seizure decrease. Tremor occurred in six patients; urinary incontinence and ataxia in one. Skin rash also occurred, as an early manifestation, in two patients, both with a previous history of hypersensitivity to antiepileptic drugs. Causes for discontinuation were inefficacy of treatment in six patients and presence of adverse effects in two. In our series, seizure control was obtained in most children with refractory epilepsy, some of whom had a previous history of unsatisfactory response to lamotrigine and valproate, either in monotherapy or polytherapy. Adverse effects were uncommon, but skin rash was observed in higher proportions than in other series with lamotrigine or valproate. Nevertheless, these risks may be lessened with slow introduction and by exclusion of patients with a previous history of hypersensitivity.     

Intermittent prophylaxis in febrile convulsions with oral diazepam]

Intermittent prophylaxis with oral diazepam is presented as an optional treatment for febrile seizures. This proposition is justified by the severe side effects of the currently used chronic anticonvulsant drug therapy in febrile seizures (phenobarbital and valproate). Nineteen patients aged between 3 months and 5 years were treated. They had either simple or complex febrile seizures. Sixteen patients had at least one prognostic factor for recurrence of febrile seizures: first febrile seizure before 15 months of age, positive family history for epilepsy or febrile seizures, occurrence of a complex febrile seizure or abnormal neurological examination. Three patients had none (cases 8, 12 and 13). We recommended 2.5mg b.i.d. for children younger than 12 months, 5mg b.i.d. for children older than 12 months and younger than 3 years, and 7.5 b.i.d. for children older than 3 years. The results showed that only one patient had febrile convulsions while taking adequate diazepam dosage. Transient side effects occurred in 36.8% of the cases.     

Newly treated childhood epilepsy: a prospective study of recurrences and side effects

Eighty-two newly diagnosed children were started on anticonvulsant therapy and followed prospectively for 12 to 36 months. Compliance was excellent. However, 41% had a recurrent seizure within 6 months of starting therapy despite "adequate" serum levels. Recurrences were least frequent in those with generalized tonic-clonic seizures or those with a single seizure plus epileptiform EEG before treatment. Toxicity screening led to unnecessary drug change in two children. Seven other children had behavioral side effects requiring drug change.     

Use of topiramate in childhood generalized seizure disorders

Topiramate is a sulfamate derivative of the naturally occurring monosaccharide D-fructose. It was initially approved in the United States as adjunctive therapy for partial seizures in 1997. However, there is increasing evidence that it is effective in the treatment of generalized seizures and epilepsy syndromes. Initially, open-label studies using topiramate as add-on therapy in children with refractory generalized seizure types were performed. These showed improvement in patients with the following generalized seizure types: typical and atypical absence, atonic, myoclonic, generalized tonic-clonic, and juvenile myoclonic epilepsy. Double-blind, placebo-controlled multicentered studies in patients with refractory primary generalized tonic-clonic seizures and epilepsy syndromes were performed. The median reduction in seizure frequency for primary generalized tonic-clonic seizures was 56.7% for topiramate and 9% for placebo. Additionally, 13.6% of topiramate-treated patients were primary generalized tonic-clonic seizure free for the study period. In the topiramate-treated juvenile myoclonic epilepsy patients, primary generalized tonic-clonic seizures were reduced > 50% in 73% of patients. Open-label extension showed that primary generalized tonic-clonic seizures were reduced >50% in 63% of topiramate-treated patients for > or = 6 months, and 16% were primary generalized tonic-clonic seizure free > or = 6 months. Accumulating evidence suggests that topiramate has a broad spectrum of antiepileptic effect. Moreover, life-threatening organ toxicity has not been attributed to topiramate. Topiramate is an effective treatment for refractory generalized seizure types and epilepsy syndromes encountered in children.     

Broad-spectrum efficacy of zonisamide at 12 months in children with intractable epilepsy

In a retrospective study of 35 children (ages 8 months to 22 years; mean age 9 years) with intractable epilepsy, seizure frequency was determined before and after 12 months of zonisamide therapy. Charts were reviewed for seizure type (focal, generalized, or mixed), cognitive function (no special education versus special education), concomitant anticonvulsant medications, and the number of previous anticonvulsant drugs. Good to excellent seizure control (50-100% reduction) was attained in seven (54%) patients with generalized seizures, two (40%) patients with focal seizures, five (35%) patients with mixed seizures, and one (33%) patient with infantile spasms. In this group of children, the efficacy of zonisamide was comparable for focal, generalized, and mixed seizures. The efficacy of zonisamide was independent of cognitive status.Adverse effects were not associated with a higher mean dose. This could be attributable to different rates of metabolism or represent idiosyncratic responses to the medication. Our finding that those children taking the combination of zonisamide and levetiracetam had a significantly worse outcome than those on levetiracetam and a different drug warrants further study, both clinically and from the standpoint of mechanisms of action of zonisamide and levetiracetam and/or their pharmacodynamic interactions.     

Carbamazepine Efficacy and Utilization in Children

Summary: Carbamazepine is effective for preventing partial and generalized tonic-clonic seizures in children. Although absence epilepsies are more common in children than adults, an estimated 80% of children with epilepsy have seizure types or epilepsies that are potentially responsive to carbamazepine. The differential diagnosis of ictal staring is an especially important issue in children because absence and atypical absence seizures are more prevalent in children than adults. Age-related pharmacokinetic differences and drug interactions are major considerations in children. On average, children have higher clearance rates of carbamazepine, shorter half-lives, and higher ratios of carbamazepine-10, 11-epoxide to carbamazepine than adults. In addition, children with severe epilepsy are more likely to require multiple-drug therapy, which can lead to complex drug interactions. When carbamazepine is administered along with valproate, drug protein binding interactions can cause intermittent side effects.     

Do serum sodium levels predict febrile seizure recurrence within 24 hours?

The American Academy of Pediatrics Practice Parameter, The Neurodiagnostic Evaluation of a Child with a First Simple Febrile Seizure, does not recommend serum electrolytes be obtained routinely. Two reports from Europe, however, identified relative hyponatremia as a risk factor for febrile seizure recurrence within 24 hours. If confirmed, this would have potential impact on the approach to these patients. The charts of 175 sequential children ages 6 months to 5 years who presented to the Children's Hospital of Buffalo emergency room in 1999 with generalized seizures lasting less than 15 minutes were retrospectively reviewed. One hundred thirty-six patients were febrile and 39 (control group) were afebrile. Serum electrolytes were performed on all. The mean serum sodium for the 27 children with more than 1 febrile seizure in 24 hours (135.48 mmol/L) did not differ from those 109 febrile children whose seizures did not recur within 24 hours (135.56 mmol/L). Of interest, the mean serum sodium for the 109 children with simple febrile seizures, as well as those with recurrent "simple" febrile seizures were significantly lower than the control group of children with afebrile seizures. These findings reaffirm the recommendation of the American Academy of Pediatrics Practice Parameter to not routinely obtain electrolytes.     

Seizure-inducing effects of antiepileptic drugs: a review

Seizure-inducing effects can be observed in the treatment of epileptic patients with antiepileptic drugs (AED). This may be a paradoxical reaction (for example the increase of complex focal seizures due to carbamazepine, vigabatrin or phenytoin treatment) or a result of AED-induced encephalopathy (commonly induced by valproate in patients with complex focal seizures). A seizure increase during intoxication with AEDs is a rare phenomenon, thus, it is not directly related to this condition. An incorrect choice of drugs in the treatment of an epileptic syndrome or seizure type may provoke seizures (as for example the provocation of absences due to carbamazepine or phenytoin). The possible seizure-inducing effect of AEDs has to be differentiated from seizure occurrence due to the natural course of epilepsy. This may be especially difficult in patients suffering from West syndrome or Lennox-Gastaut syndrome, in whom seizure frequency may vary even without medication. However, especially in these patients, drug-induced worsening of seizure manifestation is often observed. In general, a seizure-inducing effect of antiepileptic drugs has to be considered when a seizure increase is observed soon after the initiation of therapy, when a stepwise increase of the dosage is followed by a further increase of seizures, a decrease of seizures is seen with tapering of the dosage and a renewed increase of seizures can be observed after this therapy has been reestablished. Finally, one knows that the clinical condition of encephalopathy due to valproate or carbamazepine is accompanied by seizure increase. In spite of these clinical aspects, the underlying mechanisms of seizure increase mostly remain unclear. From animal experiments it is obvious that especially carbamazepine and phenytoin may provoke generalized seizures as absences or myoclonic seizures. A seizure increase during vigabatrin therapy has been attributed to the increase of the cerebral amount of gamma-amino-butyric acid, which is known to possibly exhibit inhibitory or excitatory neuronal effects. The occurrence of tonic seizures in patients with Lennox-Gastaut syndrome has been attributed to the sedative effect of the drugs; however, this conclusion is controversial. From a clinical point of view, one should consider young age of the patient, mental retardation, antiepileptic polytherapy, high frequency of seizures or prominent epileptic activity in the electroencephalogram previous to medication as risk factors for a possible seizure-inducing effect of antiepileptic drugs.     

Therapy of Infantile Spasms with Valproate: Results of a Prospective Study

In a prospective study, 22 children with recently manifested infantile spasms (18 patients with symptomatic and 4 with idiopathic infantile spasms) were treated with sodium valproate (VPA). Before VPA was instituted, a loading test was performed to exclude abnormal patterns of VPA metabolites by gas chromatography and mass spectroscopy of serum and urine. This test was repeated during VPA therapy; an abnormal pattern of VPA metabolites was not observed. VPA was started in increasing dosage until infantile spasms were controlled or a maximum dose of 100 mg/kg/day was reached. If VPA did not control seizures or at least reduce frequency significantly after a trial of 4-6 weeks, dexamathasone was added to VPA. If focal seizures occurred in association with localized epileptogenic EEG discharges, carbamazepine (CBZ) was added to VPA. After 4 weeks of VPA monotherapy, infantile spasms were controlled in 11 children. After 3 months of therapy, 16 children were free of seizures (14 patients VPA monotherapy), and 4 children had reduction of seizure frequency to less than 25%. VPA doses varied between 40 and 100 mg/kg/day (mean 74). The mean plasma concentration was 113 micrograms/ml (range 46-177). After 6 months of therapy, total seizure control was achieved in 20 of 22 patients (16 children VPA monotherapy). The mean observation time was 16 1/2 months (range 6-36 months). There were seven relapses in six children during the first 7 months of therapy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Temporary pure red-cell aplasia during valproate monotherapy: clinical observations and spectral electroencephalographic aspects

We report the case of a 4-year-old boy with pure red-cell aplasia associated with sodium valproate monotherapy. Treatment with valproate was initiated because of idiopathic tonic-clonic seizures; he became free of seizures. During the introduction of and ongoing antiepileptic drug treatment, clinical and laboratory controls using electroencephalographic (EEG) spectral analysis were performed at regular intervals and disclosed normal values. Ten months after the introduction of valproate, clinical examination was normal except for marked pallor. Peripheral blood showed macrocytic anemia and the bone marrow finding was isolated absolute erythroblastopenia. At the same time, significant changes in EEG background activity were present as well-defined slowing. There was an increase in the relative power of theta activity and a decrease in alpha 2 activity in the occipital regions. Valproate was discontinued and phenobarbital therapy introduced. A complete resolution of the hematologic damage was observed after valproate withdrawal. Recovery of the hematologic parameters started 14 days after discontinuation of valproate therapy, while normalization of EEG background activity was observed earlier. The patient maintained stable hematologic values and seizure control without disturbances of the spectral EEG. After 6 months of phenobarbital therapy, re-administration of sodium valproate was not followed by recurrence of any clinical or electrophysiologic symptoms or abnormalities.