Valproate in the Treatment of Partial Epilepsies

Summary: Review of randomized controlled trials (RCTs) shows that valproate (VPA) is effective against partial seizures with or without becoming secondarily generalized. A number of RCTs show little difference in the efficacy of VPA and carbamazepine in this patient group, particularly where patients are randomized at the time of diagnosis. The length of time that it has taken to arrive at these conclusions emphasizes the importance of large active-controlled RCTs at an early stage in drug development in informing clinical practice.     

Felbamate in the Treatment of Partial-Onset Seizures

Summary: Felbamate (FBM, Felbatol/Taloxa) has been the object of several trials that are innovative and unique. First, FBM is the first antiepileptic drug (AED) to have been submitted to a controlled efficacy study in patients with the Len-nox-Gastaut syndrome (LGS) before being submitted for regulatory approval. Second, FBM was tested in patients discontinued from other AEDs for presurgical monitoring. Third, FBM was the first experimental AED to have been tested in controlled monotherapy trials. Overall, these studies succeeded in demonstrating that FBM is relatively safe and effective against both partial-onset seizures and the generalized seizures occurring in the LGS. The results of some of these studies could not always be expressed by using the more familiar concept of percent seizure reduction because, for ethical reasons, the efficacy variable had to be defined in terms of time to the n^lh seizure or in terms of escape criteria. This may make it more difficult to evaluate just how effective FBM is in comparison with other AEDs. Another reason why the efficacy of FBM cannot yet be fully assessed is that in all the studies the FBM dosage was limited to a maximum of 3,600 mg/day or 45 mg/kg/day. At this dosage, FBM produced no toxicity in the majority of patients, and its full therapeutic effect may have to be re-evaluated in the future at higher dosages.     

Lamotrigine: A Review of Antiepileptic Efficacy

Summary: Lamotrigine (LTG) is a chemically novel anti-epileptic drug (AED) that blocks voltage-sensitive sodium channels, leading to inhibition of neurotransmitter release, principally glutamate. LTG is active in a wide range of pharmacologic models of epilepsy, demonstrating a potency and duration of action generally superior to currently available AEDs. Preliminary evidence of efficacy was provided by single-dose studies showing effects on reducing interictal spike activity and photoconvulsive response. A total of eight randomized, double-blind, placebo-controlled, crossover trials have established the efficacy of LTG in patients with refractory partial epilepsy. Literature reports suggest LTG also is effective in patients with idiopathic generalized epilepsy, including absence seizures, and in patients with Lennox-Gastaut syndrome. Other reports suggest that LTG is useful in the pediatric population, and an interim report of an open monotherapy trial suggests that the efficacy of LTG was comparable to that of carbamazepine (CBZ) but the adverse experiences leading to discontinuation were less frequent.     

Felbamate: A Clinical Trial for Complex Partial Seizures

We performed a randomized, double-blind, three-period cross-over study of felbamate (FBM, 2-phenyl-1,3-propanediol dicarbamate: Carter-Wallace 554) in patients with complex partial seizures. Patients continued carbamazepine (CBZ) throughout the study and were observed in the hospital for the entire trial period. The entry criteria required at least six seizures in a 3-week baseline period (and no more than 1 week with a single seizure) with CBZ alone. Thirty subjects were randomized. Two left the study after randomization, 1 owing to seizure exacerbation, and 1 owing to hyponatremia, which may have been related to CBZ therapy. The daily dosage of 50 mg/kg (maximum 3,000 mg) FBM per day was well tolerated by all 28 patients who completed the study. Only mild adverse experience were observed during the trial. FBM reduced CBZ level (p less than 0.0001; 95% confidence interval -28%, -20%). There was no significant difference in seizure frequency between placebo and FBM periods (one-sided p = 0.172), but when a correction was made for the lower CBZ level noted during FBM periods, the data suggested a strong antiseizure effect of FBM.     

207例全面性强直阵挛发作患者抗癫痫药物治疗状况分析

目的了解邗江农村全面性强直阵挛发作(GTCS)患者抗癫痫药物治疗状况,为进一步开展农村社区癫痫防治工作提供依据.方法采用随机抽样的方法选取207例GTCS患者进行调查.结果调查的207例患者中接受正规治疗的患者仅68例(32.85%),其中单药治疗21例(30.88%),联合用药47例(69.12%);正规服药患者与未正规服药患者的疗效比较差异有显著性(P＜0.001).结论江苏邗江地区GTCS患者中正规服用抗癫痫药物者比例较小,且单药比例明显偏低,剂量偏小,存在较多的不良反应,患者依从性差,控制情况不理想,管理水平较落后,还存在较大的治疗缺口.     

Natural History and Prognosis of Partial Seizures Evolving to Secondarily Generalized Tonic-Clonic Seizures

Abstract: A survey was conducted in order to obtain reliable information on the natural history and prognosis of partial seizures evolving to secondarily generalized tonic-clonic seizures (GTC) under a modern treatment approach. One-hundred and fifty-one patients have had partial seizures evolving to secondarily GTC and the rate of patients with this seizure type was 32.1% out of 470 epileptic patients in the Outpatient Clinic of the Department of Neuropsychiatry, Kanazawa University Hospital, in 1982. Out of the 151, 142 patients were successfully followed up. The rate of complete remission of seizures in those patients was 42.3%. The number of patients who were successfully followed up in the initial EEG and the present EEG together were 124 cases. The rate of complete improvement of EEG findings in those cases was 12.1%.     

Correlative Study of Interictal Electroencephalogram and Aura in Complex Partial Seizures

To understand further relationships of the interictal electroencephalogram to the aura in complex partial seizures (CPS), we studied the interictal EEG and aura in 144 patients with CPS. The ages of the patients studied ranged from 31 to 80 years (average 52.44 years). The duration of seizures ranged from 1 to 60 years (average 15.69 years). Seventy patients (49%) reported auras which were classified according to the guidelines recommended by the Commission of the International League Against Epilepsy. Statistical analysis revealed no relationship between presence, laterality, or localization of EEG abnormality and the number or type of aura. The results emphasize that more factors than electrophysiologic localization alone participate in the determination of aura in CPS. Our data support the position that aura has, at most, a limited relationship to lateralization or localization of interictal cerebral dysfunction in CPS.     

Complex Partial Seizures in Young Children

Summary: We retrospectively analyzed the clinical manifestations of complex partial seizures (CPS) in children aged 10 years using video and EEG telemetry and evaluated their course, investigations, management, and seizure status at follow-up. Seventeen patients with CPS were studied at the Prince of Wales Children's Hospital (POWCH) and Prince Henry Hospital (PHH) between 1987 and 1992. Because 1.5 of the 17 patients had intractable seizures, the population was selective. Mean age was 6.5 years; 4 patients were aged 2 years. Clinical features were normal or mild intellectual handicap (1 3); hemiplegia (5); and infantile spasms preceding CPS (4); of these, 2 also had simple partial motor seizures. Structural abnormalities were noted on scanning in 9 patients. Eighty-seven seizures were reviewed. Mean duration of each clinical seizure was 59.7 s (total population), 108 s (subgroup 1, aged 2 > years), and 48.5 s (subgroup 2, aged 2 years). Major ictal manifestations were auras (9), staring (9), autonomic changes (6), and automatisms (17). In subgroup 1, automatisms were simple and mainly oroalimentary and gestural. Two patients had no change in surface ictal recordings, and 2 had normal interictal EEGs. At follow-up, 8 patients were seizure-free for 6 months, 1 was partially controlled (more than two seizures a month), and 8 had intractable seizures (two or more seizures a month). Seven patients underwent operation for intractable epilepsy, and 4 achieved a class 1A outcome (Engel classification).     

The Influence of Electroencephalographic Focus Laterality on Efficacy of Carbamazepine in Complex Partial and Secondarily Generalized Tonic-Clonic Seizures

Forty-five outpatients with chronic epilepsy with complex partial seizures (CPS) alone or associated with secondarily generalized tonic-clonic seizures (SGTCS) were treated with carbamazepine (CBZ) monotherapy. All patients had only a unilateral scalp electroencephalographic (EEG) focus. Left- (n = 29) and right- (n = 16) sided foci patients were comparable for age, sex, duration, and etiology of epilepsy as well as total and free CBZ serum levels. CBZ significantly improved CPS irrespective of the side of the EEG focus, whereas SGTCS were controlled for greater than 1 year in 15 of 19 patients with left focus and in three of 11 patients with right focus. When patients with poorly controlled seizures discontinued CBZ and changed to other therapies, they achieved a significant reduction in number of SGTCS, whereas the number of CPS was unchanged. The side of EEG focus seemed to be relevant to the control of SGTCS by CBZ. Interhemispheric neurotransmitter asymmetries may be involved in the EEG focus side-dependent CBZ response.     

Generalized Tonic-Clonic Seizures in Patients with Complex-Partial Seizures: Natural History and Prognostic Relevance

Clinical course and long-term seizure prognosis were studied in 155 patients with complex-partial seizures during a follow-up of 10.1 +/- 1 (SD) years. In 79% of the patients generalized tonic-clonic seizures were recorded, mostly within the first 3 years of epilepsy but occurring as late as 20 years after the onset of epilepsy. Seizure control was defined as complete absence of all seizures, including auras, for a minimum of 2 years. Seizure control occurred in 20 of 32 patients (63%) with complex-partial seizures only and in 76 of 123 patients (62%) with complex-partial seizures and generalized tonic-clonic seizures. The onset of the epilepsy with generalized tonic-clonic seizures or complex-partial seizures did not influence the therapeutic outcome despite differences in their natural history. A family history of epilepsy and other generalized seizures (e.g., absence) were more frequent in patients with generalized tonic-clonic seizures at the onset of epilepsy. Seizure control was significantly lower (44%) in patients with a history of a maximum frequency of one or more generalized tonic-clonic seizures per month when compared to patients (79%) with a total of less than six generalized tonic-clonic seizures (p less than 0.05). The frequency of generalized tonic-clonic seizures is of predictive value for the seizure prognosis of patients with complex-partial seizures.     

Ictal Contralateral Paresis in Complex Partial Seizures

Summary: Certain behaviors that occur during a complex partial seizure (CPS) are useful in lateralizing the side of seizure onset. In 5 (5.3%) of 94 consecutive patients with partial epilepsy, we observed ictal unilateral arm and hand paresis during 27 of 34 CPS. In all these seizures, this behavior occurred contralateral to an epileptogenic temporal lobe, as determined by video-EEG monitoring and surgical outcome. In 5 of the 27 seizures, an observer demonstrated that the paretic arm and hand were flaccid. None of these patients had postictal (Todd's) paralysis. In most of the seizures, the arm ipsilateral to seizure onset had simultaneous purposeful movements or automatisms, sometimes with awkward posturing. Ictal unilateral paresis is distinctly different from ictal dystonia or postictal paralysis and consistently lateralizes seizure onset to the contralateral temporal lobe. Recognition of this particular ictal behavior and comparison to other simultaneous behaviors can aid in the lateralization and possibly localization of the epileptogenic zone.     

A Retrospective Study of 113 Epileptic Patients Treated with Sustained-Release Valproate

Summary: A retrospective study of 113 patients treated with a sustained-release form of valproate (SRF-VPA), known as the "chrono" formulation in most European countries, led to the following conclusions: Patients treated with the old VPA formulation could immediately receive the same daily dosage of SRF-VPA without loss of seizure control when administered as a single evening dose. The tolerability of SRF-VPA was good and twice or single daily dosing was preferred by all our patients. Whether or not SRF-VPA should be used as first or second-line treatment in partial seizures that do or do not secondarily generalize is unclear. Our study demonstrates that the efficacy of SRF-VPA is comparable with that of other major antiepileptic drugs such as carbamazepine (CBZ). In refractory seizures, the combination of SRF-VPA and CBZ seemed to be the most satisfactory treatment. Based on these results SRF-VPA is a promising drug for all types of seizures even in low daily dosage, but further clinical work is required to confirm our observations.     

Surgical Treatment of Complex Partial Seizures: Results, Lessons, and Problems

Summary: The underlying seizure tendency of complex partial seizures often involves the temporal region of the brain, but the frontal lobe can also produce similar complex partial seizures. By the end of 1980, 1,210 patients with medically refractory temporal lobe epilepsy had been operated on at the Montreal Neurological Institute. Nontumoral epileptogenic lesions were present in 1,034 patients, 169 had tumors, and 7 had major vascular malformations. Thirty-seven percent of the 894 evaluable patients with nontumoral epileptogenic lesions have become and remained seizure-free. Two hundred thirty-six (26%) patients had a marked reduction of seizure tendency. Within the seizure-free group, 63% had a complete or nearly complete reduction of their medically refractory tendency following temporal lobectomy. Of the patients with temporal lobe epilepsy due to tumoral lesions, 46% of the evaluable patients have become and remained seizure-free, and 76% have had a complete or nearly complete reduction of seizure tendency.     

Effect of Naloxone Infusion on the Rate of Epileptiform Discharges in Patients with Complex Partial Seizures

In experimental studies, endogenous opioids have shown protective effects on seizure recurrence and facilitatory effects on postictal inhibition that were reversed by the opioid antagonist, naloxone. We evaluated the effect of all-night continuous infusion of 10 mg naloxone on the rate of focal interictal epileptiform discharges (FIEDs) during sleep in eight men with complex partial seizures (CPS) during 2 consecutive nights. Patients with abundant FIEDs during the control night showed a mean increase of 39% in the rate of FIEDs per unit of time during the naloxone infusion night. During the naloxone infusion night, mean nocturnal plasma prolactin (PRL) concentrations in this group of patients showed significant elevation, which was correlated with increased density of FIEDs. All-night infusion of naloxone failed to show any effect on the remaining three patients with minimal or no FIEDs during the control night. Mean nocturnal plasma PRL concentrations in this group of patients was significantly lower than in the former group. Our data support the notion that, in response to interictal or ictal discharges, endogenous opioid peptides may exert an inhibitory action that is reversible by administration of naloxone.     

Complex Partial Seizures Associated with a Temporomandibular Joint Defect

A case of a 32-year-old man is reported with complex partial seizures secondary to a right inferior temporal epileptic focus immediately overlying an abnormality of the temporomandibular joint, with a defect in the middle temporal fossa that allowed the mandibular condyle to contuse the temporal lobe.     

Complex Partial Seizures of Hippocampal and Amygdalar Origin

We studied the first clinical manifestations of 72 complex partial seizures (CPS) in 17 drug-resistant patients. CPS were indicated to be of hippocampal-amygdalar origin by scalp and depth EEG. We asked: (a) Do all CPS of hippocampal-amygdalar origin start with an initial motionless stare and/or oroalimentary automatisms? (b) If not, what other clinical manifestations appear at onset of the CPS? Results showed that approximately 39% of CPS begin with motionless staring, 25% with nonfocal discrete movements, 21% with oroalimentary automatisms, 10% with perseverative stereotyped automatisms, and 6% with vocalizations. Nonfocal discrete movements and oroalimentary automatisms were identified as the most common second and third clinical sequential manifestations during a CPS. We conclude that although approximately 60% of CPS of hippocampal-amygdalar origin start with motionless staring or oroalimentary automatisms, 40% do not.     

Postictal Psychosis After Partial Complex Seizures: A Multiple Case Study

Bouts of unusually frequent partial complex seizures originating in the temporal lobe, that sometimes became secondarily generalized, induced psychotic episodes in 9 patients. In 7, the increase in seizures occurred at a time when antiepileptic drugs (AEDs) were being reduced during intensive EEG monitoring with a view to surgical treatment of intractable epilepsy. According to DSM-III-R criteria, the postictal psychosis resembled an organic delusional syndrome which was paranoid in 7 and schizophreniform in 1 and an organic mood syndrome in 1. A high incidence of ictal fear, of bilateral independent epileptogenic discharge, and of small foreign tissue lesion were unexpected findings and appeared to represent risk factors, especially in patients otherwise handicapped by an epileptic personality disorder. Recognition of postictal psychosis in this setting and in others is important both prognostically and therapeutically. Postictal psychosis does not constitute a contraindication to surgical treatment of epilepsy.     

Association Between Regularly Occurring Complex Partial Seizures and Thyroid Function Parameters

A 28-year-old man with regularly occurring clusters of complex partial seizures was studied over a total of 224 days. His seizure periods lasted 2-4 days and occurred at intervals of 5-6 weeks. Several parameters were studied. The most striking finding was an increase in the serum concentration of thyroxine prior to and during the seizure periods. The concentrations of urine catecholamines and serum cortisol also varied with the seizure periods, but these hormones increased after the seizure periods had begun. To determine if there is a general 4-6-week rhythm in thyroid hormone concentrations, 12 weekly blood samples from 10 healthy male students were analyzed. No rhythmicity was found.     

添加托吡酯治疗难治性癫痫部分性发作临床疗效的初步观察

目的 观察添加托吡酯对难治性癫痫部分性发作的临床疗效。方法 选择难治性癫痫部分性发作11例,保持原用AEDS不变,逐步递增托吡酯剂量,目标剂量200mg/日。结果 完全控制2例,显效2例,有效4例,无效3例,有效率73％（8／11）。结论 添加托吡酯对难治性癫痫部分性发作有较好疗效。     

Tiagabine Monotherapy in the Treatment of Partial Epilepsy

Summary: Three studies were conducted to assess tiagabine (TGB) hydrochloride monotherapy in patients with partial seizures. The first was a double-blind, placebo-controlled trial of 11 patients (seven TGB, four placebo) undergoing evaluation for epilepsy surgery. Baseline antiepileptic drug (AED) therapy was discontinued abruptly before monotherapy. Although 24-h seizure rates increased during monotherapy in both groups, patients receiving TGB experienced fewer seizures than placebo patients. Subsequent studies (an open-label, dose-ranging study; n = 31 and a double-blind, randomized comparison of 6 and 36 mg/day TGB; n = 102 and 96, respectively) involved discontinuation of baseline AEDs. In the dose-ranging study, 19 of 31 patients (61%) converted to TGB monotherapy, with a mean final dose of 38.4 mg/day (range 24–54 mg/day) in those who completed the study ( n = 12). In the low- vs. high-dosage study, median 4-week complex partial seizure rates decreased significantly in patients from both dose groups who completed the monotherapy period ( p <0.05 compared with baseline). In the intent-to-treat analysis, significantly more patients in the high-dose group experienced a reduction in seizures of at least 50% compared with the low-dose group ( p = 0.038). Overall, the types of adverse events with TGB monotherapy were similar to those observed in add-on trials. These initial trials in difficult-to-treat epilepsy patients indicate that TGB monotherapy may provide a new approach to the treatment of patients with partial seizures refractory to other AEDs.