Clobazam Has Equivalent Efficacy to Carbamazepine and Phenytoin as Monotherapy for Childhood Epilepsy

Summary: Purpose: To compare the effectiveness of mono-therapy clobazam (CLB) to carbamazepine (CBZ) and phenytoin (PHT) in children with epilepsy.
Methods: Children aged 2–16 years with newly diagnosed epilepsy or previous failure of one drug (for poor efficacy or side effects) were assigned to one of two study arms and then randomized–CLB versus CBZ or CLB versus PHT. Eligible children had partial epilepsies or only generalized tonic-clonic seizures. After a drug initiation protocol, monotherapy treatment mimicked the usual routines used by Canadian child neurologists. Blinding used a "double dummy" technique with blinded medication serum levels (6–point scale). Intention to treat analysis using survival curves assessed the primary end-point–length of retention on the initial medication during the year after randomization.
Results: Fifteen centers entered 235 patients: 159 randomized to CLB versus CBZ and 76 to CLB versus PHT. Altogether, in all study arms, 119 received CLB, 78 CBZ, and 38 PHT. Overall, 56% continued to receive the original medication for l year with no difference between CLB and standard therapy (CBZ and PHT). Seizure control was equivalent for all three medications, as were side effects. PHT and CBZ induced more biologic side effects, such as rash, while CLB induced slightly more behavioral effects. Tolerance developed in 7.5% of patients receiving CLB, 4.2% with CBZ and 6.7% with PHT.
Conclusions: CLB should be considered as "first line" monotherapy along with CBZ and PHT for all partial and selected generalized childhood epilepsies.     

Nonconvulsive Status Epilepticus in Childhood Localization-Related Epilepsy

PURPOSE: To report on three children with localization-related epilepsy who exhibited minor seizures (atypical absences, brief atonic, and myoclonic) and nonconvulsive status epilepticus (NCSE) consisting of these minor seizures, and to elucidate their significance. METHODS: We studied the electroclinical characteristics of these children. Ictal electroencephalograms (EEGs) of NCSE were evaluated by using simultaneous video-EEG-electromyogram (EMG) polygraphic recordings. RESULTS: All patients began to have partial seizures between the ages of 6 months and 2 years 7 months, with minor seizures appearing later, between the ages of 1 year 11 months and 6 years 6 months. These minor seizures evolved into NCSE. Complex partial seizures remained after suppression of the minor seizures. Interictal EEGs taken when the minor seizures appeared showed excessive diffuse epileptic discharges in addition to multifocal spike-waves. Before and after suppression of the minor seizures, focal epileptic discharges predominated on the EEGs. On ictal EEGs of brief atonic and myoclonic seizures, diffuse spike-wave and polyspike-wave bursts were detected. Ictal EEGs of the atypical absences revealed diffuse spike-wave bursts mixed with irregular high-voltage slow waves, often interspersed with brief atonic and myoclonic seizures. When atypical absences lasted for a long time, patients manifested NCSE. Polytherapy might be related to the occurrence of minor seizures and NCSE, because all patients were treated with polytherapy at their appearance, and simplification of antiepileptic drug (AED) therapy seemed to be effective. CONCLUSIONS: We concluded that this NCSE is a type of atypical absence status which is an age-dependent, transient, electroclinical condition. The mechanism of occurrence of these minor seizures might be related to secondary bilateral synchrony.     

Partial epilepsy manifesting atonic seizure: report of two cases

PURPOSE: Atonic seizures are commonly seen in patients with generalized epilepsy but only infrequently in patients with partial epilepsy. Clinically generalized atonic seizures as a partial epilepsy have not been studied in detail with video/EEG monitoring. Here we describe the clinical and physiologic characteristics of atonic seizures due to partial epilepsy and discuss the underlying mechanism. METHODS: Two patients with partial epilepsy manifesting atonic seizures, one with frontal lobe epilepsy (FLE) and the other with parietal lobe epilepsy (PLE), were reported. The long-term video/EEG monitoring, magnetic resonance imaging (MRI), and interictal fluorodeoxyglucose-positron emission tomography (FDG-PET) were investigated in each patient. RESULTS: Paroxysmal diminution of muscle tone mainly involved the axial muscles in both patients. In contrast with the abrupt falls seen in patients with Lennox-Gastaut syndrome, the falls in these patients were slow, taking 2-5 s to fall down. Ictal EEG records showed low-voltage fast activity in the frontocentral area followed by repetitive spikes at the midline frontocentral area in the patient with FLE, and rhythmic spikes in the left central area in the patient with PLE. Interictal FDG-PET disclosed hypometabolic regions consistent with the clinical and EEG findings. CONCLUSIONS: Slow falls might be a feature of atonic seizures in partial epilepsy. Long-lasting atonia in partial epilepsy could be due to either one of the following two possible mechanisms: (a) epileptic activities arising from the negative motor area, of which 50-Hz electric stimulation causes motor inhibition, or (b) sustained atonia with successive electromyogram (EMG) silent periods caused by epileptic discharges arising from the inhibitory area of the primary sensorimotor area.     

Towards early diagnosis and treatment to save children from catastrophic epilepsy – Focus on epilepsy surgery

Objective: To analyze and to discuss whether by paying attention to the many recent advancements in the field of pediatric epilepsy surgery catastrophic childhood epilepsies caused by definitive or suspected structural lesions can be prevented more often these days in comparison to the past. Methods: Based on data from the literature and supplemented by the authors own experience, risks for children suffering from structural focal epilepsies that the epilepsy becomes catastrophic and ways how such evolutions can possibly be prevented are discussed for the different lesion-types separately – in the order of their frequency as they are seen at pediatric epilepsy surgery centers. Special emphasis is put on data regarding attempts to prevent permanent severe mental retardations. Results: There are common factors predisposing to catastrophic courses in all structural focal epilepsies, such as early onset and a longer duration of epilepsy (with respect to cognitive outcome not with respect to seizure outcome), but there are also differences. Moreover the better perspectives now in comparison to the past for children with conditions like MRI-negative focal epilepsies, subtle focal cortical dysplasias, epilepsies post hypoxic–ischemic events, tuberous sclerosis etc. are not well recognized yet. While there is agreement that “early” (and successful) surgery is essential in many instances to prevent permanent mental retardations there is insufficient data regarding the issue that “early surgery “might not be early enough under certain circumstances and there is also only little data regarding variables which would allow to keep calm when a child is presenting with early onset difficult to control seizures. One of the biggest changes seen over the last decade is the fact that children with very severe epilepsies, who have unilateral lesions, but “generalized” seizures and/or “generalized” EEGs, are not excluded anymore from considerations for epilepsy surgery. Even children with bilateral lesions can be surgical candidates. Conclusion: The gradually widening spectrum of indications for epilepsy surgery in children is resulting in an increasing number of preventions of catastrophic epilepsies. Insufficient data regarding timing of surgery in order to prevent permanent mental retardations are calling for prospective multi-center studies.     

γ-Vinyl-GABA (Vigabatrin) in the Therapy of Lennox-Gastaut Syndrome: An Open Study

Summary: The antiepileptic effect of vigabatrin (γ-vinyl GABA, VGB) in children has been demonstrated in controlled and open studies. According to the literature, results were good to excellent in partial seizures (with and without becoming secondarily generalized) and promising in infantile spasms (IS). In patients with myoclonic epilepsies of early childhood and especially those with Lennox-Gastaut syndrome (LGS), the effect of VGB has been investigated only to a limited extent and the pattern of response was variable. The present open, add-on, dose-ranging study was initiated to assess the long-term effect and safety of VGB in a cohort of 20 children with LGS who were not responding sufficiently to first-line drug monotherapy with valproate (VPA) instead of adding classical second-line antiepileptic drugs [AEDs: benzodiazepines (BZD), phenobarbital (PB), primidone (PRM)], which usually are associated with rapid diminution of their antiepileptic properties and a high frequency of side effects. Eighty-five percent of children experienced a 50–100% reduction in seizure frequency, even after dose reduction of VPA. No serious side effects occurred except in 1 patient who experienced dyskinesia. Mood changes, sedation, ataxia, and hypersalivation, well-known complications of other AEDs, were not observed.     

Uncovered primary seizure foci in Lennox-Gastaut syndrome after corpus callosotomy

Purpose

Corpus callosotomy (CC) is a palliative surgical procedure to control atonic, tonic, or generalized tonic-clonic seizure in Lennox-Gastaut syndrome (LGS). Here, we report patients with LGS who underwent resective surgery, following CC better delineating the presumed seizure foci localized in one hemisphere.

Methods

We retrospectively reviewed seven patients with LGS who underwent CC and subsequent cortical resection. The median follow-up duration after lobectomy was 20 months (range, 15-54 months) and three patients had follow-up periods over 24 months. The findings of video electroencephalography (EEG) monitoring, structural and functional neuroimagings were compared between pre- and post-CC.

Results

Four patients had Engel class I and one patient had Engel class II outcomes following cortical resection; post-CC, compared to pre-CC, showed better localized ictal/interictal epileptiform discharges in the unilateral frontal area in two patients, in the unilateral parieto-temporo-occipital areas in one patient and in the unilateral fronto-temporal areas in the remaining two patients. Two patients had Engel Class III outcome following cortical resection; post-CC EEG continued to show multifocal epileptiform discharges but predominantly arising from a unilateral frontal area. Following CC, positron emission tomography showed localized glucose hypometabolism of which location was concordant with post-CC EEG abnormalities in all patient. Similarly, ictal/interictal single photon emission computed tomography also showed localized abnormalities concordant with post-CC EEG abnormalities in five of the six patients. Pathological assessment revealed cortical dysplasia in six patients, whereas no pathological abnormality was found in the remaining patient, who obtained Engel Class I outcome following cortical resection.

Conclusion

CC could change EEG findings, glucose metabolisms and cerebral blood flows, and it is sometimes helpful in delineating the primary seizure focus in patients with LGS.     

Fenfluramine in the treatment of Dravet syndrome: Results of a third randomized,placebo-controlled clinical trial

Objective

This study was undertaken to assess the safety and efficacy of fenfluramine in the treatment of convulsive seizures in patients with Dravet syndrome.

Methods

This multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 clinical trial enrolled patients with Dravet syndrome, aged 2–18 years with poorly controlled convulsive seizures, provided they were not also receiving stiripentol. Eligible patients who had ≥6 convulsive seizures during the 6-week baseline period were randomized to placebo, fenfluramine .2 mg/kg/day, or fenfluramine .7 mg/kg/day (1:1:1 ratio) administered orally (maximum dose = 26 mg/day). Doses were titrated over 2 weeks and maintained for an additional 12 weeks. The primary endpoint was a comparison of the monthly convulsive seizure frequency (MCSF) during baseline and during the combined titration–maintenance period in patients given fenfluramine .7 mg/kg/day versus patients given placebo.

Results

A total of 169 patients were screened, and 143 were randomized to treatment. Mean age was 9.3 ± 4.7 years (±SD), 51% were male, and median baseline MCSF in the three groups ranged 12.7–18.0 per 28 days. Patients treated with fenfluramine .7 mg/kg/day demonstrated a 64.8% (95% confidence interval = 51.8%–74.2%) greater reduction in MCSF compared with placebo (p < .0001). Following fenfluramine .7 mg/kg/day, 72.9% of patients had a ≥50% reduction in MCSF compared with 6.3% in the placebo group (p < .0001). The median longest seizure-free interval was 30 days in the fenfluramine .7 mg/kg/day group compared with 10 days in the placebo group (p < .0001). The most common adverse events (>15% in any group) were decreased appetite, somnolence, pyrexia, and decreased blood glucose. All occurred in higher frequency in fenfluramine groups than placebo. No evidence of valvular heart disease or pulmonary artery hypertension was detected.

Significance

The results of this third phase 3 clinical trial provide further evidence of the magnitude and durability of the antiseizure response of fenfluramine in children with Dravet syndrome.     

切除性手术治疗学龄儿童病灶性Lennox-Gastaut 综合征

目的：研究MRI阳性的学龄期儿童Lennox-Gastaut 综合征（ LGS）患者切除性手术的疗效,并分析手术适应证。方法回顾性分析解放军总医院第一附属医院神经外科收治的学龄期LGS儿童患者14例,其中左侧大脑半球切除术1例,单脑叶切除术9例,多脑叶切除术4例。对患者的人口学特征和临床特征,手术方法,手术结果进行分析。结果本组患者MRI显示局限性异常6例,广泛性异常8例。病理灶全切除9例。术后1年和3年的癫痫无发作率为64．3％和57．1％。其中病理灶全切除和MRI显示局限病理者术后3年无发作率分别为75％和83．3％。术后较术前QOL改善者11例,术后IQ改善者9例。术后3年总体患者满意度评分为86．07％±12．66％。满意度与术后无癫痫发作有明显相关性（ P＝0．001）。术后使用AEDs较术前显著下降。结论切除性手术治疗学龄期儿童合并病理灶相关的LGS癫痫控制效果良好,QOL和IQ显著改善,安全性高。 MRI显示局限性病理灶的患者应当优先考虑切除性手术,完整切除病理灶疗效可能更好。     

Levetiracetam in the treatment of Lennox-Gastaut syndrome

Lennox-Gastaut syndrome is an epileptic encephalopathy characterized by multiple seizure types, mental retardation, and a slow spike-and-wave pattern on electroencephalography. Medical intractability is common. We identified a case series of six patients diagnosed with Lennox-Gastaut syndrome in which levetiracetam was initiated as add-on therapy for the management of seizures. At follow-up, four patients experienced 100% reduction of their myoclonic seizures; two patients had greater than 50% reduction of their atonic seizures, and four patients experienced 100% reduction in their generalized tonic-clonic seizures. Tonic seizures were not responsive to treatment. The most common side effect was irritability; the most positive change involved alertness. In this small sample, levetiracetam appeared effective in reducing seizures in Lennox-Gastaut syndrome. This preliminary study is limited by its retrospective design and small number of patients, but positive findings warrant a larger scale, multicenter study.     

Brief Atonia Associated with Electroencephalographic Paroxysm in an Infant with Infantile Spasms

The loss of muscular tone or muscular inhibition associated with sharp waves observed during abnormal tonic posture in a patient with infantile spasms of early onset is described. The latency between the beginning of a sharp wave and the muscular inhibition varied from 30 to 700 msec, and the duration of the inhibition ranged from 100 to 400 msec. These brief muscular inhibitions may sometimes precede tonic seizures, and these phenomena might be noticeable only in the state of steady tonic muscular contraction.     

Nitrazepam for the treatment of Lennox-Gastaut syndrome

Lennox-Gastaut syndrome is a severe childhood epileptic syndrome with encephalopathy and multiple seizure types, which are often intractable to treatment. Most of these children will ultimately become mentally retarded and dependent on others for their daily care. Antiepileptic drugs are the mainstay of treatment, however, no particular drug is entirely effective. Apart from the use of antiepileptic drugs, nonpharmacologic treatments are also considered (i.e., callosotomy, ketogenic diet, and vagus nerve stimulation), which have proven to be partially effective. We prospectively studied 14 children (11 months-8 years of age) with medication-resistant Lennox-Gastaut syndrome, being treated with nitrazepam (open-label compassionate protocol). We compared the 1-month baseline seizure frequency with the median seizure rate reduction during the first 12 months of treatment with nitrazepam. The median seizure rate reduction during the first 12 months of treatment with nitrazepam was 41% (P = 0.001), with more than 50% seizure reduction in 60% of patients. Two patients became seizure free, five patients demonstrated at least 50% reduction in seizure rates, six patients had at least 25% seizure rate reduction, and one patient did not respond. No patient had any serious adverse effects. Side effects included sedation in six children (40%) and drooling in nine patients (60%).     

拉莫三嗪治疗Lennox-Gastaut综合征的临床观察

应用拉莫三嗪添加、开放性自身对照法观察Lennox-Gastaut综合征患者8例,观察时间为3～31个月。结果:应用LTG后,2例患者(25%)癫痫发作停止,4例患者(50%)癫痫发作减少大于75%,总有效率75%。LTG对Lennox-Gastaut综合征的各型癫痫发作均有较好效果,脑电图有改善的倾向。部分患者应用LTG治疗后生活质量有一定的改善。副作用少。治疗前后各项实验室检查未见有临床意义的异常改变。     

Status Epilepticus Characterized by Repetitive Asymmetrical Atonia: Two Cases Accompanied by Partial Seizures

Two cases of discontinuous status epilepticus (SE) characterized by repetitive asymmetrical atonic episodes associated with diffuse but asymmetrical spike waves are reported. Both patients also had partial seizures and interictal rolandic discharges. Dynamic EEG topography was performed to investigate the location or propagation of each ictal discharge overlying the scalp during status and showed immediate bilateral spread of discharges originating from a primary epileptogenic focus from a rolandic area.     

The Natural History of Myoclonic Astatic Epilepsy (Doose Syndrome) and Lennox-Gastaut Syndrome

Summary:  The purpose of this article is to present a short review of the natural history of myoclonic astatic epilepsy (MAE; Doose syndrome) and the Lennox-Gastaut syndrome (LGS). In the 1989 classification of the International League Against Epilepsy (ILAE, 1989), MAE and LGS were initially included in group 2.2: "Cryptogenic or symptomatic generalized epilepsies and syndromes." The subsequent classification of the Proposed Diagnostic Scheme for People with Epileptic Seizures and with Epilepsy (see Ref. 8 ) placed MAE in axis 3 in the "generalized epilepsy" group and LGS, severe myoclonic epilepsy of infancy (SMEI or Dravet syndrome) and atypical benign partial epilepsy/pseudo-Lennox syndrome (ABPE/PLS) in the "epileptic encephalopathy" group. The semiology of MAE and LGS and their differential diagnosis from SMEI and ABPE/PLS are described. Before the onset of SMEI, MAE, and ABPE/PLS, the development of the child is usually normal. In contrast, in LGS, development is frequently retarded at the onset, depending on the etiopathogenesis of the underlying brain disease. The course of MAE is highly variable with regard to seizure outcome (complete remission in some cases, persistent epilepsy in others) and cognitive development (normal or delayed). The course of LGS and SMEI is generally poor, both with regard to the epilepsy and to the cognitive development whereas the course and seizure outcome of ABPE/PLS is favorable; the patients will be seizure-free at puberty. However, the neuropsychological outcome is less favorable; most patients remain mentally retarded.     

儿童灾难性癫痫手术治疗的探讨(附10例报告)

目的探讨儿童灾难性癫痫的手术治疗。方法回顾性分析10例手术治疗的儿童灾难性癫痫患者资料，比较手术前后癫痫发作情况及智能情况。结果除1例脱失外，余随访12月以上，所有患者术后无并发神经功能损害和智能障碍的加重。疗效评定为癫痫控制满意4例，显著改善2例，良好2例，较差1例。行为异常、语言障碍术后均有改善和提高；与术前比较。术后智商提高不明显。结论积极的手术治疗不仅能有效地控制儿童灾难性癫痫的发作，还能改善部分智能障碍。     

Long-Term Prognosis of the Lennox-Gastaut Syndrome

Abstract: A long-term follow-up study of 89 patients of Lennox-Gastaut syndrome (LGS) disclosed the persistent occurrence of seizures in 68 patients (76.4%) and severe mental defect in 48 (53.9%). An analysis of the correlation between the mental and seizure prognoses confirmed that the persistence of minor seizures could result in mental deterioration. An examination of the evolutional changes in EEG demonstrated that diffuse slow spike-waves characteristic of LGS gradually disappeared, while focal epileptic discharges, especially multifocal spikes, appeared in spite of the persistence of minor seizures. The diagnostic criteria were satisfied in only 31 (47.0%) of 66 patients with the persistence of minor seizures. Patients with multiple independent spike foci and minor seizures were considered to belong to a specific type of epilepsy, namely the severe epilepsy with multiple independent spike foci (the severe epilepsy with MISF). The seizure and mental prognoses were poorer in patients who evolved into the severe epilepsy with MISF than others.     

Vagus nerve stimulation in children with refractory seizures associated with Lennox-Gastaut syndrome

PURPOSE: Vagus nerve stimulation (VNS) is approved for use for refractory partial seizures. Nevertheless, information regarding VNS therapy for special populations, including Lennox-Gastaut syndrome (LGS) is limited. We discuss the effectiveness, tolerability, and safety of VNS therapy in patients with LGS. METHODS: A six-center, retrospective study evaluated the effectiveness of VNS therapy in patients with LGS at 3 and 6 months and compared preimplant and postimplant seizure frequency. Adverse effects and quality of life (QOL) were included as secondary measures. RESULTS: Fifty patients, median age 13 years, with medically refractory epilepsy, were implanted. Median age at onset of seizures was 1.4 years, and a median of nine anticonvulsants (AEDs) had been tried before implantation. Data-collection forms were designed for retrospectively gathering data on each patient's preimplant history, seizures, implants, device settings, QOL, and adverse events. Median reductions in total seizures were 42% at 1 month, 58.2% at 3 months, and 57.9% at 6 months. The most common adverse events reported were voice alteration and coughing during stimulation. Other uncommon adverse events included increased drooling and behavioral changes. Investigators noted that QOL had improved for some patients in the study. CONCLUSIONS: VNS is an effective treatment for medically refractory epilepsy in LGS. This treatment is well tolerated, safe, and may improve QOL.