The Problem of Intractability: The Continuing Need for New Medical Therapies in Epilepsy

Summary: Treatment of epilepsy, one of the most common neurologic disorders, has evolved from "institutional" poly-therapy to "dogmatic" monotherapy, and, most recently, to "rational" polypharmacy. The introduction of bromides for the treatment of epilepsy was followed first by phenobarbital and then by phenytoin as therapeutic options. Although attempts to combine medications were legion, none was supported by studies that demonstrated the benefit of such combinations. The issue of adverse effects became a principal argument in favor of monotherapy. Monotherapy, using newly developed drugs, avoided problems due to drug interactions but was ineffective in 20–30% of patients. A greater understanding of basic disease mechanisms and developments in molecular biology have led to an increased number of effective drugs for the estimated 6–12% of patients with epilepsy whose condition is intractable. Clinical research continues to build on the work of basic scientists in attempting to develop treatments based on a desire to move beyond the palliative and to affect the causative mechanisms of the disease. Novel medical approaches now under exploration include the use of drugs with complementary mechanisms of action, stimulation of various components of the nervous system, biochemical manipulations, focal intracerebral drug perfusion, and gene therapy.     

多靶点调控手术治疗难治性精神病80例近期疗效观察

目的:探讨立体定向技术和多靶点组合对难治性精神病的治疗意义,综合评估临床疗效。方法:在立体定向基础上,应用CT、电阻值和微电极电生理进行核团定位,对80例难治性精神病患者,采用杏仁核、内侧隔区、扣带回等多靶点组合射频热凝治疗。应用临床疗效总评量表(clinicalgrobalimpressionsscale,CGl)、简明精神病评定量表(briefpsychiatricratingscale,BPRS)、阴性和阳性综合量表(thepostitveandnegativesyndrome,PNSS)精神病评定量表在术后6个月对治疗效果进行评定。结果:依据减分率标准,80例患者中,显著进步46例,进步31,无变化3例。手术前后量表评分有显著差异(P<0.05)无严重并发症和后遗症发生。结论:多靶点组合的立体定向技术是难治性精神病的有效治疗方法之一,靶点组合设计和亚核团的准确定位,对提高疗效,降低并发症有较大意义。     

Diagnostic significance of Wada procedure in very young children and children with developmental delay

Localization of vital components of neurological functioning has to be performed before epilepsy surgery can be considered in children with intractable epilepsy. This study reports the experience with the Wada procedure in very young children and/or developmentally delayed children with an a priori considerable chance of failing the procedure. The aim of this study was to indicate the applicability of this procedure in this patient group. The Wada procedure is described in 16 children under 10 years of age and/or have intelligence quotient scores below 50 and/or are critically ill and/or are behaviourally disturbed. Information on motor, language and memory functioning is obtained in respectively 13/15, 9/13, and 5/11 children. Nine children underwent epilepsy surgery without postoperative impairment of neurological functioning. In five children epilepsy surgery was not performed because of the results of the Wada procedure or the lack of information during the Wada procedure. One child became seizure-free before surgery. Even in very young, developmentally delayed or behaviourally disturbed children, the Wada test can provide important information with respect to the decision pro or contra epilepsy surgery.     

Quality-of-life trajectories in epilepsy: a review of the literature

The potential psychosocial sequelae of epilepsy are well-documented, but it cannot be assumed that trajectories for quality of life (QOL) of people with epilepsy will inevitably follow its clinical course. In this article, we draw on available literature to suggest likely QOL trajectories associated with epilepsy and the broad range of disease-, patient-, and other-focused factors that appear important in determining them. We conclude that both the likely shape and time frame for QOL trajectories associated with particular clinical scenarios can be delineated, but that their shape can be altered by a much wider range of factors than those represented as epilepsy disease progression. We identify contributory factors currently relatively unexplored and highlight implications for treatment and areas for future research.     

The Progression of Epilepsy

Summary:  Prognosis for seizure control and cognitive development varies considerably among syndromes. Several factors may interact to influence outcome of an epilepsy including a causative etiology, ictal and interictal discharges, seizure-related trauma or systemic perturbations, and antiepileptic drug (AED) effects. Clinical evidence convincingly supporting Gowers' hypothesis that seizures beget seizures is lacking. Short-term seizure suppression by early treatment does not appear to influence long-term prognosis.
Malignant epilepsy syndromes usually begin in infancy or childhood, have a high seizure frequency, resist the initial AED, and are often associated with progressive cognitive dysfunction. Prompt management of some severe epilepsy syndromes may lessen cognitive decline. However, aggressive AEDs therapy must be balanced against the potential for cognitive side effects, particularly if multiple AEDs are used.
Several experimental paradigms closely parallel human TLE as both have an initial precipitating injury (IPI), a latent period, then recurrent spontaneous seizures. In humans, an IPI is any medical event with neurological implications. Although transition from a latent period to a seizure disorder certainly constitutes "progression" of the disorder, convincing clinical evidence of subsequent worsening has not emerged. Substantial clinical and experimental evidence indicates some cognitive regression and focal atrophy with time for TLE and other intractable syndromes. However, seizure frequency and severity, established early in the disorder, appear stable in most patients, and even regress in benign syndromes. Factors mitigating or extinguishing epilepsies need to be further sought.     

难治性精神分裂症的立体定向手术治疗——术后一年随访结果

目的探讨立体定向手术治疗难治性精神分裂症的临床疗效。方法对251例难治性精神分裂症患者,采用CT定位立体定向双侧杏仁核、内囊前肢、扣带回等多靶点组合毁损治疗,术中用电阻值和微电极电生理验证靶点,其中17例患者因首次手术后3~6个月疗效不佳而接受二次手术。术后1年由精神科医生对治疗效果进行评定。结果251例患者中,恢复13例、显著进步200例、进步29例、无变化9例,无严重并发症发生。结论CT导向立体定向多靶点组合毁损术安全,是难治性精神分裂症的有效治疗方法之一。     

Involvement of genes encoding apoptosis regulatory factors (FAS,FASL, TRAIL,BCL2, TNFR1 and TNFR2) in the pathogenesis of autoimmune thyroid diseases

Apoptosis is necessary for the maintenance of self-tolerance by eliminating autoreactive immune cells in the periphery. To clarify the association between the pathogenesis of autoimmune thyroid disease (AITD) and genes encoding apoptosis regulatory factors, we genotyped the FAS −1377G/A, −670A/G, FASL −844C/T, TRAIL −716C/T, BCL2 −938C/A, +127G/A, TNFR1 −383A/C and TNFR2 +676T/G polymorphisms. The frequencies of the FASL −844CC and BCL2 −938AA genotypes were significantly lower in AITD patients than in control subjects (P = 0.0101 and 0.0307, respectively). The frequency of the TNFR2 +676TT genotype was significantly lower in Graves’ disease (GD) patients than in controls (P = 0.0284). The serum sFasL level was significantly higher in GD and Hashimoto’s disease (HD) patients than in control subjects (P = 0.0003 and 0.0017, respectively). The serum sFasL levels in control subjects were significantly lower than those in intractable GD, GD in remission, and HD without treatment (P = 0.0310, 0.0007 and 0.0002, respectively). The serum sFasL levels in HD with treatment were significantly lower than those in HD without treatment (P = 0.0490). The polymorphisms in genes encoding apoptosis regulatory factors (FASL, BCL2) and serum levels of sFasL may be associated with immune dysregulation.     

Striking differences in individual anticonvulsant response to phenobarbital in rats with spontaneous seizures after status epilepticus

PURPOSE: More than one third of patients with epilepsy have inadequate control of seizures with drug therapy, but mechanisms of intractability are largely unknown. Because of this large number of pharmacoresistant patients with epilepsy, the existing process of antiepileptic drug (AED) discovery and development must be reevaluated with a focus on preclinical models of therapy-resistant epilepsy syndromes such as mesial temporal lobe epilepsy (TLE). However, although various rodent models of TLE are available, the pharmacoresponsiveness of most models is not well known. In the present study, we used a post-status epilepticus model of TLE to examine whether rats with spontaneous recurrent seizures (SRSs) differ in their individual responses to phenobarbital (PB). METHODS: Status epilepticus was induced in Sprague-Dawley rats by prolonged electrical stimulation of the basolateral amygdala. Once the rats had developed SRSs, seizure frequency and severity were determined by continuous EEG/video recording over a 6-week period (i.e., a predrug control period of 2 weeks, followed by PB treatment for 2 weeks, and a postdrug control period of 2 weeks). PB was administered twice daily at maximal tolerated doses. RESULTS: Analysis of plasma drug concentrations showed that drug concentrations within the therapeutic range (10-40 microg/ml) were maintained in all rats throughout the period of treatment. In six (55%) of 11 rats, complete control of seizures was achieved, and another rat exhibited a >90% reduction of seizure frequency. These seven rats were considered responders. The remaining four (36%) rats showed either no response at all (n=3) or only moderate reduction in seizure frequency and were therefore considered nonresponders. Plasma drug concentrations did not differ between these two groups of rats. CONCLUSIONS: These data demonstrate that, similar to patients with epilepsy, rats with SRSs markedly differ in their individual responses to AED treatment. Pharmacoresistant rats selected by prolonged drug treatment from groups of rats with SRSs may provide a unique model to study mechanisms of pharmacoresistance and to identify novel AEDs for treating seizures of patients currently not controlled with existing therapies.