Cryptogenic Partial Epilepsies with Anti-GM1 Antibodies: A New Form of Immune-Mediated Epilepsy?

Summary: Purpose : We wished to study immune system dysfunction which has been proposed as a potential cause of epilepsy. Epileptogenic action of antibodies directed against GM1 gangliosides was demonstrated in rats, but the potential role of anti-GMI antibodies in human epilepsy has not yet been studied.
Methods : We investigated the presence of IgG or IgM anti-GMI antibodies in the sera of 64 patients with various types of epileptic syndromes: idiopathic generalized epilepsy (ICE) (n = 6), symptomatic or cryptogenic generalized epilepsy (SCGE) (n = 7), symptomatic partial epilepsy (SPE) (n = 26), and cryptogenic partial epilepsy (CPE) (n = 25).
Results : Two patients had elevated titers of IgM anti- GMl antibodies, one patient had elevated titers of both IgM and IgG anti-GM1 antibodies, and I patient had elevated titers of IgG anti-GMI antibodies. All 4 patients had complex partial seizures (CPS) secondarily generalized, generalized, drug resistance, psychiatric disorders, and normal brain imaging. Anti-GMI antibodies were never associated with ICE, SCGE, or SPE. We compared the reactivity of sera from these patients with the sera from 5 patients with motor neuropathies with conduction block (MNCB) against different gangliosides and concluded that epilepsy sera did not react with the Gal(β1-3)GalNAc epitope. Two anti-GM1-positive patients were treated successfully with high-dose intravenous immunoglobulins (IgIV).
Conclusions : Our findings suggest that detection of anti-GM1 antibodies could allow identification of a subgroup of patients with partial epilepsy associated with an autoimmune response. If anti-GM1 antibodies prove pathogenic, they could be an important prognostic factor for drug resistance and worsening of seizures.     

Nonpharmacologic Treatment of the Catastrophic Epilepsies of Childhood

Summary:  The catastrophic epilepsy syndromes of childhood are initially treated with a pharmacologic intervention in most cases. However, due to the poor response patients often have to pharmacologic interventions, nonpharmacologic treatment options are an important part of a comprehensive treatment plan for this group of children. Additionally, nonpharmacologic therapy may offer a method to minimize associated morbidity and mortality. This article discusses the use of epilepsy surgery, the ketogenic diet, and vagus nerve stimulation in the treatment of patients with infantile spasms, Lennox-Gastaut syndrome, and progressive myoclonic epilepsy. Efficacy of the nonpharmacologic treatment options, as measured by reduction in seizure frequency, as well as by developmental progress or behavioral improvement, varies according to the specific catastrophic epilepsy disorder and the treatment option.     

Systematic Testing of Medical Intractability for Carbamazepine, Phenytoin, and Phenobarbital or Primidone in Monotherapy for Patients Considered for Epilepsy Surgery

Summary: Purpose: To assess medical intractability in patients considered for restrictive epilepsy surgery.
Methods: Seventy-four patients received single drug treatment with carbamazepine (CBZ), phenytoin (PHT), and either phenobarbital (PB) or primidone (PRM). Medical intractability was established if seizure control was not obtained despite maximum tolerable doses of the drug. In all, 120 single drug treatments were administered with the drugs that has not been administered at maximal doses in monotherapy before the study.
Results: Complete seizure control was not achieved in any patient. However, 7 patients (9.5%) had significant seizure reduction of at least 80%. In 4 patients, only the third antiepileptic drug (AED) proved effective.
Conclusion: The poor result of AED monotherapy in our patients may be attributed to the patients'long-standing chronic epilepsies and high seizure frequencies. Our findings suggest that despite the failure of one or two major AEDs in controlling seizures completely, further single drug treatment may still improve the quality of life in some patients who are candidates for epilepsy surgery.     

Ictal Characteristics of Cryptogenic Partial Epilepsies in Infancy

Twenty-three patients with onset of partial seizures (PS) during the first 2 years of life were collected in a single neuropediatric center and ictal events were analyzed. All patients initially had normal developmental and neurologic examinations, negative etiologic investigations, and at least two nonfebrile PS of a single type. Mean follow-up from first seizure to the last contact with the patient was 51 months (SEM 8.17 months). Ictal semiology was characterized by three types of seizures: simple PS with motor signs, complex partial seizures (CPS) with impairment of consciousness at onset followed by motor manifestations, and CPS with motor activity at onset. Versive phenomena, oroalimentary automatisms, and vegetative manifestations were frequently associated. The topography of the ictal discharges and the elementary ictal events, suggested involvement of the temporal lobe and somatomotor area. The diagnosis of PS can be difficult during the first year of life since some patients beginning with generalized seizures may evolve into partial seizures. The prognosis is guarded with regard to seizure persistence, but the neurologic outcome is better as a whole than is reported for infancy-onset epilepsies.     

Treatment algorithms in refractory partial epilepsy

An algorithm is a "step-by-step procedure for solving a problem or accomplishing some end....in a finite number of steps." ( Merriam-Webster, 2009 ). Medical algorithms are decision trees to help with diagnostic and therapeutic decisions. For the treatment of epilepsy there is no generally accepted treatment algorithm, as individual epilepsy centers follow different diagnostic and therapeutic guidelines. This article presents two algorithms to guide decisions in the treatment of refractory partial epilepsy. The treatment algorithm describes a stepwise diagnostic and therapeutic approach to intractable medial temporal and neocortical epilepsy. The surgical algorithm guides decisions in the surgical treatment of neocortical epilepsy.     

药物难治性癫痫外科治疗展望

癫痫是危害较大的神经系统疾病,其发病率在4‰～6‰.在我国有近600万癫痫患者,其中20%～30%患者对内科药物治疗效果不佳,是癫痫外科治疗的主要目标[1,2].近二十年来,随着神经电生理技术和神经影像学的飞速发展,药物难治性癫痫患者的术前定位和评估取得了明显的突破,外科手术已成为癫痫治疗的一种重要手段[2].同时,随着外科麻醉和手术技巧的不断改进,尤其是显微神经外科技术的应用,使癫痫的外科治疗越来越安全有效,外科治疗已成为治疗药物难治性癫痫患者的主要手段[2,3].     

Low-Grade Glial Neoplasms and Intractable Partial Epilepsy: Efficacy of Surgical Treatment

Summary: We performed a retrospective study of 51 consecutive patients who underwent operation for intractable partial epilepsy related to low-grade intracerebral neoplasms between 1984 and 1990. All patients had medically refractory partial seizures and a mass lesion identified on neuroimaging studies. Lesionectomy was performed on 17 patients, and 34 had lesion resection and corticectomy. Mean postoperative follow-up was 4.4 years (range 2–8 years). Sixty-six percent of patients were seizure-free, and 88% experienced a significant reduction in seizure frequency. In 16 patients (31%), antiepileptic drugs (AEDs) were successfully discontinued. Twenty-five of 31 (81%) eligible patients obtained a driver's license after successful operation. Patients with complete tumor resection and no interictal epileptiform activity on postoperative EEG studies had the best operative outcome. Epilepsy surgery can result in long-term improvement in seizure control and quality of life (QOL) in selected patients with intractable tumor-related epilepsy. Our results should be useful to clinicians considering treatment options for patients with intractable seizures related to low-grade intracerebral neoplasms.     

Pharmacologic Treatment of the Catastrophic Epilepsies

Summary:  Treatment of the catastrophic epilepsies [infantile spasms (IS), Lennox-Gastaut syndrome (LGS), and progressive myoclonic epilepsy (PME)] remains a challenge to clinicians. For IS, adrenocorticotropic hormone has traditionally been the drug of choice in the United States but may be associated with serious side effects in some patients. Vigabatrin has shown promise in treating IS patients, particularly those with tuberous sclerosis. However, the drug is associated with visual field loss and is not commercially available in the United States. Newer antiepilepsy drugs (AEDs), such as zonisamide, topiramate (TPM), and lamotrigine (LTG), may be useful in patients with IS. Although LTG, TPM, and felbamate are approved in the United States for the treatment of LGS, the overall effectiveness of therapy in patients with LGS is poor. For PME, valproate is a first-line treatment. Zonisamide and levetiracetam also show promise. Supplementation with certain cofactors to correct deficiencies and increase mitochondrial function may be useful in some patients with PME, but response to such therapy is not well documented. Advances in our understanding of the etiologies, mechanisms, and genetics underlying the catastrophic epilepsies may facilitate more effective pharmacologic interventions.     

Partial Epilepsies in Infancy: A Study of 40 Cases

Forty patients with partial epilepsy that began before they were aged 3 years were recorded at the Centre Saint-Paul between 1981 and 1986 with a follow-up ranging from 1 year 9 months to 20 years. We analyzed the following data: age at onset, clinical features of seizures at onset and during the follow-up period, ictal and interictal EEG features, etiologic circumstances, evolution of the epilepsy, and psychomotor development. The age of onset was mostly between 2 months and 2 years (more than two thirds of cases). Most had partial symptomatic epilepsy. In nine cases, epilepsy was preceded by febrile convulsions. Seizures at onset were of the following type (in order of decreasing occurrence): unilateral seizures, complex partial seizures, elementary partial seizures, and other seizures, often difficult to classify. A few patients with infantile spasms associated with focal or multifocal EEG abnormalities, differing from West's syndrome, were included in this study. We discuss the problem arising from the classification of infantile seizures and epilepsies.     

Predictors of Intractable Epilepsy in Childhood: A Case-Control Study

Summary: Little is known about what factors predict intractable epilepsy at the time of initial diagnosis. We performed a case-control study to identify early predictors of medically intractable epilepsy in children. Cases were children who had an average of one seizure or more a month over a 2-year period and who, during that time, had failed trials of at least three different antiepileptic drugs (AEDs). Controls were children who had epilepsy, who had been seizure-free for 2 years, and who had never, before becoming seizure-free, met the definition for intractable epilepsy. Strong univariate associations were noted between intractability and several factors: infantile spasms (IS) remote symptomatic epilepsy, a history of status epilepticus (SE) before the diagnosis of epilepsy, neonatal seizures, and microcephaly. Cases were significantly younger than controls at onset (1.8 vs. 5.8 years); this was not due solely to cases with onset during the first year of life but was an association apparent throughout the age range studied. With multiple logistic regression, independent predictors of intractability were IS, odds ratio (OR) = 10.42, p = 0.03; age at onset with a decreasing risk with increasing age, OR = 0.77 per year, p < 0.0001; remote symptomatic epilepsy, OR = 2.24, p = 0.04; and SE, OR = 3.30, p = 0.04. These findings complement those of recent cohort studies of remission of epilepsy and provide useful leads for future prospective studies of intractable epilepsy.     

Nonsymptomatic generalized epilepsy in children younger than six years: excellent prognosis,but classification should be reconsidered after follow-up: the Dutch Study of Epilepsy in Childhood

PURPOSE: To assess the prognosis and the accuracy of the epilepsy classification in young children with nonsymptomatic generalized epilepsy. METHODS: Of the cohort of the Dutch Study of Epilepsy in Childhood (n = 466), all children younger than 6 years with a diagnosis of idiopathic (IGE) or cryptogenic (CGE) generalized epilepsy either at intake (n = 108) and/or after 2 years of follow-up (n = 102) were included. The number of reclassifications after 2 years was determined, and the reasons for reclassification were analyzed. All children receiving a diagnosis of IGE or CGE at 2 years were followed up for 5 years to study their outcome in terms of terminal remission (TR). Data on their level of intellectual functioning were collected at the start of this analysis. RESULTS: The epilepsy syndrome was reclassified in 17 children. In 14 of them, the seizure type also was reclassified, and in three, the course of the epilepsy determined the new epilepsy type. Two other children had a reclassification of their seizure types without a change of the epilepsy type. Many children were categorized as having IGE not otherwise specified. In all probability, this is a heterogeneous group, containing patients with various epilepsy syndromes, with generalized tonic-clonic seizures as a common hallmark. Of the 102 children with IGE or CGE at 2 years of follow-up, 75% had a TR of >6 months after 2 years, and 85% a TR of >or=1 year after 5 years. CONCLUSIONS: In a fair proportion of children with nonsymptomatic generalized epilepsy in this age group, it is not possible to classify firmly the epilepsy and/or the seizures immediately after the intake. Instead, they are reclassified during the course of the disease. This and the apparent heterogeneity of the category IGE not otherwise specified point to inherent drawbacks of the current International League Against Epilepsy (ILAE) classification of epilepsy and epileptic syndromes. The prognosis of IGE at this young age is generally excellent.     

Childhood Secondary (Symptomatic) Epilepsy, Seizure Control, and Intellectual Handicap in a Nontropical Region of South Africa

PURPOSE: To determine the prevalence of secondary (symptomatic) epilepsy and to ascertain levels of seizure control and intellectual function in a clinic population of children drawn from a poor community in a temperate region of South Africa. METHODS: Detailed review of the records of every child with recurrent seizures who attended a special epilepsy outpatient clinic during 1995. RESULTS: A total of 1,017 children was studied. In 432 (43%), there was historic, clinical, and radiologic evidence to suggest that epilepsy was symptomatic of underlying brain damage or defect. Acceptable seizure control was maintained with a single standard anticonvulsant drug (AED) in 65% of cases. In the 6 months preceding the study, 37% of the subjects had remained seizure free. Forty-seven percent of the study population were considered to be of subnormal intelligence. CONCLUSIONS: In a children's hospital outpatient population in the Western Cape region of South Africa, the prevalence of secondary epilepsy is higher than is found in developed countries. There is need within the community for preventive measures aimed at reducing the prevalence of perinatal insults, meningitis, tuberculosis, neurocysticercosis, and cerebral trauma.     

Identifying potential surgical candidates in patients with evidence of bitemporal epilepsy

PURPOSE: To determine which patients with evidence of medically refractory bitemporal epilepsy are potentially good candidates for surgical therapy. METHODS: We reviewed 42 adults with intractable seizures who were found to have bitemporal ictal onsets, based on scalp video-EEG long-term monitoring (LTM). All underwent invasive LTM before surgery. Surgical outcomes were classified as seizure free, >75% reduction in seizures, or <75% reduction in seizures, >or=1 year after resection. We related the following factors to outcome: (a). >75% preponderance of interictal scalp EEG discharges to one temporal region; (b). magnetic resonance imaging (MRI) findings; (c). lateralizing deficits on verbal or visual reproduction memory testing; and (d). memory failure with injection contralateral to side of surgery on Wada testing. RESULTS: Twenty-six (62%) of 42 patients had unilateral ictal onsets based on intracranial studies. Seizure freedom (occurring in 64% of this group), or >75% seizure reduction (found in 12% of subjects) occurred only when at least one of the following three factors was concordant with the side of surgery: preponderance of interictal scalp EEG discharges, unilateral temporal lesion on MRI, or lateralizing verbal or visual reproduction memory deficits on neuropsychological tests (p = 0.004). Seven subjects with bilateral ictal onsets based on intracranial studies had resections based on preponderance of seizures to one side, or other lateralizing noninvasive abnormality. Five of these (all of whom had >or=80% of seizures originating from one side) had >75% reduction in seizures. CONCLUSIONS: Invasive monitoring to pursue possible surgical therapy for patients with surface EEG evidence of bitemporal epilepsy may be justified only when some lateralizing feature is found in other noninvasive assessments.     

High-resolution MRI enhances identification of lesions amenable to surgical therapy in children with intractable epilepsy

PURPOSE: Many children with refractory epilepsy can achieve better seizure control with surgical therapy. An abnormality on magnetic resonance imaging (MRI), along with corroborating localization by other modalities, markedly increases chances of successful surgical outcome. We studied the impact of high-resolution MRI on the surgical outcome of intractable epilepsy. METHODS: High-resolution MRI using four-coil phased surface array was obtained as part of the comprehensive presurgical protocol for children with focal onset intractable seizures evaluated by our epilepsy center during the first half of 2002. RESULTS: Thirteen consecutive children, ages 5 to 18 years, entered this prospective study. For four patients with a lesion on a recent MRI examination with a standard head coil, management did not change with high-resolution MRI. Standard MRI in the other nine patients did not identify a lesion. However, high-resolution MRI with the phased-array surface coil found previously undiagnosed focal abnormalities in five of nine patients. These abnormalities included hippocampal dysplasia, hippocampal atrophy, and dual pathology with frontal cortical dysplasia. In four of nine patients, no identifiable lesion was identified on the high-resolution MRI. All patients underwent invasive monitoring. In three of five patients, newly diagnosed lesions correlated with EEG abnormalities, and resection was performed. CONCLUSIONS: In our center, high-resolution MRI identified lesions not detected by standard MRI in more than half the children (56%). Technical advances such as four-coil phased surface array MRI can help identify and better delineate lesions, improving the diagnosis of patients who are candidates for surgical treatment of refractory epilepsy.     

Prevalence of the Epilepsies in Children and Adolescents

The prevalence of epilepsy in children and adolescents from birth through age 19 years was determined for residents of two counties in central Oklahoma. Cases, identified from hospitals, clinics, private physicians' offices, and EEG laboratory and emergency room records, numbered 1,159, yielding a prevalence rate of 4.71 per 1,000. The prevalence was highest in children aged 1-4 years. Overall, males had a slightly higher prevalence rate than females (M:F = 1.1). However, the male/female ratio varied by age, with the group aged less than 1 year having the highest ratio (M:F = 1.5), and by type of epilepsy, with males having higher rates of simple partial epilepsy (M:F = 1.8) and infantile spasms (M:F = 1.5). The prevalence of epilepsy was higher in blacks than in whites. Differences in prevalence by race were confined primarily to generalized epilepsies (B:W = 1.8). The most common types of epilepsy were tonic, clonic, and tonic-clonic (1.14 per 1,000), complex partial (0.39 per 1,000), and partial seizures secondarily generalized (0.33 per 1,000). Approximately 70% of cases were considered idiopathic. Among the presumed causes were perinatal factors (7%), trauma (4%), central nervous system (CNS) infection (3%), and congenital/developmental factors (3). Sixty-five percent of cases had at least one additional medical problem. The most common types of comorbidity were motor handicap (13%) and developmental delay (24%).     

Gene Mapping in the Idiopathic Generalized Epilepsies: Juvenile Myoclonic Epilepsy, Childhood Absence Epilepsy, Epilepsy with Grand Mai Seizures, and Early Childhood Myoclonic Epilepsy

Summary: Idiopathic generalized epilepsies, i.e., juvenile myoclonic epilepsy (JME), childhood absence epilepsy, and epilepsy with grand mal [generalized tonic-clonic seizures (GTCS)], are the most common genetic epilepsies. Linkage studies using Bf, HLA serologic, and DNA markers by three independent investigators, one from Los Angeles and two from Berlin, have localized the JME locus to the short arm of chromosome 6 (6p). Because members of the same JME family have the same JME phenotype of childhood absence epilepsy, epilepsy with grand mal (GTCS) seizures, or early childhood myoclonic epilepsy (ECME), our observations give evidence for a single-locus etiology in 6p for JME and for at least some of the childhood absence seizures, epilepsy with grand mal (GTCS) seizures, and ECME. Studies should now address whether locus heterogeneity exists within childhood absence epilepsy, epilepsy with grand mal (GTCS) seizures, or ECME. Markers linked to JME (Bf, HLA serologic, and DNA markers in the DQ region) can be used to resolve etiologic heterogeneity. Using such markers, both linked and unlinked forms of phenotypes that are clinically indistinguishable may be detected and provide evidence for etiologic heterogeneity. Studies should also concentrate on narrowing the JME locus to 2 to 3 cm by screening families with recombinant events using RFLPs, candidate genes, and new expressed sequences on chromosome 6.     

Rational Treatment of Refractory Epilepsy in Childhood

Abstract: A multifaceted study on childhood refractory epilepsy disclosed an insufficient classification of epilepsies and epileptic seizures, and inappropriate polypharmacy as the most important factors preventing appropriate therapy. By means of an adjustment of AEDs based on the accurate classification of epilepsies and epileptic seizures, the number of AEDs could be reduced in 37.5% and monotherapy was successful in 13.8% of refractory cases. Most of the latter were those of partial epilepsy and generalized epilepsy with the monoseizure type. The exacerbation of seizures due to AEDs was also mentioned as one of the important side effects of AEDs.     

Pediatric intractable epilepsy: the role of presurgical evaluation and seizure outcome

Surgical experience with long-term follow-up is limited in childhood intractable epilepsy, compared with adult epilepsy. To assess the role of each presurgical evaluation modality and to identify prognostic factors for favorable seizure control after epilepsy surgery, 38 children with intractable epilepsy who underwent surgery were retrospectively reviewed. Among the available preoperative evaluation modalities, PET and neuropsychological testing showed the highest rates of positive results, whereas MRI was the most concordant with EEG findings. During a follow-up period of at least 12 months, 26 of the 38 patients showed favorable seizure control (Engel classifications I and II). The best seizure control was achieved in patients with a temporal resection and discrete lesion on magnetic resonance imaging. In spite of the invasive study, the less satisfactory results followed an extratemporal resection. We conclude that epilepsy surgery benefits children with intractable epilepsy and that the role of invasive study should be re-established according to the area of resection and presence of discrete lesion on MRI. Received: 23 June 1999 Revised: 7 August 1999