Chronic Partial Epilepsy Research Articles

Cerebellar white matter changes in patients with newly diagnosed partial epilepsy of unknown etiology

ObjectiveWe hypothesize that pre-existing susceptible structures in the brain may be associated with the development of newly diagnosed partial epilepsy of unknown etiology. MethodsTwenty-two patients with newly diagnosed partial epilepsy of unknown etiology and 36 healthy controls were enrolled in this study. In addition, we included 24 patients with chronic partial epilepsy of unknown etiology as a disease control group. We analyzed whole-brain T1-weighted MRIs using FreeSurfer 5.1. The volumes of the hippocampus, amygdala, thalamus, caudate, putamen, pallidum, brainstem, cerebellar gray and white matter, as well as cerebral gray and white matter were compared between the groups. We also analyzed the changes in brain volumes associated with the chronicity of epilepsy in the patients with chronic epilepsy compared to newly diagnosed epilepsy. ResultsThe volume of cerebellar white matter in patients with newly diagnosed epilepsy was significantly smaller than that which was observed in the healthy controls (p=0.0001). This finding was also observed in patients with chronic epilepsy (p<0.0001). Cerebral white matter volume was negatively correlated with the duration of epilepsy (r=−0.4, p=0.04). ConclusionThese findings support our hypothesis that cerebellar white matter changes may constitute a pre-existing susceptible structure in the brain that is associated with the development of partial epilepsy of unknown etiology. In addition, cerebral white matter was the structure that was the most vulnerable to the progression of epilepsy.

Original article Angiocentric glioma: a rare intractable epilepsy-related tumour in children

Angiocentric glioma is a low-grade tumour that occurs in children and young adults with a long-standing epilepsy. The typical histopathological features of this tumour is the presence of spindle-shaped cells, radially oriented around the cortical blood vessels. We present two teenage cases of the angiocentric variant of glioma: 1) a 15-year-old girl with a chronic and intractable partial epilepsy with cystic tumour located in the right temporal lobe and 2) a 14-year-old boy with intractable seizures and an extensive cortical lesion in the left parieto-occipital area. In both cases, the total tumours excision was performed. The histopathological findings revealed a characteristic angiocentric pattern that was composed of elongated cells arranging in pseudorosette-like structures around blood vessels. Moreover, schwannoma-like areas and subpial neoplastic infiltration with palisading of tumour cells at the brain surface were seen. The neoplastic cells displayed immunoreactivity for GFAP, S-100 protein and vimentin. A slight "dot-like" EMA staining, suggesting ependymal differentiation, was detected. The clinical and pathological picture allowed to establish the diagnosis of angiocentric gliomas. The patients were discharged home in a good condition and without seizures. During the 4-year follow-up, the tumour recurrence and seizures were not observed. The appropriate diagnosis of this peculiar type of usually low-grade glial tumour is important for adequate and successful treatment. The differential diagnosis requires the exclusion of other tumours with an angiocentric pattern, i.e. ependymoma, astroblastoma, which are associated with more aggressive biology.

Preclinical antiepileptic actions of selective serotonin reuptake inhibitors—Implications for clinical trial design

Selective serotonin reuptake inhibitors (SSRIs) can reduce seizure frequency in humans, but no large-scale clinical trials have been done to test the utility of SSRIs as potential antiepileptic drugs. This may be caused in part by a small number of reports on seizures triggered by SSRI treatment. The preclinical literature on SSRIs is somewhat conflicting, which is likely to contribute to the hesitance in accepting SSRIs as possible anticonvulsant drug therapy. A careful review of preclinical studies reveals that SSRIs appear to have region-specific and seizure subtype-specific effects, with models of chronic partial epilepsy being more likely to respond than models of acute generalized seizures. Moreover, this preclinical profile is similar to that of clinical antiepileptic drugs. These observations suggest that SSRIs are promising antiepileptic agents, and that clinical trials may benefit from defining patient groups according to the underlying pathology.

18Fluoroethyl-l-tyrosine-PET in long-term epilepsy associated glioneuronal tumors

Long-term epilepsy associated tumors (LEATs) are a frequent cause of drug-resistant partial epilepsy. A reliable tumor diagnosis has an important impact on therapeutic strategies and prognosis in patients with epilepsy, but often is difficult by magnetic resonance imaging (MRI) only. Herein we analyzed a large LEAT cohort investigated by 18fluoroethyl-L-tyrosine-positron emission tomography (FET-PET). Thirty-six patients with chronic partial epilepsy and a LEAT-suspect MRI lesion were analyzed by FET-PET using visual inspection and quantitative analysis of standard uptake values (SUV). PET results were correlated with clinical and histopathologic data. FET-PET study was positive in 22 of 36 analyzed lesions and in 14 of 22 histologically verified LEAT lesions. The precise World Health Organization (WHO) tumoral entity was not predicted by FET-PET. Notably, FET uptake correlated strikingly with age at epilepsy onset (p = 0.001). Further correlations were seen for age at surgery (p = 0.007) and gadolinium-contrast enhancement on MRI (p < 0.05). FET-PET is a helpful tool for LEAT diagnosis, particularly when MRI readings are ambiguous. FET uptake, which is likely mediated by the l-amino acid transporter (LAT) family, might indicate a principally important biologic property of certain LEATs, since LAT molecules also are involved in cell growth regulation.

Neurocutaneous Melanosis Presenting as Chronic Partial Epilepsy

BackgroundNeurocutaneous melanosis (NCM) is a rare neurocutaneous syndrome characterized by the presence of multiple congenital melanocytic nevi (CMN) and the proliferation of melanocytes in the central nervous system, usually involving the leptomeninges. Chronic partial epilepsy as a sole manifestation is rare in NCM.Case ReportA 32-year-old man suffering from chronic partial epilepsy presented with multiple CMN on his trunk and scalp. Brain MRI demonstrated a focal lesion in the right amygdala that was consistent with interictal epileptiform discharges in the right temporal region on electroencephalography (EEG). An anterior temporal lobectomy was performed, and the pathology investigation revealed numerous melanophages in the amygdala. The patient was seizure-free after surgery.ConclusionsWe report a patient with NCM presenting as chronic partial epilepsy who was successfully treated by anterior temporal lobectomy.

Cognitive functioning over 3 years in community dwelling older adults with chronic partial epilepsy

Little is known about cognitive functioning of older adults with chronic partial epilepsy. We examined cognitive performance of this epilepsy patient group over 2-3 years. Seventeen older adults with epilepsy and 17 healthy older adults were administered measures of overall cognition and verbal memory at baseline and 2-3 years later. At baseline, older adults with epilepsy performed below controls on overall cognition and verbal memory (p's<0.001). These deficits generally remained stable at follow-up, although executive control appeared to decline (p<0.05). Older adults with epilepsy showed a failure to benefit from practice on a verbal memory measure (p=0.017). Older adults with epilepsy demonstrated cognitive deficits that generally are not progressive. A failure to benefit from repeat exposure to a Delayed Recall task could indicate learning deficits. These patients may also progressively lose executive control, possibly as a result of accelerated aging.

Medical decision-making abilities in older adults with chronic partial epilepsy

Little is known about the medical decision-making abilities of older adults with chronic partial epilepsy, although these patients are often faced with medical decisions that impact their health care. Twenty-one older adults with epilepsy and 21 healthy older adults completed the Capacity to Consent to Treatment Instrument (CCTI) and Dementia Rating Scale II (DRS-II). Older adults with epilepsy performed significantly below controls on the CCTI standards Evidencing Choice, Appreciation, and Understanding and the DRS-II Total Score. DRS-II was positively associated with performance on the standards Appreciation and Understanding. Number of antiepileptic drugs, duration of epilepsy, and age at seizure onset were related to performance on Understanding. Older adults with epilepsy demonstrated deficits in their capacity to give informed consent for medical treatment that appear to be associated with cognition and seizure variables. Physicians should consider the decisional abilities of their older adult patients with epilepsy when presenting treatment options.

Long-term effects of tiagabine monotherapy on cognition and mood in adult patients with chronic partial epilepsy

The long-term effects of tiagabine monotherapy on cognition and mood were evaluated in adult patients with chronic partial epilepsy in a 48-week, open-label extension period that followed an 8-week, double-blind, titration study. Cognitive function was evaluated using neuropsychological evaluations that measured learning and memory, general intellectual ability, attention and mental speed, and reaction speed. Mood was assessed using a Finnish modification of the Profile of Mood States. Of the 34 patients who entered the open-label extension period, 18 successfully continued long-term monotherapy and underwent neuropsychological evaluation at 48 weeks of tiagabine monotherapy. The mean daily dose of tiagabine monotherapy at the end of open-label treatment was 19.7 mg/day (range, 5–35 mg/day). Tiagabine monotherapy did not adversely affect cognitive function. No significant changes in mood were observed. The median number of seizures was 2 (range, 0–71), and 8 patients (44%) were seizure-free during the 48 weeks of open-label tiagabine treatment. The results of this small open-label extension study indicate that patients with chronic partial epilepsy who were successfully converted to long-term tiagabine monotherapy demonstrated no adverse effects on cognitive function or mood.

Neuropsychiatric porphyria in patients with refractory epilepsy: report of three cases

Objectives: Although epileptic seizures are an infrequent feature of acute attacks of the neuropsychiatric porphyrias, there are no significant reports of porphyria in chronic epilepsy. This paper attempts to redress...

Cognitive Functioning in Community Dwelling Older Adults with Chronic Partial Epilepsy

To examine cognitive functioning in community-dwelling older adults with chronic partial epilepsy and demographically matched healthy older adults. Standardized measures of neurocognitive function were collected as part of an ongoing study investigating health-related quality-of-life issues in older adults with epilepsy. Cognitive tests consisted of the Mattis Dementia Rating Scale (subscales include attention, initiation/perseveration, construction, conceptualization, memory), Logical Memory subtest from the WMS-III (immediate and delayed recall scores), and word fluency. Mood was measured with the Geriatric Depression Scale. Older adults with epilepsy (n=25) and healthy older adults (n=27) completed testing. All participants were at least 60 years old, living independently in the community, and had no history of drug/alcohol abuse or life-threatening medical conditions. All older adults with epilepsy had been diagnosed as having medically intractable partial complex seizures, including those with histories of secondary generalization. Older adults with epilepsy demonstrated impairments across all cognitive measures compared with the healthy controls. Seizure onset (age) and seizure duration (years) were not statistically associated with neurocognitive function or self-reported mood. Older adults with epilepsy who were receiving antiepileptic drug (AED) polytherapy (n=11) displayed worse performance on the attention, initiation/perseveration, and memory subscales of the DRS and Logical Memory delayed recall score compared with those older adults with epilepsy receiving monotherapy (n=14). The number of AEDs taken was not associated with seizure frequency. Negative effects on cognitive function are experienced by older adults with chronic partial epilepsy. AED polytherapy may increase the risk for negative cognitive dysfunction.

Association of partial epilepsy with brain-derived neurotrophic factor (BDNF) gene polymorphisms

In search of a gene polymorphism that may contribute to the development of partial epilepsy, we focused on brain-derived neurotrophic factor (BDNF), since the functional effects of insult-induced neurotrophin changes are reported to be protection against neuronal damage and stimulation of synaptic reorganization. Two hundred nineteen patients with partial epilepsy were selected for study and 311 individuals were used as healthy controls. A single base pair (bp) polymorphism at position 240 in the non-coding region of the BDNF gene and at position 480 within the proBDNF sequence were analyzed, and the frequency of the 240T allele was found to be significantly increased in partial epilepsy patients as compared with the controls ( χ 2=8.59, P=0.0034). In contrast, no significant differences were found between the two groups in any combination of the G480A BDNF gene polymorphism. Our results suggest that the 240T allele in the BDNF gene may be a genetic marker that indicates an enhanced susceptibility to seizures, setting up a cascade leading eventually to chronic partial epilepsy in patients with such a genetic predisposition.

More on the Timing and Meaning of FDG-PET Abnormalities in Partial Epilepsy.

Low Incidence of Abnormal FDG-PET in Children with New-onset Partial Epilepsy: A Prospective Study Gaillard W, Kopylev L, Weinstein S, Conry J, Pearl P, Spanaki M, Fazilat S, Venzina L, Dubovsky E, Theodore W Neurology 2002;58:717–722 Objective Patients with refractory partial epilepsy often exhibit regional hypometabolism. It is unknown whether the metabolic abnormalities are present at seizure onset or develop over time. Methods The authors studied 40 children within 1 year of their third unprovoked partial seizure with EEG, magnetic resonance imaging (MRI), and [18F]-fluorodeoxyglucose (18FDG)-positron emission tomography (PET) (mean age at seizure onset, 5.8 years; range, 0.9–11.9 years; mean epilepsy duration, 1.1 years; range, 0.3–2.3 years; mean number of seizures, 30; range, 3–200). The authors excluded children with abnormal structural MRI, except four with mesial temporal sclerosis and two with subtle hippocampal dysgenesis. 18FDG-PET was analyzed with a region-of-interest template. An absolute asymmetry index, |AI|, &gt;0.15 was considered abnormal. Results Thirty-three children had a presumptive temporal lobe focus, five frontotemporal, and two frontal. Mean AI for all regions was not different from that in 10 normal young adults, even when children less likely to have a temporal focus were excluded. Eight (20%) of 40 children had focal hypometabolism, all restricted to the temporal lobe, especially inferior mesial and inferior lateral regions. Abnormalities were ipsilateral to the presumed temporal lobe ictal focus. Conculsions Abnormalities of glucose utilization may be less common and profound in children with new-onset partial seizures than in adults with chronic partial epilepsy. Although these patients’ prognosis is uncertain, resolution of epilepsy after three documented seizures is uncommon. If the subjects develop a higher incidence of hypometabolism in the future with planned follow-up studies, metabolic dysfunction may be related to persistent epilepsy rather than present at seizure onset.

Low incidence of abnormal (18)FDG-PET in children with new-onset partial epilepsy: a prospective study.

Patients with refractory partial epilepsy often exhibit regional hypometabolism. It is unknown whether the metabolic abnormalities are present at seizure onset or develop over time. The authors studied 40 children within 1 year of their third unprovoked partial seizure with EEG, MRI, and [(18)F]-fluorodeoxyglucose ((18)FDG)-PET (mean age at seizure onset = 5.8 years, range 0.9 to 11.9 years; mean epilepsy duration = 1.1 years, range 0.3 to 2.3 years; mean number of seizures = 30, range 3 to 200). The authors excluded children with abnormal structural MRI, except four with mesial temporal sclerosis and two with subtle hippocampal dysgenesis. (18)FDG-PET was analyzed with a region of interest template. An absolute asymmetry index, [AI], greater than 0.15 was considered abnormal. Thirty-three children had a presumptive temporal lobe focus, five frontotemporal, and two frontal. Mean AI for all regions was not different from 10 normal young adults, even when children less likely to have a temporal focus were excluded. Eight of 40 children (20%) had focal hypometabolism, all restricted to the temporal lobe, especially inferior mesial and inferior lateral regions. Abnormalities were ipsilateral to the presumed temporal lobe ictal focus. Abnormalities of glucose utilization may be less common and profound in children with new-onset partial seizures than in adults with chronic partial epilepsy. Although these patients' prognosis is uncertain, resolution of epilepsy after three documented seizures is uncommon. If the subjects develop a higher incidence of hypometabolism in the future with planned follow-up studies, metabolic dysfunction may be related to persistent epilepsy rather than present at seizure onset.

Neurocognitive development of children with congenital unilateral brain lesion and epilepsy.

The aim of this study was to specify the neuropsychological deficits characteristic of children with unilateral non-progressive brain lesion. In order to assess these specific functions, we used a comprehensive model of congenital hemiparesis with partial epilepsy and newly diagnosed partial epilepsy without hemiparesis. The neuropsychological examination was performed using the NEPSY test battery on 44 children aged from 4 to 9 years. The children were divided into three groups: 18 children suffering from congenital hemiparesis with chronic partial epilepsy, 12 children with newly diagnosed partial epilepsy prior to anti-epileptic treatment, and 14 healthy controls matched by sex, age, and socioeconomic status. Children with congenital hemiparesis and epilepsy had a more clearly expressed cognitive dysfunction, especially in language, visuo-perceptual and memory tasks, than children with newly diagnosed partial epilepsy. The profile of cognitive weakness appears to be diffuse and quite similar in both groups, and it did not demonstrate a clear effect of lateralization, according to the side of epileptic electroencephalogram discharges. Children within both groups are likely to have a high risk of developing attention, phonological, visuo-perceptual, and memory deficits in their life. Especially interesting and surprising was the fact that the newly diagnosed epilepsy group demonstrated impairment not only in attention, visuo-perceptual and short-term memory skills, but also in auditory perception, lexical function, and the comprehension of speech. Therefore, it is recommended that children with epilepsy would undergo neuropsychological examination in order to assess their cognitive abilities.

La chirurgie fonctionnelle de l’épilepsie

Introduced at the end of the last century, epilepsy surgery is indicated in patients with intractable partial seizures and based on the resection of the epileptogenic cerebral tissue from which ictal discharges originate. Palliative procedures include seizure spread pathways interruption (callosotomy, multiple subpial transections) and chronic stimulation of the vagus nerve. Complete preoperative investigations including seizure observation, clinical tests, video-EEG, MRI and functional MRI, and PET-scan are performed in order to identify the epileptogenic zone. In difficult cases, invasive seizure monitoring through depth electrode implantation (SEEG) is performed. Resections for temporal lobe seizures are associated with favorable outcome : 60 to 90 % of patients will be seizure-free after surgery. A less favorable outcome is observed after extra-temporal resections : 40 to 60 % seizure-free patients. A better outcome is observed after surgery for epilepsy associated with an image-defined lesion, most often a tumor, rather than for cryptogenic epilepsy. Tumors associated with chronic partial epilepsy are indolent, most of them are dysembryoplastic neuroepithelial tumors (DNET). Outcome after palliative procedures are more variable, depending on the etiology of epilepsy.

Long-term retention rates of lamotrigine, gabapentin, and topiramate in chronic epilepsy.

We sought to determine the long-term retention rates of lamotrigine (LTG), gabapentin (GBP), and topiramate (TPM) therapy for patients at a tertiary referral clinic for chronic, refractory epilepsy. We analyzed 424 consecutive patients with chronic, refractory partial and/or generalized epilepsy who were started on LTG, 158 patients who were started on GBP, and 393 patients who were started on TPM. The percentages of patients who continued therapy with LTG, GBP, and TPM were estimated with the use of Kaplan-Meier survival analysis. Factors that influence retention were analyzed with the use of Cox regression analysis. Kaplan-Meier survival analysis showed that at 3 years, 30% continued therapy on TPM compared with 29% on LTG and fewer than 10% on GBP. Adverse events resulted in therapy withdrawal in 40% of patients on TPM compared with GBP (37%) and LTG (22%). Perceived lack of efficacy led to treatment withdrawal in 39% of patients on GBP compared with 34% on LTG and 19% on TPM. Cox regression estimated that a fourth or fewer of patients with chronic partial epilepsy are likely to continue therapy with a new antiepileptic drug beyond 5 years. The impact of these new antiepileptic drugs on the long-term course of chronic partial epilepsy is likely to be small, as approximately three of four patients will discontinue therapy. More patients appear to continue on TPM compared with LTG or GBP, with a possible reason being better perceived efficacy of TPM, despite having the highest incidence of adverse events.

Frontal Nonconvulsive Status Epilepticus Associated with High‐Dose Tiagabine Therapy in a Child with Familial Bilateral Perisylvian Polymicrogyria

Antiepileptic drugs are known to exacerbate absence and myoclonic seizures, especially in patients with idiopathic generalized epilepsies. Exacerbation of nonconvulsive generalized seizures in patients with partial epilepsy is less common. Recently, however, a number of cases of putative generalized nonconvulsive status epilepticus (NCSE) or NCSE without further specification have been reported in patients with chronic partial epilepsy treated with the gamma-aminobutyric acid reuptake inhibitor tiagabine. Although complex partial status epilepticus during tiagabine therapy has also been reported, possible precipitation of NCSE specifically associated with frontal lobe discharges does not appear to have been recognized. In this communication, we describe the case of a boy with familial bilateral perisylvian polymicrogyria who developed frontal NCSE after being stabilized on high-dose tiagabine A 12-year-old boy with familial bilateral perisylvian polymicrogyria, mental retardation, and refractory partial seizures was administered tiagabine in addition to sodium valproate. The tiagabine dosage was increased gradually up to 10 mg t.i.d. (1 mg/kg per day), resulting in complete seizure control. After 1 week on maintenance treatment, seizures were completely controlled, but the child developed hypoactivity, decreased reactivity, and affective detachment. An EEG recording revealed subcontinuous sharp-wave discharges with irregular runs of atypical spike-wave complexes over the anterior regions of both hemispheres, consistent with a diagnosis of frontal NCSE. A reduction in tiagabine dosage to 15 mg/day led to complete regression of the behavioral and affective changes and to disappearance of the subcontinuous EEG discharges. Although tiagabine-induced NCSE has been described previously, particularly in patients with preexisting spike-wave abnormalities, this is the first report that identifies its potential role in the precipitation of frontal NCSE.

Monotherapy clinical trials of new antiepileptic drugs: design, indications, and controversies.

The focus in assessing new antiepileptic drugs (AEDs) varies with the needs of the assessor. Patients and doctors seek evidence-based clinical information, regulatory agencies look for efficacy and safety, and the health-care industry demands data on the risk-benefit ratio attached to a product. The pharmaceutical companies attempt to satisfy the interests of all parties involved. Most new AEDs obtain a first license based on placebo-controlled, randomized clinical trials as add-on therapy in patients with chronic refractory partial epilepsy, a method which, in fact, explores the efficacy of different drug combinations rather than measuring the efficacy of the new drug itself. Although that methodology satisfies the requirements of the licensing authorities, it fails to provide the clinical community with the information necessary to make rational treatment decisions, as would be derived from monotherapy studies. This article reviews controversies surrounding monotherapy studies and the design of comparative monotherapy clinical trials. A persuasive argument can be made that the goal of clinical trial design should be ethically acceptable, clinically meaningful studies in which new AEDs are compared with optimal doses of standard AEDs to inform clinical practice, meet licensing requirements, guide reasonable marketing efforts, and allow appropriate reimbursement.

High resolution magnetic resonance imaging in adults with partial or secondary generalised epilepsy attending a tertiary referral unit.

In the past the underlying structural abnormalities leading to the development of chronic seizure disorders have usually only been disclosed by histological examination of surgical or postmortem material, due to their often subtle nature that was beyond the resolution of CT or early MRI. The MRI findings in 341 patients with chronic, refractory epilepsy attending The National Hospital for Neurology and Neurosurgery and Chalfont Centre for Epilepsy are reported. Studies were performed on a 1.5 Tesla scanner with a specific volumetric protocol, allowing the reconstruction of 1.5 mm contiguous slices throughout the whole brain. Direct visual inspection of the two dimensional images without the use of additional quantitative measures showed that 254/341 (74%) were abnormal. Twenty four (7%) patients had more than one lesion. The principal MRI diagnoses were hippocampal asymmetry (32%), cortical dysgenesis (12%), tumour (12%), and vascular malformation (8%). Pathological confirmation was available from surgical specimens in 70 patients and showed a very high degree of sensitivity and specificity for the different entities. The advent of more widely available high resolution MRI should make it possible to identify the underlying pathological substrate in most patients with chronic partial epilepsy. This will allow a fundamental reclassification of the epilepsies for both medical and surgical management, with increasing precision as new methods (both of acquisition and postprocessing) are added to the neuroimaging battery used in clinical practice.

Increasing the yield from volumetric MRI in patients with epilepsy

Volumetric magnetic resonance imaging has become a routine investigation in the management of patients with chronic partial epilepsy. However, even with the use of reformatted images, an underlying cause for epileps can-not be found in many of these patients. We show that further processing of the data, including three-dimensional reconstruction and quantitative analysis of the volume and complexity of the images in three dimensions, reveals additional positive information in up to 75% of patients. This may be useful for surgical planning, prognostication, and understanding of the structure and development of the human brain.