Drug-resistant Complex Partial Seizures Research Articles

Autosomal dominant cortical tremor, myoclonus, and epilepsy: is the origin in the cerebellum? Editorial

In 1990, Ikeda et al. described an action and postural tremor that originated from the cerebral cortex and was thus termed “cortical tremor.” Due to its peculiar electrophysiological features, this involuntary movement was considered to be a variant of cortical reflex myoclonus [1]. Cortical tremor was then recognized to occur in Japanese families often in association with tonic– clonic seizures, and this observation led to the definition of an autosomal dominant trait named Benign Adult Familial Myoclonic Epilepsy (BAFME), which was mapped on chromosome 8q [2, 3]. Over the past decade, several European kindreds with overlapping clinical features have been reported under different acronyms, such as autosomal dominant cortical myoclonus and epilepsy and familial cortical myoclonic tremor with epilepsy (FCMTE) [4–7]. The available literature now suggests a worldwide distribution (more than 60 families have been reported) and genetic heterogeneity, yet with evidence that 2p11.1-q12.2 is a major locus for the kindreds of European origin [8]. Most affected individuals experience tonic–clonic seizures, which begin later than “tremor.” Seizures are generally rare (about five to ten episodes during life) and are not preceded by any warning. However, in some cases, they may be heralded by progressively increasing myoclonic jerks. Precipitating factors such as sleep deprivation, emotional stress, pain, and photic stimulation are often reported [3, 7]. In some cases, severe myoclonus can alter the quality of life. Although the epilepsy is usually benign, in rare cases, patients may present with drug-resistant complex partial seizures and focal EEG abnormalities [4]. Patients usually have normal cognition; however, mildto-moderate mental retardation may be present in some cases, especially in a more advanced age [6, 9]. Both the severity of seizures and the use of antiepileptic drugs could contribute to cognitive impairment. Cerebellar symptoms are usually mild: postural ataxia, downbeat nystagmus, impaired smooth pursuit. MRI may demonstrate a cerebellar atrophy. A pseudo-parkinsonism has also been reported. FCTME is usually diagnosed between the ages of 20 and 45 years. Myoclonus and EEG abnormalities progressively worsen from early to late adulthood. Clonazepam and sodium valproate are usually effective therapies. Thus far, the pathophysiological and biochemical bases of this condition remain poorly understood. Mutations in genes encoding ion channels have been excluded by several authors [3–7]. Patients typically show giant somatosensory evoked potentials and strong corticoand intermuscular coherence in the 8to 30-Hz range, thus suggesting an underlying cortical hyperexcitability, which can be the result of a decreased cortical inhibition by the cerebellum via its cerebello-thalamocortical projections [6]. Indeed, rare post-mortem histological studies have shown evidence of cerebellar pathology reminiscent of SCA type 6 [3, 5], and although P. Striano (*) Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, “G. Gaslini” Institute, Largo Gaslini 5, Pediatric Neurology and Muscular Diseases Unit, Padiglione 16, IV Piano, 16147 Genoa, Italy e-mail: pstriano@email.it

PO.01 IDDM associated with cerebellar ataxia; drug resistant complex partial seizures and intrathecal synthesis of anti GAD-Ab

High levels of antibodies to glutamic acid decarboxylase (anti GAD-Ab) are an uncommon association in neurological conditions. We describe a patient who initially presented with cerebellar ataxia. Four years later...

Still an elusive target

Experts in epilepsy care know that uncontrolled seizures result in poor quality of life and increase the risk of injuries and death. They also know that surgery is superior to medical therapy in carefully selected patients. On the other hand, publications from epilepsy centers around the world show that patients with surgically treatable epilepsy either are not referred or wait about 20 years before an evaluation for surgery. The long delay of potentially effective surgery occurs during the most formative years, when poorly controlled seizures have dire vocational and psychosocial consequences. Clinical practice guidelines (CPG) aim to assist in clinical decision-making—particularly in situations of controversy or variation in practice. In 2003, the American Academy of Neurology published evidence-based CPGs endorsing at the strongest level (Level A) the referral of patients with drug-resistant complex partial seizures for surgical evaluation, and offering surgical treatment to those with temporal lobe epilepsy (TLE).1 Have …

New Antiepileptic Drugs: Lacosamide, Rufinamide, and Vigabatrin

The treatment of epilepsy is complicated by the multiple seizure types and epilepsy syndromes needing therapy. In addition, seizures in up to 30% of epilepsy patients are resistant to available medications. The three newest antiepileptic medications (lacosamide, rufinamide, and vigabatrin) all putatively have novel mechanisms of action, which might increase the chance of treatment success in patients failing previous antiepilepsy drug trials and the chance of successful synergy with currently available medications. In our experience, all three drugs generally are well tolerated, although the risk for serious long-term complications with vigabatrin presents special challenges and precautions. Lacosamide is approved for the adjunctive therapy of complex partial seizures in adults and also is available in an intravenous formulation. Rufinamide is a new treatment option for seizures associated with Lennox-Gastaut syndrome, and although it is not FDA approved for partial seizures, it has shown efficacy for that indication as well. Vigabatrin has been approved in adults for drug-resistant complex partial seizures and in infants as a treatment option for infantile spasms.

Crossed cerebellar diaschisis in intracarotid sodium amytal procedures: a SPECT study

Eight patients with drug-resistant complex-partial seizures were subjected to left- and right-sided intracarotid sodium amytal (ISA) procedures during preoperative investigations for surgical treatment. Regional changes of cerebral and cerebellar blood flow during barbiturization were measured by [99mTc]-HMPAO-SPECT. Crossed cerebellar diaschisis (CCD) was observed in 13 out of 16 tests (81%) as well as ipsilateral cerebral hypoperfusion (87%). Thus CCD occurred more frequently in ISA procedures than in previously studied patients with cerebral infarctions and tumors. Since intracarotid injections of sodium amytal lead to hypoperfusion mainly in those areas of the brain that are supplied by the middle cerebral artery, functional suppression of these regions is supposed to be one of the main preconditions of CCD. Our findings suggest that CCD as demonstrated by the SPECT-technique is a common phenomenon in ISA procedures.

TEMPORAL LOBOTOMY IN THE SURGICAL MANAGEMENT OF EPILEPSY: TECHNICAL REPORT

To describe the technique of temporal lobotomy and demonstrate that it may produce results equivalent to anterior temporal lobectomy in the control of drug-resistant complex partial seizures of anterior temporal lobe origin. Patient selection and evaluation was similar to that for other patients undergoing anterior temporal lobectomy, with the exception that the 10 selected patients all demonstrated extensive lobar or hemispheral atrophy on magnetic resonance imaging or computed tomographic scans. The lobotomy technique involved posterior and superior disconnection, each of which was broken down into lateral and mesial components. At last follow-up, seven patients were seizure-free, one had rare seizures, and two had a less than 90% decrease in seizures. These outcomes are similar to those in our overall temporal lobectomy series. One patient who underwent left-sided temporal lobotomy had a speech fluency deficit postoperatively. Temporal lobotomy seems to be an effective disconnective procedure in the treatment of drug-resistant temporal lobe epilepsy. Larger series will be needed to better define its role in the management of this condition.

Tumore neuroepiteliale disembrioplastico

Dysembryoplastic neuroepithelial tumors (DNTs) are mainly benign cortical lesions composed of glial and neuronal elements. DNTs accounted for 0.6–07% of pediatric brain tumors. Clinically these tumors are usually associated with chronic epilepsy in adolescents and adults. We report a case of six-year-old boy who presented drug-resistant complex partial seizures whit neurological and intellectual integrity, but a mild attention deficit. MRI disclosed a subcortical lesion, located on the left the temporal lobe. The pathological tissue was hyperintense on both T1 and T2-weighted images; CT showed very well intratumoral calcifications. These neuroradiological findings suggested a differential diagnosis with extraventricular neurocytoma and ganglioglioma. The child underwent surgery; the histological examination diagnosed a complex DNT (1st grade of WHO classification). At follow-up after 6 months, he was seizure-free; the neurological examination was normal.

Association study of idiopathic primary generalized epilepsy (IGE)

s 429 with a 25year history of anticonvulsant drug-resistant complex partial seizures. Computer analysis of captured images revealed over 100 differentially regulated genes, some involved in neurotransmitter release, plasticity and signalling mechanisms. Other candidate genes were novel. Secondary validation with selected candidate clones re-gridded was undertaken by hybridizing newly constructed probes derived from further RNA samples from the same epileptic patient and control. This technology is an effective approach to analysing gene expression changes and may yield new targets from therapeutic intervention in epilepsy. Association study of idiopathic primary generalized epilepsy (IGE) A. Makoff*+, B. Chioza’i, N. Currant, F! Ashersod & L. Nashefsl *Department of Psychological Medicine, institute of Psychiatry, London, UK; t Department of Neuroscience, institute of Psychiatry, London, UK; $ Social Genetic & Developmental Psychiatry Research Centre, Institute of Psychiatry, London, UK; 5 Kent and Canterbury Hospital, Canterbury IKings College Hospital, London, UK Twin studies have demonstrated concordance rates of up to 95% for idiopathic generalized epilepsy (IGE) in monozygotic twin pairs. There are a few rare mendelian forms of IGE, but most show a complex pattern of inheritance. The relative risk for IGE among first-degree relatives is in the range 5-10 suggesting that association studies will be required to detect the expected small gene effects. We have collected an initial sample of 100 probands with IGE and 100 ethnically matched controls. Our initial studies have focused on the metabotropic glutamate receptor type 7 (mGluR7) and the (r4 nicotinic acetylcholine receptor subunit (nAchRo4). Mouse knockouts of mGluR7 result in an epileptic phenotype. Studies of a biallelic polymorphisms in mGluR7 are in progress. Mutations within nAchRo4 have been shown to cause the rare dendelian epilepsy autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). An association study with a mixture of different IGE syndromes provides some evidence for association to nAchrcr4. The gene for nAchRo4 lies only 50 Kb from a voltage-sensitive potassium channel gene (KCNQ2) in which mutations cause one type of another mendelian epilepsy, benign familial neonatal convulsions (BFNC). We are currently utilizing polymorphisms in the nAchRa4 gene and KCNQ2 in our sample. Functional and structural findings in epilepsy demonstrated with diffusion weighted imaging U.C. Wieshamnn, MR. Symms & S.D. Shorvon Epilepsy Research Group, institute of Neurology, Queen Square, London, UK Diffusion weighted imaging (DWI) is a magnetic resonance imaging technique which is sensitive to molecular motion of water. Transient or permanent changes of the microstructural organization of tissue, for example, widening or shrinkage of the extracellular space cause diffusion changes which can be detected by DWI. We used DWI to investigate patients with epilepsy. In a patient with focal status we detected transient diffusion changes which were likely to reflect neuronal dysfunction. During the interictal stage we found an increased diffusion in structural lesions associated with epilepsy. These included hippocampal sclerosis, tumours and most forms of brain damage. These changes were associated with a reduced anisotropy of water diffusion which is likely to reflect a breakdown of the structural organization. A reduction of anisotropy was the predominant finding in cortical dysgenesis. In conclusion, DWI can show changes of water diffusion in focal status epilepticus. In addition, DWI provides information about the microstructure in lesions which may help to understand the pathophysiology of seizures.

Sudden unexpected death in ‘epilepsy’—a missed opportunity to diagnose a long QT syndrome

s 429 with a 25year history of anticonvulsant drug-resistant complex partial seizures. Computer analysis of captured images revealed over 100 differentially regulated genes, some involved in neurotransmitter release, plasticity and signalling mechanisms. Other candidate genes were novel. Secondary validation with selected candidate clones re-gridded was undertaken by hybridizing newly constructed probes derived from further RNA samples from the same epileptic patient and control. This technology is an effective approach to analysing gene expression changes and may yield new targets from therapeutic intervention in epilepsy. Association study of idiopathic primary generalized epilepsy (IGE) A. Makoff*+, B. Chioza’i, N. Currant, F! Ashersod & L. Nashefsl *Department of Psychological Medicine, institute of Psychiatry, London, UK; t Department of Neuroscience, institute of Psychiatry, London, UK; $ Social Genetic & Developmental Psychiatry Research Centre, Institute of Psychiatry, London, UK; 5 Kent and Canterbury Hospital, Canterbury IKings College Hospital, London, UK Twin studies have demonstrated concordance rates of up to 95% for idiopathic generalized epilepsy (IGE) in monozygotic twin pairs. There are a few rare mendelian forms of IGE, but most show a complex pattern of inheritance. The relative risk for IGE among first-degree relatives is in the range 5-10 suggesting that association studies will be required to detect the expected small gene effects. We have collected an initial sample of 100 probands with IGE and 100 ethnically matched controls. Our initial studies have focused on the metabotropic glutamate receptor type 7 (mGluR7) and the (r4 nicotinic acetylcholine receptor subunit (nAchRo4). Mouse knockouts of mGluR7 result in an epileptic phenotype. Studies of a biallelic polymorphisms in mGluR7 are in progress. Mutations within nAchRo4 have been shown to cause the rare dendelian epilepsy autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). An association study with a mixture of different IGE syndromes provides some evidence for association to nAchrcr4. The gene for nAchRo4 lies only 50 Kb from a voltage-sensitive potassium channel gene (KCNQ2) in which mutations cause one type of another mendelian epilepsy, benign familial neonatal convulsions (BFNC). We are currently utilizing polymorphisms in the nAchRa4 gene and KCNQ2 in our sample. Functional and structural findings in epilepsy demonstrated with diffusion weighted imaging U.C. Wieshamnn, MR. Symms & S.D. Shorvon Epilepsy Research Group, institute of Neurology, Queen Square, London, UK Diffusion weighted imaging (DWI) is a magnetic resonance imaging technique which is sensitive to molecular motion of water. Transient or permanent changes of the microstructural organization of tissue, for example, widening or shrinkage of the extracellular space cause diffusion changes which can be detected by DWI. We used DWI to investigate patients with epilepsy. In a patient with focal status we detected transient diffusion changes which were likely to reflect neuronal dysfunction. During the interictal stage we found an increased diffusion in structural lesions associated with epilepsy. These included hippocampal sclerosis, tumours and most forms of brain damage. These changes were associated with a reduced anisotropy of water diffusion which is likely to reflect a breakdown of the structural organization. A reduction of anisotropy was the predominant finding in cortical dysgenesis. In conclusion, DWI can show changes of water diffusion in focal status epilepticus. In addition, DWI provides information about the microstructure in lesions which may help to understand the pathophysiology of seizures.

Surgical Treatment of Complex Partial Seizures: 20 Years' Experience

From 1972 to 1992 inclusive, the author performed 263 surgical procedures for the relief of intractable epilepsy. The purpose of this report is to review 112 temporal lobectomies for the treatment of drug-resistant complex partial seizures. There were 90 adults and 22 children, in whom there were 61 left-sided procedures and 51 right-sided ones. All these cases represent 10% of 2,676 epileptics seen at the Osler Clinic during the last 20 years. The results were evaluated in four groups: 60 patients belonging to group A were seizure-free, group B comprised 24 patients with a reduction in seizures of 75%, group C which included 17 cases had minimal improvement, and finally group D with 11 patients showed no improvement at all. The factors of good surgical outcome were analyzed in 60 patients. The total number of patients that substantially improved after surgery represented 74.5% of the whole series with no mortality and a morbidity of 1.8%.

Effect of Long-Term Vigabatrin Therapy on Selected Neurotransmitter Concentrations in Cerebrospinal Fluid

Ten patients, suffering from drug-resistant complex partial seizures were treated for a period of up to 3 years with vigabatrin (Sabril). Vigabatrin is a novel antiepileptic agent, whose action is based on the inhibition of gamma-aminobutyric acid (GABA) aminotransferase, the enzyme responsible for the catabolism of the neurotransmitter GABA. Samples of lumbar cerebrospinal fluid were obtained from the patients prior to commencing vigabatrin therapy, and thereafter at 6 months, 1 year, 2 years, and up to 3 years following the initiation of vigabatrin treatment. The influence of vigabatrin on the cerebrospinal fluid concentrations of free and total GABA, homocarnosine, homovanillic acid, 5-hydroxyindoleacetic acid, and 3-methoxy-4-hydroxyphenylethylene glycol, as well as of the drug itself, was assessed. All patients demonstrated a clinical response to vigabatrin, and the drug was well tolerated over the entire observation period. Mean (+/- SD) reduction of seizure frequency was 65% +/- 23% (range, 26% to 100%) when comparing the end of the treatment period to the previgabatrin baseline. The cerebrospinal fluid concentrations of both free and total GABA and of the dipeptide homocarnosine showed approximately 2- to 5-fold increases over baseline values, with free GABA and homocarnosine being the more sensitive variables. Cerebrospinal fluid concentrations of homovanillic acid, 5-hydroxyindoleacetic acid, and 3-methoxy-4-hydroxyphenylethylene glycol were not altered in a significant manner over the observation period. These findings support the concept that the effects of vigabatrin are restricted to an effect on GABA catabolism and do not extend to the neurotransmitters dopamine and norepinephrine. Clinical efficacy and elevation of GABA and homocarnosine concentration were sustained over the period of observation.

Vigabatrin in drug‐resistant partial epilepsy

We treated 75 patients with drug-resistant complex partial seizures and secondarily generalized seizures with vigabatrin as additional therapy for 6 months. Twenty-one patients either showed no benefit from vigabatrin treatment or had side effects. The remaining 54 patients entered into the long-term study. The median monthly seizure frequency decreased from 12.5 at baseline to 3.3 at the 3-month visit, and was 3.9 after 5 years of therapy in 28 patients who continued using the drug after the 5-year period. During 5 years of therapy with vigabatrin, 26 patients have withdrawn from the study because of various reasons: loss of efficacy (14), suspected side effects (5), noncompliance (3), administrative reasons (2), pregnancy (1), and epilepsy surgery (1). In all, 19 patients had a greater than 50% seizure frequency reduction at 5 years, representing 35% of the 54 patients who entered the long-term study, or 25% of the 75 patients who were initially recruited into the efficacy study.

Pharmacokinetic effects of vigabatrin on cerebrospinal fluid amino acids in humans.

A study was conducted to assess the impact of single dosing and different dosing intervals of vigabatrin [gamma vinyl GABA (GVG)] in 11 patients with drug-resistant complex partial seizures. Cerebrospinal fluid (CSF) concentrations of total GABA, free GABA, homocarnosine, homovanillic acid (HVA), GVG, and 5-hydroxyindolacetic acid were measured up to seven days after a single dose. GVG levels were maximal within 24 h, suggesting that GVG acts to inhibit GABA-transaminase, and may also increase biogenic amines.

Factors relating to dramatic response to clobazam therapy in refractory epilepsy

Twenty-five out of 41 (61%) patients with drug-resistant complex partial seizures showed an initial dramatic response to clobazam. Sixteen of these responders developed tolerance to the effects of clobazam so that only 9 (22%) maintained a dramatic response for 1 year. Factors which appeared important in predicting a dramatic response to treatment were a known aetiology for the epilepsy, the occurrence of complex partial seizures alone (i.e., without secondary generalisation) and the absence of mental retardation.

Is amygdala kindling in rats a model for drug-resistant partial epilepsy?

Amygdala-kindled female rats were used to compare the effects of seven antiepileptic drugs that are clinically used for treatment of partial epilepsy with complex symptomatology, on (a) generalized seizures, (b) focal seizures, or (c) electrographic seizure activity at the focus. As a second approach of drug evaluation, drug effects on mean latency, severity, and duration of the seizures were determined. Anticonvulsant potencies obtained were compared with those determined in the maximal electroshock seizure test in female rats. Phenobarbital, phenytoin, carbamazepine, valproic acid, diazepam, clonazepam, but not primidone dose-dependently suppressed generalized motor seizures in kindled rats; however, except for the benzodiazepines, ED 50s were substantially higher than those determined in the maximal electroshock seizure test. Compared with their effect on generalized motor seizures, all drugs were much less potent in blocking focal seizures and afterdischarges recorded from the amygdala. The data suggest that with respect to behavioral and pharmacologic characteristics of the amygdala kindling model, fully kindled rats may be a useful model for drug-resistant complex partial seizures with secondary generalization. Results of experiments with novel inhibitors of GABA uptake, which were inactive in the maximal electroshock seizure test but highly potent against kindled seizures, suggest that such drugs might be more effective than current antiepileptic drugs for treatment of partial epilepsy.

The ‘foramen ovale electrode’: a new recording method for the preoperative evaluation of patients suffering from mesio-basal temporal lobe epilepsy

A technique to record from the mesio-basal aspect of the temperal lobe by a subdural electrode inserted through the foramen ovale (FO) is described. For this purpose a special electrode was developed that, in addition, allowed epicortical DC recording. After having tested its value experimentally in dogs with penicillin-induced hippocampal seizure foci, this ‘FO electrode’ was subsequently applied to 10 patients. Nine of them suffered from drug-resistant complex partial seizures suspected to be of mesio-basal limbic origin. Seven patients had in addition to the FO electode depth electrodes stereotactically implanted within the hippocampus and nucleus amygdalae, thus allowing an evaluation of this new FO recording technique by direct comparison with stereo-EEG. Our results indicate that interictal epileptiform potentials as well as ictal discharges are reliably picked up by the FO electrode whenever nucleus amygdalae, hippocampus and parahippocampal gyrus show synchronous epileptic activity. As a rule, these events are not reflected in conventional scalp EEG records. Epileptiform activity in subcompartments of the mesio-basal limbic structures is not reliably reflected by the FO electrode. Negative epicortical DC shifts recorded by the FO electrode are a sensitive indicator of epileptic activity within the underlying deeper structures. In conclusion, in certain patients with drug-resistant epilepsy of suspected mesio-basal limbic origin the use of FO recording in the presurgical evaluation might provide sufficient information to give an indication for resective surgery, either by anterior temporal lobectomy or by selective amygdalo-hippocampectomy.