March 2006
Brain Homocarnosine and Seizure Control of Patients on Gabapentin or Topiramate
Ognen A.C. Petroff, Fahmeed Hyder, Douglas L. Rothman, and Richard H. Mattson

Yale researchers in pioneering work have been able to study the effects of antiepileptic drugs on the brain chemistry of people with epilepsy in a safe and painless manner using the principles of MRI. Neurons in the human brain make homocarnosine from GABA (the brain’s main inhibitory neurotransmitter) and histidine in larger amounts than the neurons of almost all animals. Three of the newer antiepileptic drugs, gabapentin (Neurontin), topiramate (Topamax) and vigabatrin (Sabril), increase human homocarnosine levels. We measured homocarnosine and GABA levels of 20 patients with complex partial seizures taking gabapentin and 17 patients taking topiramate. Homocarnosine levels were higher in patients with better seizure control than those whose seizure control was below the middle value (median) for the two groups. There were no differences in the GABA levels between the patients, who showed a better response to gabapentin or topiramate, compared with those, who did not. Higher homocarnosine levels (above the median) were associated with better seizure control in the patients taking gabapentin or topiramate; higher brain GABA levels appeared to offer no additional protection. The current results are similar to our published findings, which showed higher brain homocarnosine levels in patients with juvenile myoclonic epilepsy with excellent seizure control, taking valproate (Depakote) or lamotrigine (Lamictal), than the levels of patients with more frequent seizures. The data support the hypothesis that increased homocarnosine and GABA levels contribute to the anticonvulsant properties of gabapentin and topiramate, perhaps, by limiting the spread of seizures from the areas where seizures start. Epilepsia 2006;47(3).

The Effect of Antiepileptic Drugs on 5-HT1A Receptor Binding Measured by Positron Emission Tomography

William H. Theodore, Giampiero Giovacchini, Robert Bonwetsch, Anto Bagic, Patricia Reeves-Tyer, Peter Herscovitch, and Richard E. Carson

Serotonin is one of the most important brain neurotransmitters. It has strong effects on mood, and may help to regulate nerve cell excitability, leading to effects on epilepsy. There are at least thirteen different brain serotonin receptors subtypes. The 1A subtype appears to be the most important for mood and seizures. Activity is reduced in patients with depression and epilepsy. Studies in animals suggest that some antiepileptic drugs (AEDs) may work in part through serotonin 1A receptors. Positron emission tomography (PET) can be used to study the distribution and activity of receptors in the brain. In our study, we used the PET tracer FCWAY to measure the effect of AEDs on serotonin 1A receptors in 31 patients with temporal lobe epilepsy. The results were compared with brain scans in ten healthy volunteers. We performed a correction for brain atrophy using magnetic resonance imaging. AEDs did increase the amount of FCWAY that was attached to blood proteins, and this had to be corrected for in data analysis. Our study shows that AEDs do not seem to have a strong effect on brain serotonin receptors. AEDs did not change the distribution or activity of serotonin 1A receptors. We found reductions in the seizure focus. Patients with both epilepsy and depression had lower activity than those with epilepsy alone. Epilepsia 2006;47(3).

Changes in the Disposition of Oxcarbazepine and its Metabolites during Pregnancy and Puerperium

Iolanda Mazzucchelli, Filiz Yilmaz Onat, Cigdem Ozkara, Dilek Atakli, Luigi M. Specchio, Angela La Neve, Giuliana Gatti, and Emilio Perucca

Pregnancy can have different effects on epilepsy. Usually seizure control does not change during pregnancy, but there are women in whom seizures get better or even get worse. Worsening of seizures during pregnancy occurs in less than 20% of cases, and may have several explanations. These include random variation (e.g., a spontaneous occurrence, purely due to chance); an effect of hormonal changes; a self-imposed reduction in medication, triggered by anxiety about possible undesirable effects of antiepileptic drugs on the fetus; and a change in the way drugs are handled by the patient’s metabolism. In particular, it is known that the body’s ability to break down some antiepileptic drugs, particularly lamotrigine, increases during pregnancy: this leads to a fall in the blood level of the drug, and reduced protection against seizures. In this paper, observations made in five women suggest that pregnancy can lead to marked changes in the handling of oxcarbazepine (Trileptal), a relatively new antiepileptic drug. After intake, oxcarbazepine is converted to an active principle called 10-hydroxycarbazepine, and in our patients the levels of this substance decreased markedly during pregnancy and increased after delivery. This could explain why in some women taking oxcarbazepine seizures get worse during pregnancy. These observations are only preliminary, and need to be confirmed. Doctors need to be alerted about the possibility of changes in oxcarbazepine’s handling during pregnancy, and may wish to monitor the levels of this drug before, during and after pregnancy in order to be able to make rational treatment decisions if needed. Epilepsia 2006;47(3).

Vitamin D Levels and Bone Turnover in Epilepsy Patients Taking Carbamazepine or Oxcarbazepine

Scott Mintzer, Prashanthi Boppana, Jeanne Toguri, and Anthony DeSantis

There is mounting evidence that some older seizure medicines, such as phenytoin (Dilantin) and carbamazepine (Tegretol), produce significant bone loss (i.e. osteoporosis) over time. The theory is that these drugs reduce the body’s levels of Vitamin D, which is crucial for maintaining bone mass. There is also evidence that they increase bone turnover, which eventually leads to bone loss. We looked at the effects of carbamazepine and the newer, related drug oxcarbazepine (Trileptal) on Vitamin D levels in blood and on three different markers of bone turnover in the blood and urine. We compared epilepsy patients who were taking one of these drugs with normal non-medicated control subjects. We then switched all the carbamazepine patients to oxcarbazepine, waited six weeks, and checked these markers again. We found that the two drugs had very similar effects on these variables, with significantly decreased Vitamin D and significant elevations in one of the bone turnover markers relative to controls. Carbamazepine-treated patients also had increases in a second bone turnover marker. Switching the carbamazepine patients to oxcarbazepine made no difference in any of these values. We conclude that epilepsy patients taking either carbamazepine or oxcarbazepine have lower Vitamin D levels and higher bone turnover, and may be at increased risk for bone loss over time. More studies are needed to determine whether reduced Vitamin D is the root cause of these changes, but in the meantime it may be prudent for carbamazepine- or oxcarbazepine-treated patients to take Vitamin D supplements (at least 800 IU/day). Epilepsia 2006;47(3).

Onset of Action of Levetiracetam: An RCT Trial using Therapeutic Intensive Seizure Analysis (TISA)

Hermann Stefan, Ying Wang-Tilz, Elisabeth Pauli, Alexandra Genow, Frank Kerling, Bogdan Lorber, Britta Fraunberger, Petra Halboni, Corinna Koebnick, Olaf Geffeller, and Christian Tilz

Drug treatment is the main therapeutic strategy in epilepsy. The clinical evaluation of new antiepileptic drugs (AED) is a very important procedure. The traditional clinical evaluation needs a relative long period and involves a large group of patients. With the introduction of video-EEG monitoring in clinical practice it is now possible to objectively quantify the seizure severity, for example, the seizure duration and seizure frequency. It led to the development of a new method in AED evaluation in the setting of presurgical evaluation that called TISA (therapeutic intensive seizure analysis). In comparison to the traditional evaluation, all parameters used in TISA were based on video-EEG recording, other than patient report. It could therefore guarantee the accuracy and reduce the evaluation period and sample size. In this study, the clinical anticonvulsive effects and the onset of action of a new antiepileptic drug “Levetiracetam” as two days after drug initiation were confirmed by using TISA method and these results were comparable to that found in studies involving more patients and lasting longer period. Epilepsia 2006;47(3).

February 2006
Vigabatrin Retinopathy in an Irish Cohort: Lack of Correlation with Dose
Peter Kinirons, Gianpiero L Cavalleri, Deirdre O'Rourke, Colin P Doherty, Irene Reid, Patricia Logan, Brenda Liggan, and Norman Delanty

Vigabatrin (VGB) is a effective medication used to treat epilepsy. However it causes causes irreversible constriction of vision as a side effect in about 40% of individuals. It is unclear if the development of this relates to the amount of the drug taken over time. We conducted an analysis of patients on long-term VGB treatment to examine if toxicity is related to the daily dose, duration of therapy or cumulative dose taken. Information from 93 patients on chronic, stable VGB therapy was analyzed. We recorded patient demographics, how much vigabatrin they had taken and for how long, and the results of all visual field assessments. We then compared the amount of visual field constriction to the daily dose, duration of therapy and cumulative dose of vigabatrin. Our results show 53% of patients developed visual field constriction. Males and females were affected equally. We found no correlation between the amount of visual field constriction and either the maximum dose of vigabatrin taken, the duration of exposure or the cumulative dose. The shortest exposure time to development of constriction was 1.1 years. All patients with normal fields on initial assessment continued to have normal fields on follow up. Most patients who had evidence of constriction on initial assessment and remained on VGB showed no progression on follow up. One patient had substantial recovery of vision after discontinuation of VGB. In conclusion, development of visual constriction in patients on chronic, standard doses of VGB does not depend on the daily dose, duration of exposure or cumulative dose. Our data suggests that field defects may develop within the first few years of therapy and possibly remain stable thereafter.

Predictors of Lamotrigine-associated Rash

Lawrence J. Hirsch, David B. Weintraub, Richard Buchsbaum, Hilary T. Spencer, Tara Straka, Melissa Hager, and Stanley R. Resor

Lamotrigine is an antiepileptic drug (AED) approved in the Unites States in 1994. It is effective for multiple types of seizures and is well tolerated overall. Rash is one of the known adverse effects. However, which patients are at particularly high or low risk of rash is unclear. Therefore, we performed this study to determine the predictors of lamotrigine-associated rash (LTG-rash) in order to individualize risk assessment in a given patient. We reviewed the charts of all 988 out-patients seen at the Columbia Comprehensive Epilepsy Center between January 1, 2000 and December 23, 2003 who received LTG. Charts were reviewed for documentation of rash developing from any medication, including antiepileptic drugs (AEDs) and non-AEDs, and including remote histories of drug-related rashes. Demographics, medical history, and medication variables were tested as potential predictors of LTG-rash. Fifty-six (5.7%) of 988 patients experienced rash attributed to LTG, and 39 (3.9%) of 988 discontinued LTG because of rash. No patients required hospitalization due to LTG-rash. A history of rash to another AED was the strongest predictor of LTG-rash, with children under 13 also experiencing significantly more LTG-rash. In children with a rash to another AED, 18% experienced LTG-rash while in adults without a rash to another AED, 3% experienced LTG-rash. Based on this retrospective analysis, a history of another AED-related rash is the greatest risk factor for developing rash to LTG; age under 13 is also a risk factor. Severe rash is rare when using the currently recommended titration rate. Epilepsia 2006;47(2).

Ginkgo Biloba Use in Nursing Home Elderly with Epilepsy or Seizure Disorder

Susan L. Harms, Judith Garrard, Paul Schwinghammer, Lynn E. Eberly, Yanping Chang, and Ilo E. Leppik

The purpose of this study was to discuss how Ginkgo, commonly used to treat memory loss, may affect seizures and to look at how often Ginkgo is prescribed to nursing home (NH) residents, particularly those with epilepsy or seizure disorder (Epi/Sz). Ginkgo trees contain certain compounds that may produce seizures. Conversely, they also contain substances that reduce the likelihood of seizures. The seizure-causing compounds are largely found in Ginkgo seeds rather than leaves. Though most US Ginkgo products do not contain seeds, there are no federal standards governing ingredients in herb products. There is no assurance that contamination of Ginkgo products with seeds will not occur. Another feature of Ginkgo is that its chemical makeup is affected by growing season and age and gender of the tree. Consequently, the amount and types of medically active substances that are present differs between trees. There is no guarantee that one Ginkgo product will have the same affect in the body as another. While reports of seizures following Ginkgo use are rare, consumers and prescribers should be aware that Ginkgo could cause seizures and use Ginkgo cautiously. This study found that the level of herb use in NHs is well below that of community elderly (0.41% vs. 29-50%). Among NH residents using herbs, Ginkgo was the most commonly prescribed herb for those both with Epi/Sz (62%) and without Epi/Sz (58%). Residents without Epi/Sz were prescribed a wide selection of herbs. Among residents with Epi/Sz, physicians prescribed herbs primarily for dementia or depression. Epilepsia 2006;47(2).

AEDs Availability and Professional Practices in Delivery Outlets in a City Center in Southern Vietnam

Tu Luong Mac, Van Tuan Le, Anh Nhi Vu, Pierre-Marie Preux, and Voa Ratsimbazafy

In developing countries, a multitude of factors such as nonavailability of AEDs contributes to the treatment gap in epilepsy. Eighty percent of the people suffering from active epilepsy do not have access to treatment. Our study in southern Vietnam showed that the availability of AEDs is sufficient. A small quantity of older AEDs is available. The pharmacies that delivered these AEDs are located in specific areas like the market area or the hospital area. However, pharmacists could be absent. These conditions do not allow an adequate treatment for a long period of time. An effort needs to be made to sensitize professional health workers to decrease the treatment gap in epilepsy. Epilepsia 2006;47(2).

A Controlled Clinical Trial of Cathodal DC Polarization in Patients with Refractory Epilepsy

Felipe Fregni, Sigride Thome-Souza, Michael Nitsche, Steven Freedman, Kette Valente, and Alvaro Pascual-Leone

Some patients with epilepsy do not have an adequate seizure control with use of medications. For these patients, new therapeutic approaches have been investigated. In this context, brain stimulation might be a good therapeutic option. Therefore, we aimed to investigate the effects of a novel technique of noninvasive brain stimulation, namely brain DC polarization, in patients with refractory epilepsy. Nineteen patients with refractory seizures and malformations of cortical development participated in this study. DC polarization is a simple technique that induces a continuous (DC – direct current) electric current into the brain. In this technique, electric current flows from cathode to anode electrode; and, thus, its effects depend on the electrode polarity: cathodal stimulation inhibits brain activity and anodal stimulation facilitates it. Therefore we placed the cathode electrode over the epileptogenic area (that is, the brain area in which seizures are originated) and the anode electrode over the silent area (that is, the brain area with normal brain activity). We measured epileptic activity before and after the treatment using an electroencephalogram (EEG) and the frequency of seizures. The results of this study showed that active treatment (DC polarization) compared to sham treatment was associated with a significant decrease in the number of epileptiform discharges (abnormal brain activity in the EEG related to seizure activity) and a trend toward a significant decrease in the frequency of actual seizures. This treatment was not associated with detectable adverse effects. The results of this study encourage future investigations of this new method of brain stimulation for epilepsy treatment. Epilepsia 2006;47(2).

Temporal and Extra-temporal BOLD Responses to Temporal Lobe Interictal Spikes

Eliane Kobayashi, Andrew P. Bagshaw, Christian-George Bénar, Yahya Aghakhani, Frederick Andermann, François Dubeau, and Jean Gotman

Simultaneous EEG and functional MRI (fMRI) allows measuring metabolic changes related to interictal spikes, which are characteristic discharges in the EEG of patients with epilepsy. Our objective was to investigate responses to temporal lobe (TL) spikes using EEG-fMRI recording. We studied 35 patients with a diagnosis of temporal lobe epilepsy (TLE) and active TL spiking on a routine EEG. Two-hour sessions of continuous EEG-fMRI were recorded and spikes were identified after off-line artifact removal and used as events in the fMRI analysis. Each type of spike was analyzed separately, as one EEG-fMRI study. We determined significant positive (activation) and negative (deactivation) fMRI changes for each study. Twenty-seven patients had spikes during scanning (19 unilateral and 8 bilateral). From a total of 35 fMRI studies, 29 (83%) showed changes: 14 had both activations and deactivations, 12 activations only and 3 deactivations only. Six (17%) showed no responses. Nineteen studies had mainly neocortical TL activation: 16/19 (84%) concordant with spikes, 12/16 with concomitant activation of the contralateral TL, and 16/19 with additional extra-temporal activation; few showed exclusively mesial TL activation. Seventeen studies showed deactivation, either extra-temporal plus temporal (n=8) or exclusively extra-temporal (n=9). In conclusion, fMRI responses to TL spikes occurred in 83% of studies, predominated in the spiking temporal lobe, and manifested as activation or deactivation. Responses often involved the contralateral homologous cortex at the time of unilateral spikes and were frequently observed in extra-temporal regions, suggesting that TL epileptic spikes can affect neuronal activity at a distance through synaptic connections. Epilepsia 2006;47(2).

Single and Multiple Clusters of Magnetoencephalographic Dipoles in Neocortical Epilepsy: Significance in Characterizing the Epileptogenic Zone

Makoto Oishi, Shigeki Kameyama, Hiroshi Masuda, Jun Tohyama, Osamu Kanazawa, Mutsuo Sasagawa, and Hiroshi Otsubo

Surgeons must locate the epileptogenic zone that generates seizures to surgically eliminate epileptic seizures, One method of localization is invasive subdural electroencephalography (SEEG). A new method using dipoles for epileptogenic source localization is noninvasive magnetoencephalography (MEG). We characterized the relationships of MEG dipoles (sources of epileptic discharges) with SEEG-defined seizure onset zones (SOZs) and correlated the findings with MRIs, surgical areas, and postsurgical outcomes for 20 patients with drug-resistant neocortical epilepsy who underwent resection. We referred to MEG findings as either single- or multiple-dipole cluster areas. Fourteen patients had single MEG dipole clusters; 6 had multiple clusters. Single MEG clusters coincided with SEEG SOZs in 9 patients; a single cluster was within or partially overlapped the SOZ in 4 patients; multiple-cluster sections overlapped SOZs in 5 patients; and no overlap with the SOZ occurred in 2 patients (1 with single cluster; 1 with multiple). More single clusters than multiple clusters coincided with the SOZ. More patients with single clusters (10 of 14) had seizure-free outcomes than did patients with multiple clusters (1 of 6). Eight of 9 patients with a single cluster that coincided to the SOZ had seizure-free outcomes, while only 3 of the 11 remaining patients were seizure free after surgery. MRI findings had no significant correlation with postsurgical outcomes. We concluded that, in neocortical epilepsy, MEG dipole clusters correlated with SEEG SOZs: single clusters indicated discrete epileptogenic zones for complete resection and seizure-free outcome; multiple clusters indicated multiple or extensive epileptogenic zones that required complete identification and delineation by SEEG for improved seizure control. Epilepsia 2006;47(2).

Epileptogenicity of Supratentorial Medullary Venous Malformation

Takato Morioka, Kimiaki Hashiguchi, Shinji Nagata, Yasushi Miyagi, Fumiaki Yoshida, Futoshi Mihara, Ayumi Sakata, and Tomio Sasaki

Abnormal blood vessels in the brain, called vascular malformations, are common causes of epilepsy. Vascular malformations come in several types. Arteriovenous malformations (made of arteries and veins) and cavernous angiomas (made of capillaries) are known to produce seizures. The role of venous malformations is less clear. The purpose of this study was to evaluate the epileptogenicity of a type of venous malformation called a medullary venous malformations (MVM). Special consideration was given to any associations with intracerebral hemorrhage with or without other vascular malformations, including cavernous angioma (CA). A total of 10 patients with angiographically or histologically verified MVM were examined. The patients were divided into two groups with or without intracerebral hemorrhage, and their clinical, neuroradiological, interictal and ictal EEG findings were reviewed retrospectively. Although three of five patients in the non-hemorrhagic group presented with epilepsy, there was no concordance between the location of the MVM location and the EEG seizure focus. On the contrary, four of five patients in the hemorrhagic group developed epilepsy, and concordance between the hemorrhagic MVM location and the EEG focus was noted. One patient with a hemorrhagic MVM and an associated CA in the hippocampus had an electro-clinical picture of intractable medial temporal lobe epilepsy on this side. Although a supratentorial MVM itself is not epileptogenic, the development of an intracerebral hemorrhage may cause epilepsy. In particular, an associated CA may be highly epileptogenic. Epilepsia 2006;47(2).

Extended, One-stage Callosal Section for Treatment of Refractory Secondary Generalized Epilepsy in Patients with Lennox-Gastaut and Lennox-like Syndrome

Arthur Cukiert, Jose Augusto Burattini, Pedro Paulo Mariani, Ródio Brandão Câmara, Lauro Seda, Cristine Mella Baldauf, Meire Argentoni, Carla Baise-Zung, Cássio Roberto Forster, and Valeria Antakli Mello

Epilepsy surgery is an accepted treatment modality for patients with refractory epilepsy. Usually these patients are evaluated by a multiprofessional team; and resective, disconnective and stimulatory procedures are used for seizure control. Although we would always prefer to offer resective procedures, which may ultimately render the patients seizure-free, some patients are not candidates for cortical resection and palliative procedures then might be considered. Callosal section, also known as callosotomy, is the most widely performed disconnective palliative procedure. With callosotomy, the large band of fibers connecting the two halves of the brain is severed. As a result, seizures cannot spread so rapidly through the brain. In this paper, we analyzed the effect of callosal section on 76 patients with the syndrome called Lennox-Gastaut and Lennox-like secondary generalized epilepsy. These patients usually present with refractory epilepsy, including frequent drop attacks and developmental delay, and their treatment always represents a challenge. We were able to show that extensive callosal section could be safely obtained in a one-stage procedure by means of careful microsurgical techniques and that the clinical outcome regarding seizures was better than performing a small callosal section. Patients presented with an acute disconnection syndrome that lasted for two weeks; there was no other morbidity or mortality. Worthwhile improvement (>50%) was noted in 69 out of 76 patients; 52 patients had at least a 90% reduction in seizure frequency. Seven patients were seizure-free after surgery. The seizure patterns most responsive to surgery were atonic (92%), atypical absence (82%) and tonic-clonic (57%) seizures. Parallel to the seizure frequency reduction, a consistent increase in attention level was observed postoperatively. Callosal section was found to be a good palliative option for these severely ill patients. It is the only procedure available so far that was capable of disrupting secondary bilateral synchrony, which is the electroencephalographic hallmark of these syndromes. Epilepsia 2006;47(2).

Seizure Recurrence and Risk Factors after Anti-epilepsy Drug Withdrawal in Children with Brain Tumors

Raja B. Khan and Arzu Onar

Brain tumors are the second most common tumor in children, after acute leukemia. Approximately 20% of children with brain tumors will develop seizures. The majority of these patients will achieve seizure control with appropriate medical therapy. Until now, risk for seizure recurrence was not known after discontinuation of seizure medications in brain tumor patients. We report rate and predictors of seizure recurrence in 62 children with brain tumors, in whom seizure medications were withdrawn. Based on our data, the estimated risk of seizure recurrence is 18% at two years and 27% at five years. We found that risk of seizure recurrence increased substantially if the child was treated with whole brain radiation therapy and required more than one brain surgery to treat the tumor. Younger age at tumor diagnosis and initial difficulty in controlling seizures may also increase the risk of seizure recurrence after medication withdrawal. Our data shows that the risk of seizure recurrence in childhood brain tumor patients is comparable to that in children with medically controlled seizures without brain tumors. We also show that seizure medications can be successfully withdrawn in carefully selected patients with childhood brain tumors and controlled seizures. Epilepsia 2006;47(2).

Epilepsy in Menkes Disease: Analysis of Clinical Stages

Nadia Bahi-Buisson, Anna Kaminska, Rima Nabbout, Christine Barnerias, Isabelle Desguerre, Pascale De Lonlay, Michele Mayer, Perrine Plouin, Olivier Dulac, and Catherine Chiron

Menkes disease (MD) is a rare X-linked recessive disorder with a primary generalized defect in copper transport. It results in a copper deficiency and subsequent impairment of activity of multiple copper dependent enzymes. Epilepsy is one of the main features of MD. In order to better determine the spectrum of epilepsy, we retrospectively analyzed the evolution of electroclinical features of 12 patients with confirmed MD based on clinical charts. Epilepsy could be divided into three successive periods. First, an early stage (median age 3 months) characterized by focal clonic status epilepticus, usually triggered by fever (10 patients). Ictal EEG showed runs of slow spike-waves and slow waves in the posterior regions, and interictal EEG multifocal and polymorphic slow waves (3 cases), or mixed slow spike-waves and slow waves (7 cases). Partial seizure control was obtained in 9 patients during 5.9 months. The second period or intermediate stage (median age 10 months) was characterized by intractable infantile spasms (11 patients) in which interictal EEG demonstrated modified hypsarrhythmia (7 cases), diffuse irregular slow waves and spike-waves (4 cases). Six patients died at the median age of 15 months. The third period or late stage in the 6 remaining patients (median age 25 months), was characterized by multifocal seizures, tonic spasms and myoclonus in 4 patients whereas 2 patients became seizure-free. Interictal EEG showed multifocal high amplitude activity, mixed with irregular slow waves in all 6 cases. These patients died at the median age of 3.6 years. Based on a relatively large series of MD patients with a quite prolonged survival, we individualized three successive periods in the course of epilepsy: early focal status, followed by infantile spasms, and then myoclonic and multifocal epilepsy after 2 years of age. Epilepsia 2006;47(2).

Benign Myoclonic Epilepsy in Infants: Electroclinical Features and Long-term Follow-up of 34 Patients.

Auvin Stéphane, Pandit Florence, De Bellecize Julitta, Badinand Nicole, Isnard Hervé, Motte Jacques, Villeneuve Nathalie, Lamblin Marie-Dominique, Vallée Louis, and the Epilepsy Study Group of the French Pediatric Neurology Society

Benign myoclonic epilepsy in infants (BMEI) is a rare epileptic syndrome characterized only by generalized myoclonic seizures (MS) in normal children during the first two years. Our aim was to assess the follow-up of this syndrome. Methods: BMEI was confirmed by electroencephalogram (EEG) in four neuropediatric units in France between 1981 and 2002. Clinical and electroencephalographic findings at diagnosis and during the follow-up were collected. The Vineland scale and/or Wechsler scale were used to perform neuropsychological evaluations. Results: We report 34 patients. BMEI is clinically characterized by myoclonic seizures involving the upper part of the body occurring many times a day. The ictal EEG showed a generalized discharge of polyspike, polyspike and wave or spike and wave. The interictal EEG was usually normal. Reflex MS were frequently observed and could suggest the diagnosis. A family history of febrile seizures (FS) or epilepsy was noted in six patients. A history of FS was noted in 11 patients. Monotherapy with valproate acid was effective in 23/30 treated patients. Four patients presented seizures after the initial symptoms. Juvenile myoclonic epilepsy developed in two patients and cryptogenic partial epilepsy in another. Neuropsychological outcome was evaluated in 20 patients (10 with Wechsler scales and 17 with Vineland scale). Cognitive functions were normal in 17 patients, while developmental delay was observed in three others.Despite a generally favorable neuropsychological outcome, cognitive impairment and developmental delay can be observed more frequently than in the general population. Further prospective studies are needed to better understand the existence of factors that contribute to these conditions. Epilepsia 2006;47(2).

Absence of Seizures Despite High Prevalence of Epileptiform EEG Abnormalities in Children with Autism Monitored in a Tertiary Care Center

Howard L. Kim, Joseph H. Donnelly, Anne E. Tournay, Teri M. Book, and Pauline Filipek

Seizures and EEG abnormalities are more common in children with autism than normal children, but the relationship is poorly understood. We studied 32 children with autism using prolonged video-EEG (VEEG) recording; twenty two of these children were suffering from recurrent seizures. The VEEG evaluations revealed that the majority of these children had epileptiform EEG abnormalities. These types of abnormalities can occur in children with epilepsy, or who have a higher risk for having epileptic seizures. However, in our study, these EEG abnormalities occurred in 60% of children who did not have seizures. Of the children who had their “seizures” recorded on VEEG, none of them were epileptic, even though 59% of these children had epileptiform EEG abnormalities. Most of the recorded “seizures” were staring spells, resembling absence seizures or bland complex partial seizures. The findings of our study demonstrate the peril of making a clinical diagnosis of epilepsy in children with autism. Our study also highlights the important role of video-EEG monitoring in establishing an accurate diagnosis of epilepsy in these children. Epilepsia 2006;47(2).

Thalamic Atrophy in Childhood Absence Epilepsy

Chow Huat (Patrick) Chan, Regula S. Briellmann, Gaby S. Pell, Ingrid E. Scheffer, David F. Abbott, and Graeme D. Jackson

Childhood absence epilepsy (CAE) is a common childhood epilepsy with frequent, but very short absence seizures. Patients with CAE have no abnormalities of their brain structure. Seizures may be caused by a functional disturbance of brain networks, prominently involving the cortex and the thalamus. We used automated voxel-by-voxel statistical assessment to assess for subtle volume differences of gray and white matter of cortex and thalamus. We recruited 13 patients with a clinical and EEG diagnosis of CAE (mean age at examination 17 ±8 years), and compared them to a consecutive series of 109 controls (mean age 29 ±9 years). Each subject performed a high-resolution magnetic resonance scan, which was analysed with an optimised protocol for voxel-based volume assessment. Compared to controls, CAE patients showed areas of grey matter decrease in the thalamus as well as less pronounced in other structures. White matter decrease was found around the thalamus, and in the white matter of the forebrain. Grey and white matter increase was restricted to small areas. Therefore, there is evidence of thalamic volume reduction in CAE patients. Bilateral thalamic atrophy may either be a result of damage from seizures or a reflection of a primary underlying pathology as the cause of absence seizures. Epilepsia 2006;47(2).

Postsurgical Outcome in Pediatric Patients with Epilepsy: A Comparison of Patients with Intellectual Disabilities, Sub-average Intelligence, and Average-range Intelligence

Ulrike Gleissner, Hans Clusmann, Robert Sassen, Christian E. Elger, and Christoph Helmstaedter

The chances of becoming seizure free after focal epilepsy surgery are often considered to be worse in developmentally delayed patients because intellectual disabilities frequently are associated with bilateral or diffuse morphologic brain damage thus increasing the risk of multiple epileptic foci. Moreover, the risk of postoperative cognitive deficits could increase since diffuse brain damage lowers the patient’s ability to compensate for surgically induced deficits. Recently, several studies in adult patients have indicated that the intelligence quotient (IQ) alone is not a good predictor of postoperative cognitive and seizure outcome but there is no study specifically evaluating this subject in children and adolescents. In our study, we compared pediatric patients with intellectual disabilities (IQ ≤ 70), sub-average intelligence ( IQ between 71 and 85), or average-range intelligence (IQ > 85) who were matched according to several clinical and etiological criteria to determine the isolated impact of IQ. The results indicated no dependency of seizure outcome, postoperative cognitive development, and behavioral outcome on the IQ level. Between 67 and 78% were seizure free one year after surgery. School placement remained unchanged for the majority of patients. We conclude, that IQ alone is not a good predictor of postoperative outcome in pediatric patients with epilepsy. As with patients of average-range intelligence, the decision to operate on intellectually disabled patients should depend on the results of the presurgical diagnostics. Diffuse functional cognitive impairment should not hinder further steps, if all other findings are consistent. Epilepsia 2006;47(2).

School Performance of Nigerian Adolescents with Epilepsy

Abiodun O. Adewuya, Saheed B.A. Oseni, and John A.O. Okeniyi

This study assesses the school performance, over the past one academic year, of 73 Nigerian adolescents with epilepsy, compared with their healthy classmates matched for age, gender, socio-economic status and presence of psychopathology. Results indicated that the mean school grades of adolescents with epilepsy are significantly lower than their healthy controls in all the subjects. The variables that significantly predict poor school performance of adolescents with epilepsy include psychopathology in the caretaker; adolescents’ perceived poor family functioning; adolescents’ attitude towards the illness; adolescents’ felt stigma; externalising symptoms in the adolescents and duration of illness. It is evident that the determinants of poor school performance in Nigerian adolescents with epilepsy are multivariate, with psychosocial factors most important. These should be noted for early identification and screening of those children at greatest risk for academic failure and the need for appropriate educational remediation services. Epilepsia 2006;47(2).

A Modified Atkins Diet is Effective for the Treatment of Intractable Pediatric Epilepsy

Eric H. Kossoff, Jane R. McGrogan, Renee M. Bluml, Diana J. Pillas, James E. Rubenstein, and Eileen P. Vining

The ketogenic diet has been used since 1921 to treat intractable childhood epilepsy. Over the past 85 years, it has not changed significantly. A modified Atkins diet may similarly induce ketosis without an admission or fasting period, and does not restrict protein, fluids, and calories. In a follow-up to our case series from 2003, we report on the first prospective study of a modified Atkins diet. Children ages 3-18 years, with at least 3 seizures per week, who had been treated with at least two anticonvulsants, were enrolled and received the diet for the 6-month study period. Carbohydrates initially were limited to 10 grams per day. All children became ketotic within days. After 6 months, 13 (65%) had >50% improvement and 7 (35%) had >90% improvement. Sixteen (80%) completed the 6-month study; 14 chose to remain on the diet afterwards. Side effects were minimal and weight did not significantly decrease. In fact, children who had their heights and weights remain relatively stable had better seizure control. A modified Atkins diet appears to be an effective and well-tolerated therapy. Epilepsia 2006;47(2).

The Outcome of Children with Intractable Seizures - A 3-6 Year Follow-up of 67 Children Who Remained on the Ketogenic Diet Less than One Year

Elisabeth B. Marsh, John M. Freeman, Eric H. Kossoff, Eileen P. Vining, James E. Rubenstein, Paula L. Pyzik, and Cheryl Hemingway

Children who have epilepsy that have not responded to two appropriately administered medications are termed “difficult-to-control”, or “intractable” and are widely believed to have only a 10-30 percent chance of responding to any additional medication. Our prior study of the effectiveness of the ketogenic diet in 150 children with these seizures documented that after one year, more than 25% had a 90% decrease in seizures. Similar seizure control was found 3-6 years later, when most children had discontinued the diet and were off medications. However, in that study, almost half of the children discontinued the diet during the first year, 1/3 within 3 months, 2/3 by 6 months. Discontinuation was usually because of failure of the diet to adequately control their seizures. These children were also assessed by questionnaire 3-6 years later. To our surprise, 22% had become seizure-free and an additional 10% were mostly seizure-free (>90% decrease). Half had a greater than 50% reduction in seizures with or without surgery. It was unclear whether this improvement in seizure control was due to the natural history of the conditions causing the seizures, or to the use of newer anticonvulsant medications. In either event, the outlook for children with “difficult-to-control” or “intractable” seizures is not as bleak as was once believed. Epilepsia 2006;47(2).

Defining Intractability: Comparisons Among Published Definitions

Anne T. Berg and Molly Kelly

Although most epilepsy is well-controlled by available medications, intractable epilepsy affects a substantial minority of patients and accounts for a disproportionate amount of resources devoted to care of people with epilepsy. There is no single definition of intractability, and different authors have used different definitions. This creates difficulties for comparing results across studies and synthesizing the literature. In this study, we performed a head-to-head comparison of six different published definitions within a single prospective study of 613 children with newly diagnosed epilepsy. We examined the extent of agreement or disagreement among the definitions and the longer term implications of meeting each definition. The definitions were assessed at various times within the first five years after diagnosis with the exact timing reflecting how they were originally reported. Observed and agreement adjusted for chance were computed. The associations of each definition with remission status 7-10 years after diagnosis were quantified. The different definitions classified 9-24% of children as intractable. Observed agreements among the definitions ranged from a low of 83% to a high of 96%. Agreement adjusted for chance ranged from low of 45% to 79%. All definitions were strongly associated with remission status as of last follow-up. Agreement among the different definitions is strong but imperfect. All definitions were significantly associated with longer term outcome. There is no single preferred definition of intractable epilepsy. Consideration should be given to whether a single definition will suit all purposes or whether different types of definitions are needed for different purposes. Epilepsia 2006;47(2).

Contralateral Smile and Laughter, but no Mirth, Induced by Electrical Stimulation of the Cingulate Cortex

Francesca Sperli, Laurent Spinelli, Claudio Pollo, and Margitta Seeck

The cerebral representation of laughter is dissociated. The emotional aspects seem to be processed in the temporal lobe; whereas, the motor features apparently rely on the frontal cortex. In a few prior studies of patients in whom laughter was elicited by electrical stimulation (ES), it always was associated with mirth. We report a patient in whom ES in the right cingulate gyrus elicited smile and laughter, but no mirth. At low voltages, smiling was seen first contralaterally, and became bilateral with increasing currents. Our observation supports the concept of the motor representation of laughter in the mesial frontal cortex. Epilepsia 2006;47(2).

Linking Generalized Spike and Wave Discharges and Resting State Brain Activity Using EEG/fMRI in a Patient with Absence Seizures

Helmut Laufs, Ulrike Lengler, Khalid Hamandi, Andreas Kleinschmidt, and Karsten Krakow

Epilepsy is a condition of the brain in which the balance between the millions of nerve cells (neuron) is disturbed. This can lead to an epileptic seizure when too many neurons fire at the same time. This can be visualized using an electroencephalogram (EEG, which measures electricity generated by neurons). Synchronous activity can affect most of the brain that on the EEG can appear as a typical pattern of generalized “spike and wave” activity, reflecting the shape of the recorded signal. The associated seizure type is called an absence seizure. During an absence seizure, it appears as if all brain activity comes to a halt, and the patient stops whatever he or she was doing. Afterwards, recollection for the time during the seizure would be lost. In this study, we showed that spike-and-wave activity - even those lasting not longer than a second - can disrupt brain activity such as spontaneous thought and self-reflection occurring when one is “at rest.” This was possible by combining EEG with functional magnetic resonance imaging that allows to see activity changes in different brain regions. Which function a particular brain area roughly subserves can be looked up in a database containing results of many other research studies. Epilepsia 2006;47(2).

January 2006
Efficacy and Safety of Levetiracetam (up to 2000 mg/d) in Taiwanese Patients with Refractory Partial Seizures: A Multicenter, Randomized, Double-blind, Placebo-controlled Study
Jing-Jane Tsai, Der-Jen Yen, Mo-Song Hsih, Shung-Sheng Chen, Reinhard Hiersemenzel, Pascal Edrich, and Chi-Wan Lai

Despite new treatment options for epilepsy, around a quarter of patients still suffer from uncontrolled seizures or medication side effects. As such, there continues to be a need to develop new treatments. Levetiracetam (LEV) is a novel new antiepileptic drug (AED), for which the effectiveness and safety have been proven in clinical testing in the USA and Europe. It has been registered in over 50 countries for the treatment of adult patients with partial epilepsy. LEV has an ideal pharmacokinetic profile and is not expected to have differences when used in non-Caucasian populations. This clinical trial was designed to test the effectiveness and safety of LEV in a Taiwanese population. Ninety-four patients aged 16-60 years with treatment-resistant epilepsy were enrolled into this trial which compared the effect of LEV to placebo when added on to current treatment. The maximum dose used was 2000 mg and the testing period lasted for 14 weeks. Nearly half of the LEV patients had their seizure number reduced by half compared to around 10% in the placebo group. The most common side effects experienced in both groups were tiredness/fatigue, dizziness and headache. They were more commonly reported in the LEV group, but the majority of these were considered mild in intensity. In summary, this clinical trial demonstrates that LEV is an effective and safe adjunctive treatment for Taiwanese patients with treatment-resistant partial epilepsy. It confirms previous clinical testing done in Caucasian patients and suggests that LEV is likely to be ethnically insensitive. Epilepsia 2006;47(1).

Effects of Levetiracetam on Nocturnal Sleep and Daytime Vigilance in Healthy Volunteers

Alessandro Cicolin, Umberto Magliola, Alessandra Giordano, Anna Terreni, Caterina Bucca, and Roberto Mutani

Individuals with epilepsy commonly report daytime sleepiness, attributed to sleep disruption (frequent arousals, awakenings, and stage shifts) induced by ictal and interictal activity and/or antiepileptic drugs (AEDs). In order to study the effect of levetiracetam (LEV) on sleep, at full doses but without the interference of epilepsy, we investigated the sleep architecture and daytime vigilance in healthy adults after three weeks of treatment. The study was of a double-blind, crossover design with random allocation of multiple doses of two different treatments (randomly first LEV up to 2000 mg/day or placebo for three weeks, wash-out for four weeks, then the alternative treatment for other three weeks). Fourteen healthy volunteers were studied by polysomnography (PSG) and Multiple Sleep Latency Test (MSLT). Epworth Sleepiness Scales (ESS) and sleep logs also were evaluated. After treatment with LEV, statistically significant increases were observed in total sleep time, sleep efficiency and time spent in non-rapid eye movement (NREM) sleep stage 2 and 4. Stage-shifts and wake-after-sleep-onset were significantly decreased. Sleep latency was normal at PSG and MSLT in all subjects, and did not statistically differ between placebo and LEV. No changes were found in ESS. Our findings show that in healthy volunteers LEV consolidates sleep and does not modify vigilance, two appreciated qualities in patients with epilepsy, sleep disturbance and daytime sleepiness. Epilepsia 2006;47(1).

December 2005
Pregabalin Add-on Treatment in Patients with Partial Seizures: A Novel Evaluation of Flexible-dose and Fixed-dose Treatment in a Double-blind, Placebo Controlled Study
Christian E. Elger, Martin J. Brodie, Henning Anhut, Caroline M. Lee, and Jeannette A. Barrett

Pregabalin is an antiepileptic medication introduced in many countries in 2004-2005 for the treatment of partial epilepsy in adults, when administered in combination with other antiepileptic drugs (AEDs). Clinical trials traditionally employ fixed doses throughout, while in clinical practice, the dose of most AEDs is adjusted gradually, with the dual aim of enhancing tolerability and allowing for optimum effective dosing. The current study included a novel flexible dose regimen in which patients were started on the lowest effective dose of 150 mg/day of pregabalin, followed by a step-wise increase in dose for those patients with inadequate seizure control, up to 600 mg/d The study goal was to compare the step-wise regimen in terms of both efficacy in seizure reduction and tolerability with a fixed high dose regimen of 600 mg/d. To be eligible for the 12-week study, patients (n=341) had to be receiving at least one other AED and still experiencing at least four partial seizures in the previous six weeks. Both pregabalin regimens were highly effective at reducing the frequency of seizures, with reductions of 35% for flexible dose, and 49% for fixed dose, compared to 11% for placebo. Both regimens were well-tolerated, with most side-effects being mild or moderate. However, 78% of the patients completed the study in the flexible dose group, versus 58% for the fixed dose group, and more had side effects in the fixed dose group. In conclusion, there appears to be a treatment advantage to adjusting the dose of pregabalin within the therapeutic range of 150-600 mg/d, according to the patient’s optimal efficacy and tolerability. Epilepsia 2005;46(12).

October 2005
Pharmacokinetics of Gabapentin During Delivery, in the Neonatal Period, and Lactation: Is There a Fetal Accumulation During Pregnancy?
Inger Öhman, Sigurd Vitolsa, and Torbjörn Tomson

Although introduced fairly recently, gabapentin is a drug that has become widely used in the treatment of epilepsy and in particular for different pain syndromes. As such gabapentin is often prescribed to women of child-bearing potential. It is therefore surprising that information on gabapentin during pregnancy and breast-feeding has been lacking. The present study therefore investigated gabapentin concentrations in maternal and cord blood and in the newborn at delivery as well as drug levels in breast-milk and in the nursed infant of six mothers treated with gabapentin during pregnancy and breast-feeding. Gabapentin concentrations in cord blood were 70% higher than in the mother suggesting an active transport of gabapentin over the placenta with accumulation in the fetus as a consequence. The capacity to eliminate gabapentin appeared to be slightly lower in the newborns than adults. Gabapentin was excreted into breast-milk, but plasma concentrations appear to be low in the breast-fed infants and no adverse effects were observed. Our limited observations suggest that breast-feeding while taking gabapentin is probably safe. Epilepsia 2005;46(10).

Non-convulsive Status Epilepticus and Tiagabine Therapy Revisited

Matthias J. Koepp, Mark Edwards, Jayne Collins, Fiona Farrel, and Shelagh Smith

Treatment with antiepileptic drugs (AED) can sometimes worsen seizure control. Since launching the new AED tiagabine (TGB), there have been about 33 reports of non-convulsive status epilepticus (NCSE) in association with TGB treatment in focal epilepsies. These case reports were criticized for the lack of a denominator: it is usually not known how many patients were treated with TGB without NCSE developing, and how many patients not treated with TGB, but with equally severe epilepsy, would develop NCSE over a similar time period. Further strengthening the argument for a pro-convulsive effect of TGB is the recent Federal Drug Agency safety alert that there have been more than 30 post-marketing reports of new-onset seizures and status epilepticus in patients without epilepsy in association with TGB use. We reviewed retrospectively the medical and EEG records of all in-patients with refractory focal epilepsy treated with TGB between January 1997 and December 2000. Clinical and electroencephalographic (EEG) data before, during and after TGB therapy were evaluated in those patients who experienced a deterioration in seizure control suspicious of NCSE. Frequency of NCSE was determined in a comparable, non-TGB treated patient population. Seven of 90 TGB-treated patients (7.8 %) were identified who experienced episodes of electro-clinically confirmed NCSE. Serial EEGs showed deterioration during TGB treatment with resolution of abnormality on withdrawal of TGB in all seven patients. During the same observation period, 32 of 1165 non-TGB-treated patients (2.7 %) developed electro-clinically defined NCSE. We can conclude that treatment with TGB is associated with an increased frequency of NCSE in patients with refractory focal epilepsy. Epilepsia 2005;46(10).

Reversible Cytotoxic Edema in the Splenium of the Corpus Callosum Related to Antiepileptic Treatment Report of Two Cases and Literature Review

Olga Prilipko, Jaqueline Delavelle, Francois Lazeyras, and Margitta Seeck

Several reports of clinically silent lesion in the splenium of the corpus callosum (i.e. the posterior region of the main interhemispheric connection route) of patients receiving antiepileptic treatment have been previously published. The lesion consists of cellular swelling, which usually spontaneously resolves within 3 or 4 weeks. Several causes for this phenomenon have been proposed such as altered permeability of blood vessels, hormonal (arginine vasopressin, AVP) imbalance induced by rapid antiepileptic drugs changes, secondary to seizure spread, antiepileptic drugs toxicity or alteration of the isolating myelin sheath of nervous cells secondary to vitamin B deficiency. However, so far a satisfactory explanation is missing. We describe two further patients who presented this transient splenial lesion phenomenon. Our data suggest that the lesion represents cellular swelling without neuronal damage, as demonstrated by intact neuronal fibers on the diffusion tensor imaging. It is probably due to abrupt antiepileptic drug concentration changes and consecutive alterations of AVP secretion. These results confirm the previous impression of the benign character of this phenomenon, which does not necessitate other investigations or therapeutic interventions except a control MRI after 1 month. Epilepsia 2005;46(10).

September 2005
Pregabalin Drug Interaction Studies: Lack of Effect on the Pharmacokinetics of Carbamazepine, Phenytoin, Lamotrigine, and Valproate in Patients with Partial Epilepsy
Martin J. Brodie, Elaine A. Wilson, David L. Wesche, Christine W. Alvey, Edward J. Randinitis, Edward L. Posvar, Neil J. Hounslow, Nicola J. Bron, G.L. Gibson, and Howard N. Bockbrader

Pregabalin (Lyrica®) is a new drug that has been approved in the EU as add-on treatment for partial seizures, and as treatment of peripheral neuropathic pain, in adults. Because many patients with partial seizures require more than one antiepileptic drug (AED) to achieve the best seizure control they can, it is important to determine whether new drugs for treating partial seizures may interact with commonly used AEDs. This paper reports the results of several drug–drug interaction studies of pregabalin and commonly used AEDs.

In these studies, pregabalin was given to patients who were each taking one AED, either valproate, phenytoin, lamotrigine, or carbamazepine, to treat their epilepsy. Adding pregabalin to monotherapy with valproate, phenytoin, lamotrigine, or carbamazepine had no effect on the concentrations in the blood of any of these four drugs. Likewise, when concentrations of pregabalin in the blood were measured in these same patients, the concentrations were similar to those seen in the blood of subjects from earlier studies who had received pregabalin by itself. These findings indicate that pregabalin does not interact with any of these four common AEDs.

The combinations of pregabalin with either valproate, phenytoin, lamotrigine, or carbamazepine were generally well tolerated by the patients in these studies, and when side effects did occur, they were typically mild to moderate and resolved quickly. Together, these studies demonstrate that pregabalin may be safely added to therapy with valproate, lamotrigine, phenytoin, or carbamazepine without concern for drug–drug interactions. Epilepsia 2005;46(9).

Ethinyl Estradiol, Not Progestogens, Reduces Lamotrigine Serum Concentrations

Arne Reimers, Grethe Helde, and Eylert Brodtkorb

This work studies the interaction between the antiepileptic medicine lamotrigine (LTG, Lamictal®), and hormonal contraception. The participants were females using either no hormonal contraception (18 patients), an ethinyl estradiol (EE)-containing (11 patients) or a progestogen (PG)-only-containing compound (16 patients). Drug fasting blood levels of LTG were analyzed. Comedication with other drugs known to alter LTG blood levels was not allowed. Some patients changed group after the first blood sample and thus served as their own controls. We found that women using EE had only half as much LTG in their blood compared to the women in the control group or the PG-group. There was no difference between women using PG, and controls. Also, there was no difference between women using either oral, topical or parenteral PG. Five women switched from the control-group to the EE-group and experienced a considerable reduction in their blood levels of LTG. A rise of LTG in blood towards control levels was seen in the two women who changed from EE to PG.

We conclude that it is the EE-component of oral contraceptives which reduces LTG blood levels. The PG-only compounds did not influence LTG blood levels in this study. These findings should be considered when counselling women with epilepsy in childbearing age. Epilepsia 2005;46(9).

August 2005
Fast and Sustained Efficacy of Levetiracetam During Titration and the First Three Months of Treatment in Refractory Epilepsy
Jacqueline French, Sylvie di Nicola, and Celestina Arrigo

Levetiracetam (LEV) is a new antiepileptic drug (AED), introduced in 2000. LEV is indicated as add-on therapy in the treatment of adults with partial onset seizures. Research has shown that LEV is a well tolerated AED, effective from the first day of treatment. Its efficacy and tolerability were demonstrated in short-term and long-term studies. Further analysis was performed to assess variability in efficacy throughout the duration of the trials. This study investigated whether the efficacy of LEV was sustained in adult patients with refractory partial seizures over a 3-month period. A post-hoc analysis was conducted on pooled data from three randomized, double-blind, placebo-controlled trials. Proportions of seizure-free days were compared between LEV and placebo during each week of the 3-month period after the initiation of treatment. Results showed significantly greater mean proportions of seizure-free days in the LEV group than in the placebo group as early as the first week after the initiation of treatment. The difference was higher in the first week of treatment, and subsequently was maintained for each week over the 3-month period. Patients in the LEV group had on average 74% to 81% days each week seizure free, compared with 69% to 72% in the placebo group. In conclusion, LEV is efficient in controlling seizures from the first week of drug initiation, during up-titration, and throughout the first 3 months of treatment. There is an interesting amplification of efficacy in the first week of therapy, which is intriguing and warrants further investigation. Epilepsia 2005;46(8).

Quality of Phenobarbital Solid Dosage Forms in the Urban Community of Nouakchott (Mauritania)

Marie-Laure Laroche, Hamidou Traore, Louis Merle, Jean-Michel Gaulier, Marylene Viana, and Pierre-Marie Preux

Epilepsy is a serious health problem in Africa. Treatment rests on several medications and especially on phenobarbital, which is fairly cheap and widely available. However the quality of this drug could be questioned. In order to know if phenobarbital preparation could be relied upon to treat epilepsy we conducted a study in Nouakchott (Mauritania) in March of 2003. Phenobarbital ordered on a prescription was bought by in 45 randomly selected pharmaceutical sources of Nouakchott. We thus collected 146 phenobarbital tablet samples from 3 brand names originating from France, Morocco, Senegal and Egypt. The phenobarbital content of the tablets was then assayed using a liquid chromatographic method. 13.7 % of the samples were considered of poor quality as their content lay outside 85 and 115 % of the stated content printed on the packet. All samples from Morocco were underdosed. The active content of the generic was satisfactory. A generic medication contained saccharose, an inert substance known to have occasional side effects. We identified two factors associated with a good quality of phenobarbital preparations: manufacturing in France, and generic medication available in loose packaging. This study shows the quality of phenobarbital, a widely available anticonvulsant in Mauritania, is fairly good but could still be improved. Availability of the generic form of this anticonvulsant, considering the good quality and the low price of this type of medication, should be promoted. More generally a drug control agency should be set up in the country with enough power to enforce regulations. Epilepsia 2005;46(8).

July 2005
Growth and Lipid Metabolism in Girls and Young Women with Epilepsy during Pubertal Maturation
Kirsi Mikkonen, Mikael Knip, Arto J. Pakarinen, Peter Lanning, Jouko I. T. Isojärvi, and Leena K. Vainionpää

This study assessed growth and serum lipid concentrations in girls with epilepsy taking different antiepileptic drugs as single drug treatment at a mean age of 12.6 years and approximately 6 years later.

Seventy-seven girls with epilepsy and 49 healthy control girls participated in this follow-up study including two evaluations (age range 8-18.5 years on the first evaluation, and 12.5-25.8 years on the second evaluation) in the same subjects. Forty of the patients were initially taking valproate, 19 carbamazepine, and 18 oxcarbazepine. Growth data were compiled, body mass index (BMI), which reflects body weight, was calculated, and serum total, high-density lipoprotein and low-density lipoprotein cholesterol and triglyceride concentrations were analyzed. Growth and final height did not differ between the patients and the control subjects. At follow-up, the mean BMI of the patients whose medication had been discontinued (61%) was similar to that of the control subjects, while the patients initially treated with valproate who were still on any medication had a higher BMI. On the first evaluation, the patients on valproate had low serum high-density lipoprotein cholesterol levels and those on carbamazepine or oxcarbazepine high serum total and low-density lipoprotein concentrations. At follow-up, serum lipid levels were similar in the patients not taking medication and the control subjects. Neither epilepsy nor antiepileptic therapy affects growth or final height in girls with epilepsy, but they may have unfavorable effects on body weight and serum lipid concentrations. Changes in serum lipid levels seem to be transient if the medication is discontinued. Overweight is common in patients treated with valproate during puberty if epilepsy and medication continue into adulthood. Epilepsia 2005;46(7).

A Comparative Study of the Effect of Carbamazepine and Valproic Acid on the Pharmacokinetics and Metabolic Profile of Topiramate at Steady-State in Patients with Epilepsy

Dorit Mimrod, Luigi M. Specchio, Malka Britzi, Emilio Perucca, Nicola Specchio, Angela La Neve, Stefan Soback, Rene H. Levy, Giuliana Gatti, Dennis R. Doose, Bruce E. Maryanoff, and Meir Bialer

The study’s aim was to compare the influence of co-medication by carbamazepine (CBZ) and valproic acid (VPA) on the pharmacokinetics and metabolism of topiramate (TPM). Three groups were assessed: a) patients receiving TPM mostly alone (control group, n =13); b) patients receiving TPM with CBZ (n=13); c) patients receiving TPM with VPA (n=12). TPM and its metabolites were assayed in plasma and urine. There were no significant differences in TPM total and renal clearance between the VPA-group and the control group. Mean TPM total and renal clearance values were higher in the CBZ-group than in controls (2.1 vs 1.2L/h and 1.1 vs 0.6L/h respectively, p<0.05). In all groups, the urinary recovery of unchanged TPM was extensive and accounted for 42% to 52% of the dose (p>0.05). Urinary recovery of 2,3-O-des-isopropylidene-TPM (2,3-diol-TPM) accounted for 3.5% of the dose in controls, 2.2% in the VPA-group (p>0.05) and 13% in the CBZ-group (p<0.05). The recovery of 10-hydroxy-TPM (10-OH-TPM) was two-fold higher in the CBZ-group than in controls, but it only accounted for less than 2% of the dose. The plasma concentrations of TPM metabolites were several-fold lower than of the parent drug.

Renal excretion remains a major route of TPM elimination even in the presence of enzyme induction by concurrently taken other seizure medications. The two-fold increase in TPM metabolism and excretion in patients taking CBZ can be ascribed, at least in part, to stimulation of the oxidative pathways in the liver leading to formation of 2,3-diol-TPM and 10-OH-TPM. VPA was not found to have any clinically significant influence on TPM pharmacokinetic and metabolic profile. Epilepsia 2005;46(7).

Retinal Electrophysiological Results in Patients on Lamotrigine Monotherapy

Carl F. Arndt, Jeremie Husson, Philippe Derambure, Jean Claude Hache, Bernard Arnaud, and Sabine Defoort-Dhellemmes

Lamotrigine is an anti-epileptic drug effective against both partial and generalized seizures, including generalized absence seizures. Among the documented side effects, visual blurring is reported by 23% of the patients treated with lamotrigine. The objective of the study was to evaluate more precisely the effects on vision in patients on lamotrigine. Twenty-four consecutive patients on lamotrigine for partial seizures were referred for a routine ophthalmologic examination. Automatic visual field evaluation, electro-oculogram and electroretinogram were then performed after informed consent was obtained. In 18 patients finally included in the study, the clinical ophthalmologic examination showed no abnormality. Four patients complained of blurring; among them one patient had a visual field constriction in both eyes which however was of unclear significance, as the changes could be due to poor understanding of the procedure. This patient also had an abnormal electro-oculogram. One other patient with blurred vision had an abnormal electro-oculogram but the visual field was normal. Two patients had abnormal electro-oculograms but no visual symptoms. Considering the whole group of patients on lamotrigine, the electro-oculogram was altered in a dose dependent fashion. The electroretinogram was normal in all patients. Thus, no irreversible visual field impairment in patients treated with lamotrigine was encountered, although there might be a dose-dependent retinal toxicity. The exact cellular mechanism of the electrophysiological changes in patients on lamotrigine remain to be explained.. Epilepsia 2005;46(7).

June 2005
Drug Resistance in Epilepsy: Putative Neurobiological and Clinical Mechanisms
Dieter Schmidt and Wolfgang Loescher

Drug-resistant epilepsy, with uncontrolled severe seizures despite the best available drug treatment, continues to be a major clinical problem for up to one in three patients with epilepsy. Although drug resistance may emerge or disappear in the course of epilepsy or its treatment, in most patients so-called de novo drug resistance seems to exist already when treatment starts. Unfortunately, current antiepileptic drugs (AEDs) do not seem to prevent or to reverse drug resistance in most patients. However, add-on therapy with novel AEDs is able to exert a modest seizure reduction in as many as 50% of patients in short-term clinical trials, and a few percent become seizure-free during the trial. It is not known why and how epilepsy becomes drug-resistant, while other patients with seemingly identical seizure types can achieve seizure control with medication. Several possible mechanisms underlying drug resistance in epilepsy have been identified in recent years. Based on experimental and clinical studies, two major neurobiological theories have been put forward: i) removal of AEDs out of the epileptogenic tissue (where AEDs exert their effect) through excessive activity of multidrug transporters and, ii) reduced efficacy through lower target sensitivity to drugs in brain tissue involved in epilepsy. On the clinical side, genetic and clinical features and structural brain lesions have been associated with drug resistance in epilepsy. In this article, we review the laboratory and clinical evidence to-date supporting the drug-transport and the drug-target hypotheses and provide directions for future research to more clearly define the role of these hypotheses in the clinical spectrum of drug-resistant epilepsy. Epilepsia 2005;46(6).

MAY 2005

Levetiracetam Concentrations in Serum and in Breast Milk at Birth and during Lactation

Svein I. Johannessen, Grethe Helde, and Eylert Brodtkorb

We studied the concentration of the antiepileptic drug levetiracetam (LEV, Keppra®) in blood and in breast milk at birth and during lactation. Eight consecutive breast-feeding women with epilepsy treated with LEV twice daily and their infants were included in the study. The mean ratio between the concentration of LEV in the umbilical cord blood and the mothers´ blood was 1.14, ranging from 0.97 to 1.45) (n=4). The mean ratio between the concentration in the milk and the concentration in the mothers´ blood was 1.00, ranging from 0.76 to 1.33 at three to five days after delivery (n=7). At sampling two weeks to 10 months after delivery (n=5) it was similar (range, 0.85-1.38). By three to five days after delivery, the infants had very low blood concentrations of LEV (less than 10-15 µmol/L), a finding that persisted during continued breast-feeding. No malformations were detected, and none of the infants developed signs of adverse effects. In conclusion, levetiracetam readily crosses the placenta and is excreted into breast milk. Breast-fed infants usually have very low concentrations of the drug in the blood probably due to a rapid elimination. Women with epilepsy should in general be encouraged to nurse their infants. Treatment with levetiracetam forms no exception. Epilepsia 2005;46(5).

Plasma Concentrations of Risperidone and Olanzapine during Co-administration with Oxcarbazepine

Maria Rosaria Muscatello, Monica Pacetti, Massimo Cacciola, Diletta La Torre,
Rocco Zoccali, Concetta D’Arrigo,Gaetana Migliardi, and Edoardo Spina

Oxcarbazepine is a second-generation antiepileptic with mood-stabilizing properties. Unlike carbamazepine which is an inducer of the cytochrome P450 isoforms and may accelerate the elimination of several therapeutic agents, oxcarbazepine seems to have only a modest inducing action. In order to investigate the interaction between oxcarbazepine and the novel antipsychotics risperidone and olanzapine, we carried out drug monitoring of plasma concentrations of these antipsychotics in patients with bipolar or schizoaffective disorder given oxcarbazepine as a mood stabilizer. Oxcarbazepine, at a dose of 900-1200 mg/day, was administered for 5 consecutive weeks to 25 outpatients, 10 men and 15 women, aged 25 to 64 years. Twelve patients were stabilized on risperidone therapy (2-6 mg/day) and 13 on olanzapine (5-20 mg/day). Plasma concentrations of risperidone and its active metabolite 9-hydroxyrisperidone (9-OH-risperidone) and olanzapine were measured by HPLC before addition of oxcarbazepine and after 5 weeks from the start of adjunctive treatment. Co-administration of oxcarbazepine caused only minimal and no significant changes in the mean steady-state plasma levels of risperidone, 9-OH-risperidone and olanzapine. In addition, its combination with either risperidone or olanzapine was well tolerated. These results indicate that oxcarbazepine does not affect the elimination of risperidone and olanzapine and confirm that this agent has a low potential for metabolically-based drug interactions. Based on these findings, oxcarbazepine may be added safely to psychiatric or epileptic patients receiving maintenance treatment with risperidone or olanzapine.

Cost-effectiveness of First-line Antiepileptic Drug Treatments in the Developing World: A Population-level Analysis

Dan Chisholm

Despite the negative impact of epilepsy on public health, there remains a yawning treatment gap in most developing regions of the world. In order to stimulate new investment into its appropriate management, there is a need to clearly demonstrate that interventions for epilepsy are not only effective and sustainable, but also affordable.

WHO has embarked on a new initiative to assemble information on the cost-effectiveness of key health interventions in different sub-regions of the world. As part of this, costs and effects of older and newer anti-epileptic drugs (AEDs) provided in primary care were compared to a 'do nothing' scenario (i.e. the untreated natural history of epilepsy). Effectiveness was expressed in terms of disability-adjusted life years or DALYs averted (a population-level summary measure of reduced burden) and costs were expressed in international dollars.

Across nine developing WHO sub-regions, extending AED treatment coverage to 50% of primary epilepsy cases would avert between 150-650 DALYs per one million population (equivalent to 13-40% of the current burden), at an annual cost per capita of I$ 0.20-1.33. Older first-line AEDs (phenobarbital, phenytoin) were most cost-effective on account of their similar efficacy but lower acquisition cost (I$ 800-2,000 for each DALY averted).

The main conclusion of the study is that a significant proportion of the current burden of epilepsy in developing countries is avertable by scaling-up the routine availability of low-cost anti-epileptic drugs. Critical factors in the successful implementation of such a scaled-up level of service delivery, apart from renewed political support and investment, relate to appropriate training and continuity of drug supply. Epilepsia 2005;46(5).

Time Course of Adverse Events in Patients with Localization-related Epilepsy Receiving Topiramate Added to Carbamazepine

Jerzy Majkowski, Walter Neto, Robert Wapenaar, and Joop C. Van Oene

When antiepileptic agents are approved for use, the company must list all the side effects that occurred while patients took the drug. This study explores possible side effects when patients with epilepsy take topiramate in addition to carbamazepine to control their symptoms. Most patients (71%) who took topiramate had at least one side effect in the first few days of therapy. The most common side effects were sleepiness, headache, loss of appetite, nervousness, fatigue, dizziness, and upper respiratory tract infection. Of note, however, 63% of 92 patients who took a sugar pill (placebo) also complained of these same side effects. Almost all side effects appeared early during treatment and disappeared during treatment. The side effects that continued after the early period of treatment were weight loss and “paraesthesia”, which is a tingly or numb feeling in the arms and legs. Therefore, patients who are prescribed topiramate to control their epilepsy may experience side effects during the first weeks of treatment. However for the vast majority, these effects will disappear with continued treatment, allowing for a complete course of therapy.Epilepsia 2005;46(5).

Lack of Association between the C3435T Polymorphism in the Human Multidrug Resistance (MDR1) Gene and Response to Antiepileptic Drug Treatment

Graeme J. Sills, Rajiv Mohanraj, Elaine Butler, Sheila McCrindle, Lindsay Collier, Elaine A. Wilson, and Martin J. Brodie

Certain individuals with epilepsy appear resistant to multiple or all antiepileptic medications. Among several reasons that can account for this resistance, one has been thought to be an excessive amount of a protein that transports drugs into and out of cells, called the P-glycoprotein (P-gp) drug transporter. The amount of P-gp is determined by a family of genes, one of which is called the multiple drug resistance gene, MDR1. We have investigated the prevalence of this genetic variant in a series of patients attending a specialist epilepsy clinic in an effort to explore the role of MDR1 in drug resistance. DNA samples were obtained from 400 patients, irrespective of seizure type or drug treatment. A total of 170 patients were classified as drug responders, with at least 12 months seizure freedom on current treatment. The remaining 230 patients were classified as non-responders. Comparison of responders and non-responders revealed no significant difference in the prevalence of the important variant of the MDR1 gene. This study failed to corroborate a previously reported association between a known genetic variant in the human MDR1 gene and drug resistant epilepsy. Other factors should continue to be investigated to explain antiepileptic drug resistance. Epilepsia 2005;46(5).

April 2005
Seizure Frequency, Cortisol and Dehydroepiandrosterone Sulfate (DHEAS) Levels in Women with Epilepsy on Antiepileptic Drug Treatment
Carlo Andrea Galimberti, Flavia Magri, Francesco Copello, Carla Arbasino, Luca Cravello, Massimo Casu, Vittoriana Patrone, and Giovanni Murialdo

Naturally occuring steroids, such as the male and female adrenal gland-produced sex hormones and their chemical relatives, influence the tendency of brain to have seizures, with some increasing and others decreasing the risk. Conversely, seizures can influence hormones. Hormonal changes occur in epilepsy because of seizures themselves and because of antiepileptic drug (AED) effects on steroid production, binding and metabolism.. This study was aimed at evaluating the steroids, cortisol and dehydroepiandrosterone sulfate (DHEAS), levels in female epilepsy patients with different disease severity, as assessed by a seizure frequency score (SFS).

Morning serum levels of cortisol and DHEAS were assayed in 113 consecutive females, 16-47 years old, with varied epilepsy syndromes, on mono- or polytherapy with various AEDs. Hormonal data were correlated with clinical parameters (age, body mass index, epilepsy syndrome, disease onset and duration, SFS, AED therapy and AED blood levels) and compared with those of 30 age matched healthy women. In epilepsy patients, cortisol levels and cortisol to DHEAS ratios (C/Dr) were significantly higher, while DHEAS levels were significantly lower than in controls. Patients with more frequent seizures showed higher cortisol and C/Dr values, and lower DHEAS levels than those with rarer or absent seizures during the previous six months.

SFS mainly explained the increase of cortisol levels and C/Dr in patients with more active disease. Changes in DHEAS levels correlated with SFS and epilepsy syndrome, as well as with AED treatments and ages. In conclusion, women with more frequent seizures presented alterations of their adrenal steroids characterized by an increase of cortisol and a decrease of DHEAS levels. Such hormonal changes might be relevant in seizure control and in patient health. Epilepsia 2005;46(4).