Epilepsy Research: 2002-2006
     
Klin Padiatr. 2006 Sep-Oct;218(5):264-9.
[Indications for intermittent diazepam prophylaxis in febrile seizures.]
[Article in German]
Pavlidou E, Tzitiridou M, Ramantani G, Panteliadis C.
III. Abteilung fur Kinderheilkunde, Ippokration Krankenhaus, Universitat Thessaloniki, Griechenland.

BACKGROUND: In a prospective controlled study we evaluated the efficacy of intermittent diazepam prophylaxis in the recurrence rate of febrile seizures (FS). PATIENTS: A total of 139 children aged between 6 and 36 months, who had a first FS, were enrolled in the study and were randomly allocated to two groups: group (A) that received diazepam prophylaxis and group (B) without prophylaxis. METHODS: All children were followed up for at least 3 years after their first FS. The prophylaxis group (n = 68) received rectal diazepam the first two days of a febrile illness, whenever the temperature was > 38 degrees C (0.33 mg/kg every 8 h on the first day, and 0.33 mg/kg every 12 h on the second day of fever, max. dosage 7.5 mg). The no-prophylaxis group (n = 71) did not receive any prophylaxis at all. Each group was stratified to low, intermediate and high risk subgroups according to the following clinical data: age at the first febrile seizure </= 15 months, positive family history of febrile seizure or epilepsy in first degree relatives, complex first febrile seizure and frequent febrile illness. RESULTS: The 3-year recurrence rates in the no-prophylaxis group were 83 % in high- risk, 55 % in intermediate-risk and 46 % in low-risk patients. In the prophylaxis group we established a reduction of febrile seizure recurrence at 38 %, 35 % and 33 % in the three risk subgroups respectively. CONCLUSION: The intermittent prophylaxis with rectal diazepam during febrile episodes lead to a reduction of febrile seizure recurrence, especially in high-risk patients. The results of our study set the indication for the use of intermittent diazepam prophylaxis in this subgroup.

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Pediatr Neurol. 2006 Sep;35(3):173-176.
Oxcarbazepine Therapy in Very Young Children: A Single-Center Clinical Experience.
Kothare SV, Mostofi N, Khurana DS, Mohsem B, Melvin JJ, Hardison HH, Valencia I, Legido A.
Division of Pediatric Neurology, Department of Pediatrics, St. Christopher's Hospital for Children, Drexel University College of Medicine, Philadelphia, Pennsylvania.

Oxcarbazepine is indicated for use as monotherapy or adjunctive therapy in the treatment of partial seizures in adults and children >/=4 years of age. The purpose of this retrospective chart review was to assess efficacy and tolerability of oxcarbazepine in children </=4 years of age. A single-center retrospective chart review of patients </=4 years old with epilepsy receiving oxcarbazepine between 2001 to 2004 was conducted. Twenty patients (male = 13, female = 7; ages 6-45 months [mean age 22.8 months]) who received oxcarbazepine were identified. Seizure types included partial onset (75%), symptomatic generalized (15%), and other (n = 2, 10%). Oxcarbazepine doses ranged between 14-71 mg/kg/day (mean dose: 36.5 mg/kg/day). Oxcarbazepine was prescribed as monotherapy in 15 patients and as first-line therapy in 73% patients. Overall, 70% experienced a significant reduction in seizures, and 50% became seizure-free while receiving oxcarbazepine. Transient drowsiness was reported in 20% of patients during dose escalation. No adverse events were observed in children <2 years old. The findings from this small series suggest that oxcarbazepine as monotherapy and adjunctive therapy may be effective and well tolerated in pediatric patients </=4 years of age.

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Eur J Neurol. 2006 Sep;13(9):942-6.
Assessment of a dose-response relationship of levetiracetam.
Meencke HJ, Buyle S.
Epilepsie-Zentrum Berlin Brandenburg, Ev. Krankenhaus Konigin Elisabeth Herzberge, Berlin, Germany. h.meencke@keh-berlin.de

The aim of this study was to assess the relationship between levetiracetam dose and both efficacy and safety in adult patients with refractory partial epilepsy. Dose-response relationships for levetiracetam efficacy were evaluated using pooled data from three trials including adults with refractory partial epilepsy. Two were randomized, double-blind, placebo-controlled, parallel-group trials in which doses of 1000-3000 mg/day of levetiracetam were administered as adjunctive therapy. The third consisted of the two parts of a crossover randomized, double-blind study in which levetiracetam (1000 or 2000 mg/day) or placebo was added to ongoing therapy. Data from each part of the crossover trial were included as if it was an independent parallel-group study. A fourth randomized double-blind trial was added for the safety evaluation. It included data from adults receiving placebo or 2000 mg/day of levetiracetam as adjunctive therapy for refractory partial seizures. The combined analysis showed an increasing effect with increasing dose. The responder rates (> or = 50% reduction in seizures) for placebo and levetiracetam 1000, 2000, and 3000 mg/day were 13.1%, 28.5%, 34.3%, and 41.3%, respectively. The respective values for seizure freedom were 0.8%, 4.7%, 6.3%, and 8.6%. There was no evidence of a dose-response relationship with regard to adverse events, including those (asthenia, dizziness, somnolence) most commonly associated with this antiepileptic drug. Patients who do not become seizure-free at the lowest recommended levetiracetam dose (1000 mg/day) should be titrated to 2000 or 3000 mg/day to provide the greatest opportunity for efficacy with little or no increased risk for adverse events.

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Epilepsy Behav. 2006 Aug 23; [Epub ahead of print]
Improved quality of life in patients with partial seizures after conversion to oxcarbazepine monotherapy.
Sachdeo RC, Gates JR, Bazil CW, Barkley GL, Tatum W, D'Souza J, McCague K.
Princeton Medical Center, Princeton, NJ 08540, USA.

OBJECTIVE: Quality of life (QOL) was assessed in patients who switched to oxcarbazepine monotherapy because of the lack of efficacy or poor tolerability of their current antiepileptic drug (AED). METHOD: This open-label, single-arm study consisted of patients aged 12 years with partial onset seizures. Oxcarbazepine (8-10mg/kg/day for children, 600mg/day for adults) was titrated up over 4 weeks while the existing AED was tapered off. QOL was evaluated at baseline and end of study (Week 16) using the validated-in-epilepsy QOLIE-31 questionnaire. RESULTS: For all patients who completed the QOLIE-31 at baseline and completion, a statistically significant improvement was noted for both the composite and multi-item subscale QOL scores (P<0.05 vs baseline). Statistically significant mean percentage improvements of 10% from baseline (range=10.8-50.1%) were also noted. Significant improvements were seen in health-related QOL for patients who experienced seizure freedom or 50% reductions in seizure frequency with oxcarbazepine monotherapy. CONCLUSIONS: Patients with partial seizures who switched to oxcarbazepine monotherapy showed statistically significant, clinically relevant improvements in QOL.

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Nervenarzt. 2006 Aug 22; [Epub ahead of print]
[Refractory status epilepticus : Diagnosis, therapy, course, and prognosis.]
[Article in German]
Bosebeck F, Moddel G, Anneken K, Fischera M, Evers S, Ringelstein EB, Kellinghaus C.
Klinik und Poliklinik fur Neurologie, Universitatsklinikum Munster, Albert-Schweitzer-Strasse 33, 48129, Munster, frank_boesebeck@web.de.

Status epilepticus (SE) is a frequent neurological emergency with an annual incidence of 10-20/100,000 individuals. The overall mortality is about 10-20%. Patients present with long-lasting fits or series of epileptic seizures or extended stupor and coma. Furthermore, patients with SE can suffer from a number of systemic complications possibly also due to side effects of the medical treatment. In the beginning, standardized treatment algorithms can successfully stop most SE. A minority of SE cases prove however to be refractory against the initial treatment and require intensified pharmacologic intervention with nonsedating anticonvulsive drugs or anesthetics. In some partial SE, nonpharmacological approaches (e.g., epilepsy surgery) have been used successfully. This paper reviews scientific evidence of the diagnostic approach, therapeutic options, and course of refractory SE, including nonpharmacological treatment.

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Curr Treat Options Neurol. 2006 Jul;8(4):280-8.
Overview of treatment guidelines for epilepsy.
Stern JM.
Department of Neurology, Geffen School of Medicine at UCLA, 710 Westwood Plaza, Suite 1250, Los Angeles, CA 90095, USA. jstern@ucla.edu.

The selection of an antiepileptic drug (AED) for the newly diagnosed patient is a critical decision because patients who are successfully treated usually respond to the first medication tried and changing the medication when treatment has been successful usually is avoided. However, the evidence needed to choose an AED wisely is incomplete, which is demonstrated by multiple practice guidelines that have been produced using systematic reviews of the medical literature. No individual AED or group of AEDs has been found to have superior efficacy for seizure control, nor can any AED or group of AEDs be considered first-line therapy. Nevertheless, the AEDs differ in their efficacy for different seizure types. Therefore, initial treatment should be based in part on the seizure type diagnosis or, at least, on whether the epilepsy syndrome is focal or generalized. The AEDs also differ in their safety, tolerability, and potential for pharmacologic interactions. These issues and the patient's comorbid conditions are additional bases for AED selection. The failure of AEDs to produce complete seizure control should lead to consideration of epilepsy surgery, especially for patients with mesial temporal lobe epilepsy. However, consensus does not exist regarding how many AEDs should be tried before determining the condition to be pharmacoresistant. Vagus nerve stimulation is an alternative treatment for patients who have pharmacoresistant epilepsy and choose not to have epilepsy surgery or have undergone unsuccessful epilepsy surgery. Infantile spasms are a seizure type requiring their own specific treatment. At present, the best evidence supports treatment with adrenocorticotropic hormone or vigabatrin.

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Curr Treat Options Neurol. 2006 Jul;8(4):271-9.
Epilepsy and sleep.
Herman ST.
Hospital of the University of Pennsylvania, Department of Neurology, 3 West Gates, 3400 Spruce Street, Philadelphia, PA 10104, USA. susan.herman@uphs.upenn.edu.

A sleep history should be taken routinely in patients with epilepsy. Treatment of sleep disorders and improvement in sleep hygiene may improve seizure control, daytime cognitive functioning, and quality of life. Patients with recurrent sleepiness interfering with daily activities or an Epworth Sleepiness Scale score more than 10 should be considered for additional evaluation by a sleep specialist. Treatment options for insomnia include improvements in sleep hygiene, cognitive behavior therapies, and sedative or hypnotic drugs. Alterations in the timing or type of antiepileptic drugs (AEDs) may be helpful (for example, using sedating medications before bedtime and avoiding evening use of drugs that may exacerbate insomnia ). Improvements in sleep hygiene alone are less effective than cognitive behavioral therapy or pharmacologic therapy. Cognitive behavioral therapy is more efficacious and its effects longer lasting than pharmacologic treatments. Sedative and hypnotic drugs may exacerbate AED cognitive adverse effects during the day and should be used only after other therapies have failed. Excessive daytime sleepiness (EDS) in patients with epilepsy may be secondary to AEDs, nocturnal seizures, or a concomitant sleep disorder such as sleep apnea or restless leg syndrome. Sedating AEDs should be minimized during the day, and activating AEDs should be used as appropriate. Video electroencephalogram polysomnography should be performed when EDS interferes with daily activities and the etiology of sleepiness is unclear. AEDs that are associated with weight gain should be avoided in patients with sleep apnea. AEDs that may promote weight loss should be considered for obese patients with sleep apnea. Continuous positive airway pressure is the treatment of choice for sleep apnea.

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Nat Clin Pract Neurol. 2006 Apr;2(4):190-200.
Therapy Insight: clinical management of pregnant women with epilepsy.
Pack AM.
AM Pack is an assistant professor of clinical neurology at Columbia University College of Physicians and Surgeons, New York, NY, USA.

In pregnant women with epilepsy who are being treated with antiepileptic drugs (AEDs), careful clinical management is vital because seizure frequency can change during pregnancy, and both seizure activity and AED treatment can have consequences for the developing fetus. Complications of epilepsy and AED treatment include stillbirths, prematurity, low birth weight, major and minor malformations, and cognitive delay later in life. Certain AEDs probably have more adverse effects than others; data from prospective studies indicate that phenobarbital and valproate are associated with significant increases in major malformations, and retrospective studies show lower verbal IQs and greater need for extra assistance in school for children whose mothers received valproate during pregnancy. Monitoring of AED levels and dosage adjustment are warranted throughout pregnancy, and vitamin K(1) at a dose of 10 mg/day should be given in the last month, particularly when cytochrome P450 enzyme-inducing AEDs are being administered. In the postpartum period, breastfeeding is recommended; however, there is differential transfer of individual AEDs in breast milk, and the infant should be observed clinically. For all women of reproductive age, preconceptual counseling is important, and includes optimization of the AED regimen and advising the mother to take supplemental folic acid.

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Paediatr Drugs. 2006;8(2):113-29.
Valproate as a mainstay of therapy for pediatric epilepsy.
Guerrini R.
Division of Child Neurology and Psychiatry, University of Pisa and IRCCS Fondazione Stella Maris, Pisa, Italy.

This article reviews relevant pharmacologic and clinical information gathered for valproate since it was introduced into clinical practice 37 years ago and the application of this information for the treatment of childhood epilepsy.Valproate is available for oral and parenteral use. Oral forms are almost completely bioavailable but the rate of absorption varies between formulations. The Chrono((R)) tablet formulation has not been adapted for children aged <6 years, in whom the oral solution or syrup, requiring two or three daily administrations, has been used until recently. A new formulation specifically adapted for children, Chronosphere((R)), administrated once or twice daily, is a modified-release formulation of valproate that minimizes fluctuations in serum drug concentrations during a dosage interval.Plasma protein binding is 80-94% and tends to decrease with increasing drug concentration. Valproate elimination is markedly decreased in newborns compared with older children and adults. Elimination by glucuronidation only becomes fully effective by the age of 3-4 years. In children aged 2-10 years receiving valproate, plasma clearances are 50% higher than those in adults. Over the age of 10 years, pharmacokinetic parameters approximate those of adults. Valproate can increase plasma concentrations of concomitant drugs, such as phenobarbital and lamotrigine, by inhibiting their metabolism.As a result of its broad spectrum of efficacy in a wide range of seizure types and epilepsy syndromes, valproate is a drug of choice for children with newly diagnosed epilepsy (focal or generalized), idiopathic generalized epilepsy, epilepsies with prominent myoclonic seizures or with multiple seizure types, and photosensitive epilepsies. In the group of cognitive epilepsies, in which severe spike and wave discharges are accompanied by cognitive deterioration, valproate, ethosuximide, or both should be tested before using corticosteroids. In comparative trials with carbamazepine, phenytoin, and phenobarbital in focal epilepsy and with ethosuximide in absence epilepsy, valproate was as effective and showed a favorable tolerability profile, with minimal adverse cognitive and CNS effects. The low potential for paradoxical seizure aggravation and the long-term efficacy of the drug are additional important factors that contribute to its excellent profile. Intravenous valproate may be effective for the treatment of convulsive and non-convulsive status epilepticus that is refractory to conventional drugs. In infants, potential benefits should be carefully weighed against the risk of liver toxicity. Gastrointestinal intolerance is a relatively frequent, dose-related adverse effect of the drug in children. Bodyweight increase and tremor may be observed in older children and adolescents.Despite the challenge of newer drugs, valproate remains a gold standard antiepileptic drug for the treatment of children.

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Expert Opin Pharmacother. 2006 Apr;7(6):811-23.
Topiramate and its clinical applications in epilepsy.
Guerrini R, Parmeggiani L.
Division of Child Neurology and Psychiatry, University of Pisa, IRCCS Fondazione Stella Maris, 56018 Calambrone, Pisa, Italy. renzo.guerrini@inpe.unipi.it

Topiramate, a derivative of the monosaccharide d-fructose, has shown a wide spectrum of antiepileptic efficacy in both animal models and clinical trials. Multiple putative mechanisms of action include voltage-sensitive sodium channel blockade, calcium channel inhibition, increase of potassium conductance, GABA-mediated chloride current increment, glutamate-mediated neurotransmission inhibition and carbonic anhydrase isoenzyme inhibition. In general, the clinical response is maintained in the long-term. The most common side effects include somnolence, fatigue, headache, psychomotor slowing, confusion, difficulty with memory, impaired concentration and attention, speech and language problems and weight loss. If slowly titrated and used at a low-to-medium dosage, it is well tolerated and offers a valid therapeutic option, the relevance of which is comparable to that of the most widely used 'old' antiepileptic drugs. As it is not yet wholly clear which specific epilepsy syndromes may benefit most from topiramate with respect to other drugs, more accurate indications for initial monotherapy would require syndrome-oriented trials and more clinical experience.

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Lancet. 2006 Apr 1;367(9516):1087-100.
Adult epilepsy.
Duncan JS, Sander JW, Sisodiya SM, Walker MC.
Department of Clinical and Experimental Epilepsy, Institute of Neurology UCL, Queen Square, London WC1N 3BG, UK. j.duncan@ion.ucl.ac.uk

The epilepsies are one of the most common serious brain disorders, can occur at all ages, and have many possible presentations and causes. Although incidence in childhood has fallen over the past three decades in developed countries, this reduction is matched by an increase in elderly people. Monogenic Mendelian epilepsies are rare. A clinical syndrome often has multiple possible genetic causes, and conversely, different mutations in one gene can lead to various epileptic syndromes. Most common epilepsies, however, are probably complex traits with environmental effects acting on inherited susceptibility, mediated by common variation in particular genes. Diagnosis of epilepsy remains clinical, and neurophysiological investigations assist with diagnosis of the syndrome. Brain imaging is making great progress in identifying the structural and functional causes and consequences of the epilepsies. Current antiepileptic drugs suppress seizures without influencing the underlying tendency to generate seizures, and are effective in 60-70% of individuals. Pharmacogenetic studies hold the promise of being able to better individualise treatment for each patient, with maximum possibility of benefit and minimum risk of adverse effects. For people with refractory focal epilepsy, neurosurgical resection offers the possibility of a life-changing cure. Potential new treatments include precise prediction of seizures and focal therapy with drug delivery, neural stimulation, and biological grafts.

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Neurology. 2006 Mar 28;66(6 Suppl 3):S37-45.
Antiepileptic drugs and hormonal contraceptives in adolescent women with epilepsy.
Zupanc ML.
Department of Pediatrics and Neurology, Pediatric Comprehensive Epilepsy Program, Medical College of Wisconsin, Children's Hospital of Wisconsin, Milwaukee, Wisconsin, USA. mzupanc@mcw.edu

Both estrogen and progesterone influence seizure activity in women with epilepsy, with estrogen generally demonstrating proconvulsant and progesterone anticonvulsant effects. Women with epilepsy exhibit a variety of endocrine disturbances, probably due to a combination of factors, including the epilepsy syndrome and the effect of interictal and ictal epileptic discharges in the brain. The direct effects of some antiepileptic drugs (AEDs) further increase this risk, apparently related to a specific drug's effect on hepatic microsomal enzymes of the cytochrome P-450 system. AEDs that induce hepatic microsomal enzymes also interact with hormonal contraception to increase estrogen's metabolism and progesterone's protein binding, decreasing concentrations of both hormones and thus reducing contraceptive efficacy. Some evidence indicates that concurrent use of hormonal contraceptives and lamotrigine significantly decreases the plasma concentration of lamotrigine, suggesting that close monitoring is warranted. Nevertheless, hormonal contraception confers comparable or superior efficacy compared with such other contraceptives as the intrauterine device and barrier methods and remains an appropriate option in women with epilepsy. Importantly, concurrent use of hormonal contraception and AEDs does not adversely affect seizure control. Careful patient management, including the use of increased estrogen doses (> or =50 microg) in patients receiving enzyme-inducing AEDs, may further minimize the risk for unintended pregnancy. Special considerations in women of childbearing age include decreased compliance and disease prevention. Although adequate seizure control is the critical requirement of an AED, the potential for interactions with hormonal contraception and the increased risk for endocrine disturbances caused by drugs that alter hepatic microsomal enzymes suggest additional potential advantages for AED treatment that does not affect these enzymes. Both the constellation of physicians treating women with epilepsy and the patients themselves have a poor understanding of the spectrum of reproductive health issues involved, and increased awareness is needed to improve patient management.

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Seizure. 2006 Mar 21; [Epub ahead of print]
Cognitive rehabilitation of memory problems in patients with epilepsy.
Ponds RW, Hendriks M.
Psychiatric Hospital Vijverdal, Department of Neuropsychiatry, P.O. Box 88, 6200 AB Maastricht, The Netherlands.

People with epilepsy often complain about their memory. Memory deficits are also most commonly observed during neuropsychological evaluation. Many patients with memory problems ask for some kind of memory training. General memory improvement is not possible, but learning mnemonics clearly will help to solve some of the most common everyday memory problems of patients. Most mnemonics follow the general rules for good learning or memory. In the design of a memory rehabilitation program some specific aspect should be taken into account, such as the need for psycho-education into the effects of cognitive deficits in daily life, the impact of personality and emotional reactions, and the individual perception of memory problems. Training goals must be tailor-made, small and as concrete as possible and fully adjusted to the needs and wishes of the patients. Generalization of the learned mnemonics is mostly modest or even absent.

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Tidsskr Nor Laegeforen. 2006 Mar 23;126(7):896-8.
[Vagal nerve stimulation in children with drug-resistant epilepsy]
[Article in Norwegian]
Bremer A, Eriksson AS, Roste GK, Knudtzen B, Nakken KO.
Nevroklinikken-barneavdelingen, Spesialsykehuset for epilepsi, Postboks 53, 1306 Baerum postterminal. anna.bremer@epilepsy.no

BACKGROUND: To evaluate the clinical efficacy and side effects of vagal nerve stimulation (VNS) in Norwegian children with difficult-to-treat epilepsy. MATERIAL AND METHODS: We have performed an open retrospective study of 60 children with pharmaco-resistant epilepsy who had a VNS implantation between October 1996 and May 2003. The effects and side effects of VNS were evaluated on the basis of the medical records and a questionnaire filled in by the patients and/or their relatives. RESULTS: Forty-six patients (77%), 25 females and 21 males, aged 4-16 years at the time of implantation, filled in the questionnaire. All patients had tried > or = 6 antiepileptic drugs prior to the implantation. Five of them had undergone resective epilepsy surgery. After a mean of 2.5 years of follow up, 33 patients (72 %) reported positive effects of VNS. Twenty-nine patients (63%) reported decreased seizure frequency and/or less severe seizures, 20 (43%) achieved > or = 50 % seizure reduction, but only two became seizure free. Sixteen (35%) experienced a shorter and milder postictal phase. In 10 patients (22%) the need of diazepam treatment to terminate seizures was considerably reduced. Twenty-eight of the children (61%) experienced a positive effect of magnet activation. Twenty-three patients (50%) reported minor and waning side effects. Because most of the patients (32) had their antiepileptic medication changed after the implantation, the results should be interpreted with caution. CONCLUSIONS: A majority of the patients (72%) reported positive effects on seizure frequency and/or epilepsy-related symptoms. The side effects were modest. Our findings support previous reports about VNS being an effective additional treatment in children with refractory epilepsy.

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Seizure. 2006 Mar 20; [Epub ahead of print]
Open prospective study on oxcarbazepine in epilepsy in children: A preliminary report.
Franzoni E, Garone C, Sarajlija J, Gualandi S, Malaspina E, Cecconi I, Moscano FC, Marchiani V.
Child Neuropsychiatry Unit, Bologna University, Italy.

PURPOSE: To evaluate the long-term efficacy, tolerability, and safety of oxcarbazepine (OXC) in children with epilepsy. METHODS: We enrolled 36 patients (median age 7.75) with new diagnosis of partial epilepsy in an open prospective study. All type of epilepsy were included: 25 patients were affected by idiopathic epilepsy, eight by symptomatic epilepsy and three by cryptogenic epilepsy. Patients were then scheduled to come back for controls at 3 months (T1), 12 months (T2) and 24 months (T3) after the beginning of OXC-monotherapy (T0). At each control we evaluated patients through their seizure diary, a questionnaire on side effects, their level of 10-monohydroxy (MHD) metabolite and laboratory analysis. RESULTS: At T1, 21/36 patients (58.3%) were seizure-free, 3/36 patients (8.3%) showed an improvement higher than 50%, 3/36 (8.3%) lower than 50%, while 2/36 worsened (5.6%). In 7/36 (19.5%) patients, no improvement was reported. At T2 13/18 patients (72.2%) were seizure-free, 1/18 showed a response to therapy higher than 50% while 2/18 worsened (11%). In two patients no improvement was reported. A correspondence between MHD plasmatic levels and clinical response (r=0.49; p<0.05) was only registered at T1. An EEG normalization was observed in 25% of cases. Side effects were reported in 25% of cases, but symptoms progressively disappeared at follow-up. CONCLUSIONS: We can therefore conclude that OXC can be considered, for its efficacy and safety, as a first line drug in children with epilepsy.

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Prescrire Int. 2005 Dec;14(80):203-6.
Pregabalin: new drug. Very similar to gabapentin.
[No authors listed]

(1) The first-line treatment for partial epilepsy is carbamazepine monotherapy; gabapentin monotherapy is an alternative, given its lower risk of drug-drug interactions. (2) The standard treatment for neuropathic pain associated with diabetes or post-herpetic neuralgia is a tricyclic antidepressant, with gabapentin as an alternative. Few drugs are available in this setting, and their efficacy is often modest. (3) Pregabalin is a GABA analogue closely related to gabapentin. Both drugs are marketed by Pfizer. Pregabalin has been approved for use in two indications: refractory partial epilepsy and neuropathic pain. (4) In patients with partial epilepsy inadequately controlled by a combination of two or possibly three antiepileptics, three placebo-controlled double-blind trials lasting 12 weeks suggest that adjunctive pregabalin treatment, at a dose of 600 mg/day divided in two or three doses, at least halves the frequency of seizures in 50% of patients. Pregabalin has not been compared with other second-line antiepileptics. (5) In neuropathic pain, there are 12 double-blind placebo-controlled trials involving patients with diabetes or post-herpetic neuralgia. Depending on the trial, between one-third and one-half of patients treated with pregabalin at a dose of 600 mg/day given in two or three doses had at least a 50% reduction in their pain score. In the only trial that included a group treated with amitriptyline (75 mg/day), the latter was significantly more effective than placebo, while pregabalin was not. (6) There are no comparative trials of pregabalin after amitriptyline and gabapentin failure. (7) The adverse effects profile of pregabalin is similar to that of gabapentin, and includes mainly neuropsychological reactions (dizziness and drowsiness). (8) Pregabalin, like gabapentin, can lead to weight gain and peripheral oedema especially in elderly patients. (9) Cases of visual field restriction have been reported with pregabalin in clinical trials. Animal studies suggest a possible risk of haemangiosarcoma, although no human cases have yet been described. (10) Pregabalin, like gabapentin, is eliminated unchanged in urine, implying a limited risk of interactions involving cytochrome P450, and suggesting that the dose should be reduced in patients with even moderate renal failure (creatinine clearance below 60 ml/min). (11) In practice, pregabalin offers nothing new for patients with partial epilepsy, for whom several other antiepileptics are available. The few available treatments for neuropathic pain have limited efficacy, and pregabalin may therefore be tried when both tricyclics and gabapentin fail. However, it is in no way certain that pregabalin is effective in such patients, and comparative trials are lacking.

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Epilepsia. 2005;46 Suppl 11:49-53.
Mortality after epilepsy surgery.
Sperling MR, Harris A, Nei M, Liporace JD, O'Connor MJ.
Department of Neurology, Jefferson Comprehensive Epilepsy Center, Thomas Jefferson University, Philadelphia, 19107, USA. sperling@jefferson.edu

Mortality rates are higher in people with refractory epilepsy than in the general population. We assessed mortality rates in a prospectively followed cohort who had epilepsy surgery, to examine the factors related to mortality and to assess the relationship between seizure control and mortality. Five hundred eighty-three patients were evaluated. Mortality was strongly related to seizure control (p = 0.001), with 18 deaths observed in patients with recurrent seizures (mortality rate = 11.4 per 1,000 person-years) and 1 death in patients with no recurrent seizures (mortality rate = 0.85 deaths per 1,000 person-years). Patients with generalized epilepsy who had corpus callosotomy had a higher mortality rate than patients who had resective or transective surgery. The side of surgery and gender did not influence mortality rates. The standardized mortality ratio was 5.75 for patients with recurrent seizures and was significantly higher for females than males. These data show that the excess mortality associated with refractory epilepsy is eliminated after epilepsy surgery when seizures are abolished and suggest that epilepsy surgery reduces the risk of epilepsy-associated death.

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Epilepsy Behav. 2005 Dec 30; [Epub ahead of print]
Pharmacological outcomes in older people with newly diagnosed epilepsy.
Stephen LJ, Kelly K, Mohanraj R, Brodie MJ.
Epilepsy Unit, Division of Cardiovascular and Medical Sciences, Western Infirmary, Glasgow, Scotland, UK.

BACKGROUND: Old age is the most common time in life to develop epilepsy. Despite this, there are few published data exploring pharmacological outcomes in this population. METHODS: We analyzed outcomes in 117 older patients (median age, 73; range, 65-92) for whom localization-related epilepsy was newly diagnosed and treatment begun at a single center over a 20-year period. RESULTS: Seventy-three (62%) patients became seizure-free for at least 12 months on their first AED, with 30 (26%) failing to respond and 14 (12%) not tolerating the treatment. Following pharmacological manipulation, 93 (79%) patients attained remission, 87 (93%) on monotherapy and 6 (7%) on duotherapy. No individual AED was more likely to confer seizure freedom than any other. Patients attaining remission were more likely to have had fewer pretreatment seizures (P=0.0078) than those who did not obtain full seizure control. CONCLUSION: The prognosis in epilepsy may be better in older than younger people, perhaps reflecting lower lesional epileptogenicity and genetic predisposition.

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Epilepsy Res. 2005 Dec 26; [Epub ahead of print]
Treatment of seizure emergencies: Convulsive and non-convulsive status epilepticus.
Treiman DM, Walker MC.
Newsome Chair in Epileptology, Director Epilepsy Center, Barrow Neurological Institute, 350 W. Thomas Rd., 8th Floor, Phoenix, AZ 85013, AZ, USA.

Status epilepticus (SE), defined as recurrent epileptic seizures without complete recovery between seizures, is one of the most serious manifestations of epilepsy. Generalized convulsive status epilepticus (GCSE) is the most common and most life-threatening form of SE, and aging increases the mortality risk. In a recent study of treatment of GCSE, 226 of 518 evaluable patients (43.6%) were of age 65 or older. In the 157 elderly patients with overt GCSE, phenobarbital was successful as first-line treatment in 71.4%, lorazepam in 63%, diazepam and phenytoin in 53.3%, and phenytoin alone in 41.5%. Phenobarbital and lorazepam were more successful than phenytoin alone. In the 69 elderly patients with subtle GCSE, success as the first treatment was 30.8% for phenobarbital, 14.3% for lorazepam, 11.8% for phenytoin, and 7.7% for diazepam and phenytoin. Overall, the results were similar to those reported for the entire study. Lorazepam, because of ease of use, is probably the best drug for the initial treatment of overt GCSE in the elderly; phenobarbital may be the best drug for subtle GCSE in this group, but more data are needed. The term "nonconvulsive SE" has been used to include complex partial SE and absence SE - both of which present as an "epileptic twilight state" - and SE in comatose patients. The diagnosis can be challenging, particularly in the elderly, as overlapping clinical features and electroencephalogram patterns can be seen in SE and in a variety of encephalopathic conditions. There is a suggestion that aggressive treatment of elderly patients with nonconvulsive SE may worsen prognosis. Clearly, there is a need for more data to better understand management of elderly patients with both convulsive and nonconvulsive SE.

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Epilepsy Res. 2005 Dec 24; [Epub ahead of print]
Epilepsy, surgery, and the elderly.
Gallo BV.
Department of Neurology University of Miami, School of Medicine, 1501 NW 9th Ave., 2nd Floor, Miami, FL 33136, USA.

Treatment of elderly patients with epilepsy may present unique challenges to physicians. Co-morbid conditions and drugs to treat such conditions are common in elderly patients, possibly complicating epilepsy therapies that are dependent on drugs alone. For this reason, surgical intervention may be an attractive option for elderly patients with epilepsy, particularly for medically intractable patients with key disease features, such as lateralization and precisely localized epileptic foci. Curative procedures, including lobectomy and lesionectomy, are most likely to lead to seizure freedom, but not all patients are candidates for such procedures. When a curative surgical procedure is not an option, palliative procedures, including vagus nerve stimulation and deep brain stimulation, may be viable options. Vagus nerve stimulation has been reported to reduce seizure rates and improve quality of life in elderly patients with epilepsy. Currently, widespread therapeutic application of deep brain stimulation is limited by risks, costs, and pending studies.

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Brain Dev. 2005 Dec 20; [Epub ahead of print]
Treatment of epilepsy with electrical status epilepticus during slow sleep and its related disorders.
Inutsuka M, Kobayashi K, Oka M, Hattori J, Ohtsuka Y.
Department of Child Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, and Okayama University Hospital, Okayama 700-8558, Japan; Department of Pediatrics, Sasebo Chuo Hospital, Sasebo, Nagasaki 857-1195, Japan.

To elucidate an effective therapeutic strategy for 'ESES syndrome', epilepsy with electrical status epilepticus during slow sleep (ESES) and its related epileptic disorders, we studied the effect of treatment on the EEG pattern of continuous spike-waves during slow wave sleep (CSWS) in 15 afflicted patients. Basically performed in the following order, the employed therapies included (1) high-dose valproate (VPA) therapy (serum level >100mug/ml); (2) a combination therapy of VPA and ethosuximide (ESM); (3) short cycles of high-dose diazepam (oral or intrarectal DZP, 0.5-1mg/kg per day for 6-7 days); and (4) intramuscular synthetic ACTH-Z therapy (0.01-0.04mg/kg per day for 11-43 days). Regarding the initial EEG effect, a remission of CSWS was achieved by high-dose VPA therapy in 7 of 15 trials (47%), by the combination therapy of VPA and ESM in 3/7 trials (43%), by short cycles of high-dose DZP in 2/4 trials (50%), and by ACTH-Z therapy in 2/5 trials (40%). A permanent remission of ESES syndrome was achieved by high-dose VPA therapy and/or combination therapy of VPA and ESM in 10 patients (67%). The effects of short cycles of high-dose DZP and ACTH-Z therapy were at best temporary. Our strategy for the treatment of ESES syndrome is therefore considered valid.

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Epilepsy Behav. 2005 Dec 19; [Epub ahead of print]
Vagus nerve stimulation use and effect in epilepsy: What have we learned?
Tecoma ES, Iragui VJ.
Department of Neurosciences, University of California, San Diego, Epilepsy Center, UCSD Thornton Hospital, La Jolla, CA 92037-7740, USA; VA San Diego Healthcare System, USA.

Vagus nerve stimulation (VNS) for epilepsy has been available in the United States for 8 years. Pivotal randomized, blinded clinical trials leading to FDA approval in patients age 12 and older with refractory partial seizures have not been performed for other age groups or epilepsy syndromes. This practical review takes stock of the current information about VNS use and efficacy in various types of epilepsy. We review the evidence for commonly used stimulation parameters, end of battery life, predictors of response including duration of epilepsy, seizure type/epilepsy syndrome, bihemispheric seizures, age at implant, and prior cranial surgery. We review adverse events and VNS effects on respiratory patterns, cardiac function, and mood and behavior. With the recent U.S. approval of VNS for treatment-resistant depression, we anticipate that lessons learned from treating patients with epilepsy will be useful to physicians using VNS to treat patients with depression and possibly other conditions.

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Neurology. 2005 Dec 13;65(11):1810-2.
Low-glycemic-index treatment: a liberalized ketogenic diet for treatment of intractable epilepsy.
Pfeifer HH, Thiele EA.
Pediatric Epilepsy Program, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

The ketogenic diet is often effective for intractable epilepsy, but many patients have trouble complying with the strict regimen. The authors tested an alternative diet regimen, a low-glycemic-index treatment, with more liberal total carbohydrate intake but restricted to foods that produce relatively little increase in blood glucose (glycemic index < 50). Ten of 20 patients treated with this regimen experienced a greater than 90% reduction in seizure frequency.

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Neurology. 2005 Dec 13;65(11):1744-9.
Changes in depression and anxiety after resective surgery for epilepsy.
Devinsky O, Barr WB, Vickrey BG, Berg AT, Bazil CW, Pacia SV, Langfitt JT, Walczak TS, Sperling MR, Shinnar S, Spencer SS.
New York University School of Medicine, New York, NY, USA. od4@nyu.edu

OBJECTIVE: To determine changes in depression and anxiety after resective surgery. METHODS: Data from subjects enrolled in a prospective multicenter study of resective epilepsy surgery were reviewed with the Beck Psychiatric Symptoms Scales (Beck Depression Inventory [BDI] and Beck Anxiety Inventory [BAI]) and Composite International Diagnostic Interview (CIDI) up to a 24-month period. chi2 analyses were used to correlate proportions. RESULTS: A total of 358 presurgical BDI and 360 BAI results were reviewed. Moderate and severe levels of depression were reported in 22.1% of patients, and similar levels of anxiety were reported by 24.7%. Postoperative rates of depression and anxiety declined at the 3-, 12-, and 24-month follow-up periods. At the 24-month follow-up, moderate to severe levels of depression symptoms were reported in 17.6 and 14.7% of the patients who continued to have postoperative seizures. Moderate to severe depression and anxiety were found in 8.2% of those who were seizure-free. There was no relationship, prior to surgery, between the presence or absence of depression and anxiety and the laterality or location of the seizure onset. There were no significant relationships between depression or anxiety at 24-month follow-up and the laterality or location of the surgery. CONCLUSIONS: Depression and anxiety in patients with refractory epilepsy significantly improve after epilepsy surgery, especially in those who are seizure-free. Neither the lateralization nor the localization of the seizure focus or surgery was associated with the risk of affective symptoms at baseline or after surgery.

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Neurology. 2005 Dec 13;65(11):1737-43.
Double-blind, placebo-controlled study of lamotrigine in primary generalized tonic-clonic seizures.
Biton V, Sackellares JC, Vuong A, Hammer AE, Barrett PS, Messenheimer JA.
Arkansas Epilepsy Program, Little Rock, AR 72205, USA. vbiton@alltel.net

OBJECTIVE: To evaluate the efficacy and tolerability of adjunctive lamotrigine in primary generalized tonic-clonic (PGTC) seizures in a randomized, double-blind, placebo-controlled trial. METHODS: Patients with a diagnosis of epilepsy with PGTC seizures who were receiving one or two antiepileptic drugs at study entry were eligible. Patients with partial seizures were excluded on the basis of seizure history and screening EEGs. The study comprised a baseline phase, an escalation phase during which study medication was titrated to a target dose, and a 12-week maintenance phase during which doses of lamotrigine/placebo and concomitant antiepileptic drugs were maintained. RESULTS: Of the 121 randomized patients ages 2 to 55 years, 117 (58 lamotrigine, 59 placebo) entered the escalation phase and received study medication. During the escalation and maintenance phases combined, median percent reduction in PGTC seizure frequency was 66.5% with lamotrigine compared with 34.2% with placebo (p = 0.006). The corresponding numbers for lamotrigine and placebo were 60.6% and 32.8% (p = 0.038) during the escalation phase and 81.9% and 43.0% (p = 0.006) during the maintenance phase. During the maintenance phase, 72% of lamotrigine-treated patients compared with 49% of placebo-treated patients experienced a > or = 50% reduction in frequency of PGTC seizures (p = 0.014). A similar pattern of results was observed for all generalized seizures. The most common drug-related adverse events were dizziness (5% lamotrigine, 2% placebo), somnolence (5% lamotrigine, 2% placebo), and nausea (5% lamotrigine, 3% placebo). CONCLUSIONS: Adjunctive lamotrigine is effective in the treatment of primary generalized tonic-clonic seizures and has a favorable tolerability profile.

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Eur J Paediatr Neurol. 2005 Oct 27; [Epub ahead of print]
Beneficial effects on sleep of vagus nerve stimulation in children with therapy resistant epilepsy.
Hallbook T, Lundgren J, Kohler S, Blennow G, Stromblad LG, Rosen I.
Department of Paediatrics, University Hospital, SE-221 85 Lund, Sweden.

The study purpose was to evaluate sleep structure following Vagus Nerve Stimulation (VNS) in 15 children with therapy resistant epilepsy and to correlate possible alterations with changes in epileptiform activity and clinical effects. Fifteen children were examined with ambulatory polysomnographic recordings initially, and after 3 and 9 months of VNS-treatment. Sleep parameters, all-night delta power activity and movement times (MTs), used to account for arousals were estimated. Epileptiform activity was evaluated by spike detection. Seizure frequency was recorded in a diary. The severity of the seizures was scored with the National Hospital Seizure Severity Scale (NHS3). Quality of life (QOL) was assessed by a visual analogue scale. Behaviour problems were quantified by using the total score of the Child Behaviour Checklist (CBCL). VNS induces a significant increase in slow wave sleep (SWS) and a decrease in sleep latency and in stage 1 sleep. The number and density of MTs during total night sleep were significantly increased. There was also a significant increase in the number of MTs immediately related to the VNS stimulation periods. Of the 14 children with increased MTs, 10 had a reduction in epileptiform activity, and in clinical seizures, all had an improvement in NHS3, and 11 in QOL. Of the 10 children with increased SWS, eight also improved in QOL and eight in behaviour. Our findings indicate that VNS counteracts known adverse effects of epilepsy on sleep and increases slow wave sleep. This possibly contributes to the reported improvement in well-being. We also see an increase in MTs. This arousal effect seems to be of minor importance for QOL and could possibly be related to the antiepileptic mechanisms in VNS.

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Epilepsy Behav. 2005 Oct 21; [Epub ahead of print]
Psychosocial intervention in pediatric epilepsy: A critique of the literature.
Wagner JL, Smith G.
Division of Developmental Pediatrics, Medical University of South Carolina, Charleston, SC, USA; Division of Pediatric Neurosciences, Medical University of South Carolina, Charleston, SC, USA.

It is well documented that youth with epilepsy are at increased risk for psychopathology. The current literature supports a biopsychosocial model of adjustment to pediatric epilepsy, and implies that interventions focused on changing youths' cognitions and illness appraisals, as well as enhancing their coping skills, may be an effective treatment for psychosocial maladjustment associated with pediatric epilepsy. The purpose of this article is to review and critique the extant literature covering psychological interventions that target psychosocial adjustment in youth with seizures followed by those aimed at reducing seizure frequency. For health care professionals treating epilepsy, establishing evidence-based interventions that target psychiatric difficulties in youth with epilepsy should be paramount in the promotion of optimal epilepsy outcomes. Thus, future recommendations for clinical endeavors and research proposals are also presented.

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Cochrane Database Syst Rev. 2005 Oct 19;(4):CD003723.
Anticonvulsant therapy for status epilepticus.
Prasad K, Al-Roomi K, Krishnan P, Sequeira R, Prasad K.

BACKGROUND: Status epilepticus is a medical emergency associated with significant mortality and morbidity, which requires immediate and effective treatment. OBJECTIVES: (1) To determine whether a particular anticonvulsant is more effective or safer to use in status epilepticus compared to another and compared to placebo.(2) To delineate reasons for disagreement in the literature regarding recommended treatment regimens and to highlight areas for future research. SEARCH STRATEGY: We searched the following electronic databases using the highly sensitive search strategy for identifying published randomised controlled trials: (1) Cochrane Epilepsy Group Specialized Register (July 2005); (2) Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2,2005); (3) MEDLINE (1966 - August 2004); (4) EMBASE (1966 - January 2003). SELECTION CRITERIA: Randomised controlled trials of participants with premonitory, early, established or refractory status epilepticus using a truly random or quasi-random allocation of treatments were included. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, assessed trial quality and extracted data. MAIN RESULTS: Eleven studies with 2017 participants were included. Few studies used the same interventions. Diazepam was better than placebo in reducing the risk of non-cessation of seizures (RR 0.73, 95% CI 0.57 to 0.92), requirement for ventilatory support (RR 0.39, 95% CI 0.16 to 0.94) or continuation of status epilepticus requiring use of a different drug or general anaesthesia (RR 0.73, 95% CI 0.57 to 0.92). Lorazepam was better than placebo for risk of non-cessation of seizures (RR 0.52, 95% CI 0.38 to 0.71) and for risk of continuation of status epilepticus requiring a different drug or general anaesthesia (RR 0.52, 95% CI 0.38 to 0.71). Lorazepam was better than diazepam for reducing risk of non-cessation of seizures (RR 0.64, 95% CI 0.45 to 0.90) and had a lower risk for continuation of status epilepticus requiring a different drug or general anaesthesia (RR 0.63, 95% CI 0.45 to 0.88). Lorazepam was better than phenytoin for risk of non-cessation of seizures (RR 0.62, 95% CI 0.45 to 0.86). Diazepam (30 mg intrarectal gel) was better than a lower dose (20 mg intrarectal gel) in premonitory status epilepticus for the risk of seizure continuation (RR 0.39, 95% CI 0.18 to 0.86). AUTHORS' CONCLUSIONS: Lorazepam is better than diazepam or phenytoin alone for cessation of seizures and carries a lower risk of continuation of status epilepticus requiring a different drug or general anaesthesia. Both lorazepam and diazepam are better than placebo for the same outcomes. In the treatment of premonitory seizures, diazepam 30 mg in an intrarectal gel is better than 20 mg for cessation of seizures without a statistically significant increase in adverse effects. Universally accepted definitions of premonitory, early, established and refractory status epilepticus are required.

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Cochrane Database Syst Rev. 2005 Oct 19;(4):CD003032.
Ethosuximide, sodium valproate or lamotrigine for absence seizures in children and adolescents.
Posner E, Mohamed K, Marson A, Posner E.

BACKGROUND: Absence seizures are brief epileptic seizures which present in childhood and adolescence. They are characterised by sudden loss of awareness and an electroencephalogram (EEG) typically shows generalised spike wave discharges at three cycles per second. Ethosuximide, valproate and lamotrigine are currently used to treat absence seizures. This review aims to determine the best choice of anticonvulsant for a child with typical absence seizures. OBJECTIVES: To review the evidence for the effects of ethosuximide, valproate and lamotrigine as treatments for children and adolescents with absence seizures, when compared with placebo or each other. SEARCH STRATEGY: We searched the Cochrane Epilepsy Group's Specialised Register (March 2005), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2005), MEDLINE (1966 to March 2005) and EMBASE (1988 to March 2005). No language restrictions were imposed. In addition, we contacted Sanofi Winthrop, Glaxo Wellcome (now GlaxoSmithKline) and Parke Davis (now Pfizer), manufacturers of sodium valproate, lamotrigine and ethosuximide respectively. SELECTION CRITERIA: Randomised parallel group monotherapy or add-on trials which include a comparison of any of the following in children or adolescents with absence seizures: ethosuximide; sodium valproate; lamotrigine or placebo. DATA COLLECTION AND ANALYSIS: Outcome measures were: (1) proportion of individuals seizure free at 1, 3, 6, 12 and 18 months post randomisation; (2) people with a 50% or greater reduction in seizure frequency; (3) normalisation of EEG and/or negative hyperventilation test and (4) adverse effects. Data were independently extracted by two review authors. Results are presented as relative risks (RR) with 95% confidence intervals (95% CI). MAIN RESULTS: Five small trials were found, four of them were of poor methodological quality. One trial (29 participants) compared lamotrigine with placebo using a response conditional design. Individuals taking lamotrigine were significantly more likely to be seizure free than participants taking placebo during this short trial. Another trial compared lamotrigine with sodium valproate, the study lacked power to detect the difference in efficacy. Three studies compared ethosuximide, but because of diverse study designs and populations studied, we decided not to pool results in a meta-analysis. None of these studies found a difference between valproate and ethosuximide with respect to seizure control, but confidence intervals were wide and the existence of important differences could not be excluded. AUTHORS' CONCLUSIONS: Although ethosuximide, lamotrigine and valproate are commonly used to treat people with absence seizures we have insufficient evidence to inform clinical practice, and the few trials included in this review were of poor methodological quality and did not have sufficient number of participants. More trials of better quality are needed.

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Cochrane Database Syst Rev. 2005 Oct 19;(4):CD002029.
Psychological treatments for epilepsy.
Ramaratnam S, Baker G, Goldstein L, Ramaratnam S.

BACKGROUND: Psychological interventions such as relaxation therapy, cognitive behaviour therapy, bio-feedback and educational interventions have been used alone or in combination in the treatment of epilepsy, to reduce the seizure frequency and improve the quality of life. OBJECTIVES: To assess whether the treatment of epilepsy with psychological methods is effective in reducing seizure frequency and/or leads to a better quality of life. SEARCH STRATEGY: We searched the Cochrane Epilepsy Group's Specialized Register (July 2005), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2005), and MEDLINE (1966 to March 2005). No language restrictions were imposed. We checked the reference lists of retrieved studies for additional reports of relevant studies. SELECTION CRITERIA: Randomized or quasi-randomized studies assessing one or more types of psychological or behaviour modification techniques for people with epilepsy. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the trials for inclusion and extracted data. Primary analyses were by intention to treat. Outcomes included reduction in seizure frequency and quality of life. MAIN RESULTS: We found three small trials (50 participants) of relaxation therapy. They were of poor methodological quality and a meta-analysis was therefore not undertaken. No study found a significant effect of relaxation therapy on seizure frequency. One trial found cognitive behavioural therapy to be effective in reducing depression, among people with epilepsy with a depressed affect, whilst another did not.One trial of group cognitive therapy found no significant effect on seizure frequency. Two trials of combined relaxation and behaviour therapy and one of EEG bio-feedback and four of educational interventions did not provide sufficient information to assess their effect on seizure frequency. One small study of galvanic skin response biofeedback reported significant reduction in seizure frequency. Combined use of relaxation and behaviour modification was found beneficial for anxiety and adjustment in one study. In one study EEG bio-feedback was found to improve the cognitive and motor functions in individuals with greatest seizure reduction. Educational interventions were found to be beneficial in improving the knowledge and understanding of epilepsy, coping with epilepsy, compliance to medication and social competencies. AUTHORS' CONCLUSIONS: In view of methodological deficiencies and limited number of individuals studied, we have found no reliable evidence to support the use of these treatments and further trials are needed.

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Cochrane Database Syst Rev. 2005 Oct 19;(4):CD001416.
Zonisamide add-on for drug-resistant partial epilepsy.
Chadwick D, Marson A, Chadwick D.

BACKGROUND: The majority of people with epilepsy have a good prognosis and their seizures can be well controlled with the use of a single antiepileptic agent, but up to 30% develop refractory epilepsy, especially those with partial seizures. In this review we summarize the current evidence regarding zonisamide, when used as an add-on treatment for drug-resistant partial epilepsy. OBJECTIVES: To evaluate the effects of zonisamide when used as an add-on treatment for people with drug-resistant partial epilepsy. SEARCH STRATEGY: We searched the Cochrane Epilepsy Group Specialized Register (August 2005), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3, 2005). In addition, we contacted Eisai Limited (makers and licensees of zonisamide) and experts in the field to seek any ongoing/unpublished studies. SELECTION CRITERIA: Randomized placebo controlled add-on trials of zonisamide in people with drug-resistant partial epilepsy. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion and extracted data. Outcomes were: (1) 50% or greater reduction in total seizure frequency; (2) treatment withdrawal; (3) adverse events. Primary analyses were intention-to-treat. Summary relative risks (RRs) were estimated for each outcome. MAIN RESULTS: Four trials (850 participants) were included. The overall RR with 95% confidence intervals (CIs) for 50% reduction in seizure frequency compared to placebo for 300 to 500 mg/day of zonisamide was 2.44 (95% CI 1.81 to 3.30). The RR for any dose zonisamide (100 to 500 mg per day) was 2.35 (1.74 to 3.17). Two trials provide evidence of a dose response relationship for this outcome. The RR for treatment withdrawal for 300 to 500 mg/day zonisamide compared to placebo was 1.64 (1.20 to 2.26), and for 100 to 500 mg per day was 1.47 (1.07 to 2.02). The CIs of the following adverse effects indicate that they are significantly associated with zonisamide: ataxia 4.50 (99% CI 1.05 to 19.22); dizziness 1.77 (99% CI 1.00 to 3.12); somnolence 1.96 (99% CI 1.12 to 3.44); agitation 2.37 (99% CI 1.00 to 5.64); and anorexia 3.00 (99% CI 1.31 to 6.88). AUTHORS' CONCLUSIONS: Zonisamide has efficacy as an add-on treatment in people with drug-resistant partial epilepsy. Minimum effective and maximum tolerated doses cannot be identified. The trials reviewed were of 12 week duration and results cannot be used to confirm longer periods of effectiveness in seizure control. The results cannot be extrapolated to monotherapy or to people with other seizure types or epilepsy syndromes.

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Clin Neurol Neurosurg. 2005 Oct 10; [Epub ahead of print]
Post-traumatic epilepsy: An overview.
Agrawal A, Timothy J, Pandit L, Manju M.
Department of Neurosurgery, K.S. Hegde Medical Academy, Deralakatte, 575018 Mangalore, Karnataka, India.

Post-traumatic epilepsy (PTE) is a recurrent seizure disorder secondary to brain injury following head trauma. PTE is not a homogeneous condition and can appear several years after the head injury. The mechanism by which trauma to the brain tissue leads to recurrent seizures is unknown. Cortical lesions seem important in the genesis of the epileptic activity, and early seizures are likely to have a different pathogenesis than late seizures. Anti-epileptic drugs available for treatment are phenytoin, sodium valproate, and carbamazepine. Newer anti-epileptics are helpful, particularly in patients with associated post-traumatic stress disorders; however, no randomized controlled studies are available to prove that one of these drugs is better than the other. Current evidence is that the treatment of early post-traumatic seizures does not influence the incidence of post-traumatic epilepsy. Routine preventive anticonvulsants are not indicated for patients with head injuries, and treatment in the acute phase does not reduce death or disability rates.

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Arq Neuropsiquiatr. 2005 Sep;63(3b):733-737. Epub 2005 Oct 18.
Topiramate for the treatment of juvenile myoclonic epilepsy.
Sousa PD, Araujo Filho GM, Garzon E, Sakamoto AC, Yacubian EM.
Unidade de Pesquisa e Tratamento das Epilepsias, Escola Paulista de Medicina, Universidade Federal de Sao Paulo, Sao Paulo, SP, Brazil.

OBJECTIVE: The aim of this study was to evaluate the efficacy and tolerability of topiramate (TPM) in juvenile myoclonic epilepsy (JME). METHOD: We assessed seizure control and adverse effects of TPM in 22 patients (18 females) aged 13 to 53 years. Target TPM dosage was up to 200 mg/day. The patients were subdivided into 3 groups: those treated with seizure control plus side effects (n=4); treated with non-controlled seizures (n=15) and with JME newly diagnosed (n=3). RESULTS: Sixteen patients completed the first year of the follow-up. Generalized tonic-clonic seizures were completely controlled in 10 (62.5%); more than 50% of reduction in 4 (25.0%) and less than 50% in 2 (12.5%). Myoclonia were controlled in 11 (68.8%) and persisted in 5 (31.2%) patients. Absence seizures were present in 5 (22.7%) of whom 2 (9.0%) showed more than 50% of seizure reduction while 3 (13.6%) presented worsening. Discontinuations were due to inadequate seizure control and adverse events (N=4), low compliance and loss of follow-up (N=2) and subject choice (N=1). CONCLUSION: TPM showed to be an effective and well-tolerated drug in the treatment of JME. Although frequently observed, TPM side effects were tolerable and the drug could be maintained in the majority of patients.

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Acta Neurol Scand Suppl. 2005;181:40-6.
Issues when treating epilepsy in the elderly.
Pohlmann-Eden B.
Bethel Epilepsy Center, Bielefeld, Germany.

Single seizures and epilepsy are one of the most commonly encountered neurologic disorders in elderly individuals, arising as a result of complex and often multiple acquired underlying pathologies. Ischemia is by far the most frequent etiology, and is found in up to one-third of these patients, followed by tumors, which are diagnosed in approximately 10% of affected individuals. Thus, a multidisciplinary approach to its diagnosis and management is required. Antiepileptic drug (AED) therapy is the mainstay of treatment for epilepsy in the elderly, but age-specific changes in drug metabolism, increased sensitivity to side effects, and the risk of drug interactions must be considered. Some newer AEDs seem to offer advantages over the older agents in terms of their reduced drug interaction potential (due to lack of enzyme induction), and improved tolerability profiles, which is supported by few recent clinical trials. In order to achieve seizure freedom without causing intolerable side effects, treatment should be initiated with monotherapy at low doses and titrated slowly to within the recommended dose range.

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Acta Neurol Scand Suppl. 2005;181:17-20.
Epilepsy in children: the evidence for new antiepileptic drugs.
Verdru P.
Clinical Research, UCB, Smyrna, GA, USA.

Childhood epilepsy remains a challenge to treat. Despite the availability of antiepileptic drugs (AEDs), >25% of children with childhood epilepsy continue to have seizures. Conventional AEDs have been the mainstay of therapy for many years but are often poorly tolerated and have a tendency to interact with other drugs. Current American Academy of Neurology guidelines support the use of four of the newer AEDs (gabapentin, lamotrigine, topiramate, and oxcarbazepine) as adjunctive treatment of refractory partial seizures in children, based on class I evidence. This paper includes a summary of the results from a recent randomized, double-blind, placebo-controlled study, which shows that levetiracetam is also effective and well tolerated in this pediatric population, and provides evidence supporting its use in refractory partial seizures in children.

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Seizure. 2005 Aug 5; [Epub ahead of print]
Steroids in intractable childhood epilepsy: Clinical experience and review of the literature.
Verhelst H, Boon P, Buyse G, Ceulemans B, D'Hooghe M, Meirleir LD, Hasaerts D, Jansen A, Lagae L, Meurs A, Coster RV, Vonck K.
Department of Pediatrics, Division of Pediatric Neurology, Ghent University Hospital, De Pintelaan 185, 9000 Gent, Belgium.

Steroids and adrenocorticotrophic hormone (ACTH) have been used for the treatment of infantile spasms for several years. However, the use of steroids in the treatment of epilepsy beyond infantile spasms has been limited to only a few studies. We report the experience with steroids in 32 children with intractable epilepsy, not including West syndrome. In 47% there was a decrease in seizure frequency, 25% became seizure free, 11% had a seizure reduction of >50% and 11% had a seizure reduction of <50%. Our study confirms the conclusions of few previous reports of effective adjunctive steroid treatment for children with intractable epilepsy. The possible side effects, however, especially during prolonged therapy remain an important concern.

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Seizure. 2005 Aug 5; [Epub ahead of print]
The efficacy and side effects of topiramate on refractory epilepsy in infants and young children: A multi-center clinical trial.
Al Ajlouni S, Shorman A, Daoud AS.
Department of Pediatrics, King Hussain Medical Center, Amman, Jordan.

OBJECTIVES:: This study has been conducted to assess the efficacy and safety of topiramate in refractory epilepsies in infants and young children. METHODS:: A prospective clinical trial was performed in three tertiary care hospitals, on 47 children aged 6-60 months with refractory epilepsy. Topiramate was added to at least two baseline anti-epileptic drugs. The efficacy was rated according to seizure type, frequency and duration. RESULTS:: Children with refractory epilepsy were classified according to their clinical, neuro-imaging, and neurophysiological profile into infantile spasms (IS) (9 cases, 19%), Lennox-Gastaut syndrome (LGS) (25 cases, 53%) and other epilepsies (13 cases, 28%). Children were also classified into cryptogenic and symptomatic epilepsy. Topiramate was introduced as add-on therapy in a daily dose of 1mg/kg/day for 2 weeks, followed by increments of 1-3mg/kg/day at 2-week intervals, up to a maximum of 10mg/kg/day. After a minimum treatment period of 6 months, 28 (60%) of the children had a satisfactory response (completely seizure free, or more than a 50% seizure reduction). The remaining 19 children (40%) had an unsatisfactory response (50% or less reduction in seizure frequency, no change or increased seizure frequency). Topiramate appeared to be equally effective in infantile spasms, Lennox-Gastaut syndrome and children with other types of epilepsy, with no significant difference between those with a satisfactory and an unsatisfactory response (p=0.089). There was also no significant difference in response between patients with cryptogenic and symptomatic epilepsy (p=0.360). Mild to moderate adverse effects, mainly somnolence, anorexia and nervousness, were present in 25 (53%) of children. One of the children developed hypothyroidism. CONCLUSION:: Although the long term safety and possible adverse effects of topiramate have not been fully established in infants and young children, this study has shown that it is a useful option for children with frequent seizures unresponsive to standard anti-epileptic drugs.

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Epilepsia. 2005 Aug;46(8):1304-7.
Fast and Sustained Efficacy of Levetiracetam during Titration and the First 3 Months of Treatment in Refractory Epilepsy.
French J, di Nicola S, Arrigo C.
Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A.

Summary: Purpose: To investigate whether the efficacy of levetiracetam (LEV) is sustained in adult patients with refractory partial seizures over a 3-month period. Methods: Treatment effect was assessed in a post hoc analysis by determining the proportion of seizure-free days during each week of a 3-month period after the initiation of treatment. Pooled data from three randomized, double-blind, placebo-controlled trials (n = 883) were analyzed. Results: The mean proportion of seizure-free days was greater in the LEV group than in the placebo group. The difference, which was statistically significant, was observed as early as the first week after the initiation of treatment. It was higher in the first week of treatment and subsequently was maintained for each week over the 3-month period (p < 0.001 or p = 0.002 at each time point). Patients in the LEV group had on average 74% to 81% days each week without any seizure, compared with 69% to 72% in the placebo group. Conclusions: LEV is efficient in controlling seizures from the first week of drug initiation, during uptitration, and throughout the first 3 months of treatment. An interesting amplification of efficacy occurs in the first week of therapy, which is intriguing and warrants further investigation.

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Klin Padiatr. 2005 Jul-Aug;217(4):222-9.
[Optimizing epilepsy therapy in children and adolescents with lamotrigine]
[Article in German]
Siemes H, Brandl U, Helmstadter C, Kurlemann G, Rating D, Salke-Kellermann RA, Stephani U, Uberall M, Wiemer-Kruel A, Bergmann L.
Fachklinik Hohenstucken, Neurologisches Rehabilitationszentrum fur Kinder und Jugendliche. hartmut.siemes@t-online.de

Lamotrigine is a broadly effective antiepileptic drug in mono- and add-on therapy for children and adolescents with focal and generalized epilepsies. Some epileptologists consider lamotrigine as the drug of primary choice in older school children and adolescents because of its good tolerability (no increase of body weight, no impairment of cognitive functions, due to new data probably no teratogenic properties). Lamotrigine can be used with good efficacy in numerable epilepsy diseases, such as tuberous sclerosis, juvenile neuronal lipofuscinosis and Rett syndrome. The first studies show that lamotrigine is also effective in children under 2 years of age. For therapy of difficult-to-treat epilepsies the combination of lamotrigine with valproate has proved as especially useful. This clinical observation is supported by new results of animal experiments. The dose-dependant and typical CNS side effects vertigo, ataxia, nausea, tremor and diplopia are found most frequently. The rate of allergic skin rashes which was very high before 1998 has decreased markedly by new dosage guidelines and is now as low as in older antiepileptic drugs. Lamotrigine does not impair cognitive functions, especially not memory and language. It has mood-stabilizing features and may improve quality of life. In animal experiments lamotrigine shows antiepileptogenic and neuroprotective effects.

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Epilepsy Behav. 2005 Jul 27; [Epub ahead of print]
Transcranial magnetic stimulation treatment for epilepsy: Can it also improve depression and vice versa?
Fregni F, Schachter SC, Pascual-Leone A.
Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA.

Comorbidity with depression is an important determinant of the quality of life for patients with epilepsy. Antidepressant medications can effectively treat depression in epileptic patients, but drug-drug interactions and epileptogenic effects of these drugs pose therapeutic challenges. The mood-stabilizing effects of antiepileptic medications may not be sufficient to treat depression. Therefore, treatments that alleviate the burden of depression without increasing seizure risk or, better yet, with the possibility of improving seizure control are worth exploring. Neuroimaging techniques, such as functional magnetic resonance imaging, are providing novel insights into the pathophysiology of depression in epilepsy. For example, there appears to be prominent brain prefrontal hypoactivity, which may be sustained by the hyperactivity of the seizure focus. If so, neuromodulatory approaches that suppress epileptic focus hyperactivity and concurrently enhance prefrontal activity may be ideally suited. Indeed, vagus nerve stimulation has been shown to yield simultaneous antiseizure and mood effects. Another neuromodulatory technique, transcranial magnetic stimulation (TMS), can also modulate brain activity, but in a noninvasive, painless, and focal manner. Depending on the stimulation parameters, it is possible to enhance or reduce activity in the targeted brain region. Furthermore, TMS has been shown to be effective in treating depression, and preliminary data suggest that this treatment may also be effective for epilepsy treatment. This article reviews these data and explores further the question of whether depression and epilepsy can be simultaneously treated with TMS for optimal therapeutic impact.

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Epilepsy Behav. 2005 Jul 23; [Epub ahead of print]
Focal cooling for epilepsy: An alternative therapy that might actually work.
Rothman SM, Smyth MD, Yang XF, Peterson GP.
Department of Neurology, Washington University School of Medicine, St Louis, MO 63110, USA.

The therapy of focal epilepsy remains inadequate. Many patients who have localization-related seizures find themselves either overmedicated with anticonvulsants or suffering from frequent seizures. While surgical resection can lead to excellent outcomes in up to 60% of patients with neocortical epilepsy, there are obviously many who either fail surgery or are deemed inappropriate surgical candidates. We are currently determining the efficacy of local cooling for the therapy of certain focal epilepsies. We have attempted to adapt new technologies borrowed from electrical and mechanical engineering to develop cooling devices that will ultimately improve the diagnosis and therapy of these focal epilepsies. The present review describes the rationale for this research and our progress to date.

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Curr Opin Investig Drugs. 2005 Jul;6(7):680-5.
Cannabinoids as potential anti-epileptic drugs.
Smith PF.
Department of Pharmacology and Toxicology, School of Medical Sciences, University of Otago, Dunedin, New Zealand. paul.smith@stonebow.otago.ac.nz

Cannabinoids have long been recognized as having the potential for both anticonvulsant and proconvulsant effects. The increased understanding of the cannabinoid receptors and their endogenous ligands over the last decade has provided a potential mechanism of action for these apparently paradoxical effects. Although the anticonvulsant effects of cannabinoids appear to be mediated by their action at presynaptic cannabinoid receptors, which inhibit the release of excitatory neurotransmitters such as glutamate, it is clear that they are also capable of producing proconvulsant effects through the activation of cannabinoid receptors on terminals releasing inhibitory neurotransmitters, such as gamma-amino-butyric acid. In the brain, the activation of cannabinoid receptors is carefully controlled by the rapid synthesis and degradation of endocannabinoids in a way that targets the endogenous ligands to specific sets of cannabinoid receptors. The potential problem in delivering a cannabinoid drug to treat epilepsy is the inability to control its actions at different cannabinoid receptors regulating the release of different neurotransmitters. Since the action of cannabinoids is complex, and there is a dearth of clinical trial data, it is currently unclear whether cannabinoids might be both efficacious and safe in the treatment of epilepsy.

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Lancet. 2005 Jul 16-22;366(9481):205-10.
Safety and efficacy of buccal midazolam versus rectal diazepam for emergency treatment of seizures in children: a randomised controlled trial.
McIntyre J, Robertson S, Norris E, Appleton R, Whitehouse WP, Phillips B, Martland T, Berry K, Collier J, Smith S, Choonara I.
Academic Division of Child Health, University of Nottingham, Derbyshire Children's Hospital, Uttoxeter Road, Derby DE22 3DT, UK. john.mcintyre@nhs.net

BACKGROUND: Rectal diazepam and buccal midazolam are used for emergency treatment of acute febrile and afebrile (epileptic) seizures in children. We aimed to compare the safety and efficacy of these drugs. METHODS: A multicentre, randomised controlled trial was undertaken to compare buccal midazolam with rectal diazepam for emergency-room treatment of children aged 6 months and older presenting to hospital with active seizures and without intravenous access. The dose varied according to age from 2.5 to 10 mg. The primary endpoint was therapeutic success: cessation of seizures within 10 min and for at least 1 hour, without respiratory depression requiring intervention. Analysis was per protocol. FINDINGS: Consent was obtained for 219 separate episodes involving 177 patients, who had a median age of 3 years (IQR 1-5) at initial episode. Therapeutic success was 56% (61 of 109) for buccal midazolam and 27% (30 of 110) for rectal diazepam (percentage difference 29%, 95% CI 16-41). Analysing only initial episodes revealed a similar result. The rate of respiratory depression did not differ between groups. When centre, age, known diagnosis of epilepsy, use of antiepileptic drugs, prior treatment, and length of seizure before treatment were adjusted for with logistic regression, buccal midazolam was more effective than rectal diazepam. INTERPRETATION: Buccal midazolam was more effective than rectal diazepam for children presenting to hospital with acute seizures and was not associated with an increased incidence of respiratory depression.

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Arch Dis Child. 2005 May;90(5):512-5.
Pyridoxal phosphate is better than pyridoxine for controlling idiopathic intractable epilepsy.
Wang HS, Kuo MF, Chou ML, Hung PC, Lin KL, Hsieh MY, Chang MY.
Division of Pediatric Neurology, Chang Gung Children's Hospital, and Medical College of Chang Gung University, Taoyuan, Taiwan. wanghs444@cgmh.org.tw

AIM: To study the difference between pyridoxine (PN) and its active form, pyridoxal phosphate, (PLP) in control of idiopathic intractable epilepsy in children. METHODS: Among 574 children with active epilepsy, 94 (aged 8 months to 15 years) were diagnosed with idiopathic intractable epilepsy for more than six months. All received intravenous PLP 10 mg/kg, then 10 mg/kg/day in four divided doses. If seizures recurred within 24 hours, another dose of 40 mg/kg was given, followed by 50 mg/kg/day in four divided doses. For those patients whose seizures were totally controlled, PLP was replaced by the same dose of oral PN. If the seizure recurred, intravenous PLP was infused followed by oral PLP 50 mg/kg/day. RESULTS: Fifty seven patients had generalised seizures (of whom 13 had infantile spasms) and 37 had focal seizure. Eleven had dramatic and sustained responses to PLP; of these, five also responded to PN. Within six months of treatment with PLP or PN, five of the 11 patients were seizure free and had their previous antiepileptic medicine tapered off gradually. Two were controlled with pyridoxine and the other three needed PLP to maintain seizure freedom. The remaining six responders needed PLP exclusively for seizure control. Six of the 11 responders to PLP had infantile spasms (46%); four of them needed PLP exclusively. The other five responders were in the remaining 81 patients with other seizure type. CONCLUSIONS: PLP could replace PN in the treatment of intractable childhood epilepsy, particularly in the treatment of infantile spasms.

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J Neurol Neurosurg Psychiatry. 2005 May;76(5):710-3.
Seizure outcome after epilepsy surgery in patients with normal preoperative MRI.
Chapman K, Wyllie E, Najm I, Ruggieri P, Bingaman W, Luders J, Kotagal P, Lachhwani D, Dinner D, Luders HO.
The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. wylliee@ccf.org.

OBJECTIVE: To determine outcome after epilepsy surgery in patients with normal preoperative magnetic resonance imaging (MRI). METHODS: 24 adult and paediatric patients with normal preoperative MRIs were studied. They underwent epilepsy surgery between 1994 and 2001 and had at least one year of follow up. RESULTS: At the most recent follow up, nine patients (37%) were seizure-free and 18 (75%) had at least a 90% reduction in seizure frequency with weekly or monthly seizures. Seizure freedom was not significantly different after resections in frontal (5/9) or temporal regions (4/13) (p = 0.24, Fisher's exact test), or among patients with or without localising features on EEG, PET, or ictal SPECT. Subdural grids, used in 15 of 24 patients, helped tailor resections but were not associated with differences in outcome. Histopathology showed cortical dysplasia in 10 patients (42%), non-specific findings in 13 (54%), and hippocampal sclerosis in one (4%). Cortical dysplasia was seen in seven patients with frontal resection (78%) and non-specific findings in nine (69%) with temporal resection. Seizure outcome did not differ on the basis of location of resection or histopathology. CONCLUSIONS: While these results were less favourable than expected for patients with focal epileptogenic lesions seen on MRI, they represented worthwhile improvement for this patient population with high preoperative seizure burden. In this highly selected group, no single test or combination of tests further predicted postoperative seizure outcome.

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Cochrane Database Syst Rev. 2005 Apr 18;(2):CD004304.
Vitamins for epilepsy.
Ranganathan L, Ramaratnam S.
Institute of Neurology, Madras Medical College, 18 Appa Kannu Lane, 1st floor, "Garuda Sailam", Royapetta, Chennai, Tamil Nadu, INDIA, 600014.

BACKGROUND: Vitamins have been reported to be effective in controlling certain types of seizures and to prevent some of the harmful effects of antiepileptic drugs (AEDs). In this review we will summarize evidence from randomized controlled trials. OBJECTIVES: To assess if vitamins improve seizure control, reduce adverse effects of AEDs or improve the quality of life in people with epilepsy. SEARCH STRATEGY: We searched MEDLINE from 1966 to 2004, the Cochrane Epilepsy Group trials register (December 2004), CENTRAL (the Cochrane Controlled Trials Register) (TheCochraneLibrary Issue 4, 2004), and cross-references from identified studies. SELECTION CRITERIA: Randomized or quasi-randomized studies investigating the effects of one or more vitamins given alone or in addition to AEDs to people of any age with any type of epilepsy. DATA COLLECTION AND ANALYSIS: Both reviewers assessed the trials for inclusion and extracted the data. Outcomes assessed included seizure frequency, gingival hyperplasia, neuropathy, changes in bone mineral content, serum calcium, alkaline phosphatase, hemogram, serum levels of AEDs, neuropsychological and quality of life outcomes. Primary analyses were by intention to treat. MAIN RESULTS: Fifteen studies met our inclusion criteria and were of poor methodological quality. None described randomization methods and most enrolled small numbers of participants. Nine studies (331 participants) investigated folic acid. Two studies (75 participants) found no effect for the outcome 50% or greater reduction in seizure frequency (OR 0.96; 95% CI 0.32 to 2.29). Also, no evidence was found for an effect on gingival health, intelligence, behavior, mental health or personality, or measures of red blood volume and hemoglobin content. Folic acid was not associated with any consistent changes in serum phenytoin or phenobarbitone levels or improvement in the mean motor conduction velocities of peripheral nerves. One small study (72 participants) found that thiamine improves neuropsychological functions related to psychomotor speed, visuospatial abilities, selective attention and verbal abstracting ability. One study (226 participants) found a significantly higher bone mineral content (BMC) among patients with epilepsy taking AEDs with vitamin D supplementation compared to controls who were not given supplementation (OR 3.6; 95% CI 2.48 to 4.72; p < 0.00001). The studies found no significant effects on serum calcium, alkaline phosphatase or general well-being. One small study (24 participants) found a significant decrease in seizure frequency in those treated with vitamin E compared to placebo (p = 0.00005; Peto OR 26.73; 95% CI 5.46 to 130.92). AUTHORS' CONCLUSIONS: In view of methodological deficiencies and limited number of individual studies, we have found no reliable evidence to support the routine use of vitamins in patients with epilepsy. Further trials are needed, especially to assess the utility of vitamin D supplementation to prevent osteomalacia and the role of vitamin E on seizures and thiamine in improving cognitive functions.

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Health Technol Assess. 2005 Apr;9(15):1-172.
Clinical effectiveness, tolerability and cost-effectiveness of newer drugs for epilepsy in adults: a systematic review and economic evaluation.
Wilby J, Kainth A, Hawkins N, Epstein D, McIntosh H, McDaid C, Mason A, Golder S, O'meara S, Sculpher M, Drummond M, Forbes C.
Centre for Reviews and Dissemination, University of York, UK.

OBJECTIVES: To examine the clinical effectiveness, tolerability and cost-effectiveness of gabapentin (GBP), lamotrigine (LTG), levetiracetam (LEV), oxcarbazepine (OXC), tiagabine (TGB), topiramate (TPM) and vigabatrin (VGB) for epilepsy in adults. DATA SOURCES: Electronic databases. Internet resources. Pharmaceutical company submissions. REVIEW METHODS: Selected studies were screened and quality assessed. Separate analyses assessed clinical effectiveness, serious, rare and long-term adverse events and cost-effectiveness. An integrated economic analysis incorporating information on costs and effects of newer and older antiepileptic drugs (AEDs) was performed to give direct comparisons of long-term costs and benefits. RESULTS: A total of 212 studies were included in the review. All included systematic reviews were Cochrane reviews and of good quality. The quality of randomised controlled trials (RCTs) was variable. Assessment was hampered by poor reporting of methods of randomisation, allocation concealment and blinding. Few of the non-randomised studies were of good quality. The main weakness of the economic evaluations was inappropriate use of the cost-minimisation design. The included systematic reviews reported that newer AEDs were effective as adjunctive therapy compared to placebo. For newer versus older drugs, data were available for all three monotherapy AEDs, although data for OXC and TPM were limited. There was limited, poor-quality evidence of a significant improvement in cognitive function with LTG and OXC compared with older AEDs. However, there were no consistent statistically significant differences in other clinical outcomes, including proportion of seizure-free patients. No studies assessed effectiveness of AEDs in people with intellectual disabilities or in pregnant women. There was very little evidence to assess the effectiveness of AEDs in the elderly; no significant differences were found between LTG and carbamazepine monotherapy. Sixty-seven RCTs compared adjunctive therapy with placebo, older AEDs or other newer AEDs. For newer AEDs versus placebo, a trend was observed in favour of newer drugs, and there was evidence of statistically significant differences in proportion of responders favouring newer drugs. However, it was not possible to assess long-term effectiveness. Most trials were conducted in patients with partial seizures. For newer AEDs versus older drugs, there was no evidence to assess the effectiveness of LEV, LTG or OXC, and evidence for other newer drugs was limited to single studies. Trials only included patients with partial seizures and follow-up was relatively short. There was no evidence to assess effectiveness of adjunctive LEV, OXC or TPM versus other newer drugs, and there were no time to event or cognitive data. No studies assessed the effectiveness of adjunctive AEDs in the elderly or pregnant women. There was some evidence from one study (GBP versus LTG) that both drugs have some beneficial effect on behaviour in people with learning disabilities. Eighty RCTs reported the incidence of adverse events. There was no consistent or convincing evidence to draw any conclusions concerning relative safety and tolerability of newer AEDs compared with each other, older AEDs or placebo. The integrated economic analysis for monotherapy for newly diagnosed patients with partial seizures showed that older AEDs were more likely to be cost-effective, although there was considerable uncertainty in these results. The integrated analysis suggested that newer AEDs used as adjunctive therapy for refractory patients with partial seizures were more effective and more costly than continuing with existing treatment alone. Combination therapy, involving new AEDs, may be cost-effective at a threshold willingness to pay per quality-adjusted life year (QALY) greater than pound20,000, depending on patients' previous treatment history. There was, again, considerable uncertainty in these results. There were few data available to determine effectiveness of treatments for patients with generalised seizures. LTG and VPA showed similar health benefits when used as monotherapy. VPA was less costly and was likely to be cost-effective. The analysis indicated that TPM might be cost-effective when used as an adjunctive therapy, with an estimated incremental cost-effectiveness ratio of pound34,500 compared with continuing current treatment alone. CONCLUSIONS: There was little good-quality evidence from clinical trials to support the use of newer monotherapy or adjunctive therapy AEDs over older drugs, or to support the use of one newer AED in preference to another. In general, data relating to clinical effectiveness, safety and tolerability failed to demonstrate consistent and statistically significant differences between the drugs. The exception was comparisons between newer adjunctive AEDs and placebo, where significant differences favoured newer AEDs. However, trials often had relatively short-term treatment durations and often failed to limit recruitment to either partial or generalised onset seizures, thus limiting the applicability of the data. Newer AEDs, used as monotherapy, may be cost-effective for the treatment of patients who have experienced adverse events with older AEDs, who have failed to respond to the older drugs, or where such drugs are contraindicated. The integrated economic analysis also suggested that newer AEDs used as adjunctive therapy may be cost-effective compared with the continuing current treatment alone given a QALY of about pound20,000. There is a need for more direct comparisons of the different AEDs within clinical trials, considering different treatment sequences within both monotherapy and adjunctive therapy. Length of follow-up also needs to be considered. Trials are needed that recruit patients with either partial or generalised seizures; that investigate effectiveness and cost-effectiveness in patients with generalised onset seizures and that investigate effectiveness in specific populations of epilepsy patients, as well as studies evaluating cognitive outcomes to use more stringent testing protocols and to adopt a more consistent approach in assessing outcomes. Further research is also required to assess the quality of life within trials of epilepsy therapy using preference-based measures of outcomes that generate cost-effectiveness data. Future RCTs should use CONSORT guidelines; and observational data to provide information on the use of AEDs in actual practice, including details of treatment sequences and doses.

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Best Pract Res Clin Gastroenterol. 2005 Apr;19(2):263-74.
Abdominal epilepsy.
Zinkin NT, Peppercorn MA.
Beth Israel Deaconess Medical Center, Harvard Medical school, 330 Brookline Ave., Rabb 4, Cambridge, MA 02215, USA.

Abdominal epilepsy is an uncommon syndrome in which gastrointestinal complaints, most commonly abdominal pain, result from seizure activity. It is characterized by (1) otherwise unexplained, paroxysmal gastrointestinal complaints, (2) symptoms of a central nervous system disturbance, (3) an abnormal electroencephalogram with findings specific for a seizure disorder, and (4) improvement with anticonvulsant medication. We review the history of the syndrome and analyze all 36 cases reported in the English literature from the last 34 years. The most common gastrointestinal symptoms include abdominal pain, nausea and vomiting, while the most common neurological symptoms include lethargy and confusion. After exclusion of more common etiologies for the presenting complaints, workup should proceed with an electroencephalogram. Where the diagnosis is seriously considered, neurological consultation should be considered. Treatment typically begins with anticonvulsant medication, and resolution of symptoms with therapy helps to confirm the diagnosis.

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Brain. 2005 Apr 13; [Epub ahead of print]
Epilepsy surgery does not harm motor performance of children and adolescents.
van Empelen R, Jennekens-Schinkel A, Gorter JW, Volman MJ, van Nieuwenhuizen O, Helders PJ.
Department of Paediatric Physical Therapy and Exercise Physiology, University Medical Centre, Wilhelmina Children's Hospital, Utrecht, The Netherlands; Rudolf Magnus Institute of Neuroscience, Utrecht, The Netherlands.

The impact of epilepsy surgery on motor performance, activities of daily life (ADL) and caregiver assistance was assessed in 37 children (age range 0.1-15.4 years) with pharmacologically untreatable epilepsy, 17 of whom were also diagnosed as having spasticity of cerebral origin. All patients underwent epilepsy surgery between 1996 and 2001 at the Wilhelmina University Children's Hospital and were assessed using a standard protocol at fixed intervals: before surgery and 6 months, 1 year and 2 years after surgery. The type of surgery was hemispherectomy (n = 14) and temporal (n = 14), frontal (n = 4), parietal (n = 2) and central (n = 2) resection. One child underwent callosotomy. Engel's classification was used to determine seizure outcome. Impairments were measured in terms of muscle strength, range of motion and muscle tone. Motor performance of infants and children without spasticity was measured using the Movement Assessment Battery for Children (M-ABC). The Gross Motor Function Measure (GMFM-88) was used in children with spasticity, the severity of motor disability in this group being determined by means of the Gross Motor Function Classification System (GMFCS). Daily activities and caregiver's assistance were measured in all children using the Pediatric Evaluation of Disability Inventory (PEDI). Twenty-four months after surgery 74% of the children could be classified as Engel class 1, indicating a significant seizure reduction. Impairments revealed some decrease in muscle strength and range of motion in the group with spasticity. Scores improved statistically significantly at group level on M-ABC and GMFM (P < 0.05). Improvement in activities of daily life and caregiver's assistance could not be measured in children without spasticity because of the ceiling effect of the PEDI, but children with spasticity improved significantly with respect to these parameters (PEDI) (P < 0.05). Hence, epilepsy surgery does not harm motor performance in children with or without spasticity.

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Expert Rev Neurother. 2005 Mar;5(2):165-176.
Divalproex sodium in the treatment of pediatric psychiatric disorders.
Rana M, Khanzode L, Karnik N, Saxena K, Chang K, Steiner H.
Stanford University , School of Medicine, Department of Psychiatry and Behavioral Sciences, Division of Child Psychiatry and Child Development, 401 Quarry Road, Stanford, CA 94305 5719, USA Tel.: +1 650 723 5420 Fax: +1 650 723 5531 mrana@stanford.edu.

Divalproex sodium is an anticonvulsant that is used extensively in adults with indications for epilepsy, acute mania and migraine prophylaxis. It has been used in children and adolescents as a first-line agent for mania in bipolar disorder. Its efficacy as a mood stabilizer has been established, and there have been studies outlining its efficacy as an agent effective in the treatment of conduct disorder, disruptive behavior disorders, aggression and explosive disorder. Longer-acting formulations are now available that cause less gastrointestinal side effects and can also be taken once a day, thus potentially increasing adherence, an important factor in this patient population. Future directions would include developing a more potent valproic acid formulation with fewer side effects, completing randomized controlled trials to establish the efficacy of divalproex sodium in various other pediatric psychiatric disorders, establishing the relative efficacy of the compound in head-to-head comparisons with other mood stabilizers, examining systematically the value of the compound in multimodal pediatric psychiatric treatment packages, and complete effectiveness trials that demonstrate the short- and long-term effectiveness of the compound in the real world of clinicians. In this drug profile, divalproex sodium and its uses in the pediatric population for psychiatric conditions are reviewed.

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J Child Neurol. 2005 Mar;20(3):212-9.
Clinical experience with zonisamide monotherapy and adjunctive therapy in children with epilepsy at a tertiary care referral center.
Kim HL, Aldridge J, Rho JM.
Department of Neurology, University of California, Irvine Medical Center, Orange, CA 92868, USA. kimhl@uci.edu

We evaluated our clinical experience with zonisamide, a broad-spectrum antiepileptic drug, in a group of children with predominantly medically refractory epilepsy. A retrospective chart review was conducted on patients at our tertiary referral center following Institutional Review Board approval. Observers documented reports of seizure frequency, and seizure types were identified either clinically or by prior video-electroencephalography monitoring. We identified 68 patients (age range 1.9-18.1 years [median 6.9 years]; male to female ratio 1.3:1) treated with zonisamide for 0.7 to 28.9 months; at the last visit, 22% and 78% were on monotherapy and adjunctive therapy, respectively. The median duration of treatment and maintenance dose at the end of the follow-up were 11.2 months and 8.0 mg/kg/day, respectively. Seizure types included generalized (primary generalized tonic-clonic, myoclonic, tonic, atonic, absence) and partial (simple, complex, and secondarily generalized tonic-clonic seizures); 10 (15%) patients had both partial and generalized seizures. Sixteen (25.8%) patients were seizure free, although five of them were already in remission prior to starting zonisamide. Thirteen (21.0%) patients had a > 50% seizure reduction, 10 (16.1%) patients had a < 50% seizure reduction, 14 (22.6%) had no improvement in baseline seizures, and 9 (14.5%) reported having increased seizures. The latter were mostly associated with dosage alterations in concomitant antiepileptic drugs. Common side effects were central nervous system related, including behavioral or psychiatric (23.5%), cognitive dysfunction (12.0%), and sedation (10.3%). Eleven (16.2%) patients ultimately discontinued zonisamide, but only five were strictly due to side effects. Zonisamide is clinically effective against multiple seizure types in a significant proportion of children with epilepsy across a broad age range. Drug discontinuation as a result of side effects is uncommon.

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Neuroscientist. 2005 Feb;11(1):25-36.
Adenosine and epilepsy: from therapeutic rationale to new therapeutic strategies.
Boison D.
Institute of Pharmacology and Toxicology, University of Zurich. boison@pharma.unizh.ch.

Adenosine, as the brain's endogenous anticonvulsant, is considered to be responsible for seizure arrest and postictal refractoriness. On the other hand, deficiencies within the adenosine-based neuromodulatory system may contribute to epileptogenesis. Based on these natural mechanisms and on findings that adenosine and its analogs can suppress pharmacoresistant seizures, a new field of adenosine-based therapies has emerged, including the use of adenosine receptor agonists and adenosine transport inhibitors, or the inhibition of adenosine kinase, which is thought to be the key enzyme for the regulation of intra- and extracellular adenosine levels. However, most of these pharmacological approaches are limited by strong systemic side effects ranging from a decrease of heart rate, blood pressure, and body temperature to sedation. Recently, new strategies have been developed aimed at the local reconstitution of the inhibitory adenosinergic tone by intracerebral implantation of cells engineered to release adenosine. Adenosine-releasing cells or devices implanted into or near a seizure focus offer new hopes for a side effect-free therapy for pharmacoresistant epilepsy.

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Seizure. 2005 Jan;14(1):66-71.
Clinical experience with levetiracetam in childhood epilepsy: an add-on and mono-therapy trial.
Lagae L, Buyse G, Ceulemans B.
University Hospitals KULeuven, Department of Paediatric Neurology, Herestraat 49, B3000 Leuven, Belgium; Epilepsy Centre Pulderbos, Belgium.

We examined the efficacy, optimum dosage and adverse effects of levetiracetam in two prospective trials in children with epilepsy. In the add-on trial, 67 children between 6 months and 16 years were included. In the mono-therapy trial, 10 children between 4 years and 16 years were included. Levetiracetam was titrated up to an optimal dosage for every individual patient, depending on efficacy and tolerability, and reflecting clinical practice. The range of dosages used was between 12 and 62mg/kg/day, with a median of 33mg/kg/day. Overall, 20 weeks after the start of levetiracetam, there was a median seizure reduction of 60% (add-on trial 50%; mono-therapy trial 81%). Levetiracetam was equally effective for partial and generalized seizures. Side effects were less common in the mono-therapy trial. Tiredness (7.8%) and aggressiveness (5%) were the most common side effects, and were dose-related, but were no reason to discontinue levetiracetam. In 25% of the children, a positive effect was seen on behaviour and/or alertness. This could not be related directly to seizure control. Overall, these two clinical trials confirm that levetiracetam is a broad spectrum anti-epileptic drug with a favourable safety profile. The positive effect on behaviour needs further quantitative study.

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Seizure. 2005 Jan;14(1):23-7.
Levetiracetam in refractory epilepsy: a prospective observational study.
Mohanraj R, Parker PG, Stephen LJ, Brodie MJ.
Epilepsy Unit, Division of Cardiovascular & Medical Sciences, Western Infirmary, Glasgow, Scotland, UK.

This prospective open-label study used flexible dosing schedules of levetiracetam (LEV) in patients with refractory epilepsy attending a single centre to explore its effectiveness in everyday clinical practice. One hundred and fifty-six patients with uncontrolled localisation-related or idiopathic-generalised epilepsy were prescribed adjunctive LEV following a 3-month baseline. The primary end points were seizure freedom for at least 6 months, >/=50% reduction (responder) or <50% reduction for 6 months, or discontinuation of LEV due to lack of efficacy, adverse effects or both. Overall, 40 (26%) patients became seizure free on adjunctive LEV, including 8 (40%) with idiopathic-generalised epilepsy. Twenty-five (63%) of the seizure-free patients took 1000mg LEV per day or less. A further 33 (21%) patients were classified as responders. LEV was withdrawn in 46 (29%) patients (27 adverse effects, 8 lack of efficacy, 11 both). Intolerable sedation, reported by 20 (13%) patients, was the commonest complaint leading to treatment failure. Behavioural side effects led to LEV withdrawal in 7 (5%) patients. LEV is an effective adjunctive treatment for refractory idiopathic and localisation-related epilepsies. Many patients who responded optimally to LEV did so at 1000mg per day or less.

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Seizure. 2005 Jan;14(1):10-8.
Vagus nerve stimulation in patients with catastrophic childhood epilepsy, a 2-year follow-up study.
Majoie HJ, Berfelo MW, Aldenkamp AP, Renier WO, Kessels AG.
Department of Neurology and Neuropsychology, Epilepsy Center Kempenhaeghe, P.O. 61, 5590 AB Heeze, The Netherlands.

Purpose: To establish the long-term efficacy and tolerability of vagus nerve stimulation (VNS) in children with a Lennox-like syndrome. Method: This study was a longitudinal observational prospective cohort analysis. Baseline: 6 months. Follow-up: 24 months. Screening (baseline and every 6 months): MRI (baseline only), EEG, neuropsychological evaluation, ECG and blood sampling for antiepileptic drug levels. Nineteen children are included. Results: A seizure frequency reduction of 20.6% was found at the end of the follow-up period. No relationship was detected between the length of the stimulation period and the reduction in the seizure frequency. 21% of the patients showed a reduction in seizure frequency of 50% or more. The seizure severity showed improvement in the first 12 months of treatment. The largest seizure reduction was found in the patients with highest frequency of background activity at the baseline EEG. Neuropsychological findings: no negative impact on behaviour, moderate improvement in function, behaviour and mood. Largest seizure reduction was found in the group with the highest baseline mental function. The scores for mental age improved independently of the seizure control. Twelve patients (63%) experienced minor side effects, which subsided after 1 month. Conclusion: (1) There was a significant reduction in seizure frequency and severity. (2) No serious side effects were recorded. (3) No negative effects on cognition or quality of life were apparent. (4) Patients with highest baseline mental functioning showed the highest seizure reduction. (5) Those patients with less disturbed EEG (high background activity and less interictal epileptic activity) showed the highest seizure reduction.

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Epileptic Disord. 2004 Dec 1;6(4):267-270.
Efficacy and tolerability of zonisamide in juvenile myoclonic epilepsy.
Kothare SV, Valencia I, Khurana DS, Hardison H, Melvin JJ, Legido A.
Division of Child Neurology, Department of Pediatrics, St. Christopher's Hospital for Children.

The recommended treatment for juvenile myoclonic epilepsy (JME) is valproate (VPA). Recently, topiramate and lamotrigine have also been shown to be effective. The objective of this study was to evaluate the efficacy and tolerability of zonisamide (ZNS) in the treatment of JME. We retrospectively analyzed the records of 15 patients (three M, 12 F, ages 11-20 years) diagnosed with JME at our institution during 2001-2003, and treated with ZNS. Generalized tonic-clonic (GTC), myoclonic and absence seizure response was assessed. The ZNS dose range was 200-500 mg/day (2.0-8.5 mg/kg/day). ZNS was started as the first drug, and as monotherapy, in 13 and was added to VPA in two patients. Follow-up range was 2-24 months (mean 12 months). Overall, 80% of patients on ZNS monotherapy showed good control (>/= 50% seizure reduction). Sixty-nine, 62 and 38% of patients were free of GTC, myoclonic, and absence seizures, respectively. Seizure control was achieved within four to eight weeks of attaining the maintenance dose. One patient on polytherapy had a 75% reduction in seizure frequency, whereas the other patient showed no response. There were no ZNS-VPA interactions. One patient stopped ZNS and was switched to VPA because of poor seizure control. Three patients (20%) experienced side effects (weight loss, headache, dizziness) during escalation, which resolved during maintenance. In this open-label, retrospective study, ZNS was shown to be an effective and well-tolerated drug in the treatment of patients with JME. The ease of titration, good safety profile, once-a-day dosing, lack of significant drug interaction, and short latency for onset of efficacy make ZNS an attractive therapeutic alternative for the treatment of JME.

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Epileptic Disord. 2004 Dec;6(4):223-39.
Frontal lobe epilepsy.
Kellinghaus C, Luders HO.
Dept. of Neurology, The Cleveland Clinic Foundation, Cleveland, Ohio, USA ; Dept. of Neurology, University of Munster, Germany.

Frontal lobe epilepsy accounts for only 10-20% of the patients in surgical series, but the incidence in non-surgical patient cohorts seems to be much higher. The typical clinical presentation of the seizures includes contralateral clonic movements, uni- or bilateral tonic motor activity as well as complex automatism. The yield of surface EEG may be limited due to the difficulty in detection of mesial or basal foci, and the patient may be misdiagnosed as having non-epileptic events. In addition, in patients with mesial frontal foci the epileptiform discharges may be mislateralized ("paradoxical lateralization"). Therefore, epilepsy surgery has been commonly considered as less promising in patients with frontal lobe epilepsy. However, the advent of sophisticated neuroimaging techniques, particularly MRI with epilepsy-specific sequences, has made it possible to delineate the epileptogenic lesion and detect a specific etiology, in an increasing number of patients. Thus, the success rate of epilepsy surgery in frontal lobe epilepsy is currently comparable to temporal lobe epilepsy, if the candidates are carefully selected. Patients with frontal lobe epilepsy who do not respond to anticonvulsive medication, and who are not eligible for epilepsy surgery may benefit from alternative approaches such as electrical brain stimulation.

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Neurology. 2004 Dec 28;63(12):2298-302.
Resective reoperation for failed epilepsy surgery: seizure outcome in 64 patients.
Siegel AM, Cascino GD, Meyer FB, McClelland RL, So EL, Marsh WR, Scheithauer BW, Sharbrough FW.
Division of Epilepsy, Mayo Clinic, Rochester, MN 55905, USA. gcasc

OBJECTIVE: To determine the surgical outcome and factors of predictive value in patients undergoing reoperation for intractable partial epilepsy. METHODS: The authors retrospectively studied the operative outcome in 64 consecutive patients who underwent reoperation for intractable partial epilepsy. Demographic data, results of comprehensive preoperative evaluations, and the seizure and neurologic outcome after reoperation were determined. All patients were followed a minimum of 1 year subsequent to their last operative procedure. RESULTS: Fifty-three patients had two surgeries, and 11 patients had three or more operations. The first surgery involved a lesionectomy (n = 33), "nonlesional" temporal lobe resection (n = 28), and a "nonlesional" extratemporal resection (n = 3). The mean duration between the first and second procedure was 5.5 years. Fifty-five patients underwent an intralobar reoperation, whereas nine had a resection of a different lobe. After reoperation, 25 patients (39%) were free of seizure, 6 patients (9%) had rare seizures, 12 patients (19%) had a worthwhile improvement, and 21 patients (33%) failed to respond to surgery. Predictors of seizure-free outcome were age at seizure onset >15 years (p = 0.01), duration of epilepsy < or =5 years at the time of initial surgery (p = 0.03), and focal interictal discharges in scalp EEG (p = 0.03). Using a logistic regression model, two significant predictors emerged: duration of epilepsy < or =5 years (odds ratio, 3.18; p = 0.04) and preoperative focal interictal discharge (odds ratio, 4.45; p = 0.02). Complications of reoperation included visual field deficits (n = 9), wound infection (n = 2), subdural hematoma (n = 1), and hemiparesis (n = 1). CONCLUSION: Reoperation may be an appropriate alternative form of treatment for selected patients with intractable partial epilepsy who fail to respond to initial surgery.

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Epilepsy Behav. 2004 Dec;5(6):878-83.
Levetiracetam for people with mental retardation and refractory epilepsy.
Kelly K, Stephen LJ, Brodie MJ.
Epilepsy Unit, Division of Cardiovascular and Medical Sciences, Western Infirmary, Glasgow G11 6NT, Scotland, UK.

Levetiracetam (LEV) is a novel antiepileptic drug (AED) with efficacy against a wide range of seizures types. The aim of this observational study was to assess its effectiveness in patients with mental retardation and refractory epilepsy. Sixty-four patients were started on adjunctive LEV after a 3-month baseline. LEV was initially dosed at 250 mg daily and increased by 250 mg every 2 weeks thereafter according to clinical response. Caregivers rated the patient's sleep, appetite, alertness, and behavior as poor (1), reasonable (2), or good (3) at each clinic visit. Patients were reviewed until one of four endpoints was reached: seizure freedom for at least 6 months, > or = 50% reduction in seizure frequency (responder) over a 6-month period, <50% reduction in seizure frequency (marginal effect) over a 6-month period, or LEV withdrawal due to lack of efficacy, adverse effects, or both. Twenty-four (38%) patients became seizure-free, 10 of whom were controlled on LEV 250 mg twice daily. An additional 18 (28%) patients were classified as responders, and 8 (12%) reported only marginal benefit from adjunctive LEV. Fourteen (22%) patients discontinued LEV (6 worsening seizures, 1 lack of efficacy, 7 adverse effects). Caregivers rated combined sleep, appetite, alertness, and behavior scores as "improved" at the end of follow-up (P<0.001). LEV improved seizure control in the majority of patients with mental retardation and may also have enhanced their quality of life.

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Epileptic Disord. 2004 Jun;6(2):57-75.
Antiepileptic drugs: indications other than epilepsy.
Spina E, Perugi G.
Section of Pharmacology, Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Messina, ITALY.

Antiepileptic drugs (AEDs) are increasingly used for the treatment of several non-epileptic neurological conditions and psychiatric disorders. Most of the information available on the use of these agents in clinical disorders outside epilepsy is from case series, uncontrolled studies or small randomised clinical trials, and their apparent efficacy requires confirmation through well designed, large, phase III trials. With regard to neurological conditions other than epilepsy, experimental evidence for the efficacy of AEDs is only available for the treatment of patients with trigeminal neuralgia, neuropathic pain syndromes, migraine and essential tremor. Carbamazepine is commonly prescribed as first-line therapy for patients with trigeminal neuralgia. Gabapentin has been recently marketed for the management of neuropathic pain syndromes, particularly diabetic neuropathy and postherpetic neuralgia. Valproic acid (sodium valproate), in the form of divalproex sodium, is approved for migraine prophylaxis. Primidone can be considered a valuable option for the treatment of essential tremor. AEDs are also used to treat psychiatric conditions, in particular bipolar disorder. So far, the most commonly utilized AEDs in the treatment of this disorder have been carbamazepine and valproic acid, which have showed an antimanic efficacy and a probable long-term, mood-stabilizing effect in many bipolar patients, including those refractory or intolerant to lithium. The availability of a new generation of AEDs has broadened the therapeutic options in bipolar disorder. Lamotrigine, oxcarbazepine, gabapentin and topiramate appear to be promising in the treatment of refractory bipolar disorder, as a monotherapy as well as in combination with traditional mood stabilizers. In addition, newer AEDs appear to have a more favourable tolerability and drug interaction profile as compared to older compounds, so thus improving compliance to treatment. Copyright John Libbey Eurotext 2003.

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Adv Exp Med Biol. 2004;548:239-47.
Brain stimulation as a therapy for epilepsy.
Goodman JH.
Center for Neual Recovery and Rehabilitation Research, Helen Hayes Hospital, New York State Department of Health, West Havenstraw, USA.

The failure of current antiepileptic therapies to adequately treat a significant number of epileptic patients highlights the need for the development of new treatments for the disorder. A new strategy that is currently being developed is to deliver electrical stimulation directly to the brain to decrease or prevent seizure activity. Clinical evidence that electrical stimulation could interfere with seizure activity was initially reported in the 1930's. However, many of these early studies consisted of case reports or were poorly controlled. In addition, there were a number of studies that failed to observe any beneficial effect of brain stimulation on seizures. More recently, deep brain stimulation has been used successfully to treat patients with movement disorders and vagus nerve stimulation has been shown to effectively decrease seizure activity in a select population of epilepsy patients. These advances have led to a reexamination of the potential therapeutic benefits of deep brain stimulation for the treatment of epilepsy. There is now experimental and clinical evidence that direct electrical stimulation of the brain can prevent or decrease seizure activity. However, several fundamental questions remain to be resolved. They include where in the brain the stimulus should be delivered and what type of stimulation would be most effective. One goal of this research is to combine the beneficial aspects of electrical stimulation with seizure detection technology in an implantable responsive stimulator. The device will detect the onset of a seizure and deliver an electrical stimulus that will safely block seizure activity without interfering with normal brain function.

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Epilepsia. 2004;45 Suppl 2:34-40.
Therapy for neurobehavioral disorders in epilepsy.
Devinsky O.
Departments of Neurology, Neurosurgery, and Psychiatry New York University School of Medicine, New York, New York, USA. od4@nyu.edu

Neurobehavioral disorders commonly affect patients with epilepsy. In addition to the behavioral changes during and immediately after seizures, the epileptogenic disorder of function often extends further into the postictal and interictal period. Cognitive impairments commonly affect attention, memory, mental speed, and language, as well as executive and social functions. Reducing seizure frequency and the antiepileptic drug burden can reduce these problems. Attentional deficits may respond to therapies for attention-deficit/hyperactivity disorder, but apart from patients with this comorbid disorder, their efficacy is unproven in other epilepsy patients. No effective therapies are established for other cognitive problems, but pragmatic, compensatory strategies can be helpful. Behavioral disorders include fatigue, depression, anxiety, and psychosis. Many of these disorders usually respond well to pharmacotherapy, which can be supplemented by psychotherapy. Cognitive and behavioral disorders can be the greatest cause of morbidity and impaired quality of life, often overshadowing seizures. Yet these problems often go unrecognized and, even when identified, are often undertreated or untreated.

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Epilepsy Behav. 2004 Jun;5(3):380-7.
Topiramate in clinical practice: long-term experience in patients with refractory epilepsy referred to a tertiary epilepsy center.
Bootsma HP, Coolen F, Aldenkamp AP, Arends J, Diepman L, Hulsman J, Lambrechts D, Leenen L, Majoie M, Schellekens A, de Krom M.
Department of Neurology, Epilepsy Centre Kempenhaeghe, Heeze, The Netherlands. bootsmaHP@kempenhaeghe.nl

For the treatment of patients with chronic refractory epilepsies, information about the long-term efficacy and safety profile of any new antiepileptic drug is crucial. Topiramate has been proven to be effective in patients with refractory chronic partial epilepsies in short-term controlled clinical trials, but the long-term retention, long-term efficacy, and long-term side-effect profile have not been sufficiently investigated. We analyzed all patients who had been treated with topiramate in the Epilepsy Centre Kempenhaeghe from the introduction of the drug in the spring of 1993 up to a final assessment point in mid-2002. In total, 470 patients were identified. The data show that the clinical dose achieved was about 200mg/day, reached after approximately 6 months of treatment. Further dose escalation in the survivors was slow, with a mean dose of about 300 mg/day after 24 months of treatment. Mean titration dose is 25mg/week, but titration strategy is mostly individual and responds to patient complaints. With respect to seizure frequency, 10-15% of the patients were seizure-free at the 6-month evaluation; 4 patients achieved a 2-year remission. Retention rate was 53% after 1 year, 45% after 2 years, 38% after 3 years, and 30% after 4 years. At 4 years, almost 70% of the patients had discontinued topiramate. The main reason was adverse events, which accounted for about 65% of the discontinuations. Behavioral side effects were dominant, with mental slowing (27.6%), dysphasia (16.0%), and mood problems (agitation: 11.9%) being the most frequently reported side effects. In about 10% of the patients side effects led to discontinuation despite the obvious favorable effects on seizure frequency. Comparisons between the patients who discontinued topiramate treatment and those who continued topiramate showed that discontinuation was associated with comedication (vigabatrin and lamotrigine). Our conclusion is that TPM is associated with a high incidence of side effects in clinical practice, affecting long-term retention. Meaningful prognostic factors that may help us in clinical decision making, i.e., to prevent the side effects or to help us identify those at risk, have not been found.

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Epilepsy Behav. 2004 Jun;5(3):316-21.
Add-on melatonin improves quality of life in epileptic children on valproate monotherapy: a randomized, double-blind, placebo-controlled trial.
Gupta M, Aneja S, Kohli K.
Department of Pharmacology, Lady Hardinge Medical College and Associated Hospitals, New Delhi, India. madhurgupta@hotmail.com

This randomized, double-blind, placebo-controlled study in epileptic children aged 3-12 years evaluated the effects of add-on melatonin administration on the quality of life of these children on sodium valproate (VPA) monotherapy using a parental questionnaire. Quality of Life in Childhood Epilepsy is a questionnaire designed to assess a variety of age-relevant domains such as physical function, emotional well-being, cognitive function, social function, behavior, and general health. Of the 31 patients, 16 randomly received add-on melatonin (MEL), whereas 15 received add-on placebo (P). The questionnaire had good internal consistency reliability, because for most of the multi-item scales Cronbach's [Formula: see text] reliability exceeded 0.5 (range: 0.59-0.94). To our knowledge, this is the first study assessing quality of life in epileptic children with add-on melatonin administration in the form of a randomized, double-blind, placebo-controlled trial. The study suggests a potential use of melatonin as an adjunct to antiepileptic therapy due to its diverse spectrum of action as an antioxidant, neuroprotector, and free radical scavenger, thus offering the advantage of reducing oxidant stress and subsequent damage. The beneficial effects of melatonin on sleep, its wide safety window, and its ability to cross the blood-brain barrier have the potential to improve quality of life in pediatric epilepsy.

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Epilepsy Behav. 2004 Jun;5(3):296-300.
Antiepileptic drugs and reduced bone mineral density.
Ali II, Schuh L, Barkley GL, Gates JR.
Department of Neurology, Medical College of Ohio, Toledo, OH, USA. iali@mco.edu

There is a growing interest in recognizing the association between antiepileptic drugs and reduced bone mineral density. Although the literature regarding this association has been available for more than three decades, the management of this complication remains unclear. We review the relevant literature regarding antiepileptic drugs and reduction in bone mineral density with the aim of developing some guidelines for practical management of this problem. This review focuses on the mechanism of antiepileptic drug-induced bone loss, its recognition, and its management.

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Epilepsia. 2004 Jun;45(6):690-4.
Does glucocorticoid administration prevent late seizures after head injury?
Watson NF, Barber JK, Doherty MJ, Miller JW, Temkin NR.
Neurology and Sleep Disorders Center, University of Washington, Seattle, Washington 98104-2499, USA. nwatson@u.washington.edu

PURPOSE: Preventing posttraumatic epilepsy has been a difficult challenge. In this study we evaluated the association between glucocorticoid administration after traumatic brain injury (TBI) and posttraumatic seizures. METHODS: We examined a seizure-prevention trial database of 404 patients with severe TBI for exposure to glucocorticoids in the early (<1 week) posttraumatic period. After controlling for seizure risk, we compared the odds of developing first and second late posttraumatic seizures between those that received glucocorticoids and those that did not. RESULTS: Patients dosed with glucocorticoids within 1 day of their TBI were more likely to develop first late seizures than were those without [p = 0.04; hazard ratio = 1.74; 95% confidence interval (CI), 1.01-2.98]; whereas those receiving glucocorticoids > or =2 days after their injury had no similar association (p = 0.66; hazard ratio = 0.77; 95% CI, 0.23-2.56; p = 0.10 among the three groups). Receiving glucocorticoids within 1 day, or > or =2 days after TBI was not associated with second late seizure development. CONCLUSIONS: Glucocorticoid treatment after TBI is not associated with decreased late posttraumatic seizures, and early treatment is associated with increased seizure activity.

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Epilepsia. 2004 Jun;45(6):650-60.
Cognitive, psychosocial, and family function one year after pediatric epilepsy surgery.
Smith ML, Elliott IM, Lach L.
Department of Psychology, Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada. smithml@psych.utoronto.ca

PURPOSE: Assumptions regarding the benefits of seizure control after pediatric epilepsy surgery for cognitive, psychosocial, and family function were explored in a prospective study of 51 children with intractable epilepsy. METHODS: Thirty children who underwent surgery were studied before and 1 year after surgery, and a comparison group of 21 children with medically refractory seizures was examined at comparable times. RESULTS: One year after surgery, 57% of the surgical group was seizure free. Seizure status after surgery did not predict change over time in any of the areas measured. Cognitive and psychosocial status did not change over time in either group, and the strongest predictor of individual change in psychosocial status in the surgical group was baseline level of function. Within the surgical group, a trend toward an increase in independence promotion was noted in the family, but the children's satisfaction with the family declined. CONCLUSIONS: These findings challenge the assumption that elimination of seizures will result in improved cognitive, psychosocial, and family functioning, at least within the first year after surgery.

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Epilepsia. 2004 Jun;45(6):641-9.
Parietal lobe epilepsy: the semiology, yield of diagnostic workup, and surgical outcome.
Kim DW, Lee SK, Yun CH, Kim KK, Lee DS, Chung CK, Chang KH.
Department of Neurology, Seoul National University College of Medicine, Seoul, Korea.

PURPOSE: To characterize the clinical features, the prognostic value, and diagnostic sensitivities of various presurgical evaluations and the surgical outcomes in parietal lobe epilepsy (PLE), we describe 40 patients who were diagnosed as having PLE, including 27 surgically treated patients. METHODS: The diagnosis was established by means of a standard presurgical evaluation, including magnetic resonance imaging (MRI), fluorodeoxyglucose-positron emission tomography (FDG-PET), ictal single-photon emission tomography (SPECT), and scalp video-electroencephalography (EEG) monitoring, with additional intracranial EEG monitoring in selected cases. RESULTS: Among the 40 patients, 27 experienced at least one type of aura. The most common auras were somatosensory (13 patients), followed by affective, vertiginous, and visual auras. The patients had diverse manifestations. Eighteen patients showed simple motor seizure, followed by automotor seizure, and dialeptic seizure. Two patients manifested generalized tonic-clonic seizures only, and 19 patients experienced more than one type of seizure. The surgical outcome was favorable in 22 of 26 patients including 14 who were seizure free. Patients with localized MRI abnormality had a higher probability to be seizure free, with marginal significance (p = 0.062), whereas other diagnostic modalities failed to predict the surgical outcome. In the seizure-free group, localization sensitivity was 64.3% by MRI, 50% by PET, 45.5% by ictal SPECT, and 35.7% by ictal EEG. The concordance rate of the various diagnostic modalities was higher in the seizure-free group than in the non-seizure-free group, although it did not reach statistical significance. CONCLUSIONS: Seizures, in the case of PLE, can manifest themselves in a wider variety of ways than was previously thought. Surgical outcome was favorable in most of the patients. MRI abnormality and concordance of different diagnostic modalities were associated with high seizure-free rate.

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Epilepsia. 2004 Jun;45(6):610-7.
Randomized, controlled clinical trial of zonisamide as adjunctive treatment for refractory partial seizures.
Sackellares JC, Ramsay RE, Wilder BJ, Browne TR 3rd, Shellenberger MK.
University of Florida and Malcolm Randall VA Medical Center, Gainesville, Florida 32610-0244, USA. sackellares@epilepsy.health.ufl.edu

PURPOSE: This study was designed to evaluate efficacy and safety of zonisamide (ZNS) as adjunctive treatment for patients with refractory partial seizures. METHODS: This randomized, double-blind, placebo-controlled study was conducted at four epilepsy treatment centers. It included a baseline phase (8 to 12 weeks) and a double-blind treatment phase (12 weeks). Initially, patients randomized to ZNS treatment were given a 7-mg/kg/d dosage. When investigators found that adverse effects could be reduced by gradually introducing ZNS, patients were allowed to begin treatment at lower doses (100 mg or approximately 1.5 mg/kg/d) titrated over several weeks to a maximum of 400 to 600 mg/d. Primary and secondary efficacy measures were the median percentage reduction from baseline in seizure frequency and the proportion of patients achieving a > or =50% reduction from baseline (responder rate). Patient and physician global assessments also served as indicators of efficacy. Safety was assessed primarily by treatment-emergent adverse events. RESULTS: ZNS-treated patients had a 28.9% reduction in seizure frequency, which differed significantly from the 4.7% increase in placebo-treated patients. The responder rate for ZNS-treated patients was 26.9%, compared with 16.2% for placebo-treated patients. At study's end, 66.2% of ZNS-treated patients and 12.3% of placebo-treated patients considered their condition improved; similarly, physicians assessed 63.6% of ZNS-treated patients and 10.8% of placebo-treated patients as improved. The most frequently reported adverse events with ZNS treatment included somnolence, irritability, dizziness, nausea, and fatigue. CONCLUSIONS: As adjunctive treatment, ZNS was generally well tolerated and significantly improved seizure control among patients with refractory partial seizures.

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Epilepsia. 2004 May;45(5):504-15.
Gamma knife surgery in mesial temporal lobe epilepsy: a prospective multicenter study.
Regis J, Rey M, Bartolomei F, Vladyka V, Liscak R, Schrottner O, Pendl G.
Stereotactic and Functional Neurosurgery Department, Timone Hospital, Marseille (APM), France. j.regis@ap-hm.fr

PURPOSE: This article is the first prospective documentation of the efficacy and safety of gamma knife surgery (GKS) in the treatment of drug-resistant epilepsies of mesial temporal lobe origin. METHODS: From July 1996 to March 2000, three European centers selected 21 patients with mesial temporal lobe epilepsy (MTLE) for a temporal lobectomy. The preoperative investigations included video-EEG with foramen ovale electrodes, magnetic resonance imaging, neuropsychological testing, and the ESI-55 quality-of-life questionnaire. In place of a cortectomy, radiosurgical treatment was performed by using the Leksell Gamma Knife (LGK) at a dose of 24 +/- 1 Gy at the margin. The target included the anterior parahippocampal cortex and the basal and lateral part of the amygdala and anterior hippocampus (head and body). One patient (a heavy smoker) died of a myocardial infarction. Twenty patients were available for prospective evaluation. A minimum 2-year follow-up period included clinical, neuropsychological, and radiologic evaluations. RESULTS: At each 6-month follow-up evaluation, the frequency of seizures was significantly smaller than that at the previous visit. The median seizure frequency of 6.16 the month before treatment was reduced to 0.33 at 2 years after treatment. At 2 years, 65% of the patients (13 of 20) were seizure free. Five patients had transient side effects, including depression, headache, nausea, vomiting, and imbalance. There was no permanent neurological deficit reported except nine visual field deficits. No neuropsychological deterioration was observed 2 years after treatment. The quality of life was significantly better than that before surgery. CONCLUSIONS: The safety and efficacy of the radiosurgical treatment of MTLEs appears good in this group of patient over short-to-middle term. Delay of the seizure cessation was the major disadvantage of GKS. A longer follow-up period is required for confirmation of these results.

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Epilepsia. 2004 May;45(5):401-9.
Efficacy and tolerability of the new antiepileptic drugs, I: Treatment of new-onset epilepsy: report of the TTA and QSS Subcommittees of the American Academy of Neurology and the American Epilepsy Society.
French JA, Kanner AM, Bautista J, Abou-Khalil B, Browne T, Harden CL, Theodore WH, Bazil C, Stern J, Schachter SC, Bergen D, Hirtz D, Montouris GD, Nespeca M, Gidal B, Marks WJ Jr, Turk WR, Fischer JH, Bourgeois B, Wilner A, Faught RE Jr, Sachdeo RC, Beydoun A, Glauser TA; American Academy of Neurology Therapeutics and Technology Assessment Subcommittee; American Academy of Neurology Quality Standards Subcommittee; American Epilepsy Society Quality Standards Subcommittee; American Epilepsy Society Therapeutics and Technology Assessment Subcommittee.
Neurological Institute, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. frenchj@mail.med.upenn.edu

PURPOSE: To assess the evidence demonstrating efficacy, tolerability, and safety of seven new antiepileptic drugs [AEDs; gabapentin (GBP), lamotrigine (LTG), topiramate (TPM), tiagabine (TGB), oxcarbazepine (OXC), levetiracetam (LEV), and zonisamide (ZNS), reviewed in the order in which these agents received approval by the U.S. Food and Drug Administration] in the treatment of children and adults with newly diagnosed partial and generalized epilepsies. METHODS: A 23-member committee, including general neurologists, pediatric neurologists, epileptologists, and doctors in pharmacy, evaluated the available evidence based on a structured literature review including MEDLINE, Current Contents, and Cochrane Library for relevant articles from 1987 until September 2002, with selected manual searches up to 2003. RESULTS: Evidence exists, either from comparative or dose-controlled trials, that GBP, LTG, TPM, and OXC have efficacy as monotherapy in newly diagnosed adolescents and adults with either partial or mixed seizure disorders. Evidence also shows that LTG is effective for newly diagnosed absence seizures in children. Evidence for effectiveness of the new AEDs in newly diagnosed patients with other generalized epilepsy syndromes is lacking. CONCLUSIONS: The results of this evidence-based assessment provide guidelines for the prescription of AEDs for patients with newly diagnosed epilepsy and identify those seizure types and syndromes for which more evidence is necessary.

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Epilepsia. 2004 May;45(5):410-23.
Efficacy and tolerability of the new antiepileptic drugs, II: Treatment of refractory epilepsy: report of the TTA and QSS Subcommittees of the American Academy of Neurology and the American Epilepsy Society.
French JA, Kanner AM, Bautista J, Abou-Khalil B, Browne T, Harden CL, Theodore WH, Bazil C, Stern J, Schachter SC, Bergen D, Hirtz D, Montouris GD, Nespeca M, Gidal B, Marks WJ Jr, Turk WR, Fischer JH, Bourgeois B, Wilner A, Faught RE Jr, Sachdeo RC, Beydoun A, Glauser TA; American Academy of Neurology Therapeutics and Technology Assessment Subcommittee; American Academy of Neurology Quality Standards Subcommittee; American Epilepsy Society Therapeutics and Technology Assessment Subcommittee; American Epilepsy Society Quality Standards Subcommittee.
Neurological Institute, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. jfrench@mail.med.upenn.edu

PURPOSE: To assess the evidence demonstrating efficacy, tolerability, and safety of seven new antiepileptic drugs (AEDs) [gabapentin (GBP), lamotrigine (LTG), topiramate (TPM), tiagabine (TGB), oxcarbazepine (OXC), levetiracetam (LEV), and zonisamide (ZNS)] in the treatment of children and adults with refractory partial and generalized epilepsies. METHODS: A 23-member committee, including general neurologists, pediatric neurologists, epileptologists, and doctors in pharmacy, evaluated the available evidence based on a structured literature review including MEDLINE, Current Contents, and Cochrane Library for relevant articles from 1987 to March 2003. RESULTS: All of the new AEDs were found to be appropriate for adjunctive treatment of refractory partial seizures in adults. GBP can be effective for the treatment of mixed seizure disorders, and GBP, LTG, OXC, and TPM for the treatment of refractory partial seizures in children. Limited evidence suggests that LTG and TPM also are effective for adjunctive treatment of idiopathic generalized epilepsy in adults and children, as well as treatment of the Lennox-Gastaut syndrome. CONCLUSIONS: The choice of AED depends on seizure and/or syndrome type, patient age, concomitant medications, and AED tolerability, safety, and efficacy. The results of this evidence-based assessment provide guidelines for the prescription of AEDs for patients with refractory epilepsy and identify those seizure types and syndromes for which more evidence is necessary.

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Neurologia. 2004 Apr;19(3):92-8.
[Prognostic factors in temporal lobe epilepsy surgery]
[Article in Spanish]
Villanueva V, Peral E, Albisua J, de Felipe J, Serratosa JM.
Unidad de Epilepsia, Servicio de Neurologia, Fundacion Jimenez Diaz, Madrid. serratosa@telefonica.es

INTRODUCTION: Temporal lobe epilepsy surgery represents the majority of surgical interventions in patients with refractory epilepsy. In consequence, knowledge of prognostic factors in this type of epilepsy surgery is of major importance. The objective of this study is to study series of prognostic factors in a group of patients who underwent temporal lobe epilepsy surgery and to correlate Engel's Classification of Postoperative Outcome, now used in most epilepsy centers, and the Proposal for New Classification in regards to Epileptic Seizures Following Epilepsy Surgery of the International League Against Epilepsy (ILAE). METHODS: We analyzed 41 consecutive patients who underwent temporal lobe epilepsy surgery in the Epilepsy Surgery Program of the Epilepsy Unit in the Fundacion Jimenez Diaz. The following prognostic factors were analyzed: age at surgery, time since the first seizure (excluding febrile seizures), risk factors for the development of epilepsy, presence of simple partial seizures, presurgical complex partial seizure frequency, findings in brain magnetic resonance imaging, interictal and ictal electroencephalogram, neuropsychological assessment, Wada test and neuropathological study of the surgical specimen. Two outcome classifications were used: Engel's classification of postoperative outcome and the proposal for a new classification of outcome in regards to epileptic seizures following epilepsy surgery of the ILAE. Statistical analysis was performed using non-parametric tests. RESULTS: The presence of temporal unilateral interictal epileptiform activity and the presence of less than 20 seizures complex partial seizures per month before surgery were associated with a better prognosis using both classifications. The electronencephalographic unilateral temporal ictal onset recording was associated with a better prognosis using Engel's classification but not ILAE's outcome classification. The presence of febrile seizures was associated with a better prognosis in regards to ILAE's outcome classification but not in regards to Engel's classification. The remaining factors were not associated with outcome. CONCLUSIONS: The following factors were associated with a good prognosis: presence of unilateral temporal interictal epileptiform activity, presurgery seizure frequency below 20 complex partial seizures per month, unilateral temporal ictal onset, and presence of febrile seizures. A good correlation was found between both outcome classifications in regards to most of the analyzed prognostic factors.

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Brain Dev. 2004 Apr;26(3):158-63.
Vagus nerve stimulation for drug-resistant epilepsy in children and young adults.
Buoni S, Mariottini A, Pieri S, Zalaffi A, Farnetani MA, Strambi M, Palma L, Fois A.
Department of Pediatrics, Obstetric and Reproductive Medicine, Section of Pediatrics, Policlinico Le Scotte, Viale Bracci, 53100, University of Siena, Siena, Italy.

We present our experience with the use of intermittent vagal nerve stimulation in 13 patients with medically intractable epilepsy. A surgical approach, with the exception of callosotomy, was impossible. The age range was 6-28 years (median 17 years). In all patients the epilepsy was severe and in six of them was symptomatic. Seven patients had Lennox-Gastaut syndrome, one epilepsy with myoclonic-astatic seizures, four localization-related and one symptomatic generalized epilepsy. The length of the follow-up averaged 22 months (range 8 months-3 years). Of the 13 patients, five (38.4%) had a 50% or more reduction in the number of seizures compared with preimplantation. Of these patients, one with a localization-related epilepsy had a 90% reduction as well as a significant improvement in alertness. Three patients showed no improvement with regard to the number of seizures but there was an improvement in alertness and, in one case in hyperactivity. Some seizure types responded better than others did: complex partial seizures with secondary generalization and atonic seizures. All our responsive patients improved in the first 2 months of VNS activation and only one case with further improvement was observed after this period. Considering the severity of the epilepsy the results can be considered satisfactory. We think that this treatment appears to be a safe adjunctive therapy for children and adults with medically and surgically intractable epilepsy.

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Neurosurg. 2004 Mar;100(3):452-62.
Multimodality image-guided surgery for the treatment of medically refractory epilepsy.
Murphy MA, O'Brien TJ, Morris K, Cook MJ.
Centre for Clinical Neuroscience and Neurological Research, St. Vincent's Hospital, University of Melbourne, Australia. murphyma@svhm.org.au

OBJECT: The aim of this study was to review seizure outcome, imaging modalities used, and complications following surgery in patients with epilepsy who had undergone multimodality image-guided surgery at our institution. METHODS: Data from patients with epilepsy who had undergone surgery between April 1999 and October 2001 were reviewed. During this time period, 116 operations were performed in 109 patients with medically refractory epilepsy. Among these patients, 22 were selected to undergo multimodality image-guided surgery primarily on the basis of whether they had no lesion visible on conventional magnetic resonance (MR) imaging sequences, multiple lesions, or one very large lesion that could not be completely resected without the risk of significant postoperative morbidity. A fourth group of patients in whom there was a single lesion in the eloquent cortex, a location associated with a significant risk of postoperative morbidity, was also included in the analysis. This latter group was assessed with the aid of intracranial grid electrodes that were coregistered to the MR image and were used intraoperatively to minimize electrode position error. Other imaging modalities used included positron emission tomography (PET), fluid-attenuated inversion recovery (FLAIR) MR imaging, and subtracted ictal-interictal single-photon positron emission computerized tomography (SPECT) coregistered with MR imaging (SISCOM). After coregistration, images were then downloaded onto an image-guided surgical system and the epileptogenic area was then resected. The mean patient age was 33 years (range 17-46 years), and there was a mean follow up of 27 months (range 14-41 months). Multimodality coregistrations used were as follows: nine PET scans, seven subdural electrode grids, four SISCOM studies, one FLAIR MR image, and one combined PET/subdural grid. Seizure outcome was excellent in 17 patients (77%) and not excellent in five (23%), or favorable in 19 (86%) and unfavorable in three (14%). Six patients (27%) had a transient neurological deficit, one patient (5%) a permanent major deficit, and three patients (15%) a permanent minor deficit. Five patients (24%) had a transient psychiatric problem postoperatively. CONCLUSIONS: Multimodality image-guided surgery offers a new perspective in surgery for epilepsy. Functional imaging modalities previously lateralized and often localized a seizure focus, but did not provide enough anatomical information to resect the epileptogenic zone confidently and safely. The coregistration of these modalities to a volumetric MR image and their incorporation into an image-guided system has allowed surgeons to offer surgery to patients who may not previously have been considered eligible, with outcomes comparable to those in patients with more straightforward lesional epilepsy.

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J Child Neurol. 2004 Feb;19(2):135-41.
Topiramate, carbamazepine, and valproate monotherapy: double-blind comparison in children with newly diagnosed epilepsy.
Wheless JW, Neto W, Wang S; EPMN-105 Study Group.
Department of Neurology, University of Texas Health Science Center at Houston, Houston, TX, USA. James.W.Wheless@uth.tmc.edu

In a novel double-blind trial, topiramate was compared with the investigator's choice of carbamazepine or valproate as first-line therapy in patients as young as 6 years of age with newly diagnosed epilepsy. Among 613 patients enrolled in the trial, 119 (19%) were children or adolescents (6-16 years of age). No differences between fixed doses of topiramate (100 and 200 mg/day) and carbamazepine (600 mg/day) or valproate (1250 mg/day) were observed in efficacy measures: time to exit, time to first seizure, and the proportion of patients who were seizure free during the last 6 months of treatment. Topiramate 100 mg/day (2.0 mg/kg/day in this study population) was associated with the fewest discontinuations owing to side effects. Based on efficacy and tolerability, the recommended target dose for topiramate as first-line therapy in children and adolescents is 100 mg/day.

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J Neurol Neurosurg Psychiatry. 2004 Apr;75(4):583-587.
Cognitive changes after epilepsy surgery in the posterior cortex.
Luerding R, Boesebeck F, Ebner A.
Department of Neurology, University of Regensburg, Universitatsstrasse 84, D-93053 Regensburg, Germany. Von Bodelschwinghsche Anstalten Bethel, Clinic Gilead IV, D-33164 Bielefeld, Germany. Epilepsy Centre Bethel, Clinic Mara I, Epilepsy Surgery Program, D-33164 Bielefeld, Germany.

OBJECTIVE: The relationship between the posterior cortex and cognitive functions is still a relatively open field. There are no studies on populations in which functions of posterior structures were examined by a standardised neuropsychological examination before and after posterior resections. Changes in cognitive performance are regularly observed after epilepsy surgery in the temporal lobe. However, information about neuropsychological impairments after resections in the posterior cortex is poor, owing to the relatively low proportion of cortical resections in this area. METHODS: We retrospectively studied changes in cognition in the neuropsychological data of 28 patients prior to and 6 months after posterior cortical resections. RESULTS: Cognition significantly showed differences in performance intelligence quotient compared with verbal intelligence quotient. Post-operative verbal intelligence consistently increased, whereas performance intelligence decreased. There was no effect regarding the lesion side, continuation of seizures, or reduction of visual field after surgery. Epilepsy surgery in this area did not lead to significant differences in general intelligence after surgery. CONCLUSION: Functions of posterior areas could be described by standardised neuropsychological measures. Posterior regions contribute to explicit attentional and visuoconstructional abilities. Epilepsy surgery in the posterior cortex bears no risk for substantial decline in general cognition although some discrete impairment in performance intelligence may occur.

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CNS Drugs. 2004;18(4):201-12.
Should antiepileptic drugs be withdrawn in seizure-free patients?
Specchio LM, Beghi E.
Clinic of Neurology, University of Foggia, Ospedali Riuniti, Foggia, Italy.

Discontinuation of antiepileptic drug (AED) treatment is a valuable option in patients with epilepsy who have been seizure free for 2 years or longer. However, the decision to withdraw AEDs must be based on a balanced view of the overall risk of seizure relapse, the factors most likely to affect that risk, and the medical, emotional and social implications of treatment continuation versus treatment withdrawal.In a critical review of 28 studies accounting for 4571 patients (2758 children, 1020 adults and a combined group of 793), most with at least 2 years of seizure remission, the proportion of patients with relapses during or after AED withdrawal ranged from 12 to 66%. Using life-table analysis, the cumulative probability of remaining seizure-free in children was 66-96% at 1 year and 61-91% at 2 years after withdrawal of AEDs. The corresponding values in adults were 39-74% and 35-57%, respectively. The relapse rate was highest in the first 12 months (especially in the first 6 months) after withdrawal and tended to decrease thereafter. Based on a previously published meta-analysis of data published up to 1992, the pooled relapse risk was 25% (95% CI 21, 30%) at 1 year and 29% (95% CI 24, 34%) at 2 years after AED withdrawal.The factors associated with a higher-than-average risk of seizure relapse included adolescent-onset epilepsy, partial seizures, the presence of an underlying neurological condition, and abnormal EEG findings at the time of AED withdrawal in children. Factors associated with a lower-than-average risk were childhood-onset epilepsy, idiopathic generalised epilepsy and - for children - a normal EEG. Selected epilepsy syndromes (e.g. benign epilepsy with centrotemporal spikes and juvenile myoclonic epilepsy) may be associated with significantly different outcomes after AED withdrawal.All these factors and their combinations may contribute to the development of guidelines for practising physicians to help them in making the best decision related to treatment discontinuation. The decision plan should also take into account social factors (driving license, job and leisure activities) as well as emotional and personal factors, and must be tailored to and discussed with the individual patient and his/her family.

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Nutr Neurosci 2003 Apr;6(2):67-79
The ketogenic diet for the treatment of epilepsy: a challenge for nutritional neuroscientists.
Stafstrom CE, Bough KJ.
Department of Neurology and the Neuroscience Training Program, University of Wisconsin, Madison, WI 53792, USA.

The ketogenic diet (KD) is a high-fat, low-carbohydrate, adequate-protein diet that has been used for more than eight decades for the treatment of refractory epilepsy in children. Despite this long history, the mechanisms by which the KD exerts its anti-seizure action are not fully understood. Questions remain regarding several aspects of KD action, including its effects on brain biochemistry and energetics, neuronal membrane function and cellular network behavior. With the explosion of the KD use in the last 10 years, it is now imperative that we understand these factors in greater detail, in order to optimize the formulation, administration and fine-tuning of the diet. This review discusses what is known and what remains to be learned about the KD, with emphasis on clinical questions that can be approached in the laboratory. We encourage scientists with a primary interest in nutritional neuroscience to join with those of us in the epilepsy research community to address these urgent questions, for the benefit of children ravaged by intractable seizures.

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Presse Med 2003 Mar 8;32(9):410-9
[New epileptic treatments. Current modalities and their utilization]
[Article in French]
Thomas P.
Unite Fonctionnelle EEG-Epileptologie Service de neurologie Hopital Pasteur, 30, voie romaine, B.P. 69, 06002 Nice. piertho@wanadoo.fr

NINE NEW MOLECULES: Since 1990, nine antiepileptic drugs have been launched in France: vigabatrin (Sabril), felbamate (Taloxa), gabapentin (Neurontin), lamotrigine (Lamictal), tiagabine (Gabitril), fosphenytoin (Prodilantin), topiramate (Epitomax), oxcarbazepine (Trileptal) and levetiracetam (Keppra). INDICATIONS EXTENDING: The indications for these new antiepileptic molecules, initially indicated in the case of insufficient efficacy or intolerance to first (phenobarbital, phenytoin) or second generation (valproate, carbamazepine) antiepileptics are in fact progressively extending, notably with the approval of first line monotherapy with gabapentin (partial epileptic seizures in adults), lamotrigine (partial and generalised epilepsy, and in addition in children) and oxcarbazepine (partial epilepsy). PROBLEMS OF TOLERANCE: Two molecules (vigabatrin and felbamate) had their prescription reduced because of rare but severe side effects, which had not been detected during the studies preceding marketing authorisation. The availability of these new antiepileptics has broadened and diversified but also complicated the medical management of epilepsy. Although the efficacy of the molecules has been demonstrated, particularly in certain specific indications, some products (felbamate, tiagabine, topiramate) exhibit an average efficacy/safety profile, whereas others (felbamate, lamotrigine) expose the patients to rare but potentially severe idiosyncratic effects. Moreover, some drugs with limited spectrum (vigabatrin, gabapentin, tiagabine and oxcarbazepine) may even worsen the symptoms of epilepsy. INTEREST AND LIMITS: The new antiepileptics often lead to remarkable results in cases of moderate epilepsy. However, they do not appear to change the conditions of the small percentage of patients who suffer from truly severe epilepsy. More targeted indications, notably in children, warrant specification in rigorous clinical trails that are still difficult to elaborate. All these data justify the efforts made in the development of new drugs, and the emergence of surgical and alternative approaches.

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Br Med Bull 2003;65:179-92
Epilepsy and surgical mapping.
Richardson MP.
Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, UK.

Drug treatment resistant epilepsy is an important public health problem. Patients with epilepsy of focal origin may have an excellent outcome following surgery that removes the source of seizures. Identification of the precise cortical region producing seizures is crucial to a good outcome; additionally, identification of eloquent cortical areas near the region to be resected is essential to prevent postoperative neurological deficit. A wide range of imaging techniques is valuable for imaging the epileptogenic zone, including high-resolution T1 MRI, T2 signal quantitation, MR spectroscopy, diffusion imaging, PET, SPECT and simultaneous EEG-fMRI. Eloquent cortex has in the past been mapped using highly invasive techniques; fMRI of motor and cognitive tasks holds great promise for future non-invasive mapping strategies.

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Seizure 2003 Apr;12(3):154-6
Levetiracetam monotherapy for newly diagnosed epilepsy patients.
Alsaadi TM, Thieman C.
Department of Neurology, University of California Davis, Sacramento, CA 95817, USA. taoufik.alsaadi@ucdmc.ucdavis.edu

We retrospectively reviewed the charts of all of our patients with a history of partial seizures, with and without secondarily generalisation, who received levetiracetam (LEV; Keppra) for treatment of their seizures during the years 2000-2002. Forty-five patients were identified, 13 of whom began LEV as first line therapy. Eleven patients continued on LEV for at least 6 months; six of whom became seizure free and five had >50% reduction in their seizures. The remaining two patients discontinued LEV because of adverse effects. LEV monotherapy can be effective and well tolerated in adults with new onset seizures. A prospective, large, double-blind monotherapy study for newly diagnosed patients is needed to confirm this finding.

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Seizure 2003 Apr;12(3):150-3
Levetiracetam monotherapy for primary generalised epilepsy.
Cohen J.
Beth Israel-Singer Division, 170 East End Avenue at 87th Street, New York, NY 10128, USA. jcohen@ehpnet.org

PURPOSE: To evaluate the efficacy of levetiracetam in cases of refractory primary generalised epilepsy. METHODS: Three patients with refractory primary generalised epilepsy were treated with levetiracetam monotherapy; one with absence seizures, myoclonic jerks and generalised tonic-clonic (GTC) seizures one with myoclonic jerks and GTC seizures, and one with only GTC seizures. All three patients had generalised spike wave on the EEG and had failed at least three antiepileptic drugs (AEDs) before trying levetiracetam. RESULTS: All three patients tolerated levetiracetam well and became seizure free for at least 6 months. Therapeutic doses of levetiracetam ranged from 1250 to 3000 mg/day. CONCLUSION: Levetiracetam, a new AED with a novel mechanism(s) of action, should be considered for patients with refractory primary generalised epilepsy.

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Seizure 2003 Apr;12(3):141-9
An open-label study of levetiracetam at individualised doses between 1000 and 3000 mg day(-1) in adult patients with refractory epilepsy.
Abou-Khalil B, Hemdal P, Privitera MD.
Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37212, USA. abou-khalil@vanderbilt.edu

BACKGROUND: The novel antiepileptic drug (AED) levetiracetam (LEV, Keppra) is indicated as adjunctive therapy for partial epilepsy. The primary aim of this study was to measure the safety and tolerability of LEV individualised dosing in a heterogeneous refractory epilepsy population.METHODS: LEV was evaluated in a 10- to 16-week open-label, multicentre study in adult patients with epilepsy refractory to previous treatment with at least two AEDs. Individualised LEV doses up to 3000 mg x day(-1) were determined in an initial up-titration phase, and optimal doses were administered as adjunctive treatment during an 8- to 10-week evaluation period. Concomitant AEDs and their doses could not be changed during the study. Safety and tolerability were monitored by expression of adverse events as well as by retention rate. The effect of LEV on concomitant AED concentration was also studied. Efficacy was assessed using global clinical evaluation (GCE) scores, seizure frequency, and >or=50% responder rate. RESULTS: LEV therapy was initiated in 219 patients; 183 had localisation-related epilepsy and 37 had generalised epilepsy. In one patient, epileptic syndrome was defined as both localisation-related and generalised. About 81.7% (179/219) continued and completed treatment throughout the study, and 79% (172/219) chose to continue LEV in a follow-up study. The most common adverse events were asthenia, dizziness, and somnolence. Most adverse events occurred during up-titration. LEV treatment did not alter the concentration of concomitant AEDs. LEV improved GCE scores in 79.5% (152/191) of patients. LEV reduced the median total seizure frequency of all patients from a median of 2.25 seizures per week at baseline (n=219) to 1.10 seizures per week during the evaluation period (n=191 patients with at least one seizure count during evaluation). The >or=50% responder rate was 48.2% for all seizure types, 49.4% for partial-onset, and 51.4% for generalised-onset seizures. Throughout the evaluation period (i.e. from the start of the evaluation period until completion or early discontinuation), 26/191 (13.6%) had a 100% reduction in total seizure frequency, while in a follow-up study, 10.5% (18/172) were seizure-free for at least 6 months and 6.4% (11/172) were seizure-free for at least 1 year. CONCLUSION: LEV was well tolerated, as evidenced by limited adverse event reporting and the high retention rate, and appeared effective in both generalised and partial epilepsy.

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Seizure 2003 Apr;12(3):136-40
Clinical experience of marketed Levetiracetam in an epilepsy clinic-a one year follow up study.
Betts T, Yarrow H, Greenhill L, Barrett M.
Birmingham University Seizure Clinic, Queen Elizabeth Psychiatric Hospital, Birmingham, B15 2QZ, UK. t.a.betts@bham.ac.uk

Levetiracetam is a new anti-convulsant with impressive pivotal trial credentials. We examined its effectiveness in refractory clinic patients with epilepsy with a year's follow up. Six months after initiation 32% of the patients were seizure free, and 26% at one year.By the end of the 12 months follow up 77% of patients were still taking the drug, having gained benefit from it: 23% had dropped out due to intolerable side effects, seizure increase or lack of efficacy. There is evidence that the drug is broad spectrum and as effective in primary generalised epilepsy as in partial onset epilepsy. Our audit of its use and effectiveness has led us to position it as our first choice add-on drug if the initial monotherapy drug fails.

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J Child Neurol 2003 Feb;18(2):109-12
Use of methylphenidate for attention-deficit hyperactivity disorder in patients with epilepsy or electroencephalographic abnormalities.
Gucuyener K, Erdemoglu AK, Senol S, Serdaroglu A, Soysal S, Kockar AI.
Department of Pediatric Neurology, Faculty of Medicine, Gazi University, Ankara, Turkey.

Methylphenidate is commonly believed to lower seizure threshold. The safe use of methylphenidate has not been clarified in patients with attention-deficit hyperactivity disorder (ADHD) and concomitant active seizure or electroencephalographic (EEG) abnormalities. Patients with ADHD and active seizures (n = 57) and patients with ADHD and EEG abnormalities (n = 62), 6 to 16 years of age, were included in the study. The safety and efficacy of treatment with antiepilepsy drugs combined with methylphenidate were determined by assessing seizure frequency, changes in ADHD symptoms, the Conners' Rating Scales, EEG differences, and side effects. The Conners' Rating Scales, performed by parents and teachers, and mean total ADHD symptom scores at the beginning of the study and at the end were significantly different (P = .05 for the Conners' Rating Scales and P = .001 for ADHD symptom scores). Methylphenidate had a beneficial effect on EEG. Seizure frequency did not change from baseline. The side effects of methylphenidate were mild and transient Methylphenidate is safe and effective in children with ADHD and concomitant active seizures or EEG abnormalities.

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J Assoc Physicians India 2003 Jan;51:43-4
Prophylactic use of clobazam in hot water epilepsy.
Dhanaraj M, Jayavelu A.
Department of Neurology, Government Stanley Medical College and Hospital, Chennai-600 001.

OBJECTIVE: To assess the efficacy of intermittent administration of clobazam to prevent hot water epilepsy. MATERIAL AND METHODS: Ten adults with 1:1 ratio of hot water epilepsy were administered 10 mg of clobazam about one and half hour before each hot water head bath. They were followed up for nine months. RESULTS: Nine out of 10 patients did not develop recurrence of seizure following regular hot water head bath during nine month follow up period. One continued to get mild giddiness. The adverse effects observed were sleepiness in two and fall in memory in one on the day of drug intake. CONCLUSION: Intermittent oral administration of clobazam before hot water bath alone is effective in preventing hot water epilepsy with 1:1 ratio.

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Med Arh 2003;57(1):49-51
[A modified approach to the diagnosis and therapy of epileptic seizures in the third stage of life]
[Article in Serbo-Croatian (Roman)]
Gavranovic M, Delilovic J, Kurtovic A, Alibegovic S, Rajic Z, Ajanovic Z.
Neuroloska klinika KCU Sarajevo.

Incidence of seizures in the elderly is nowadays greater than the one characteristic for children up to 10 years of age. Epileptic seizures are the third most common serious neurological disorder in this age group, after stroke and dementia. Optimal care for those patients, regarding to the seizures, demands some modification in diagnostic and treatment approach. Aim of this report was to point out problems in diagnostics, treatment and most common mistakes in practice. Fifty one patients were assessed, aged 65-83 years, (30 female and 21 male), with diagnosis of epilepsy and established antiepileptic treatment. All patients were re-examined, and following procedures were utilised: auto and heteroanamnesis (especially data provided by eyewitnesses), clinical examination, biochemical status, complete cardiological examination, EEG registration, serum concentrations of antiepileptic drugs, CT and MRI scan. Out of 51 patients 11 were misdiagnosed (syncope, provoked seizures, TIA). The most common form of seizures were partial seizures with or without secondary generalization (31 cases). Etiologic factors: stroke (25 cases), arteriosclerosis (7 cases), tumours (3 cases), trauma (2 cases), unknown (3 cases) cardiovascular diseases (29 casec) diabetes mellitus (20 cases), respiratory disturbance (12 cases) renal disturbances (8 cases). Treatment: Only 30 patients had monotherapy from the beginning, with either carbamazepine or valproate. Rest were treated from the beginning with 2 antiepileptic drugs (phenobarbital + carbamazepine or pheytoin + phenobarbital). Adverse effects were recorded in 21 patients. I. It is crucial to distingiush unprovoked and provoked seizures during diagnostic procedures, as well as epileptic and non-epileptic attacks; 2. Principle of monotherapy is conditio sine qua non, and in treatment attention should be paid to co-morbidity, multitherapy, drug interactions, intoxication, diminished detoxication and elimination of drugs, as well as increased susceptibility for antiepiletic drugs and other medicaments.

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J Neurosurg 2003 Apr;98(4):751-63
Long-term seizure outcomes following amygdalohippocampectomy.
Wieser HG, Ortega M, Friedman A, Yonekawa Y.
Department of Neurology, University Hospital Zurich, Switzerland. hgwepi@neurol.unizh.ch

OBJECT: Analyses of the results of surgery for epilepsy are hindered by inconsistent classifications of seizure outcome, small numbers of patients, and short postoperative follow-up periods. The authors conducted a retrospective study with a reassessment of the long-term seizure outcomes in patients who underwent selective amygdalohippocampectomy (SelAH) for pharmacotherapy-resistant mesial temporal lobe epilepsy (MTLE) at the Zurich University Hospital from 1975 to 1999. METHODS: Year-by-year data and the last available data on seizure outcomes were retrospectively assessed for 369 consecutively surgically treated patients who had participated in a follow-up period longer than 1 year as of 1999 and whose outcomes were classified according to the Engel scale and the proposed new International League Against Epilepsy (ILAE) scale. Patients were grouped into nonlesional and lesional MTLE groups depending on whether they harbored a gross anatomical lesion that caused the MTLE. Differentiation was made between curative and palliative operations. Complications related to surgery are reported for 453 patients who underwent SelAH and participated in more than 3 months of follow-up review. The last available outcome data according to the Engel scale were found to be generally similar to those of the new ILAE classification, with 66.9% of patients free from disabling seizures (Engel Class I) compared with 57.1% who were completely seizure and aura free (ILAE Class 1). The last available data on seizure outcome were not significantly different between patients in the lesional and nonlesional MTLE groups. In the lesional group, seizure outcomes were significantly better when patients underwent surgery early in the course of the disease. Overall, 70% of the patients received reductions in their antiepileptic drug treatment at the time of the last available follow-up review. Complications related to the surgical procedures were rare. CONCLUSIONS: The authors conclude that SelAH is a safe and effective surgical procedure for MTLE.

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Mayo Clin Proc 2003 Apr;78(4):508-18
New management strategies in the treatment of status epilepticus.
Manno EM.
Department of Neurology, Mayo Clinic, Rochester, Minn 55905, USA.

Status epilepticus is a neurologic emergency associated with high mortality and long-term disability. Recent advances in our understanding of the pathophysiological mechanisms involved in the initiation and perpetuation of seizure activity have revealed that status epilepticus is a dynamic and evolving process. Alterations at the cellular level parallel physiological, physical, and electrical changes at the bedside. Loss of cerebral autoregulation and neuronal damage begin after 30 minutes of continuous seizure activity. This understanding has led to changes in treatments of status epilepticus, which must be multidisciplinary and occur simultaneously in many different areas. The goals of pharmacological therapy are to terminate seizures early and prevent recurrence. Two recent large clinical studies have shown the benefit of early administration of benzodiazepines to control status epilepticus. Pharmacological algorithms designed to focus medical management have trended toward earlier and more aggressive treatment. The hope is that continued exploration into the basic mechanisms involved in status epilepticus and future controlled clinical trials defining optimal medical management will produce further advances.

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Prescrire Int 2003 Apr;12(64):53-4
Levetiracetam: new preparation. For some patients with refractory partial epilepsy.

According to four placebo-controlled trials, levetiracetam (a piracetam derivative) reduces the frequency of seizures in 20 to 30% of patients with partial epilepsy when added to an existing but inadequate treatment. An indirect comparison suggests that levetiracetam is as effective as other second-line antiepileptics used for combination therapy.

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Indian J Pediatr 2003 Feb;70(2):147-51
Management of childhood epilepsy.
Kalra V.
Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India. vkalra@hotmail.com

Epilepsy is a common childhood neurological morbidity needs careful evaluation, relevant investigations and precise therapy with appropriate antiepileptic drugs for optimal duration. Majority of childhood epilepsy remits with antiepileptic drugs and should be managed in the community. Practising pediatricians must counsel the family for possible etiology of epilepsy, compliance during treatment and possible outcome. It is important to distinguish pseudo seizures and nonepileptic events from true epilepsy, as this would reduce the burden of unwanted medication. It is also equally important to enable ourselves to recognize early predictors of intractability and refer them to appropriate referral units. Epilepsy is a social and an economic burden for the family. Preventive strategies by improved perinatal care, prevention and managemnt of neuro infections and infestations which will mitigate epilepsy burden in the community are essential. In this context it is important to familarize appropriate and relevant use of investigations. Inappropriate antiepileptic drug usage is common in the community and drug therapy should be rationalized. Epilepsy management requires a close interaction between the patient, family and the treating physician and a concerted effort is essential.

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Pediatr Neurol 2003 Jan;28(1):48-52
Reduction of seizures with low-dose clonazepam in children with epilepsy.
Dahlin MG, Amark PE, Nergardh AR.
Department of Pediatrics, Astrid Lindgren Children's Hospital, Stockholm, Sweden.

The acute effects of low-dose clonazepam on seizure frequency in children with epilepsy was evaluated. In an open study, 19 children with epilepsy (15 generalized and four partial) were examined during hospitalization with recordings of seizures by trained personnel. Seizures were counted during two 24-hour periods: before and after a single intramuscular injection of clonazepam 0.01-0.04 mg/kg body weight. Plasma concentrations of clonazepam were determined. The median number of seizures in all children on control days was 22 (range = 1-180) and, on days after low-dose clonazepam, the median was 6 (range = 0-73). The relative changes demonstrated a median of -70% (range from -100% to + 43%). A significant reduction of seizures (P = 0.0031) at median maximal plasma levels of clonazepam of 23 nmol/L (range = 11-41 nmol/L) was found. Thus in this study of the acute effects of a low-dose level of clonazepam on seizure frequency a significant reduction was found at plasma levels below those usually recommended. Inhibition of seizure activity seems to be achieved already at low plasma levels of clonazepam. These results suggest to start treatment at low doses of clonazepam and evaluate the individual effect carefully during dose escalation aiming at lowest possible dose with therapeutic effect.

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Pediatr Neurol 2003 Jan;28(1):37-41
Oxcarbazepine in the treatment of childhood epilepsy.
Serdaroglu G, Kurul S, Tutuncuoglu S, Dirik E, Sarioglu B.
Department of Pediatrics, Division of Child Neurology, Ege University Faculty of Medicine, Izmir, Turkey.

In this study, oxcarbazepine was began as monotherapy to evaluate the efficacy and safety of the drug. Forty-two patients (19 females, 23 males) with partial or generalized epilepsy more than 4 years of age were included (mean age, 11.9 +/- 3.4 years). The mean age at epilepsy onset 8.9 +/- 4 years. Complete blood count, liver function tests, electrolytes, lipid levels, electrocardiography, electroencephalography, and magnetic resonance imaging were performed in all patients. Oxcarbazepine dose was begun at 10 mg/kg/day twice daily and increased to 30 mg/kg/day at the end of the second week. Patients with inadequate seizure control even with the dose of 45 mg/kg/day or intolerable side effects were excluded. Intolerable headache and leukopenia led to discontinuation of the drug in two patients. At the sixth month, 35 of the patients (87.5%) were seizure free (91.7% of the generalized epilepsy patients and 81.2% of the partial epilepsy patients). The most frequent tolerable side effect was drowsiness in 12 patients. As a result, we found oxcarbazepine safe and effective in children with either generalized or partial epilepsy.

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Pediatr Neurol 2003 Jan;28(1):16-9
Nitrazepam for the treatment of Lennox-Gastaut syndrome.
Hosain SA, Green NS, Solomon GE, Chutorian A.
Weill Medical College of Cornell University, New York, New York, USA.

Lennox-Gastaut syndrome is a severe childhood epileptic syndrome with encephalopathy and multiple seizure types, which are often intractable to treatment. Most of these children will ultimately become mentally retarded and dependent on others for their daily care. Antiepileptic drugs are the mainstay of treatment, however, no particular drug is entirely effective. Apart from the use of antiepileptic drugs, nonpharmacologic treatments are also considered (i.e., callosotomy, ketogenic diet, and vagus nerve stimulation), which have proven to be partially effective. We prospectively studied 14 children (11 months-8 years of age) with medication-resistant Lennox-Gastaut syndrome, being treated with nitrazepam (open-label compassionate protocol). We compared the 1-month baseline seizure frequency with the median seizure rate reduction during the first 12 months of treatment with nitrazepam. The median seizure rate reduction during the first 12 months of treatment with nitrazepam was 41% (P = 0.001), with more than 50% seizure reduction in 60% of patients. Two patients became seizure free, five patients demonstrated at least 50% reduction in seizure rates, six patients had at least 25% seizure rate reduction, and one patient did not respond. No patient had any serious adverse effects. Side effects included sedation in six children (40%) and drooling in nine patients (60%).

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Seizure 2003 Apr;12(3):167-70
Epilepsy surgery, delays and referral patterns—are all your epilepsy patients controlled?
Benbadis SR, Heriaud L, Tatum WO, Vale FL.
Departments of Neurology & Neurosurgery, University of South Florida and Tampa General Hospital, Tampa, FL 33606, USA. sbenbadi@hsc.usf.edu

RATIONALE: Epilepsy surgery is a standard of care in the treatment of medically intractable epilepsy, but is underutilised. We describe the results of epilepsy surgery and the referral patterns at a referral epilepsy programme. METHODS: We reviewed the outcome of epilepsy surgery performed at the University of South Florida and Tampa General Hospital epilepsy programme for the years 2000 and 2001. The typical presurgical evaluation included clinical evaluation, EEG-video monitoring, MRI with dedicated epilepsy protocol, PET, SPECT, neuropsychological testing and Wada testing. We used the Engel outcome classification, and focused on the referral information to determine how and when in the course of their illness patients arrive at a referral epilepsy centre. RESULTS: In the 2-year period (2000-2001), a total of 36 epilepsy surgeries were performed. Twenty-nine temporal lobectomies, six extratemporal resections and one corpus callosotomy. Ages varied from 17 to 65 years. Overall results were: 30 (83%) seizure-free [class I], 5 (17%) rare seizures or almost seizure-free [class II] and 1 no improvement. Of the 29 temporal lobectomies, 27 (93%) are completely seizure-free [class I] and 2 (7%) are >90% improved [class II]. Duration of seizures before being seen at the epilepsy centre averaged 18 years (range 2-58 years). Twenty-two (61%) were sent by their neurologists, while 14 (39%) came self-referred without having discussed surgery with their neurologists. Five (14%) were specifically advised by their neurologist to not consider surgery. Two had participated in clinical trials of antiepileptic drugs (AEDs) before being seen at the epilepsy centre. CONCLUSIONS: Epilepsy surgery has high efficacy and very low morbidity. Yet, there continues to be a long delay in the referral of patients to the epilepsy centre, suggesting that surgery for epilepsy is underutilised.

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Pediatr Neurosurg 2003 Apr;38(4):195-205
Pediatric temporal lobectomy for epilepsy.
Sinclair DB, Aronyk K, Snyder T, McKean J, Wheatley M, Bhargava R, Hoskinson M, Hao C, Colmers W.
Comprehensive Epilepsy Program, University of Alberta Hospitals, Edmonton, Alta, Canada. bsinclair@cha.ab.ca

BACKGROUND: Temporal lobectomy in adults is an accepted form of treatment for patients with intractable complex partial seizures. There have been few long-term studies of children undergoing temporal lobectomy for epilepsy. METHODS: We reviewed the pediatric cases of temporal lobectomy for intractable epilepsy performed by the Comprehensive Epilepsy Program at the University of Alberta Hospitals between 1988 and 2000. All patients had preoperative and postoperative clinical evaluations, seizure charts, drug levels, EEG, CT/MRI, long-term video EEG monitoring and neuropsychological testing. The patients were reassessed at 6 weeks, 6 months and 1 year postoperatively, then yearly. The duration of follow up was 1-10 years (mean 5 years). RESULTS: Forty-two patients were studied (25 males and 17 females). Age at surgery ranged from 18 months to 16 years. The interictal EEG was abnormal in 38 of the 42 patients. Twenty-two patients had focal epileptic discharge and 1 had generalized epileptic discharge. Focal slowing was seen in 9 patients and diffuse slowing in 5 patients. CT scan was abnormal in 17 of 39 patients and normal in 22 of 39. MRI was abnormal in 34 of 42 patients and normal in 8 of 42. Pathology included brain tumors in 14 patients, mesial temporal sclerosis in 8, focal cortical dysplasia in 4, tuberous sclerosis in 4, dual pathology in 4, porencephalic cyst in 1 and normal pathology or gliosis in 6. Thirty-three of 42 patients (78%) were seizure-free following surgery and an additional 5 (12%) had a decrease in seizure frequency. Three patients had complications, but there were no deaths. CONCLUSION: Temporal lobectomy is a safe and effective treatment for children with intractable complex partial seizures. Seventy-eight percent of patients are seizure-free following the surgery and there are few complications. MRI is superior to CT scan for detection of temporal lobe pathology yet failed to detect abnormalities in some patients. The most common pathologies found were brain tumors, mesial temporal sclerosis and developmental lesions. In addition to seizure control, many patients experienced improvement in cognitive and psychosocial function following surgery. Copyright 2003 S. Karger AG, Basel

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Am J Manag Care 2003 Mar;9(3):253-76; quiz 277-9
Review of the newer antiepileptic drugs.
Tidwell A, Swims M.
Regional Medical Center, Memphis, Tenn, USA.

This review article discusses the newer anti-epileptic drugs gabapentin, lamotrigine, tiagabine, topiramate, levetiracetam, oxcarbazepine, and zonisamide. Emphasis is given to FDA-approved indications and place in therapy. The mechanisms of action and pharmacokinetics of each drug is provided and the most common adverse effects are reviewed. Clinical studies leading to FDA approval are discussed. Practical points on proper dosing and monitoring are stressed, and drug interactions are also included.

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Mayo Clin Proc 2003 Mar;78(3):371-8
Therapeutics in pediatric epilepsy, Part 2: Epilepsy surgery and vagus nerve stimulation.
Buchhalter JR, Jarrar RG.
Division of Child and Adolescent Neurology, Mayo Clinic, Rochester, Minn 55905, USA.

When antiepileptic drugs fail to relieve seizures adequately in children and adolescents, more invasive therapies such as epilepsy surgery and an implanted device to stimulate the vagus nerve should be considered. Temporal lobectomy is an effective treatment of complex partial and secondarily generalized tonic-clonic seizures arising in the mesial structures or lateral temporal neocortex. Excellent outcomes (seizure free or rare, nondisabling seizures) are achieved in at least 70% of children. The most common adverse effect is a superior quadrant field cut that is usually asymptomatic. Transient and more long-lasting language difficulties have been reported when the surgery involves the dominant temporal lobe. The excellent outcome rate for extratemporal surgery ranges from approximately 20% to 80%, with better results seen in patients with an identifiable lesion. Potential morbidity is related to the region of resected neocortex. Corpus callosotomy is an excellent procedure for palliation but is not a cure for seizures that cause falls, with substantial improvement seen in more than 80% of patients. Potential adverse effects include more intense focal seizures and dysphasia, depending on the developmental level of the individual. Hemispherectomy provides seizure relief in 60% to 80% of patients with hemispherical pathologies such as Sturge-Weber or Rasmussen syndromes. Operative mortality has been reported in the range of 0% to 6%; other morbidities include infection and hydrocephalus. Stimulation of the vagus nerve has reduced partial seizures by 50% or more in approximately one third of patients. No adverse cognitive or systemic effects are associated with use of the implanted vagus nerve stimulator.

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Mayo Clin Proc 2003 Mar;78(3):359-70
Therapeutics in pediatric epilepsy, Part 1: The new antiepileptic drugs and the ketogenic diet.
Jarrar RG, Buchhalter JR.
Department of Neurology, Mayo Clinic, Rochester, Minn 55905, USA.

Epilepsy is one of the most common and challenging neurologic disorders affecting children. Although various modalities exist to treat pediatric-onset seizures, seizures in 25% of children who are diagnosed as having epilepsy remain refractory to available therapies. Of the 8 new antiepileptic drugs (AEDs) (felbamate, gabapentin, lamotrigine, topiramate, tiagabine, levetiracetam, oxcarbazepine, and zonisamide), all but 2 (zonisamide and levetiracetam) have received Food and Drug Administration approval for adjunctive use in the pediatric population. However, most of the new AEDs used in adults have also been used in children, beyond the AEDs' approved indications. The ultimate goal of patient management is to choose the therapeutic option that provides the best chance of improving the patient's quality of life. Issues that relate to treatment choice include the likelihood of seizure recurrence, type and severity of seizures, available AED efficacies and toxicities, need for hematologic monitoring, ease of dosing, underlying medical conditions, medication interactions, urgency of initiating therapy, and cost. In this review, we discuss these issues for each of the 8 new AEDs; we also discuss the ketogenic diet and briefly review the older AEDs. Knowledge of the available AEDs will enable the practitioner to choose the best drug or drugs for individual patients.

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Acta Neurol Scand 2003 Mar;107(3):165-75
Topiramate, carbamazepine and valproate monotherapy: double-blind comparison in newly
diagnosed epilepsy.
Privitera MD, Brodie MJ, Mattson RH, Chadwick DW, Neto W, Wang S; EPMN 105 Study Group.
Department of Neurology, University of Cincinnati Medical Center, Cincinnati, OH 45267, USA. michael.privitera@uc.edu

OBJECTIVES: To compare topiramate (TPM) with investigator's choice of carbamazepine (CBZ) or valproate (VPA) for initial treatment in patients with newly diagnosed epilepsy. MATERIAL AND METHODS: In patients with epilepsy diagnosed within previous 3 months, investigators selected CBZ (600 mg/day) or VPA (1250 mg/day) as preferred therapy based on the patient's clinical presentation. Based on investigators' treatment choice, patients (n=613) were assigned to the CBZ or VPA treatment branch. Within each branch, patients were randomized to double-blind treatment with the traditional antiepileptic drugs (CBZ or VPA), TPM 100 mg/day, or TPM 200 mg/day. Patients continued double-blind treatment until exiting the study or until 6 months after last patient randomized. RESULTS: No statistically significant differences between fixed doses of TPM and CBZ or VPA were observed in efficacy measures: time to exit, time to first seizure, and the proportion of patients seizure-free during the last 6 months of treatment. TPM 100 mg/day was associated with the fewest discontinuations due to adverse events. CONCLUSION: In patients with newly diagnosed epilepsy, an initial target dose of TPM 100 mg/day is at least as effective as therapeutic doses of CBZ and VPA.

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Zh Nevrol Psikhiatr Im S S Korsakova 2003;103(1):30-4
[Experience with lamictal in the treatment of outpatients with resistant epilepsy]
[Article in Russian]
Perunova NIu, Sorokina EV, Shershever AS.

The article summarizes the results of lamictal treatment in 93 patients with resistant epilepsy. Lamictal was used in a dose of 50-200 mg a day as an auxiliary drug in the treatment with other anticonvulsants. Its therapeutic efficacy was analyzed in relation to the form of epilepsy, the type of seizures, dosage of lamictal duration of therapy, and as patients' sex, age, and social activity. In the total group, 17.2% of the patients have remissions, in 48.4% the frequency of seizures was reduced (> 50%) and 34.4% of the patients exhibited a less pronounced effect (< 50%). When combining lamictal and valproates, the best results were obtained in generalized seizures, especially in idiopathic generalized epilepsy, and in young and middle-age female patients with active social functioning.

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Mayo Clin Proc 2003 Feb;78(2):238-48
Neurostimulation therapy for epilepsy: current modalities and future directions.
Cohen-Gadol AA, Britton JW, Wetjen NM, Marsh WR, Meyer FB, Raffel C.
Department of Neurologic Surgery, Mayo Clinic, Rochester, Minn 55905, USA.

Neurostimulation is a recent development in the treatment of epilepsy. Vagus nerve stimulation (VNS), the only approved neurostimulation therapy for epilepsy to date, has proved to be a viable adjunctive treatment option. The exact mechanism of action of VNS is not fully understood. In 2 randomized double-blind trials, seizure frequency declined approximately 30% after 3 months of treatment. Long-term follow-up studies suggest that response improves over time, with approximately 35% of patients experiencing a 50% reduction and 20% experiencing a 75% reduction in seizure frequency after 18 months of treatment. Unfortunately, the number of patients rendered medication-free and seizure-free with VNS is low. Vagus nerve stimulation is best viewed as an option for patients who are not surgical candidates or who hesitate to take the risk of surgery yet continue to have seizures despite maximal medical therapy. Stimulation of other regions of the central nervous system for treating epilepsy, including the anterior and centromedian nuclei of the thalamus, the hippocampus, the subthalamic nucleus, and the cerebral neocortex, is currently under investigation. We review the history, proposed mechanisms of action, clinical trials, adverse effects, and future direction of VNS and other modalities of neurostimulation therapy for epilepsy.

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Acta Neurol Scand 2003 Feb;107(2):117-21
VNS in patients with previous unsuccessful resective epilepsy surgery: antiepileptic and
psychotropic effects.
Koutroumanidis M, Binnie CD, Hennessy MJ, Alarcon G, Elwes RD, Toone BK, Chandler C, Selway R, Polkey CE, O'Connor SA.
Department of Neurology, King's College Hospital, London, UK. m.koutroumanidis@iop.kcl.ac.uk

OBJECTIVES: To assess the efficacy of vagus nerve stimulation (VNS) in patients with medically and surgically intractable complex partial seizures (CPS). PATIENTS AND METHODS: Sixteen patients with previous temporal [15] and frontal [one] resections were treated with VNS between 1994 and 1999 at King's College Hospital, London, UK. Post-operative video-electroencephalogram telemetry had shown that CPS started from the operated side in 12 patients, contralaterally in three and bilaterally independently in one. RESULTS: Three patients (18.75%) had 50% or more reduction in seizure frequency, but one showed severe worsening of epilepsy, which remitted upon VNS discontinuation. The antiepileptic effect of VNS was not different with respect to the type of operation (anterior temporal lobectomy vs amygdalohippocampectomy), the side of operation, or the side of seizure onset. We observed psychotropic effects in two patients with post-ictal psychosis, in two others with depression, and in a child with severe behavioral disorder. CONCLUSIONS: VNS may have a rather limited antiepileptic role to play in patients with persistent seizures following epilepsy surgery, but may independently possess useful antipsychotic and mood-stabilizing properties.

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Neuropediatrics 2003 Apr;34(2):105-9
Treatment with sulthiame (ospolot(r)) in benign partial epilepsy of childhood and related syndromes: an open clinical and EEG study.
Engler F, Maeder-Ingvar M, Roulet E, Deonna T.
Neuropediatric Unit, University Hospital, Lausanne, Switzerland.

The effect of Sulthiame on the EEG and on clinical seizures was evaluated in an open uncontrolled study in 25 children with focal sharp waves on the EEG (FSW). 16 children had typical benign partial epilepsy with rolandic spikes (BPERS), 5 children with atypical forms and 4 children with no clinical seizures but cognitive disturbances possibly related to the FSW. The effect of Sulthiame in suppressing the EEG discharges was evaluated on the waking and sleep EEG before introduction of the drug, and at 3 - 6 months, 6 to 12 months and beyond while under therapy. The children were followed clinically for one to several years. The EEG discharges disappeared or decreased under Sulthiame in 13/21 cases at 3 to 6 months but reappeared in 3/13 cases beyond this period. No case had a worsening of the EEG or of clinical seizures under Sulthiame, and no cognitive stagnation was noted. Our data confirm the good tolerance and positive effects on the EEG and justify systematic trials of this drug in the partial "functional" epilepsies, especially when negative cognitive consequences of the epileptic discharges are suspected.

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Expert Opin Pharmacother 2003 Feb;4(2):243-51
Review of lamotrigine and its clinical applications in epilepsy.
Choi H, Morrell MJ.
Department of Neurology, Columbia University, New York, USA. HC323@columbia.edu

Lamotrigine is an anti-epileptic agent with broad efficacy. Lamotrigine works at voltage-sensitive sodium channels, thereby stabilising the neuronal membrane and inhibiting the release of excitatory neurotransmitters such as glutamate and aspartate. Early preclinical animal studies indicate its broad-spectrum efficacy, which was later confirmed in clinical trials. Multiple randomised, placebo-controlled and comparative trials demonstrate its efficacy against partial and secondarily generalised seizures. Open-label trials show its efficacy against generalised seizures, especially absence seizures of childhood absence epilepsy and generalised seizures of juvenile myoclonic epilepsy. Lamotrigine has a wide clinical dose range and possesses favourable pharmacokinetic properties. It has a good tolerability and safety profile, which enhance compliance. Its small risk of serious skin rash should be weighed against its potential benefits when choosing lamotrigine on an individual basis. Lamotrigine is an excellent therapeutic option in epilepsy.

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Neurology 2003 Jan 28;60(2):332-4
The use of topiramate in refractory status epilepticus.
Towne AR, Garnett LK, Waterhouse EJ, Morton LD, DeLorenzo RJ.
Virginia Commonwealth University, Richmond, VA, 23298-0599, USA. atowne@hsc.vcu.edu.

In cases of refractory status epilepticus (RSE) unresponsive to sequential trials of multiple agents, a suspension of topiramate administered via nasogastric tube was effective in aborting RSE, including one patient in a prolonged pentobarbital coma. Effective dosages ranged from 300 to 1,600 mg/d. Except for lethargy, no adverse events were reported.

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Cochrane Database Syst Rev 2003;(1):CD001904
Carbamazepine versus phenobarbitone monotherapy for epilepsy.
Tudur SM, Marson AG, Williamson PR.
Division of Statistics and Operational Research, Department of Mathematical Sciences, University of Liverpool, Mathematics & Oceanography Building, Peach Street, Liverpool, UK, L69 7ZL. cat1@liverpool.ac.uk

BACKGROUND: In developing countries, phenobarbitone is commonly used but its use in Europe and the USA has decreased due to concerns over adverse effects. Carbamazepine is recommended as the drug of choice for partial onset seizures, and there is concern that it may worsen some generalized onset seizure types. We report a review using individual patient data in which carbamazepine and phenobarbitone are compared. OBJECTIVES: To review the effects of carbamazepine compared to phenobarbitone monotherapy for people with partial onset seizures or generalized onset tonic-clonic seizures. SEARCH STRATEGY: The Cochrane Controlled trials register (Cochrane Library Issue 2, 2002); MEDLINE; EMBASE; handsearching; contacting experts and original trial investigators; contacting manufacturers of carbamazepine. SELECTION CRITERIA: Randomized or quasi-randomized, blinded or unblinded controlled trials in children or adults with partial onset seizures or generalized onset tonic-clonic seizures. DATA COLLECTION AND ANALYSIS: Outcome measures were (i) time to withdrawal of allocated treatment, (ii) time to 12 month remission, and (iii) time to first seizure. Data were analysed using a stratified logrank analysis with results expressed as hazard ratios (HR) and 95% confidence intervals (CIs), where a HR>1 indicates an event is more likely on phenobarbitone. A test for interaction between treatment and seizure type (partial versus generalized onset) was also undertaken. MAIN RESULTS: Data are available for 684 participants from four trials, representing 59% of the participants recruited into the nine trials that met our inclusion criteria. The main overall results (HR 95% CI) adjusted for seizure type were, (i) time to withdrawal 1.63(1.23 to 2.15), (ii) time to 12 month remission 0.87(0.65 to 1.17), (iii) time to first seizure 0.85(0.68 to 1.05). The review suggests that time to withdrawal is significantly improved with carbamazepine compared to phenobarbitone. No overall difference between drugs is identified for the outcomes 'time to 12 month remission' and 'time to first seizure'. Statistical heterogeneity was not encountered. An interaction between treatment and seizure type, confirmed statistically, was identified for time to first seizure, where phenobarbitone was favoured for partial onset seizures and carbamazepine for generalized onset tonic-clonic seizures. REVIEWER'S CONCLUSIONS: We found no overall difference between carbamazepine and phenobarbitone for time to 12 month remission or time to first seizure, however, subgroup analyses for time to first seizure suggest an advantage with phenobarbitone for partial onset seizures and a clinical advantage with carbamazepine for generalized onset tonic-clonic seizures. Phenobarbitone is significantly more likely to be withdrawn, indicating that it is less well tolerated than carbamazepine.

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J Neurol Neurosurg Psychiatry 2003 Mar;74(3):339-43
A controlled study comparing visual function in patients treated with vigabatrin and tiagabine.
Krauss GL, Johnson MA, Sheth S, Miller NR.
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, USA. gkrauss@jhmi.edu

OBJECTIVE: Vigabatrin treatment is frequently associated with irreversible retinal injury and produces retinal electrophysiological changes in nearly all patients. Concern has been raised that tiagabine and other antiepilepsy drugs (AEDs) that increase brain gamma-aminobutyric acid (GABA) might produce similar electrophysiological and clinical changes in visual function. The study compared visual function between groups of patients with epilepsy treated long term with tiagabine, vigabatrin, and patients treated with other AEDs. METHODS: A cross sectional study comparing visual acuity, colour vision, static and kinetic perimetry, and electroretinograms between groups of patients treated with tiagabine, vigabatrin, and other AEDs (control patients). Patients were adults receiving stable AED treatment for >6 months. RESULTS: Vigabatrin treated patients had marked visual field constrictions in kinetic perimetry (mean radius 39.6 degrees OD, 40.5 degrees OS), while tiagabine patients had normal findings (mean 61 degrees OD, 62 degrees OS) (differences OD and OS, p=0.001), which were similar to epilepsy control patients (mean 60 degrees OD, 61 degrees OS). Vigabatrin patients had abnormal electroretinographic photopic B wave, oscillatory, and flicker responses, which correlated with visual field constrictions. These electroretinographic responses were normal for tiagabine patients and control patients. Patients were treated with vigabatrin for a median of 46 months compared with 29 months for tiagabine. Patients taking other AEDs that may change brain GABA had normal visual function. CONCLUSION: Unlike vigabatrin, tiagabine treatment is associated with normal electroretinography and visual fields and ophthalmological function similar to epilepsy control patients. Differences between vigabatrin and other GABA modulating AEDs in retinal drug concentrations and other effects might explain why tiagabine increases in GABA reuptake do not cause retinal injury.

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Pediatr Neurol 2003 Mar;28(3):194-8
Prednisone therapy in pediatric epilepsy.
Sinclair DB.
Comprehensive Epilepsy Program, University of Alberta, Edmonton, Alberta, Canada

Steroids are often an effective treatment for the West's syndrome. There have been few reports of steroid use in children with epilepsy outside the first year of life. I report my experience with prednisone for the treatment of older children with intractable epilepsy. Twenty-eight children (17 boys, 11 girls) aged 18 months to 10 years with intractable epilepsy were studied. Prednisone 1 mg/kg/day for 12 weeks (6 weeks daily and 6 weeks alternate therapy) was prescribed in addition to their regular antiepileptic medications. The parents kept seizure diaries, and the patients were regularly assessed for seizure frequency and side effects. The follow-up period was for 1 to 5 years. Thirteen patients (46%) became seizure free on prednisone and another 18 (40%) had a significant decrease in seizure frequency. Five patients (19%) had no change in seizure frequency. The best outcomes were seen in the absence group in which six out of seven patients became seizure free and in the Lennox-Gastaut syndrome group in which seven out of 10 became seizure free. Side effects were uncommon and included weight gain in five patients and aggression in four patients. Prednisone therapy is a safe and effective adjunctive treatment for epilepsy. It should be considered as an alternative treatment for older children with intractable generalized epilepsy who have failed conventional antiepileptic therapy.

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Med Arh 2002;56(5-6):277-80
[Antiepileptic agents in the treatment of symptomatic epileptic seizures during and after
cerebrovascular insult (CVI)]
[Article in Serbo-Croatian (Roman)]
Alajbegovic A, Suljic E, Kantardzic D, Alajbegovic S, Hrnjica M, Resic H.
Neuroloska klinika Klinickog centra Univerziteta u Sarajevu.

The epileptic seizures occur as the consequence of THE cerebrovascular insult. The morphologic changes at the brain after cerebrovascular insult are responsible for its occurrence. The pathophysioloogic basis of the late epileptic manifestations (after the second week after CVI) are the epyleptic activities of the morphological brain changes which behave according to the type of the "epileptogene focus". The epileptic seizures which occur during CVI are the result of the moleculary changes which occur in ischemia as the primary, and in haemohagia as secondary ones. The aim of our paper is to see the therapeutic aspects of the early and late epileptic seizures during and after cerebrovascular insult. In the course of the retrospective processed treatment of the patients at our clinic, and in the ten years period (01.01.1989-31.12.1998), we treated 7001 patients with the various types and subtypes of CVI. The incidence of the epileptic seizure moved from 0.65% (1994) till 3.14% (1998). In our sample we had 111 patients with late epileptic seizures, and 56 patients with early epileptic seizures. The early epileptic seizures in most cases were treated by Diazemap intravenously, while in the group of the patients with late seizures, most frequently we applied Fenobarbiton, and later diazepam intravenously. After the seizures and admission at the Clinic and in the future treatment most often we recommended and gave diazemap, phenobarbiton and karabo zepine. The therapeutic effects of the applied therapy were statistically significant. It is significant that there were more patients of the applied therapy statistically significantly. It is significant that there were more patients had no later seizures or of whose the seizures were more rarely (Hi2 = 14.209, n = 2, p < 0.01). On the basis of our research we can conclude that the therapeutic principle of the symptomatic epileptic seizures during and after cerebrovascular insult is the principle of the MONOTHERAPY. On the basis of our material we came to the conclusion that kabazepin optimally antiepileptic for this group of symptomatic epileptic seizures.

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Neurol Clin 2002 Nov;20(4):1163-82
New antiepileptic drug therapies.
Bergin AM, Connolly M.
Division of Epilepsy and Clinical Neurophysiology, Children's Hospital, 300 Longwood Avenue, HU2, Boston, MA 02115, USA. ann.bergin@tch.harvard.edu

The introduction of these new antiepileptic drugs, from felbamate to levetiracetam, raised hope of control of epilepsy with fewer adverse effects and improved quality of life. Unfortunately, many patients continue to experience refractory epilepsy despite the use of these new agents, and dose-related adverse effects and idiosyncratic reactions continue to be problematic. A recent report describes six new compounds in preclinical development, and five in clinical trials [131]. As the number of available, effective, but imperfect antiepileptic drugs increases, many challenges remain. These include: choosing the drug appropriate for the epileptic syndrome, assessing accurately the range of a drug's adverse effects in an individual patient, and considering carefully the drug's interactions in combination drug therapy. In considering drug combinations, differing mechanisms of drug action and favorable pharmacodynamic interactions (an area requiring additional studies) are of importance. Clinicians caring for children who have epilepsy anticipate further advances in the pharmacogenetics and molecular pathophysiology of epilepsy, leading to individually tailored, effective, and safe therapy.

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Epileptic Disord 2002 Dec;4(4):257-60
Tolerability of tiagabine: a prospective open-label study.
Bauer J, Bergmann A, Reuber M, Stodieck SR, Genton P.
Department of Epileptology, University of Bonn, Germany. juergen.bauer@ukb.uni-bonn.de

Tiagabine was used as add-on therapy in the treatment of epilepsy with partial and/or secondarily generalised seizures to evaluate tolerability and efficacy. Five hundred and seventy-four patients (299 men and 275 women, mean age 38.1 years), with refractory partial seizures, were enrolled in this prospective, open-label study. Tiagabine was added to one (44.1%) or more (up to nine) antiepileptic drugs. The median daily dose of tiagabine was 30 mg (mean 29.1, SD 12.0). The mean duration of follow-up was 94.9 42.7 days. 12.3% of patients were completely seizure-free at the end of the observation period. Median total seizure frequency decreased from 4.5 to 2.0 seizures/4 weeks. Adverse events occurred in 78 patients (13.6%). Tiagabine proved to be a well-tolerated AED.

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Neurol Sci 2002 Oct;23(4):177-82
Continuous infusion of midazolam in the treatment of refractory generalized convulsive status epilepticus.
Ulvi H, Yoldas T, Mungen B, Yigiter R.
Department of Neurology, Firat Medical Center, Firat University, Elazig, 23119 Turkey.

We studied the efficacy and safety of midazolam given as a continuous infusion in the treatment of refractory generalized convulsive status epilepticus (RGCSE). We carried out a prospective, open study, in 19 patients (11 men) with RGCSE in the intensive care unit at Firat Medical Center in Elazig. When intravenous administration of 0.3 mg/kg diazepam (three times at 5-min intervals), 20 mg/kg phenytoin, and 20 mg/kg phenobarbital failed to bring the episode under control, patients were administered an intravenous bolus of midazolam (200 microg/kg) followed by a continuous infusion at 1 microg/kg min. The dose was increased by 1 microg/kg min every 15 min until the episode of seizure was brought under control. The time from beginning of treatment to control of seizures, infusion rate, and side-effects were monitored. The mean age of the patients was 40.4 years (range 16-87 years). The clinical etiology of RGCSE was idiopathic epilepsy (6 cases), anoxicischemic cerebral insult due to cardiac arrest (3), viral encephalitis (2), intrahemispheric hematoma due to hemorrhagic stroke (1), cerebral infarct due to ischemic stroke (1), pituitary adenoma (1), post-traumatic epilepsy (1), renal failure (1), tuberculous meningitis (1), and unknown (2). In eighteen (94.7%) patients, seizures were completely controlled in a mean time of 45 min (range, 5-120 min) at a mean infusion rate of 8 microg/kg min (range, 3-21 microg/kg min). In one patient seizures did not stop. Midazolam administration did not cause any significant change in blood pressure, heart rate, oxygen saturation, or respiratory status. The mean time to full consciousness for patients after stopping the infusion was 1.6 hours (range, 2.0-8.5 hours). The mean infusion duration of midazolam was 14.5 hours (range, 12-25 hours). Midazolam is an effective and safe drug to control RGCSE, and may represent a substantial improvement over current therapeutic approaches such as pentobarbital anesthesia.

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