Memory processes and prefrontal network dysfunction in cryptogenic epilepsy.

PURPOSE: Impaired memory performance is the most frequently reported cognitive problem in patients with chronic epilepsy. To examine memory deficits many studies have focused on the role of the mesiotemporal lobe, mostly with hippocampal abnormalities. However, the role of the prefrontal brain remains unresolved. To investigate the neuronal correlates of working memory dysfunction in patients without structural lesions, a combined study of neurocognitive assessment, hippocampal and cerebral volumetry, and functional magnetic resonance imaging of temporal and frontal memory networks was performed. METHODS: Thirty-six patients with cryptogenic localization-related epilepsy and 21 healthy controls underwent neuropsychological assessment of intelligence (IQ) and memory. On T(1) -weighted images obtained by 3-Tesla magnetic resonance imaging (MRI), volumetry of the hippocampi and the cerebrum was performed. Functional MRI (fMRI) was performed with a novel picture encoding and Sternberg paradigm that activated different memory-mediating brain regions. Functional connectivity analysis comprised cross-correlation of signal time-series of the most strongly activated regions involved in working memory function. KEY FINDINGS: Patients with epilepsy displayed lower IQ values; impaired transient aspects of information processing, as indicated by lower scores on the digit-symbol substitution test (DSST); and decreased short-term memory performance relative to healthy controls, as measured with the Wechsler Adult Intelligence Scale subtests for working memory, and word and figure recognition. This could not be related to any hippocampal volume changes. No group differences were found regarding volumetry or fMRI-derived functional activation. In the Sternberg paradigm, a network involving the anterior cingulate and the middle and inferior frontal gyrus was activated. A reduced strength of four connections in this prefrontal network was associated with the DSST and word recognition performance in the patient group. SIGNIFICANCE: Deficits in the processes involved in transient working memory, and to a lesser extent in short-term memory, in patients with localization-related epilepsy of both temporal and extratemporal origin cannot be attributed to hippocampal atrophy or function only, but are also related to reduced functional connectivity in the prefrontal brain. Because patients with symptomatic lesions or mesiotemporal sclerosis were excluded from this study, the results cannot be explained by structural lesions. Therefore, the current findings highlight the influence of epilepsy on the prefrontal network integrity as a possible underlying problem of memory impairment.

'Stand still ... , and move on', a new early intervention service for cardiac arrest survivors and their caregivers: rationale and description of the intervention.

UNLABELLED: This series of articles for rehabilitation in practice aims to cover a knowledge element of the rehabilitation medicine curriculum. Nevertheless they are intended to be of interest to a multidisciplinary audience. The competency addressed in this article is 'The trainee demonstrates a knowledge of diagnostic approaches for specific impairments including cognitive dysfunction as a result of cardiac arrest.' Abstract Objective: To describe a new early intervention service for survivors of cardiac arrest and their caregivers, and to explain the evidence and rationale behind it. RATIONALE: A cardiac arrest may cause hypoxic-ischaemic brain injury, which often results in cognitive impairments. Survivors of cardiac arrest can also encounter emotional problems, limitations in daily life, reduced participation in society and a decreased quality of life. A new early intervention service was designed based on literature study, expert opinion and patient experiences. Description of the intervention: The early intervention service is an individualized programme, consisting of one to six consultations by a specialized nurse for the patient and their caregiver. The intervention starts soon after discharge from the hospital and can last up to three months. The intervention consists of screening for cognitive and emotional problems, provision of information and support, promotion of self-management strategies and can include referral to further specialized care if indicated. DISCUSSION: This intervention is assumed to reduce future problems related to hypoxic-ischaemic brain injury in the patient and caregiver, and its effectiveness is currently being investigated in a randomized controlled multicentre trial.

The impact of side effects on long-term retention in three new antiepileptic drugs.

OBJECTIVE: To determine long-term retention, percentage of patients withdrawing because of adverse events, percentage of patients achieving seizure freedom, safety profile of the new anti-epileptic drugs lamotrigine, levetiracetam and topiramate. METHODS: All patients treated with lamotrigine, levetiracetam or topiramate in the Epilepsy Centre were identified. Each drug was analyzed from introduction of the drug in the Netherlands up to a final assessment point 2 years later. RESULTS: Data from 1066 patients were included: 336 for lamotrigine, 301 for levetiracetam, 429 for topiramate. Two-year retention rates were 69.2% (lamotrigine), 45.8% (levetiracetam), 38.3% (topiramate); (LTG vs. LEV at p<0.001; LTG vs. TPM at p<0.001; LEV vs. TPM at p=0.005). Seizure freedom rates were lowest for lamotrigine and highest for levetiracetam. Adverse events played a role in drug discontinuation in 154/429 patients (35.9%) on topiramate, 52/336 patients (15.5%) on lamotrigine (p<0.001), 68/301 patients (22.5%) on levetiracetam (p<0.001). Mood and general CNS-effects are common in patients on lamotrigine and levetiracetam, and neurocognitive side effects are most prevalent in patients on topiramate. A positive effect on cognition is frequently noted in patients on lamotrigine. CONCLUSION: A drug that is only modestly efficacious but has a favourable safety profile may look better than a drug that is more efficacious but produces clinically meaningful adverse events. Therefore, a drug's retention rate is mainly determined by its side effect profile. As a consequence, retention rate was highest for lamotrigine and lowest for topiramate. Intermediate retention rates were seen with levetiracetam use.

Cognitive fMRI and neuropsychological assessment in patients with secondarily generalized seizures.

OBJECTIVES: Cognitive dysfunction is a frequent comorbid disorder in epilepsy which has been associated with high seizure frequency. We examined the effect of secondarily generalized tonic-clonic seizures (SGTCS) on cognitive dysfunction using neuropsychological assessment and fMRI. PATIENTS AND METHODS: Sixteen patients with localization-related epilepsy of varying etiologies and SGTCS underwent extensive neuropsychological assessment. Functional MRI was performed probing the frontal and temporal lobes with two paradigms aimed at investigating speed of mental processing and working memory. RESULTS: A high number of total lifetime SGTCS was associated with lower intelligence scores. Moreover, a trend towards cognitive decline related to the number of SGTCS was observed. A relatively increased prefrontal activation related to the number of SGTCS was demonstrated, plus a trend towards a decreased activation in the frontotemporal areas. CONCLUSION: High numbers of SGTCS are associated with a drop in intelligence scores and altered prefrontal brain activation. A shift from frontotemporal to prefrontal activation seems to have occurred, suggesting that a functional reorganization of working memory is induced by a high number of SGTCS. It remains uncertain if this reorganization reflects a compensation mechanism, or the underlying pathological processes of cognitive dysfunction.

Activity and Life After Survival of a Cardiac Arrest (ALASCA) and the effectiveness of an early intervention service: design of a randomised controlled trial.

BACKGROUND: Cardiac arrest survivors may experience hypoxic brain injury that results in cognitive impairments which frequently remain unrecognised. This may lead to limitations in daily activities and participation in society, a decreased quality of life for the patient, and a high strain for the caregiver. Publications about interventions directed at improving quality of life after survival of a cardiac arrest are scarce. Therefore, evidence about effective rehabilitation programmes for cardiac arrest survivors is urgently needed. This paper presents the design of the ALASCA (Activity and Life After Survival of a Cardiac Arrest) trial, a randomised, controlled clinical trial to evaluate the effects of a new early intervention service for survivors of a cardiac arrest and their caregivers. METHODS/DESIGN: The study population comprises all people who survive two weeks after a cardiac arrest and are admitted to one of the participating hospitals in the Southern part of the Netherlands. In a two-group randomised, controlled clinical trial, half of the participants will receive an early intervention service. The early intervention service consists of several consultations with a specialised nurse for the patient and their caregiver during the first three months after the cardiac arrest. The intervention is directed at screening for cognitive problems, provision of informational, emotional and practical support, and stimulating self-management. If necessary, referral to specialised care can take place. Persons in the control group will receive the care as usual. The primary outcome measures are the extent of participation in society and quality of life of the patient one year after a cardiac arrest. Secondary outcome measures are the level of cognitive, emotional and cardiovascular impairment and daily functioning of the patient, as well as the strain for and quality of life of the caregiver. Participants and their caregivers will be followed for twelve months after the cardiac arrest.A process evaluation will be performed to gain insight into factors that might have contributed to the effectiveness of the intervention and to gather information about the feasibility of the programme. Furthermore, an economic evaluation will be carried out to determine the cost-effectiveness and cost-utility of the intervention. DISCUSSION: The results of this study will provide evidence on the effectiveness of this early intervention service, as well as the cost-effectiveness and its feasibility. TRIAL REGISTRATION: Current Controlled Trials [ISRCTN74835019].

Incidence of epilepsy and predictive factors of epileptic and non-epileptic seizures.

PURPOSE: To estimate the incidence of unprovoked seizures (US) and epilepsy in a general population from the southern part of the Netherlands, in relation to age, sex, etiology and seizure type, and to identify predictive factors of the epileptic and non-epileptic seizures. METHODS: All patients aged > or =14 years with a first seizure or who had undiagnosed seizures before the study period were included. Patients were identified from different sources and were independently evaluated and classified by a team of neurologists. A predictive profile for the occurrence of epileptic and non-epileptic seizures was obtained by stepwise logistic regression analysis. RESULTS: The overall annual incidence was 55/100,000 and 30/100,000 for US and epilepsy, respectively. The age-specific annual incidence of US and epilepsy increased with age and reached 120/100,000 and 62/100,000 for the > or =65 years of age group, respectively. The incidence of epilepsy and US in males was higher than in females and partial seizures prevailed over generalized seizures (40 versus 9/100,000). In up to 35% of the cases with US or epilepsy, the etiology was mainly cerebrovascular disease and brain tumors. Predictors for epileptic versus non-epileptic seizures of organic origin were an epileptiform EEG pattern (OR=0.06) versus a history of hypertension (OR=2.8) or cardiovascular disease (OR=5.4). Strong predictors for seizures of non-organic origin were female sex (OR=2.2) and head injury (OR=2.4). CONCLUSIONS: The incidence of US and epilepsy (overall, and age-, sex-, seizure-specific) was similar to those reported by other developed countries. The predictive factors found in this study may assist in the early diagnosis of seizures.

Early neurologically-focused follow-up after cardiac arrest improves quality of life at one year: A randomised controlled trial.

BACKGROUND: Survivors of a cardiac arrest frequently have cognitive and emotional problems and their quality of life is at risk. We developed a brief nursing intervention to detect cognitive and emotional problems, provide information and support, promote self-management, and refer them to specialised care if necessary. This study examined its effectiveness. METHODS: Multicentre randomised controlled trial with measurements at two weeks, three months and twelve months after cardiac arrest. 185 adult cardiac arrest survivors and 155 caregivers participated. Primary outcome measures were societal participation and quality of life of the survivors at one year. Secondary outcomes were the patient's cognitive functioning, emotional state, extended daily activities and return to work, and the caregiver's well-being. Data were analysed using 'intention to treat' linear mixed model analyses. RESULTS: After one year, patients in the intervention group had a significantly better quality of life on SF-36 domains Role Emotional (estimated mean differences (EMD)=16.38, p=0.006), Mental Health (EMD=6.87, p=0.003) and General Health (EMD=8.07, p=0.010), but there was no significant difference with regard to societal participation. On the secondary outcome measures, survivors scored significantly better on overall emotional state (HADS total, EMD=-3.25, p=0.002) and anxiety (HADS anxiety, EMD=-1.79, p=0.001) at one year. Furthermore, at three months more people were back at work (50% versus 21%, p=0.006). No significant differences were found for caregiver outcomes. CONCLUSION: The outcomes of cardiac arrest survivors can be improved by an intervention focused on detecting and managing the cognitive and emotional consequences of a cardiac arrest. TRIAL REGISTRATION: Current controlled trials, ISRCTN74835019.

Conservative treatment options for carpal tunnel syndrome: a systematic review of randomised controlled trials.

Carpal tunnel syndrome (CTS) is a common disorder, for which various conservative treatment options are available. The objective of this study is to determine the efficacy of the various conservative treatment options for relieving the symptoms of CTS. Computer-aided searches of MEDLINE (1/1966 to 3/2000), EMBASE (1/1988 to 2/2000) and the Cochrane Controlled Trials Register (2000, issue 1) were conducted, together with reference checking. Included were randomised controlled trials evaluating the efficacy of conservative treatment options in a study population of CTS patients, with a full report published in English, German, French or Dutch. Two reviewers independently selected the studies. Fourteen randomised controlled trials were included in the review. Assessment of methodological quality and data-extraction was independently performed by two reviewers. A rating system, based on the number of studies and their methodological quality and findings, was used to determine the strength of the available evidence for the efficacy of the treatment. Diuretics, pyridoxine, non-steroidal anti-inflammatory drugs, yoga and laser-acupuncture seem to be ineffective in providing short-term symptom relief (varying levels of evidence) and steroid injections seem to be effective (limited evidence). There is conflicting evidence for the efficacy of ultrasound and oral steroids. For providing long-term relief from symptoms there is limited evidence that ultrasound is effective, and that splinting is less effective than surgery. In conclusion, there is still little known about the efficacy of most conservative treatment options for CTS. To establish stronger evidence more high quality trials are needed.

The diagnosis of epileptic and non-epileptic seizures.

The aim of this prospective population-based study was to systematically define a cluster of diagnostic items which can assist in the early identification and classification of epileptic and non-epileptic seizures. A cohort of patients aged > or =14 years, suspected with a first epileptic seizure, were included in this study. A team of neurologists evaluated and classified all cases. Diagnostic items for epileptic and non-epileptic seizures were identified using logistic regression analysis. Three hundred and fifty cases entered this study. Distinctive features for epileptic seizures were postictal confusion (OR 0.09), an epileptiform EEG pattern (OR 0.02), and abnormal neuroimaging findings (OR 0.07), whereas for non-epileptic seizures of organic origin there was a history of hypertension (OR 7.5), and provoking factors (OR 13.4) such as exercise and warmth. Diagnostic items for seizures of non-organic origin were a history of febrile seizures (OR 5.8), treatment by a psychologist or psychiatrist (OR 9.1), and presentiment of the seizure (OR 3.7) such as a feeling of choking and palpitations. A separate analysis for the patients who were systematically investigated provided some additional diagnostic items for the different subgroups of patients. For instance, back arching during the seizure for the patients with seizures of non-organic origin and female sex for the patients with non-epileptic seizures of organic origin.

The costs of epilepsy in three different populations of patients with epilepsy.

The purpose of this study was to estimate the costs of care in three different populations of patients with epilepsy (general practices (GP), University Hospital (UH), and Epilepsy Center (EC)), and to analyse the distribution of costs by type of services for each patient group. A cost diary was developed to obtain prospective information on epilepsy-attributable service use over a period of 3 months. Similar information over the previous 3 months was obtained from a cost questionnaire. In addition, a quality of life inventory (QOLIE-31) was used. Standard cost lists were applied for the valuation of the direct cost items. A sensitivity analysis was performed for certain cost items for which no reliable data were available. One hundred and sixteen patients with established epilepsy were included, and the mean costs per patient per month (in Euros) ranged from 52.08 to 357.63. Patients from GP appeared to have lower direct costs, spent less time in seeking or undergoing a treatment, and reported lower seizure frequencies and less severe seizure types than the patients from the other patient groups. Patients from the EC reported the highest productivity changes and unemployment rates and also had the lowest scores on the QOLIE-31. The cost items anti-epileptic drugs, hospital services, unpaid care, and transportation accounted for the majority of the total direct costs.

Pharmacokinetics and tolerability of nasal versus intravenous midazolam in healthy Dutch volunteers: a single-dose, randomized-sequence, open-label, 2-period crossover pilot study.

BACKGROUND: Intranasal (IN) midazolam is a potential alternative to rectal diazepam for the acute treatment of epileptic seizures. OBJECTIVE: The purpose of this pilot study was to investigate the pharmacokinetics and tolerability of IN midazolam (50 mg/mL) compared with intravenous (IV) midazolam (2.5 mg) in healthy adult volunteers. METHODS: In this single-dose, randomized-sequence, open-label, 2-period crossover pilot study subjects were randomly assigned to receive IN or IV midazolam, with a washout period of at least 5 days between treatments. The 50-mg/mL IN midazolam formulation consisted of 5 mg midazolam base per 0.1 mL (1 spray) and was administered once in 1 nostril. The IV midazolam solution (2.5 mg) was infused over 10 seconds. Blood samples were taken before and at regular intervals up to 240 minutes after dosing. Pharmacokinetic data (ie, C(max), T(max), t(½), and AUC) were analyzed using a 2-compartment model. RESULTS: Of 9 volunteers screened and enrolled, 7 completed the study (mean age 34.1 [9.0] years; mean weight, 68.6 [10.4] kg, range 53-89 kg; 6 men, 3 women; all white). The mean C(max) of 78 (40) ng/mL was reached 44 minutes after IN administration, whereas the mean C(max) was 51 (5) ng/mL after IV administration. The mean estimated C(t=5 min) was 31.4 (28.1) ng/mL after IN administration. The elimination t(½) was 1.9 (0.41) hours for IN midazolam and 2.3 (0.19) hours for IV midazolam. The bioavailability of IN midazolam was 82%. There were few adverse events, with a local burning feeling in the nose being the most reported event (6 of 7 subjects). CONCLUSIONS: In this select group of healthy volunteers, concentrations of midazolam >30 ng/mL were reached within 5 minutes of IN administration at a dose of 5 mg/0.1 mL. A burning feeling in the nostril was the main adverse effect. Additional research is needed to evaluate the safety profile, convenience, satisfaction, and efficacy of nasal midazolam in the treatment of adults with seizures. This trial is registered at www.isrctn.org, No. ISRCTN79059168.

Functional MRI in chronic epilepsy: associations with cognitive impairment.

Chronic epilepsy is frequently accompanied by serious cognitive side-effects. Clinical factors are important, but cannot account entirely for this cognitive comorbidity. Therefore, research is focusing on the underlying cerebral mechanisms to understand the development of cognitive dysfunction. In the past two decades, functional MRI techniques have been applied extensively to the study of cognitive impairment in chronic epilepsy. However, because of wide variation in study designs, analysis methods, and data presentation, interpretation of these studies has become increasingly difficult for clinicians. In patients with localisation-related epilepsy, whether findings of functional MRI represent the underlying neuronal substrate for cognitive decline remains a subject of debate.

Hippocampal MRI volumetry at 3 Tesla: reliability and practical guidance.

OBJECTIVES: Although volumetry of the hippocampus is considered to be an established technique, protocols reported in literature are not described in great detail. This article provides a complete and detailed protocol for hippocampal volumetry applicable to T1-weighted magnetic resonance (MR) images acquired at 3 Tesla, which has become the standard for structural brain research. MATERIALS AND METHODS: The protocol encompasses T1-weighted image acquisition at 3 Tesla, anatomic guidelines for manual hippocampus delineation, requirements of delineation software, reliability measures, and criteria to assess and ensure sufficient reliability. Moreover, the validity of the correction for total intracranial volume size was critically assessed. The protocol was applied by 2 readers to the MR images of 36 patients with cryptogenic localization-related epilepsy, 4 patients with unilateral hippocampal sclerosis, and 20 healthy control subjects. RESULTS: The uncorrected hippocampal volumes were 2923 +/- 500 mm3 (mean +/- SD) (left) and 3120 +/- 416 mm3 (right) for the patient group and 3185 +/- 411 mm3 (left) and 3302 +/- 411 mm3 (right) for the healthy control group. The volume of the 4 pathologic hippocampi of the patients with unilateral hippocampal sclerosis was 2980 +/- 422 mm3. The inter-reader reliability values were determined: intraclass-correlation-coefficient (ICC) = 0.87 (left) and 0.86 (right), percentage volume difference (VD) = 7.0 +/- 4.7% (left) and 6.0 +/- 3.8% (right), and overlap ratio (OR) = 0.82 +/- 0.04 (left) and 0.82 +/- 0.03 (right). The positive Pearson correlation between hippocampal volume and total intracranial volume was found to be low: r = 0.48 (P = 0.03, left) and r = 0.62 (P = 0.004, right) and did not significantly reduce the volumetric variances, showing the limited benefit of the brain size correction. CONCLUSIONS: A protocol was described to determine hippocampal volumes based on 3 Tesla MR images with high inter-reader reliability. Although the reliability of hippocampal volumetry at 3 Tesla was similar to the literature values obtained at 1.5 Tesla, hippocampal border definition is argued to be more confident and easier because of the improved signal-to-noise characteristics.

White matter lesions in patients with localization-related epilepsy.

OBJECTIVES: White matter lesions (WML) have been proven to be associated with cognitive impairment. As (1) the decline of cognitive function is the most frequent comorbid disorder in epilepsy, and (2) patients with epilepsy have a relatively high prevalence of WML, the question is raised whether WML in patients with epilepsy are also associated with cognitive decline. MATERIALS AND METHODS: A high-resolution magnetic resonance imaging examination was performed at 3.0 T, comprising T1-weighted, T2 relaxometry, and fluid-attenuated inversion recovery (FLAIR) sequences. Patients with localization-related epilepsy with impaired and unimpaired cognitive functioning and a healthy control group were included. Furthermore, the performance of an automated WML detection algorithm, based on regional intensity evaluation, was assessed. RESULTS: The prevalence of WML, detected on 3.0 T FLAIR images, is 63% in healthy volunteers and 46% in patients with localization-related, cryptogenic epilepsy. No relationship between WML volume and cognitive performance was observed. The WML volumes from the automated segmentation method were found to be significantly correlated to the volumes obtained by neuroradiologic assessment. CONCLUSIONS: No relations could be found between WML and cognition in the well-defined population of patients with epilepsy. Other clinical characteristics of chronic epilepsy, such as seizures, age of onset, and medication are more likely to play an important role in cognitive decline. Furthermore, the automated WML detection algorithm using a regional Z-score analysis can successfully segment and quantify the WML on FLAIR images.

A cost-effectiveness decision model for antiepileptic drug treatment in newly diagnosed epilepsy patients.

OBJECTIVE: To establish cost-effectiveness of antiepileptic drug (AED) treatment strategies of newly diagnosed patients with epilepsy. METHODS: A decision analysis was carried out comparing effectiveness and treatment cost of six treatment strategies comprising carbamazepine (CBZ), lamotrigine (LTG), and valproate (VPA) as first-line and second-line drugs. Three outcome groups were defined: complete success, partial success, and failure. Data on seizure control and failure due to adverse effects were derived from the literature. Data on resource use and costs were collected for each outcome group by means of a patient survey. RESULTS: Cost data were obtained from 71 patients. Cost increased from complete success to failure outcome groups. The probability of obtaining complete success varied from 64% (VPA-CBZ strategy) to 74% (LTG-VPA strategy). The strategy LTG-VPA was more effective than the least expensive strategy CBZ-VPA, but at higher costs per additional effectively treated patient. Probabilistic sensitivity analysis confirmed these findings to be robust. Subsequent analysis showed that changing inclusion criteria used in the selection of the studies from the literature had a major effect on cost-effectiveness ratios of the various strategies. The probability that LTG first-line therapy is the most cost-effective option remains small, even defining a high cost-effectiveness threshold. Nevertheless, LTG second-line strategies can be cost-effective depending on the willingness to pay for patient improvement. CONCLUSIONS: Only a few studies satisfied our inclusion criteria for employment in our decision model. Our model supports the use of conventional AEDs as first-line options for patients with newly diagnosed epilepsy. LTG second-line therapy is likely to be the most cost-effective option in case society is willing to pay more than Euro 6000 for an additional successfully treated patient. This study also illustrates that, with the data presently available, the outcome of decision analysis for AED treatment choice depends on the inclusion criteria used to select trials. Prospective real-life studies are needed in which first- and second-line treatment strategies are compared with respect to both effectiveness and costs.

The Effect of Antiepileptic Drugs on Cognition: Patient Perceived Cognitive Problems of Topiramate versus Levetiracetam in Clinical Practice.

INTRODUCTION: Neurocognitive complaints may interfere with long-term antiepileptic drug (AED) treatment and are an important issue in clinical practice. Most data about drug-induced cognitive problems are derived from highly controlled short-term clinical trials. We analyzed such cognitive complaints for the two most commonly used AEDs in a clinical setting using patient perceived problems as primary outcome measure. METHOD: All patients of the epilepsy center Kempenhaeghe that received topiramate (TPM) or levetiracetam (LEV) from the introduction to mid 2004 were analyzed using a medical information system, an automated medical file. Patients were analyzed after 6, 12, and 18 months of treatment. RESULTS: Four hundred and two patients used either TPM (n = 260) or LEV (n = 142); 18 months retention showed a statistically significant difference, revealing 15% more patients that continued LEV compared to TPM: 18 months retention 46% for TPM and 61% for LEV [F (1.400) = 3.313, p = 0.043]. Neurocognitive complaints accounted for a significant number of drug discontinuations and especially the high frequency of neurocognitive complaints in the first period of TPM treatment appeared to be significant different from LEV [F(2,547) = 3.192, p = 0.042]. In the remaining patients, the difference in neurocognitive complaints was not statistically significant. CONCLUSION: cognitive complaints are common in TPM treatment and frequently lead to drug withdrawal. The impact of LEV on cognitive function is only mild. This leads to a much higher (15%) drug discontinuation rate for TPM compared to LEV.

Functional MRI reveals declined prefrontal cortex activation in patients with epilepsy on topiramate therapy.

Functional magnetic resonance imaging of covert word generation was used to examine brain activation abnormalities associated with topiramate-induced cognitive language impairment in patients with epilepsy. Compared with a control epilepsy group, in the topiramate-treated group, there was significantly less activation in the language-mediating regions of the prefrontal cortex; the topiramate group also had significantly lower neuropsychological language scores. These findings suggest that topiramate has a critical effect on the cerebral neural systems that mediate expressive language.

Mood effects of antiepileptic drugs.

This article reviews our knowledge about a specific subgroup of chronic CNS-related side effects of antiepileptic drugs (AED) treatment, i.e., the effects of AEDs on mood. In line with a recent hypothesis, using the experience of AED treatment in psychiatry, we examined whether mood effects are related to the known anticonvulsant mechanisms of action of the AEDs. Specifically we examined whether AEDs, acting through potentiation of GABAergic neurotransmitter release, have "sedating" effects on mood, whereas AEDs that act through the reduction of excitatory glutamate neurotransmitter release have "activating" effects on mood. The results of this review yield evidence that there are relationships between the known anticonvulsant mechanisms of action of the AEDs and mood effects. Mood effects occur especially when the drugs have a sustained effect on neuronal mechanisms, in particular when the inhibitory or excitatory neurotransmitter release is altered. Drugs with "use-dependent" impact on sodium or calcium channels probably have a more transient impact and do not lead to interictal stable mood effects. Drugs with multiple mechanisms of action seem to combine a favorable efficacy profile with an increased risk of severe mood problems. The quality of the evidence, however, is not conclusive and there are many paradoxical results. One reason for this lack of "fit" may be the use in this review of a simplified classification, based only on the predominant mechanism of action to classify a drug. Only a limited number of AEDs (ethosuximide, tiagabine) are characterized by a single anticonvulsant mechanism of action. Probably more detailed coupling of mechanisms of action (e.g., inspecting the type and route of impact on GABA release) and mood effects may give less confusing results. The use of magnetic resonance imaging techniques such as spectroscopy may provide interesting results.