Comparative effectiveness of antiepileptic drugs in juvenile myoclonic epilepsy.

OBJECTIVE: To study the effectiveness and tolerability of antiepileptic drugs (AEDs) commonly used in juvenile myoclonic epilepsy (JME). METHODS: People with JME were identified from a large database of individuals with epilepsy, which includes detailed retrospective information on AED use. We assessed secular changes in AED use and calculated rates of response (12-month seizure freedom) and adverse drug reactions (ADRs) for the five most common AEDs. Retention was modeled with a Cox proportional hazards model. We compared valproate use between males and females. RESULTS: We included 305 people with 688 AED trials of valproate, lamotrigine, levetiracetam, carbamazepine, and topiramate. Valproate and carbamazepine were most often prescribed as the first AED. The response rate to valproate was highest among the five AEDs (42.7%), and significantly higher than response rates for lamotrigine, carbamazepine, and topiramate; the difference to the response rate to levetiracetam (37.1%) was not significant. The rates of ADRs were highest for topiramate (45.5%) and valproate (37.5%). Commonest ADRs included weight change, lethargy, and tremor. In the Cox proportional hazards model, later start year (1.10 [1.08-1.13], P < 0.001) and female sex (1.41 [1.07-1.85], P = 0.02) were associated with shorter trial duration. Valproate was associated with the longest treatment duration; trials with carbamazepine and topiramate were significantly shorter (HR [CI]: 3.29 [2.15-5.02], P < 0.001 and 1.93 [1.31-2.86], P < 0.001). The relative frequency of valproate trials shows a decreasing trend since 2003 while there is an increasing trend for levetiracetam. Fewer females than males received valproate (76.2% vs 92.6%, P = 0.001). SIGNIFICANCE: In people with JME, valproate is an effective AED; levetiracetam emerged as an alternative. Valproate is now contraindicated in women of childbearing potential without special precautions. With appropriate selection and safeguards in place, valproate should remain available as a therapy, including as an alternative for women of childbearing potential whose seizures are resistant to other treatments.

Validity of health insurance data to identify people with epilepsy.

BACKGROUND: Large administrative databases may prove useful to assess epilepsy-related comorbidity and mortality. Despite their increased use, their validity as data source in epilepsy is yet under-ascertained. METHODS: Achmea is a large Dutch health insurance company covering about 25% of the population. We performed a retrospective cohort study using data from the Achmea Health Insurance Database (AHID) over the period 2006-2009. To assess the validity of epilepsy codes in the AHID, we randomly invited 1000 individuals (age 18-75 years insured by Achmea), attending an epilepsy centre or a district hospital during 2006-2009, to participate. Informed consent was provided and 293 were eligible for inclusion. We compared the diagnostic codes for epilepsy in AHID with the diagnosis in their case-notes (reference standard). As additional measure of validity, we compared prevalence of epilepsy codes in AHID (based on anonymized data of all 26.297 subjects with this code in AHID) with epilepsy prevalence rates in the general Dutch population to estimate an age-specific standardized prevalence ratio. RESULTS: We identified 293 participants with an epilepsy code in AHID. The majority (278) of them had a definite or possible diagnosis of epilepsy in the case-notes; i.e. a positive predictive value of 0.95 (95% CI 0.92-0.97). The overall prevalence of epilepsy codes in the AHID was slightly higher than the putative prevalence in the general Dutch population (7.4/1.000 vs. 6.8/1.000) with a Standardized Prevalence Ratio of 1.08 (95% CI: 1.08-1.09). CONCLUSIONS: Our findings demonstrate the validity of AHID data for a diagnosis of epilepsy and confirm previous work on using administrative data for epilepsy research.

Comparative effectiveness of antiepileptic drugs in patients with mesial temporal lobe epilepsy with hippocampal sclerosis.

OBJECTIVE: Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) is a common epilepsy syndrome that is often poorly controlled by antiepileptic drug (AED) treatment. Comparative AED effectiveness studies in this condition are lacking. We report retention, efficacy, and tolerability in a cohort of patients with MTLE-HS. METHODS: Clinical data were collected from a European database of patients with epilepsy. We estimated retention, 12-month seizure freedom, and adverse drug reaction (ADR) rates for the 10 most commonly used AEDs in patients with MTLE-HS. RESULTS: Seven hundred sixty-seven patients with a total of 3,249 AED trials were included. The highest 12-month retention rates were observed with carbamazepine (85.9%), valproate (85%), and clobazam (79%). Twelve-month seizure freedom rates varied from 1.2% for gabapentin and vigabatrin to 11% for carbamazepine. Response rates were highest for AEDs that were prescribed as initial treatment and lowest for AEDs that were used in a third or higher instance. ADRs were reported in 47.6% of patients, with the highest rates observed with oxcarbazepine (35.7%), topiramate (30.9%), and pregabalin (27.4%), and the lowest rates with clobazam (6.5%), gabapentin (8.9%), and lamotrigine (16.6%). The most commonly reported ADRs were lethargy and drowsiness, dizziness, vertigo and ataxia, and blurred vision and diplopia. SIGNIFICANCE: Our results did not demonstrate any clear advantage of newer versus older AEDs. Our results provide useful insights into AED retention, efficacy, and ADR rates in patients with MTLE-HS.

Photosensitivity in Dravet syndrome is under-recognized and related to prognosis.

OBJECTIVE: To detect determinants for photoparoxysmal EEG response (PPR) in SCN1A-related Dravet syndrome (DS). METHODS: Data were studied from nationwide medical histories and EEGs of DS-patients (n=53; 31 males, age 2-19years). Detailed questionnaires on visual stimuli were completed by parents (n=49). RESULTS: PPR was found in 22 patients (42%; median age 1.25yr), and repeatedly in 17%. PPR (17% of 249 intermittent photic stimulation (IPS)-EEGs) occurred more often with optimal IPS protocols (OR 2.11 [95%CI 1.09-4.13]) and in EEGs showing spontaneous epileptiform abnormalities (OR 5.08 [95%CI 2.05-12.55]). PPR-positive patients tended to be younger at first (p=0.072) and second seizure (p=0.049), showed severe intellectual disability (p=0.042), and had more often spontaneous occipital epileptiform abnormalities (p<0.001). Clinical sensitivity was reported in medical files in 22% of patients and by parents in 43% (self-induction 24%). Clinical or EEG proven visual sensitivity was detected in 65% of cases. CONCLUSIONS: Sensitivity to visual stimuli is very common in DS and more often noticed by parents than confirmed by EEG. Detection of PPR improves with repetitive tests using accurate IPS protocols. SIGNIFICANCE: Photosensitivity is an important feature in DS and seems to be a marker of the severity of the disorder. Therefore repeated standardized IPS should be encouraged.

Sudden cardiac arrest in people with epilepsy in the community: Circumstances and risk factors.

OBJECTIVE: To ascertain whether characteristics of ventricular tachycardia/fibrillation (VT/VF) differed between people with epilepsy and those without and which individuals with epilepsy were at highest risk. METHODS: We ascertained 18 people with active epilepsy identified in a community-based registry of sudden cardiac arrest (SCA) with ECG-confirmed VT/VF (cases). We compared them with 470 individuals with VT/VF without epilepsy (VT/VF controls) and 54 individuals with epilepsy without VT/VF (epilepsy controls). Data on comorbidity, epilepsy severity, and medication use were collected and entered into (conditional) logistic regression models to identify determinants of VT/VF in epilepsy. RESULTS: In most cases, there was an obvious (10/18) or presumed cardiovascular cause (5/18) in view of preexisting heart disease. In 2 of the 3 remaining events, near-sudden unexpected death in epilepsy (SUDEP) was established after successful resuscitation. Cases had a higher prevalence of congenital/inherited heart disease (17% vs 1%, p = 0.002), and experienced VT/VF at younger age (57 vs 64 years, p = 0.023) than VT/VF controls. VT/VF in cases occurred more frequently at/near home (89% vs 58%, p = 0.009), and was less frequently witnessed (72% vs 89%, p = 0.048) than in VT/VF controls. Cases more frequently had clinically relevant heart disease (50% vs 15%, p = 0.005) and intellectual disability (28% vs 1%, p < 0.001) than epilepsy controls. CONCLUSION: Cardiovascular disease rather than epilepsy characteristics is the main determinant of VT/VF in people with epilepsy in the community. SCA and SUDEP are partially overlapping disease entities.

Seizure precipitants in Dravet syndrome: What events and activities are specifically provocative compared with other epilepsies?

OBJECTIVES: This study aimed to describe seizure precipitants in Dravet syndrome (DS) compared with other epilepsies. METHODS: Seizure precipitants as reported in a Dutch cohort of patients with DS with pathogenic SCN1A mutations (n=71) were compared with those of a cohort with childhood epilepsy (n=149) and of a community-based cohort with epilepsy (n=248); for all three Dutch cohorts, the same type of questionnaire was used. Seizure precipitants were categorized as 'fever', 'visual stimuli', 'sleep deprivation', 'stress, including physical exercise', 'auditory stimuli', and 'other'. RESULTS: For 70 (99%) of 71 patients with DS, at least one seizure precipitant was recalled by parents. Seizure precipitants that were reported in more than half of the cohort with DS were as follows: having a fever (97%), having a cold (68%), taking a bath (61%), having acute moments of stress (58%), and engaging in physical exercise (56%). Seizure precipitants freely recalled by parents were often related to ambient warmth or cold-warmth shifts (41%) and to various visual stimuli (18%). Patients with DS had more positive seizure precipitant categories (median 4) compared with the cohort with childhood epilepsy (median 2) and the community-based cohort with epilepsy (median 0) (p<0.001) and showed the highest percentage in each category (all p<0.001). Within the category 'stress, including physical exercise', physical exercise was more often reported to provoke seizures in stress-sensitive patients in the cohort with DS than in the cohort with childhood epilepsy (78% vs. 35%, p<0.001). In the cohort with childhood epilepsy, physical exercise was more often reported in fever-sensitive children than in other children (25% vs. 12%, p=0.042). CONCLUSIONS: Our study shows a high prevalence of a range of seizure precipitants in DS. Our results underscore elevated body temperature as an important seizure precipitant, whether caused by fever, warm bath, ambient warmth, or physical exercise. Knowledge of these seizure precipitants may improve preventive strategies in the otherwise difficult treatment of DS.

Seizure precipitants in a community-based epilepsy cohort.

Epileptic seizures can be provoked by several factors. Better understanding of these factors may improve a patient's sense of control and could reduce seizures. In daily practice, the recognition of seizure precipitants relies heavily on clinical or video-EEG evidence, which can be difficult to obtain. Studies of seizure provocation are largely based on selected hospital-based patient populations, which may lead to biased occurrence estimates. Self-reported seizure precipitants are rarely studied, yet are necessary to understand the experiences of patients and improve epilepsy management. We performed a cross-sectional community-based study of 248 epilepsy patients, selected by pharmacy records of anti-epileptic drug use. Self-reported seizure precipitants and potential associated characteristics were assessed using questionnaires. Almost half of all patients (47 %) reported one or more seizure precipitants, of which stress, sleep deprivation, and flickering lights were the most common. In this community-based setting, light-provoked seizures were especially frequent compared to the literature. Idiopathic generalized epilepsy (IGE), a lower age at seizure onset, and having auras or prodromes were found to be important independent prognostic factors associated with provoked seizures. IGE and a younger age at seizure onset have been linked to provoked seizures in earlier reports. The finding of auras or prodromes as a prognostic factor was unexpected, though case reports have described provoked seizures in patients having auras. Assessment of these factors may facilitate the early recognition of seizure precipitants in daily clinical practice. This is important for the optimization of epilepsy management for a large group of patients, as provoked seizures are expected to occur frequently.

Treatment of epilepsy in daily clinical practice: have outcomes improved over the past 10 years?

In the past decade, many new antiepileptic drugs have become available, but their influence on patient outcomes in daily practice is not well known. In a community-based study, we assessed changes in epilepsy treatment and outcomes over a 10-year period. We compared two cross-sectional community-based samples that were obtained from the same Dutch suburban region in 2000 and 2010 using pharmacy records for recruitment, including 344 and 248 epilepsy patients, respectively. The main outcome was self-reported quality of life (QoL, using the QOLIE-31). Potential predictors of QoL (adverse effects, seizure control, seizure acceptability, demographic, epilepsy- or treatment-related determinants) were assessed by multivariable linear regression. New antiepileptic drugs were used by 9 % of patients in 2000 and 34 % in 2010, P < 0.001. More than 80 % in both samples reported to be treated by a neurologist. We found no significant differences in QOLIE-31 scores (72.57 vs. 72.44), or in the proportion of patients with complete seizure control (51 vs. 54 %), between the two study samples. Seizure control and adverse effects were important independent predictors of quality of life, explaining 58 % of the variance. We found no evidence that in this community the QoL of epilepsy patients has improved in the last decade, despite unrestricted availability of healthcare resources, including accessibility to new AEDs. The relatively low proportion with complete seizure control and the high rate of adverse effects in these community-based samples suggest that the effectiveness of epilepsy treatment is still far from optimal.

Prognostic factors for medically intractable epilepsy: a systematic review.

OBJECTIVE: One third of all epilepsy patients have medically intractable epilepsy. Knowledge of prognostic factors that, in an early therapeutic stage of epilepsy, herald intractability could facilitate patient management. In this systematic review, we examined the evidence for independent prognostic factors of intractability in patients with epilepsy. METHODS: MEDLINE and EMBASE were searched for cohort studies reporting on prognostic factors for medically intractable epilepsy. After selection of abstracts, full-text articles were obtained and their quality was assessed by two reviewers, using the QUIPS checklist. All independent prognostic factors in the individual studies were summarized. RESULTS: Eleven cohort studies were included, of which ten hospital-based. Younger age at seizure onset, symptomatic etiology, high initial seizure frequency, medical history, epileptic EEG abnormalities, and failure of previous antiepileptic-drugs (AEDs) were documented as independent prognostic factors of intractability in at least 2 of the 11 studies; none of these factors was reported in all 11 studies. None of the studies considered genetic, neurobiological, or immunological factors. The studies were of moderate quality, mostly because they did not provide a conceptual model for the choice of predictors. Heterogeneity in study design, population, candidate prognostic factors, and outcome definitions precluded statistical pooling. CONCLUSIONS: While potentially relevant prognosticators of medically intractable epilepsy have been identified, the evidence for these factors is not consistent. There is a need for well-designed prognostic population-based cohort studies that also include pharmacological, genetic, neurobiological, and immunological factors. A valid model for the early prediction of medically intractable epilepsy could improve patient management.

Computed tomography for the diagnosis of lumbar spinal pathology in adult patients with low back pain or sciatica: a diagnostic systematic review.

AIM: In low back pain if serious pathology is suspected diagnostic imaging could be performed. One of the imaging techniques available for this purpose is computed tomography (CT), however, insight in the diagnostic performance of CT is unclear. METHOD: Diagnostic systematic review. Studies assessing the diagnostic accuracy of CT in adult patients suggested having low back pain caused by specific pathology were selected. Two review authors independently selected studies for inclusion, extracted data and assessed risk of bias. Pooled summary estimates of sensitivity and specificity with 95% CI were calculated. RESULTS: Seven studies were included, all describing the diagnostic accuracy of CT in identifying lumbar disc herniation. Six studies used surgical findings as the reference standard and were considered sufficiently homogenous to carry out a meta-analysis. The pooled summary estimate of sensitivity was 77.4% and specificity was 73.7%. CONCLUSIONS: We found no studies evaluating the accuracy of CT for pathologies such as vertebral cancer, infection and fractures and this remains unclear. Our results should be interpreted with some caution. Sensitivity and specificity, regarding the detection of lumbar disc herniation, showed that a substantial part of the patients is still classified as false-negative and false-positive. In future, the diagnostic performance of CT must be assessed in high quality prospective cohort studies with an unselected population of patients with low back pain.

Magnetic resonance imaging for diagnosing lumbar spinal pathology in adult patients with low back pain or sciatica: a diagnostic systematic review.

PURPOSE: In about 5% of all cases LBP is associated with serious underlying pathology requiring diagnostic confirmation and directed treatment. Magnetic resonance imaging (MRI) is often used for this diagnostic purpose yet its role remains controversial. Consequently, this review aimed to summarize the available evidence on the diagnostic accuracy of MRI for identifying lumbar spinal pathology in adult low back pain (LPB) or sciatica patients. METHODS: MEDLINE, EMBASE and CINAHL were searched (until December 2009) for observational studies assessing the diagnostic accuracy of MRI compared to a reference test for the identification of lumbar spinal pathology. Two reviewers independently selected studies for inclusion, extracted data and assessed methodological quality. Pooled summary estimates of sensitivity and specificity with 95% confidence intervals were calculated for homogenous subsets of studies. RESULTS: Eight studies were included in this review. Strata were defined for separate pathologies i.e. lumbar disc herniation (HNP) and spinal stenosis. Five studies comparing MRI to findings at the surgery for identifying HNP were included in a meta-analysis. Pooled analysis resulted in a summary estimate of sensitivity of 75% (95% CI 65-83%) and specificity of 77% (95% CI 61-88%). For spinal stenosis pooling was not possible. CONCLUSIONS: The results suggest that a considerable proportion of patients may be classified incorrectly by MRI for HNP and spinal stenosis. However, the evidence for the diagnostic accuracy of MRI found by this review is not conclusive, since the results could be distorted due to the limited number of studies and large heterogeneity.

Predicting sequelae and death after bacterial meningitis in childhood: a systematic review of prognostic studies.

BACKGROUND: Bacterial meningitis (BM) is a severe infection responsible for high mortality and disabling sequelae. Early identification of patients at high risk of these outcomes is necessary to prevent their occurrence by adequate treatment as much as possible. For this reason, several prognostic models have been developed. The objective of this study is to summarize the evidence regarding prognostic factors predicting death or sequelae due to BM in children 0-18 years of age. METHODS: A search in MEDLINE and EMBASE was conducted to identify prognostic studies on risk factors for mortality and sequelae after BM in children. Selection of abstracts, full-text articles and assessment of methodological quality using the QUIPS checklist was performed by two reviewers independently. Data on prognostic factors per outcome were summarized. RESULTS: Of the 31 studies identified, 15 were of moderate to high quality. Due to substantial heterogeneity in study characteristics and evaluated prognostic factors, no quantitative analysis was performed. Prognostic factors found to be statistically significant in more than one study of moderate or high quality are: complaints > 48 hours before admission, coma/impaired consciousness, (prolonged duration of) seizures, (prolonged) fever, shock, peripheral circulatory failure, respiratory distress, absence of petechiae, causative pathogen Streptococcus pneumoniae, young age, male gender, several cerebrospinal fluid (CSF) parameters and white blood cell (WBC) count. CONCLUSIONS: Although several important prognostic factors for the prediction of mortality or sequelae after BM were identified, the inability to perform a pooled analysis makes the exact (independent) predictive value of these factors uncertain. This emphasizes the need for additional well-conducted prognostic studies.