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1.  Clinical features, proximate causes and consequences of active convulsive epilepsy in Africa 
Epilepsia  2013;55(1):76-85.
SUMMARY
Purpose
Epilepsy is common in sub-Saharan Africa (SSA), but the clinical features and consequences are poorly characterized. Most studies are hospital-based and few studies have compared different ecological sites in SSA. We described active convulsive epilepsy (ACE) identified in cross-sectional community-based surveys in SSA, to understand the proximate causes, features, and consequences.
Methods
We performed a detailed clinical and neurophysiological description of ACE cases identified from a community survey of 584,586 people using medical history, neurological examination and electroencephalograph (EEG) data from five sites in Africa: South Africa; Tanzania; Uganda; Kenya and Ghana. The cases were examined by clinicians to discover risk factors, clinical features, and consequences of epilepsy. We used logistic regression to determine the epilepsy factors associated with medical comorbidities.
Key findings
Half (51%) of the 2,170 people with ACE were children and 69% of seizures began in childhood. Focal features (EEG, seizure types and neurological deficits) were present in 58% of ACE cases, and varied significantly with site. Status epilepticus occurred in 25% of people with ACE. Only 36% received antiepileptic drugs (phenobarbital was the commonest drug (95%)), and the proportion varied significantly with the site. Proximate causes of ACE were adverse perinatal events (11%) for onset of seizures before 18 years; acute encephalopathy (10%) and head injury prior to seizure-onset (3%). Important comorbidities were malnutrition (15%), cognitive impairment (23%) and neurological deficits (15%). The consequences of ACE were burns (16%), head injuries (post seizures) (1%), lack of education (43%) and being unmarried (67%) or unemployed (57%) in adults; all significantly more common than those without epilepsy.
Significance
There were significant differences in the co-morbidities across sites. Focal features are common in ACE suggesting identifiable and preventable causes. Malnutrition, cognitive and neurological deficits are common in people with ACE and should be integrated into the management of epilepsy in this region. Consequences of epilepsy such as burns, lack of education, poor marriage prospects and unemployment need to be addressed.
doi:10.1111/epi.12392
PMCID: PMC4074306  PMID: 24116877
sub-Saharan Africa; clinical features; active convulsive epilepsy; co-morbidity; population-based study
2.  Seizures and epilepsy in oncological practice: causes, course, mechanisms and treatment 
There are few data available on the causes and mechanistic basis, outcome and treatment of seizures and epilepsy in people with systemic cancer. Seizures and epilepsy in people with cancers other than primary brain tumours are reviewed here. Articles published in English, which discussed the neurological manifestations and complications of cancer and its treatment, were searched and information on the frequency, aetiology, and course of seizures and epilepsy was extracted. The frequency, aetiology and outcome of seizure disorders in patients with cancer differ from those in the general population. Intracranial metastasis, cancer drugs and metabolic disturbances are the most common causes. Infections, cerebrovascular complications of systemic cancer and paraneoplastic disorders are among the rarer causes of seizures in patients with neoplasms. Several drugs used in the treatment of cancer, or complications arising from their use, can trigger seizures through varied mechanisms. Most drug‐induced seizures are provoked and do not require long‐term treatment with antiepileptic drugs.
doi:10.1136/jnnp.2006.106211
PMCID: PMC2077803  PMID: 17369589
3.  Burden of epilepsy in rural Kenya measured in disability-adjusted life years 
Epilepsia  2014;55(10):1626-1633.
Objectives
The burden of epilepsy, in terms of both morbidity and mortality, is likely to vary depending on the etiology (primary [genetic/unknown] vs. secondary [structural/metabolic]) and with the use of antiepileptic drugs (AEDs). We estimated the disability-adjusted life years (DALYs) and modeled the remission rates of active convulsive epilepsy (ACE) using epidemiologic data collected over the last decade in rural Kilifi, Kenya.
Methods
We used measures of prevalence, incidence, and mortality to model the remission of epilepsy using disease-modeling software (DisMod II). DALYs were calculated as the sum of Years Lost to Disability (YLD) and Years of Life Lost (YLL) due to premature death using the prevalence approach, with disability weights (DWs) from the 2010 Global Burden of Disease (GBD) study. DALYs were calculated with R statistical software with the associated uncertainty intervals (UIs) computed by bootstrapping.
Results
A total of 1,005 (95% UI 797–1,213) DALYs were lost to ACE, which is 433 (95% UI 393–469) DALYs lost per 100,000 people. Twenty-six percent (113/100,000/year, 95% UI 106–117) of the DALYs were due to YLD and 74% (320/100,000/year, 95% UI 248–416) to YLL. Primary epilepsy accounted for fewer DALYs than secondary epilepsy (98 vs. 334 DALYs per 100,000 people). Those taking AEDs contributed fewer DALYs than those not taking AEDs (167 vs. 266 DALYs per 100,000 people). The proportion of people with ACE in remission per year was estimated at 11.0% in males and 12.0% in females, with highest rates in the 0–5 year age group.
Significance
The DALYs for ACE are high in rural Kenya, but less than the estimates of 2010 GBD study. Three-fourths of DALYs resulted from secondary epilepsy. Use of AEDs was associated with 40% reduction of DALYs. Improving adherence to AEDs may reduce the burden of epilepsy in this area.
doi:10.1111/epi.12741
PMCID: PMC4238788  PMID: 25131901
Burden; Disability-adjusted life years; Epilepsy; Remission; Treatment gap
4.  External Validation of a Prognostic Model for Seizure Recurrence Following a First Unprovoked Seizure and Implications for Driving 
PLoS ONE  2014;9(6):e99063.
Objective
In the United Kingdom and other European Union countries guidelines for driving following a first unprovoked seizure require the risk of another seizure in the next year to be less than 20%. Using data from one clinical trial, we previously developed a prognostic model to inform driving guidelines. The objective of this work is to externally validate our published model and demonstrate its generalisability.
Methods
A cohort of 620 people with a first unprovoked seizure was used to develop the original model which included variables for aetiology, first degree relative with epilepsy, seizures only while asleep, electroencephalogram, computed tomography or magnetic resonance scan result, and treatment policy. The validation cohorts consisted of 274 (United Kingdom), 305 (Italy), and 847 (Australia) people. The model was evaluated using discrimination and calibration methods. A covariate, missing from the Italian dataset, was handled via five imputation methods. Following external validation, the model was fitted to a pooled population comprising all validation datasets and the development dataset. The model was stratified by dataset.
Results
The model generalised relatively well. All methods of imputation performed fairly similarly. At six months, the risk of a seizure recurrence following a first ever seizure, based on the pooled datasets, is 15% (95% CI: (12% to 18%)) for patients who are treated immediately and 18% (95% CI: (15 to 21%)) otherwise. Individuals can be reliably stratified into risk groups according to the clinical factors included in the model.
Significance
Our prognostic model, used to inform driving regulations, has been validated and consequently has been proven as a valuable tool for predicting risk of seizure recurrence following a first seizure in people with various combinations of risk factors. Additionally, there is evidence to support one worldwide overall prognostic model for risk of second seizure following a first.
doi:10.1371/journal.pone.0099063
PMCID: PMC4053525  PMID: 24919184
5.  Postictal generalized EEG suppression 
Neurology  2013;81(14):1252-1256.
Objective:
To determine the consistency and facilitating cofactors of postictal generalized EEG suppression (PGES) of >20 seconds after convulsive seizures (CS), a suggested predictor of sudden unexpected death in epilepsy risk.
Methods:
We retrospectively reviewed video-EEG data of people with ≥2 recorded CS. Presence and duration of PGES were assessed by 2 independent observers blinded to patient status. Intraindividual consistency of PGES >20 seconds was determined and correlations with clinical characteristics were analyzed after correction for individual effects and the varying number of seizures.
Results:
One hundred fifty-four seizures in 59 people were analyzed. PGES >20 seconds was found in 37 individuals (63%) and 57 (37%) of CS. The proportion of persons in whom PGES occurred consistently (presence or absence of PGES >20 seconds in all CS) was lower in those with more CS. PGES of >20 seconds was more frequent in seizures arising from sleep (odds ratio 3.29, 95% confidence interval 1.21–8.96) and when antiepileptic medication was tapered (odds ratio 4.80, 95% confidence interval 1.27–18.14).
Conclusion:
Apparent PGES consistency was less frequent in people with more CS recorded, suggesting that PGES is an inconsistent finding in any one individual. Thus, we believe that PGES >20 seconds is not a reliable predictor of sudden unexpected death in epilepsy. Sleep and antiepileptic drug reduction appear to facilitate the occurrence of PGES.
doi:10.1212/WNL.0b013e3182a6cbeb
PMCID: PMC3795608  PMID: 23966251
6.  Postictal generalized EEG suppression is not associated with peri-ictal cardiac autonomic instability in people with convulsive seizures 
Epilepsia  2012;54(3):523-529.
Purpose
Postictal generalized EEG suppression (PGES) seems to be a pathophysiological hallmark in ictal recordings of sudden unexpected death in epilepsy (SUDEP). It has recently been suggested that presence and duration of PGES might be predictors of SUDEP risk. Little is known about the aetiology of PGES.
Methods
We conducted a retrospective case-control study in 50 people with convulsive seizures (CS) recorded on digital video-EEG. One CS per individual was reviewed for presence and duration of PGES by two independent observers: Pre- and postictal heart rate (HR) (1 minute before seizure onset and 1, 3, 5, 15 and 30 minutes after seizure end) and frequency domain measures of heart rate variability (HRV) including the ratio of low versus high frequency power were analyzed. The relationship between PGES and peri-ictal autonomic changes was evaluated, as well as its association with several clinical variables.
Key Findings
Thirty seven (74%) individuals exhibited PGES and 13 (26%) did not. CS resulted in a significant increase of peri-ictal HR and the LF/HF ratio. PGES was associated with neither peri-ictal HR (mean HR difference between PGES+ and PGES− seizures: −2 bpm, 95% CI −10 to +6 bpm) nor HRV change. There was no association between the duration of PGES and peri-ictal HR change. People with PGES were more likely to be asleep prior to seizure onset (OR 4.7, 95% CI 1.2-18.3) and had a higher age of onset of epilepsy (median age 15 vs. 4 years).
Significance
PGES was not associated with substantial changes in measures of cardiac autonomic instability but was more prevalent in CS arising from sleep.
doi:10.1111/epi.12021
PMCID: PMC3580122  PMID: 23157655
Epilepsy; Postictal generalized EEG suppression (PGES); Sudden unexpected death in epilepsy (SUDEP); Heart rate (HR); Heart rate variability (HVR)
7.  Premature mortality in active convulsive epilepsy in rural Kenya 
Neurology  2014;82(7):582-589.
Objective:
We estimated premature mortality and identified causes of death and associated factors in people with active convulsive epilepsy (ACE) in rural Kenya.
Methods:
In this prospective population-based study, people with ACE were identified in a cross-sectional survey and followed up regularly for 3 years, during which information on deaths and associated factors was collected. We used a validated verbal autopsy tool to establish putative causes of death. Age-specific rate ratios and standardized mortality ratios were estimated. Poisson regression was used to identify mortality risk factors.
Results:
There were 61 deaths among 754 people with ACE, yielding a rate of 33.3/1,000 persons/year. Overall standardized mortality ratio was 6.5. Mortality was higher across all ACE age groups. Nonadherence to antiepileptic drugs (adjusted rate ratio [aRR] 3.37), cognitive impairment (aRR 4.55), and age (50+ years) (rate ratio 4.56) were risk factors for premature mortality. Most deaths (56%) were directly related to epilepsy, with prolonged seizures/possible status epilepticus (38%) most frequently associated with death; some of these may have been due to sudden unexpected death in epilepsy (SUDEP). Possible SUDEP was the likely cause in another 7%.
Conclusion:
Mortality in people with ACE was more than 6-fold greater than expected. This may be reduced by improving treatment adherence and prompt management of prolonged seizures and supporting those with cognitive impairment.
doi:10.1212/WNL.0000000000000123
PMCID: PMC3963418  PMID: 24443454
8.  Drug therapy for solitary cysticercus granuloma 
Neurology  2013;80(2):152-162.
Objective:
The effectiveness of anthelminthic and corticosteroid drug therapy in parenchymal neurocysticercosis is well established. The treatment of parenchymal solitary cysticercus granuloma (SCG), however, remains controversial. We attempted to obtain a consistent estimate of the efficacy of anthelminthic and corticosteroid drug treatment in SCG.
Methods:
Randomized-controlled trials (RCTs) comparing rates of seizure freedom, granuloma resolution, and residual calcification in individuals with SCG treated with anthelminthic or corticosteroid drugs with those treated with antiepileptic drugs (AEDs) alone were systematically reviewed and quantified using fixed- or random-effects meta-analysis.
Results:
Fifteen RCTs were identified for inclusion. Ten RCTs assigned 765 people with SCG to AED treatment with or without anthelminthic drug (albendazole) treatment. A further 5 RCTs assigned 457 people with SCG to AED treatment with or without corticosteroid drugs. Anthelminthic treatment was associated with significantly increased rates of seizure freedom (nonevent odds ratio: 2.45; 95% confidence interval: 1.49–4.03; p = 0.0004) and significantly higher rates of granuloma resolution (odds ratio: 2.09; 95% confidence interval: 1.41–3.00; p = 0.0003), but did not alter the risk of residual calcification. Corticosteroid treatment was not significantly associated with any outcome.
Conclusions:
Anthelminthic treatment with albendazole provides improved rates of seizure freedom and hastens resolution of the granuloma. The role of corticosteroid treatment remains uncertain. The benefits (or lack thereof in the case of corticosteroids) are consistent when measured across different time points after treatment.
doi:10.1212/WNL.0b013e31827b90a8
PMCID: PMC3589189  PMID: 23269591
9.  Prevalence of active convulsive epilepsy in sub-Saharan Africa and associated risk factors: cross-sectional and case-control studies 
Lancet Neurology  2013;12(3):253-263.
Summary
Background
The prevalence of epilepsy in sub-Saharan Africa seems to be higher than in other parts of the world, but estimates vary substantially for unknown reasons. We assessed the prevalence and risk factors of active convulsive epilepsy across five centres in this region.
Methods
We did large population-based cross-sectional and case-control studies in five Health and Demographic Surveillance System centres: Kilifi, Kenya (Dec 3, 2007–July 31, 2008); Agincourt, South Africa (Aug 4, 2008–Feb 27, 2009); Iganga-Mayuge, Uganda (Feb 2, 2009–Oct 30, 2009); Ifakara, Tanzania (May 4, 2009–Dec 31, 2009); and Kintampo, Ghana (Aug 2, 2010–April 29, 2011). We used a three-stage screening process to identify people with active convulsive epilepsy. Prevalence was estimated as the ratio of confirmed cases to the population screened and was adjusted for sensitivity and attrition between stages. For each case, an age-matched control individual was randomly selected from the relevant centre's census database. Fieldworkers masked to the status of the person they were interviewing administered questionnaires to individuals with active convulsive epilepsy and control individuals to assess sociodemographic variables and historical risk factors (perinatal events, head injuries, and diet). Blood samples were taken from a randomly selected subgroup of 300 participants with epilepsy and 300 control individuals from each centre and were screened for antibodies to Toxocara canis, Toxoplasma gondii, Onchocerca volvulus, Plasmodium falciparum, Taenia solium, and HIV. We estimated odds ratios (ORs) with logistic regression, adjusted for age, sex, education, employment, and marital status.
Results
586 607 residents in the study areas were screened in stage one, of whom 1711 were diagnosed as having active convulsive epilepsy. Prevalence adjusted for attrition and sensitivity varied between sites: 7·8 per 1000 people (95% CI 7·5–8·2) in Kilifi, 7·0 (6·2–7·4) in Agincourt, 10·3 (9·5–11·1) in Iganga-Mayuge, 14·8 (13·8–15·4) in Ifakara, and 10·1 (9·5–10·7) in Kintampo. The 1711 individuals with the disorder and 2032 control individuals were given questionnaires. In children (aged <18 years), the greatest relative increases in prevalence were associated with difficulties feeding, crying, or breathing after birth (OR 10·23, 95% CI 5·85–17·88; p<0·0001); abnormal antenatal periods (2·15, 1·53–3·02; p<0·0001); and head injury (1·97, 1·28–3·03; p=0·002). In adults (aged ≥18 years), the disorder was significantly associated with admission to hospital with malaria or fever (2·28, 1·06–4·92; p=0·036), exposure to T canis (1·74, 1·27–2·40; p=0·0006), exposure to T gondii (1·39, 1·05–1·84; p=0·021), and exposure to O volvulus (2·23, 1·56–3·19; p<0·0001). Hypertension (2·13, 1·08–4·20; p=0·029) and exposure to T solium (7·03, 2·06–24·00; p=0·002) were risk factors for adult-onset disease.
Interpretation
The prevalence of active convulsive epilepsy varies in sub-Saharan Africa and that the variation is probably a result of differences in risk factors. Programmes to control parasitic diseases and interventions to improve antenatal and perinatal care could substantially reduce the prevalence of epilepsy in this region.
Funding
Wellcome Trust, University of the Witwatersrand, and South African Medical Research Council.
doi:10.1016/S1474-4422(13)70003-6
PMCID: PMC3581814  PMID: 23375964
10.  Significant hypotension following buccal midazolam administration 
BMJ Case Reports  2010;2010:bcr0920103371.
Buccal midazolam is a rescue medication to reduce the duration of or stop an epileptic seizure, and is used to prevent status epilepticus. It is available in various forms, including a buccal preparation with a strength of 10 mg/1 ml. Midazolam is a licensed medication, but the buccal formulation is currently used off-licence. The prescriber takes ultimate responsibility for its use in this way. Administered by a trained person, it is receiving widespread acceptance as an alternative and effective treatment to rectally-administered diazepam in the community. The commonest side effects of midazolam are drowsiness and somnolence, although respiratory depression and paradoxical reactions, for example, agitation, restlessness and disorientation, may also occur. Hypotension is said to be a rare side effect, but with no reported cases in people administered buccal midazolam. The authors report a case of significant hypotension associated with administration of buccal midazolam for seizure management.
doi:10.1136/bcr.09.2010.3371
PMCID: PMC3029668  PMID: 22802329
11.  Correction: Epilepsy Is a Risk Factor for Sudden Cardiac Arrest in the General Population 
PLoS ONE  2012;7(9):10.1371/annotation/847ccbb3-45b2-4338-9ff3-ee5f35c58551.
doi:10.1371/annotation/847ccbb3-45b2-4338-9ff3-ee5f35c58551
PMCID: PMC3525695
12.  Atypical face shape and genomic structural variants in epilepsy 
Brain  2012;135(10):3101-3114.
Many pathogenic structural variants of the human genome are known to cause facial dysmorphism. During the past decade, pathogenic structural variants have also been found to be an important class of genetic risk factor for epilepsy. In other fields, face shape has been assessed objectively using 3D stereophotogrammetry and dense surface models. We hypothesized that computer-based analysis of 3D face images would detect subtle facial abnormality in people with epilepsy who carry pathogenic structural variants as determined by chromosome microarray. In 118 children and adults attending three European epilepsy clinics, we used an objective measure called Face Shape Difference to show that those with pathogenic structural variants have a significantly more atypical face shape than those without such variants. This is true when analysing the whole face, or the periorbital region or the perinasal region alone. We then tested the predictive accuracy of our measure in a second group of 63 patients. Using a minimum threshold to detect face shape abnormalities with pathogenic structural variants, we found high sensitivity (4/5, 80% for whole face; 3/5, 60% for periorbital and perinasal regions) and specificity (45/58, 78% for whole face and perinasal regions; 40/58, 69% for periorbital region). We show that the results do not seem to be affected by facial injury, facial expression, intellectual disability, drug history or demographic differences. Finally, we use bioinformatics tools to explore relationships between facial shape and gene expression within the developing forebrain. Stereophotogrammetry and dense surface models are powerful, objective, non-contact methods of detecting relevant face shape abnormalities. We demonstrate that they are useful in identifying atypical face shape in adults or children with structural variants, and they may give insights into the molecular genetics of facial development.
doi:10.1093/brain/aws232
PMCID: PMC3470710  PMID: 22975390
epilepsy; dysmorphism; structural variants; genomics; dense surface models
13.  Epilepsy Is a Risk Factor for Sudden Cardiac Arrest in the General Population 
PLoS ONE  2012;7(8):e42749.
Background
People with epilepsy are at increased risk for sudden death. The most prevalent cause of sudden death in the general population is sudden cardiac arrest (SCA) due to ventricular fibrillation (VF). SCA may contribute to the increased incidence of sudden death in people with epilepsy. We assessed whether the risk for SCA is increased in epilepsy by determining the risk for SCA among people with active epilepsy in a community-based study.
Methods and Results
This investigation was part of the Amsterdam Resuscitation Studies (ARREST) in the Netherlands. It was designed to assess SCA risk in the general population. All SCA cases in the study area were identified and matched to controls (by age, sex, and SCA date). A diagnosis of active epilepsy was ascertained in all cases and controls. Relative risk for SCA was estimated by calculating the adjusted odds ratios using conditional logistic regression (adjustment was made for known risk factors for SCA). We identified 1019 cases of SCA with ECG-documented VF, and matched them to 2834 controls. There were 12 people with active epilepsy among cases and 12 among controls. Epilepsy was associated with a three-fold increased risk for SCA (adjusted OR 2.9 [95%CI 1.1–8.0.], p = 0.034). The risk for SCA in epilepsy was particularly increased in young and females.
Conclusion
Epilepsy in the general population seems to be associated with an increased risk for SCA.
doi:10.1371/journal.pone.0042749
PMCID: PMC3419243  PMID: 22916156
14.  The Limbic System Conception and Its Historical Evolution 
TheScientificWorldJournal  2011;11:2428-2441.
Throughout the centuries, scientific observers have endeavoured to extend their knowledge of the interrelationships between the brain and its regulatory control of human emotions and behaviour. Since the time of physicians such as Aristotle and Galen and the more recent observations of clinicians and neuropathologists such as Broca, Papez, and McLean, the field of affective neuroscience has matured to become the province of neuroscientists, neuropsychologists, neurologists, and psychiatrists. It is accepted that the prefrontal cortex, amygdala, anterior cingulate cortex, hippocampus, and insula participate in the majority of emotional processes. New imaging technologies and molecular biology discoveries are expanding further the frontiers of knowledge in this arena. The advancements of knowledge on the interplay between the human brain and emotions came about as the legacy of the pioneers mentioned in this field. The aim of this paper is to describe the historical evolution of the scientific understanding of interconnections between the human brain, behaviour, and emotions.
doi:10.1100/2011/157150
PMCID: PMC3236374  PMID: 22194673
Limbic system; behaviour; emotions; neurosciences; historical article
15.  Evidence-Based Guidelines for Mental, Neurological, and Substance Use Disorders in Low- and Middle-Income Countries: Summary of WHO Recommendations 
PLoS Medicine  2011;8(11):e1001122.
Shekhar Saxena and colleagues summarize the recent WHO Mental Health Gap Action Programme (mhGAP) intervention guide that provides evidence-based management recommendations for mental, neurological, and substance use (MNS) disorders.
doi:10.1371/journal.pmed.1001122
PMCID: PMC3217030  PMID: 22110406
16.  Clinical and neurophysiological features of active convulsive epilepsy in rural Kenya: a population based study 
Epilepsia  2010;51(12):2370-2376.
Purpose
Epilepsy is common in sub-Saharan Africa but is poorly characterized. Most studies are hospital-based, and may not reflect the situation in rural areas with limited access to medical care. We examined people with active convulsive epilepsy (ACE), to determine if the clinical features could help elucidate the causes.
Methods
We conducted a detailed descriptive analysis of 445 people with ACE identified through a community-based survey of 151,408 people in rural Kenya, including the examination of electroencephalograms.
Results
Approximately half of the 445 people with ACE were children or adolescents. Seizures began in childhood in 78% of those diagnosed. An episode of status epilepticus was recalled by 36% cases, with an episode of status epilepticus precipitated by fever in 26%. Overall 169 had an abnormal electroencephalogram, 29% had focal features, 34% had epileptiform activity. In the 146 individuals who reported generalised tonic-clonic seizures only, 22% had focal features on their electroencephalogram. Overall 71% of patients with ACE had evidence of focal abnormality, documented by partial onset seizures, focal neurological deficits or focal abnormalities on the electroencephalogram. Increased seizure frequency was strongly associated with age and cognitive impairment in all ages and non-attendance at school in children (p < 0.01).
Discussion
Children and adolescents bear the brunt of epilepsy in a rural population in Africa. The predominance of focal features and the high proportion of patients with status epilepticus, suggests that much of the epilepsy in this region has identifiable causes, many of which could be prevented.
doi:10.1111/j.1528-1167.2010.02653.x
PMCID: PMC3188844  PMID: 20608962
epilepsy; convulsions; partial seizures; electroencephalogram; status epilepticus; sub-Saharan Africa
17.  Assessing suicidal risk with antiepileptic drugs 
Recently, the US Food and Drug Administration issued an alert about an increased risk for suicidality during treatment with antiepileptic drugs (AEDs) for different indications, including epilepsy. We discuss the issue of suicide in epilepsy with special attention to AEDs and the assessment of suicide in people with epilepsy. It has been suggested that early medical treatment with AEDs might potentially reduce suicide risk of people with epilepsy, but it is of great importance that the choice of drug is tailored to the mental state of the patient. The issue of suicidality in epilepsy is likely to represent an example of how the underdiagnosis of psychiatric symptoms, the lack of input from professionals (eg, psychologists, social workers, and psychiatrists), and the delay in an optimized AED therapy may worsen the prognosis of the condition with the occurrence of severe complications such as suicide.
doi:10.2147/NDT.S11999
PMCID: PMC2951743  PMID: 20957120
epilepsy; suicide; adverse effect; depression
18.  Common genetic variation and susceptibility to partial epilepsies: a genome-wide association study 
Brain  2010;133(7):2136-2147.
Partial epilepsies have a substantial heritability. However, the actual genetic causes are largely unknown. In contrast to many other common diseases for which genetic association-studies have successfully revealed common variants associated with disease risk, the role of common variation in partial epilepsies has not yet been explored in a well-powered study. We undertook a genome-wide association-study to identify common variants which influence risk for epilepsy shared amongst partial epilepsy syndromes, in 3445 patients and 6935 controls of European ancestry. We did not identify any genome-wide significant association. A few single nucleotide polymorphisms may warrant further investigation. We exclude common genetic variants with effect sizes above a modest 1.3 odds ratio for a single variant as contributors to genetic susceptibility shared across the partial epilepsies. We show that, at best, common genetic variation can only have a modest role in predisposition to the partial epilepsies when considered across syndromes in Europeans. The genetic architecture of the partial epilepsies is likely to be very complex, reflecting genotypic and phenotypic heterogeneity. Larger meta-analyses are required to identify variants of smaller effect sizes (odds ratio <1.3) or syndrome-specific variants. Further, our results suggest research efforts should also be directed towards identifying the multiple rare variants likely to account for at least part of the heritability of the partial epilepsies. Data emerging from genome-wide association-studies will be valuable during the next serious challenge of interpreting all the genetic variation emerging from whole-genome sequencing studies.
doi:10.1093/brain/awq130
PMCID: PMC2892941  PMID: 20522523
partial epilepsy; genome-wide association; genetics; common variants
19.  Importance of competing risks in the analysis of anti-epileptic drug failure 
Trials  2007;8:12.
Background
Retention time (time to treatment failure) is a commonly used outcome in antiepileptic drug (AED) studies.
Methods
Two datasets are used to demonstrate the issues in a competing risks analysis of AEDs. First, data collection and follow-up considerations are discussed with reference to information from 15 monotherapy trials. Recommendations for improved data collection and cumulative incidence analysis are then illustrated using the SANAD trial dataset. The results are compared to the more common approach using standard survival analysis methods.
Results
A non-significant difference in overall treatment failure time between gabapentin and topiramate (logrank test statistic = 0.01, 1 degree of freedom, p-value = 0.91) masked highly significant differences in opposite directions with gabapentin resulting in fewer withdrawals due to side effects (Gray's test statistic = 11.60, 1 degree of freedom, p = 0.0007) but more due to poor seizure control (Gray's test statistic = 14.47, 1 degree of freedom, p-value = 0.0001). The significant difference in overall treatment failure time between lamotrigine and carbamazepine (logrank test statistic = 5.6, 1 degree of freedom, p-value = 0.018) was due entirely to a significant benefit of lamotrigine in terms of side effects (Gray's test statistic = 10.27, 1 degree of freedom, p = 0.001).
Conclusion
Treatment failure time can be measured reliably but care is needed to collect sufficient information on reasons for drug withdrawal to allow a competing risks analysis. Important differences between the profiles of AEDs may be missed unless appropriate statistical methods are used to fully investigate treatment failure time. Cumulative incidence analysis allows comparison of the probability of failure between two AEDs and is likely to be a more powerful approach than logrank analysis for most comparisons of standard and new anti-epileptic drugs.
doi:10.1186/1745-6215-8-12
PMCID: PMC1853111  PMID: 17394663
20.  Epilepsy and driving 
BMJ : British Medical Journal  2005;331(7508):60-61.
PMCID: PMC558600  PMID: 16002855
21.  Socioeconomic variation in incidence of epilepsy: prospective community based study in south east England 
BMJ : British Medical Journal  2002;325(7371):1013-1016.
Objective
To determine the incidence of epilepsy in a general practice population and its variation with socioeconomic deprivation.
Design
Prospective surveillance for new cases over an 18 or 24 month period.
Participants
All patients on practice registers categorised for deprivation with the Carstairs score of their postcode.
Setting
20 general practices in London and south east England.
Main outcome measure
Confirmed diagnosis of epilepsy.
Results
190 new cases of epilepsy were identified during 369 283 person years of observation (crude incidence 51.5 (95% confidence interval 44.4 to 59.3) per 100 000 per year). The incidence was 190 (138 to 262) per 100 000 in children aged 0-4 years, 30.8 (21.3 to 44.6) in those aged 45-64 years, and 58.7 (42.5 to 81.0) in those aged ⩾65 years. There was no apparent difference in incidence between males and females. The incidence showed a strong association with socioeconomic deprivation, the age and sex adjusted incidence in the most deprived fifth of the study population being 2.33 (1.46 to 3.72) times that in the least deprived fifth (P=0.001 for trend across fifths). Adjustment for area (London v outside London) weakened the association with deprivation (rate ratio 1.62 (0.91 to 2.88), P=0.12 for trend).
Conclusions
The incidence of epilepsy seems to increase with socioeconomic deprivation, though the association may be confounded by other factors.
What is already known on this topicEpilepsy is associated with a wide range of markers of social and economic disadvantageA small number of epidemiological studies have confirmed this association but have not established the direction of causalityWhat this study addsThe incidence of epilepsy, adjusted for age and sex, in the most deprived fifth of the study population was 2.3 times that in the least deprived fifthSocioeconomic deprivation is an important risk factor for the development of epilepsy, though the results may partly reflect differences in incidence within and outside London
PMCID: PMC131020  PMID: 12411362
23.  Estimation of the burden of active and life-time epilepsy: A meta-analytic approach 
Epilepsia  2010;51(5):883-890.
Purpose
To estimate the burden of lifetime epilepsy (LTE) and active epilepsy (AE) and examine the influence of study characteristics on prevalence estimates.
Methods
We searched online databases and identified articles using prespecified criteria. Random-effects meta-analyses were used to estimate the median prevalence in developed countries and in urban and rural settings in developing countries. The impact of study characteristics on prevalence estimates was determined using meta-regression models.
Results
The median LTE prevalence for developed countries was 5.8 per 1,000 (5th–95th percentile range 2.7–12.4) compared to 15.4 per 1,000 (4.8–49.6) for rural and 10.3 (2.8–37.7) for urban studies in developing countries. The median prevalence of AE was 4.9 per 1,000 (2.3–10.3) for developed countries and 12.7 per 1,000 (3.5–45.5) and 5.9 (3.4–10.2) in rural and urban studies in developing countries. The estimates of burden for LTE and AE in developed countries were 6.8 million (5th–95th percentile range 3.2–14.7) and 5.7 million (2.7–12.2), respectively. In developing countries these were 45 (14–145) million LTE and 17 (10–133) million AE in rural areas and 17 (5–61) million LTE and 10 (5–17) million AE in urban areas. Studies involving all ages or only adults showed higher estimates than pediatric studies. Higher prevalence estimates were also associated with rural location and small study size.
Conclusions
This study estimates the global burden of epilepsy and the proportions with AE, which may benefit from treatment. There are systematic differences in reported prevalence estimates, which are only partially explained by study characteristics.
doi:10.1111/j.1528-1167.2009.02481.x
PMCID: PMC3410521  PMID: 20067507
Epilepsy; Prevalence; Burden; Meta-analysis
24.  Incidence of convulsive epilepsy in a rural area in Kenya 
Epilepsia  2013;54(8):1352-1359.
Summary
Purpose
There are only a few studies of incidence of epilepsy in low and middle income countries (LMICs). These are often small and conducted in specific age groups or areas where the prevalence of risk factors is high; therefore, these studies are not representative of the wider populations. We determined the incidence of convulsive epilepsy (CE) in a large rural population in Kenya.
Methods
We conducted two cross‐sectional surveys 5 years apart within a health and demographic surveillance system. Initially we identified residents without epilepsy who were then reexamined in the follow‐up survey to determine incidence. We estimated the overall incidence of CE and incidence by age‐group, sex, and by administrative location. Estimates were adjusted for attrition during case identification and for the sensitivity of the screening method.
Key Findings
In a cohort of 151,408 people, 194 developed CE over the 5 years. The minimum crude incidence rate was 37.6/100,000 persons per year (95% confidence interval (CI) 32.7–43.3) and adjusted for loss to follow‐up, and the sensitivity of the survey methodology was 77.0/100,000 persons per year (95% CI 67.7–87.4). Incidence was highest in children 6–12 years (96.1/100,000 persons per year; 95% CI 78.4–117.9), and was lowest in the 29–49 year age group (37.4/100,000 persons per year; 95% CI 25.7–54.7).
Significance
We estimated a high incidence of convulsive epilepsy in this population. Incidence was highest early and late in life, suggesting that preventive interventions should target exposures that occur in these age groups. Incidence of focal epilepsy was more than twice that of generalized epilepsy, suggesting that etiologies that are amenable to intervention were most important in this population. It is likely that incidence is underestimated because of the early mortality of incident cases.
doi:10.1111/epi.12236
PMCID: PMC4114531  PMID: 23750825
Epilepsy; Convulsive epilepsy; Incidence; Kenya
25.  Clinical features, proximate causes, and consequences of active convulsive epilepsy in Africa 
Epilepsia  2013;55(1):76-85.
Purpose
Epilepsy is common in sub-Saharan Africa (SSA), but the clinical features and consequences are poorly characterized. Most studies are hospital-based, and few studies have compared different ecological sites in SSA. We described active convulsive epilepsy (ACE) identified in cross-sectional community-based surveys in SSA, to understand the proximate causes, features, and consequences.
Methods
We performed a detailed clinical and neurophysiologic description of ACE cases identified from a community survey of 584,586 people using medical history, neurologic examination, and electroencephalography (EEG) data from five sites in Africa: South Africa; Tanzania; Uganda; Kenya; and Ghana. The cases were examined by clinicians to discover risk factors, clinical features, and consequences of epilepsy. We used logistic regression to determine the epilepsy factors associated with medical comorbidities.
Key Findings
Half (51%) of the 2,170 people with ACE were children and 69% of seizures began in childhood. Focal features (EEG, seizure types, and neurologic deficits) were present in 58% of ACE cases, and these varied significantly with site. Status epilepticus occurred in 25% of people with ACE. Only 36% received antiepileptic drugs (phenobarbital was the most common drug [95%]), and the proportion varied significantly with the site. Proximate causes of ACE were adverse perinatal events (11%) for onset of seizures before 18 years; and acute encephalopathy (10%) and head injury prior to seizure onset (3%). Important comorbidities were malnutrition (15%), cognitive impairment (23%), and neurologic deficits (15%). The consequences of ACE were burns (16%), head injuries (postseizure) (1%), lack of education (43%), and being unmarried (67%) or unemployed (57%) in adults, all significantly more common than in those without epilepsy.
Significance
There were significant differences in the comorbidities across sites. Focal features are common in ACE, suggesting identifiable and preventable causes. Malnutrition and cognitive and neurologic deficits are common in people with ACE and should be integrated into the management of epilepsy in this region. Consequences of epilepsy such as burns, lack of education, poor marriage prospects, and unemployment need to be addressed.
doi:10.1111/epi.12392
PMCID: PMC4074306  PMID: 24116877
Sub-Saharan Africa; Clinical features; Active convulsive epilepsy; Comorbidity; Population-based study

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