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1.  Epilepsy Care in Ontario: An Economic Analysis of Increasing Access to Epilepsy Surgery 
In August 2011 a proposed epilepsy care model was presented to the Ontario Health Technology Advisory Committee (OHTAC) by an Expert Panel on a Provincial Strategy for Epilepsy Care in Ontario. The Expert Panel recommended leveraging existing infrastructure in the province to provide enhanced capacity for epilepsy care. The point of entry for epilepsy care and the diagnostic evaluation for surgery candidacy and the epilepsy surgery would occur at regional and district epilepsy centres in London, Hamilton, Toronto, and Ottawa and at new centres recommended for northern and eastern Ontario.
This economic analysis report was requested by OHTAC to provide information about the estimated budgetary impact on the Ontario health care system of increasing access to epilepsy surgery and to examine the cost-effectiveness of epilepsy surgery in both children and adults.
A prevalence-based “top-down” health care system budgetary impact model from the perspective of the Ministry of Health and Long-Term Care was developed to estimate the potential costs associated with expanding health care services to increase access to epilepsy care in general and epilepsy surgery in particular. A 5-year period (i.e., 2012–2016) was used to project annual costs associated with incremental epilepsy care services. Ontario Health Survey estimates of epilepsy prevalence, published epilepsy incidence data, and Canadian Census results for Ontario were used to approximate the number of individuals with epilepsy in the province. Applying these population estimates to data obtained from a recent field evaluation study that examined patterns of care and costs associated with epilepsy surgery in children, a health care system budget impact was calculated and the total costs and incremental costs associated with increasing access to surgery was estimated.
In order to examine the cost-effectiveness of epilepsy surgery in children, a decision analysis compared epilepsy surgery to continued medical management in children with medically intractable epilepsy. Data from the field evaluation were combined with various published data to estimate the costs and outcomes for children with drug-refractory epilepsy over a 20-year period. Outcomes were defined as the number of quality-adjusted life years (QALYs) accumulated over 20 years following epilepsy surgery.
There are about 20,981 individuals with medically intractable epilepsy in Ontario. Of these, 9,619 (1,441 children and 8,178 adults) could potentially be further assessed at regional epilepsy centres for suitability for epilepsy surgery, following initial evaluation at a district epilepsy care centre. The health care system impact analysis related to increasing access to epilepsy surgery in the Ontario through the addition of epilepsy monitoring unit (EMU) beds with video electroencephalography (vEEG) monitoring (total capacity of 15 pediatric EMU beds and 35 adult EMU beds distributed across the province) and the associated clinical resources is estimated to require an incremental $18.1 million (Cdn) annually over the next 5 years from 2012 to 2016. This would allow for about 675 children and 1050 adults to be evaluated each year for suitability for epilepsy surgery representing a 150% increase in pediatric epilepsy surgery evaluation and a 170% increase in adult epilepsy surgery evaluation.
Epilepsy surgery was found to be cost-effective compared to continued medical management in children with drug-refractory epilepsy with the incremental cost-effectiveness ratio of $25,020 (Cdn) to $69,451 (Cdn) per QALY for 2 of the scenarios examined. In the case of choosing epilepsy surgery versus continued medical management in children known to be suitable for surgery, the epilepsy surgery was found to be less costly and provided greater clinical benefit, that is, it was the dominant strategy.
Epilepsy surgery for medically intractable epilepsy in suitable candidates has consistently been found to provide favourable clinical outcomes and has been demonstrated to be cost-effective in both adult and child patient populations. The first step to increasing access to epilepsy surgery is to provide access to evidence-based care for all patients with epilepsy, both adults and children, through the provision of resources to expand EMU bed capacity and associated clinical personnel across the province of Ontario.
Plain Language Summary
Epilepsy, characterized by recurrent, unpredictable, and spontaneous seizures, affects approximately 70,000 people in Ontario. About 30% continue to suffer from seizures despite using 2 or more anti-seizure medications. For these individuals epilepsy surgery is a treatment option to stop the seizures or at least reduce their frequency. Awareness of this treatment option is not widespread and people are not commonly referred to those hospitals in Ontario where this surgery is available. A proposal to increase access to epilepsy care and surgery has been made by an expert committee that provided a report to the Ontario Health Technology Advisory Committee (OHTAC). In order to address the lack of access of patients with medically intractable epilepsy to the possibility of curative surgical treatment, it is necessary to design a system that provides equal availability of evidence-based treatment for all epilepsy patients in Ontario, both adults and children. To this end, the establishment of district epilepsy care centres and the further development of the existing regional epilepsy care centres in the province have been proposed. This report outlines the estimated additional funds that will be required to implement the proposal. It also examines the cost-effectiveness of referral to these centres and epilepsy surgery.
For the 21,000 people in the province with drug-refractory epilepsy, referral to an epilepsy monitoring unit (EMU) located at one of the epilepsy care centres is the first step to determining if epilepsy surgery is an option for them. The expert committee proposal suggests that the number of EMU beds be increased from the current 19 to 50 to allow for the assessment of those individuals with drug-refractory epilepsy. The health care system budget impact model presented in this report estimates that it would cost approximately $18 million (Cdn) each year over the next 5 years to increase the number of EMU beds and expand associated epilepsy care centres to permit the systematic evidence-based care of all Ontarians with epilepsy and evaluate more people for surgery candidacy. This amount would provide appropriate care for patients with epilepsy and ensure that about 675 children and 1050 adults could be assessed each year for suitability for epilepsy surgery. Surgery could then be made available to just over 300 people per year.
Epilepsy surgery over the long term is a less expensive treatment alternative for adults and children with medically refractory epilepsy compared with continued drug treatment. In addition, drug treatment does not always work for some patients; nor does it necessarily provide improved quality of life.
This report includes a cost-effectiveness analysis comparing referral for assessment for epilepsy surgery with continuing medical management in children with drug-refractory epilepsy. In all the cases examined epilepsy surgery provides good value for money over a 20-year period. Similar studies have found that the benefits from epilepsy surgery outweigh those of continuing medical management in adult patients with medically refractory epilepsy.
PMCID: PMC3428718  PMID: 23074428
2.  Epilepsy (partial) 
Clinical Evidence  2011;2011:1214.
About 3% of people will be diagnosed with epilepsy during their lifetime, but about 70% of people with epilepsy eventually go into remission.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of starting antiepileptic drug treatment following a single seizure? What are the effects of drug monotherapy in people with partial epilepsy? What are the effects of additional drug treatments in people with drug-resistant partial epilepsy? What is the risk of relapse in people in remission when withdrawing antiepileptic drugs? What are the effects of behavioural and psychological treatments for people with epilepsy? What are the effects of surgery in people with drug-resistant temporal lobe epilepsy? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2009 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
We found 83 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
In this systematic review we present information relating to the effectiveness and safety of the following interventions: antiepileptic drugs after a single seizure; monotherapy for partial epilepsy using carbamazepine, gabapentin, lamotrigine, levetiracetam, phenobarbital, phenytoin, sodium valproate, or topiramate; addition of second-line drugs for drug-resistant partial epilepsy (allopurinol, eslicarbazepine, gabapentin, lacosamide, lamotrigine, levetiracetam, losigamone, oxcarbazepine, retigabine, tiagabine, topiramate, vigabatrin, or zonisamide); antiepileptic drug withdrawal for people with partial or generalised epilepsy who are in remission; behavioural and psychological treatments for partial or generalised epilepsy (biofeedback, cognitive behavioural therapy (CBT), educational programmes, family counselling, relaxation therapy (alone or plus behavioural modification therapy, yoga); and surgery for drug-resistant temporal lobe epilepsy ( lesionectomy, temporal lobectomy, vagus nerve stimulation as adjunctive therapy).
Key Points
During their lifetime, about 3% of people will be diagnosed with epilepsy, but about 70% of people with epilepsy eventually go into remission.
After a first seizure, antiepileptic drugs may delay or prevent subsequent seizures, but they can cause adverse effects, and their long-term benefit is unknown. Antiepileptic drug treatment after a single seizure does not reduce the risk of drug refractory epilepsy in the long term.
Carbamazepine, gabapentin, lamotrigine, levetiracetam, phenobarbital, phenytoin, sodium valproate, and topiramate are widely considered effective in controlling seizures in newly diagnosed partial epilepsy, but we found no RCTs comparing them with placebo, and a placebo-controlled trial would now be considered unethical. Systematic reviews found no reliable evidence on which to base a choice among antiepileptic drugs. Adding second-line drugs to usual treatment reduces seizure frequency in people with drug-resistant partial epilepsy, but it increases adverse effects such as dizziness and somnolence. We don't know if any one antiepileptic drug is more likely to reduce seizures compared with the others.
CAUTION: Vigabatrin, which may be used as second-line treatment, causes concentric visual-field abnormalities in about 40% of people, which are probably irreversible.
In people who have been seizure free for at least 2 years on treatment, almost 60% of those with partial or generalised epilepsy who withdraw from antiepileptic treatment will remain seizure free, compared with almost 80% of people who continue treatment.
Educational programmes may reduce seizure frequency and improve psychosocial functioning in people with partial or generalised epilepsy, but we don't know whether relaxation, yoga, biofeedback, CBT, relaxation plus behavioural modification, or family counselling are beneficial.
There is consensus that temporal lobectomy or amygdalohippocampectomy can improve seizure control and quality of life in people with drug-resistant temporal lobe epilepsy, but they can cause neurological adverse effects.
High-level vagus nerve stimulation may reduce seizure frequency in people with drug-resistant partial seizures, but it may cause hoarseness and dyspnoea, and long-term effects are unknown. We don't know whether different stimulation cycles are more effective at reducing seizure frequency or at increasing the proportion of responders.
We don't know whether lesionectomy improves seizure control in people with drug-resistant temporal lobe epilepsy.
PMCID: PMC3217777  PMID: 21549021
3.  Association of Human Herpesvirus-6B with Mesial Temporal Lobe Epilepsy 
PLoS Medicine  2007;4(5):e180.
Human herpesvirus-6 (HHV-6) is a β-herpesvirus with 90% seroprevalence that infects and establishes latency in the central nervous system. Two HHV-6 variants are known: HHV-6A and HHV-6B. Active infection or reactivation of HHV-6 in the brain is associated with neurological disorders, including epilepsy, encephalitis, and multiple sclerosis. In a preliminary study, we found HHV-6B DNA in resected brain tissue from patients with mesial temporal lobe epilepsy (MTLE) and have localized viral antigen to glial fibrillary acidic protein (GFAP)–positive glia in the same brain sections. We sought, first, to determine the extent of HHV-6 infection in brain material resected from MTLE and non-MTLE patients; and second, to establish in vitro primary astrocyte cultures from freshly resected brain material and determine expression of glutamate transporters.
Methods and Findings
HHV-6B infection in astrocytes and brain specimens was investigated in resected brain material from MTLE and non-MTLE patients using PCR and immunofluorescence. HHV-6B viral DNA was detected by TaqMan PCR in brain resections from 11 of 16 (69%) additional patients with MTLE and from zero of seven (0%) additional patients without MTLE. All brain regions that tested positive by HHV-6B variant-specific TaqMan PCR were positive for viral DNA by nested PCR. Primary astrocytes were isolated and cultured from seven epilepsy brain resections and astrocyte purity was defined by GFAP reactivity. HHV-6 gp116/54/64 antigen was detected in primary cultured GFAP-positive astrocytes from resected tissue that was HHV-6 DNA positive—the first demonstration of an ex vivo HHV-6–infected astrocyte culture isolated from HHV-6–positive brain material. Previous work has shown that MTLE is related to glutamate transporter dysfunction. We infected astrocyte cultures in vitro with HHV-6 and found a marked decrease in glutamate transporter EAAT-2 expression.
Overall, we have now detected HHV-6B in 15 of 24 patients with mesial temporal sclerosis/MTLE, in contrast to zero of 14 with other syndromes. Our results suggest a potential etiology and pathogenic mechanism for MTLE.
Steve Jacobson and colleagues report finding human herpesvirus-6B DNA in brain resections from 11 of 16 patients with mesial temporal lobe epilepsy, strengthening the evidence for a role for this virus in this condition.
Editors' Summary
Epilepsy is a common brain disorder caused by a sudden, excessive electrical discharge in a cluster of neurons—the cells that transmit electrical messages between the body and the brain. Its symptoms depend on which part of the brain is affected by this electrical firestorm and how far the disturbance spreads. When only part of the brain is affected (a partial seizure or fit), patients may see or smell strange things, recall forgotten memories, or have part of their body jerk uncontrollably. When the electrical disturbance spreads across the whole brain (a generalized seizure), there may be loss of consciousness and/or the whole body may become rigid or jerk. Epilepsy is usually controlled with anti-epileptic drugs or, in very severe focal cases, surgery to the area of the brain where the seizure starts. Although head injuries or brain tumors can trigger epilepsy, the cause of most cases of epilepsy is unknown.
Why Was This Study Done?
Knowing what causes epilepsy might lead to better treatments for it. One possibility is that infections trigger epilepsy. The researchers in this study asked whether infections with human herpesvirus 6B (HHV-6B) are associated with a common type of epilepsy called mesial temporal lobe epilepsy (MTLE). Patients with MTLE often have extensive scarring in the hippocampus, a brain region responsible for memory that lies deep within a bigger region called the temporal lobe. Hippocampal scarring and MTLE are associated with a history of fever-induced fits, and HHV-6B infection can cause such fits in young children. Most people become infected with HHV-6B (or the closely related HHV-6A) early in life. The virus then remains latent for years within the brain and elsewhere. Given these facts and a previous investigation that showed that brain tissue from several patients with MTLE contained HHV-6B, the researchers reasoned that it was worth investigating HHV-6B as a cause of MTLE.
What Did the Researchers Do and Find?
The researchers first looked for HHV-6B DNA in brain tissue surgically removed from patients with MTLE or another type of epilepsy. Tissue from 11 of 16 patients with MTLE (but from 0 of 7 control patients) contained HHV-6B DNA. When the researchers grew astrocytes (a type of brain cell) from some of these samples, only those from HHV-6B DNA-positive samples from patients with MTLE expressed an HHV-6-specific protein. Next, the researchers investigated in detail a patient with MTLE who had four sequential operations to control his epilepsy. This patient's hippocampus, which was removed in his first operation, contained a higher level of HHV-6B DNA than the tissues removed in later operations. After the fourth operation (which removed half of his brain and cured his epilepsy), astrocytes grown from the temporal lobe and the frontal/parietal lobe (a brain region next to the temporal lobe) but not the frontal and occipital lobes contained HHV-6B DNA and expressed a viral protein. The researchers also measured the production by these various astrocytes of a substance that moves glutamate (an amino acid that also acts as a neurotransmitter) across cell membranes—MTLE has been associated with a glutamate transporter deficiency. Consistent with this, astrocytes from the patient's temporal lobe made no glutamate transporter mRNA (mRNA is an essential precursor for protein to be produced). Finally, infection of astrocytes isolated from a patient without MTLE with HHV-6B greatly reduced expression of glutamate transporter in these astrocytes.
What Do These Findings Mean?
These findings, together with those from the previous study, reveal that nearly two-thirds of patients with MTLE (but no patients with other forms of epilepsy) have an active HHV-6B infection in the brain region where their epilepsy originates. Overall, they provide strong support for the idea that HHV-6B infections might cause MTLE, particularly given the results obtained from the patient whose condition only improved after multiple brain operations had removed all the virally infected material. Furthermore, the demonstration that HHV-6B infection reduces glutamate transporter expression in astrocytes suggests that HHV-6B infection might cause astrocyte dysfunction. This dysfunction could lead to injury of the sensitive neurons in the hippocampus and trigger MTLE. Additional patients now need to be studied both to confirm the association between HHV-6B infection and MTLE and to discover exactly how this virus triggers epilepsy.
Additional Information.
Please access these Web sites via the online version of this summary at
MedlinePlus encyclopedia page on epilepsy (in English and Spanish)
World Health Organization fact sheet on epilepsy (in English, French, Spanish, Russian, Arabic, and Chinese)
US National Institute for Neurological Disorders and Stroke epilepsy information page (in English and Spanish)
UK National Health Service Direct information for patients on epilepsy (in several languages)
Neuroscience for kids, an educational Web site prepared by Eric Chudler (University of Washington, Seattle, Washington, United States), who also has a site that includes information on epilepsy and a list of links to epilepsy organizations (mainly in English but some sections in other languages as well)
A short scientific article on human herpes virus 6 in the journal Emerging Infectious Diseases
PMCID: PMC1880851  PMID: 17535102
4.  Greater Response to Placebo in Children Than in Adults: A Systematic Review and Meta-Analysis in Drug-Resistant Partial Epilepsy 
PLoS Medicine  2008;5(8):e166.
Despite guidelines establishing the need to perform comprehensive paediatric drug development programs, pivotal trials in children with epilepsy have been completed mostly in Phase IV as a postapproval replication of adult data. However, it has been shown that the treatment response in children can differ from that in adults. It has not been investigated whether differences in drug effect between adults and children might occur in the treatment of drug-resistant partial epilepsy, although such differences may have a substantial impact on the design and results of paediatric randomised controlled trials (RCTs).
Methods and Findings
Three electronic databases were searched for RCTs investigating any antiepileptic drug (AED) in the add-on treatment of drug-resistant partial epilepsy in both children and adults. The treatment effect was compared between the two age groups using the ratio of the relative risk (RR) of the 50% responder rate between active AEDs treatment and placebo groups, as well as meta-regression. Differences in the response to placebo and to active treatment were searched using logistic regression. A comparable approach was used for analysing secondary endpoints, including seizure-free rate, total and adverse events-related withdrawal rates, and withdrawal rate for seizure aggravation. Five AEDs were evaluated in both adults and children with drug-resistant partial epilepsy in 32 RCTs. The treatment effect was significantly lower in children than in adults (RR ratio: 0.67 [95% confidence interval (CI) 0.51–0.89]; p = 0.02 by meta-regression). This difference was related to an age-dependent variation in the response to placebo, with a higher rate in children than in adults (19% versus 9.9%, p < 0.001), whereas no significant difference was observed in the response to active treatment (37.2% versus 30.4%, p = 0.364). The relative risk of the total withdrawal rate was also significantly lower in children than in adults (RR ratio: 0.65 [95% CI 0.43–0.98], p = 0.004 by metaregression), due to higher withdrawal rate for seizure aggravation in children (5.6%) than in adults (0.7%) receiving placebo (p < 0.001). Finally, there was no significant difference in the seizure-free rate between adult and paediatric studies.
Children with drug-resistant partial epilepsy receiving placebo in double-blind RCTs demonstrated significantly greater 50% responder rate than adults, probably reflecting increased placebo and regression to the mean effects. Paediatric clinical trial designs should account for these age-dependent variations of the response to placebo to reduce the risk of an underestimated sample size that could result in falsely negative trials.
In a systematic review of antiepileptic drugs, Philippe Ryvlin and colleagues find that children with drug-resistant partial epilepsy enrolled in trials seem to have a greater response to placebo than adults enrolled in such trials.
Editors' Summary
Whenever an adult is given a drug to treat a specific condition, that drug will have been tested in “randomized controlled trials” (RCTs). In RCTs, a drug's effects are compared to those of another drug for the same condition (or to a placebo, dummy drug) by giving groups of adult patients the different treatments and measuring how well each drug deals with the condition and whether it has any other effects on the patients' health. However, many drugs given to children have only been tested in adults, the assumption being that children can safely take the same drugs as adults provided the dose is scaled down. This approach to treatment is generally taken in epilepsy, a common brain disorder in children in which disruptions in the electrical activity of part (partial epilepsy) or all (generalized epilepsy) of the brain cause seizures. The symptoms of epilepsy depend on which part of the brain is disrupted and can include abnormal sensations, loss of consciousness, or convulsions. Most but not all patients can be successfully treated with antiepileptic drugs, which reduce or stop the occurrence of seizures.
Why Was This Study Done?
It is increasingly clear that children and adults respond differently to many drugs, including antiepileptic drugs. For example, children often break down drugs differently from adults, so a safe dose for an adult may be fatal to a child even after scaling down for body size, or it may be ineffective because of quicker clearance from the child's body. Consequently, regulatory bodies around the world now require comprehensive drug development programs in children as well as in adults. However, for pediatric trials to yield useful results, the general differences in the treatment response between children and adults must first be determined and then allowed for in the design of pediatric RCTs. In this study, the researchers investigate whether there is any evidence in published RCTs for age-dependent differences in the response to antiepileptic drugs in drug-resistant partial epilepsy.
What Did the Researchers Do and Find?
The researchers searched the literature for reports of RCTs on the effects of antiepileptic drugs in the add-on treatment of drug-resistant partial epilepsy in children and in adults—that is, trials that compared the effects of giving an additional antiepileptic drug with those of giving a placebo by asking what fraction of patients given each treatment had a 50% reduction in seizure frequency during the treatment period compared to a baseline period (the “50% responder rate”). This “systematic review” yielded 32 RCTs, including five pediatric RCTs. The researchers then compared the treatment effect (the ratio of the 50% responder rate in the treatment arm to the placebo arm) in the two age groups using a statistical approach called “meta-analysis” to pool the results of these studies. The treatment effect, they report, was significantly lower in children than in adults. Further analysis indicated that this difference was because more children than adults responded to the placebo. Nearly 1 in 5 children had a 50% reduction in seizure rate when given a placebo compared to only 1 in 10 adults. About a third of both children and adults had a 50% reduction in seizure rate when given antiepileptic drugs.
What Do These Findings Mean?
These findings, although limited by the small number of pediatric trials done so far, suggest that children with drug-resistant partial epilepsy respond more strongly in RCTs to placebo than adults. Although additional studies need to be done to find an explanation for this observation and to discover whether anything similar occurs in other conditions, this difference between children and adults should be taken into account in the design of future pediatric trials on the effects of antiepileptic drugs, and possibly drugs for other conditions. Specifically, to reduce the risk of false-negative results, this finding suggests that it might be necessary to increase the size of future pediatric trials to ensure that the trials have enough power to discover effects of the drugs tested, if they exist.
Additional Information.
Please access these Web sites via the online version of this summary at
This study is further discussed in a PLoS Medicine Perspective by Terry Klassen and colleagues
The European Medicines Agency provides information about the regulation of medicines for children in Europe
The US Food and Drug Administration Office of Pediatric Therapeutics provides similar information for the US
The UK Medicines and Healthcare products Regulatory Agency also provides information on why medicines need to be tested in children
The MedlinePlus encyclopedia has a page on epilepsy (in English and Spanish)
The US National Institute for Neurological Disorders and Stroke and the UK National Health Service Direct health encyclopedia both provide information on epilepsy for patients (in several languages)
Neuroscience for Kids is an educational Web site prepared by Eric Chudler (University of Washington, Seattle, US) that includes information on epilepsy and a list of links to epilepsy organizations (mainly in English but some sections in other languages as well)
PMCID: PMC2504483  PMID: 18700812
5.  Epilepsy and seizure ontology: towards an epilepsy informatics infrastructure for clinical research and patient care 
Epilepsy encompasses an extensive array of clinical and research subdomains, many of which emphasize multi-modal physiological measurements such as electroencephalography and neuroimaging. The integration of structured, unstructured, and signal data into a coherent structure for patient care as well as clinical research requires an effective informatics infrastructure that is underpinned by a formal domain ontology.
We have developed an epilepsy and seizure ontology (EpSO) using a four-dimensional epilepsy classification system that integrates the latest International League Against Epilepsy terminology recommendations and National Institute of Neurological Disorders and Stroke (NINDS) common data elements. It imports concepts from existing ontologies, including the Neural ElectroMagnetic Ontologies, and uses formal concept analysis to create a taxonomy of epilepsy syndromes based on their seizure semiology and anatomical location.
EpSO is used in a suite of informatics tools for (a) patient data entry, (b) epilepsy focused clinical free text processing, and (c) patient cohort identification as part of the multi-center NINDS-funded study on sudden unexpected death in epilepsy. EpSO is available for download at
An epilepsy ontology consortium is being created for community-driven extension, review, and adoption of EpSO. We are in the process of submitting EpSO to the BioPortal repository.
EpSO plays a critical role in informatics tools for epilepsy patient care and multi-center clinical research.
PMCID: PMC3912711  PMID: 23686934
Epilepsy and Seizure Ontology; Patient Data Capture; Clinical Free Text Processing; Clinical Data Integration
6.  Prevalence and characteristics of epilepsy in the Belgian shepherd variants Groenendael and Tervueren born in Denmark 1995–2004 
The Belgian shepherd Groenendael and Tervueren is believed to be at higher risk of developing epilepsy than dogs of the common population. This epidemiological study was designed to estimate the prevalence of epilepsy in the Danish population of Groenendael and Tervueren born between 1995 and 2004. Furthermore, it was the intention to describe the clinical manifestation (seizure types and phenomenology) of epilepsy and to identify risk factors for euthanasia once the dog was diagnosed as having epilepsy.
All owners of Groenendael and Tervueren dogs born between January 1995 and December 2004 and registered in the Danish Kennel Club (1,248 dogs) were contacted and asked to answer a mailed questionnaire concerning epilepsy. Positive responders were subsequently validated in a follow-up interview conducted by telephone using a standardized questionnaire. Owners were questioned about age at first seizure, seizure frequency, seizure duration, a detailed description of seizure phenomenology, post-ictal signs and if a veterinarian had diagnosed the dog with epilepsy.
Prevalence of epilepsy was estimated at 9.5%. Mean age of epilepsy debut was 3.3 years (range 0.5–8.0 years). There was an almost equal number of Groenendael (25) and Tervueren (24). The distribution of females and males was 31 and 18 respectively. Twenty-five per cent experienced focal seizures, 53% experienced focal seizures with secondary generalization and 18% experienced primary generalized seizures. In four percent seizures were unclassifiable. The most commonly reported focal seizure phenomenology included ataxia, crawling, swaying, fearful behavior, salivation, excessive attention seeking and disorientation. In 16% of the cases, epilepsy led to euthanasia. Intact dogs with epilepsy had a significantly increased risk of being euthanized because of epilepsy compared to neutered dogs with epilepsy. In 22% of the cases the owners reported that anxiety/hyperactivity/stress could act as a seizure provoking factor.
A high prevalence of epilepsy appears to be present in the Danish Groenendael and Tervueren population. The relatively late debut age of epilepsy in this breed contributes greatly to the increased prevalence of epileptic individuals, because dogs developing epilepsy late in life are used for breeding unintended.
PMCID: PMC2633289  PMID: 19102738
7.  Abnormal white matter correlates with neuropsychological impairment in children with localization-related epilepsy 
Epilepsia  2013;54(6):10.1111/epi.12208.
The white matter (WM) is considered critical for linking cortical processing networks necessary for cognition. The aim of this study was to assess diffusion tensor imaging (DTI) measures of regional WM in children with nonlesional localization-related epilepsy in comparison to controls, and to determine the relation between lobar WM and neuropsychological performance.
Forty children with nonlesional localization-related epilepsy and 25 healthy controls with no neurological or psychiatric disorders and normal magnetic resonance imaging (MRI) were recruited. All patients and controls underwent neuropsychological testing that evaluated intelligence, language, memory, executive function, and motor function, as well as DTI to assess regional WM measures of fractional anisotropy (FA) and mean diffusivity (MD). The regional FA and MD were compared between patients and controls, and correlated with neuropsychological function. The relations between regional FA and MD with age at seizure onset and duration of epilepsy were assessed.
Key Findings
Twenty-one patients had left-sided and 19 patients had right-sided epilepsy. There were no significant differences in seizure-related variables including age at seizure onset, duration of epilepsy, seizure frequency, and number of antiepileptic medications, as well as no significant differences in neuropsychological function and DTI measures of white matter in left-sided compared to right-sided epilepsy. Therefore, all the patients with epilepsy were treated as one group. Patients with epilepsy performed significantly worse on intelligence (p < 0.001), language (p < 0.001), and executive function (p = 0.001) evaluation than controls. Patients had significantly reduced FA in left frontal (p = 0.015), right frontal (p = 0.004), left temporal (p = 0.039), right temporal (p = 0.003), right parietal (p = 0.014), and right occipital (p = 0.025) WM relative to controls. There were no significant regional WM differences (all p > 0.05) in MD between patients and controls. There was a significant positive correlation between right temporal FA with language (r = 0.535, p < 0.001) and executive function (r = 0.617, p < 0.001), as well as between body of corpus callosum FA with intelligence (r = 0.536, p < 0.001) and language (r = 0.529, p < 0.001) in patients. Left parietal MD was significantly correlated with language (r = −0.545, p < 0.001) in patients. FA of right temporal WM was significantly associated with age at seizure onset (t = 4.97, p < 0.001).
There was widespread regional WM abnormality in children with nonlesional localization-related epilepsy, which was associated with impaired neuropsychological function. The impairment in WM may reflect disruption in the connectivity for cortical processing networks, which is necessary for the development of cognition.
PMCID: PMC3867411  PMID: 23650911 CAMSID: cams3764
Diffusion tensor imaging; Pediatric epilepsy; Neuropsychological function
8.  A neuropsychological assessment, using computerized battery tests (CANTAB), in children with benign rolandic epilepsy before AED therapy  
Journal of Medicine and Life  2012;5(1):114-119.
Rationale: Benign rolandic epilepsy (BRE) is a form of partial idiopathic epilepsy according to the International League Against Epilepsy (ILAE) syndromes classification (1989). Recent studies have identified cases of BRE that do not meet the initial definition of ‘benign’; these included reports of cases with specific cognitive deficits. It is still a matter of debate, whether these deficits are due to epilepsy per se, to treatment or other associated factors.
Objectives: The aim of this study was to evaluate if BRE children have cognitive deficits at the onset of their seizures, prior to their participation in any anti-epileptic drug therapy (AED).
Methods and Results: We performed a neuropsychological assessment of 18 BRE children compared with a corresponding age-matched control group. We used the Cambridge Neuropsychological Test Automated Battery (CANTAB). Subjects were at their first neurological evaluation, before any AED therapy. We assessed: visual memory, induction and executive functions. In our group, the BRE children performed comparably with the control children for the induction and executive functions. Substantial differences were identified for the visual memory subtests: PRM percent correct (t = -2.58, p = 0.01) and SRM percent correct (t = -2.73, p = 0.01). Age of seizure onset had a negative impact on the visual memory subtest performances (PRM mean correct latency). We found significant correlations between the different CANTAB subtests results and characteristics of the centrotemporal spikes (CTS).
Discussion: Our results are consistent with the findings of other similar studies. This form of epilepsy is associated with subtle neuropsychological deficits, present at seizure onset. Neuropsychological deficits identified, suggest a more diffuse brain involvement in the epileptiform process.
Abbreviations: AED – AntiEpileptic Drug; BECTS - benign childhood epilepsy with centrotemporal spikes; BRE – Benign Rolandic Epilepsy; CANTAB - the Cambridge Neuropsychological Test Automated Battery; CTS – centrotemporal spikes; DMS – Delayed Matching Sample; EEG – electroencephalogram; ILAE – International league Against Epilepsy; MOT – Motor screening Test; PAL - Paired Associates Learning; PRM - Pattern Recognition Memory; SPSS - Statistical Package for the Social Sciences; SRM - Spatial Recognition Memory; SSP - Spatial Span, SWM - Spatial Working Memory
PMCID: PMC3307071  PMID: 22574100
benign; rolandic; children; epilepsy; CANTAB
9.  Predictors of outcome and pathological considerations in the surgical treatment of intractable epilepsy associated with temporal lobe lesions 
OBJECTIVES—To evaluate the influence of clinical, investigative, and pathological factors on seizure remission after temporal lobectomy for medically intractable epilepsy associated with focal lesions other than hippocampal sclerosis.
METHODS—From a series of 234 consecutive "en bloc" temporal resections for medically intractable epilepsy performed between 1976 and 1995, neuropathological examination disclosed a focal lesion in 80. The preoperative clinical, neuropsychological, interictal EEG, and neuroimaging characteristics of these patients were assembled in a computerised database. The original neuropathological material was re-examined for lesion classification and completeness of removal. The presence of additional cortical dysplasia and mesial temporal sclerosis was also noted. Survival analysis was performed using Kaplein-Meier curves and actuarial statistics. Logistic regression analysis was used to establish the independent significance of the clinical variables.
RESULTS—The probability of achieving a 1 year seizure remission was 71% by 5 years of follow up. Factors predicting a poor outcome on multivariate analysis included the need for special schooling and a long duration of epilepsy. Generalised tonic-clonic seizures, interictal EEG discharges confined to the resected lobe, demonstration of the lesion preoperatively on CT, and complete histological resection of the lesion were not predictive of outcome. Neuropsychological tests correctly predicted outcome in left sided cases but apparently congruent findings in right sided resections were associated with a poor outcome. Pathological reclassification established the dysembryoplastic neuroepithelial tumour as the commonest neoplasm (87%) in this series, with a significantly better seizure outcome than for developmental lesions, such as focal cortical dysplasia.
CONCLUSIONS—The findings highlight the importance of dysembryoplastic neuroepithelial tumour in the pathogenesis of medically refractory lesional temporal lobe epilepsy and the prognostic significance of preoperative duration of epilepsy emphasises the need for early recognition and surgical treatment. Cognitive and behavioural dysfunction, however, is associated with a lower seizure remission rate, independent of duration of epilepsy.

PMCID: PMC1737320  PMID: 11254766
10.  Characteristics of late-onset epilepsy and EEG findings in children with autism spectrum disorders 
Korean Journal of Pediatrics  2011;54(1):22-28.
To investigate the clinical characteristics of late-onset epilepsy combined with autism spectrum disorder (ASD), and the relationship between certain types of electroencephalography (EEG) abnormalities in ASD and associated neuropsychological problems.
Thirty patients diagnosed with ASD in early childhood and later developed clinical seizures were reviewed retrospectively. First, the clinical characteristics, language and behavioral regression, and EEG findings of these late-onset epilepsy patients with ASD were investigated. The patients were then classified into 2 groups according to the severity of the EEG abnormalities in the background rhythm and paroxysmal discharges. In the severe group, EEG showed persistent asymmetry, slow and disorganized background rhythms, and continuous sharp and slow waves during slow sleep (CSWS).
Between the two groups, there was no statistically significant difference in mean age (P=0.259), age of epilepsy diagnosis (P=0.237), associated family history (P=0.074), and positive abnormal magnetic resonance image (MRI) findings (P=0.084). The severe EEG group tended to have more neuropsychological problems (P=0.074). The severe group statistically showed more electrographic seizures in EEG (P=0.000). Rett syndrome was correlated with more severe EEG abnormalities (P=0.002). Although formal cognitive function tests were not performed, the parents reported an improvement in neuropsychological function on the follow up checkup according to a parent's questionnaire.
Although some ASD patients with late-onset epilepsy showed severe EEG abnormalities, including CSWS, they generally showed an improvement in EEG and clinical symptoms in the long-term follow up. In addition, severe EEG abnormalities tended to be related to the neuropsychological function.
PMCID: PMC3040362  PMID: 21359057
Autism spectrum disorder; Epilepsy; Electroencephalography; Regression; Child
11.  Risk factors of childhood epilepsy in Kerala 
We aimed to identify the risk factors for epilepsy in children.
Materials and Methods:
This case–control retrospective study was carried out in the pediatric neurology outpatient service of the Trivandrum Medical College. All children (1–12 years) with epilepsy satisfying the selection criteria were included, after obtaining consent from parents. Those with single seizures or febrile seizures were excluded. Controls were children without epilepsy attending the same hospital. Parents were interviewed and clinical data were obtained from medical records. Statistical analysis included chi-square test, odds ratio (OR), and logistic regression.
There were 82 cases and 160 controls whose mean age was 6.9 + 3.6 and 5.2 + 3.1, years respectively. On univariate analysis, family history of epilepsy, prolonged labor, cyanosis at birth, delayed cry after birth, admission to newborn intensive care unit, presence of congenital malformations, neurocutaneous markers, incessant cry in the first week, delayed developmental milestones, meningitis, encephalitis, and head trauma were found to be significant. On logistic regression, family history of epilepsy (OR 4.7), newborn distress (OR 8.6), delayed developmental milestones (OR 12.6), and head trauma (OR 5.8) were found to be significant predictors. Infants who had history of newborn distress are likely to manifest epilepsy before 1 year if they are eventually going to have epilepsy (OR 3.4).
Modifiable factors such as newborn distress and significant head trauma are significant risk factors for childhood epilepsy. Newborn distress is a risk factor for early-onset (<1 year age) epilepsy.
PMCID: PMC3271468  PMID: 22346018
Epilepsy; Kerala; risk factor
12.  Identifying Neural Drivers with Functional MRI: An Electrophysiological Validation 
PLoS Biology  2008;6(12):e315.
Whether functional magnetic resonance imaging (fMRI) allows the identification of neural drivers remains an open question of particular importance to refine physiological and neuropsychological models of the brain, and/or to understand neurophysiopathology. Here, in a rat model of absence epilepsy showing spontaneous spike-and-wave discharges originating from the first somatosensory cortex (S1BF), we performed simultaneous electroencephalographic (EEG) and fMRI measurements, and subsequent intracerebral EEG (iEEG) recordings in regions strongly activated in fMRI (S1BF, thalamus, and striatum). fMRI connectivity was determined from fMRI time series directly and from hidden state variables using a measure of Granger causality and Dynamic Causal Modelling that relates synaptic activity to fMRI. fMRI connectivity was compared to directed functional coupling estimated from iEEG using asymmetry in generalised synchronisation metrics. The neural driver of spike-and-wave discharges was estimated in S1BF from iEEG, and from fMRI only when hemodynamic effects were explicitly removed. Functional connectivity analysis applied directly on fMRI signals failed because hemodynamics varied between regions, rendering temporal precedence irrelevant. This paper provides the first experimental substantiation of the theoretical possibility to improve interregional coupling estimation from hidden neural states of fMRI. As such, it has important implications for future studies on brain connectivity using functional neuroimaging.
Author Summary
Our understanding of how the brain works relies on the development of neuropsychological models, which describe how brain activity is coordinated among different regions during the execution of a given task. Knowing the directionality of information transfer between connected regions, and in particular distinguishing neural drivers, or the source of forward connections in the brain, from other brain regions, is critical to refine models of the brain. However, whether functional magnetic resonance imaging (fMRI), the most common technique for imaging brain function, allows one to identify neural drivers remains an open question. Here, we used a rat model of absence epilepsy, a form of nonconvulsive epilepsy that occurs during childhood in humans, showing spontaneous spike-and-wave discharges (nonconvulsive seizures) originating from the first somatosensory cortex, to validate several functional connectivity measures derived from fMRI. Standard techniques estimating interactions directly from fMRI data failed because blood flow dynamics varied between regions. However, we were able to identify the neural driver of spike-and-wave discharges when hemodynamic effects were explicitly removed using appropriate modelling. This study thus provides the first experimental substantiation of the theoretical possibility to improve interregional coupling estimation from hidden neural states of fMRI. As such, it has important implications for future studies on connectivity in the functional neuroimaging literature.
Neural long-range interactions can be distinguished from hemodynamic confounds in functional magnetic resonance imaging using new data analysis techniques that will allow experimental validation of models of brain function.
PMCID: PMC2605917  PMID: 19108604
13.  Health-related quality of life in childhood epilepsy: Moving beyond 'seizure control with minimal adverse effects' 
Childhood epilepsy is one of the most important and prevalent neurological conditions in the developing years. Persons with childhood onset epilepsy are at a high risk for poor psychosocial outcomes, even without experiencing co-morbidities. The goal of management of children with epilepsy should be to enable the child and the family to lead a life as free as possible from the medical and psychosocial complications of epilepsy. This comprehensive care needs to go beyond simply trying to control seizures with minimal adverse drug reactions. Seizure frequency and severity is only one important outcome variable. Other factors such as social, psychological, behavioural, educational, and cultural dimensions of their lives affect children with epilepsy, their families and their close social networks.
A number of epilepsy-specific health-related quality of life (HRQL) scales for children have been developed with the aim to include and measure accurately the impact and burden of epilepsy. Their target populations, details of the origin of the items, and psychometric properties vary significantly. Their strengths and weaknesses will be identified more clearly through their continued use in the clinical setting and in research studies. Only a few studies to date have utilized these or generic HRQL measures to assess the HRQL of specific populations with epilepsy.
Future research needs to develop theory driven models of HRQL and identify measurable factors that have important correlations with outcomes. Since biomedical variables like seizure frequency and severity have only moderate correlations with HRQL, other independent factors including the child's resilience, co-morbid conditions, parental well-being, family factors and societal/cultural variables may play a major role. We also need to learn what encompasses comprehensive patient care, define the goals of management and evaluate the impact of different interventions. Future studies need to include the children's own perspectives of their HRQL in addition to parental reports.
Finally, clinicians need to familiarize themselves with outcome measures, be able to evaluate them, and use them routinely in their day-to-day practice.
PMCID: PMC201010  PMID: 14498989
review; health-related quality of life; outcome; measures; children; epilepsy; self-report measure; parents; proxy; goals of care
14.  The natural history of epilepsy in tuberous sclerosis complex 
Epilepsia  2009;51(7):1236-1241.
Although epilepsy affects most patients with tuberous sclerosis complex (TSC), little is known about the natural history of epilepsy in this genetic disease.
A retrospective chart review of all patients with TSC seen between January 2002 and October 2008. Charts were reviewed for a history of infantile spasms (IS), seizure other than IS, refractory epilepsy, Lennox-Gastaut syndrome (LGS), anticonvulsant medication use, ages of seizure onset, last seizure, last clinic visit, clinical seizure phenotype(s), cognitive impairment, and genetic mutation.
Two hundred ninety-one patients were included. Among these patients, 37.8% had a history of IS; 85.2% had a history of seizure; 54.1% developed multiple seizure types, not including IS; 63.2% had seizure onset in the first year of life; and 12.1% of adults without a seizure history developed epilepsy. Of epilepsy patients, 62.5% developed refractory epilepsy and 33.5% achieved epilepsy remission; 37.5% of these patients achieved medication freedom. IS was a risk factor for refractory epilepsy (p<0.0001) and LGS (p<0.0001). History of seizure, IS, age at seizure onset, and refractory epilepsy each correlated with poor cognitive outcome (p<0.0001). Epilepsy remission correlated with better cognitive outcome (p<0.0001). TSC2 was a risk factor for IS and epilepsy; patients without an identified mutation were more likely to achieve remission.
Most patients with TSC develop epilepsy and most develop multiple seizure types. Onset typically occurs in the first year of life; however, adults remain at risk. Although refractory epilepsy is common, many patients achieve seizure control. Many features of seizure history are predictive of cognitive and epilepsy outcome.
PMCID: PMC3065368  PMID: 20041940
Epilepsy; Infantile spasms; Outcome; Genetics; Tuberous sclerosis complex
15.  Clinical predictors of 2-year outcome of resective epilepsy surgery in adults with refractory epilepsy: a cohort study 
BMJ Open  2014;4(4):e004852.
Resective epilepsy surgery is currently a standard treatment for intractable epilepsy. Seizure freedom and discontinuation of antiepileptic drugs are the ultimate goals of epilepsy treatment. This study was carried out to delineate (1) possible differences in the success rate of epilepsy surgery 6 and 24 months after surgery; and (2) the clinical predictors of a good response to surgery.
This is a cohort study performed at a tertiary care unit of a university hospital.
In this cohort study, 189 adults with intractable epilepsy who underwent epilepsy surgery were included. We collected clinical data at three time points, that is, preoperative and 6 and 24 months after surgery.
Primary and secondary outcome measures
Engel class I–IV classification was the primary outcome measure of epilepsy surgery. The authors statistically adjusted Engel class I–IV classification for postoperative changes in antiepileptic drugs and used this new classification as a secondary outcome variable.
The success rate was 78.8% 6 months after surgery and increased to 88.3% 24 months after surgery. This success rate was reflected not only by the reduced number of seizures postsurgery, but also by a reduced dosage and use of antiepileptic drugs. Logistic regression analysis showed that a successful outcome of surgery is predicted by having temporal rather than extratemporal lobe epilepsy and less than nine presurgery seizures per month, while a positive familial history of epilepsy, younger age and dysphoric symptoms, the first 3 months after surgery, significantly worsened the outcome of surgery. Duration of illness, age at onset, epilepsy location, type of lesions and the presence of psychosis were not significant in predicting treatment outcome.
These findings have clinical relevance in that a better selection of patients based on the significant clinical predictors will increase the success rate of epilepsy surgery and treatment.
PMCID: PMC4010813  PMID: 24755212
16.  The quality of care for adults with epilepsy: an initial glimpse using the QUIET measure 
We examined the quality of adult epilepsy care using the Quality Indicators in Epilepsy Treatment (QUIET) measure, and variations in quality based on the source of epilepsy care.
We identified 311 individuals with epilepsy diagnosis between 2004 and 2007 in a tertiary medical center in New England. We abstracted medical charts to identify the extent to which participants received quality indicator (QI) concordant care for individual QI's and the proportion of recommended care processes completed for different aspects of epilepsy care over a two year period. Finally, we compared the proportion of recommended care processes completed for those receiving care only in primary care, neurology clinics, or care shared between primary care and neurology providers.
The mean proportion of concordant care by indicator was 55.6 (standard deviation = 31.5). Of the 1985 possible care processes, 877 (44.2%) were performed; care specific to women had the lowest concordance (37% vs. 42% [first seizure evaluation], 44% [initial epilepsy treatment], 45% [chronic care]). Individuals receiving shared care had more aspects of QI concordant care performed than did those receiving neurology care for initial treatment (53% vs. 43%; X2 = 9.0; p = 0.01) and chronic epilepsy care (55% vs. 42%; X2 = 30.2; p < 0.001).
Similar to most other chronic diseases, less than half of recommended care processes were performed. Further investigation is needed to understand whether a shared-care model enhances quality of care, and if so, how it leads to improvements in quality.
PMCID: PMC3024216  PMID: 21199575
17.  Mild Cognitive Impairment: A Concept and Diagnostic Entity in Need of Input from Neuropsychology 
This virtual issue consists of studies previously published in the Journal of the International Neuropsychological Society and selected on the basis of their content related to one of the most highly researched concepts in behavioral neurology and neuropsychology over the past decade: mild cognitive impairment (MCI). The reliance on cognitive screening measures, staging-based rating scales, and limited neuropsychological testing in diagnosing MCI across most research studies may miss individuals with subtle cognitive declines or mis-diagnose MCI in those who are otherwise cognitively normal on a broader neuropsychological battery of tests. The assembled articles highlight the perils of relying on these conventional criteria for MCI diagnosis and reveal how the reliability of diagnosis is improved when sound neuropsychological approaches are adopted. When these requirements are met, we illustrate with a second series of articles that neuropsychological measures associate strongly with biomarkers and often reflect pathology beyond or instead of typical AD distributions. The final set of articles reveal that people with MCI demonstrate mild but identifiable functional difficulties, and a challenge for neuropsychology is how to incorporate this information to better define MCI and distinguish it from early dementia. Neuropsychology is uniquely positioned to improve upon the state of the science in MCI research and practice by providing critically important empirical information on the specific cognitive domains affected by the predominant neurodegenerative disorders of late life as well as on the diagnostic decision-making strategies used in studies. When such efforts to more comprehensively assess neuropsychological functions are undertaken, better characterizations of spared and impaired cognitive and functional abilities result and lead to more convincing associations with other biomarkers as well as to prediction of clinical outcomes.
PMCID: PMC4039178  PMID: 24490866
Mild cognitive impairment; Alzheimer’s disease; Neuropsychology; Episodic memory; Semantic memory; Executive functions; Neuroimaging; Magnetic resonance imaging; Functional MRI; Diffusion tensor imaging; Cerebrospinal fluid; Biomarkers; Activities of daily living; Functional capacity
18.  Approaches to refractory epilepsy 
Annals of Indian Academy of Neurology  2014;17(Suppl 1):S12-S17.
Epilepsy is one of the most common serious neurological conditions, and 30 to 40% of people with epilepsy have seizures that are not controlled by medication. Patients are considered to have refractory epilepsy if disabling seizures continue despite appropriate trials of two antiseizure drugs, either alone or in combination. At this point, patients should be referred to multidisciplinary epilepsy centers that perform specialized diagnostic testing to first determine whether they are, in fact, pharmacoresistant, and then, if so, offer alternative treatments. Apparent pharmacoresistance can result from a variety of situations, including noncompliance, seizures that are not epileptic, misdiagnosis of the seizure type or epilepsy syndrome, inappropriate use of medication, and lifestyle issues. For patients who are pharmacoresistant, surgical treatment offers the best opportunity for complete freedom from seizures. Surgically remediable epilepsy syndromes have been identified, but patients with more complicated epilepsy can also benefit from surgical treatment and require more specialized evaluation, including intracranial EEG monitoring. For patients who are not surgical candidates, or who are unwilling to consider surgery, a variety of other alternative treatments can be considered, including peripheral or central neurostimulation, ketogenic diet, and complementary and alternative approaches. When such alternative treatments are not appropriate or effective, quality of life can still be greatly improved by the psychological and social support services offered by multidisciplinary epilepsy centers. A major obstacle remains the fact that only a small proportion of patients with refractory epilepsy are referred for expert evaluation and treatment.
PMCID: PMC4001229  PMID: 24791078
Complementary and alternative medicine; diagnostic approaches; epilepsy surgery; ketogenic diet; neurostimulation; refractory epilepsy
19.  Hughlings Jackson's Dr Z: the paradigm of temporal lobe epilepsy revealed 
On 10 January 1894, a distinguished physician died in London of an overdose of chloral hydrate. The event was of vital interest to Hughlings Jackson who attended the post-mortem examination with a bevy of witnesses. He begged his colleague Walter Colman “to search the taste region of Ferrier on each half of the brain very carefully.” They were rewarded by finding “ a very small focus of softening in that region (in the uncinate gyrus) of the left half of the brain.” Jackson had thus discovered the most discrete and circumscribed lesion of the temporal lobe yet described to assoicate with the most detailed and elegant self report of psychomotor epilepsy yet published. For the physician, whom Jackson and Colman called “Dr Z” in their report in Brain2 had been Jackson's patient since 1877 and his own account of his epileptic experience had occupied six pages of Jackson's 1888 article “On a particular variety of epilepsy....”7 Jackson had himself witnessed several of Dr Z's attacks. The case enabled Jackson to argue that the complex symptomatology of the seizure was due to “reflex” effects of epileptic discharges in that area of brain. It is the paradigm of temporal lobe epilepsy.
PMCID: PMC490665  PMID: 6999129
20.  Neuropsychological status at seizure onset in children 
Neurology  2009;73(7):526-534.
This large, prospective, community-based study characterized neuropsychological functioning and academic achievement at the time of the first recognized seizure and identified risk factors for cognitive deficits.
We compared 282 children (ages 6–14 years, IQ ≥70) with a first recognized seizure to 147 healthy siblings on a battery of well-standardized and widely used neuropsychological and academic achievement tests and examined relationships with demographic and clinical variables.
In this intellectually normal cohort, 27% with just one seizure and up to 40% of those with risk factors exhibited neuropsychological deficits at or near onset. Risk factors associated with neuropsychological deficits included multiple seizures (i.e., second unprovoked seizure; odds ratio [OR] = 1.96), use of antiepileptic drugs (OR = 2.27), symptomatic/cryptogenic etiology (OR = 2.15), and epileptiform activity on the initial EEG (OR = 1.90); a child with all 4 risks is 3.00 times more likely than healthy siblings to experience neuropsychological deficits by the first clinic visit. Absence epilepsy carried increased odds for neuropsychological impairment (OR = 2.00).
A subgroup of intellectually normal children with seizures showed neuropsychological deficits at onset. Academic achievement was unaffected, suggesting that there is a window early in the disorder for intervention to ameliorate the impact on school performance. Therefore, the risk factors identified here (especially if multiple risks are present) warrant swift referral for neuropsychological evaluation early in the course of the condition.
= antiepileptic drug;
= analysis of variance;
= Clinical Evaluation of Language Fundamentals;
= confidence interval;
= Comprehensive Test of Phonological Processing;
= odds ratio;
= prior unrecognized seizure;
= Wisconsin Card Sorting Test;
= Wide Range Assessment of Memory and Learning.
PMCID: PMC2730794  PMID: 19675309
21.  Accuracy of Serological Testing for the Diagnosis of Prevalent Neurocysticercosis in Outpatients with Epilepsy, Eastern Cape Province, South Africa 
Few studies have estimated prevalence of neurocysticercosis (NCC) among persons with epilepsy in sub-Saharan Africa. While the limitations of serological testing in identification of NCC are well known, the characteristics of persons who are misdiagnosed based on serology have not been explored. The first objective of this pilot study was to estimate the prevalence of NCC in epilepsy outpatients from an area of South Africa endemic for cysticercosis. The second objective was to estimate the accuracy of serological testing in detecting NCC in these outpatients and characterize sources of disagreement between serology and neuroimaging.
Methodology/Principal Findings
All out-patients aged 5 or older attending the epilepsy clinic of St. Elizabeth's Hospital in Lusikisiki, Eastern Cape Province, between July 2004 and April 2005 were invited to participate. Epidemiological data were collected by local study staff using a standardized questionnaire. Blood samples were tested by ELISA for antibody and antigen for Taenia solium. Four randomly chosen, consenting participants were transported each week to Mthatha for brain CT scan. The proportion of persons with epilepsy attending St. Elizabeth clinic with CT-confirmed NCC was 37% (95% CI: 27%–48%). Using CT as the gold standard, the sensitivity and specificity of antibody testing for identifying NCC were 54.5% (36.4%–71.9%) and 69.2% (52.4%–83.0%), respectively. Sensitivity improved to 78.6% (49.2%–95.3%) for those with active lesions. Sensitivity and specificity of antigen testing were considerably poorer. Compared to false negatives, true positives more often had active lesions. False positives were more likely to keep pigs and to have seizure onset within the past year than were true negatives.
The prevalence of NCC in South African outpatients with epilepsy is similar to that observed in other countries where cysticercosis is prevalent. Errors in classification of NCC using serology alone may reflect the natural history of NCC.
Author Summary
Epilepsy is a significant contributor to morbidity world-wide in persons of all ages. Little is known, however, about its causes. In the developing world, parasitic infections of the brain, in particular Taenia solium neurocysticercosis (NCC) are thought to be important factors. Determining whether or not there is infection in the brain is difficult since to be certain, specialized imaging studies, such as CT scans, are required. These are expensive and not widely available. In addition, they are not appropriate for use in large, population-based studies. Thus, blood tests for evidence of infection with T. solium are often done instead to estimate the presence of NCC. In this study's population of persons with epilepsy being seen at a hospital out-patient clinic in South Africa, 37% had CT evidence of NCC, a percentage similar to that reported in other developing countries. The study also found that blood tests were not generally useful compared to CT for correctly identifying those persons who did or did not have NCC, and thus, they cannot be relied upon for field studies of NCC.
PMCID: PMC2780704  PMID: 19997629
22.  Familial clustering of epilepsy and behavioral disorders: Evidence for a shared genetic basis 
Epilepsia  2011;53(2):301-307.
To examine whether family history of unprovoked seizures is associated with behavioral disorders in epilepsy probands, thereby supporting the hypothesis of shared underlying genetic susceptibility to these disorders.
We conducted an analysis of the 308 probands with childhood onset epilepsy from the Connecticut Study of Epilepsy with information on first degree family history of unprovoked seizures and of febrile seizures whose parents completed the Child Behavior Checklist (CBCL) at the 9-year follow-up. Clinical cut-offs for CBCL problem and DSM-Oriented scales were examined. The association between first degree family history of unprovoked seizure and behavioral disorders was assessed separately in uncomplicated and complicated epilepsy and separately for first degree family history of febrile seizures. A subanalysis, accounting for the tendency for behavioral disorders to run in families, adjusted for siblings with the same disorder as the proband. Prevalence ratios were used to describe the associations.
Key findings
In probands with uncomplicated epilepsy, first degree family history of unprovoked seizure was significantly associated with clinical cut-offs for Total Problems and Internalizing Disorders. Among Internalizing Disorders, clinical cut-offs for Withdrawn/Depressed, and DSM-Oriented scales for Affective Disorder and Anxiety Disorder were significantly associated with family history of unprovoked seizures. Clinical cut-offs for Aggressive Behavior and Delinquent Behavior, and DSM-Oriented scales for Conduct Disorder and Oppositional Defiant Disorder were significantly associated with family history of unprovoked seizure. Adjustment for siblings with the same disorder revealed significant associations for the relationship between first degree family history of unprovoked seizure and Total Problems and Agressive Behavior in probands with uncomplicated epilepsy; marginally significant results were seen for Internalizing Disorder, Withdrawn/Depressed and Anxiety Disorder.
There was no association between family history of unprovoked seizure and behavioral problems in probands with complicated epilepsy. First degree family history of febrile seizure was not associated with behavioral problems in probands with uncomplicated or in those with complicated epilepsy.
Increased occurrence of behavioral disorders in probands with uncomplicated epilepsy and first degree family history of unprovoked seizure suggests familial clustering of these disorders. This supports the idea that behavioral disorders may be another manifestation of the underlying pathophysiology involved in epilepsy or closely related to it.
PMCID: PMC3267857  PMID: 22191626
epilepsy; psychiatric disorders; family history; epidemiology
23.  Epilepsy-related knowledge, attitudes and practices among Zambian police officers 
Epilepsy & behavior : E&B  2007;10(3):456-462.
In Zambia, where emergency medical services are very limited, the police are frequently called to the scene for unaccompanied people experiencing seizures or people who have exhibit disturbed behaviors during a seizure. Police officers receive no formal medical training to manage such encounters. We developed and administered a police-specific survey to assess their knowledge, attitudes, and practices (KAP) regarding epilepsy in Zambia.
In 2004, a 28-item KAP questionnaire that included queries specific to police encounters with seizures and epilepsy was developed and delivered to a random sample of 200 police officers stationed in Lusaka. Descriptive data were reviewed and open text questions post-coded and categorized.
The response rate was 87.5% (n=175). Police were familiar with epilepsy with 85% having witnessed a seizure. Although 77.1% recognized epilepsy as a brain disorder, almost 20% blamed spirit possession, 13.9% associated epilepsy with witchcraft and over half the respondents believe epilepsy is contagious. When asked how they would treat someone brought in for peace disturbance during a seizures, most police provided supportive or neutral responses, but 8% reported taking harmful actions (arrest, detain, handcuff, restrain) and 14.3% indicated that people with epilepsy in police custody require quarantine.
A significant number of police officers in Zambia lack critical knowledge regarding epilepsy and self-report detrimental actions towards people with seizures. In regions of the developing world where the police provide emergency medical services, police officers need to be a target for educational and social intervention programs.
PMCID: PMC2749646  PMID: 17363333
stigma; police; tolerance; knowledge; epilepsy; law enforcement; prison
24.  Beating the Odds: Intact Neuropsychological Functioning despite TLE 
Annals of Neurosciences  2014;21(4):155-159.
Patients with Temporal lobe epilepsy (TLE) frequently display cognitive comorbidity and can have widespread network abnormalities, which might affect a variety of cognitive and intellectual functions. As a result, refractory TLE seems to be associated with slow but ongoing cognitive deterioration. The case is of a 32 year old, right handed male, engineering graduate, diagnosed with TLE- right mesial, 12 years ago. A number of head injuries were caused due to the seizure present, which includes a fall from height of 12 feet in childhood. The neuropsychological tests administered were Gesell’s Drawing Test, Mini Mental State Examination, PGI Memory Scale, Battery of Performance Tests of Intelligence, Verbal Adult Intelligence Scale, Hamilton Rating Scale for Depression, Bender Visual Motor Gestalt Test and Dysfunction Analysis Questionnaire. No impairment found on orientation; average cognitive functioning; above average attention and concentration, verbal working memory, visual and verbal memory; average practical ability, abstract ability, average verbal intellectual ability; superior ability on comprehension and average performance ability. Mild to moderate impairment on perceptuo-motor functioning and an evidence of depression were present. Patient showed high dysfunction in personal, social, vocational and cognitive areas. The study highlights that even despite chronic epilepsy, with a series of head injuries due to the seizures; an individual can still have average neuropsychological abilities. Holistic neuropsychological rehabilitation along with Vocational Retraining would go a long way in the functional independence of the patient. Neuropsychologists have a significant role in the assessment, treatment, and rehabilitation of people with epilepsy.
PMCID: PMC4248473  PMID: 25452679
Neuropsychological functioning; Temporal Lobe Epilepsy (TLE); Cognition; Neuropsychological Assessment; India
25.  Describing the genetic architecture of epilepsy through heritability analysis 
Brain  2014;137(10):2680-2689.
Epilepsy is highly heritable, but its genetic architecture is poorly understood. Speed et al. estimate the number of susceptibility loci, show that common variants account for the majority of heritability, and demonstrate that epilepsy consists of genetically distinct subtypes. They conclude that gene-based prediction models may have clinical utility in first-seizure settings.
Epilepsy is a disease with substantial missing heritability; despite its high genetic component, genetic association studies have had limited success detecting common variants which influence susceptibility. In this paper, we reassess the role of common variants on epilepsy using extensions of heritability analysis. Our data set consists of 1258 UK patients with epilepsy, of which 958 have focal epilepsy, and 5129 population control subjects, with genotypes recorded for over 4 million common single nucleotide polymorphisms. Firstly, we show that on the liability scale, common variants collectively explain at least 26% (standard deviation 5%) of phenotypic variation for all epilepsy and 27% (standard deviation 5%) for focal epilepsy. Secondly we provide a new method for estimating the number of causal variants for complex traits; when applied to epilepsy, our most optimistic estimate suggests that at least 400 variants influence disease susceptibility, with potentially many thousands. Thirdly, we use bivariate analysis to assess how similar the genetic architecture of focal epilepsy is to that of non-focal epilepsy; we demonstrate both significant differences (P = 0.004) and significant similarities (P = 0.01) between the two subtypes, indicating that although the clinical definition of focal epilepsy does identify a genetically distinct epilepsy subtype, there is also scope to improve the classification of epilepsy by incorporating genotypic information. Lastly, we investigate the potential value in using genetic data to diagnose epilepsy following a single epileptic seizure; we find that a prediction model explaining 10% of phenotypic variation could have clinical utility for deciding which single-seizure individuals are likely to benefit from immediate anti-epileptic drug therapy.
PMCID: PMC4163034  PMID: 25063994
epilepsy; association studies; heritability analysis; complex trait prediction

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