Epilepsy in systemic lupus erythematosus: prevalence and risk factors.

BACKGROUND AND PURPOSE: The aim was to study the prevalence of epilepsy in a hospital-based systemic lupus erythematosus (SLE) cohort and to investigate the relationship between epilepsy and other manifestations of neuropsychiatric SLE (NPSLE). METHODS: The study population consisted of 440 SLE patients recruited from 1998 to 2012. An epilepsy-screening questionnaire was sent to all patients, where those screening positive were invited to a neurological examination with documentation of NPSLE symptoms according to the American College of Rheumatology nomenclature. Occurrences of autoantibodies (double stranded DNAantibody, antinuclear antibody, lupus anticoagulant, Sjögren's syndrome A, Sjögren's syndrome B) and the antiphospholipid syndrome (APS) were tabulated. RESULTS: Out of 440 patients, 14% were dead and 2.7% were lost to follow-up. The questionnaire was sent to 368 patients; 312 (85%) responded. Of these, 131 (42%) screened positive. Epilepsy was confirmed in 36 (11.5%), of whom 30 (83%) had focal onset. Ten (3.2%) patients had isolated or provoked seizures. Manifestations of NPSLE occurred in 50%. The rates of cerebrovascular disease and psychosis were elevated two- and three-fold in NPSLE patients with epilepsy versus NPSLE patients without epilepsy, respectively (P = 0.001 and P = 0.0006). APS was more common in patients with epilepsy compared to epilepsy-free SLE patients with or without NPSLE (P = 0.02). In 50% of patients with epilepsy, no other etiology than SLE was detected. CONCLUSIONS: A high prevalence of epilepsy in SLE patients is reported, with association to concurrent cerebrovascular disease, APS and psychosis. Our findings support the notion of a multifactorial background for epilepsy in SLE including both vascular disease and features consistent with autoimmunity.

Increased risk of epilepsy in biopsy-verified celiac disease: a population-based cohort study.

OBJECTIVES: Celiac disease (CD) is associated with several neurologic disorders but it is unclear whether CD is associated with epilepsy. We therefore investigated whether biopsy-verified CD is associated with epilepsy. METHODS: Cohort study. Using biopsy report data from all Swedish pathology departments (n = 28), we identified individuals with CD who were diagnosed from 1969 to 2008 (Marsh 3: villous atrophy). Through Cox regression, we calculated hazard ratios (HRs) for epilepsy (defined as a diagnosis of epilepsy in the Swedish National Patient Register) in 28,885 individuals with CD and 143,166 controls matched for age, sex, calendar period, and county. RESULTS: Individuals with CD were at an increased risk of future epilepsy (HR = 1.42; 95% confidence interval [CI] = 1.24-1.62) (272 individuals with CD had a diagnosis of epilepsy vs an expected 192). The absolute risk of future epilepsy in patients with CD was 92/100,000 person-years (excess risk = 27/100,000 person-years). This risk increase was seen in all ages, including children with CD. The HR for having at least 2 interactions with health care due to epilepsy was 1.41 (95% CI = 1.19-1.66). When we restricted epilepsy to those with both a diagnosis of epilepsy and an independent record of antiepileptic drug prescriptions, CD was associated with a 1.43-fold increased risk of epilepsy (95% CI = 1.10-1.86). CONCLUSION: Individuals with CD seem to be at a moderately increased risk of epilepsy.

Sociodemographic differences in antiepileptic drug prescriptions to adult epilepsy patients.

BACKGROUND: According to the Swedish Health Care Act, patients should be provided with the health care they need, regardless of sociodemographic status. We investigated whether in Sweden sociodemographic differences are associated with access to expert health care and antiepileptic drug (AED) prescriptions in epilepsy. METHOD: Patients with epilepsy were identified in the National Patient Register. Persons >or=18 years on continuous AED treatment in 2006 were identified in the recently established Swedish Prescribed Drug Register. Data on sociodemographic variables were obtained from several other national registers. We linked data to examine whether epilepsy patients' access to neurologists and the prescription of individual AEDs are related to sex, age, educational level, area of residence, region of birth, or income. We also assessed whether AEDs are prescribed differently to patients with epilepsy by neurologists as compared to non-neurologists. RESULTS: We identified 26,124 epilepsy patients in the register who were on continuous AED treatment (effective sample). Being women, young, highly educated, having high incomes, and residing in a larger city meant being more often treated by a neurologist than by other specialists. The prescriptions of AEDs differed according to gender, age, education, place of residence, and income. Lamotrigine and levetiracetam were prescribed to a larger extent by a neurologist rather than by other specialists. CONCLUSIONS: This nationwide cross-sectional study of epilepsy patients indicates that sociodemographic characteristics are important for access to neurologists and prescriptions of individual antiepileptic drugs. Prospective studies using patient-related outcomes are needed to analyze the consequences of these differences.

Pregnancy registries in epilepsy: a consensus statement on health outcomes.

Most pregnant women with epilepsy require antiepileptic drug (AED) therapy. Present guidelines recommend optimizing treatment prior to conception, choosing the most effective AED for seizure type and syndrome, using monotherapy and lowest effective dose, and supplementing with folate. The Epilepsy Therapy Project established the international Health Outcomes in Pregnancy and Epilepsy (HOPE) forum to learn more about the impact of AEDs on the developing fetus, particularly the role of pregnancy registries in studying AED teratogenicity. The primary outcome of interest in these registries is the occurrence of major congenital malformations, with some data collected on minor malformations. Cognitive and behavioral outcomes are often beyond the timeframe for follow-up of these registries and require independent study. The HOPE consensus report describes the current state of knowledge and the limitations to interpretations of information from the various sources. Data regarding specific risks for both older and newer AEDs need to be analyzed carefully, considering study designs and confounding factors. There is a critical need for investigations to delineate the underlying mechanisms and explain the variance seen in outcomes across AEDs and within a single AED.

Heart rate variability in patients with untreated epilepsy.

BACKGROUND: Several studies have reported reduced heart rate variability (HRV) in patients with chronic epilepsy under treatment with antiepileptic drugs. This impairment in cardiac autonomic control might be of relevance in relation to the risk of sudden unexpected death in patients with chronic refractory epilepsy. Little information is, however, available on HRV in untreated patients with newly diagnosed epilepsy. METHODS: We used spectral analysis to assess HRV based on 24h ambulatory EKG recordings in 22 consecutive untreated patients with epilepsy (15 with localization-related, 4 with generalized idiopathic and 3 with undetermined epilepsy). The HRV in these patients was compared with 22 age and sex matched healthy controls. RESULTS: When analysing the full 24h recordings, there were no significant difference between the patients and the controls in any of the analyzed measures of HRV: standard deviation of RR-intervals (P=0.191), total power (P=0.170), very low frequency power (P=0.329), low frequency power (LF) (P=0.161), high frequency power (HF) (P=0.186) and the LF/HF ratio (P=0.472). The results were very similar for daytime and nighttime recordings. CONCLUSION: Our results suggest that there is no major effect of epilepsy as such on HRV in patients with untreated epilepsy. It should be emphasized that this study assessed newly diagnosed patients and that the results may not be applicable to patients with chronic epilepsy.

Therapeutic monitoring of antiepileptic drugs for epilepsy.

BACKGROUND: The aim of drug treatment for epilepsy is to prevent seizures without causing adverse effects. To achieve this, drug dosages need to be individualised. Measuring antiepileptic drug levels in body fluids (therapeutic drug monitoring) is frequently used to optimise drug dosage for individual patients. OBJECTIVES: To review the evidence regarding the effects of therapeutic drug monitoring upon outcomes in epilepsy. SEARCH STRATEGY: We searched the Cochrane Epilepsy Group Specialised Register (September 2006), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2005, Issue 4), MEDLINE (January 1966 to April 2005) and EMBASE (1974 to May 2005). No language restrictions were imposed. We checked the reference lists of retrieved articles for additional reports of relevant studies. SELECTION CRITERIA: Randomised controlled trials comparing the outcomes of antiepileptic drug monotherapy guided by therapeutic drug monitoring with drug treatment without the aid of therapeutic drug monitoring. DATA COLLECTION AND ANALYSIS: We based this review on published aggregate data. The main outcomes measured were the proportions of patients achieving a 12-month remission from seizures, reporting adverse effects, and being withdrawn from the treatment they had been randomised to receive. MAIN RESULTS: Only one study met the inclusion criteria for the review. In this open study, 180 patients with newly-diagnosed, untreated epilepsy were randomised to treatment with the antiepileptic drug selected by their physician either with or without therapeutic drug serum level monitoring as an aid to dosage adjustments. The antiepileptic drugs used were carbamazepine, valproate, phenytoin, phenobarbital and primidone. A 12-month remission from seizures was achieved by 60% of the patients randomised to therapeutic drug monitoring (intervention group) and by 61% in the control group. A total of 56% in the intervention group and 58% in the control group were seizure free during the last 12 months of follow up. Adverse effects were reported by 48% in the intervention group and 47% of the control group patients. Of those randomised to therapeutic drug monitoring, 62% completed the two-year follow up compared with 67% of the control group. AUTHORS' CONCLUSIONS: We found no clear evidence to support routine antiepileptic drug serum concentration measurement with the aim of reaching predefined target ranges for the optimisation of treatment of patients with newly-diagnosed epilepsy with antiepileptic drug monotherapy. However, this does not exclude the possible usefulness of therapeutic drug monitoring of specific antiepileptic drugs during polytherapy, in special situations or in selected patients, although evidence is lacking.

Valproate effects on kinetics of lamotrigine in pregnancy and treatment with oral contraceptives.

In eight women treated with lamotrigine monotherapy, the lamotrigine dose/plasma concentration (D/C) ratio increased by 295% from baseline outside pregnancy to midgestation, whereas in six women treated with lamotrigine in combination with valproate, the increase was only 60%. No difference in lamotrigine D/C ratio was found between users and nonusers of oral contraceptives comedicated with valproate. Valproate seems to reduce the induction of lamotrigine metabolism associated with pregnancy or use of contraceptives.

Role of valproate across the ages. Treatment of epilepsy in adults.

A workshop was held in Göteborg in June 2005 to discuss the place of valproate in treating adult epilepsies. Consensus positions were developed on the epilepsy types for which the drug is most suitable and the use of valproate in women of child-bearing age, in men and in patients with psychiatric comorbidity. Valproate was considered to be effective across a broad variety of epilepsy syndromes and seizure types and should be considered a suitable choice for first-line monotherapy of juvenile myoclonic epilepsy and other idiopathic generalized epilepsies. The use of valproate by women of child-bearing age is associated with potential harm to the foetus. A conservative approach to treatment is recommended in these patients whereby alternative antiepileptic drugs should be proposed to women planning pregnancies wherever satisfactory seizure control can be thereby maintained. In cases where valproate is used during pregnancy, either because the pregnancy was unplanned or because alternative treatment options of equivalent efficacy are unavailable, appropriate counselling, precautionary measures and monitoring should be provided. The evidence for an impact of valproate on male reproductive health is equivocal and considerations of male fertility should not be taken into account in deciding whether to prescribe valproate to men. Valproate can be proposed safely to patients with comorbid psychiatric disease or underlying psychiatric vulnerability.

Epilepsy as a risk factor for cancer.

AIM: Epilepsy and long term use of antiepileptic drugs have been suggested to be associated with an increased risk of cancer. The authors therefore set out to analyse previous diagnosis of epilepsy as a risk factor for certain cancer forms in a case control study. METHODS: Incident cases of leukaemia, lymphoma, myeloma, and pancreatic cancer were identified from the Swedish Cancer Registry 1987-99, a total of 52 861 cases. Controls (n = 137 485) were randomly selected from the Swedish Population Registry stratified on age, sex, and year of cancer diagnosis. Cases and controls were linked to the Swedish Hospital Discharge Registry for 1969-99 to identify individuals with first time hospital discharge for epilepsy. RESULTS: While an epilepsy diagnosis the same year as a cancer diagnosis carried an increased risk of non-Hodgkin's lymphoma (OR = 2.89, 95% CI 1.89 to 4.41), Hodgkin's disease (OR = 4.77, 95% CI 1.77 to 13.30), leukaemia (OR = 2.55, 95% CI 1.50 to 4.32), acute myeloid leukaemia (OR = 3.65, 95% CI 1.68 to 7.93), and pancreatic cancer (OR = 2.05, 95% CI 1.22 to 3.45), the authors found no support for an association between discharge with a diagnosis of epilepsy two years or more before the diagnosis of cancer and an increased risk of any of the types of cancer included in this analysis. The lack of association was also evident for individuals with an epilepsy diagnosis preceding malignancy/reference year by >10 years. CONCLUSIONS: Clinical examinations prompted by seizure onset probably mainly explain the observed association between epilepsy diagnoses the year before a cancer diagnosis. However, these results lend no support to the suggestion that epilepsy, and presumably long term exposure to antiepileptic drugs, is associated with an increased risk of the types of cancer included in the present study.

No apparent effect of surgery for temporal lobe epilepsy on heart rate variability.

BACKGROUND: Impaired cardiac autonomic function may contribute to the risk of sudden unexpected death in epilepsy (SUDEP). Clinical observations indicate that successful epilepsy surgery is associated with a reduced risk of SUDEP. However, in a previous study we found impaired cardiac control pre-surgically in patients with poor outcome of surgery, indicating an a priori lower risk in responders to epilepsy surgery. We have now examined the effect of surgery on cardiac autonomic control in the same patients. METHODS: We used 24 h EKG recordings to assess heart rate variability (HRV) by spectral analysis in 21 consecutive patients after temporal lobe epilepsy surgery. The HRV was compared with healthy controls, with pre-surgical HRV in the same patients, and analyzed in relation to seizure control 1 year after surgery. RESULTS: The patients with poor outcome after surgery had significantly lower SD of RR-intervals, total power, very low frequency power and low frequency power than matched healthy controls. The patients with favorable outcome did not differ from the controls, and the postoperative HRV was not different from HRV before surgery in any of the patient groups. CONCLUSION: We could not demonstrate any effect on HRV of temporal lobe epilepsy surgery in these patients. The observed lower HRV in the poor outcome group was present already before epilepsy surgery as previously reported. Although our results need confirmation in a larger study, the observations suggest that the increased risk of SUDEP in patients failing epilepsy surgery may be due to a common factor predisposing to surgical failure, impaired HRV as well as to an increased risk of SUDEP.

A combination of DNA vaccines targeting human papillomavirus type 16 E6 and E7 generates potent antitumor effects.

Human papillomavirus (HPV) infects large numbers of women worldwide and is present in more than 99% of all cervical cancers. HPV E6 and E7 are two viral oncoproteins that are consistently expressed in HPV infections and HPV-associated malignancies. We have previously developed DNA vaccines encoding calreticulin (CRT) linked either to HPV type 16 (HPV-16) E6 or to HPV-16 E7, both of which generated significant antitumor effects against E6- and E7-expressing tumors. In this study, we demonstrate that simultaneous vaccination of C57BL/6 mice or HLA-A2 transgenic mice with both CRT/E6 and CRT/E7 DNA vaccines generates significant E6- and E7-specific T-cell immune responses in vaccinated mice. Furthermore, combined vaccination with both CRT/E6 and CRT/E7 DNA generates significantly better therapeutic antitumor effects against HPV E6- and E7-expressing tumors than vaccination with either CRT/E6 DNA or CRT/E7 DNA alone. Our data suggest that it may be desirable to combine DNA vaccines targeting E6 with DNA vaccines targeting E7 to develop effective immunotherapeutic strategies for control of HPV infection and HPV-associated lesions in a clinical setting.

Preoperative heart rate variability in relation to surgery outcome in refractory epilepsy.

BACKGROUND: Epilepsy patients may have an impaired autonomic cardiac control, which has been associated with an increased incidence of sudden unexpected death among people with epilepsy (SUDEP). The risk of SUDEP is particularly high among epilepsy surgery candidates with refractory epilepsy. This risk seems to be reduced after successful surgery but whether this is an effect of surgery or reflects pre-existing differences between good and poor responders is under debate. METHODS: We used spectral analysis to analyze prospectively heart rate variability (HRV) preoperatively in 21 consecutive patients with temporal lobe epilepsy who were planned for epilepsy surgery. The presurgical HRV based on ambulatory 24 hours EKG recordings was analyzed in relation to seizure control at 1 year after surgery. RESULTS: Patients had significantly lower SD of RR-intervals, total power, very low frequency power and low frequency power than matched healthy controls. Patients with good outcome of surgery (Engel class I; n = 11) did not differ from their controls while those with poor outcome (Engel class II-IV; n = 10) had significantly lower power in all domains than those with a favorable outcome. CONCLUSIONS: Measurements of heart rate variability preoperatively indicate that patients with a poor outcome of surgery have a more pronounced impairment of sympathetic as well as parasympathetic cardiac control than those with good outcome. Reduced heart rate variability may be associated with an increased risk of sudden unexpected death among people with epilepsy (SUDEP). Good surgery candidates may a priori have a lower risk of SUDEP.

Knowledge, attitudes and smoking behavior among Lao doctors.

The aim of this study was to describe the knowledge, attitudes and smoking behavior among doctors at Mahosot University Hospital in Lao PDR. A cross-sectional, descriptive study used a self-administered anonymous questionnaire. The study population comprised 164 doctors. Answers were retrieved from 151 (92%) of the doctors. The prevalence of smoking among male doctors was 35%, 16% smoked daily and 19% occasionally. None of the female doctors reported to have ever smoked. Out of the five diseases related to smoking, 5% of the doctors recognized all and 10% recognized only one. Doctors were significantly more likely to advise patients with symptoms related to smoking. However, approximately one in two doctors reported that they did not always counsel smokers with severe smoking related symptoms to stop smoking. Almost all doctors, independent of smoking behavior, perceived tobacco prevention to be important. The findings indicate a lack of comprehensive knowledge on tobacco related issues. Most doctors expressed a positive attitude towards tobacco prevention. An effort is needed to get doctors in Lao PDR to stop smoking engage in smoking assation support.

Risk of extremity fractures in adult outpatients with epilepsy.

PURPOSE: To study the incidence of extremity fractures in a group of adult patients with epilepsy attending an outpatient clinic compared with the incidence of fractures in the general population in the same geographic area. METHODS: We selected 177 consecutive adult patients with epilepsy attending the outpatient clinic at the Department of Neurology at Karolinska Hospital in Stockholm in 1995. This study population was matched with an Injury Registry to identify those epilepsy patients who during 1991 through 1995 attended the emergency department for an extremity fracture. The observed number of fractures in the epilepsy group was compared with the corresponding number of expected cases based on regional fracture rates. Relative-risk estimates for fractures were calculated with respect to the duration of epilepsy, mono- or polytherapy, and history of tonic-clonic seizures. RESULTS: Twenty (11%) of 177 patients sustained 23 fractures that prompted a visit to the emergency department. The incidence of fractures in the epilepsy patients was 23.8/1,000 person-years. The overall Standardized Morbidity Ratio (SMR) was 2.39 (95% CI, 1.52-3.59). A significantly higher risk for fractures was thus found in patients with epilepsy. Risk factors were age 45 years or older, male sex, and occurrence of generalized seizures. It also was found that the relative risk of fractures was higher during the first and second year compared with >or=5 years after diagnosis (RR, 3.71; 95% CI, 1.20-11.48). CONCLUSIONS: Our results highlight the risk of fractures in outpatients with epilepsy. In this patient group, 43% of the fractures were definitely or possibly seizure related. Males 45 years or older are a particular risk group. Special attention is required for this group of patients who are at higher risk for fractures. The risk is apparently higher in the first 2 years after diagnosis, although potential bias in ascertainment of fracture incidents in our study may have underestimated the long-term risk for fractures.

[Malformations in the offspring of pregnant women with epilepsy. Presentation of an international registry of antiepileptic drugs and pregnancy (EURAP)]. / Malformaciones en los hijos de embarazadas con epilepsia. Presentación de un registro internacional de fármacos antiepilépticos y embarazo (EURAP).

The interaction between epilepsy and pregnancy has been studied for many years; nonetheless the risk associated with individual antiepileptic drug has not been adequately characterized up to date. Moreover, virtually nothing is known about the possible human teratogenicity of the newer antiepileptic drugs. Because of the complexity of the mechanisms involved, the crucial evidence needed can only come from very large population based studies, and a collaborative European multicentre investigation has been set up to this purpose. Specific objectives include the evaluation of the risk of major foetal malformations and of delay in prenatal growth following exposure to antiepileptic drugs, assessment of the pattern of congenital abnormalities associated with older and newer antiepileptic drugs and their combinations, and identification of possible relationships with dosage and with a variety of other risk factors. All women exposed to antiepileptic drugs at the time of conception are eligible for entry. The protocol is purely observational and does not entail any change in prescribing pattern or management policies, which are left to the discretion of the treating physician. Data obtained during prospective monitoring for up to 1 year after birth are regularly collected in especially designed forms and entered into Regional Registries prior to transfer to a Central European Registry of Antiepileptic Drugs and Pregnancy (EURAP). Evaluations of incidence and prevalence of teratogenic endpoints will be based exclusively on cases enrolled before foetal outcome is known and in any case not after the 16th week of pregnancy. Cases enrolled after birth, after the 16th week of pregnancy or after prenatal diagnosis will only be reported descriptively. The study is being implemented gradually in 19 countries in Western and Eastern Europe. Wide participation from interested physicians is essential for the achievement of the study objectives, which are expected to lead to important advances in pre pregnancy counselling and overall clinical management of women with epilepsy.

Psychomotor development in preschool children exposed to antiepileptic drugs in utero.

UNLABELLED: The aim of this study was to assess psychomotor development with the Griffiths' test in preschool children exposed to antiepileptic drugs (AED) in utero. The study sample consisted of 76 children exposed to AED in utero and 71 unexposed children. The children (exposed and unexposed) have since birth been included in a population-based longitudinal follow-up study of children born to women with meticulously treated epilepsy during pregnancy, initiated in 1985. In total, 67 exposed and 66 unexposed children were tested with the Griffiths' test, which consists of 6 subsets: locomotor function, personal and social behaviour, hearing and speech, eye and hand coordination, performance, and practical reasoning. There was no significant difference in the global scores of the Griffiths' test between the two groups of children. Children exposed to phenytoin in utero (n = 16) showed a significant but subtle reduction in the scores for locomotor development compared with the unexposed children (mean scores: 98 vs 106: 95% confidence interval for the difference in mean scores: -14.0 to -0.4). There was no such difference for the children exposed to carbamazepine in utero (n = 35). The exposed children had significantly fewer siblings (p < 0.01). A significant number of the mothers with AED treatment had no higher level of education than compulsory school (p < 0.01). No other differences in socioeconomic status were observed between the groups. CONCLUSION: The subtle delay in locomotor development evaluated with the Griffiths' test at 4.5-5 y of age in children exposed to phenytoin may indicate a subtle influence on psychomotor development, which may be more obvious at school age: thus, larger studies and further follow-up are warranted.

Malformaciones en los hijos de embarazadas con epilepsia. Presentación de un registro internacional de fármacos antiepilépticos y embarazo (EURAP) / Malformations in the offspring of pregnant women with epilepsy. Presentation of an international registry of antiepileptic drugs and pregnancy (EURAP)

La interacción entre la epilepsia y el embarazo ha sido estudiada durante muchos años. No obstante, hasta la fecha, el riesgo asociado con fármacos antiepilépticos particulares no se ha caracterizado debidamente. Es más, no se sabe prácticamente nada acerca de la posible teratogénesis humana de los fármacos antiepilépticos más nuevos. Debido a la complejidad de los mecanismos que intervienen, la evidencia decisiva necesaria sólo puede venir de estudios basados en grandes poblaciones y se ha programado una investigación cooperada de varios centros europeos con este propósito. Sus objetivos específicos incluyen la evaluación de los riesgos de graves malformaciones fetales y del retraso del crecimiento prenatal después de su exposición a fármacos antiepilépticos; la evaluación del patrón de anormalidades congénitas asociadas con los fármacos antiepilépticos más viejos y más nuevos -y sus combinaciones-; y la identificación de las relaciones posibles con las dosis y con una variedad de otros factores de riesgo. Todas las mujeres expuestas a fármacos antiepilépticos en la fecha de la concepción son elegibles para participar. El protocolo es puramente de observación y no implica ningún cambio en el patrón de prescripción o de las políticas de manejo, que quedan a cargo de médico responsable del tratamiento. Los datos obtenidos durante el control prospectivo hasta un año después de nacimiento son recogidos con regularidad en formularios diseñados especialmente y son anotados en registros regionales antes de su traslado a la Central Europea para el Registro de Fármacos Antiepilépticos y Embarazo (EURAP). Las evaluaciones acerca de la incidencia o prevalencia de puntos máximos teratogénicos se basará exclusivamente en casos incorporados antes que se conozca el desenlace fetal y, en ningún caso, nunca después de la semana 16 del embarazo. Los casos incorporados después del nacimiento, después de la semana 16 del embarazo o después del diagnóstico prenatal, sólo se comunicarán de forma descriptiva. El estudio está siendo implementado gradualmente en 19 países de Europa occidental y oriental. Una participación amplia de los médicos interesados es esencial para lograr los objetivos del estudio, que se espera que conduzca a avances importantes en los consejos a las embarazadas y en el manejo clínico general de las mujeres que padecen epilepsia (AU)

Harnessing the clinical potential of antiepileptic drug therapy: dosage optimisation.

For patients with epilepsy, effective seizure control is the most important determinant of good quality of life. To achieve this, antiepileptic drug (AED) dosages should be individualised to maximise therapeutic benefit and to avoid most--if not all--adverse effects. Several studies suggest that, in routine clinical practice, dosage individualisation is often suboptimal. This may lead to patients receiving unnecessarily large dosages. Conversely, it may lead to patients switching to an alternative therapy (when clinical response is deemed insufficient), without exploration of the full dosage range. Indeed, dosage optimisation--which should involve consideration of the treatment setting and individual patient characteristics--can be a complicated process requiring skill and patience. In general neurological practice, most AEDs should be started at a low dosage and gradually titrated upwards. Starting dosages are similar in most types of epilepsy; however, if a rapid onset of therapeutic action is required, phenytoin, phenobarbital (phenobarbitone), levetiracetam and gabapentin are probably the best tolerated AEDs for starting at full dosage. The initial target maintenance dosage of an AED should be based on the dose-response profile of the drug, and on specific patient characteristics. Usually, the lowest effective daily dose expected to provide seizure control should be used, although various factors (e.g. stage and severity of epilepsy, pharmacokinetic and pharmacodynamic considerations, attitude of the patient) will markedly influence dosage selection. If seizures are not controlled on the initial target dose, the dosage should be increased gradually until complete seizure control is achieved or intolerable adverse effects occur. In most patients who fail to respond to the initially prescribed drug, switching to another AED (monotherapy) is the best option. Combination therapy may be appropriate for patients unresponsive to 2 or more sequential monotherapies. Therapeutic drug monitoring (measurement of serum drug concentrations) is useful in various settings, such as when drug interactions are expected, toxicity is suspected, or when AEDs with nonlinear pharmacokinetics (e.g. phenytoin, carbamazepine) are used. No indications currently exist for routine therapeutic drug monitoring of the newer AEDs. In summary, dosage regimens of AEDs should be assessed regularly, and adjusted if necessary, so that patients can derive optimal therapeutic benefit. For patients considered 'difficult to treat' (i.e. those in whom seizures remain incompletely controlled after several attempts at treatment), referral to a specialist is recommended.

Antiepileptic drug therapy and its management in sudden unexpected death in epilepsy: a case-control study.

PURPOSE: Because frequent seizures constitute a major risk factor for sudden unexpected death in epilepsy (SUDEP), the treatment with antiepileptic drugs (AEDs) may play a role for the occurrence of SUDEP. We used data from routine therapeutic drug monitoring (TDM) to study the association between various aspects of AED treatment and the risk of SUDEP. METHODS: A nested case-control study was based on a cohort consisting of 6,880 patients registered in the Stockholm County In Ward Care Register with a diagnosis of epilepsy. Fifty-seven SUDEP cases, and 171 controls, living epilepsy patients, were selected from the cohort. Clinical data including data on TDM were collected through medical record review. RESULTS: The relative risk (RR) of SUDEP was 3.7 (95% CI, 1.0-13.1) for outpatients who had no TDM compared with those who had one to three TDMs during the 2 years of observation. RR was 9.5 (1.4-66.0) if carbamazepine (CBZ) plasma levels at the last TDM were above and not within the common target range (20-40 microM). High CBZ levels were associated with a higher risk in patients receiving polytherapy and in those with frequent dose changes. Although the subgroup of patients with high CBZ levels was small (six cases of 33 with CBZ therapy), and the result should be interpreted with caution, no similar associations were demonstrated for phenytoin plasma levels and risk of SUDEP. No association was found between SUDEP risk and within-patient variation in AED levels over time. CONCLUSIONS: Polytherapy, frequent dose changes, and high CBZ levels as identified risk factors for SUDEP all point to the risks associated with an unstable severe epilepsy. It is unclear whether high CBZ levels per se represent a risk factor or just reflect other unidentified aspects of a severe epilepsy. Our results, however, prompt further detailed analyses of the possible role of AEDs in SUDEP in larger cohorts and suggest that reasonable monitoring of the drug therapy may be useful to reduce risks.