Electromagnetic source imaging in presurgical workup of patients with epilepsy: A prospective study.

OBJECTIVE: To determine the diagnostic accuracy and clinical utility of electromagnetic source imaging (EMSI) in presurgical evaluation of patients with epilepsy. METHODS: We prospectively recorded magnetoencephalography (MEG) simultaneously with EEG and performed EMSI, comprising electric source imaging, magnetic source imaging, and analysis of combined MEG-EEG datasets, using 2 different software packages. As reference standard for irritative zone (IZ) and seizure onset zone (SOZ), we used intracranial recordings and for localization accuracy, outcome 1 year after operation. RESULTS: We included 141 consecutive patients. EMSI showed localized epileptiform discharges in 94 patients (67%). Most of the epileptiform discharge clusters (72%) were identified by both modalities, 15% only by EEG, and 14% only by MEG. Agreement was substantial between inverse solutions and moderate between software packages. EMSI provided new information that changed the management plan in 34% of the patients, and these changes were useful in 80%. Depending on the method, EMSI had a concordance of 53% to 89% with IZ and 35% to 73% with SOZ. Localization accuracy of EMSI was between 44% and 57%, which was not significantly different from MRI (49%-76%) and PET (54%-85%). Combined EMSI achieved significantly higher odds ratio compared to electric source imaging and magnetic source imaging. CONCLUSION: EMSI has accuracy similar to established imaging methods and provides clinically useful, new information in 34% of the patients. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that EMSI had a concordance of 53%-89% and 35%-73% (depending on analysis) for the localization of epileptic focus as compared with intracranial recordings-IZ and SOZ, respectively.

Patient-reported outcome (PRO) measure-based algorithm for clinical decision support in epilepsy outpatient follow-up: a test-retest reliability study.

OBJECTIVES: Patient-reported outcome (PRO) measures have been used in epilepsy outpatient clinics in Denmark since 2011. The patients' self-reported PRO data are used by clinicians as a decision aid to support whether a patient needs contact with the outpatient clinic or not based on a PRO algorithm. Validity and reliability are fundamental to any PRO measurement used at the individual level in clinical practice. The aim of this study was to evaluate the test-retest reliability of the PRO algorithm used in epilepsy outpatient clinics and to analyse whether the method of administration (web and paper) would influence the result. DESIGN AND SETTING: Test-retest reliability study conducted in three epilepsy outpatient clinics in Central Denmark Region, Denmark. PARTICIPANTS: A total of 554 epilepsy outpatients aged 15 years or more were included from August 2016 to April 2017. The participants completed questionnaires at two time points and were randomly divided into four test-retest groups: web-web, paper-paper, web-paper and paper-web. In total, 166 patients completed web-web, 112 paper-paper, 239 web-paper and 37 paper-web. RESULTS: Weighted kappa with squared weight was 0.67 (95% CI 0.60 to 0.74) for the pooled PRO algorithm, and perfect agreement was observed in 82% (95% CI 78% to 85%) of the cases. There was a tendency towards higher test-retest reliability and agreement estimates within same method of administration (web-web or paper-paper) compared with a mixture of methods (web-paper and paper-web). CONCLUSIONS: The PRO algorithm used for clinical decision support in epilepsy outpatient clinics showed moderate to substantial test-retest reliability. Different methods of administration produced similar results, but an influence of change in administration method cannot be ruled out.

Effect of patient-initiated versus fixed-interval telePRO-based outpatient follow-up: study protocol for a pragmatic randomised controlled study.

BACKGROUND: The traditional system of routine outpatient follow-up of chronic disease in secondary care may involve a waste of resources if patients are well. The use of patient-reported outcomes (PRO) could support more flexible, cost-saving follow-up activities. AmbuFlex is a PRO system used in outpatient follow-up in the Central Denmark Region. PRO questionnaires are sent to patients at fixed intervals. The clinicians use the PRO data to decide whether a patient needs a visit or not (standard telePRO). PRO may make patients become more involved in their own care pathway, which may improve their self-management. Better self-management may also be achieved by letting patients initiate contact. The aim of this study is to obtain data on the effects of patient-initiated follow-up (open access telePRO) on resource utilisation, quality of care, and the patient perspective. METHODS: The study is a pragmatic, randomised, controlled trial in outpatients with epilepsy. Participants are randomly assigned to one of two follow-up activities: a) standard telePRO or b) open access telePRO. Inclusion criteria are age ≥ 15 years and previous referral to standard telePRO follow-up at Aarhus University Hospital, Denmark. Furthermore, patients must have answered the last questionnaire via the Internet. The number of contacts will be used as the primary outcome measure. Secondary outcome measures include well-being (WHO-5 Well-Being Index), general health, number of seizures, treatment side effects, mortality, health literacy (Health Literacy Questionnaire), self-efficacy (General Self-Efficacy scale), patient activation, confidence, safety, and satisfaction. In addition, the patient perspective will be explored by qualitative methods. Data will be collected at baseline and 18 month after randomisation. Inclusion of patients in the study started in January 2016. Statistical analysis will be performed on an intention-to-treat and per-protocol basis. For qualitative data, the interpretive description strategy will be used. DISCUSSION: The benefits and possible drawbacks of the PRO-based open access approach will be evaluated. The present study will provide important knowledge to guide future telePRO interventions in relation to effect on resource utilisation, quality of care, and the patient perspective. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02673580 (Registration date January 28, 2016).

Added diagnostic value of magnetoencephalography (MEG) in patients suspected for epilepsy, where previous, extensive EEG workup was unrevealing.

OBJECTIVE: To elucidate the possible additional diagnostic yield of MEG in the workup of patients with suspected epilepsy, where repeated EEGs, including sleep-recordings failed to identify abnormalities. METHODS: Fifty-two consecutive patients with clinical suspicion of epilepsy and at least three normal EEGs, including sleep-EEG, were prospectively analyzed. The reference standard was inferred from the diagnosis obtained from the medical charts, after at least one-year follow-up. MEG (306-channel, whole-head) and simultaneous EEG (MEG-EEG) was recorded for one hour. The added sensitivity of MEG was calculated from the cases where abnormalities were seen in MEG but not EEG. RESULTS: Twenty-two patients had the diagnosis epilepsy according to the reference standard. MEG-EEG detected abnormalities, and supported the diagnosis in nine of the 22 patients with the diagnosis epilepsy at one-year follow-up. Sensitivity of MEG-EEG was 41%. The added sensitivity of MEG was 18%. MEG-EEG was normal in 28 of the 30 patients categorized as 'not epilepsy' at one year follow-up, yielding a specificity of 93%. CONCLUSIONS: MEG provides additional diagnostic information in patients suspected for epilepsy, where repeated EEG recordings fail to demonstrate abnormality. SIGNIFICANCE: MEG should be included in the diagnostic workup of patients where the conventional, widely available methods are unrevealing.

Comparing maximum autonomic activity of psychogenic non-epileptic seizures and epileptic seizures using heart rate variability.

PURPOSE: The semiology of psychogenic non-epileptic seizures (PNES) can resemble epileptic seizures, and differentiation between epileptic seizures with no EEG-correlate and PNES can be challenging even for trained experts. Therefore, there has been a search for a quantitative measure, other than EEG and semiology that could distinguish PNES from epileptic seizures. We used ECG to measure heart rate variability (HRV) in order to compare maximum autonomic activity of epileptic seizures and PNES. These comparisons could potentially serve as biomarkers for distinguishing these types of clinical episodes. METHOD: Forty-nine epileptic seizures from 17 patients and 24 PNES from 7 patients with analyzable ECG were recorded during long-term video-EEG monitoring. Moving windows of 100 R-R intervals throughout each seizure were used to find maximum values of Cardiac Sympathetic Index (CSI) (sympathetic tonus) and minimum values of Cardiac Vagal Index (CVI), Root-Mean-Square-of-Successive-Differences (RMSSD) and HF-power (parasympathetic tonus). In addition, non-seizure recordings of each patient were used to compare HRV-parameters between the groups. RESULTS: The maximum CSI for epilepsy seizures were higher than PNES (P=0.015). The minimum CVI, minimum RMSSD and HF-power did not show significant difference between epileptic seizures and PNES (P=0.762; P=0.152; P=0.818). There were no statistical difference of non-seizure HRV-parameters between the PNES and epilepsy patients. CONCLUSION: We found the maximum sympathetic activity accompanying the epileptic seizures to be higher, than that during the PNES. However, the great variation of autonomic response within both groups makes it difficult to use these HRV-measures as a sole measurement in distinguishing epileptic seizures from PNES.

AmbuFlex: tele-patient-reported outcomes (telePRO) as the basis for follow-up in chronic and malignant diseases.

PURPOSE: A tele-patient-reported outcome (telePRO) model includes outpatients' reports of symptoms and health status from home before or instead of visiting the outpatient clinic. In the generic PRO system, AmbuFlex, telePRO is used to decide whether a patient needs an outpatient visit and is thus a tool for better symptom assessment, more patient-centred care, and more efficient use of resources. Specific PROs are developed for each patient group. In this paper we describe our experiences with large-scale implementations of telePRO as the basis for follow-up in chronic and malignant diseases using the generic PRO system AmbuFlex. METHODS: The AmbuFlex concept consists of three generic elements: PRO data collection, PRO-based automated decision algorithm, and PRO-based graphical overview for clinical decision support. Experiences were described with respect to these elements. RESULTS: By December 2015, AmbuFlex was implemented in nine diagnostic groups in Denmark. A total of 13,135 outpatients from 15 clinics have been individually referred. From epilepsy clinics, about 70 % of all their outpatients were referred. The response rates for the initial questionnaire were 81-98 %. Of 8256 telePRO-based contacts from epilepsy outpatients, up to 48 % were handled without other contact than the PRO assessment. Clinicians as well as patients reported high satisfaction with the system. CONCLUSION: The results indicate that telePRO is feasible and may be recommended as the platform for follow-up in several patient groups with chronic and malignant diseases and with many consecutive outpatient contacts.

Visualizing spikes in source-space: Rapid and efficient evaluation of magnetoencephalography.

OBJECTIVE: Reviewing magnetoencephalography (MEG) recordings is time-consuming: signals from the 306 MEG-sensors are typically reviewed divided into six arrays of 51 sensors each, thus browsing each recording six times in order to evaluate all signals. A novel method of reconstructing the MEG signals in source-space was developed using a source-montage of 29 brain-regions and two spatial components to remove magnetocardiographic (MKG) artefacts. Our objective was to evaluate the accuracy of reviewing MEG in source-space. METHODS: In 60 consecutive patients with epilepsy, we prospectively evaluated the accuracy of reviewing the MEG signals in source-space as compared to the classical method of reviewing them in sensor-space. RESULTS: All 46 spike-clusters identified in sensor-space were also identified in source-space. Two additional spike-clusters were identified in source-space. As 29 source-channels can be easily displayed simultaneously, MEG recordings had to be browsed only once. Yet, this yielded a global coverage of the recorded signals and enhanced detectability of epileptiform discharges because MKG-artefacts were suppressed and did not impede evaluation in source-space. CONCLUSIONS: Our results show that reviewing MEG recordings in source-space is accurate and much more rapid than the classical method of reviewing in sensor-space. SIGNIFICANCE: This novel method facilitates the clinical use of MEG.

Long-term mortality in children and young adults with epilepsy--A population-based cohort study.

PURPOSE: Epilepsy is associated with an increased mortality. This study estimates the effects of co-morbid disorders on short-term and long-term mortality and presents cause-specific mortality for children and young adults with epilepsy. METHODS: We established a population-based cohort of 1,855,946 children born in Denmark from 1977 to 2006. Children were followed from the 29th day of life until death, emigration or 31 December 2006. Data was retrieved from Danish longitudinal civil service, health and cause of death registries. Overall, 25,244 persons were diagnosed with epilepsy and 10,647 persons died during 26.2 million person years of follow-up. Among those who died, 803 were diagnosed with epilepsy prior to death. Mortality rate ratio (MRR) was estimated by comparing the mortality rate among persons with epilepsy with the mortality rate in persons without epilepsy. RESULTS: The mortality among children and young adults with epilepsy was almost 15 times increased compared with persons without epilepsy (MRR: 14.9 (95% CI: 13.9-16.1)). After excluding persons with adverse birth outcomes and persons with comorbid neurological disorders (other than epilepsy), the MRR was still more than four times increased (MRR: 4.20 (95% CI: 3.28-5.30)). Short- and long-term MRRs were particularly high for those diagnosed with epilepsy before 5 years of age (short-term mortality (<1 year); MRR: 41.5 (95% CI: 35.4-48.3), long term mortality (≥ 1 year); MRR: 21.6 (95% CI: 19.5-23.8)). The cumulative mortality 20 years after the first epilepsy diagnosis was 7.6% (95% CI: 6.8-8.4%) among males and 5.8% (95% CI: 5.1-6.5%) among females.

Exploring the capability of wireless near infrared spectroscopy as a portable seizure detection device for epilepsy patients.

PURPOSE: Near infrared spectroscopy (NIRS) has proved useful in measuring significant hemodynamic changes in the brain during epileptic seizures. The advance of NIRS-technology into wireless and portable devices raises the possibility of using the NIRS-technology for portable seizure detection. METHODS: This study used NIRS to measure changes in oxygenated (HbO), deoxygenated (HbR), and total hemoglobin (HbT) at left and right side of the frontal lobe in 33 patients with epilepsy undergoing long-term video-EEG monitoring. Fifteen patients had 34 focal seizures (20 temporal-, 11 frontal-, 2 parietal-lobe, one unspecific) recorded and analyzed with NIRS. Twelve parameters consisting of maximum increase and decrease changes of HbO, HbR and HbT during seizures (1 min before- to 3 min after seizure-onset) for left and right side, were compared with the patients' own non-seizure periods (a 2-h period and a 30-min exercise-period). In both non-seizure periods 4 min moving windows with maximum overlapping were applied to find non-seizure maxima of the 12 parameters. Detection was defined as positive when seizure maximum change exceeded non-seizure maximum change. RESULTS: When analyzing the 12 parameters separately the positive seizure detection was in the range of 6-24%. The increase in hemodynamics was in general better at detecting seizures (15-24%) than the decrease in hemodynamics (6-18%) (P=0.02). CONCLUSION: NIRS did not seem to be a suitable technology for generic seizure detection given the device, settings, and methods used in this study. There are still several challenges to overcome before the NIRS-technology can be used as a home-monitoring seizure detection device.

Detection of epileptic seizures with a modified heart rate variability algorithm based on Lorenz plot.

PURPOSE: In order to assess whether focal epileptic seizures can be detected and distinguished from exercise we evaluated four different heart rate variability (HRV) methods with short term moving window analysis of 30, 50 or 100 R-R intervals or seconds per analyzed window. METHODS: The four methods consisted of: (1) reciprocal high frequency power based on Fast Fourier Transformation, (2) Cardiac Sympathetic Index (CSI), (3) Modified CSI both based on Lorenz plot, and (4) heart rate differential method. Seventeen patients (12 males, 5 females; age 20-55) had 47 seizures (including three secondary generalized tonic-clonic (sGTC)), which were analyzed during their long term video-EEG monitoring of 1-5 days duration. Positive seizure detection was regarded, when the HRV-value during seizures (1min before to 3min after seizure-onset) exceeded 105% of the highest value during exercise and non-seizure sample-periods of the same patient. RESULTS: Modified CSI100 was the most accurate method: it detected all seizures for 13 of the 17 patients within 6s before till 50s after seizure onset time, even though exercise maximum HR of each patient exceeded that of the seizures. The three sGTC seizures were all detected more than half a minute before the tonic-clonic phase. CONCLUSION: The results indicate a detectable, sudden and inordinate shift toward sympathetic overdrive in the sympathovagal balance of the autonomic nervous system around seizure-onset time, for most patients. The Modified CSI is a promising parameter for a portable ECG-based epilepsy alarm, detecting both focal and sGTC seizures.

Using Lorenz plot and Cardiac Sympathetic Index of heart rate variability for detecting seizures for patients with epilepsy.

Tachycardia is often seen during epileptic seizures, but it also occurs during physical exercise. In order to assess whether focal epileptic seizures can be detected by short term moving window Heart Rate Variability (HRV) analysis, we modified the geometric HRV method, Lorenz plot, to consist of only 30, 50 or 100 R-R intervals per analyzed window. From each window we calculated the longitudinal (L) and transverse (T) variability of Lorenz plot to retrieve the Cardiac Sympathetic Index (CSI) as (L/T) and "Modified CSI" (described in methods), and compared the maximum during the patient's epileptic seizures with that during the patient's own exercise and non-seizure sessions as control. All five analyzed patients had complex partial seizures (CPS) originating in the temporal lobe (11 seizures) during their 1-5 days long term video-EEG monitoring. All CPS with electroencephalographic correlation were selected for the HRV analysis. The CSI and Modified CSI were correspondently calculated after each heart beat depicting the prior 30, 50 and 100 R-R intervals at the time. CSI (30, 50 and 100) and Modified CSI (100) showed a higher maximum peak during seizures than exercise/non-seizure (121-296%) for 4 of the 5 patients within 4 seconds before till 60 seconds after seizure onset time even though exercise maximum HR exceeded that of the seizures. The results indicate a detectable, sudden and inordinate shift towards sympathetic overdrive in the sympathovagal balance of the autonomic nervous system just around seizure-onset for certain patients. This new modified moving window Lorenz plot method seems promising way of constructing a portable ECG-based epilepsy alarm for certain patients with epilepsy who needs aid during seizure.

Epidemiology of epilepsy in adults: implementing the ILAE classification and terminology into population-based epidemiologic studies.

The new proposal for Revised Terminology for Organization of Seizures and Epilepsies published in 2010 poses challenges to all fields of epilepsy including epidemiology. We describe efforts to incorporate the new terminology and classification into population-based health registers in Denmark in order to provide the background for assessment of the quality of epilepsy care, epidemiologic studies of epilepsy, and clinical trials in adults.

Detection of epileptic-seizures by means of power spectrum analysis of heart rate variability: a pilot study.

OBJECTIVE: To investigate whether epileptic seizures could be predicted or detected by means of spectral analysis of heart rate variability (HRV). METHODS: Six patients with temporal lobe epilepsy (4 females, 2 males) participated in the prospective pilot study while enrolled for video/EEG monitoring (24 h/day, 2-4 days). ECG was continuously recorded and 30 min seizure-sessions (25-30 min pre-seizure to 30 sec-5 min post-seizure onset) and 30 min non-seizure-sessions (day- and night sessions for each patient, as control) were chosen for further HRV-analysis. Low frequency (LF) (0.04-0.15 Hz), High frequencies (HF) (0.15-0.40 Hz), LF/HF, LF/(LF+HF) and reciprocal HF-power was determined using continuous FFT- spectral analysis of 64 R-R interval windowing with maximum overlapping. RESULTS: Six seizures were recorded and analyzed from three patients (2 females, 1 male). All of the analyzed EEG-correlated seizures showed reciprocal HF-power peaks between 10 sec pre seizure-onset and 24 sec post seizure-onset with peak amplitudes 2.96-93.63 times higher than control maximum peak. For the other parameters we could not find significant difference between seizure and non-seizure sessions. CONCLUSION: Specifically high reciprocal HF-power peaks suggest suppressed parasympathetic activity just around seizure-onset time. Seizure detection using HRV-analysis seems to be a promising method for non-invasive seizure detection in the early phase of the clinical event (even preceding the onset).

[Epilepsy treatment by vagus nerve stimulation]. / Behandling af epilepsi ved stimulation af nervus vagus.

Epilepsy is a common neurological disorder, and between one fourth and one third of the patients do not obtain seizure freedom after treatment with antiepileptic drugs. If the epileptic seizures in such patients have severe consequences, the patients should be assessed for epilepsy surgery. In case epilepsy surgery is not feasible, vagus nerve stimulation (VNS) should be offered. VNS seems to have an effect in all epilepsy syndromes and seizure types. VNS is generally well-tolerated, and may even improve mood and quality of life. Many more epilepsy patients in Denmark should be offered VNS.

Long-term risk of epilepsy after traumatic brain injury in children and young adults: a population-based cohort study.

BACKGROUND: The risk of epilepsy shortly after traumatic brain injury is high, but how long this high risk lasts is unknown. We aimed to assess the risk of epilepsy up to 10 years or longer after traumatic brain injury, taking into account sex, age, severity, and family history. METHODS: We identified 1 605 216 people born in Denmark (1977-2002) from the Civil Registration System. We obtained information on traumatic brain injury and epilepsy from the National Hospital Register and estimated relative risks (RR) with Poisson analyses. FINDINGS: Risk of epilepsy was increased after a mild brain injury (RR 2.22, 95% CI 2.07-2.38), severe brain injury (7.40, 6.16-8.89), and skull fracture (2.17, 1.73-2.71). The risk was increased more than 10 years after mild brain injury (1.51, 1.24-1.85), severe brain injury (4.29, 2.04-9.00), and skull fracture (2.06, 1.37-3.11). RR increased with age at mild and severe injury and was especially high among people older than 15 years of age with mild (3.51, 2.90-4.26) and severe (12.24, 8.52-17.57) injury. The risk was slightly higher in women (2.49, 2.25-2.76) than in men (2.01, 1.83-2.22). Patients with a family history of epilepsy had a notably high risk of epilepsy after mild (5.75, 4.56-7.27) and severe brain injury (10.09, 4.20-24.26). INTERPRETATION: The longlasting high risk of epilepsy after brain injury might provide a window for prevention of post-traumatic epilepsy.

Incidence and prevalence of epilepsy in Denmark.

PURPOSE: To estimate the occurrence of epilepsy in Denmark between 1977 and 2002, taking gender, age, and secular trends into consideration. METHODS: We used the Danish Civil Registration System to identify all persons born in Denmark and the Danish National Hospital Register to identify persons registered with epilepsy between 1977 and 2002. RESULTS: Between 1977 and 2002 the average incidence of epilepsy was 68.8 new epilepsy patients per 100,000 person-years at risk. However, the incidence changed with calendar time and increased steeply from 1990 to 1995, probably due to changes in diagnostic system and inclusion of outpatients. From 1995 to 2002 the incidence rate was reasonable constant with an average of 83.3 new cases per 100,000 person-years at risk, except for patients over 60 years of age where we observed an increase in incidence with calendar time. The age-specific incidence rates declined from a high level in children to a low level between 20 and 40 years of age, and thereafter a gradual increase was seen. The incidence rate was slightly higher in men than in women except for the age range 10-20 years. About 2% of the population was diagnosed with epilepsy at some point during the first 25 years of life. The overall 5-year prevalence proportion of epilepsy was 0.6% with a slight variation with age and gender between 0.4 and 0.8% of the population. CONCLUSION: The occurrence of epilepsy is age and gender specific. The estimated incidence rate of epilepsy furthermore increased over time for persons older than 60 years of age.

Validation of epilepsy diagnoses in the Danish National Hospital Register.

PURPOSE: To validate the diagnosis of epilepsy in the Danish National Hospital Register. METHODS: We randomly selected 200 patients registered with epilepsy in the Danish National Hospital Register between 1977 and 2002 and validated the diagnosis according to the guidelines developed by the International League Against Epilepsy. RESULTS: We reviewed the medical records of 188 (94%) persons from 57 departments at 41 hospitals. The epilepsy diagnoses were confirmed in 153 patients, providing a positive predictive value for epilepsy of 81% (95% confidence interval (95% CI): 75-87%). Among the 35 patients who did not fulfill the criteria for epilepsy, 14 were admitted after a single, unprovoked seizure. Among patients registered with epilepsy the positive predictive value of seizure disorder was 89% (95% CI: 83-93%). Among patients classified with epilepsy syndromes, the positive predictive value for syndrome classification was 60% (95% CI: 44-74%) for epilepsy with complex focal seizures and 35% (95% CI: 22-51%) for primary generalized epilepsy. CONCLUSION: The validity of the epilepsy diagnoses in the Danish National Hospital Register has a moderate to high positive predictive value for epilepsy, but a relatively low predictive value for epilepsy syndromes.

Epilepsy and risk of suicide: a population-based case-control study.

BACKGROUND: Studies have linked epilepsy with an increased suicide risk, but the association might be modified by psychiatric, demographic, and socioeconomic factors. METHODS: Suicide cases were identified in the Cause of Death Register in Denmark from 1981 to 1997. Up to 20 controls, matched by sex, birth year, and calendar date, were assigned to each suicide case. FINDINGS: We identified 21 169 cases of suicide and 423 128 controls. 492 (2.32%) individuals who committed suicide had epilepsy compared with 3140 (0.74%) controls, corresponding to a three times higher risk (rate ratio [RR] 3.17 [95% CI 2.88-3.50]; p<0.0001). The RR remained high after excluding those with a history of psychiatric disease and adjusting for socioeconomic factors (1.99, 1.71-2.32; p<0.0001). The highest risk of suicide was identified in patients with epilepsy and comorbid psychiatric disease, even after adjusting for socioeconomic factors (13.7, 11.8-16.0; p<0.0001). In individuals with epilepsy, the highest risk of suicide was found during the first half year after diagnosis was made (5.35, 3.43-8.33; p<0.0001), and was especially high in those with a history of comorbid psychiatric disease (29.2, 16.4-51.9; p<0.0001). INTERPRETATION: Individuals with epilepsy have a higher risk of suicide, even if coexisting psychiatric disease, demographic differences, and socioeconomic factors are taken into account. Our study identifies people with newly diagnosed epilepsy as a vulnerable group that require special attention.

Oral contraceptives induce lamotrigine metabolism: evidence from a double-blind, placebo-controlled trial.

PURPOSE: This study evaluates the effect of oral contraceptives on lamotrigine (LTG) plasma concentrations and urine excretion of LTG metabolites in a double-blind, placebo-controlled, crossover study in patients with epilepsy. METHODS: Women with epilepsy, treated with LTG in monotherapy and taking combination-type oral contraceptives, were randomized to treatment with placebo or a standard combination-type contraceptive pill. The dose-corrected trough plasma concentration of LTG and the ratio of N-2-glucuronide/unchanged LTG on urine after 21 days of concomitant placebo treatment was analyzed versus those after 21 days of concomitant treatment with the oral contraceptive pill. RESULTS: The mean dose-corrected LTG concentration after placebo treatment was 84%[95% confidence interval (CI), 45-134%] higher than after oral contraceptives, signifying an almost doubling of the concentration after cessation of oral contraceptives. Most of this increase took place within the first week after oral contraceptives were stopped. The N-2-glucuronide/LTG ratio in the urine was decreased by 31% (95% CI, -20-61%) when shifting from oral contraceptives to placebo. CONCLUSIONS: Cessation of oral contraceptives leads to an 84% increase in the concentration of LTG. In parallel, the excretion of the N-2-glucuronide was decreased, indicating that the changes are caused by altered LTG glucuronidation. The change in LTG concentrations was observed within 1 week of the shift of treatment, suggesting that induction and deinduction of LTG glucuronidation is faster than that seen for other metabolic pathways (e.g., cytochrome P450).