Antiseizure medication and SUDEP - a need for unifying methodology in research.

The risk of sudden unexpected death in epilepsy (SUDEP) increases with the frequency of generalized tonic-clonic seizures. Carbamazepine (CBZ) and lamotrigine (LTG) have been suggested to increase the risk. However, the prevailing viewpoint is that the choice of antiseizure medication (ASM) does not influence the occurrence. We have explored the approach to addressing this question in relevant studies to evaluate the validity of the conclusions reached. A systematic search was performed in PubMed to identify all controlled studies on SUDEP risk in individuals on CBZ or LTG. Studies were categorized according to whether idiopathic generalized epilepsy (IGE) or females were considered separately, and whether data were adjusted for seizure frequency. Eight studies on CBZ and six studies on LTG were identified. For CBZ, one study showed a significantly increased risk of SUDEP without adjustment for seizure frequency. Another study found significantly increased risk after statistical adjustment for seizure frequency and one study found increased risk with high blood levels. Five other studies found no increase in risk. For LTG, one study showed a significantly increased risk in patients with IGE as opposed to focal epilepsy, and another study showed a significantly increased risk in females. None of the subsequent studies on LTG and none of the studies on CBZ considered females with IGE separately. Taken together the available studies suggest that LTG, and possibly CBZ, may increase occurrence of SUDEP when used in females with IGE. Additional studies with sub-group analysis of females with IGE are needed.

Cardiac Structure and Function in Epilepsy Patients with Drug-Resistant Convulsive Seizures.

High frequency of convulsive seizures and long-lasting epilepsy are associated with an increased risk of sudden unexpected death in epilepsy (SUDEP). Structural changes in the myocardium have been described in SUDEP victims. It is speculated that these changes are secondary to frequent convulsive seizures and may predispose to SUDEP. The aim of this cross-sectional study was to investigate the impact of chronic drug-resistant epilepsy on cardiac function and structure in patients with a high frequency of convulsive seizures. We consecutively included 21 patients (17 women, 4 men) aged 18-40 years, with at least 10 years with epilepsy and a minimum of six convulsive seizures in the last year and without a history of status epilepticus or nonepileptic events. A complete clinical examination, resting 12-lead electrocardiogram, 72-h Holter monitoring, and echocardiography were recorded in all patients. Ten patients were assessed by 3-Tesla cardiac magnetic resonance imaging. Echocardiography and MRI data were compared with those from age- and sex-matched healthy control individuals. No significant changes in cardiac structure or function were found among patients with chronic drug-resistant epilepsy and high frequency of convulsive seizures. However, we cannot exclude that there are subgroups of patients who are more prone to epilepsy-associated cardiac alterations.

Prevention of sudden unexpected death in epilepsy: current status and future perspectives.

Introduction: Sudden unexpected death in epilepsy (SUDEP) affects about 1 in 1000 people with epilepsy, and even more in medically refractory epilepsy. As most people are between 20 and 40 years when dying suddenly, SUDEP leads to a considerable loss of potential life years. The most important risk factors are nocturnal and tonic-clonic seizures, underscoring that supervision and effective seizure control are key elements for SUDEP prevention. The question of whether specific antiepileptic drugs are linked to SUDEP is still controversially discussed. Knowledge and education about SUDEP among health-care professionals, patients, and relatives are of outstanding importance for preventive measures to be taken, but still poor and widely neglected.Areas covered: This article reviews epidemiology, pathophysiology, risk factors, assessment of individual SUDEP risk and available measures for SUDEP prevention. Literature search was done using Medline and Pubmed in October 2019.Expert opinion: Significant advances in the understanding of SUDEP were made in the last decade which allow testing of novel strategies to prevent SUDEP. Promising current strategies target neuronal mechanisms of brain stem dysfunction, cardiac susceptibility for fatal arrhythmias, and reliable detection of tonic-clonic seizures using mobile health technologies.Abbreviations: AED, antiepileptic drug; CBZ, carbamazepine; cLQTS, congenital long QT syndrome; EMU, epilepsy monitoring unit; FBTCS, focal to bilateral tonic-clonic seizures; GTCS, generalized tonic-clonic seizures; ICA, ictal central apnea; LTG, lamotrigine; PCCA, postconvulsive central apnea; PGES, postictal generalized EEG suppression; SRI, serotonin reuptake inhibitor; SUDEP, sudden unexpected death in epilepsy; TCS, tonic-clonic seizures.

Assessment of cardiac structure and function in a murine model of temporal lobe epilepsy.

Sudden unexpected death in epilepsy (SUDEP) is a significant cause of premature seizure-related death. An association between SUDEP and cardiac remodeling has been suggested. However, whether SUDEP is a direct consequence of acute or recurrent seizures is unsettled. The purpose of this study was to evaluate the impact of status epilepticus (SE) and chronic seizures on myocardial structure and function. We used the intracortical kainate injection model of temporal lobe epilepsy to elicit SE and chronic epilepsy in mice. In total, 24 C57/BL6 mice (13 kainate, 11 sham) were studied 2 and 30 days post-injection. Cardiac structure and function were investigated in-vivo with a 9.4 T MRI, electrocardiography (ECG), echocardiography, and histology [Haematoxylin/Eosin (HE) and Martius Scarlet Blue (MSB)] for staining of collagen proliferation and fibrin accumulation. In conclusion, we did not detect any significant changes in cardiac structure and function neither in mice 2 days nor 30 days post-injection.

Epilepsy in patients with long QT syndrome type 1: A Norwegian family.

The congenital long QT syndrome (cLQTS) is an inherited cardiac disorder and is associated with sudden cardiac death. We describe a Norwegian family with mutations within the KCNQ1 gene causing cLQTS type 1 (LQT1) and epilepsy. The index patient had Jervell and Lange-Nielsen-syndrome (JLNS) with deafness and recurrent episodes of cardiac arrhythmia. The mother and the brother have Romano-Ward syndrome (RWS) with recurrent arrhythmias. Whereas the father has focal epilepsy and genetically verified LQT1, the sister has both focal epilepsy and RWS. Our findings are consistent with the notion that mutations in the KCNQ1 gene can cause epilepsy.

Seizure-like episodes and EEG abnormalities in patients with long QT syndrome.

PURPOSE: The congenital long QT-syndrome (cLQTS) is characterized by ventricular arrhythmias, syncope and sudden cardiac death. Many LQTS genes are also expressed in the brain and emerging evidence suggest that cardiac channelopathies can also cause epilepsy. The aim of the study is to explore evidence of epilepsy and/or EEG abnormalities in a cohort with a genotyped diagnosis of LQT1 or LQT2. METHODS: Adult patients were randomly selected from the outpatient clinic and a random sample of healthy controls were recruited from the general population. Ictal semiology was explored in symptomatic patients. A 1 h 64-channel awake EEG was performed and analyzed by visual assessment. Brain connectivity was quantified by Directed Transfer Function (DTF) from the current source density estimate within the theta band (4-7 Hz). RESULTS: Fifteen patients with LQT1, 20 with LQT2 and 20 controls were included. Seventy-one % of the patients reported loss of consciousness (LOC); 44% in combination with convulsions. EEG was abnormal in 34% of patients and 10% of controls (p < 0.05). Two patients had epileptiform or sharp activity. The fronto-parietal DTF connectivity was significantly altered in patients compared to controls (LQT1 p = 2.2 × 10-6, LQT2 p = 0.044). CONCLUSION: Seizure-like episodes and EEG abnormalities were common in our cohort with cLQTS patients. However, we could not find firm evidence of epilepsy. Our findings reinforce the notion that cLQTS is a cardiocerebral channelopathy. Correct classification of seizures may be challenging to the clinician, but of vital importance for patients.

Zonisamide serum concentrations during pregnancy.

PURPOSE: To investigate the change in zonisamide (ZNS) serum concentration and its consequences in pregnant women with epilepsy. METHODS: Six hospitals in Norway and Denmark screened their records for women who had been using ZNS during pregnancy. Absolute serum concentrations as well as concentration/dose (CD)-ratios were compared to non-pregnant values. Descriptive data on seizure control and obstetrical data were also collected. RESULTS: 144 serum concentrations from 23 pregnancies in 15 individual women with epilepsy were included (six on monotherapy). The mean ZNS serum concentration fell to a minimum of 58.6 ±â€¯15.1%, while the C/D-ratio fell to as low as 55.1 ±â€¯15.3% of the non-pregnant-value. The lowest values were seen in gestational months six to nine, and the individual nadir varied considerably (range: 24-81% of the non-pregnant value). Four out of ten previously seizure-free patients experienced breakthrough seizures. Gestational age, weight at birth and head circumference of the newborns were within the reference ranges. CONCLUSIONS: ZNS serum concentrations may fall by over 40% during pregnancy, with large interindividual variability. In some patients, this may lead to worsened seizure control. These findings are in line with reports on other AEDs and suggest that regular therapeutic drug monitoring and dose adjustments may be useful.

The role of antiepileptic drugs in sudden unexpected death in epilepsy.

Sudden unexpected death in epilepsy (SUDEP) primarily affects young adults and is the leading cause of death related directly to seizures. High frequency of generalized tonic-clonic seizures is the most important risk factor, and effective seizure protection is probably the most important measure to prevent these tragic deaths. For several years a potential role of antiepileptic drugs (AEDs) has been discussed, but at present there is wide agreement that choice of AED therapy does not influence the risk. However, although it is well known that the efficacy and safety profiles of AEDs may differ significantly when used in the treatment of genetic epilepsy compared to symptomatic or cryptogenic epilepsy, this has generally been overlooked in epidemiologic studies of possible relationships between AEDs and SUDEP. Consequently important information about drug safety may have been lost. This review challenges the current view that no AED can increase the risk of SUDEP.

[Sudden unexpected death in epilepsy (SUDEP)]. / Plutselig, uventet epilepsirelatert død.

Sudden unexpected death is the most frequent cause of seizure-related death in cases of epilepsy. Those primarily affected are young adults with a long disease duration and regular seizures. The deaths are often related to a nocturnal generalised tonic-clonic seizure attack. In Norway around 30 persons are thought to be affected each year. Optimisation of epilepsy treatment will probably prevent some of these deaths.

Attention deficit/hyperactivity disorder and interictal epileptiform discharges: it is safe to use methylphenidate?

PURPOSE: This study investigated whether interictal epileptiform discharges (IED) on a baseline routine EEG in children with ADHD was associated with the occurrence of epileptic seizures (Sz) or influenced the use of methylphenidate (MPH) during 2 years follow-up. METHODS: A retrospective chart-review of 517 ADHD children with EEG revealed IED in 39 cases. These patients (IED group) were matched on age and gender with 39 patients without IED (non-IED group). We measured at baseline, 1 year and 2 years Sz occurrence, the use of MPH and antiepileptic drug (AED). RESULTS: At baseline, 12 patients in the IED group had active epilepsy and three of them had Sz during the last year. 36 (92.3%) patients were treated with MPH. Initial positive response to MPH was achieved in 83.3% compared with 89.2% in the non-IED group. At 1 and 2 years follow-up, three patients who also had Sz at baseline and difficult to treat epilepsy, had Sz, without changes in seizure frequency. We found no statistically significant differences between the groups with respect to MPH use at 1 year and at 2 years. Ten patients from IED group, who did not have confirmed epilepsy diagnosis, temporarily used AEDs during the first year of follow-up. CONCLUSION: Despite the occurrence of IED, the use of MPH was safe during 2 years follow-up. IED predict the Sz occurrence in children with previous epilepsy, but does not necessarily suggest an increased seizure risk. A caution is warranted in order not to overestimate the significance of temporarily occurrence of IED.

Epilepsy in a large cohort of children diagnosed with attention deficit/hyperactivity disorders (ADHD).

PURPOSE: The knowledge about possible relationships between ADHD and epilepsy is largely based on small samples of ADHD patients and on cohorts with epilepsy. There is insufficient information about the clinical characteristics of epilepsy among children diagnosed with ADHD. The aim of this study was to investigate the prevalence and characteristics of epilepsy in a large, unselected cohort of children with ADHD. METHODS: We conducted a retrospective chart-review of children with ADHD who were evaluated in our clinic between the years 2000 and 2005. We compared age, sex, disorders of psychological development, cognitive level, pharmacological treatment for ADHD, initial response to treatment and ADHD subtype with and without epilepsy. In addition, we compared our data with data from a Norwegian study in a large general pediatric population. RESULTS: Of 607 children with ADHD (age 6-14 years; 82.4% males); 14 (2.3%) had a history of epilepsy, and 13 of these had active epilepsy. This is a higher occurrence than expected in the general pediatric population (0.5%). The majority of our patients had mild (an easily treated) epilepsy and they were more likely to be seizure free (79%) compared to the patients with epilepsy in general pediatric population. The ADHD patients with and without epilepsy did not differ regarding age, gender, disorders of psychological development, IQ level<85 or ADHD subtype. The patients had been diagnosed with epilepsy on average 1.8 years before the ADHD assessment. All patients with epilepsy were treated with methylphenidate (MPH), and initial response to MPH was achieved in 85.7%. CONCLUSION: The epilepsy diagnosis preceded the ADHD diagnosis, and was found in a significantly higher rate than would be expected in the general pediatric population. The majority of patients had mild epilepsy and ADHD-Combined Inattentive/Hyperactive-Impulsive Subtype. All cases with epilepsy and ADHD were treated with MPH, with initial response achieved in 86%.

Signal-averaged and standard electrocardiography in patients with newly diagnosed epilepsy.

Antiepileptic drugs (AEDs) have been associated with cardiac conduction abnormalities and arrhythmias, predominantly in patients with predisposing cardiac conditions. Ventricular late potentials (VLPs) detected in the signal-averaged electrocardiogram (SAECG) may imply an increased risk of ventricular tachycardia or fibrillation. Twenty-six AED-naïve patients with newly diagnosed epilepsy and no clinical evidence of heart disease were examined with SAECG and standard ECG. Fifteen patients were treated with lamotrigine and ten with carbamazepine. No significant abnormality was found in the standard ECG or SAECG three to nine months after initiation of AED therapy. In one patient, a VLP was detected at baseline and subsequent MRI demonstrated significant right ventricular pathology; therefore, this patient was excluded from the rest of the study. This exclusion along with only newly diagnosed patients with a low total seizure count being included in the study may explain the lack of AED-induced electrocardiographic abnormalities in this patient cohort.

Comorbid and underlying diseases--major determinants of excess mortality in epilepsy.

PURPOSE: The reasons why the mortality of patients with epilepsy is significantly increased, even many years after seizure onset, are not fully understood. The aim of this study was to compare the distribution of the causes of death (COD) in an epilepsy population with that in the general population and with previous findings in other epilepsy populations. In addition, we investigated the chronological relationship between the onset of epilepsy and the onset of the diseases leading to death. METHODS: The COD for patients who were registered with a diagnosis of epilepsy at Stavanger University Hospital from August 1 1995-July 31 2005 and died during the same period were obtained from the Norwegian Cause of Death Registry and the hospital records were reviewed. The distribution of the corresponding COD in the general population was obtained from Statistics Norway. RESULTS: At least 6.8% (18/266) of the deaths of epilepsy patients were directly related to seizures. Epilepsy patients who had died from brain tumors (n=46) were excluded from further analysis. Of the remaining 220 deceased epilepsy patients, 39 (17.7%) had died from heart disease, compared with 27.8% in the general population (p<0.001). No other significant differences in the distribution of COD in the epilepsy population and the general population were identified. The majority of the epilepsy patients who died from heart disease (71.8%) and cerebrovascular disease (72%) had cardiovascular disease prior to seizure onset and in at least 43% of those who died from neoplasms the onset of malignancy occurred before the first seizure. CONCLUSION: Comorbid diseases and underlying conditions were the major determinants of mortality in this population of epilepsy patients. Conditions that are not caused by epilepsy or its treatment may represent an important explanation for the previously documented excess mortality in people with epilepsy.

Increased risk of sudden unexpected death in epilepsy in females using lamotrigine: a nested, case-control study.

PURPOSE: To estimate the incidence of sudden unexpected death in epilepsy (SUDEP) in Rogaland County, Norway, in the period August 1 1995-July 31 2005, and to investigate whether use of lamotrigine (LTG) was associated with increased risk in female patients or other subgroups. METHODS: SUDEP victims were identified from autopsy reports and data from the Norwegian Cause of Death Registry. In all cases where SUDEP was considered as a possible cause of death, the hospital records were also reviewed. For each deceased, at least three living patients with epilepsy were randomly selected as controls. The market share in defined daily doses was collected for each year to estimate the number of patient-years at risk on each antiepileptic drug. KEY FINDINGS: We identified 26 cases of SUDEP: 16 definite, 3 probable, and 7 possible; 15 patients were female and 11 were male. Of these, 10 patients (38.5%) were treated with LTG: 9 of these patients were female. The incidence of SUDEP was estimated as 1.0 per 1,000 patient-years when all cases were included, and 0.7 per 1,000 patient-years for definite and probable SUDEP. Seven of 12 (58.3%) of female patients with definite and probable SUDEP and 10 of 41 (24.4%) of controls matched on age and gender were on LTG (p = 0.038). The incidence of definite and probable SUDEP in women on LTG, was estimated as 2.5 per 1,000 patient-years and 0.5 per 1,000 patient-years in female who were not taking LTG (p = 0.007). SIGNIFICANCE: The incidence of SUDEP was significantly higher among female patients with epilepsy who were being treated with LTG than among female patients with epilepsy who were not taking LTG, and a significantly higher proportion of female SUDEP cases than controls were taking LTG. Our findings may have implications for treatment of epilepsy in female patients.

New SCN5A mutation in a SUDEP victim with idiopathic epilepsy.

Many idiopathic epilepsies have been shown to be caused by ion channel dysfunction. Channelopathies also cause the long QT syndrome (LQTS) which is associated with syncopes and sudden cardiac death. It has been postulated that the same channelopathy may be associated with both epilepsy and LQTS. We report a patient with idiopathic epilepsy who died in sudden unexpected death in epilepsy (SUDEP) at the age of 25. A post mortem DNA sequencing of the LQTS-associated genes revealed a novel missense mutation in the SCN5A gene coding for the cardiac sodium channel, voltage gated, type V, alpha subunit. The possibility that the mutation may explain both the epilepsy and the sudden death is discussed. However, the patient was treated with lamotrigine which may interfere with cardiac ion channels and may also have played a part in inducing a terminal cardiac arrhythmia.