Dag Aurlien

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.

Lamotrigine in idiopathic epilepsy : increased risk of cardiac death?

Objectives –  Lamotrigine (LTG) has recently been shown to inhibit the cardiac rapid delayed rectifier potassium ion current (Ikr). Ikr‐blocking drugs may increase the risk of cardiac arrhythmia and sudden unexpected death. With this background, it may be of importance that in our outpatient clinic between August 1, 1995 and August 1, 2005 we registered four consecutive cases of sudden unexpected death in epilepsy (SUDEP) in non‐hospitalized patients that were all being treated with LTG in monotherapy. Here we describe and discuss these cases, the relevant literature, and the reasons to question whether these events were as a result of coincidence alone.

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.

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%.

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.

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.

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.

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.

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.

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.