Iris Unterberger

Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies

Idiopathic generalized epilepsies account for 30% of all epilepsies. Despite a predominant genetic aetiology, the genetic factors predisposing to idiopathic generalized epilepsies remain elusive. Studies of structural genomic variations have revealed a significant excess of recurrent microdeletions at 1q21.1, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 in various neuropsychiatric disorders including autism, intellectual disability and schizophrenia. Microdeletions at 15q13.3 have recently been shown to constitute a strong genetic risk factor for common idiopathic generalized epilepsy syndromes, implicating that other recurrent microdeletions may also be involved in epileptogenesis. This study aimed to investigate the impact of five microdeletions at the genomic hotspot regions 1q21.1, 15q11.2, 16p11.2, 16p13.11 and 22q11.2 on the genetic risk to common idiopathic generalized epilepsy syndromes. The candidate microdeletions were assessed by high-density single nucleotide polymorphism arrays in 1234 patients with idiopathic generalized epilepsy from North-western Europe and 3022 controls from the German population. Microdeletions were validated by quantitative polymerase chain reaction and their breakpoints refined by array comparative genomic hybridization. In total, 22 patients with idiopathic generalized epilepsy (1.8%) carried one of the five novel microdeletions compared with nine controls (0.3%) (odds ratio = 6.1; 95% confidence interval 2.8-13.2; chi(2) = 26.7; 1 degree of freedom; P = 2.4 x 10(-7)). Microdeletions were observed at 1q21.1 [Idiopathic generalized epilepsy (IGE)/control: 1/1], 15q11.2 (IGE/control: 12/6), 16p11.2 IGE/control: 1/0, 16p13.11 (IGE/control: 6/2) and 22q11.2 (IGE/control: 2/0). Significant associations with IGEs were found for the microdeletions at 15q11.2 (odds ratio = 4.9; 95% confidence interval 1.8-13.2; P = 4.2 x 10(-4)) and 16p13.11 (odds ratio = 7.4; 95% confidence interval 1.3-74.7; P = 0.009). Including nine patients with idiopathic generalized epilepsy in this cohort with known 15q13.3 microdeletions (IGE/control: 9/0), parental transmission could be examined in 14 families. While 10 microdeletions were inherited (seven maternal and three paternal transmissions), four microdeletions occurred de novo at 15q13.3 (n = 1), 16p13.11 (n = 2) and 22q11.2 (n = 1). Eight of the transmitting parents were clinically unaffected, suggesting that the microdeletion itself is not sufficient to cause the epilepsy phenotype. Although the microdeletions investigated are individually rare (<1%) in patients with idiopathic generalized epilepsy, they collectively seem to account for a significant fraction of the genetic variance in common idiopathic generalized epilepsy syndromes. The present results indicate an involvement of microdeletions at 15q11.2 and 16p13.11 in epileptogenesis and strengthen the evidence that recurrent microdeletions at 15q11.2, 15q13.3 and 16p13.11 confer a pleiotropic susceptibility effect to a broad range of neuropsychiatric disorders.

Safety and efficacy of a novel intravascular cooling device to control body temperature in neurologic intensive care patients: A prospective pilot study

Objective To determine the safety and efficacy of a novel intravascular cooling device (Cool Line catheter with Cool Gard system) to control body temperature (temperature goal <37°C) in neurologic intensive care patients. Design A prospective, uncontrolled pilot study in 51 consecutive neurologic intensive care patients. Setting A neurologic intensive care unit at a tertiary care university hospital. Participants Patients were 51 neurologic intensive care patients with an intracranial disease requiring a central venous catheter due to the primary (intracranial) disease. We excluded patients under the age of 19 yrs and those with active cardiac arrhythmia, full sepsis syndrome, bleeding diathesis and infection, or bleeding at the site of the intended catheter insertion. Male to female ratio was 31:20, and the median age was 55 yrs (range, 24–85 yrs). Forty-four of 51 patients (86.3%) had an initial Glasgow Coma Scale score of 3, three patients had a Glasgow Coma Scale score of 9, one patient presented with an initial Glasgow Coma Scale score of 11, two patients had an initial Glasgow Coma Scale score of 13, and one patient had an initial Glasgow Coma Scale score of 15. The mean initial tissue injury severity score was 45.1 and the median initial tissue injury severity score 45.0 (range, 19–70). Interventions Patients were enrolled prospectively in a consecutive way. Within 12 hrs after admission, the intravascular cooling device (Cool Line catheter) was placed, the temperature probe was located within the bladder (by Foley catheter), and the Cool Gard cooling device was initiated. This Cool Gard system circulates temperature-controlled sterile saline through two small balloons mounted on the distal end of the Cool Line catheter. The patient’s blood is gently cooled as it is passed over the balloons. The Cool Gard system has been set with a target temperature of 36.5°C. The primary purpose and end point of this study was to evaluate the cooling capacity of this intravascular cooling device. Efficacy is expressed by the calculation formula of fever burden, which is defined as the fever time product (°C hours) under the fever curve. Measurements and Main Results The cooling device was in operation for a mean of 152.4 hrs. The ease of insertion was judged as easy in 42 of 51 patients; in a single patient, the catheter was malpositioned within the jugular vein, requiring early removal. The rate of infectious and noninfectious complications (nosocomial pneumonia, bacteremia, catheter-related ventriculitis, pulmonary embolism, etc.) was comparable to the rate usually observed in our neurologic intensive care patients with such severe intracranial diseases. The total fever burden within the entire study period of (on average) 152.4 hrs was 4.0°C hrs/patient, being equivalent to 0.6°C hrs/patient and day. Thirty of 51 patients showed an elevation of the body temperature (>37.9°C) within 24 hrs after termination of the cooling study. One awake patient (subarachnoid hemorrhage, Glasgow Coma Scale score 15) experienced mild to moderate shivering throughout the entire period of 7 days. The mortality rate was 23.5%. Conclusion This novel intravascular cooling device (Cool Line catheter and Cool Gard cooling device) was highly efficacious in prophylactically controlling the body temperature of neurologic intensive care patients with very severe intracranial disease (median Glasgow Coma Scale score, 3–15). Morbidity and mortality rates were consistent with the ranges reported in the literature for such neurologic intensive patients.

Polycystic ovaries, obesity and insulin resistance in women with epilepsy. A comparative study of carbamazepine and valproic acid in 105 women.

Abstract. In order to investigate the possible role of valproic acid therapy in the development of obesity, hyperinsulinism and polycystic ovaries (PCOs), we have studied metabolic parameters and ovarian morphology in epileptic women. A total of 105 women, who were treated for at least 2 years with valproate (n = 52) or carbamazepine monotherapy (n = 53), were included in the examination. Menstrual disturbances were reported by 29 (28 %) of the women, 12 (11 %) of the VPA treated women, and 17 (16 %) in the CBZ group. On ultrasound scan polycystic ovaries were found in 28 patients (27 %) of the whole study population, of whom 13 (12 %) received VPA and 15 (14 %) CBZ. The mean body mass index (BMI) was significantly higher in the VPA group (24.4 kg/m2± 4.1) than in CBZ treated patients (22.9 kg/m2± 2.4;p < 0.022), and serum triglycerides tended to be increased, while total cholesterol values (178.9 ± 30.5) and LDL-cholesterol values (92.6 ± 27.4) were significantly lower in the valproate group, than in the carbamazepine group (207.1 ± 43.0 vs 115.1 ± 42.0; p < 0.001). Postprandial insulin, C-peptide and proinsulin levels were significantly higher in VPA treated patients compared with those treated with CBZ, while no differences could be found in the fasting state. In conclusion we could thus demonstrate that the frequency of PCOs in 27 % of epileptic women seems to be similar to that in the general population with a frequency of 20–30 %. The development of PCOs did not reveal a difference with the administration of VPA or CBZ. With respect to the metabolic side-effects of VPA therapy our data indicate that VPA increases glucose stimulated pancreatic insulin secretion, which might be followed by an increase in body weight.

The head nodding syndrome—Clinical classification and possible causes

Purpose:  In the 1960s in Tanzania, L. Jilek‐Aall observed a seizure disorder characterized by head nodding (HN). Decades later, “nodding disease,” reminiscent of what was seen in Tanzania, was reported from Sudan. To date this seizure disorder has not been classified and possible causes still remain obscure.

Intravenous lacosamide in status epilepticus and seizure clusters

Status epilepticus (SE) and seizure clusters (SC) represent neurologic emergencies with a case fatality rate up to 34%, depending on cause and comorbidity. As SE becomes more refractory to treatment over time, appropriate medication is important. This study aimed to investigate efficacy and tolerability of intravenous (IV) lacosamide (LCM) in treatment of SC and SE. Data of patients with SE or SC who were treated with IV LCM between December 2009 and February 2011 in two Austrian centers were analyzed retrospectively. Clinical information was extracted from patients’ charts. Forty‐eight patients (26f/22m) aged median 62 years (range 17–95 years) were identified. Thirty‐five percent of patients (17 of 48) had SC and 65% (31 of 48) had SE. SE was nonconvulsive in 10 (32%), convulsive in 11 (36%), and focal in 10 (32%) patients. SE was acute symptomatic in six (20%) and remote symptomatic in 11 (35%) patients. Fourteen (45%) had preexisting epilepsy. Median initial bolus dose was 200 mg (range 200–400 mg) in patients with SE and 200 mg in patients with SC. Maximum infusion rate was 60 mg/min. Cessation was observed in 42 patients (88%). Success rate in patients with SE receiving LCM as first or second drug was 100% (8 of 8), as third drug 81% (11 of 15), and as fourth or later drug 75% (6 of 8). There were no side effects observed except for pruritus and skin rash in two patients. These data support use of IV LCM as a potential alternative to standard antiepileptic drugs for acute treatment of seizure emergency situations, although randomized controlled studies are needed.

Psychiatric Comorbidity in Juvenile Myoclonic Epilepsy

Summary:  Objective: To assess the prevalence of psychiatric disturbances among patients with juvenile myoclonic epilepsy (JME).

Hyperandrogenism, postprandial hyperinsulinism and the risk of PCOS in a cross sectional study of women with epilepsy treated with valproate

Among a sample of 43 women with epilepsy treated for at least 2 years with valproate (n=22) or other antiepileptic drugs (AEDs) (n=21), polycystic ovary syndrome (PCOS) was diagnosed in three women, two of them were treated with valproate. Although the rate of PCOS and of menstrual disturbances, weight body mass index (BMI) and waist to hip ratio as well as fasting blood glucose levels, fasting insulin, proinsulin and C-peptide values was similar in this small sample of women treated with valproate and other AEDs, valproate exposure was associated with higher androgen levels, higher postprandial (pp) insulin and proinsulin levels, as well as lower cholesterol and low density lipoprotein (LDL) cholesterol levels. The pronounced increase in pp insulin levels during VPA treatment may indicate an effect of the fatty acid derivate VPA on pancreatic islet cells.

Long-term prognosis for childhood and juvenile absence epilepsy.

Abstract.Purpose:To analyse prognostic factors for long term seizure remission in patients with childhood (CAE) and juvenile absence epilepsy (JAE).Study design:A retrospective analysis of a hospital based prevalence cohort.Methods:The cohort consisted of 163 patients (104 females, 59 males) treated at the Universitätsklinik für Neurologie, Innsbruck between 1970 and 1997. All had absences according to the ILAE classification. Follow up was in 1999 to 2000. We assessed multiple clinical and EEG factors as predictors of outcome and compared a classification according to the predominant pattern of seizure recurrence (pyknoleptic, PA or non pyknoleptic absence, NPA) with the ILAE classification with respect to prognosis.Results:The mean age at seizure onset was 10.9 years (range, 3 to 27); age at follow up was 36.7 years (range, 13 to 81); duration of follow up was 25.8 years (range, 3 to 69). Sixty four patients (39 %) had CAE and 64 (39 %) JAE, while 35 (22%) had typical absences but could not be clearly defined as either CAE or JAE, and were therefore called “the overlap group”. Patients with JAE or patients in the overlap group developed more often generalized tonic clonic seizures (GTCS) (p<0.001) and myoclonic attacks (p<0.05) during the course of the disease. At follow up 36 (56 %) of patients with CAE, 40 (62%) with JAE and 19 (54 %) of the overlap group were seizure free for at least two years (p=ns). When classified according to the predominant absence pattern at seizure onset 42 (51%) patients with PA and 53 (65%) with NPA were in remission (p=ns). In a stepwise binary logistic regression analysis the pattern of absence (PA or NPA) together with the later development of additional seizure types (myoclonias or GTCS), but not the CAE/JAE classification was predictive for long term lack of remission with a correct prediction of 66% of all patients.Conclusion:Only 58% of patients with absences were in remission after a long term follow up. CAE and JAE are closely related syndromes with large overlap of the age of onset. A classification according to the predominant seizure pattern at onset, together with later development of myoclonic attacks or GTCS is useful in predicting seizure remission in absence epilepsies.

Video‐EEG monitoring: Safety and adverse events in 507 consecutive patients

Purpose:  Video–electroencephalography (EEG) monitoring plays a central role in the presurgical evaluation of medically refractory epilepsies and the diagnosis of nonepileptic attack disorders (NEADs). The aim of this study was to analyze safety and adverse events (AEs) during video‐EEG monitoring.

Successful surgical treatment of insular epilepsy with nocturnal hypermotor seizures

Nocturnal hypermotor seizures (NHSs) suggest seizure onset in the frontal lobe. We present a patient with NHSs and insular seizure onset who underwent successful surgical treatment.