Matthias K. Bernhard

De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy.

Epileptic encephalopathies are a phenotypically and genetically heterogeneous group of severe epilepsies accompanied by intellectual disability and other neurodevelopmental features. Using next-generation sequencing, we identified four different de novo mutations in KCNA2, encoding the potassium channel KV1.2, in six isolated patients with epileptic encephalopathy (one mutation recurred three times independently). Four individuals presented with febrile and multiple afebrile, often focal seizure types, multifocal epileptiform discharges strongly activated by sleep, mild to moderate intellectual disability, delayed speech development and sometimes ataxia. Functional studies of the two mutations associated with this phenotype showed almost complete loss of function with a dominant-negative effect. Two further individuals presented with a different and more severe epileptic encephalopathy phenotype. They carried mutations inducing a drastic gain-of-function effect leading to permanently open channels. These results establish KCNA2 as a new gene involved in human neurodevelopmental disorders through two different mechanisms, predicting either hyperexcitability or electrical silencing of KV1.2-expressing neurons.

Knowledge and attitudes of school teachers, preschool teachers and students in teacher training about epilepsy and emergency management of seizures

Problem School and preschool teachers play a key role in the care of children with epilepsy. Yet, data about their knowledge on epilepsy are scarce. Methods Assessment of knowledge and attitudes towards epilepsy in teachers by conducting a questionnaire survey in Leipzig and Blankenburg, Germany, from August 2013 to January 2014. Results 1243 questionnaires were completed by 302 school teachers, 883 preschool teachers, 56 students and two unclassified participants. Of the respondents, 140 (11%) stated to have already been actively involved in an epilepsy emergency situation, another 148 (12%) as observers. Only 214 (17%) of respondents felt sufficiently prepared for an emergency. A rescue medication had already been applied by 79 (6%) of respondents; only 186 respondents (15%) stated they would be willing to administer a prescribed rescue medication under any circumstances. In response to an open-ended question about the most common fatal outcomes of a seizure, status epilepticus and drowning were rarely mentioned. 233 (19%) of respondents assumed that epileptic seizures cannot result in death. 606 (49%) of respondents were concerned about the legal repercussions to an incorrect response to a seizure.129/403 (32%) of teachers with >20 years of professional experience claimed never to have had a child suffering from epilepsy in their care, even though the prevalence of childhood epilepsy indicates that they should. In total, 1066 (86%) respondents expressed a desire to gain more knowledge on epilepsy. Conclusions Training programmes for teachers should be established. Furthermore, a clear legal regulatory framework needs to be set up.

Use of complementary and alternative medicine (CAM) by parents in their children and adolescents with epilepsy – Prevelance, predictors and parents' assessment

BACKGROUND The use of complementary and alternative medicine (CAM) is popular. Parents of children suffering from epilepsy may also consider administering CAM to their children. Systematic data about frequency of and motivations for CAM use, however, are scarce. METHODS In a university hospitals neuropaediatric department parents of patients aged 0-18 years suffering from epilepsy were consecutively invited to take part in a structured interview during 4 months in 2014. RESULTS Of the invited parents, 164/165 (99%) agreed to participate. From those, 21/164 (13%) stated that they used CAM in their child. The highest independent predictive value of CAM use was the occurrence of adverse drug events (ADE) of anticonvulsants as judged by parents. Patients affected by ADE had a 5.6 higher chance of receiving CAM compared to patients without ADE. Most commonly used were homeopathy (14/21, 67%) and osteopathy (12/21, 57%). The internet was the most frequently used source of information (14/21, 67%). Of the parents, 10/21 (48%) described positive effects of CAM on seizure frequency, 12/21 (57%) on general condition of their child, and 20/21 (95%) wished to continue CAM for epilepsy therapy. From the non-users of CAM, 91/143 (66%) expressed the desire to learn more about CAM for epilepsy therapy. LIMITATIONS Our study was performed in a university hospital in a large urban city in Eastern Germany. CAM user rates can differ in other parts of Germany and Europe, in other institutions and for chronic diseases other than epilepsy. CONCLUSION The main reason for CAM use was the occurrence of ADE of anticonvulsants. More than half of the parents saw a benefit of CAM for their children. Almost all parents wished to continue CAM use, even those who did not see concrete positive effects.

Wide spectrum of clinical manifestations in children with tuberous sclerosis complex – Follow-up of 20 children

UNLABELLED TSC is a multisystem genetic disorder predisposing to multiple organ manifestations and developmental problems. Clinical follow-up of patients remains a challenge for the caring paediatrician. METHODS We performed a retrospective analysis of clinical manifestations, diagnostic and therapeutic data in 20 children with the diagnosis of tuberous sclerosis complex (TSC) to answer the following questions: are the clinical guidelines and imaging strategies appropriate to discover complications, are there significant early predictors of long-term prognosis, what is the age range for signs and symptoms to occur. RESULTS Cardiac rhabdomyoma were present in 18 children and occurred as earliest manifestation. 8 of these exhibited associated arrhythmia or congenital cardiac anomalies. Seizures combined with cortical tubers and subependymal nodules occurred in 18 patients and were most likely to start in infancy, which was associated with later cognitive impairment. Cutaneous manifestations (15 children) occurred in late childhood and school age, whilst renal angiomyolipomas (11) developed in puberty. DISCUSSION The clinical course and imaging strategies are compared with data from previous studies. A review of TSC in regard to the multiple manifestations is provided.

Ambulatory Care of Children Treated with Anticonvulsants – Pitfalls after Discharge from Hospital

BACKGROUND Anticonvulsants require special consideration particularly at the interface from hospital to ambulatory care. PATIENTS AND METHOD Observational study for 6 months with prospectively enrolled consecutive patients in a neuropediatric ward of a university hospital (age 0-<18 years) with long-term therapy of at least one anticonvulsant. Assessment of outpatient prescriptions after discharge. Parent interviews for emergency treatment for acute seizures and safety precautions. RESULTS We identified changes of the brand in 19/82 (23%) patients caused by hospitals discharge letters (4/82; 5%) or in ambulatory care (15/82; 18%). In 37/76 (49%) of patients who were deemed to require rescue medication, no recommendation for such a medication was included in the discharge letters. 17/76 (22%) of the respective parents stated that they had no immediate access to rescue medication. Safety precautions were applicable in 44 epilepsy patients. We identified knowledge deficits in 27/44 (61%) of parents. CONCLUSION Switching of brands after discharge was frequent. In the discharge letters, rescue medications were insufficiently recommended. Additionally, parents frequently displayed knowledge deficits in risk management.

Adult long-term health-related quality of life of congenital hydrocephalus patients.

OBJECT Congenital hydrocephalus has a major impact on the lives of patients and their relatives, as well as their long-term neurological development and social integration. The aim of this study was to assess the self-reported health-related quality of life (HRQOL) of patients after reaching adulthood. METHODS A total of 31 patients who required CSF shunt treatment for congenital hydrocephalus within the 1st year of life (between 1963 and 1987) agreed to undergo a structured SF-36 self-assessment. An age-matched German standard cohort was used as control. Additional parameters of surgical, social, and global neurological outcome were analyzed. The mean patient age was 35 years (range 26-51 years, 13 females and 18 males). Hydrocephalus etiologies were posthemorrhagic hydrocephalus (n = 9), postinfectious hydrocephalus (n = 5), aqueductal stenosis (n = 10), myelomeningocele (n = 2), and unknown cause (n = 5). RESULTS The mean modified Rankin Scale score was 1.6 (range 0-4). Hydrocephalic patients achieved lower scores for the SF-36 items physical functioning (70.5 vs. 93.5, p < 0.05), physical role functioning (74.2 vs. 88.3, p < 0.05), and general health perceptions (64.5 vs. 72.3, p < 0.05). Emotional, social role functioning, and mental health items did not differ between the groups. Assessment of vitality and pain resulted in a trend to worse values. Whereas the Physical Component Summary score was lower (46.1 vs. 54.3, p < 0.05), the Mental Component Summary score was not significantly different (50.2 vs. 48.7, p = 0.3). There was neither a statistically significant difference between subgroups of different etiologies nor an association with the number of subsequent hydrocephalus-related surgeries. CONCLUSIONS Adult HRQOL for patients with congenital hydrocephalus appears to be similar to that for healthy con with regard to mental health and social functioning aspects. Physical impairment is a predominant factor of compro quality of life.

Operative management of idiopathic spinal intradural arachnoid cysts in children: a systematic review.

BackgroundSpinal intradural arachnoid cysts are rare with only a few patients reported so far. Idiopathic, traumatic, posthemorrhagic, and postinflammatory causes have been reported in the literature. Especially, idiopathic lesions, in which other possible etiological factors have been ruled out, seem to be rare.Patients and MethodsWe systematically reviewed the literature in regards to localization within the spinal canal, treatment options, complications, and outcome. Additionally, we present management strategies in two progressively symptomatic children less than 3 years of age with idiopathic intradural arachnoid cysts.ResultsIn total, 21 pediatric cases including the presented cases have been analyzed. Anterior idiopathic spinal arachnoid cysts are predominantly located in the cervical spine in 87.5 % of all cases, whereas posterior cysts can be found at thoracic and thoracolumbar segments in 84.6 % of the patients. Most children presented with motor deficits (76.2 %). Twenty-five percent of anterior spinal arachnoid cysts caused back pain as the only presenting symptom. Open fenestration by a dorsal approach has been used in the vast majority of cases. No major surgical complications have been reported. Ninety-four percent of all patients did improve or showed no neurological deficits. Recurrence rate after successful surgical treatment was low (9.5 %).ConclusionIdiopathic spinal intradural arachnoid cysts can present with neurological deficits in children. Pathologies are predominantly located in the cervical spine anteriorly and in thoracic and thoracolumbar segments posteriorly to the spinal cord. In symptomatic cases, microsurgical excision and cyst wall fenestration via laminotomy are recommended. Our radiological, intraoperative, and pathological findings support the cerebrospinal fluid obstruction and vent mechanism theory of arachnoid cysts.

Seizure management by preschool teachers: A training concept focussing on practical skills

PURPOSE Prolonged seizures can cause severe harm and even death. For seizures lasting longer than 5min, an administration of rescue medication is therefore recommended. Caregivers such as preschool teachers should be able to administer correctly anticonvulsive rescue medication to children. METHODS A training concept for preschool teachers on seizure management focussing on practical skills was developed. To assess the success of the training, a structured interview on attitudes relating to rescue medication administration was conducted. The number of committed errors during administration of a rectal/buccal rescue medication to dummy dolls was compared before and after training. RESULTS 210 teachers from 115 preschools participated while all teachers from 303 preschools had been invited. The self-reported level of confidence in their own skills to administer anticonvulsive rescue medication increased from 5 to 8 on a scale from 1 to 10 (p<0.001). The number of participants who agreed to administer rescue medication rose from 195/210 (92.8%) before training to 209/210 (99.5%, p<0.001) after training for the rectal route, and from 173/210 (82.4%) to 209/210 (99.5%, p<0.001) for the buccal route. For teachers who administered rescue medication before and after training, the number of administrations without any administration errors rose from 1/195 (0.5%) to 117/195 (60.0%, p<0.001) for the rectal route, and from 13/173 (7.5%) to 95/173 (54.9%, p<0.001) for the buccal route. CONCLUSION A training for preschool teachers boosted the level of self-confidence relating to administration of anticonvulsive rescue medication. Teachers also committed fewer errors when administering rescue medication to dummy dolls.

The Cerebral Surfactant System and Its Alteration in Hydrocephalic Conditions

Introduction Pulmonary Surfactant reduces surface tension in the terminal airways thus facilitating breathing and contributes to host’s innate immunity. Surfactant Proteins (SP) A, B, C and D were recently identified as inherent proteins of the CNS. Aim of the study was to investigate cerebrospinal fluid (CSF) SP levels in hydrocephalus patients compared to normal subjects. Patients and Methods CSF SP A-D levels were quantified using commercially available ELISA kits in 126 patients (0–84 years, mean 39 years). 60 patients without CNS pathologies served as a control group. Hydrocephalus patients were separated in aqueductal stenosis (AQS, n = 24), acute hydrocephalus without aqueductal stenosis (acute HC w/o AQS, n = 16) and idiopathic normal pressure hydrocephalus (NPH, n = 20). Furthermore, six patients with pseudotumor cerebri were investigated. Results SP A—D are present under physiological conditions in human CSF. SP-A is elevated in diseases accompanied by ventricular enlargement (AQS, acute HC w/o AQS) in a significant manner (0.67, 1.21 vs 0.38 ng/ml in control, p<0.001). SP-C is also elevated in hydrocephalic conditions (AQS, acute HC w/o AQS; 0.87, 1.71 vs. 0.48 ng/ml in controls, p<0.001) and in Pseudotumor cerebri (1.26 vs. 0.48 ng/ml in controls, p<0.01). SP-B and SP-D did not show significant alterations. Conclusion The present study confirms the presence of SPs in human CSF. There are significant changes of SP-A and SP-C levels in diseases affecting brain water circulation and elevation of intracranial pressure. Cause of the alterations, underlying regulatory mechanisms, as well as diagnostic and therapeutic consequences of cerebral SP’s requires further thorough investigations.

Use of Levetiracetam in Neonates in Clinical Practice: A Retrospective Study at a German University Hospital.

OBJECTIVE We performed a retrospective chart analysis in neonates routinely treated with levetiracetam (LEV) in a university setting. Patients and Methods We assessed clinical characteristics of the included neonates. Documented LEV doses and the duration of treatment were evaluated. To assess LEV effectiveness, we compared the need of any additional anticonvulsant as co- and rescue therapies before and following the initiation of LEV treatment. To assess LEV tolerance, we sought to identify documented adverse drug reactions resulting in a termination of LEV treatment. RESULTS We analyzed a total of 72 neonates receiving LEV with a median gestational age at initiation of LEV treatment of 30 (4/7) gestational weeks (min., 24(5/7)/max., 43(0/7) weeks). LEV was applied in target doses of 41.7 mg/kg/d (min., 14.4/max., 106.2 mg/kg/d). Patients received LEV treatment at hospital for a median of 28 days (min., 1/max., 195 days). Additional anticonvulsant therapy decreased a week after LEV treatment was initiated (p = 0.008). We did not find any cases of terminated LEV treatment resulting from adverse drug reactions. CONCLUSION Long term use of high LEV doses is rather frequent in immature neonates. Our data indicate good effectiveness and a low risk of adverse drug reactions.