Astrid Bertsche

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.

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.

An Unusual Manifestation of a Neonatal Chlamydia Infection

A 25-day-old boy was admitted to hospital because of pneumonia and additionally developed symptoms of encephalitis. The immune fluorescence test for Chlamydia trachomatis in tracheal fluids was positive. Furthermore, ligase chain reaction for C trachomatis was positive in the cerebrospinal fluid. The antibiotic regimen was changed to erythromycin intravenously. C trachomatis encephalitis is rare in neonates and may result from a defect in the alternative pathway of complement activation which was the case in this patient.

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.

Dose-dependent effects of levetiracetam after hypoxia and hypothermia in the neonatal mouse brain

Perinatal asphyxia to the developing brain remains a major cause of morbidity. Hypothermia is currently the only established neuroprotective treatment available for term born infants with hypoxic-ischemic encephalopathy, saving one in seven to eight infants from developing severe neurological deficits. Therefore, additional treatments with clinically applicable drugs are indispensable. This study investigates a potential additive neuroprotective effect of levetiracetam combined with hypothermia after hypoxia-induced brain injury in neonatal mice. 9-day-old C57BL/6-mice (P9) were subjected either to acute hypoxia or room-air. After 90min of systemic hypoxia (6% O2), pups were randomized into six groups: 1) vehicle, 2) low-dose levetiracetam (LEV), 3) high-dose LEV, 4) hypothermia (HT), 5) HT combined with low-dose LEV and 6) HT combined with high-dose LEV. Pro-apoptotic factors, neuronal structures, and myelination were analysed by histology and on protein level at appropriate time points. On P28 to P37 long-term outcome was assessed by neurobehavioral testing. Hypothermia confers acute and long-term neuroprotection by reducing apoptosis and preservation of myelinating oligodendrocytes and neurons in a model of acute hypoxia in the neonatal mouse brain. Low-dose LEV caused no adverse effects after neonatal hypoxic brain damage treated with hypothermia whereas administration of high-dose LEV alone or in combination with hypothermia increased neuronal apoptosis after hypoxic brain injury. LEV in low- dosage had no additive neuroprotective effect following acute hypoxic brain injury.

How to improve prescription of inhaled salbutamol by providing standardised feedback on administration: a controlled intervention pilot study with follow-up.

BackgroundThe effectiveness of inhaled salbutamol in routine care depends particularly on prescribed dosage and applied inhalation technique. To achieve maximum effectiveness and to prevent drug-related problems, prescription and administration need to work in concert.MethodsWe performed a controlled intervention pilot study with 4 consecutive groups in a general paediatric unit and assessed problems in salbutamol prescribing and administration. Control group [i]: Routine care without additional support. First intervention group [ii]: We carried out a teaching session for nurses aimed at preventing problems in inhalation technique. Independently from this, a pharmacist counselled physicians on problems in salbutamol prescribing. Second intervention group [iii]: Additionally to the first intervention, physicians received standardised feedback on the inhalation technique. Follow-up group [iv]: Subsequently, without any delay after the second intervention group had been completed, sustainability of the measures was assessed. We performed the chi-square test to calculate the level of significance with p ≤ 0.05 to indicate a statistically significant difference for the primary outcome. As we performed multiple testing, an adjusted p ≤ 0.01 according to Bonferroni correction was considered as significant.ResultsWe included a total of 225 patients. By counselling the physicians, we reduced the number of patients with problems from 55% to 43% (control [i] vs. first intervention [ii], n.s.). With additional feedback to physicians, this number was further reduced to 25% ([i] vs. [iii], p < 0.001). In the follow-up [iv], the number rose again to 48% (p < 0.01 compared to feedback group).ConclusionsTeaching nurses, counselling physicians, and providing feedback on the quality of inhalation technique effectively reduced problems in salbutamol treatment. However, for success to be sustained, continuous support needs to be provided.Trial registrationGerman Clinical Trials register: DRKS00006792.

Region- and pattern-specific effects of glutamate uptake blockers on epileptiform activity in rat brain slices.

Many epileptic syndromes develop into pharmaco-resistant forms, calling for the development of new anticonvulsant strategies. The transmitter glutamate serves a double role as excitatory transmitter and as precursor for GABA, thus interfering with glutamate uptake may therefore exert complex effects on excitation-inhibition-balance in epileptic networks. In the present study we tested the effect of two different glutamate uptake blockers on acutely induced epileptiform activity in hippocampal-entorhinal cortex slices from adult rats: dihydrokainate (DHK) which blocks predominantly glial glutamate uptake, and threo-beta-benzyloxyaspartic acid (TBOA) which blocks both glial and neuronal glutamate uptake. Three different models were used to induce epileptiform discharges: (i) increasing NMDA receptor-mediated excitation by omitting Mg(2+)-ions; (ii) blocking potassium channels by 4-aminopyridine; (iii) reducing GABA(A) receptor-mediated inhibition by penicillin. Application of DHK or TBOA markedly reduced the frequency of epileptiform discharges in CA1 in the low magnesium and the 4-AP model while pathological activity was increased in the penicillin-model. In contrast, frequency of epileptiform discharges in EC was consistently increased by DHK and TBOA. Effects of DHK were more easily reversible than those of TBOA. Thus glutamate uptake blockers exert variable effects on epileptiform activity, depending on brain region and on the mechanism of ictogenesis.

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.