Manifestation of epilepsy in a patient with EED-related overgrowth (Cohen-Gibson syndrome).

Cohen-Gibson syndrome is a rare genetic disorder, characterized by fetal or early childhood overgrowth and mild to severe intellectual disability. It is caused by heterozygous aberrations in EED, which encodes an evolutionary conserved polycomb group (PcG) protein that forms the polycomb repressive complex-2 (PRC2) together with EZH2, SUZ12, and RBBP7/4. In total, 11 affected individuals with heterozygous pathogenic variants in EED were reported, so far. All variants affect a few key residues within the EED WD40 repeat domain. By trio exome sequencing, we identified the heterozygous missense variant c.581A > G, p.(Asn194Ser) in exon 6 of the EED-gene in an individual with moderate intellectual disability, overgrowth, and epilepsy. The same pathogenic variant was detected in 2 of the 11 previously reported cases. Epilepsy, however, was only diagnosed in one other individual with Cohen-Gibson syndrome before. Our findings further confirm that the WD40 repeat domain represents a mutational hotspot; they also expand the clinical spectrum of Cohen-Gibson syndrome and highlight the clinical variability even in individuals with the same pathogenic variant. Furthermore, they indicate a possible association between Cohen-Gibson syndrome and epilepsy.

Long-term effects of zonisamide in adult patients with intellectual disability.

OBJECTIVE: This study aimed to evaluate the tolerability and efficacy of zonisamide (ZNS) in adult patients with drug-resistant epilepsy and intellectual disability (ID) at our epilepsy centre. PATIENTS AND METHODS: By conducting a monocentric, open-label observational study based on standardized seizure records we retrospectively assessed 87 patients (39 female, mean age 40.6 ± 13.6, range 18-75 years) with ID and drug-resistant epilepsy. Evaluation, including calculation of retention rate, was performed for the intervals 3-6, 9-12 and 21-24 months after ZNS initiation. The Clinical Global Impressions Scale-Improvement (CGI-I) was used to detect qualitative changes in seizure severity and clinical status. Via regression analysis and the generalized estimating equations approach, we examined changes in body weight and impact of patient age also considering associations with other patient characteristics. RESULTS: The retention rate after 24 months was 60%. 28% discontinued ZNS therapy due to increasing seizure frequency, lack of efficacy or adverse events (AEs). Sedation (38%), language impairment (19%), challenging behaviour (10%), mild rash (10%) and dizziness (10%) were the commonest AEs. The responder rate was 40%, eight patients (9%) became seizure free. We found CGI-I to be dose-dependent. Regarding changes in body weight, we observed no difference between patients continuing or withdrawing ZNS therapy and responders or non-responders. Though, we identified older age as a significant risk factor for weight loss. CONCLUSIONS: Zonisamide may provide a safe and efficient therapeutic option for patients with ID and drug-resistant epilepsy. However, weight status should be carefully monitored, especially in elderly patients.

Transcutaneous vagus nerve stimulation (t-VNS) in pharmacoresistant epilepsies: a proof of concept trial.

To elucidate, in a pilot-study, whether noninvasive transcutaneous vagus nerve stimulation (t-VNS) is a safe and tolerable alternative treatment option in pharmacoresistant epilepsy. t-VNS was applied to 10 patients with pharmacoresistant epilepsies. Stimulation via the auricular branch of the vagus nerve of the left tragus was delivered three times per day for 9 months. Subjective documentation of stimulation effects was obtained from patients' seizure diaries. For a more reliable assessment of seizure frequency, we carried out prolonged outpatient video-electroencephalography (EEG) monitoring. In addition, computerized testing of cognitive, affective, and emotional functions was performed. Three patients aborted the study. Of the remaining seven patients, an overall reduction of seizure frequency was observed in five patients after 9 months of t-VNS. The noninvasive t-VNS stimulation is a safe and well-tolerated method for relatively long periods, and might be an alternative treatment option for patients with epilepsy.

Early-onset parkinsonism in PPP2R5D-related neurodevelopmental disorder.

PPP2R5D-related neurodevelopmental disorder (NDD) is a rare autosomal-dominant disease with developmental delay and mild to severe intellectual disability. So far, fewer than 30 affected individuals with mostly recurrent, de novo missense variants in PPP2R5D were reported. Recently, parkinsonism with an onset between 20 and 40 years was reported in four adult individuals with the same p.(Glu200Lys) variant in PPP2R5D. By trio exome sequencing we now identified the variant p.(Glu198Lys) in a 29 year old woman presenting with typical clinical manifestations of PPP2R5D-related neurodevelopmental disorder and additionally with motor decline and levodopa responsive, early-onset parkinsonism from her mid-twenties on. Accordingly, a clear reduction of dopamine transporter in the striatum on both sides was revealed by brain scintigraphy. Our findings further expand the molecular and clinical spectrum of PPP2R5D-related NDD and confirm the association with parkinsonism in early adulthood. This has marked implications for prognosis of PPP2R5D-related NDDs and for the therapeutic management of motor decline and parkinson-like symptoms in affected individuals.

Transient tetraplegia after cervical facet joint injection for chronic neck pain administered without imaging guidance.

We report about a patient in whom transient tetraplegia with intact proprioception occurred immediately after infiltration of a facet joint at the C6 level guided by anatomical landmarks. After positioning the patient supine and applying atropine and oxygen, respiration and circulation were stable and all symptoms resolved within the next 30 min. The type of neurological pattern and the course of disease suggest an inadvertent injection into a cervical radicular artery that reinforces the anterior spinal artery. This complication is potentially serious and may be permanently disabling or life threatening. It should be considered by any clinician performing "blind" zygapophysial joint injections in the cervical spine. Using imaging guidance should help prevent this type of complication.

Long-term experience with fractionated stereotactic radiotherapy in pharmacoresistant epilepsy: neurological and MRI changes.

PURPOSE: Radiotherapy is an option in patients with difficult-to-treat epilepsy in which pharmacological and surgical alternatives have been exhausted. However, little is known about the long-term efficacy and side effects of radiotherapy in this context. Hence, we report for the first time on the long-term outcome (median 10 years) of fractionated stereotactic radiotherapy (FSRT) in 11 patients with drug-resistant epilepsy in a retrospective study. Primary endpoint is tolerability concerning neurological and MRI findings, secondary endpoint seizure frequency. PATIENTS AND METHODS: FSRT was performed in 11 patients with cryptogenic or symptomatic epilepsy from 1996 to 2009 using a conventional linear accelerator (LINAC) in seven cases and a dedicated NOVALIS(®) LINAC in four. The biologically equivalent dose ranged from 26.3 to 58.3 Gy (α/ß=10). RESULTS: (1) None of the patients developed temporary or permanent neurological deficits. No MRI changes occurred. (2)Treatment resulted in improvement of seizure frequency in seven patients, five of them had a decrease in seizure frequency, and two of them were seizure-free at last follow-up. CONCLUSIONS: If radiation is administered with proper fractionation, dose prescription and target volume definition, long-term neurological side effects are unlikely. (2) Radiotherapy has the potential to control the frequency and intensity of seizures in epilepsy patients.

Increased spike frequency during general anesthesia with etomidate for magnetoencephalography in patients with focal epilepsies.

OBJECTIVE: Magnetoencephalography (MEG) is used for focus localization in presurgical evaluation of patients with focal epilepsies. In this proof-of-concept study, general anesthesia with etomidate was used to improve effectiveness of MEG-recordings. METHODS: MEG-recordings of six patients with focal epilepsy were performed before and after application of etomidate. Spike frequency and localization accuracy of MEG with general anesthesia were compared with spontaneous MEG. RESULTS: After application of etomidate, an increase in spike frequency occurred in all patients, and movement artifacts were prevented. In one patient, spikes could only be detected by invasive EEG but not by MEG. The results were in accordance with spontaneous MEG or presurgical hypotheses about localizations of neocortical foci in three patients. Dipole localizations were distributed over fronto-temporal areas in three patients with ipsilateral temporo-mesial focus hypotheses. CONCLUSIONS: Etomidate ameliorated spike yield and stopped movement artifacts during MEG recordings in patients with focal epilepsy. Localization results were especially accurate in patients with neocortical epilepsy. SIGNIFICANCE: These results could facilitate larger studies on the usefulness and safety of general anesthesia with etomidate that record and localize epileptic activity in patients with focal epilepsy by MEG.