Myoclonus epilepsy and ataxia due to KCNC1 mutation: Analysis of 20 cases and K+ channel properties.

OBJECTIVE: To comprehensively describe the new syndrome of myoclonus epilepsy and ataxia due to potassium channel mutation (MEAK), including cellular electrophysiological characterization of observed clinical improvement with fever. METHODS: We analyzed clinical, electroclinical, and neuroimaging data for 20 patients with MEAK due to recurrent KCNC1 p.R320H mutation. In vitro electrophysiological studies were conducted using whole cell patch-clamp to explore biophysical properties of wild-type and mutant KV 3.1 channels. RESULTS: Symptoms began at between 3 and 15 years of age (median = 9.5), with progressively severe myoclonus and rare tonic-clonic seizures. Ataxia was present early, but quickly became overshadowed by myoclonus; 10 patients were wheelchair-bound by their late teenage years. Mild cognitive decline occurred in half. Early death was not observed. Electroencephalogram (EEG) showed generalized spike and polyspike wave discharges, with documented photosensitivity in most. Polygraphic EEG-electromyographic studies demonstrated a cortical origin for myoclonus and striking coactivation of agonist and antagonist muscles. Magnetic resonance imaging revealed symmetrical cerebellar atrophy, which appeared progressive, and a prominent corpus callosum. Unexpectedly, transient clinical improvement with fever was noted in 6 patients. To explore this, we performed high-temperature in vitro recordings. At elevated temperatures, there was a robust leftward shift in activation of wild-type KV 3.1, increasing channel availability. INTERPRETATION: MEAK has a relatively homogeneous presentation, resembling Unverricht-Lundborg disease, despite the genetic and biological basis being quite different. A remarkable improvement with fever may be explained by the temperature-dependent leftward shift in activation of wild-type KV 3.1 subunit-containing channels, which would counter the loss of function observed for mutant channels, highlighting KCNC1 as a potential target for precision therapeutics. Ann Neurol 2017;81:677-689.

Efficacy of a psychological online intervention for depression in people with epilepsy: a randomized controlled trial.

OBJECTIVE: Depression is the most prevalent psychiatric disorder in persons with epilepsy (PWEs). Despite its major impact on quality of life and risk of suicide, most PWEs are not treated for depression. A current challenge in mental health care is how to close this treatment gap and increase access to psychological services. Psychological online interventions (POIs) have shown efficacy in improving depression among individuals without neurologic disorders. This pilot study aimed to assess the feasibility and efficacy of a psychological online intervention for depression (Deprexis) in PWEs who have symptoms of depression. METHODS: Participants with self-reported epilepsy and subjective complaints of depressive symptoms were randomized to an intervention condition (Deprexis) or to a waiting list control (WLC) condition. After 9 weeks, participants were invited to complete an online reassessment. RESULTS: Relative to the waiting list group, program users experienced a significant symptom decline on the Beck Depression Inventory - I (BDI-I, primary outcome) with a moderate effect size in the complete observations analysis and a small effect size in the intention-to-treat analysis. Furthermore, there was a significant improvement with a moderate effect size on the "energy/fatigue" subscale of the Quality of Life In Epilepsy Inventory - 31 (QOLIE-31). SIGNIFICANCE: The results of this trial suggest that POIs may be a feasible and beneficial tool for PWEs who have comorbid depressive symptoms.

Vascular events after transsylvian selective amygdalohippocampectomy and impact on epilepsy outcome.

OBJECTIVE: Epilepsy surgery is a standard treatment option for medically intractable temporal lobe epilepsy. Selective amygdalohippocampectomy (SAH) and anterior temporal lobectomy (ATL) are two of the standard surgical procedures in these cases. We conducted a retrospective analysis of patients treated with SAH via a modified transsylvian approach in our epilepsy center between 2008 and 2011, and we analyzed the impact of adjacent procedure-related infarctions on seizure outcome in these patients. METHODS: Infarctions were detected by magnetic resonance imaging (MRI) within the first week postoperatively and by a second MRI 9 months after surgical intervention. Neuropsychological testing was performed preoperatively. Evaluation of seizure outcome and postoperative neuropsychological testing were conducted approximately 1 year after epilepsy surgery. Correlative clinical data were analyzed by retrospective chart review. RESULTS: The postoperative MRI revealed temporal infarctions in 47.9% (n = 23/48) and frontal infarctions in 10.4% (n = 5/48) of the patients. These vascular events were asymptomatic in terms of focal neurologic deficits. Of the patients, 68.5% (n = 37/54) were free of disabling seizures (Engel class I) 1 year after the procedure. Patients with temporal infarctions were significantly more often free of disabling seizures (Engel class I, p = 0.046) than patients without temporal infarctions. Neuropsychological testing indicated a deterioration in verbal memory after SAH in patients with infarctions on the language-lateralized hemisphere compared to patients without infarction (p = 0.011). All other tested neuropsychological categories showed no significant differences between patients with or without infarctions. SIGNIFICANCE: Our results indicate a surprisingly high number of procedure-related temporal infarctions after transsylvian SAH. Hence, the volume of nonfunctional "eliminated" tissue is enlarged unintentionally, which is a possible explanation for better seizure outcome in these patients. This result supports the notion that ATL is the favorable procedure for temporal lobe epilepsy compared to SAH in the nondominant hemisphere, as neuropsychological deficits are rarely to be expected.

Quantitative MR Neurography in Multifocal Motor Neuropathy and Amyotrophic Lateral Sclerosis.

BACKGROUND: The aim of this study was to assess the phenotype of multifocal motor neuropathy (MMN) and amyotrophic lateral sclerosis (ALS) in quantitative MR neurography. METHODS: In this prospective study, 22 patients with ALS, 8 patients with MMN, and 10 healthy volunteers were examined with 3T MR neurography, using a high-resolution fat-saturated T2-weighted sequence, diffusion-tensor imaging (DTI), and a multi-echo T2-relaxometry sequence. The quantitative biomarkers fractional anisotropy (FA), radial and axial diffusivity (RD, AD), mean diffusivity (MD), cross-sectional area (CSA), T2-relaxation time, and proton spin density (PSD) were measured in the tibial nerve at the thigh and calf, and in the median, radial, and ulnar nerves at the mid-upper arm. RESULTS: MMN showed a characteristic imaging pattern of decreased FA (p = 0.018), increased RD (p = 0.014), increased CSA (p < 0.001), increased T2-relaxation time (p < 0.001), and increased PSD (p = 0.025) in the upper arm nerves compared to ALS and controls. ALS patients did not differ from controls in any imaging marker, nor were there any group differences in the tibial nerve (p > 0.05). CONCLUSIONS: MMN shows a characteristic pattern of quantitative DTI and T2-relaxometry parameters in the upper-arm nerves, primarily indicating demyelination. Peripheral nerve changes in ALS seem to be below the detection level of current state-of-the-art quantitative MR neurography.

Predicting the Outcome of Epilepsy Surgery by Covariance Pattern Analysis of Ictal Perfusion SPECT.

Previous studies on the utility of specific perfusion patterns in ictal brain perfusion SPECT for predicting the outcome of temporal lobe epilepsy surgery used qualitative visual pattern classification, semiquantitative region-of-interest analysis, or conventional univariate voxel-based testing, which are limited by intra- and interrater variability or low sensitivity to capture functional interactions among brain regions. The present study performed covariance pattern analysis of ictal perfusion SPECT using the scaled subprofile model for unbiased identification of predictive covariance patterns. Methods: The study retrospectively included 18 responders to temporal lobe epilepsy surgery (Engel I-A at 12 mo follow-up) and 18 nonresponders (≥Engel I-B). Ictal SPECT images were analyzed with the scaled subprofile model masked to group membership for unbiased identification of the 16 covariance patterns explaining the highest proportion of variance in the whole dataset. Individual expression scores of the covariance patterns were evaluated for predicting seizure freedom after temporal lobe surgery by receiver-operating-characteristic analysis. Kaplan-Meier analysis including all available follow-up data (up to 60 mo after surgery) was also performed. Results: Among the 16 covariance patterns only 1 showed a different expression between responders and nonresponders (P = 0.03). This favorable ictal perfusion pattern resembled the typical ictal perfusion pattern in temporomesial epilepsy. The expression score of the pattern provided an area of 0.744 (95% CI, 0.577-0.911, P = 0.004) under the receiver-operating-characteristic curve. Kaplan-Meier analysis revealed a statistical trend toward longer seizure freedom in patients with positive expression score (P = 0.06). The median estimated seizure-free time was 48 mo in patients with positive expression score versus 6 mo in patients with negative expression score. Conclusion: The expression of the favorable ictal perfusion pattern identified by covariance analysis of ictal brain perfusion SPECT provides independent (from demographic and clinical variables) information for the prediction of seizure freedom after temporal lobe epilepsy surgery. The expression of this pattern is easily computed for new ictal SPECT images and, therefore, might be used to support the decision for or against temporal lobe surgery in clinical patient care.

No Evidence to Favor 99mTc-HMPAO or 99mTc-ECD for Ictal Brain Perfusion SPECT for Identification of the Seizure Onset Zone.

PURPOSE: Ictal brain perfusion SPECT with the tracer 99mTc-HMPAO or 99mTc-ECD is widely used for identification of the epileptic seizure onset zone (SOZ) in presurgical evaluation if standard pointers are uncertain or inconsistent. For both tracers, there are theoretical arguments to favor it over the other for this task. The aim of this study was to compare the performance of ictal brain perfusion SPECT between 99mTc-HMPAO and 99mTc-ECD in a rather large patient sample. PATIENTS AND METHODS: The study retrospectively included 196 patients from clinical routine in whom ictal perfusion SPECT had been performed with stabilized 99mTc-HMPAO (n = 110) or 99mTc-ECD (n = 86). Lateralization and localization of the SOZ were obtained by the consensus of 2 independent readers based on visual inspection of the SPECT images. RESULTS: The 99mTc-HMPAO group and the 99mTc-ECD group were well matched with respect to age, sex, age at first seizure, duration of disease, seizure frequency, history of previous brain surgery, and findings of presurgical MRI. The proportion of lateralizing ictal SPECT did not differ significantly between 99mTc-HMPAO and 99mTc-ECD (65.5% vs 72.1%, P = 0.36). Sensitivity of ictal perfusion SPECT (independent of the tracer) for correct localization of the SOZ in 62 patients with temporal lobe epilepsy and at least worthwhile improvement (Engel scale ≤ III) 12 months after temporal epilepsy surgery was 63%. CONCLUSIONS: This study does not provide evidence to favor 99mTc-HMPAO or 99mTc-ECD for identification of the SOZ by ictal perfusion SPECT.

Long-term versus short-term memory deficits for faces in temporal lobe and generalized epilepsy patients.

It is still an open question whether short-term and long-term memory are two anatomically dissociable memory systems working in parallel or whether they are represented by neural circuits within similar cortical areas. Epilepsy may be used as a model to study these memory processes. We hypothesized that a double dissociation of short-term and long-term memory exists in temporal lobe epilepsy (TLE) and idiopathic generalized epilepsy (IGE). Immediate and 24-hour face recognition was tested in 10 TLE patients, 9 IGE patients, and 10 healthy controls. TLE patients' immediate recognition was unimpaired, but their memory scores were reduced as compared to healthy controls after 24 hours. In IGE patients, memory was already reduced during immediate recognition. These results are in line with the idea that short-term memory is a transient trace that requires consolidation supported by the medial temporal lobe to change into a more stable status of long-term memory.

Evidence of a pathogenic role for CD8(+) T cells in anti-GABAB receptor limbic encephalitis.

OBJECTIVES: To characterize the cellular autoimmune response in patients with γ-aminobutyric acid (GABA)B receptor antibody-associated limbic encephalitis (GABAB-R LE). METHODS: Patients underwent MRI, extensive neuropsychological assessment, and multiparameter flow cytometry of peripheral blood and CSF. RESULTS: We identified a series of 3 cases of nonparaneoplastic GABAB-R LE and one case of paraneoplastic GABAB-R LE associated with small cell lung cancer. All patients exhibited temporal lobe epilepsy, neuropsychological deficits, and MRI findings typical of LE. Absolute numbers of CD19(+) B cells, CD138(+) CD19(+) plasma cells, CD4(+) T cells, activated HLADR(+) CD4(+) T cells, as well as CD8(+) T cells and HLADR(+) CD8(+) T cells did not differ in peripheral blood but were elevated in CSF of patients with GABAB-R LE compared to controls. Augmented absolute numbers of CD138(+) CD19(+) plasma cells and activated HLADR(+) CD8(+) T cells in CSF corresponded to higher overall neuropsychological and memory deficits in patients with GABAB-R LE. A histologic specimen of one patient following selective amygdalohippocampectomy revealed perivascular infiltrates of CD138(+) plasma cells and CD4(+) T cells, whereas cytotoxic CD8(+) T cells were detected within the brain parenchyma in close contact to neurons. CONCLUSION: Our data suggest a pathogenic role for CD8(+) T cells in addition to the established role of plasma cell-derived autoantibodies in GABAB-R LE.

Morphometric MRI analysis enhances visualization of cortical tubers in tuberous sclerosis.

PURPOSE: Focal cortical dysplasias (FCD) type IIb and cortical tubers in tuberous sclerosis complex (TSC) are histopathologically similar and are both epileptogenic lesions frequently causing pharmacoresistant epilepsies. Morphometric analysis of T1- and T2-weighted MRI volume data sets can enhance visualization of FCD. Here, we retrospectively investigated whether morphometric MRI analysis is of equal benefit for visualizing cortical tubers. MATERIALS AND METHODS: Morphometric analysis was applied to T1- and partly also T2-weighted 1.5T or 3T MRI volume data sets of 15 TSC patients using a fully automated MATLAB(®) script (i.e. MAP07) commonly used for FCD detection. In this study, focus was on the most sensitive of the resulting morphometric feature maps (i.e. the 'junction image') which highlights blurring of the gray-white matter junction in comparison to a normal database. The visualization of tubers in these 'junction images' was quantitatively compared with that in conventional MR sequences. RESULTS: In all patients, morphometric analysis visualized almost all tubers detected in the normal MRI, and additionally highlighted on average 23% (range 3-50%) more tubers which were not detected by visual analysis of the conventional MR sequences. When T2 volume data sets from a 3T scanner were available for postprocessing, the rate of additionally detected tubers increased to 29% on average. These formerly overlooked tubers were usually smaller than the tubers already found in the conventional MRI. CONCLUSION: Morphometric analysis of MRIs in TSC can highlight cortical tubers which are likely to be overlooked in conventional MRI sequences alone. Additionally detected tubers may be of potential importance for both presurgical evaluation and initial diagnosis of TSC.

A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy.

Progressive myoclonus epilepsies (PMEs) are a group of rare, inherited disorders manifesting with action myoclonus, tonic-clonic seizures and ataxia. We sequenced the exomes of 84 unrelated individuals with PME of unknown cause and molecularly solved 26 cases (31%). Remarkably, a recurrent de novo mutation, c.959G>A (p.Arg320His), in KCNC1 was identified as a new major cause for PME. Eleven unrelated exome-sequenced (13%) and two affected individuals in a secondary cohort (7%) had this mutation. KCNC1 encodes KV3.1, a subunit of the KV3 voltage-gated potassium ion channels, which are major determinants of high-frequency neuronal firing. Functional analysis of the Arg320His mutant channel showed a dominant-negative loss-of-function effect. Ten cases had pathogenic mutations in known PME-associated genes (NEU1, NHLRC1, AFG3L2, EPM2A, CLN6 and SERPINI1). Identification of mutations in PRNP, SACS and TBC1D24 expand their phenotypic spectra to PME. These findings provide insights into the molecular genetic basis of PME and show the role of de novo mutations in this disease entity.

Unusual variability of PRRT2 linked phenotypes within a family.

BACKGROUND: Mutations in the proline-rich transmembrane protein 2 (PRRT2) gene on chromosome 16p11.2 have recently been identified as a cause of paroxysmal kinesigenic dyskinesias (PKD), infantile convulsions and choreoathetosis (ICCA) syndrome or infantile convulsions (IC). AIMS: Here, we describe a family with four affected members. They all suffer from different diseases: febrile convulsion, epileptic seizures, PKD or headache. METHODS: The whole coding region of PRRT2 gene has been analyzed. RESULTS: Molecular testing revealed the PRRT2 gene mutation c649.delC in exon 2 for all three sibs as well as for the mother. CONCLUSION: Our presented family case shows the great variability within PRRT2 linked phenotypes even within the same family. Further and more detailed studies will be needed before genetic findings enter into the daily diagnostic and the daily genetic counseling with all its consequences.

Face memory in MRI-positive and MRI-negative temporal lobe epilepsy.

PURPOSE: Effects of MRI-positive (MRI(+)) as compared to MRI-negative (MRI(-)) temporal lobe epilepsy (TLE) on face memory are not yet known. METHODS: We studied 24 MRI(-) (11 right/13 left) and 20 MRI(+) (13 right/7 left) TLE patients, 12 generalized epilepsy patients, and 12 healthy subjects undergoing diagnostic workup with 24-72-h Video-EEG-monitoring. Twenty faces were shown, and had to be recognized from 40 faces immediately and after a 24-h delay. RESULTS: MRI(+) and MRI(-) right TLE (RTLE) patients showed deficits in face recognition compared to controls or generalized epilepsy, consistent with right temporal lobe dominance for face recognition. MRI(+) RTLE patients had deficits in both immediate and delayed recognition, while MRI(-) RTLE patients showed delayed recognition deficits only. The RTLE groups showed comparable delayed recognition deficits. Separate analyses in which the MRI(+) group included patients with hippocampal sclerosis only, did not alter results. Furthermore, MRI(-) RTLE had a worse delayed recognition than MRI(-) left TLE (LTLE). On the other hand, MRI(+) RTLE did not differ from MRI(+) LTLE in delayed recognition. Combining MRI(-) and MRI(+) TLE groups, we found differences between RTLE and LTLE in delayed, but not immediate face recognition. CONCLUSIONS: Our results suggest that a delayed recognition condition might be superior to immediate recognition tests in detecting face memory deficits in MRI(-) RTLE patients. This might explain why former studies in preoperative patients did not observe an immediate face recognition dominance of the right temporal lobe when combining MRI(-) and MRI(+) TLE patients. Our data further point to an important role of the right mesial temporal region in face recognition in TLE.

Polyneuropathy in neurofibromatosis 2: clinical findings, molecular genetics and neuropathological alterations in sural nerve biopsy specimens.

Neurofibromatosis 2 (NF2) is an autosomal dominant disease characterised by development of tumours in the central and peripheral nervous system. Some NF2 patients develop acro-distal sensory motor polyneuropathy that can hardly be explained by the tumour burden alone. In the present study eight sural nerve biopsy specimens from seven NF2 patients suffering from polyneuropathy were investigated, data including clinical course of the disease, electrophysiological findings, teased fibre preparations, histopathological, morphometric, immunohistochemical, electron microscopic and molecular genetic findings. All patients suffered from distal symmetric reflex loss, symmetrical stocking-like hypalgesia and hypesthesia and loss of vibration sense later followed by a slowly progressive distal muscle atrophy and paresis. Sural nerve biopsy specimens revealed a pathological reduction of nerve fibre density correlating with age. In addition, diffuse proliferation of Schwann cells was observed in five of eight biopsies, and small endoneurial tumourlets of schwannomas and perineuriomas were found in two of eight and one of eight samples, respectively. Ki-67 labelling revealed a slight endoneurial proliferative activity in three cases. Schwann cell onion bulbs with or without central myelinated axon were seen in two cases. The findings suggest an axonopathy of multifactorial origin resulting not only from gross tumour growth but, in addition, from small endoneurial tumourlets, diffuse proliferation of Schwann cells and proliferation of perineurial cells.