Current Concepts in the Management of Idiopathic Generalized Epilepsies.

Idiopathic generalized epilepsies (IGEs) are a group of epilepsies characterized by an underlying genetic predisposition and a good response to antiseizure medicines (ASMs) in the majority of the patients. Of the various broad-spectrum ASMs, valproate is the most effective medicine for the control of seizures in IGEs. However, with the availability of many newer ASMs and evidence showing the high teratogenic potential of valproate, the choice of ASMs for IGEs has become increasingly difficult, especially in women of the child-bearing age group. In this article, we review the current evidence regarding the efficacy and safety of various ASMs in patients with IGEs and provide practical guidelines for choosing appropriate ASMs in various subgroups of patients with IGEs.

MPV17 Gene Variant Mutation Presenting as Leucoencephalopathy with Peripheral Neuropathy.

Mitochondrial DNA depletion syndromes (MDS) are rare mitochondrial disorders with evolving broad genotype and phenotype. This is a first case report from India about MPV 17, a mitochondrial inner membrane protein gene variant mutation, presenting with neuropathy, leucoencephalopathy and subclinical hepatic dysfunction with detailed clinical and imaging description.

Clinical, neuroimaging and therapeutic response in AQP4-positive NMO patients from India.

BACKGROUND: Neuromyelitis Optica (NMO) is an autoimmune astrocytopathic disorder due to AQP4 antibodies. OBJECTIVES: To analyse clinical, neuroimaging features in NMO patients and assess the efficacy of various therapeutics. METHODS: AQP4+ve NMO patients were diagnosed based on consensus diagnostic criteria. RESULTS: 101 AQP4+ve NMO patients were seen with female (90) predominance. Adult population (71.3%) formed the larger group followed by pediatric (19.8%) and late-onset (8.9%). Myelopathy (36.2%) was most commonly seen followed by optic neuritis (19.1%), brainstem (17.1%), opticomyelopathy (16.1%), area postrema involvement (10.5%) and encephalopathy (1%). Encephalopathy and brainstem/cerebellar involvement were most common in pediatric population while opticomyelopathy was more common in late-onset patients. Hyperintensities of lower medulla was seen in 67.3% subjects and 49.5% had involvement of obex. Differential T2 hyperintensity of the long segment myelitis was found in 30.7%. Plasmapheresis was given in 71 subjects followed by maintenance therapy. Most of them showed significant improvement with EDSS score of 1 in 30.7%. CONCLUSIONS: Clinical manifestations in AQP4+ve NMO patients may vary depending on the age at onset of illness. MRI features affecting cervicomedullary junction, obex, differential T2 hyperintensities of the spinal cord may form a useful diagnostic clue. Plasmapheresis is helpful in achieving remission along with immunomodulation.

Machine learning identifies "rsfMRI epilepsy networks" in temporal lobe epilepsy.

OBJECTIVES: Experimental models have provided compelling evidence for the existence of neural networks in temporal lobe epilepsy (TLE). To identify and validate the possible existence of resting-state "epilepsy networks," we used machine learning methods on resting-state functional magnetic resonance imaging (rsfMRI) data from 42 individuals with TLE. METHODS: Probabilistic independent component analysis (PICA) was applied to rsfMRI data from 132 subjects (42 TLE patients + 90 healthy controls) and 88 independent components (ICs) were obtained following standard procedures. Elastic net-selected features were used as inputs to support vector machine (SVM). The strengths of the top 10 networks were correlated with clinical features to obtain "rsfMRI epilepsy networks." RESULTS: SVM could classify individuals with epilepsy with 97.5% accuracy (sensitivity = 100%, specificity = 94.4%). Ten networks with the highest ranking were found in the frontal, perisylvian, cingulo-insular, posterior-quadrant, thalamic, cerebello-thalamic, and temporo-thalamic regions. The posterior-quadrant, cerebello-thalamic, thalamic, medial-visual, and perisylvian networks revealed significant correlation (r > 0.40) with age at onset of seizures, the frequency of seizures, duration of illness, and a number of anti-epileptic drugs. CONCLUSIONS: IC-derived rsfMRI networks contain epilepsy-related networks and machine learning methods are useful in identifying these networks in vivo. Increased network strength with disease progression in these "rsfMRI epilepsy networks" could reflect epileptogenesis in TLE. KEY POINTS: • ICA of resting-state fMRI carries disease-specific information about epilepsy. • Machine learning can classify these components with 97.5% accuracy. • "Subject-specific epilepsy networks" could quantify "epileptogenesis" in vivo.

A genetic locus for sensory epilepsy precipitated by contact with hot water maps to chromosome 9p24.3-p23.

Hot water epilepsy (HWE) is a rare form of sensory epilepsy where seizures are precipitated by a stimulus of contact with hot water. While earlier studies have suggested causal role of genes for HWE, specific underpinnings are beginning to be explored only recently. We carried out a whole genome-based linkage analysis in a family where most of its members affected by HWE and found evidence of a previously unknown locus at chromosome 9p24.3-p23. Parametric two-point analysis suggested linkage with the greatest LOD score of 3.42 for the marker D9S286 at 9p24.1 at recombination fraction (θ) = 0, 90% penetrance value and 1% phenocopy rate. The highest multipoint LODscore of 3.42 was obtained for same marker at 9p24. The critical genetic interval of about 10 Mb of DNA was defined by the markers D9S917 and D9S168 corresponding to the centromere-distal and centromere-proximal recombination boundaries, respectively. This observation along with our previous findings of hot water genetic loci at 10q21.3-q22.3 (OMIM: 613339) and 4q24-q28 (OMIM: 613340), indicates unanticipated genetic heterogeneity for the disorder in families from a relatively small geographic region in the southern parts of India.

Sub-lobar dysplasia - A comprehensive evaluation with neuroimaging, magnetoencephalography and histopathology.

Sublobar dysplasia, a rare cortical malformation has been defined in only 8 patients to date. It was identified on the basis of histopathological features and MRI findings. We report a right temporal sublobar dysplasia, with detailed evaluation including neuroimaging, magnetoencephalography and histopathology to further characterize the pathology. Additional pathological features included a deep collateral sulcus in the basal right temporal lobe, thinned out right corticospinal tract, and bilateral asymmetric basal ganglia changes. Magnetoencephalograpy localized the seizure focus to the posterior margin of the dysplasia. Histopathological evaluation helped exclude other types of dysplasia. Similar to a previous study, the child had Engel 1a outcome.

Scalp high frequency oscillations (HFOs) in absence epilepsy: An independent component analysis (ICA) based approach.

BACKGROUND: High frequency oscillations (HFOs) have provided a new insight in understanding ictogenesis and seizure localization. In absence seizures, HFOs were predominantly localized in the medial prefrontal cortex (MPFC) in MEG studies. METHODS: We studied HFOs (80-250 Hz) in scalp EEGs in patients with absence epilepsy, and evaluated their frequency bandwidth and spatial-temporal distribution. EEG of 9 patients with absence epilepsy (CAE:JAE-8:1; M:F=7:2; age: 8.1 ± 2.1 years; age at onset: 6.6 ± 1.3 years) were evaluated with scalp EEG (sampling rate: 2048 Hz). Finite impulse response filters on the unipolar or longitudinal bipolar montages were band-passed between 80 and 250 Hz using Cartool(®) and EEGLAB(®). Sensitivity and paper speed were modified accordingly to study the HFOs. Thousand four hundred and thirty eight artifact free 'spike-wave' epileptiform discharges were analyzed. Sleep ictal SW discharges, defined as runs of 3 Hz GSWDs lasting ≥ 4s in stages 1 and 2 sleep, were analyzed by independent component analysis and component time-frequency and channel time-frequency maps using cyclical tapering wavelet transform. A total of 926 HFOs were identified of 1438 GSWDS. RESULTS: The HFOs were associated with inter-ictal generalized spike-wave discharges (IiGSWDs-241/454), ictal GSWDs (IcGSWD-634/884), sporadic SWDs (sSWDs-51/100). The percentage of HFOs was higher in IcGSWD when compared to both IiGSWDs and sporadic SWDs together (χ(2)=52.864, d.o.f=1, p<0.0001). The mean frequency of HFOs was 96.4 ± 10.4 Hz. A channel wise analysis showed the maximum HFO band width in the right fronto-central region (F4=28 Hz, C4=24 Hz). CONCLUSION: Narrow bandwidth interictal and ictal HFOs can be identified in scalp EEG of patients with absence epilepsy. Further characterization of the various properties of pHFOs will be helpful in opening up a domain of clinical evaluation and interpretation of the various epileptic disorders. To improve the insights into the onset and spread of absence seizures, and to study the network properties, one could analyze the HFOs in high density EEG arrays with multimodal integration using MEG or fMRI.

Co-morbidities and outcome of childhood psychogenic non-epileptic seizures--an observational study.

PURPOSE: To assess the psychiatric diagnoses and outcome in children with psychogenic non-epileptic seizures (PNES). METHODOLOGY: This hospital based observational study was performed on 44 children aged <16 years, who suspected to have psychogenic non-epileptic seizures based on video-EEG, from August 2005 to August 2012. The parameters noted were the psychiatric diagnosis, co-morbidities, management assessment and interventions (pharmacological and psychosocial), number and duration of follow-up visits, symptoms at follow-up, functioning as reflected by involvement in the social and scholastic work. RESULTS: All forty four children completed the evaluation. Thirty four children were diagnosed as having PNES and the underlying psychiatric diagnosis was conversion disorder (n=34, 77.3%). Co-morbid psychiatric disorders were present in 17 children (50%). The common co-morbidities were intellectual disability (n=8, 23.5%), specific learning disorder (n=5, 14.7%), and depression (n=5, 14.7%). Co-morbid epilepsy was present in 8 (23.5%) children and family history of epilepsy was present in 10 (29.4%) cases. About 17 of 34 (50.0%) patients had a minimum follow-up of 6 months (13.9 ± 4.8 months). Twenty six children (76.5%) remained symptom free at the follow-up of 9.8 ± 7 months. The remaining 10 children (22.7%) had non-epileptic seizures with underlying diagnosis of Attention Deficit Hyperactivity Disorder (ADHD), gratification disorder and other physiological conditions. CONCLUSIONS: Conversion disorder is a common diagnosis underlying psychogenic non-epileptic seizures. Outcome was good in 76.5% children with PNES. A multidisciplinary approach is needed in the diagnosis and management of PNES.

Surgery for drug-resistant focal epilepsy.

During the colloquium on drug-resistant epilepsy (DRE) at National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore on August 16-18, 2013, a number of presentations were made on the surgically remediable lesional epilepsy syndromes, presurgical evaluation, surgical techniques, neuropathology of drug resistance focal epilepsy and surgical outcome. This pictorial essay with the illustrative case examples provides an overview of the various surgical techniques for the management of drug-resistant focal epilepsy.

Children with psychogenic non-epileptic seizures (PNES): a detailed semiologic analysis and modified new classification.

PURPOSE: To analyze children with psychogenic non epileptic seizures and propose a modified new classification. METHODS: This retrospective analysis included 56 children aged <18 years (M:F=26:30; mean age: 12.3±4.0 years) diagnosed PNES on video-EEG monitoring. The semiological characteristics like pattern of bodily movements, emotional signs, stereotypy, ictal vocalization, responsiveness, delay in diagnosis etc. were recorded. We analyzed our data as per previous adult classifications and proposed a modified classification. RESULTS: There were 190 recorded attacks (range: 1-9, median: 3) recorded. The age at onset of PNES was 8.9±4.1 years (range: 0.4-15.8 years; median: 9 years), age at diagnosis: 11.9±4.1 years (range: 2-17; median: 12.0 years), delay in diagnosis: 3.2±3.7 years (range: 0-15; median: 2.0 years). Anxiety disorder was seen in 9 (16.1%), stress in 6 (10.7%) children. Flexion/extension bodily movements were seen in 40 (70.1%), negative emotional signs in 17 (30.4%) and tremors in 14 (25%) cases. Thirty-three (58.9%) patients diagnosed as having true seizures initially and were on anti-epileptic drugs (AEDs), 14 patients (25.0%) initially diagnosed of PNES which remained unchanged after VEEG, nine patients (16.1%) had both PNES and true seizures. Twenty-six (46.4%) of our patients into the existing classifications. We then classified our patients into categories of a modified new classification: Hypermotor: 13 (23.2%), partial motor: 8 (14.3%), affective/emotional behaviour phenomena: 2 (3.6%), dialeptic: 8 (14.3%), 'aura': 3 (5.4%), mixed: 22 (39.3%). CONCLUSION: Incorrect diagnosis of epilepsy leads to unnecessary drug treatment. A detailed analysis of semiology and classification helps in early diagnosis of PNES. A modified systematic classification of PNES is proposed which would help in better standardization of PNES.

Utility of molecular and serodiagnostic tools in cerebral toxoplasmosis with and without tuberculous meningitis in AIDS patients: A study from South India.

BACKGROUND: Antemortem diagnosis of cerebral toxoplasmosis, the second most common opportunistic infection (OI) in HIV-infected individuals in developing countries is a challenge. MATERIALS AND METHODS: Toxoplasma gondii (T.gondii) -specific serology and nested polymerase chain reaction (nPCR) were evaluated in sera and ventricular/lumbar cerebrospinal fluid (CSF) of 22 autopsy confirmed cases of cerebral toxoplasmosis with HIV and 17 controls. Frequency of concomitant T.gondii infection was investigated in 17 cases of HIV-associated tuberculous meningitis (TBM). RESULTS: The sensitivity, specificity, and positive and negative predictive values of T. gondii IgG on CSF (ventricular and lumbar) and sera was 100% in histology proven cerebral toxoplasmosis (concentrations: 258 ± 50, 231 ± 36, and 646 ± 243 IU/mL, respectively); majority (94%) being high avidity type, suggesting reactivation/reinfection. The sensitivity of B1 nPCR was 100% on ventricular CSF, whereas it was only 77% on lumbar CSF. Based on histology, nPCR, and IgG serology, T. gondii co-infection with TBM was observed in 65% (11/17) of cases. DISCUSSION AND CONCLUSION: CSF IgG serology and nPCR are tests with high sensitivity and specificity for the diagnosis of cerebral toxoplasmosis. TBM and cerebral toxoplasmosis can coexist and should be considered in the background of HIV infection in developing countries.

Familial autosomal dominant reflex epilepsy triggered by hot water maps to 4q24-q28.

Hot water epilepsy is a reflex or sensory epilepsy in which seizures are triggered by the stimulus of bathing in hot water. Although there is evidence of a genetic basis to its etiology, no gene associated with this disorder has so far been found. In order to identify the genetic locus involved in the pathophysiology of hot water epilepsy, we performed a genome-wide linkage analysis in a four-generation family manifesting the disorder in an autosomal dominant manner. Significant linkage was detected on chromosome 4q24-q28, with the highest two-point LOD score of 3.50 at recombination value (theta) of 0 for the marker D4S402. Centromere-proximal and centromere-distal boundaries of this locus were defined by the markers D4S1572 and D4S2277, respectively. The critical genetic interval spans 22.5 cM and corresponds to about 24 megabases of DNA. The genes NEUROG2, ANK2, UGT8 and CAMK2D, which are known to be expressed in human brain, are strong positional candidates and we propose to examine these and other genes in the locus to identify the causative gene for this intriguing form of epilepsy.

A locus for autosomal dominant reflex epilepsy precipitated by hot water maps at chromosome 10q21.3-q22.3.

Hot water epilepsy (HWE) is a form of reflex or sensory epilepsy wherein seizures are precipitated by an unusual stimulus, the contact of hot water over the head and body. Genome-wide linkage analysis of a large family with ten affected members, provided evidence of linkage (Z (max) = 3.17 at theta = 0 for D10S412) to chromosome 10q21. Analysis of five additional HWE families, for markers on chromosome 10, further strengthened the evidence of linkage to the same chromosomal region with three out of five families showing concordance for the disease haplotype and providing a two-point LOD score of 4.86 at theta = 0 and 60% penetrance for D10S412. The centromere-proximal and -distal boundaries of the critical genetic interval of about 15 Mb at 10q21.3-q22.3 were defined by D10S581 and D10S201, respectively. Sequence analysis of a group of functional candidate genes, the ion channels KCNMA1, VDAC2 and solute carriers SLC25A16, SLC29A3 revealed no potentially pathogenic mutation. We propose to carry out further analysis of positional candidate genes from this region to identify the gene responsible for this unusual neurobehavioral phenotype.

NMDA receptor activation by HIV-Tat protein is clade dependent.

In countries infected with HIV clade B, some patients develop a rapidly progressive dementia that if untreated results in death. In regions of the world infected with HIV clade C, only milder forms of cognitive impairment have been recognized. HIV-infected macrophages are the principal mediators of dementia. HIV clade C, however, efficiently infects macrophages and HIV-infected macrophages are found in the brains of clade C-infected patients. HIV-infected macrophages release Tat protein, which may act directly on neurons to cause toxicity. We found that Tat released from Tat-expressing cells was at least 1000-fold more toxic than recombinant Tat protein. We determined whether Tat could interact with NMDA receptors and whether these interactions are clade dependent. It is demonstrated that Tat binds directly to the NMDA receptor leading to excitotoxicity. The Cys 30-Cys 31 motif in Tat is critical for exciting the NMDA receptor and the Cys31Ser mutation found in clade C Tat has a significantly attenuated neurotoxic response. Through molecular modeling and site-directed mutagenesis, we predict that Cys 31 disrupts the disulfide bond between Cys 744 and Cys 798 on the NR1 subunit of the NMDA receptor by directly interacting with Cys 744 leading to a free thiol group on Cys 798 and subsequent persistent activation of the NMDA receptor.

Elemental mercury poisoning probably causes cortical myoclonus.

Mercury toxicity causes postural tremors, commonly referred to as "mercurial tremors," and cerebellar dysfunction. A 23-year woman, 2 years after injecting herself with elemental mercury developed disabling generalized myoclonus and ataxia. Electrophysiological studies confirmed the myoclonus was probably of cortical origin. Her deficits progressed over 2 years and improved after subcutaneous mercury deposits at the injection site were surgically cleared. Myoclonus of cortical origin has never been described in mercury poisoning. It is important to ask patients presenting with jerks about exposure to elemental mercury even if they have a progressive illness, as it is a potentially reversible condition as in our patient.