KCTD7-related progressive myoclonic epilepsy: Report of 42 cases and review of literature.

OBJECTIVE: KCTD7-related progressive myoclonic epilepsy (PME) is a rare autosomal-recessive disorder. This study aimed to describe the clinical details and genetic variants in a large international cohort. METHODS: Families with molecularly confirmed diagnoses of KCTD7-related PME were identified through international collaboration. Furthermore, a systematic review was done to identify previously reported cases. Salient demographic, epilepsy, treatment, genetic testing, electroencephalographic (EEG), and imaging-related variables were collected and summarized. RESULTS: Forty-two patients (36 families) were included. The median age at first seizure was 14 months (interquartile range = 11.75-22.5). Myoclonic seizures were frequently the first seizure type noted (n = 18, 43.9%). EEG and brain magnetic resonance imaging findings were variable. Many patients exhibited delayed development with subsequent progressive regression (n = 16, 38.1%). Twenty-one cases with genetic testing available (55%) had previously reported variants in KCTD7, and 17 cases (45%) had novel variants in KCTD7 gene. Six patients died in the cohort (age range = 1.5-21 years). The systematic review identified 23 eligible studies and further identified 59 previously reported cases of KCTD7-related disorders from the literature. The phenotype for the majority of the reported cases was consistent with a PME (n = 52, 88%). Other reported phenotypes in the literature included opsoclonus myoclonus ataxia syndrome (n = 2), myoclonus dystonia (n = 2), and neuronal ceroid lipofuscinosis (n = 3). Eight published cases died over time (14%, age range = 3-18 years). SIGNIFICANCE: This study cohort and systematic review consolidated the phenotypic spectrum and natural history of KCTD7-related disorders. Early onset drug-resistant epilepsy, relentless neuroregression, and severe neurological sequalae were common. Better understanding of the natural history may help future clinical trials.

Current practices in epilepsy monitoring units (EMU) in India.

AIM: As an initial step to develop guidelines for epilepsy monitoring units (EMUs) appropriate for developing countries, we inquired the existing practices in EMUs in India. METHODS: After checking for the content and face validity as well for clarity, we sent a 52-item online non-anonymized questionnaire to all the 52 EMUs in India. RESULTS: The questionnaire was completed by 51 of the 52 EMUs (98% response rate). The majority of the EMUs are located in major cities and 51% are located in non-governmental corporate hospitals. There are total of 122 prolonged video-EEG monitoring (PVEM) beds in India and 70% EMUs have ≤2 beds. Approximately two-thirds of the EMUs have defined protocols for pre-procedure consent and risk assessment, management of seizure clusters and status epilepticus, continuous observation of patients, and peri­ictal testing. Only one-third of the EMUs have protocols for management of post-ictal psychosis, anti-suffocation pillows, and protected environment within bathrooms. The waiting period for PVEM is more (49.9 ± 101 vs. 4.9 ± 10.9 days; p = 0.04) and mean cost for 3-day PVEM is less (INR 8311 ± 9021 vs. 30,371 ± 17,563; p <0.0001) in public as compared to private hospitals. There was a negative correlation between cost of PVEM and the waiting period (r=-0.386; p = 0.01). Safety practices are similar in public and private hospitals. CONCLUSIONS: Although practices in EMUs in India vary widely, they are comparable to those in developed countries. India has severe shortage of EMUs and long waiting lists for affordable PVEM.

Management of Neurocysticercosis in Children: Association of Child Neurology Consensus Guidelines.

JUSTIFICATION: Neurocysticercosis (NCC) is a significant problem in India and other developing countries; however, several aspects of this disease have no clear, practical guidelines. There is a need for pragmatic guidelines, summarizing the available evidence, and filling in the gaps in evidence with expert advice to manage children with neurocysticercosis. PROCESS: An expert group (16 members) and a writing group (8 members) was constituted, consisting of members with varied expertise. It included pediatric neurologists (18), neurologist (1), Neuroradiologists (4), and a parasitologist (1). The writing group divided the six topics and reviewed the literature on the topics individually to determine the clinical questions for which no clear guidance was available from the literature. The experts were then contacted and opinions were obtained online. The Delphi consensus method was adopted to arrive at a general consensus regarding various questions, with both the experts and the writing group members contributing. The final guidelines were then drafted by the writing group. RECOMMENDATIONS: Diagnosis of NCC should be based on clinical history and neuroimaging. Contrast-enhanced magnetic resonance imaging of the brain is the modality of choice. For single enhancing lesion, albendazole therapy for 10-14 days is recommended, and it should be combined with praziquantel for 10-14 days for more than one ring-enhancing lesions. For persistent lesion, the same dose and duration of albendazole or concurrent administration of albendazole and praziquantel should be given. Pulse intravenous steroids should be used to reduce the acute symptomatic edema in children with cysticercal encephalitis. Carbamazepine or oxcarbazepine are best suited for seizure prophylaxis for those who present with seizures; phenytoin and levetiracetam are the other alternatives. In the case of NCC presenting with symptoms other than seizures, there appears to be no role for routine anti-seizure medication prophylaxis. For a single ring-enhancing lesion, six months of anti-seizure medication is sufficient if the lesion resolves on follow-up. Those with persistent lesions, calcification, or multiple lesions, require a longer treatment duration of at least 24 months.

Role of Video-EEG in Children.

Routine electroencephalogram (EEG) has many limitations, especially the inability to capture reported habitual events in question. A prolonged EEG with synchronized video (video-EEG) overcomes some of these limitations by improving the sensitivity, specificity and the diagnostic yield by attempting to record the habitual events when they are frequent and when indicated. Video-EEG is employed commonly for the diagnosis and classification of epilepsy/epilepsy syndromes, to distinguish between seizures and seizures mimickers, for pre-surgical evaluation and in the management of critically ill children. The duration of recording would vary depending on the indication and frequency of events. Ambulatory EEG is another cost effective and convenient alternative in certain circumstances. However, availability of the machines and expertise, accessibility, affordability and labor intensive nature of the procedure limit widespread use in India. This review explores the role of video-EEG in the management of children with epileptic and non-epileptic paroxysmal events with respect to routine clinical practice in India.

Centre of epileptogenic tubers generate and propagate seizures in tuberous sclerosis.

SEE DUCHOWNY DOI101093/AWW216 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Multiple seizure foci, seizure propagation and epileptic spasms complicate presurgical seizure localization in tuberous sclerosis. Furthermore, controversy exists about the contribution of tubers, perituberal cortex and the underlying genetic abnormality to epileptogenesis. We aimed to determine the epileptogenic substrate in tuberous sclerosis by studying spatio-temporal patterns of seizure onset and propagation on intracranial EEG recordings in which multiple depth and surface electrodes sampled multiple tubers and perituberal cortex. Ten intracranial EEG recordings (seven extraoperative, three intraoperative) from 10 children with tuberous sclerosis were analysed. Notable thickening and signal abnormality in the centre of many tubers on magnetic resonance imaging led to tuber centres being recorded with depth electrodes. Spatially-meaningful bipolar montages were reformatted incorporating channels recording only from the tuber centre, tuber rim and perituberal cortex. Interictal epileptiform discharges and ictal rhythms were analysed visually for location, field, morphology, frequency, latency and temporal dispersion. Fifteen electroclinically distinct seizures were recorded in the 10 patients. Seizure onset was recorded in tubers in all 15 electroclinically distinct seizures; in 9/10 electroclinically distinct seizures recorded with optimal spatial sampling, seizure onset was recorded in the tuber centre, with or without involvement of the tuber rim but not perituberal cortex. Quantitative electroencephalography analysis by pairwise cross-correlation confirmed that the tuber centre led the tuber rim and perituberal cortex during interictal, preictal and ictal spike trains. Seizure propagation was observed in 10/15 electroclinically distinct seizures, being tuber-to-tuber in all. Seven of the 17 tubers showing seizure propagation activated an independent ictal rhythm, morphologically distinct from that seen in seizure onset region (intra-ictal activation). Of the total 48 tubers sampled, 16 exhibited seizure onset, 17 were involved in seizure propagation and 40 exhibited interictal epileptiform discharges, 33 independent and seven propagated. Seizure onsets were recorded in 16/33 tubers with independent interictal epileptiform discharges, but 0/7 tubers with only propagated epileptiform discharges or 0/8 tubers with no epileptiform discharges (P = 0.003). Seizure onsets were recorded from 4/7 tubers with and 0/10 tubers without intra-ictal activation (P = 0.015). Thus, focal seizures and interictal epileptiform discharges in tuberous sclerosis arise in the centre of epileptogenic tubers and propagate to the tuber rim, perituberal cortex and other epileptogenic tubers. Rhythmic interictal epileptiform discharges and intra-ictal activation of propagated ictal rhythms are potential biomarkers of epileptogenic tubers. Interictal and ictal EEG features of epileptogenic tubers have similarities to focal cortical dysplasia type II, consistent with the reported imaging, histological and molecular similarities.

Familial cortical dysplasia caused by mutation in the mammalian target of rapamycin regulator NPRL3.

We describe first cousin sibling pairs with focal epilepsy, one of each pair having focal cortical dysplasia (FCD) IIa. Linkage analysis and whole-exome sequencing identified a heterozygous germline frameshift mutation in the gene encoding nitrogen permease regulator-like 3 (NPRL3). NPRL3 is a component of GAP Activity Towards Rags 1, a negative regulator of the mammalian target of rapamycin complex 1 signaling pathway. Immunostaining of resected brain tissue demonstrated mammalian target of rapamycin activation. Screening of 52 unrelated individuals with FCD identified 2 additional patients with FCDIIa and germline NPRL3 mutations. Similar to DEPDC5, NPRL3 mutations may be considered as causal variants in patients with FCD or magnetic resonance imaging-negative focal epilepsy.

Knowledge, attitude, and awareness of childhood cancer among undergraduate medical students in South India.

BACKGROUND: In India roughly 60000 childhood cancer cases are diagnosed annually with only nearly 100 pediatric oncologists. So it's pertinent that the physicians and pediatricians are adequately equipped to recognize and refer them appropriately. Hence this study was conducted to assess the knowledge, attitude and awareness of childhood cancer among undergraduate medical students in South India. MATERIALS AND METHODS: The study was conducted among 240 undergraduate students from all over South India in a undergraduate pediatric clinical training. A 24 point questionnaire was given to assess their understanding of pediatric malignancies and their interest towards pediatric oncology. Statistical analysis was done with SPSS 18.V software. RESULTS: 50% were interested in pursuing pediatrics as their career but 80% of them were not interested in pursuing pediatric oncology as their career. 55% of the students have not encountered any pediatric oncology patients in the ward. 40% did not have any lecture classes on pediatric oncology. 65.5% felt that their knowledge of childhood cancer did not make them competent to suspect and refer appropriately during their practice. 84% supported that there is a need to improve pediatric oncology teaching in their medical curriculum. CONCLUSIONS: The study unambiguously states that the future physicians lack confidence in identifying and managing childhood malignancies and pediatric oncology is far down in their career options. There is a need to reform the undergraduate medical students by increasing their exposure to pediatric oncology to improve their competence levels and interest in pursuing it as a career also.

The Clinical Characteristics and Treatment Response in Children with West Syndrome in a Developing Country: A Retrospective Case Record Analysis.

This study describes the clinical characteristics, treatment, and outcome of children with West syndrome in a tertiary care hospital in north India. Overall, 310 case records diagnosed from January 2009 to June 2012 were reviewed. The median age of onset of spasms was 5 months (interquartile range = 2.5-7 months). The predominant underlying etiology was perinatal cerebral ischemia (55%). Adrenocorticotropic hormone or oral steroids were received by 92% children, of whom 43% became seizure free. Median lag time for appropriate treatment initiation was significantly less in patients who became seizure free as compared to those with persisting seizures (11 vs 15 months, P = .001) soon after receiving treatment of choice. Later age at onset of spasms was associated with a favorable seizure outcome (P = .03). In a resource-limited setting, unawareness along with treatment costs and repeated visits to the hospital are significant obstacles to optimum management.

A prospective study on the attitude of post graduates in general pediatrics toward pediatric oncology subspeciality as a career.

OBJECTIVES: The health care scenario in India is experiencing an increase in the number of children affected with cancer and the number of pediatric oncologists available to treat these children are few and the awareness of childhood cancer is decimally low. Hence, the purpose of this study was to determine the attitude of post-graduate students of general pediatrics towards childhood cancer and to assess their interest in pursuing pediatric oncology as a specialty in their carrier. MATERIALS AND METHODS: The study was conducted among 188 post-graduates hailing from various Medical colleges all over South India who were attending a 2 day workshop at Chennai. The survey was a 10 point questionnaire pertaining to their previous training, competence, interest toward the field of hematooncology. The data were analyzed by SPSS 18.V software. RESULTS: Among the post-graduates, 74.7% of them reported that they did not have a pediatric oncology unit in their institution. 63.3% reported that they never been posted in pediatric oncology clinical postings before. 62% were not interested in pursuing pediatric oncology as a sub-specialty at all. 45.3% felt that pediatric oncology was too depressing to take as a specialty. 46.7% felt that late diagnosis and referral was the main factor which contributed to the failure of effective treatment of childhood cancers. 52.7% had never attended a class on pediatric oncology. 61.3% felt that they did not have sufficient knowledge to suspect and refer a child with cancer. 92% felt that there was a need to improve pediatric oncology teaching in their curriculum. 56.7% felt that the best way to imprint awareness on childhood malignancies was to improve pediatric oncology teaching in their medical curriculum. CONCLUSION: The results show that majority of post-graduates in pediatrics were not interested in pursuing pediatric oncology as a sub-specialty. The main reasons may be lack of specialized Pediatric oncology units in the majority of the medical institutions, lack of opportunity of these post-graduates to attend clinical postings and theory classes. They thus lack sufficient information in this field and hence do not want to take up a career in pediatric oncology.

Menkes disease - An important cause of early onset refractory seizures.

CONTEXT: Menkes disease is an X-linked multisystem disorder characterized by early onset of cerebral and cerebellar neurodegeneration, fair skin, hypopigmented sparse hair and connective tissue abnormalities. AIMS: We aimed to evaluate the clinical, electrophysiological and radiological features of children with Menkes disease seen at our institute. SETTING/DESIGN: The medical records of children diagnosed with Menkes disease admitted in the pediatric neurology ward or attending the special pediatric neurology clinic at a tertiary care and a referral hospital in North India, from January 2010 to December 2012, were retrospectively reviewed. The clinical data of each case was subsequently summarized and reported. STATISTICAL ANALYSIS USED: Descriptive statistics were used. RESULTS: During the study period, 1174 children were seen. Out of these, 6 cases were diagnosed as Menkes disease on the basis of clinical phenotype, low serum copper and ceruloplasmin and supportive neuroimaging. All the children were males and had disease onset within 3 months of age, with 4 children presenting in the neonatal period. Global developmental delay and refractory seizures were the predominant clinical symptoms. Two children had symptomatic West syndrome. Other seizure semiologies included tonic-clonic (4), myoclonic (2) and tonic seizures (1). The electroencephalographic abnormalities included hypsarrythmia (2) and multifocal epileptiform discharges (3). The salient radiological features included white matter changes, temporal lobe abnormalities, global atrophy, subdural hygromas and tortuous cerebral blood vessels. CONCLUSIONS: Menkes disease should be suspected in a case of refractory early onset seizures especially in the presence of subtle clinical clues. The neuroimaging findings may further support the diagnosis.

Congenital hypopituitarism presenting as dilated cardiomyopathy in a child.

Congenital hypopituitarism is commonly diagnosed either in infancy with neonatal hypoglycemia, prolonged jaundice and/or microphallus or in early to mid-childhood because of short stature. Replacement of deficient hormones allows the affected children to have a normal and productive life. We describe a 10-year-old boy with congenital hypopituitarism whose parents first sought definitive medical attention when the child developed congestive heart failure due to dilated cardiomyopathy, presumably secondary to prolonged untreated central hypothyroidism and growth hormone deficiency.