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OBJECTIVES: The utility of intraoperative electrocorticography (ECoG)-guided resective surgery for pediatric long-term epilepsy-associated tumors (LEATs) with antiseizure medication (ASM) resistant epilepsy is not supported by robust evidence. As epilepsy networks and their ramifications are different in children from those in adults, the impact of intraoperative ECoG-based tailored resections in predicting prognosis and influencing outcomes may also differ. We evaluated this hypothesis by comparing the outcomes of resections with and without the use of ECoG in children and adults by a randomized study. METHODS: From June 2020 to January 2022, 42 patients (17 children and 25 adults) with LEATs and antiseizure medication (ASM)-resistant epilepsy were randomly assigned to one of the 2 groups (ECoG or no ECoG), prior to surgical resection. The 'no ECoG' arm underwent gross total lesion resection (GTR) without ECoG guidance and the ECoG arm underwent GTR with ECoG guidance and further additional tailored resections, as necessary. Factors evaluated were tumor location, size, lateralization, seizure duration, preoperative antiepileptic drug therapy, pre- and postresection ECoG patterns and tumor histology. Postoperative Engel score and adverse event rates were compared in the pediatric and adult groups of both arms. Eloquent cortex lesions and re-explorations were excluded to avoid confounders. RESULTS: Forty-two patients were included in the study of which 17 patients were in the pediatric cohort (age < 18 years) and 25 in the adult cohort. The mean age in the pediatric group was 11.11 years (SD 4.72) and in the adult group was 29.56 years (SD 9.29). The mean duration of epilepsy was 9.7 years (SD 4.8) in the pediatric group and 10.96 (SD 8.8) in the adult group. The ECoG arm of LEAT resections had 23 patients (9 children and 14 adults) and the non-ECoG arm had 19 patients (8 children and 11 adults). Three children and 3 adults from the ECoG group further underwent ECoG-guided tailored resections (average 1.33 additional tailored resections/per patient.).The histology of the tailored resection specimen was unremarkable in 3/6 (50%).Overall, the commonest histology in both groups was ganglioglioma and the temporal lobe, the commonest site of the lesion. 88.23% of pediatric cases (n = 15/17) had an excellent outcome (Engel Ia) following resection, compared to 84% of adult cases (n = 21/25) at a mean duration of follow-up of 25.76 months in children and 26.72 months in adults (p = 0.405).There was no significant difference in seizure outcomes between the ECoG and no ECoG groups both in children and adults, respectively (p > 0.05). Additional tailored resection did not offer any seizure outcome benefit when compared to the non-tailored resections. CONCLUSIONS: The use of intraoperative electrocorticography in LEATs did not contribute to postoperative seizure outcome benefit in children and adults. No additional advantage or utility was offered by ECoG in children when compared to its use in adults. ECoG-guided additional tailored resections did not offer any additional seizure outcome benefit both in children and adults.
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Neoplasias Encefálicas , Epilepsia Resistente a Medicamentos , Epilepsia , Ganglioglioma , Adulto , Humanos , Criança , Adolescente , Eletrocorticografia , Estudos Retrospectivos , Epilepsia/etiologia , Epilepsia/cirurgia , Convulsões/cirurgia , Epilepsia Resistente a Medicamentos/cirurgia , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/cirurgia , Neoplasias Encefálicas/patologiaRESUMO
PURPOSE OF REVIEW: Our knowledge of the genetic architecture underlying Parkinson's disease has vastly improved in the past quarter century. About 5-10% of all patients suffer from a monogenic form of Parkinson's disease. RECENT FINDINGS: Mutations in autosomal dominant genes (e.g. SNCA, LRRK2, VPS35) or autosomal recessive genes (e.g. PRKN, PINK1, DJ-1) can cause genetic Parkinson's disease. Recessive DNAJC6 mutations can present predominantly as atypical parkinsonism, but also rarely as typical Parkinson's disease. Majority of Parkinson's disease is genetically complex. Mutation in RIC3 , a chaperone of neuronal nicotinic acetylcholine receptor subunit α-7 (CHRNA7), provides strong evidence for the role of cholinergic pathway, for the first time, in cause of Parkinson's disease. X-linked parkinsonism manifests at a young age accompanied by many (atypical) features such as intellectual disability, spasticity, seizures, myoclonus, dystonia, and have poor response to levodopa. SUMMARY: This review article aims to provide a comprehensive overview on Parkinson's disease genetics. MAPT , which encodes the microtubule associated protein tau, TMEM230, LRP10, NUS1 and ARSA are the five new putative disease-causing genes in Parkinson's disease. The validation of novel genes and its association with Parkinson's disease remains extremely challenging, as genetically affected families are sparse and globally widespread. In the near future, genetic discoveries in Parkinson's disease will influence our ability to predict and prognosticate the disease, help in defining etiological subtypes that are critical in implementation of precision medicine.
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Doença de Parkinson , Transtornos Parkinsonianos , Humanos , Doença de Parkinson/genética , Proteínas de Membrana/genética , Transtornos Parkinsonianos/genética , Mutação/genética , Convulsões , Proteínas Relacionadas a Receptor de LDL/genética , Receptores de Superfície Celular/genéticaRESUMO
Exogenous manganese (Mn) intoxication leads only to neurotoxicity, whereas inherited hypermanganesemia additionally can cause cirrhosis and polycythemia. We report two affected siblings in a family from South India with severe dysarthria, without dysphagia, generalized dystonia, and characteristic "cock-walk" gait which are clinical clues. Genetic study showed homozygous mutation in the first exon of solute carrier family 30 member 10 (SLC30A10) gene (c.134T>C) confirming the diagnosis of inherited hypermanganesaemia with dystonia 1 (HMNDYT1). Characteristic brain MRI finding is involvement of pontine tegmentum on T1 axial images (due to affliction of central tegmental tract [CTT]) with sparing of ventral pons giving rise to "horseshoe moustache" sign. Symmetric hyperintensities in dentate nucleus, globus pallidus, and putamen while relatively sparing caudate nucleus on T1 without signal intensity abnormalities on T2 images are highly suggestive of hypermanganesaemia. Axial diffusion tensor imaging confirmed the "horseshoe moustache" sign to be constituted by the affected CTT. Hypermanganesaemia-induced CTT involvement in T1 needs to be differentiated from the other more common pediatric causes of CTT affliction which are evident on T2 or diffusion weighted images. Identification is crucial as it is a treatable disorder of metal deposition amenable to chelation.
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Proteínas de Transporte de Cátions , Imagem de Tensor de Difusão , Criança , Marcha , Humanos , Imageamento por Ressonância Magnética , Manganês/metabolismo , Manganês/toxicidadeRESUMO
PURPOSE: Psychiatric disease is the most common co-morbidity seen in persons with epilepsy (PWE), often secondary to psychosocial disturbances due to poor adaptation to the disease. Optimizing epilepsy treatment by targeting both seizure control and addressing psychological issues go a long way in improving psychological outcome among PWE. This study aims to assess the psychological status among PWE using validated questionnaires and to assess the effect of viewing their own seizures on their psychological milieu post-viewing. METHODS: A prospective interventional study was conducted enrolling 52 PWE. Their baseline psychological scores were assessed using Hospital Anxiety Depression Scale (HADS), Self Esteem Inventory (SEI), Locus of Control (LOC) and Quality of Life in Epilepsy (QOLIE-31). The scores were reassessed 3â¯months post seizure viewing and compared with the baseline scores. RESULTS: Among the 52 patients analyzed, anxiety was present in 20 (38.4%) and depression in 8 (15.3%). The mean HADS-A (anxiety) scores for study population was 9.56⯱â¯4.12. Gender, income status, risk factors antedating index seizure, type of seizure, temporal semiology, seizure frequency, MRI or EEG characteristics did not have any significant association with baseline psychological scores. There was statistically significant reduction in HADS-A scores from 9.56⯱â¯4.12 to 8.35⯱â¯3.85 in the study population after seizure viewing (pâ¯=â¯0.049). We identified patient characteristics that benefit seizure viewing with respect to each of the psychological batteries mentioned earlier. CONCLUSION: This study emphasizes that viewing one's own seizures improves the psychological milieu of PWE and improves their quality of life by helping them cope up with their illness more judiciously.
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Epilepsia , Qualidade de Vida , Ansiedade/etiologia , Epilepsia/complicações , Humanos , Estudos Prospectivos , Convulsões , Inquéritos e QuestionáriosRESUMO
PURPOSE: We conducted this study to determine the clinical, electrophysiological and radiological predictors of outcome in Super Refractory Status Epilepticus (SRSE). METHODS: Data of patients treated for SRSE between January 2000 and November 2019, archived prospectively in our SE registry were analyzed. Functional outcome was measured by Glasgow outcome score (GOS) at the time of hospital discharge and was divided into: good i.e. GOSâ¯≥â¯3 and bad outcome i.e. GOSâ¯<â¯3. The predictors of outcome were determined using appropriate statistical tests by univariate and multivariate analysis, pâ¯<â¯0.05 was considered as statistically significant. RESULTS: Of the 384 patients with status epilepticus (SE) identified during the study, 28 (8%) were diagnosed as SRSE and were included in the final analysis. Acute symptomatic SE comprising 15 (53.6%) patients was the most common etiology of SRSE. Thirteen patients (three patients with viral encephalitis and 10 patients with clinically possible autoimmune encephalitis) had New Onset Refractory Status Epilepticus (NORSE) like clinical presentation.12 patients (42.9%) had good outcome and 16 patients (57.1%) had bad outcome. Multivariate logistic regression analysis showed that independent predictors of poor outcome were: duration of ICU stay (pâ¯<â¯0.001); EEG findings such as non-convulsive SE in coma (0.032), spontaneous burst suppression (0.001) and postictal diffuse attenuation (<0.001); delay in starting anesthesia (0.002); and delay in starting immunotherapy in NORSE due to autoimmune encephalitis (0.002). CONCLUSION: We could determine independent therapeutic and electrophysiological prognostic factors for SRSE. Early initiation of treatment and stringent management of these factors especially in an younger age-group, aided by continuous EEG monitoring and a thorough etiological work-up can result in good outcomes in more than one-third of cases.
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Encefalite , Doença de Hashimoto , Estado Epiléptico , Encefalite/complicações , Encefalite/diagnóstico , Humanos , Alta do Paciente , Sistema de Registros , Estudos Retrospectivos , Estado Epiléptico/diagnóstico , Estado Epiléptico/epidemiologia , Estado Epiléptico/etiologiaRESUMO
PURPOSE: The objective of the study was to evaluate the frequency, clinical, and video-electroencephalographic (VEEG) predictors of convlusive status epilepticus (CSE) in the epilepsy-monitoring unit (EMU). METHODS: The data of all patients who had CSE in our EMU between 2008 and 2017 were reviewed. For each case, two age- and diagnosis-matched subjects who underwent VEEG and did not develop CSE were taken as internal controls. Electro-clinical data of both the groups were compared. Predictors of CSE were assessed using logistic regression analysis. RESULTS: Out of 11,188 video-telemetries were conducted between 2008-17, forty-three events of CSE (0.38%) were recorded. On comparisons with 86 internal controls no differences were apparent on prevalence of cognitive impairment, structural lesion, number of baseline anti-seizure medications (ASM), ASM taper schedule, ictal patterns, and duration of VEEG monitoring. Inter-ictal rhythmic periodic patterns had significantly higher prevalence in cases (pâ¯=â¯0.028). Logistic regression analysis revealed that odds of CSE were higher with past history of SE [pâ¯=â¯0.008; adjusted odds ratio (OR)â¯=â¯5.48 (confidence intervals {CI} 1.55-19.28)] and in presence of rhythmic spike and wave discharges [pâ¯=â¯0.016, ORâ¯=â¯33.518(CIâ¯=â¯1.93-581.4)]; the odds were lower if the first two seizures recorded did not evolve into CSE [pâ¯=â¯0.009, ORâ¯=â¯0.247 (CIâ¯=â¯0.08-0.70)] and if there was prior history of daily seizures [pâ¯=â¯0.02, ORâ¯=â¯0.250 (CIâ¯=â¯0.07-0.84)]. CONCLUSION: CSE is a rare yet important adverse event in EMU. Clinical predictors are more relevant in comparison to EEG variables. Extent of ASM withdrawal may not directly account for occurrence of CSE; factors inherent to a patient's epilepsy are deterministic.
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Epilepsia , Estado Epiléptico , Eletroencefalografia , Epilepsia/diagnóstico , Epilepsia/epidemiologia , Humanos , Convulsões , Estado Epiléptico/diagnóstico , Estado Epiléptico/epidemiologia , TelemetriaRESUMO
PURPOSE: Locus of control (LOC) is the degree to which people believe that they have control over the outcome of events in their lives. A person's locus can be internal, external, or chance. A person with internal locus of control believes that one can control one's own life. A person with external locus of control believes that his life is controlled by external factors or people over which he has no influence. A person with chance locus of control believes that fate, chance, or luck controls his own life. The aim of the current study was to determine the health locus of control, anxiety, and depression levels in persons with epilepsy (PWE) and to assess whether locus of control has relation to anxiety, depression, and seizure control. METHODS: Patients aged 18â¯years or older with a history of epilepsy for at least 1â¯year were recruited from the outpatient epilepsy clinic or from the inpatient epilepsy monitoring unit at SCTIMST, Trivandrum from January 2019 to May 2020. Patients filled the questionnaire form consisting of demographic data, age of onset of seizures, present seizure control, and the current antiepileptic drugs. The Hospital Anxiety and Depression (HAD) scale was used to estimate the level of anxiety and depression in these patients. The Form-C of the Multidimensional Health Locus of Control (MHLC) scale was used to evaluate the health locus of control. Healthy controls aged 18â¯years or older and free of any chronic disease or psychiatric illness were also recruited. They were asked to fill the questionnaire forms with basic demographic data. HAD scale was used to estimate the level of anxiety and depression and form-C of MHLC was used to evaluate the health locus of control in the healthy controls. The mean scores of anxiety, depression, and locus of control were compared between the two groups. RESULTS: A total of 170 participants were recruited which consisted of 100 PWE and 70 healthy controls. The mean anxiety and depression scores were 8.13(SDâ¯=â¯4.23) and 5.85(SDâ¯=â¯3.66) in the PWE group and 6.75(SDâ¯=â¯3.39) and 4.14(SDâ¯=â¯2.96) in the control group, respectively. The mean internal, external, and chance LOC scores were 24.95(SDâ¯=â¯10.92), 26.94(SDâ¯=â¯4.96), and 24.41(SDâ¯=â¯6.46) in the PWE group; and 29.44(SDâ¯=â¯5.62), 26.53(SDâ¯=â¯5.79), and 19.9(SDâ¯=â¯7.13) in the control group, respectively. Persons with epilepsy had higher chance LOC scores and lower internal LOC scores compared to controls (pâ¯=â¯0.00003, pâ¯<â¯0.00001 respectively). There were no differences in the external LOC scores between the two groups (pâ¯=â¯0.620). Persons with epilepsy with some level of anxiety had lower internal LOC scores compared to patients with no anxiety (pâ¯=â¯0.04). PWE with poor seizure control had higher external LOC score and lower internal LOC scores which however did not reach statistical significance. Persons with epilepsy with poor seizure control had higher anxiety and depression scores. CONCLUSIONS: Persons with epilepsy had low perceptions of internal and strong perceptions of chance health locus of control. This means that PWE feel that luck plays an important role in their disease control. This information is important in the counseling of persons with epilepsy.
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Epilepsia , Ansiedade , Transtornos de Ansiedade , Humanos , Controle Interno-Externo , Masculino , ConvulsõesRESUMO
OBJECTIVE: We compared women with drug-resistant focal epilepsy who had undergone surgery (WWE-S) with those who were managed medically (WWE-M) for maternal and fetal outcomes of their pregnancies. METHODS: We classified all WWE-S who were enrolled in a prospective registry of epilepsy and pregnancy (1998-2015) as those who underwent the surgery before pregnancy (WWE-SF) or after pregnancy (WWE-PF). The comparator group (WWE-M) was twice that number of age-matched women with focal epilepsy in this registry. Their clinical profile, anti-epileptic drug (AED) use, and pregnancy outcomes were extracted from the records of the registry. RESULTS: The number of completed pregnancies with known outcome was 74 for WWE-S (67 WWE-SF and 7 WWE-PF) and 134 for WWE-M. Seizures increased during pregnancy for fewer WWE-SF than for WWE-M (14.9% vs 39.6%, P = .001). Compared to WWE-M, fewer WWE-SF had dose escalation during pregnancy (28.4% vs 14.9%, P = .025). Preterm deliveries were more frequent in WWE-SF than WWE-M (24.6% vs 12.2%, P = .029). The differences between the WWE-SF and WWE-M regarding the rates of fetal loss (10.4% vs 6.7%, P = .255), major congenital malformations (8.5% vs. 11.1%, P = .395), and development quotient at 1 year of age <85 (42.5% vs 42.3%, P = .569) were not statistically significant. Compared to WWE-PF, fewer WWE-SF had AED dose escalation (14.9% vs 85.7%, P = .001) or increase in seizures (14.9% vs 100%, P = .001) during pregnancy. WWE-SF had fewer infants with development quotient <85 (41.0% vs 100%, P = .005). SIGNIFICANCE: WWE-SF can expect better control of seizures and decreased AED burden during pregnancy than WWE with focal epilepsies managed with medicines only. WWE who undergo surgery for epilepsy before their pregnancies can expect fewer seizures and lower AED burden during pregnancy.
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Aborto Espontâneo/epidemiologia , Anticonvulsivantes/uso terapêutico , Anormalidades Congênitas/epidemiologia , Epilepsia Resistente a Medicamentos/terapia , Epilepsias Parciais/terapia , Procedimentos Neurocirúrgicos/métodos , Complicações na Gravidez/tratamento farmacológico , Nascimento Prematuro/epidemiologia , Adulto , Deficiências do Desenvolvimento/epidemiologia , Feminino , Humanos , Gravidez , Resultado da Gravidez , Sistema de Registros , Fatores de Tempo , Adulto JovemRESUMO
Over 100 genetically distinct causal known loci for hereditary ataxia phenotype poses a challenge for diagnostic work-up for ataxia patients in a clinically relevant time and precision. In the present study using next-generation sequencing, we have investigated pathogenic variants in early-onset cerebellar ataxia cases using whole exome sequencing in singleton/family-designed and targeted gene-panel sequencing. A total of 98 index patients were clinically and genetically (whole exome sequencing (WES) in 16 patients and targeted gene panel of 41 ataxia causing genes in 82 patients) evaluated. Four families underwent WES in family based design. Overall, we have identified 24 variants comprising 20 pathogenic and four likely-pathogenic both rare/novel, variations in 21 early onset cerebellar ataxia patients. Among the identified variations, SACS (n = 7) and SETX (n = 6) were frequent, while ATM (n = 2), TTPA (n = 2) and other rare loci were observed. We have prioritized novel pathogenic variants in RARS2 and FA2H loci through family based design in two out of four families.
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Sequenciamento do Exoma , Genes Recessivos , Variação Genética , Degenerações Espinocerebelares/genética , Adulto , Sequência de Bases , Família , Loci Gênicos , Predisposição Genética para Doença , Humanos , Mutação/genéticaRESUMO
OBJECTIVES: To explore the effect of duration of epilepsy and delay in surgery on seizure outcome in patients operated for drug-resistant temporal lobe epilepsy (TLE). MATERIALS & METHODS: A total of 664 consecutive patients who underwent anterior temporal lobectomy (ATL) for TLE from 1995 to 2008 formed the study cohort. We divided them into two, one as seizure-free with or without antiepileptic drugs after ATL as "good outcome" (Engel class I a) and seizures of any type, any time after surgery as "poor outcome." The probability of seizure freedom/seizure recurrence based on the duration of epilepsy was compared using Kaplan-Meier curves, univariate Cox regression survival analysis, and multivariate Cox proportional hazards regression model. RESULTS: A total of 136 children and 528 adults underwent ATL during this period. Mean duration of epilepsy pre-ATL was 17.1 + 9.4 years. At mean follow-up of 8.5 years, 331 patients (49.8%) had good outcome and 333 (50.2%) had poor outcome. The hazard of seizure recurrence linearly increased with duration of epilepsy pre-ATL, from 1.5 (duration of epilepsy, 5-10 years) to 1.9 (duration of epilepsy, 10-15 years) to 2 (duration of epilepsy over 15 years). In addition, encephalitis as antecedent, bilateral mesial temporal sclerosis in MRI, normal histopathology, and spikes in postoperative EEG at 3 months and 1 year predicted poor seizure outcome. CONCLUSIONS: "Epilepsy duration" independently predicted both short- and long-term seizure outcome after surgery in TLE. "Lost years" translate into poor seizure outcome after ATL. Therefore, all cases of drug-resistant TLE should be referred to a surgical center at the earliest.
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Lobectomia Temporal Anterior/métodos , Epilepsia do Lobo Temporal/cirurgia , Adolescente , Adulto , Criança , Pré-Escolar , Epilepsia Resistente a Medicamentos/cirurgia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Status epilepticus (SE) related to pregnancy is rare and carries a significant risk to both the mother and the fetus. OBJECTIVES: We conducted this study to devise a protocol for the management of SE related to pregnancy in a cohort of female patients admitted with SE during pregnancy. MATERIALS AND METHODS: All women who developed SE related to pregnancy (gestation, labor, and puerperium) between January 2000 and December 2016 were included. Data was collected using a structured proforma. RESULTS: There were 17 women who had SE related to pregnancy, of whom 10 had refractory SE. The various causes of refractory SE were eclampsia (N = 2), posterior reversible encephalopathy syndrome (PRES) due to various causes other than eclampsia (N = 3), cortical venous thrombosis (CVT) [N = 3], subarachnoid hemorrhage (SAH) [N = 1], and N-methyl-D-aspartate (NMDA) receptor antibody-mediated encephalitis (N = 1). Six out of 10 women with refractory SE (60%) and five out of 10 fetuses (50%) had a good outcome. CONCLUSION: There is a dearth of literature with regards to SE related to pregnancy and little or no guidelines exist for its management. Awareness about the diverse etiologies other than eclampsia is important. A protocol-based approach to the diagnosis and management of SE is necessary to ensure best outcomes.
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Anticonvulsivantes/uso terapêutico , Eclampsia/terapia , Síndrome da Leucoencefalopatia Posterior/complicações , Complicações na Gravidez/tratamento farmacológico , Estado Epiléptico/tratamento farmacológico , Adulto , Protocolos Clínicos , Feminino , Humanos , Unidades de Terapia Intensiva , Gravidez , Estado Epiléptico/etiologia , Resultado do TratamentoRESUMO
Familial Adult Myoclonus Epilepsy (FAME), with a prevalence of < 1/35 000, is known under different acronyms. The disease is transmitted in an autosomal dominant manner and is characterized by the occurrence of cortical myoclonic tremor, overt myoclonus, and rare bilateral tonic-clonic seizures. FAME is considered neurodegenerative, although it is relatively slow in progression. Diagnosis is based on specific neurophysiological testing, namely jerk-locked back-averaging, somatosensory evoked potentials, long latency reflex, and motor evoked potentials, among others. Imaging data, including functional magnetic resonance imaging, indicate a cortical origin of the cortical myoclonic tremor and decreased cerebellar activation. Cerebellar changes in Purkinje cells have been noted, from few neuropathology reports, in patients from isolated pedigrees. The differential diagnosis includes essential tremor, some forms of genetic generalized epilepsy, and progressive myoclonus epilepsies. Treatment is mainly symptomatic.
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Epilepsias Mioclônicas , Mioclonia , Adulto , Humanos , Tremor , Epilepsias Mioclônicas/genética , Potenciais Somatossensoriais Evocados , Reflexo , EletroencefalografiaRESUMO
Electroencephalography (EEG) is a crucial non-invasive medical tool for diagnosing neurological disorder called encephalopathy. There is a requirement for powerful signal processing algorithms as EEG patterns in encephalopathies are not specific to a particular etiology. As visual examination and linear methods of EEG analysis are not sufficient to get the subtle information regarding various neuro pathologies, non-linear analysis methods can be employed for exploring the dynamic, complex and chaotic nature of EEG signals. This work aims identifying and differentiating the patterns specific to cerebral dysfunctions associated with Encephalopathy using Recurrence Quantification Analysis and Fractal Dimension algorithms. This study analysed six RQA features, namely, recurrence rate, determinism, laminarity, diagonal length, diagonal entropy and trapping time and comparing them with fractal dimensions, namely, Higuchi's and Katz's fractal dimension. Fractal dimensions were found to be lower for encephalopathy cases showing decreased complexity when compared to that of normal healthy subjects. On the other hand, RQA features were found to be higher for encephalopathy cases indicating higher recurrence and more periodic patterns in EEGs of encephalopathy compared to that of normal healthy controls. The feature reduction was then performed using Principal Component Analysis and fed to three promising classifiers: SVM, Random Forest and Multi-layer Perceptron. The resultant system provides a practically realizable pipeline for the diagnosis of encephalopathy.
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BACKGROUND: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), classically presenting as a triad of early-onset cerebellar ataxia, lower extremity spasticity and peripheral neuropathy, is caused by mutations in SACS gene which encodes the protein sacsin. OBJECTIVE: To provide new insight into the occurrence of SACS mutations in South India. METHODS: Patients with three cardinal features of ARSACS-peripheral neuropathy, cerebellar ataxia, and pyramidal tract signs were included. Nine patients were clinically identified and genetically evaluated. Mutation screening of SACS by targeted sequencing of 40 recessive ataxia genes panel by next-generation sequencing was conducted. Additional investigations included magnetic resonance imaging (MRI), fundoscopy, optical coherence tomography (OCT) and nerve conduction studies (NCS). Functional disability was assessed by the Spinocerebellar Degeneration Functional Score. RESULTS: Two hundred and fifteen cerebellar ataxia patients were screened, and 9 patients with cerebellar ataxia with spasticity, peripheral neuropathy and MRI brain characteristics, consistent with a clinical diagnosis of ARSACS were identified, of which 7 patients were identified to have mutation in the SACS gene and are detailed hereafter. Age of presentation ranged from 20 to 55 years (29.8 ± 11.9) with a mean disease duration of 12.7 years (SD-7.65, range 5-22 years). All except one had onset of symptoms in the form of an ataxic gait noticed before 20 years of age. Additional features were subnormal intelligence (4/7), slow and hypometric saccades (1/7), seizures (1/7), kyphoscoliosis (1/7) and dysmorphic facies (1/7). SDFS was 3 in 5/7 patients signifying moderate disability with independent ambulation. MRI showed cerebellar atrophy with predominant atrophy of the superior vermis (7/7), horizontal linear T2 hypointensities in the pons(7/7), hyperintensities where lateral pons merges with the middle cerebellar peduncle (MCP) (7/7) well seen in fluid-attenuated inversion recovery (FLAIR) images, thickening of MCP (3/7), symmetric lateral thalamic hyperintensities (6/7), posterior fossa arachnoid cyst (4/7),thinning of posterior mid-body of corpus callosum (7/7), marginal mineralisation of the basal ganglia (7/7), bilateral parietal atrophy (7/7) and thinning of corticospinal tract on diffusion tensor imaging (DTI) (7/7). We identified pathogenic homozygous frameshift mutations in the SACS gene in six patients (including two siblings), while one patient had a heterozygous pathogenic deletion. CONCLUSIONS: This is the largest series of genetically confirmed ARSACS patients from India highlighting the clinical, ophthalmological, imaging and genetic features of this cohort.
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Ataxia Cerebelar , Doenças do Sistema Nervoso Periférico , Ataxias Espinocerebelares/congênito , Humanos , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Ataxia Cerebelar/diagnóstico por imagem , Ataxia Cerebelar/genética , Imagem de Tensor de Difusão , Mutação/genética , Espasticidade Muscular/diagnóstico por imagem , Espasticidade Muscular/genética , AtrofiaRESUMO
BACKGROUND: Writer's cramp is a task-specific focal hand dystonia, which is diagnosed clinically. Quantification of defect in WC is done using clinical scales, while digitized platforms are lacking. OBJECTIVE: To design and test a platform that can differentiate and quantify the abnormal kinematics of writing using a software interface and to validate it in adult-onset isolated writer's cramp (WC). METHODS: A native platform was designed using Java and Wacom Intuos pro tablet and the data analyzed using a MATLAB-based platform called Large Data-Based Evaluation of Kinematics in Handwriting (LEKH). We standardized this new platform by comparing the handwriting between patients with WC and age, and gender and education-matched healthy controls, using standard tasks to assess the kinematics. RESULTS: Comparison of the writing of right-handed WC patients (N = 21) and 39 healthy controls (N = 39) showed that patients differed from controls in the frequency of strokes (P < 0.001), number of inversions of velocity (P < 0.001), number of breaks (P = 0.02), air time and paper time (P < 0.001). CONCLUSIONS: Using the LEKH platform, the kinematic profile of patients with WC could be differentiated from healthy controls. Studies in larger samples will be needed to derive statistical models that can differentiate the flexion and extension types of WC which can help in muscle selection and to quantify the effects of treatment.
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Background and Objectives: Next-generation sequencing (NGS) has expedited the diagnostic process and unearthed many rare disorders in leukodystrophy (LD) and genetic leukoencephalopathy (gLE). Despite the progress in genomics, there is a paucity of data on the distribution of genetic white matter disorders (WMDs) and the diagnostic utility of NGS-based assays in a clinical setting. This study was initiated to explore the clinical, radiologic, and genetic spectrum of LD and gLE in the Indian population and also to estimate the diagnostic yield of clinical exome sequencing (CES). Methods: This is a retrospective descriptive analysis of patients with a diagnosis of genetic WMDs from a single tertiary referral center who had CES performed as part of the diagnostic evaluation between January 2016 and December 2021. The demographic, clinical, radiologic, and genetic data were collected. The variants were classified using the American College of Medical Genetics and Genomics criteria. Pathogenic and likely pathogenic variants were included in the calculation of the diagnostic yield. Results: In the study period, 138 patients were clinically diagnosed with either LD or gLE, of which 86 patients underwent CES. Pathogenic variants, likely pathogenic variants, and variants of uncertain significance with phenotype match were seen in 40 (41.8%), 13 (29.1%), and 15 (15.2%) patients, respectively. The mean age at onset in these 68 patients was 6.35 years (range 1 month-39 years), and 38 (55.9%) were male. LDs and gLE were diagnosed in 31 and 37 patients, respectively. 56 patients (71.8%) had autosomal recessive inheritance. The common clinical presentations were developmental delay (23.5%), psychomotor regression (20.6%), progressive myoclonic epilepsy syndrome (19.1%), and spastic ataxia (14.7%). Myelin disorders (48.5%) and leuko-axonopathies (41.2%) were the commonest type of disorders. The most frequently identified genes were ARSA, CLN5, ABCD1, CLN6, TPP1, HEXA, and L2HGDH. The diagnostic yield of the study was 61.6% (53/86), which increased to 79.1% when VUS with phenotype match were included. Discussion: This study demonstrated a high diagnostic yield from proband-only CES in the evaluation of genetic WMDs and should be considered as a first-line investigation for genetic diagnosis. Classification of Evidence: This study provides Class IV evidence that proband-only clinical exome sequencing is a useful "first-line investigation" for patients with genetic white matter disorders.