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2.  Influence of trial design, heterogeneity and regulatory environment on the results of clinical trials: An appraisal in the context of recent trials on acute stroke intervention 
The outcome of randomized controlled trials can vary depending on the eligibility criteria of the patients entering into the trial, as well as the heterogeneity of the eligible population and/or the interventions. If the subject population and/or interventions are heterogeneous, the final outcome of the trial depends on the degree of concordance of effects of the subgroups of interventions on the subgroups of the subject population. The considerations that go into the calculation of sample size and determination of the study stopping rules also would affect the nature of the outcome of the study. In this paper we try to examine these phenomena with respect to the recent trials on endovascular therapy in acute ischemic stroke.
PMCID: PMC4251006  PMID: 25506154
Heterogenity in clinical trials; discordant subgroups; endovascular acute stroke intervention; SYNTHESIS Expansion; IMS III; MR Rescue; SWIFT
3.  Next-generation sequencing and genetic diagnosis of Charcot-Marie-Tooth disease 
Over 70 different Charcot-Marie-Tooth disease (CMT)–associated genes have now been discovered and their number is growing. Conventional genetic testing for all CMT genes is cumbersome, expensive, and impractical in an individual patient. Next-generation sequencing (NGS) technology allows cost-effective sequencing of large scale DNA, even entire exome (coding sequences) or whole genome and thus, NGS platform can be employed to effectively target a large number or all CMT-related genes for accurate diagnosis. This overview discusses how NGS can be strategically used for genetic diagnosis in patients with CMT or unexplained neuropathy. A comment is made to combine simple clinical and electrophysiological algorithm to assign patients to major CMT subtypes and then employ NGS to screen for all known mutations in the subtype-specific CMT gene panel.
PMCID: PMC4251009  PMID: 25506157
CMT; exome; genetic testing; genome; next-generation sequencing
5.  Hot water epilepsy: Phenotype and single photon emission computed tomography observations 
We studied the anatomical correlates of reflex hot water epilepsy (HWE) using multimodality investigations viz. magnetic resonance imaging (MRI), electroencephalography (EEG), and single photon emission computed tomography (SPECT). Five men (mean age: 27.0 ΁ 5.8 years) with HWE were subjected to MRI of brain, video-EEG studies, and SPECT scan. These were correlated with phenotypic presentations. Seizures could be precipitated in three patients with pouring of hot water over the head and semiology of seizures was suggestive of temporal lobe epilepsy. Ictal SPECT showed hyperperfusion in: left medial temporal — one, left lateral temporal — one, and right parietal — one. Interictal SPECT was normal in all five patients and did not help in localization. MRI and interictal EEG was normal in all the patients. The clinical and SPECT studies suggested temporal lobe as the seizure onset zone in some of the patients with HWE.
PMCID: PMC4251030  PMID: 25506178
Hot water epilepsy; magnetic resonance imaging; single photon emission computed tomography; temporal lobe epilepsy
6.  Sleep disorders in children with cerebral palsy and its correlation with sleep disturbance in primary caregivers and other associated factors 
To observe prevalence of sleep disturbance (SD) in cerebral palsy (CP) children in a specific age-group and its correlation with SD in primary caregivers and other associated factors.
Materials and Methods:
This was a prospective cross-sectional study. SD assessed using Sleep Disturbance Scale for Children (SDSC) in CP children and Pittsburgh Sleep Quality Index (PSQI) in caregivers. Fifty cases of clinically diagnosed CP [27 females, mean age: 107.9 ΁ 29.5 months (range: 78-180 months)] fulfilling criteria were included.
Eighteen (36%) children had pathological sleep total score (TS) and Disorders of Initiating and Maintaining Sleep (DIMS) was the commonest SD (n = 25, 50%). All primary caregivers were mothers. Twenty-five (50%) mothers had SD on PSQI scale. DIMS, Disorders of Excessive Somnolence (DES), and TS had significant correlation with PSQI (P < 0.05). Disorders of Arousal (DA) and TS had significant correlation with seizures (P < 0.05) in CP children. Bed-sharing had significant correlation with SD in caregivers (P < 0.001) but not with CP children. No significant correlation was observed between SD in CP and gross motor function (Gross Motor Function Classification System), use of orthoses, and dental caries.
Children with CP have underreported significant SD, which negatively impacts caregiver's sleep also. Seizure disorders and medications contribute significantly to SD.
PMCID: PMC4251031  PMID: 25506179
Cerebral palsy; correlates; SDSC; seizures; sleep disturbance
7.  The national institute of health toolbox 
PMCID: PMC4162007  PMID: 25221390
8.  Mild cognitive impairment: Profile of a cohort from a private sector memory clinic 
Private hospital memory clinics might see a different clientele than university or academic institutes due to referral biases.
To characterize the profile of patients with mild cognitive impairment (MCI) from a private sector memory clinic.
Materials and Methods:
MCI was diagnosed according to revised clinical criteria of Petersen et al. For a subset of patients with MCI medial temporal atrophy and cerebral small vessel disease (white matter lesions and lacunes) were rated on magnetic resonance imaging (MRI) scans and analyzed for their contribution towards cognitive impairment.
Subjects with MCI formed one-third (113/371) of this memory clinic sample from a private hospital. MCI could be effectively diagnosed and subtyped using a brief cognitive scale (Concise Cognitive Test (CONCOG)). The amnestic MCI (single and multiple domains) subtype comprised the majority of cases with MCI. In a subsample of 33 patients, lacunar infarcts were more common than white matter lesions and hippocampal atrophy and were inversely associated with verbal fluency.
MCI may be more commonly encountered in private hospital settings probably due to early referrals. It is possible to diagnose and subtype MCI using a brief cognitive instrument such as the CONCOG. In this sample, lacunar infarcts were more commonly encountered than medial temporal atrophy in such patients.
PMCID: PMC4162025  PMID: 25221408
Brief cognitive scale; mild cognitive impairment; private hospital
10.  Lower motor neuron paralysis with extensive cord atrophy in parainfectious acute transverse myelitis 
We describe a young patient of acute transverse myelitis (ATM) who developed true lower motor neuron (LMN) type flaccid paraplegia as a result of anterior horn cell damage in the region of cord inflammation that extended from conus upwards up to the D4 transverse level. We infer that flaccidity in acute phase of ATM is not always due to spinal shock and may represent true LMN paralysis particularly if the long segment myelits is severe and extending up to last spinal segment.
PMCID: PMC4162027  PMID: 25221410
Acute disseminated encephalomyelitis; acute transverse myelitis; ascending myelitis; magnetic resonance imaging; parainfectious myelitis
12.  Intact thumb reflex in areflexic Guillain Barré syndrome: A novel phenomenon 
Areflexia is one of the cardinal clinical features for the diagnosis of Guillain Barré syndrome. However, some patients may have sluggish proximal muscle stretch reflexes. Presence of thumb reflex, a distal stretch muscle reflex has not been documented in Guillain Barré syndrome.
Materials and Methods:
We prospectively evaluated thumb reflex in Guillain Barré syndrome patients and age matched controls from April to September 2013.
There were 31 patients with Guillain Barré syndrome in whom thumb reflex could be elicited in all (24 brisk, 7 sluggish), whereas all the other muscle stretch reflexes were absent in 29 patients at presentation and the remaining two had sluggish biceps and quadriceps reflexes (P = 0.001). Serial examination revealed gradual diminution of the thumb reflex (P < 0.001). Rapid progression of weakness was associated with early loss of the thumb reflex.
Thumb reflex, a distal stretch reflex is preserved in the early phase of Guillain Barré syndrome.
PMCID: PMC4090847  PMID: 25024572
Acute flaccid paralysis; Guillain Barré syndrome; muscle stretch reflex; thumb reflex
13.  Unusual presentation of Sturge-Weber syndrome: Progressive megalencephaly with bilateral cutaneous and cortical involvement 
The Sturge Weber syndrome is characterized by developmental delay, seizures in infancy, unilateral cutaneous lesions with ipsilateral leptomeningeal enhancement. We report an unusual presentation of Sturge Weber syndrome with bilateral port wine nevus on the trunk and face along with bilateral cortical involvement in a developmentally normal child with progressive megalencephaly.
PMCID: PMC4090850  PMID: 25024575
Megalencephaly; port wine stain; Sturge Weber syndrome
15.  Functional neuro-imaging as a pre-surgical tool in epilepsy 
Annals of Indian Academy of Neurology  2014;17(Suppl 1):S56-S64.
Functional neuro-imaging techniques are helpful in the pre-surgical evaluation of epilepsy for localization of the epileptogenic zone as ancillary tools to electroencephalography (EEG) and magnetic resonance imaging (MRI) or when other localization techniques are normal, non-concordant or discordant. Positron emission tomography (PET) and ictal single photon emission computed tomography (ictal SPECT) imaging are traditional tests that have been reported to have good sensitivity and specificity although the results are better with more expertise as is true for any technique. More recently magnetoencephalogram/magnetic source imaging (MEG/MSI), diffusion tensor imaging and functional magnetic resonance imaging (fMRI) have been used in localization and functional mapping during the pre-surgical work-up of epilepsy. Newer techniques such as fMRI-EEG, functional connectivity magnetic resonance imaging and near infra-red spectroscopy, magnetic resonance spectroscopy and magneto nanoparticles hold promise for further development that could then be applied in the work-up of epilepsy surgery. In this manuscript, we review these techniques and their current position in the pre-surgical evaluation of epilepsy.
PMCID: PMC4001213  PMID: 24791091
Diffusion tensor imaging; functional connectivity magnetic resonance imaging; functional magnetic resonance imaging; functional magnetic resonance imaging-electroencephalography; magnetoencephalogram; positron emission tomography; single photon emission computed tomography; temporal lobe epilepsy
16.  Video electroencephalogram telemetry in temporal lobe epilepsy 
Annals of Indian Academy of Neurology  2014;17(Suppl 1):S45-S49.
Temporal lobe epilepsy (TLE) is the most commonly encountered medically refractory epilepsy. It is also the substrate of refractory epilepsy that gives the most gratifying results in any epilepsy surgery program, with a minimum use of resources. Correlation of clinical behavior and the ictal patterns during ictal behavior is mandatory for success at epilepsy surgery. Video electroencephalogram (EEG) telemetry achieves this goal and hence plays a pivotal role in pre-surgical assessment. The role of telemetry is continuously evolving with the advent of digital EEG technology, of high-resolution volumetric magnetic resonance imaging and other functional imaging techniques. Most of surgical selection in patients with TLE can be done with a scalp video EEG monitoring. However, the limitations of the scalp EEG technique demand invasive recordings in a selected group of TLE patients. This subset of the patients can be a challenge to the epileptologist.
PMCID: PMC4001214  PMID: 24791089
Temporal lobe epilepsy; video electroencephalogram; presurgical evaluation
17.  Refractory status epilepticus 
Annals of Indian Academy of Neurology  2014;17(Suppl 1):S32-S36.
Refractory status epilepticus is a potentially life-threatening medical emergency. It requires early diagnosis and treatment. There is a lack of consensus upon its semantic definition of whether it is status epilepticus that continues despite treatment with benzodiazepine and one antiepileptic medication (AED), i.e., Lorazepam + phenytoin. Others regard refractory status epilepticus as failure of benzodiazepine and 2 antiepileptic medications, i.e., Lorazepam + phenytoin + phenobarb. Up to 30% patients in SE fail to respond to two antiepileptic drugs (AEDs) and 15% continue to have seizure activity despite use of three drugs. Mechanisms that have made the treatment even more challenging are GABA-R that is internalized during status epilepticus and upregulation of multidrug transporter proteins. All patients of refractory status epilepticus require continuous EEG monitoring. There are three main agents used in the treatment of RSE. These include pentobarbital or thiopental, midazolam and propofol. RSE was shown to result in mortality in 35% cases, 39.13% of patients were left with severe neurological deficits, while another 13% had mild neurological deficits.
PMCID: PMC4001215  PMID: 24791086
Midazolam; pentobarb; propofol; refractory status epilepticus; status epilepticus
18.  Epilepsy in the elderly: Special considerations and challenges 
Annals of Indian Academy of Neurology  2014;17(Suppl 1):S18-S26.
The elderly are generally defined as those over 60 or 65 years old, but they are a heterogeneous group and may be subdivided into categories based on age and health status. The incidence of epilepsy is highest in the elderly. With a progressive increase in life expectancy, this is the fastest growing segment of patients with epilepsy. Older patients most often have focal seizures, with less prominent auras and automatisms, and longer duration of postictal confusion compared to younger patients. Status epilepticus is common and has a high mortality. The most common specific etiology is cerebrovascular disease, but the cause remains unknown in many patients. Diagnosis can be challenging because of several patient-related, physician-related and investigation-related factors. Over-diagnosis and under-diagnosis are common. Treatment is complicated by the presence of physiological changes related to aging, co-morbidities and cognitive problems as well as concerns regarding drug interactions and medication adherence. Seizures can be controlled in most patients with low doses of a single anti-epileptic drug (AED). Tolerability is an important factor in selection of an AED, as elderly patients tend to be highly sensitive to side effects. Drug-resistant epilepsy is uncommon. Epilepsy surgery, especially temporal lobectomy, can be performed in older patients with good results. More studies addressing the pathophysiological mechanisms of epilepsy in this age group, and greater inclusion of the elderly in clinical trials, as well as development of comprehensive care models are needed to provide optimal care to these patients.
PMCID: PMC4001216  PMID: 24791083
Diagnosis; elderly; epilepsy; treatment
19.  Brain stimulation for intractable epilepsy: Anterior thalamus and responsive stimulation 
Annals of Indian Academy of Neurology  2014;17(Suppl 1):S95-S98.
Despite medications, resective surgery, and vagal nerve stimulation, some patients with epilepsy continue to have seizures. In these patients, other approaches are urgently needed. The biological basis of stimulation of anterior thalamic nucleus and epileptogenic focus is presented. Results from two large randomized controlled trials Stimulation of Anterior Nucleus of Thalamus for Epilepsy (SANTE) and Neuropace pivotal trial are discussed. Neuromodulation provides effective treatment for a select group of refractory epilepsy patients. Future investigations into the mechanism underlying ‘response’ to brain stimulation are desired.
PMCID: PMC4001217  PMID: 24791096
Anterior thalamic nucleus; brain stimulation; epilepsy; neuromodulation; responsive neuromodulation
20.  Epilepsy surgery in context of neurocysticercosis 
Annals of Indian Academy of Neurology  2014;17(Suppl 1):S65-S68.
The association between neurocysticercosis (NCC) and epilepsy is well known and NCC is an important risk factor for epileptic seizures in many Taenia solium-endemic regions of the world. However, while the relationship between NCC and epilepsy is well known, the association between NCC and medically refractory (or surgically remediable epilepsy) has received little attention in the past. Our experience and review of the sparse literature available suggests that NCC is causally related to surgically remediable epilepsy albeit uncommonly so and that association derives its underpinnings from several different scenarios: (1) Medically refractory lesional epilepsy, in which seizures arise from the vicinity of the calcified neurocysticercus lesion (CNL), (2) Medically refractory epilepsy with dual pathology type of relationship between the hippocampal sclerosis (HS) and CNL in which both have been unequivocally demonstrated to give rise to independent seizures and (3) Mesial temporal lobe epilepsy due to HS with a distantly-located CNL, which is in itself not epileptogenic. A major point of controversy revolves around whether or not there exists a causal association between the CNL and HS. We believe that an association exists between NCC and HS and the most important factor influencing this association is the location of the CNL. Furthermore, NCC is a risk factor for medically-refractory epilepsy and that this might account for a considerable proportion of the intractable epilepsy population in endemic regions; the association has been largely ignored owing to the lack of availability of presurgical work-up facilities in these regions. Finally, from a clinical standpoint of presurgical evaluation, patients with CNL and HS should be evaluated on a case by case basis owing to disparate settings underlying the association.
PMCID: PMC4001218  PMID: 24791092
Association; medically-refractory epilepsy; mesial temporal sclerosis neurocysticercosis
21.  Magnetoencephalography: Basic principles 
Annals of Indian Academy of Neurology  2014;17(Suppl 1):S107-S112.
Magnetoencephalography (MEG) is the measurement of the magnetic field generated by the electrical activity of neurons. It is usually combined with a magnetic resonance imaging to get what is called magnetic source imaging. The technology that has helped record these minute magnetic fields is super-conducting quantum interference detector which is like a highly sensitive magnetic field meter. To attenuate the external magnetic noise the MEG is housed inside a magnetically shielded room. The actual sensors recording magnetic fields are magnetometers and/or gradiometers. MEG fields pass through the head without any distortion. This is a significant advantage of MEG over electroencephalography. MEG provides a high spatial and temporal resolution. The recording and identification information should be according to the American Clinical Magnetoencephalography Society guidelines published in 2011. MEG currently has two approved indications in the United States, one is for pre-operative brain mapping and the other is for use in epilepsy surgery. MEG studies have shown functional brain tissue inside brain tumors.
PMCID: PMC4001219  PMID: 24791076
Cortical mapping; epilepsy; magnetic source imaging; magnetoencephalography
22.  Economics of epilepsy surgery 
Annals of Indian Academy of Neurology  2014;17(Suppl 1):S120-S123.
Surgical decision-making is a complex process. First, a medical decision is made to determine if surgery is necessary. Second, another medical decision is made to determine the type of surgery. Third, a corporate decision is made if such a surgery is financially feasible. Finally, a legal decision is made to proceed or refuse the chosen surgery. This paper examines these issues in the case of surgery for medically intractable epilepsy and proposes a method of decision analysis to guide epilepsy surgery.
Materials and Methods:
A stochastic game of imperfect information using techniques of game theory and decision analysis is introduced as an analytical tool for surgical decision-making.
Surgery for appropriately chosen patients suffering from medically intractable epilepsy may not only be feasible, but may be the best medical option and the best financial option for the patient, families, society and the healthcare system. Such a situation would then make it legally or ethically difficult to reject or postpone surgery for these patients.
A process to collect data to quantify the parameters used in the decision analysis is hereby proposed.
PMCID: PMC4001220  PMID: 24791079
Decision-analysis; economics; epilepsy; game theory; surgery
23.  Surgery for childhood epilepsy 
Annals of Indian Academy of Neurology  2014;17(Suppl 1):S69-S79.
Approximately 60% of all patients with epilepsy suffer from focal epilepsy syndromes. In about 15% of these patients, the seizures are not adequately controlled with antiepileptic drugs; such patients are potential candidates for surgical treatment and the major proportion is in the pediatric group (18 years old or less). Epilepsy surgery in children who have been carefully chosen can result in either seizure freedom or a marked (>90%) reduction in seizures in approximately two-thirds of children with intractable seizures. Advances in structural and functional neuroimaging, neurosurgery, and neuroanaesthesia have improved the outcomes of surgery for children with intractable epilepsy. Early surgery improves the quality of life and cognitive and developmental outcome and allows the child to lead a normal life. Surgically remediable epilepsies should be identified early and include temporal lobe epilepsy with hippocampal sclerosis, lesional temporal and extratemporal epilepsy, hemispherical epilepsy, and gelastic epilepsy with hypothalamic hamartoma. These syndromes have both acquired and congenital etiologies and can be treated by resective or disconnective surgery. Palliative procedures are performed in children with diffuse and multifocal epilepsies who are not candidates for resective surgery. The palliative procedures include corpus callosotomy and vagal nerve stimulation while deep brain stimulation in epilepsy is still under evaluation. For children with “surgically remediable epilepsy,” surgery should be offered as a procedure of choice rather than as a treatment of last resort.
PMCID: PMC4001221  PMID: 24791093
Children; epilepsy surgery; temporal lobe epilepsy; extratemporal epilepsy; hemispherotomy
24.  Epilepsy: Indian perspective 
Annals of Indian Academy of Neurology  2014;17(Suppl 1):S3-S11.
There are 50 million people living with epilepsy worldwide, and most of them reside in developing countries. About 10 million persons with epilepsy are there in India. Many people with active epilepsy do not receive appropriate treatment for their condition, leading to large treatment gap. The lack of knowledge of antiepileptic drugs, poverty, cultural beliefs, stigma, poor health infrastructure, and shortage of trained professionals contribute for the treatment gap. Infectious diseases play an important role in seizures and long-term burden causing both new-onset epilepsy and status epilepticus. Proper education and appropriate health care services can make tremendous change in a country like India. There have been many original researches in various aspects of epilepsy across India. Some of the geographically specific epilepsies occur only in certain regions of our country which have been highlighted by authors. Even the pre-surgical evaluation and epilepsy surgery in patients with drug-resistant epilepsy is available in many centers in our country. This article attempts to provide a complete preview of epilepsy in India.
PMCID: PMC4001222  PMID: 24791085
Epilepsy in India; epilepsy surgery; hot water epilepsy; progressive myoclonic epilepsy; status epilepticus; treatment gap; women with epilepsy
25.  Evaluation of magnetic resonance imaging-negative drug-resistant epilepsy 
Annals of Indian Academy of Neurology  2014;17(Suppl 1):S80-S88.
A structural brain lesion in patients with drug-resistant epilepsy (DRE) greatly increases the likelihood of identification of the seizure focus and ultimately seizure-free outcome following resective epilepsy surgery. In contrast, surgical outcomes of true non-lesional DRE are less favorable. Therefore, discovery of an underlying lesion is paramount in the pre-surgical work-up of patients with DRE. Over the years, the surgical treatment of pharmacoresistant epilepsy has evolved from straightforward lesional cases to include cases with hippocampal sclerosis. With the advent of magnetic resonance imaging (MRI), most cases of mesial temporal sclerosis became more easily identifiable on pre-operative neuroimaging. With the widespread use of high-resolution MRI with epilepsy protocols over the last two decades, our ability to visualize subtle structural changes has been greatly enhanced. However, there are some cases of lesional epilepsy, which remain unidentified on these routine MRIs. In such “non-lesional” refractory epilepsies, further investigation with advanced neuroimaging techniques, including metabolic imaging, as well as electrophysiological studies may help to identify the previously non-visualized focal brain abnormalities. In this review, we outline the current status for evaluation of MRI-negative DRE.
PMCID: PMC4001223  PMID: 24791094
Epilepsy surgery; investigations; medically refractory epilepsy; non-lesional epilepsy; pharmacoresistant seizures

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