Changes in Optimal Stimulation Frequency with Time for Gait Disturbances in Patients with PD after STN-DBS-A Longitudinal Study.

Aim: To assess the changes in frequency parameters of STN-DBS stimulation over 6 months required to optimize gait in PD patients. Methods: It's a single center, open label longitudinal study of PD patients after STN-DBS with gait disorders. Gait assessment using stand-walk-sit (SWS) test and freezing of gait (FOG) scores were done at baseline and after 6 months. Gait was assessed in five frequencies settings, that is, 60 Hz, 90 Hz, 130 Hz, 180 Hz and stimulation "OFF" during medication ON state. Voltage was maintained. Results: Fifteen post-deep brain stimulation (DBS) patients were included. Mean duration after surgery was 3.73 ± 2.82 years. In SWS and FOG at baseline, five patients have good response at 180 Hz frequency, five at 130 Hz, one at 90 Hz, two patients at 60 Hz, one both 60 and 90 Hz, and one at both 90 and 180 HZ. And after 6 months out of the 13 patients who were able to perform the test, four patients had good response at 180 Hz frequency, four at 130 Hz, two at 90 Hz, one each for 60 Hz and battery OFF state, and one for both 130 Hz and 180 Hz. At 6 months, four patients had good response at the same frequency as baseline, while 11 patients have change in frequency from baseline. Conclusion: Optimal frequency for gait varies in patients-both low and high frequency may be useful. Optimal frequency for improving gait changes over period of time. Regular assessment and changing frequency may improve gait after DBS.

Neurocognitive Profile and 18 F-Fluorodeoxyglucose Positron Emission Tomography Brain Imaging Correlation in Children with Electrical Status Epilepticus during Sleep.

Objective Electrical status epilepticus in sleep (ESES) is defined by near-continuous epileptiform discharges during sleep along with cognitive, behavioral, and/or imaging abnormalities. We studied the neurocognitive profile and their correlation with 18 F fluorodeoxyglucose positron emission tomography (FDG PET) brain abnormalities in children with ESES. Methods Fourteen children with ESES with normal magnetic resonance imaging (MRI) from March to December 2019 were included. The intelligence quotient (IQ) and child behavior checklist (CBCL) scores were estimated using validated scales, and FDG PET brain was done at the same point of time to look for cerebral metabolic defects which was compared with a control group. Results Fourteen patients with a mean age of 8.2 ± 2.7 years were analyzed. The average duration of epilepsy was 6 ± 2.8 years. The mean IQ was 72.4 ± 18.2 and mean CBCL score was 37.3 ± 11.8. There was negative correlation between IQ and CBCL ( r = -0.55, p < 0.001). The duration of epilepsy also showed negative correlation with IQ ( r = -4.75, p < 0.001). FDG PET scan showed predominant thalamic hypometabolism in 12 of 14 patients (85.7%) on visual analysis with multiple other hypometabolic cortical and subcortical regions in the brain. The quantitative analysis showed significant difference in metabolism of basal ganglion when compared with control group. The total number of hypometabolic regions seen in the brain showed moderate positive correlation with CBCL score but no significant correlation with the IQ of cases. Conclusion This study demonstrates functional impairment of cerebral cortical, basal ganglia, and thalamic hypometabolism in a cohort of ESES patients with normal structural MRI brain study. There was a moderate correlation of extent and pattern of cerebral hypometabolism with the neuropsychological status of the child and duration of epilepsy.

South Asian medical cohorts reveal strong founder effects and high rates of homozygosity.

The benefits of large-scale genetic studies for healthcare of the populations studied are well documented, but these genetic studies have traditionally ignored people from some parts of the world, such as South Asia. Here we describe whole genome sequence (WGS) data from 4806 individuals recruited from the healthcare delivery systems of Pakistan, India and Bangladesh, combined with WGS from 927 individuals from isolated South Asian populations. We characterize population structure in South Asia and describe a genotyping array (SARGAM) and imputation reference panel that are optimized for South Asian genomes. We find evidence for high rates of reproductive isolation, endogamy and consanguinity that vary across the subcontinent and that lead to levels of rare homozygotes that reach 100 times that seen in outbred populations. Founder effects increase the power to associate functional variants with disease processes and make South Asia a uniquely powerful place for population-scale genetic studies.

3T MRI-SWI based volumetric analysis of the subthalamic and red nuclei in advanced Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disease mainly involving the dopaminergic neurons of the substantia nigra. The subthalamic nucleus (STN) also plays an important role in the disease process and now is an important target for the surgical management of the disease. However, not much is known about its morphology as the disease progresses. The aim of this study was to evaluate the volume of STN and red nucleus (RN) on 3T MRI SWI and its possible correlation with the disease in patients with advanced Parkinson's disease. METHODS: A total of 30 patients were enrolled. They were evaluated by analysis of symptomatology, UPDRS III, MOCA. Radiological evaluation included volumetric SWI images in 3T MRI. The volumes of the STN and RN were measured on SWI coronal images. RESULTS: There were 24 (80%) males and 6 (20%) females. The mean volumes of STN and RN were 118.66 mm3 (80-170 mm3) and 379.66 mm3 (270-500 mm3). There was no significant difference between right and left STN volumes and RN volumes. There was a significant positive correlation between the disease duration and RN volumes (P=0.015) and STN volumes (in 6-13 years) (P=0.001). STN and RN volumes were negatively correlated with MOCA scores in males (P=0.008 and P=0.017), with no such correlation in females. In late-onset PD, there was a significant positive correlation between RN volume and UPDRS OFF and ON scores (P=0.028 and P=0.03). CONCLUSIONS: STN volumes show a positive trend as the disease duration increases and cognition declines. RN volumes also increase as the disease progresses.

Aceruloplasminemia with Novel Mutation, with IgG4 Related Pachymeningitis - Occam's Razor or Hickam's Dictum?

To report a patient with concomitant aceruloplasminemia (with a novel mutation) and IgG4-related pachymeningitis and to hypothesize on the possible relation between the two diseases. Clinical, radiological, and laboratory features of a 56-year-old lady with chronic headache, bifacial palsy, and cerebellar signs are described. Pathophysiology of aceruloplasminemia leading to hyperferritinemia and consequent immune activation is elucidated. A coherent explanation of IgG4-related pachymeningitis resulting from aceruloplasminemia and hyperferritinemia is given. The patient has aceruloplasminemia with a novel nonsense mutation. She also suffers from biopsy-proven IgG4 related pachymeningitis as per standard criteria. These two seemingly unrelated illnesses are linked by hyperferritinemia. This case is a fine example of Occam's razor. Immune dysfunction and autoimmune disorders in aceruloplasminemia need to be explored through further studies to look for causal associations.

Volumetric analysis of subthalamic nucleus and red nucleus in patients of advanced Parkinson's disease using SWI sequences.

BACKGROUND: Parkinson's disease is associated with significant changes in morphometry of subthalamic nucleus (STN); however, not much is known as the disease progresses. The aim of present study was to investigate the volume of STN and Red nucleus (RN) on 3T-magnetic resonance imaging (MRI) and its possible correlation with disease progression in advanced Parkinson's disease patients. METHODS: Patients of advanced Parkinson's disease were prospectively followed for clinical details, motor severity scores, and radiological evaluation. Volumes of the STN and RN were measured on susceptibility weighted imaging, coronal sections in 3T MRI and were correlated with demographic and clinical features. RESULTS: A total of 52 patients were included in our study. There were 42 (80.77%) males and 10 (19.23%) females. Mean age of onset of Parkinson's disease was 49.48 + 10.90 years. Average duration of disease in the present cohort was 7.65 + 4.31 years. Average STN and RN volume were 103.46 + 21.17 mm3 and 321.73 + 67.66 mm3. Age of onset, disease duration and Unified Parkinson's Disease Rating Scale Part III scores were not found to be associated with changes in STN Volumes. Weak positive trend was noted between RN volume and disease duration (Pearson cor. 0.204, P = 0.14). Patients in early-onset Parkinson's disease group had significantly more volume of RN than patients in late-onset Parkinson's disease group (P = 0.014). CONCLUSION: Disease duration and early age of onset in Parkinson's disease can be associated with increased RN volume. Volume of STN shows relatively no change even with disease progression.

The Effect of Dual Tasking and Deep Brain Stimulation Frequency Parameters on Gait in Advanced Parkinson's Disease.

OBJECTIVE: To study the effect of dual tasking and deep brain stimulation frequency parameters on gait in advanced Parkinson's disease. MATERIALS AND METHODS: This is an open label interventional study evaluating 40 post STN-DBS patients with gait disturbances. All patients were diagnosed as PD by a movement disorder specialist using the United Kingdom Parkinson's Disease Society Brain Bank (UKPDSBB) criteria. Patients underwent bilateral subthalamic deep brain stimulation by a qualified neurosurgeon. Patients were managed on a combination of dopamine replacement therapy as well as deep brain stimulation. Patients were assessed by stand walk sit (SWS) test for a 5 meter distance and FOG scoring during medication 'ON' state and device "ON" state, at four frequencies 180, 130, 90, 60 HZ and device "OFF" state. RESULTS: Out of 40 patients, 38 patients showed a significant improvement in gait at a single frequency (best response frequency) which is different for each patient. The mean FOG score showed significant improvement at all stimulation frequencies when compared to OFF stimulation (P < 0.05). The mean number of steps was 18.9 at best response frequency and 21.48 at 130 Hz (P < 0.0001). Number of freezing episodes also were significantly less with best frequency when compared to 130 Hz stimulation (0.28 and 0.65 respectively, (P < 0.0001). The mean FOG score was 6.45 at best frequency and 9.48 at 130 Hz (P < 0.0001). Mean Dual tasking score was 3.53 at best frequency and 5.15 at 130 Hz (P < 0.0002). CONCLUSION: Optimization of frequency setting for each patient can improve gait and that each patient may have a different optimal frequency.

Corrigendum to "Wilson's Disease: Clinical Practice Guidelines of the Indian National Association for the Study of Liver (INASL), The Indian Society of Pediatric Gastroenterology, Hepatology and Nutrition (ISPGHAN) and the Movement Disorders Society of India (MDSI)" [J Clin Exp Hepatol 9 (2019) 74-98].

[This corrects the article DOI: 10.1016/j.jceh.2018.08.009.].

Wilson's Disease: Clinical Practice Guidelines of the Indian National Association for Study of the Liver, the Indian Society of Pediatric Gastroenterology, Hepatology and Nutrition, and the Movement Disorders Society of India.

Clinical practice guidelines for Wilson's disease (WD) have been published by the American Association for the Study of Liver Diseases and European Association for the Study of the Liver in 2008 and 2012, respectively. Their focus was on the hepatic aspects of the disease. Recently, a position paper on pediatric WD was published by the European Society of Pediatric Gastroenterology Hepatology and Nutrition. A need was felt to harmonize guidelines for the hepatic, pediatric, and neurological aspects of the disease and contextualize them to the resource-constrained settings. Therefore, experts from national societies from India representing 3 disciplines, hepatology (Indian National Association for Study of the Liver), pediatric hepatology (Indian Society of Pediatric Gastroenterology, Hepatology and Nutrition), and neurology (Movement Disorders Society of India) got together to evolve fresh guidelines. A literature search on retrospective and prospective studies of WD using MEDLINE (PubMed) was performed. Members voted on each recommendation, using the nominal voting technique. The Grades of Recommendation, Assessment, Development and Evaluation system was used to determine the quality of evidence. Questions related to diagnostic tests, scoring system, and its modification to a version suitable for resource-constrained settings were posed. While ceruloplasmin and 24-h urine copper continue to be important, there is little role of serum copper and penicillamine challenge test in the diagnostic algorithm. A new scoring system - Modified Leipzig score has been suggested with extra points being added for family history and serum ceruloplasmin lower than 5 mg/dl. Liver dry copper estimation and penicillamine challenge test have been removed from the scoring system. Differences in pharmacological approach to neurological and hepatic disease and global monitoring scales have been included. Rising bilirubin and worsening encephalopathy are suggested as indicators predicting need for liver transplant but need to be validated. The clinical practice guidelines provide recommendations for a comprehensive management of WD which will be of value to all specialties.

Identification of a novel splice site HSPG2 mutation and prenatal diagnosis in Schwartz Jampel Syndrome type 1 using whole exome sequencing.

Schwartz-Jampel Syndrome type 1 is a rare autosomal recessive musculoskeletal disorder (OMIM #255800) caused by various mutations in the HSPG2 gene encoding protein perlecan, a ubiquitous heparan sulfate proteoglycan, which is an integral component of basement membranes and possesses angiogenic and growth-promoting attributes primarily by acting as a co-receptor for the basic fibroblast growth factors in human body. We report a novel homozygous intronic 5' splice site mutation in this gene (c.4740 + 5G>A) in a child with clinical features of Schwartz-Jampel syndrome type 1. The mutation was detected by exome sequencing and later confirmed by Sanger sequencing. The mother was found to be heterozygous for the mutation and an ongoing pregnancy found to be unaffected. cDNA analysis revealed skipping of exon 37 of HSPG2 gene in the patient due to the splicing error caused by this mutation. This is likely to result in loss of 38 amino acids from the domain III of the perlecan protein and presumably affects its structure and function as per protein modeling predictions. This report demonstrates the utility of exome sequencing as a routine molecular diagnostic approach of choice for this rare disorder.

Incidence and spectrum of paraneoplastic neurological syndromes: single center study.

Paraneoplastic neurological syndromes (PNS) are remote effects of cancer. They are much less common, but are nevertheless important because they cause severe neurological morbidity and mortality. The present cases were studied to characterize the clinical features of patients of suspected PNS and to study their association with different types of tumors. In this study conducted from a super speciality teaching institute from South India, forty five (incidence-0.25%) patients were diagnosed with PNS based on the clinical data. They were subdivided into two groups patients with central nervous system (CNS) manifestations and those with neuromuscular manifestations. Immunological markers were assessed in a subset of patients. Majority of them (75.6%) were above 40 years. There was no sex predilection and a chronic presentation was common (42.2%). While more than half had involvement of peripheral nervous system (64.4%), CNS manifestations were present in 16 (35.6%) cases. Immunological markers were present in 10 out of 14 (58.8%) patients. Classic PNS was seen 22 cases (48.9%), while 23 (51.1%) were non classical. Most common tumor was lung cancer followed by myeloma and breast carcinoma. Present study construed that, in patients with neurological syndromes of unknown cause, search should be focused for occult malignancy based on the phenotype and onconeural antibodies, targeting the lung and breast in particular.

Series of paraneoplastic vasculitic neuropathy: a rare, potentially treatable neuropathy.

BACKGROUND: Paraneoplastic vasculitic neuropathy (PVN) is a rare paraneoplastic syndrome. It is characterized by non-systemic subacute vasculitic neuropathy. It is most commonly associated with small cell lung cancers (SCLC) and lymphomas. PVN presents as a painful symmetrical or asymmetrical sensorimotor axonal neuropathy. The neurological symptoms may predate the tumor and may be the initial manifestations, or they may develop after a tumor is diagnosed. Recognition of this entity is important because of its potential treatability. AIM: To study the clinical features of PVN and briefly review the literature. MATERIALS AND METHODS: The data was collected retrospectively from the medical records of our hospital. RESULTS: Of the 14 cases of paraneoplastic neuropathies, 4 had a PVN. The age of onset was more than 50 years and there was no sex preponderance. Pain was seen in three patients. Two patients were previously treated for a thymoma. Two patients, following their presentation with PVN, were diagnosed with a colonic carcinoma and lung carcinoma, respectively. CONCLUSIONS: The recognition of PVN is important as this syndrome may respond to immunosuppression and tumor removal.