Epidemiology of Motoric Cognitive Risk Syndrome in the Kerala Einstein Study: Protocol for a Prospective Cohort Study.

BACKGROUND: The southern India state of Kerala has among the highest proportion of older adults in its population in the country. An increase in chronic age-related diseases such as dementia is expected in the older Kerala population. Identifying older individuals early in the course of cognitive decline offers the best hope of introducing preventive measures early and planning management. However, the epidemiology and pathogenesis of predementia syndromes at the early stages of cognitive decline in older adults are not well established in India. OBJECTIVE: The Kerala Einstein Study (KES) is a community-based cohort study that was established in 2008 and is based in the Kozhikode district in Kerala state. KES aims to establish risk factors and brain substrates of motoric cognitive risk syndrome (MCR), a predementia syndrome characterized by the presence of slow gait and subjective cognitive concerns in individuals without dementia or disability. This protocol describes the study design and procedures for this KES project. METHODS: KES is proposing to enroll a sample of 1000 adults ≥60 years old from urban and rural areas in the Kozhikode district of Kerala state: 200 recruited in the previous phase of KES and 800 new participants to be recruited in this project. MCR is the cognitive phenotype of primary interest. The associations between previously established risk factors for dementia as well as novel risk factors (apathy and traumatic brain injury) and MCR will be examined in KES. Risk factor profiles for MCR will be compared between urban and rural residents as well as with individuals who meet the criteria for mild cognitive impairment (MCI). Cognitive and physical function, medical history and medications, sociodemographic characteristics, lifestyle patterns, and activities of daily living will be evaluated. Participants will also undergo magnetic resonance imaging and electrocardiogram investigations. Longitudinal follow-up is planned in a subset of participants as a prelude to future longitudinal studies. RESULTS: KES (2R01AG039330-07) was funded by the US National Institutes of Health in September 2019 and received approval from the Indian Medical Council of Research to start the study in June 2021. We had recruited 433 new participants from urban and rural sites in Kozhikode as of May 2023: 41.1% (178/433) women, 67.7% (293/433) rural residents, and 13.4% (58/433) MCR cases. Enrollment is actively ongoing at all the KES recruitment sites. CONCLUSIONS: KES will provide new insights into risk factors and brain substrates associated with MCR in India and will help guide future development of regionally specific preventive interventions for dementia. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/49933.

Clinical, Biochemical, Radiological, and Genetic Profile of Patients with Homocysteine Remethylation Pathway Defect and Spastic Paraplegia.

Objectives: The objective of this study is to describe the clinical, biochemical, radiological, and genetic profile of patients presenting with progressive spastic paraparesis due to homocysteine remethylation pathway defect. Methods: This was a retrospective study conducted by reviewing the medical records of patients with serum homocysteine levels >50 µmol/L between January 2015 and January 2019 at our hospital. We included patients presenting with progressive spastic paraparesis, having serum homocysteine >50 µmol/L with low or normal blood methionine suggesting disorders of homocysteine remethylation. Demographic details, clinical manifestations, biochemical abnormalities, neuroimaging findings, and genetic profile were analyzed. Results: A total of seven patients (M: F = 5:2) fulfilled the study eligibility criteria. The mean age at onset of the disease was 13.4 ± 2.4 years (range: 9-17 years). Spastic paraparesis was the presenting manifestation in 4/7 (57.1%) patients. Other manifestations included cognitive decline, poor scholastic performance, behavioral disturbances, seizures, and spastic bladder. Severe hyperhomocysteinemia (>100 µmol/L) was noted in 6/7 (85.7%) patients with median levels of serum homocysteine being 185.7 µmol/L (range: 85.78-338.5 µmol/L). Neuroimaging showed parieto-occipital predominant leukoencephalopathy in 5/7 (71.4%) and diffuse cerebral atrophy in 1/7 (14.2%). Genetic analysis in three patients revealed pathogenic missense variants c.459C >G (p.Ile153Met), c.973C >T (p.Arg325Cys), and c.1031G >T (p.Arg344Met) in MTHFR gene. All the patients received vitamin B12 (injection and oral), folic acid, and pyridoxine and two patients received betaine. At the last follow-up of a median duration of 12 months, there was a good clinical and biochemical response with reduction in the median value of serum homocysteine by 77.5 µmol/L. Conclusion: Evaluation of serum homocysteine and blood methionine in adolescents presenting with progressive spastic paraparesis gives clue to a treatable homocysteine remethylation disorders.

Genetically Established Familial Amyloidotic Polyneuropathy from India: Narrating the Diagnostic "Odyssey" and a Mini Review.

CONTEXT: Familial amyloidotic polyneuropathy (FAP) is often misdiagnosed as other neuropathic illnesses. AIM: To highlight the diagnostic "odyssey" in three families of Indian origin with FAP. SETTINGS AND DESIGN: Cross-sectional, hospital-based study. SUBJECTS AND METHODS: Clinical, radiological, and histological features as well as causes for delayed diagnosis were analyzed in genetically confirmed patients with FAP. STATISTICAL ANALYSIS: Descriptive. RESULTS: Age at evaluation ranged from 24 to 42 years and symptom duration from 1 to 10 years. Referral diagnoses included: (i) in patients 1 and 2-familial dysautonomia, Shy-Drager syndrome, and spino-cerebellar ataxia with seizures, (ii) in patient 3-chronic inflammatory demyelinating polyradiculoneuropathy, and (iii) in patient 4-porphyria. In addition, patients 1 and 2 developed leptomeningeal involvement that was mistaken for tubercular meningitis. Reasons for missed diagnosis included: clinician's lack of awareness, not paying sufficient attention to family history, presence of laboratory distractors such as elevated urinary porphyrins, lack of meticulous search for amyloid in the biopsy, and not performing specific stain for amyloid viz. Congo red. Evidence of amyloid in histological studies of nerve and skin supported by genetic variations in transthyretin gene clinched the diagnosis. The variants identified in our cohort included p.Gly73Glu, p.Val71Ala, and p.Val50Met. CONCLUSION: Lack of awareness and meticulous work-up by clinicians and pathologists contributed to delayed diagnosis of FAP. It is important to establish an accurate diagnosis as these patients may be candidates for upcoming therapies.

Neuroanatomical correlates of apathy and disinhibition in behavioural variant frontotemporal dementia.

Neuroanatomical correlates of apathy and disinhibition, behavioral abnormalities in behavioral variant Frontotemporal dementia (bvFTD) remain unclear. In this study 45 participants (25 bvFTD patients and 20 controls) provided data on clinical, neuropsychological, behavioral (on Frontal Systems Behavior (FrSBe) Scale), cortical volume (on voxel-based morphometry (VBM)) and tract based spatial fractional anisotropy ((FA) on magnetic resonance imaging (MRI), allowing examination of the neural correlates of apathy and disinhibition. The patients with bvFTD had predominant grey matter loss and corresponding white matter fractional anisotropy reduction in the frontal and temporal lobe compared to the controls. Grey matter loss in frontal, temporal and limbic structures correlated with apathy and degeneration in temporal limbic brain areas correlated with disinhibition. FA changes in inferior fronto-occipital fasciculus and forceps minor correlated with apathy and fibre integrity changes in the superior longitudinal fasciculus correlated with disinhibition. The current study suggests that apathy and disinhibition arises due to changes in the frontal, temporal and limbic brain areas  in bvFTD.

Exome sequencing in adult neurology practice: Challenges and rewards in a mixed resource setting.

OBJECTIVE: To share the experience of next-generation sequencing (NGS) in delineating molecular basis of neuro-genetic disorders in adults of Indian origin. PATIENTS AND METHODS: Adults (aged ≥18 years) evaluated in a single neurology unit at a tertiary-care teaching hospital between August 2014 and September 2016, underwent NGS for (i) sporadic occurrence of neurological disorder where an extensive search did not reveal an acquired cause or (ii) familial or sporadic, uncommon, seemingly genetic disorder where single monogenic cause could not be ascertained based on phenotype. Presence of pathogenic/ likely-pathogenic variants, novel genetic variants, and novel phenotype associations were noted. RESULTS: Clinical phenotypes included: neuromuscular (n = 14), extrapyramidal (n = 8), ataxia (n = 7), leukoencephalopathy (n = 6), spastic paraplegia (n = 5), stroke (n = 4), progressive myoclonic epilepsy (n = 1) and epilepsy with developmental delay (n = 1). Fifty-eight variants were identified in 43 genes in 34 patients, that included 15 (25.9%) reported variants. Genetic diagnosis could be established in 14 (30.43%) subjects. Six probands (13%) harboured previously unreported variants in a clinically relevant gene. Nine probands harboured unreported variants in two or more different genes associated with the clinical phenotype. In three probands we noted novel associations between the phenotype and genetic variation. In all patients, genetic diagnosis impacted treatment and prognostication. CONCLUSIONS: We present data of NGS in adults with suspected neuro-genetic disorders from India and this is the first report of its kind. It sets a platform for further basic science research to validate 'novel' variants and those of 'uncertain significance' as pathogenic or otherwise with specific reference to Indian ethnicity.

Pediatric opsoclonus-myoclonus-ataxia syndrome: Experience from a tertiary care university hospital.

BACKGROUND: Opsoclonus-myoclonus-ataxia syndrome (OMAS) is a rare disorder; there is limited experience regarding its clinical course and therapeutic response. AIMS AND OBJECTIVES: To describe the clinical profile, investigations, and therapeutic outcome in pediatric OMAS. PATIENTS AND METHODS: Fourteen children (age: 27.1 ± 7 months; male: female = 1:2.3) suffering from OMAS seen over a period of 10 years (2006-2015) were included in the study. Their clinicodemographic profile, investigations, therapeutic outcome at follow-up, and relapses were reviewed. RESULTS: Ten children reported antecedent events (respiratory infection: 7; gastrointestinal infection: 1; vaccination: 2). The most common referral diagnosis was acute cerebellitis (n = 8). Hypotonia (n = 9), abnormal behavior (n = 10), and neuroregression (n = 6) were also the frequent manifestations. Brain magnetic resonance imaging, cerebrospinal fluid, and urinary vanillylmandelic acid were normal in all the patients. Seven patients had an underlying tumor (abdomen: 4; thorax: 2; neck: 1) detected by ultrasound (n = 2/14), computed tomography (CT) (n = 6/12), and fluorodeoxyglucose - positron emission tomography (n = 2/2). CT scan identified the tumor in 2 patients where metaiodobenzylguanidine scintigraphy was negative. All patients received steroids for 22.3 ± 20 months (3 months to 5 years). Eight required prolonged immunomodulation (>12 months). Complete remission after follow-up of 31.3 ± 19 months (7 months to 5 years) was noted in 5 patients, whereas the rest had persisting behavioral and cognitive abnormalities. Relapses were noted in 6 patients related to intercurrent infections (n = 5) and discontinuation of steroids (n = 1). The patients presented with isolated symptoms of the full-blown syndrome during their relapses. CONCLUSION: OMAS in children runs an indolent course requiring careful monitoring and long-term immunomodulation. An abnormal behavior is common and the outcome is variable.

Palatal Tremor Revisited: Disorder with Nosological Diversity and Etiological Heterogeneity.

This case series aimed to describe clinicoradiological, electromyographic, and etiological spectra in palatal tremor (essential=1; symptomatic=26). Patients with symptomatic palatal tremor had 2 to 10 Hz arrhythmic electromyographic bursts, a spectrum of changes in inferior olivary nucleus, with/without lesions in Guillain Mollaret triangle, and varied etiologies (genetic=9, vascular=6, trauma=3, infections=3). Exome sequencing showed variations in POLG, WDR81, NDUFS8, TENM4, and EEF2. Clinical phenotypes of patients with POLG, WDR81, and NDUFS8 variations were consistent with that described in literature. We highlight salient magnetic resonance imaging features, electrophysiological observations, and diverse etiologies in a large cohort of palatal tremor.

Novel magnetic resonance imaging findings in a patient with short chain acyl CoA dehydrogenase deficiency.

Reports on magnetic resonance imaging findings in patients with short chain acyl -Coenzyme A dehydrogenase (SCAD) deficiency, an autosomal recessive disorder caused by mutations in the acyl-Coenzyme A dehydrogenase (ACADS), are limited. Many asymptomatic carriers of ACAD variants have also been described necessitating careful evaluation of clinical and biochemical findings for an accurate diagnosis. Here we report a an infant with short chain acyl -Coenzyme A dehydrogenase (SCAD) deficiency diagnosed based on the characteristic biochemical findings and confirmed by genetic testing. He presented with refractory seizures and neuro regression at 4 months of age. His metabolic work up revealed elevated butyryl carnitine in plasma and ethyl malonic acid in urine. Magnetic resonance imaging of the brain showed cortical and basal ganglia signal changes with cortical swelling. Serial scans showed progression of the lesions resulting in cystic leukomalacia with brain atrophy. Exome sequencing revealed a novel homozygous nonsense variation, c.1146C > G (p.Y382Ter) in exon ten of ACADS which was further validated by Sanger sequencing. Both parents were heterozygous carriers. Follow up at 15 months showed gross psychomotor retardation and refractory seizures despite being on optimal doses of anti-epileptic medications, carnitine and multivitamin supplementation. This report expands the phenotypic and genotypic spectrum of SCAD deficiency.

Fatal Morvan Syndrome Associated With Myasthenia Gravis.

INTRODUCTION: Morvan syndrome is a rare and complex autoimmune disorder affecting multiple sites of neuraxis. CASE REPORT: We present fulminant Morvan syndrome, developing on a background of chronic myasthenia gravis. A 54-year-old gentleman presented with fluctuating ophthalmoplegia and proximal muscles weakness of 7 years duration that remitted with pyridostigmine and prednisolone. He developed insomnia of 2 months duration, worsening of myasthenic symptoms and respiratory distress, dysautonomia, encephalopathy, and peripheral nerve hyperexcitability. Antibodies against contactin-associated protein (CASPR) 2 were detected in serum. Computed tomography of thorax showed a thymic mass. He received intravenous methyl prednisolone and plasmapheresis. Antibodies against CASPR and thymic lesion reduced with immunotherapy. However, he developed persistent hypotension and expired after 11 weeks of hospital stay. CONCLUSIONS: Clinical clues for diagnosis of Morvan syndrome and therapeutic changes faced by the treating team are highlighted in this report. Increased awareness and prompt testing for CASPR2 antibody is warranted so that early immunotherapy can be initiated.

Hypersomnolence-hyperkinetic movement disorder in a child with compound heterozygous mutation in 4-aminobutyrate aminotransferase (ABAT) gene.

Deficiency of gamma-amino-butyrate aminotransferase (ABAT) is a rare inherited disorder. A six-month-old girl presented with hyper-somnolence, hyperkinetic movements of distal extremities during wakefulness, hypotonia, bi-pyramidal signs, and impaired response to sound and visual stimuli. Brain MRI at five months showed restricted diffusion along the internal capsule and genu of corpus callosum. A follow up MRI at 18months, showed hyperintensities in brainstem, external and internal capsule, 'trilaminated' appearance of posterior limb of internal capsule and dysmyelination of sub-cortical white matter. MRS showed a peak between 2.2ppm and 2.4ppm, corresponding to glutamine, glutamate and GABA. EEG was normal at six months but showed multifocal epileptiform discharges at 18months. Targeted exome sequencing revealed compound heterozygous missense variations in ABAT resulting in its reduced function. We report the novel association of hypersomnolence and hyperkinetic movement disorder with ABAT variations thus expanding the clinical spectrum of this uncommon neuro-metabolic disorder and discuss the emerging role of GABA in pathways regulating sleep-wake cycle and movement disorders.

Huppke-Brendel syndrome in a seven months old boy with a novel 2-bp deletion in SLC33A1.

Huppke -Brendel syndrome is a new addition to the evolving spectrum of copper metabolism defects. It is an autosomal recessive disorder characterized by congenital cataract, impaired hearing, and developmental delay with low copper and ceruloplasmin. It is caused by defects in SLC33A1 that codes for acetyl CoA transporter protein. Reports on variation in this gene causing human disease is extremely scarce and the metabolic link between this gene and copper metabolism is yet to be identified. Here we report a seven months old infant with Huppke-Brendel Syndrome. In addition to the already reported features, he also had hypo pigmented hair and hypogonadism. His magnetic resonance imaging revealed hypo myelination and cerebellar hypoplasia. Clinical exome sequencing revealed a homozygous two base pair deletion, c.542_543delTG (p.Val181GlyfsTer6) in exon 1 of the SLC33A1. This report expands the phenotypic and genotypic spectrum of Huppke Brendel syndrome.

Clinical Features, Therapeutic Response, and Follow-Up in Pediatric Anti-N-Methyl-D-Aspartate Receptor Encephalitis: Experience from a Tertiary Care University Hospital in India.

AIM: To describe the clinical features in pediatric anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis with specific reference to the spectrum of involuntary movements, and therapeutic response to pulsed intravenous methyl prednisolone. METHOD: A total of 13 children with anti-NMDAR antibody positivity were evaluated. RESULTS: Abnormal behavior, global regression, and seizures were universal. Movement disorder was characterized by hyperkinetic large amplitude, complex, multidirectional movements involving the limbs and orofacial musculature. Electroencephalogram was abnormal in all during the acute phase. All received intravenous methyl prednisolone. Plasmapheresis (n = 6) and intravenous immunoglobulin (n = 2) were administered due to subtherapeutic response during the acute illness. Monthly pulsed methyl prednisolone was administered to maintain remission. All improved substantially from the acute illness which was reflected in the modified Rankin score. Ten patients were followed up for a median duration of 10.30 ± 6.7 months. Residual symptoms included hypersomnolence, hyperphagia, hyperactivity, overfamiliarity, among others. Three had recurrence of partial syndrome that was related to delay in pulsed methyl prednisolone therapy. They improved and maintained improvement with reinitiation of pulsed methyl prednisolone therapy. CONCLUSION: Anti-NMDAR encephalitis requires prolonged immunomodulatory therapy. Intravenous pulsed methyl prednisolone therapy is beneficial in inducing and maintaining remission. It is safe, effective, and well tolerated by children with anti-NMDAR encephalitis. The duration of treatment required for sustained remission and cure needs to be determined in long-term studies.