Unmasking bipolarity in recurrent depressive disorder following herpes simplex virus triggered n-methyl-D-aspartate encephalitis.

OBJECTIVE: Herpes simplex virus (HSV) infection triggered n-methyl-D-aspartate (NMDA) encephalitis can lead to varied neuropsychiatric manifestations, including movement disorders and manic symptoms. HSV is known to affect the same brain regions as in secondary mania. METHOD: We present a 35-year-old female diagnosed with recurrent depressive disorder (RDD) who developed NMDA encephalitis triggered by HSV infection. RESULT: HSV-triggered NMDA encephalitis led to a manic switch in a woman with RDD on antidepressants, along with the new onset of dyskinetic movements. CONCLUSION: A neurological insult predisposed our patient to the variable effects of antidepressant drugs.

Sexual dysfunction in men with young onset Parkinson's disease.

Sexual dysfunction (SD) is a common, yet under-reported non-motor symptom of PD. Common sexual symptoms among male PD patients include erectile dysfunction, premature ejaculation, and decreased sexual desire. Few research papers have examined sexual dysfunction in PD, especially in YOPD male patients, and there is no Indian research study on sexual dysfunction in YOPD. In this study, we determined the frequency of sexual dysfunction in men with YOPD, and its correlation with other motor and NMS. This prospective cross-sectional study was conducted on YOPD males who presented to the Department of Neurology, NIMHANS, Bangalore, India, from May 2021 to April 2023. The diagnosis of YOPD was made based on MDS criteria for IPD 2015. Sexual functions were evaluated by ASEX, PEDT, QUIP-RS, and sex hormone assay. The patients also underwent other motor and non-motor assessments. Statistical analysis was done using SPSS version 22.0. The study was funded by the PDMD fund. This study included 62 male YOPD patients. The mean age of cases was 44.74 ± 8.54 years. The mean duration of symptoms was 8.45 ± 6.23 years. 43.5% of the cases of PD were Akinetic rigid type. By ASEX Score grading, 46.8% of the cases had erectile dysfunction and 71% of the cases of YOPD had premature ejaculation by PEDT Score grading. 9.7% of the cases had hypersexuality by QUIP-RS. Duration of YOPD was a better predictor of Erectile Dysfunction and premature ejaculation when compared with other variables. SD was related to anxiety and depression and it had a negative impact on the patient's health-related quality of life (HR-QoL). SD should be investigated and treated as an integral part of the neurological assessment in YOPD.

Morphometric alterations of the mesocorticolimbic network in Parkinson's disease with impulse control disorders.

Impulse control disorders (ICDs) are a group of non-motor symptoms of Parkinson disease (PD) leading to significant psychosocial detrimental outcome. The mesocorticolimbic network plays a distinctive role in reward learning and executive decision making and has been suggested to be involved in ICDs in PD. To study morphometric changes of the mesocorticolimbic network in PD with ICD. A total of 18 patients of PD with ICD (PD + ICD), 19 patients of PD without ICD (PD - ICD) and 19 healthy controls (HC) were included in the study. ICDs were diagnosed using Questionnaire for Impulsive-Compulsive Disorders in PD-Rating Scale (QUIP-RS). MRI was done using a 3T scanner and assessment of cortical thickness and subcortical volumes were done using FreeSurfer. Brain regions known to be part of the mesocorticolimbic network were extracted and included for statistical analysis. There was no difference between PD + ICD and PD - ICD with regard to duration of illness or total dopaminergic medication. In comparison to HC, patients with PD + ICD demonstrated atrophy of the left frontal pole, and this atrophy neared significance in comparison to PD - ICD. The QUIP-RS had a negative correlation with left caudate volume in PD + ICD. The PD + ICD group showed distinct morphometric changes in regions involved in the mesocorticolimbic system which may contribute to the presence of ICD.

Ventrolateral medullary compression by vascular contact in primary hemifacial spasm: a radiological analysis.

BACKGROUND: The neurovascular conflict (NVC) causing hemifacial spasm (HFS) can also cause compression of ventrolateral medulla (VLM) which contains the central sympathetic neurons. VLM compression has been associated with hypertension. Whether the VLM compression in HFS patients is associated with hypertension is not clear. OBJECTIVE: To determine the frequency, severity of VLM compression and its association with hypertension in HFS patients. METHODS: A cross-sectional, hospital-based, case control study and recruited 120 study subjects (50 cases of primary HFS, 30 hypertensive and 40 normotensive age-, sex- matched controls). The VLM compression was assessed in magnetic resonance imaging Constructive Interference in Steady State (CISS) 3D sequences. RESULTS: Hypertension was present in 30 cases (60%). Six patients with HFS (20%) were detected to be hypertensive after the onset of HFS. VLM compression was seen in 24 cases (48%), 7 hypertensive controls (23.3%) and 5 normotensive controls (10%) (p = 0.03). Twenty-four patients with hypertension had VLM compression and remaining 6 patients with hypertension did not have VLM compression (80% vs 20%; p = 0.02). Normotensive patients did not have VLM compression. Vertebral artery was the most common artery causing VLM compression (22 patients; 7 hypertensive and 5 normotensive controls). CONCLUSION: VLM compression is more common in HFS patients as compared to hypertensive and normotensive controls. It is more common in hypertensive HFS patients in comparison with normotensive HFS patients. Microvascular decompression is an option in hypertensive HFS patients with VLM compression if the hypertension is medically refractory.

Deep brain stimulation in pediatric dystonia: calls for therapeutic realism over nihilism.

PURPOSE: Pediatric dystonia (PD) has a significant negative impact on the growth and development of the child. This study was done retrospectively to analyze functional outcomes in pediatric patients with dystonia who underwent deep brain stimulation. METHODS: In this retrospective analytical study, all the patients of age less than 18 years undergoing deep brain stimulation (DBS) for dystonia between 2012 and 2020 in a single center were analyzed and their functional outcomes were measured by the Burke-Fahn-Marsden-dystonia-rating-scale (BFMDRS). RESULTS: A total of 10 pediatric patients were included with a mean age of onset, duration of disease, and age at surgery being 5.75 years, 7.36 years, and 13.11 years, respectively, with a mean follow-up of 23.22 months. The mean pre-DBS motor score was 75.44 ± 23.53 which improved significantly at 6-month and 12-month follow-up to 57.27 (p value 0.004) and 50.38 (p value < 0.001), respectively. Limbs sub-scores improved significantly at both the scheduled intervals. There was a significant improvement in disability at 1-year follow-up with significant improvement in feeding, dressing, and walking components. There was a 27.34% and 36.64% improvement in dystonia with a 17.37% and 28.86% reduction in disability at 6 months and 12 months, respectively. There was a positive correlation between the absolute reduction of the motor score and improvement in disability of the patients at 6 months (rho = 0.865, p value 0.003). CONCLUSIONS: DBS in PD has an enormous role in reducing disease burden and achieving a sustainable therapeutic goal.

Novel CWF19L1 mutations in patients with spinocerebellar ataxia, autosomal recessive 17.

Spinocerebellar ataxia, autosomal recessive-17 (SCAR17) is a rare hereditary ataxia characterized by ataxic gait, cerebellar signs and occasionally accompanied by intellectual disability and seizures. Pathogenic mutations in the CWF19L1 gene that code for CWF19 like cell cycle control factor 1 cause SCAR17. We report here two unrelated families with the clinical characteristics of global developmental delay, cerebellar ataxia, pyramidal signs, and seizures. Cerebellar atrophy, and T2/FLAIR hypointense transverse pontine stripes were observed in brain imaging. Exome sequencing identified novel homozygous mutations including a splice acceptor site variant c.1375-2 A > G on intron 12 in a male patient and a single nucleotide variant c.452 T > G on exon 5 resulting in a missense variant p.Ile151Ser in the female patient from two unrelated families, respectively. Sanger sequencing confirmed the segregation of these variants in the family members with autosomal recessive inheritance. Transcript analysis of the splice site variant revealed activation of a novel cryptic splice acceptor site on exon 13 resulting in an alternative transcription with a loss of nine nucleotides on exon 13. Translation of this transcript predicted an in-frame deletion of three amino acids p.(459_461del). We also observed a novel exon 13 skipping which results in premature termination of the protein product. Our study expands the phenotype, radiological features, and genotypes known in SCAR17.

An Illustrative Review of the Pathomechanisms of Symptomatic Developmental Venous Anomalies.

OBJECTIVE: Symptomatic developmental venous anomalies (DVAs) are rare. Here, we illustrate the varied clinicoradiologic profiles of symptomatic DVAs and contemplate the mechanisms that render these (allegedly) benign entities symptomatic supported by a review of literature. METHODS: Institutional databases were searched to identify cases of symptomatic DVAs. Clinical and imaging (angiographic and cross-sectional) data of 9 cases with 11 neurovascular symptoms consequent to inflow/outflow perturbations and mechanical obstruction that manifested because of the strategic topography of underlying DVAs were analyzed. A review of the existing literature on DVAs in agreement with our case series was performed on publications retrieved from the PubMed database. RESULTS: Symptoms secondary to venous hypertension arising from flow-related perturbations were broadly divided into those arising from restricted outflow and increased inflow. Restricted outflow occurred because of collector vein stenosis (n = 2) and collector vein/DVA thrombosis (n = 3), whereas the latter pathomechanism was initiated by arterialized/transitional DVAs (n = 2). A mechanical/obstructive pathomechanism culminating in moderate supratentorial ventriculomegaly was noted in 1 case. One patient was given a diagnosis of hemorrhage associated with a cavernoma. CONCLUSIONS: Awareness and contextualization of potential flow-related perturbations and mechanical insults that render DVAs symptomatic aid in accurate diagnosis, management, and prognostication.

A splice altering variant in NDRG1 gene causes Charcot-Marie-Tooth disease, type 4D.

Charcot-Marie-Tooth disease, type 4D (CMT4D) is a progressive, autosomal recessive form of CMT, characterized by distal muscle weakness and atrophy, foot deformities, severe motor sensory neuropathy, and sensorineural hearing impairment. Mutations in NDRG1 gene cause neuropathy in humans, dogs, and rodents. Here, we describe clinical and genetic features of a 17-year-old male with wasting of hand muscle and foot and severe motor neuropathy. Whole exome sequencing was carried out on the patient and his unaffected parents. We identified a novel deletion of nine nucleotides (c.537 + 2_537 + 10del) on the splice donor site of intron 8 in NDRG1 gene. The Sanger sequencing confirmed the segregation of this mutation in autosomal recessive inheritance. Furthermore, transcript analysis confirmed a splice defect and reveals using of an alternate cryptic splice donor site on the downstream intronic region. It resulted in an insertion of 42 nucleotides to exon 8 of NDRG1. Translation of the resulting transcript sequence revealed an insertion of 14 amino acids in-frame to the existing NDRG1 protein. This insertion is predicted to disrupt an alpha helix which is involved in protein-protein interactions in homologous proteins. Our study expands the clinical and genetic spectrum of CMT4D. The splice defect we found in this patient reveals a novel splice isoform of NDRG1 as the potential cause for the neuropathy observed in this patient.

Pediatric Functional Movement Disorders: Experience from a Tertiary Care Centre.

OBJECTIVES: Functional movement disorders (FMDs) pose significant diagnostic and management challenges. We aimed to study the socioeconomic and cultural factors, underlying psychopathology and the phenomenology of FMDs in children. METHODS: The study is a retrospective chart review of 39 children (16 girls and 23 boys) who attended our neurology OPD and the movement disorders clinic at the National Institute of Mental Health and Neurosciences (NIMHANS) between January 2011 and May 2020. The diagnosis of FMD was based on Fahn and Williams criteria and the patients were either diagnosed as "documented" or "clinically established". All the relevant demographic data including the ethnicity, socioeconomic and cultural background, examination findings, electrophysiological, and other investigations were retrieved from the medical records. RESULTS: The mean age at onset was 12.69 ± 3.13 years. Majority of the children were from urban regions (56.41%) and belonging to low socioeconomic status (46.15%). Thirty (76.92%) were found to have a precipitating factor. Myoclonus was the most common phenomenology observed in these patients (30.76%), followed by tremor (20.51%), dystonia (17.94%), and gait abnormality (7.69%). Chorea (5.12%) and tics (2.56%) were uncommon. Tremor (37.5%) and dystonia (18.75%) were more common in girls, whereas myoclonus (39.13%) was more common in boys. CONCLUSIONS: The symptoms of FMD have great impact on the mental health, social, and academic functioning of children. It is important to identify the precipitating factors and associated psychiatric comorbidities in these children as prompt alleviation of these factors by engaging parents and the child psychiatrist will yield better outcomes.

Overview of management of infection-related movement disorders with focus on specific-infections.

Infections are important treatable causes of secondary movement disorders (MD) that can have heterogeneous presentations. According to various studies, infection-related movement disorders (IRMD) account for around 10-20% of secondary MD. Certain infections have a predilection for causing various MD, and some MD phenomenologies, such as acute cerebellar ataxia and opsoclonus-myoclonus-ataxia syndromes (OMAS), suggest a strong possibility of an underlying infectious cause. The underlying pathophysiology is multifaceted, including direct neuronal damage due to neurotropism, granulomas, abscesses causing structural damage, and inflammatory and autoimmune responses triggered by infections. Understanding the prevalence, spectrum, and pattern of these IRMD and common infections that are responsible helps in early diagnosis, and instituting appropriate, timely treatment, thereby improving the overall prognosis and avoiding unnecessary investigations. In this review, we aim to provide a brief overview of common infections associated with MD, common clinical presentations of IRMD, their underlying pathophysiology, and overall approach to their treatment, with a focus on specific treatments of prevalent and treatable IRMD.

Genetic heterogeneity of early onset Parkinson disease: The dilemma of clinico-genetic correlation.

With advances in genetic testing increasing proportion of early onset Parkinson disease (EOPD) are being identified to have an underlying genetic aetiology. This is can be in the form of either highly penetrant genes associated with phenotypes with monogenic or mendelian inheritance patterns or those genes known as risk factor genes which confer an increased risk of PD in an individual. Both of them can modify the phenotypic manifestation in a patient with PD. This improved knowledge has helped in deciphering the intricate role of various cellular pathways in the pathophysiology of PD including both early and late and even sporadic PD. However, the phenotypic and genotypic heterogeneity is a major challenge. Different deleterious alterations in a same gene can result in a spectrum of presentation spanning from juvenile to late onset and typical to atypical parkinsonism manifestation. Similarly, a single phenotype can occur due to abnormality in two or more different genes. This conundrum poses a dilemma in the clinical approach and in understanding the clinico-genetic correlation. Understanding the clinico-genetic correlation carries even more importance especially when genetic testing is either not accessible or affordable or in many regions both. In this narrative review, we aim to discuss briefly the approach to various PARK gene related EOPD and describe in detail the clinico-genetic correlation of individual type of PARK gene related genetic EOPD with respect to their classical clinical presentation, pathophysiology, investigation findings and treatment response to medication and surgery.

Clinical and genetic profile of patients with dystonia: An experience from a tertiary neurology center from India.

BACKGROUND: The genetics of dystonia have varied across different ethnicities worldwide. Its significance has become more apparent with the advent of deep brain stimulation. OBJECTIVE: To study the clinico-genetic profile of patients with probable genetic dystonia using whole exome sequencing (WES). METHODS: A prospective, cross-sectional study was conducted from May 2021 to September 2022, enrolling patients with dystonia of presumed genetic etiology for WES. The study compared genetically-determined cases harboring pathogenic/likely-pathogenic variants (P/LP subgroup) with the presumed idiopathic or unsolved cases. RESULTS: We recruited 65 patients (males, 69.2%) whose mean age of onset (AAO) and assessment were 25.0 ± 16.6 and 31.7 ± 15.2 years, respectively. Fifteen had pathogenic/likely-pathogenic variants (yield = 23.1%), 16 (24.6%) had variants of uncertain significance (VUS), 2 were heterozygous carriers while the remaining 32 cases tested negative (presumed idiopathic group). The P/LP subgroup had a significantly younger AAO (16.8 ± 12.3 vs 31.3 ± 17.0 years, p = 0.009), longer duration of illness (10.9 ± 10.3 vs 4.8 ± 4.3 years, p = 0.006), higher prevalence of generalized dystonia (n = 12, 80.0% vs n = 10, 31.3%, p = 0.004), lower-limb onset (n = 5, 33.3% vs n = 1, 3.1%, p = 0.009), higher motor (p = 0.035) and disability scores (p = 0.042). The classical DYT genes with pathogenic/likely pathogenic variants included 3 cases each of TOR1A, and KMT2B, and single cases each of SGCE, EIF2AK2, and VPS16. Non-DYT pathogenic/likely-pathogenic cases included PINK1, PANK2, CTSF, POLG, MICU1, and TSPOAP1. CONCLUSIONS: The yield of WES was 23.1% among cases of probable genetic dystonia. Pathogenic or likely pathogenic variants in TOR1A, KMT2B, and SGCE genes were commoner. The absence of family history emphasizes the importance of accurate assessment of clinical predictors before genetic testing.

Clinical and Imaging Profile of Patients with Cerebrotendinous Xanthomatosis - a Video Case Series from India.

Background: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder caused by bi-allelic pathogenic variants in CYP27A1 gene that results in the deposition of cholestanol in the eyes, tendons, soft tissues and nervous system leading to cataracts, xanthomas, and various neuropsychiatric manifestations. The aim of our study is to describe the clinical, radiological and genetic profile of patients with CTX. Methods: This is a retrospective chart review of patients with CTX diagnosed based on classical clinical and radiological findings. The available clinical details, and investigations, including imaging, electrophysiological, pathological and genetic data, were documented. Results: Five patients (4 males) were recruited in the study. The median age at presentation was 32 years (range: 21-66 years). Walking difficulty was the most common symptom at presentation. All patients had cataracts, tendon xanthomas, eye movement abnormalities, dysarthria, pyramidal signs, ataxia and gait abnormality. Dystonia was noted in three patients. Palatal tremor and parkinsonism were noted in one patient each. In MRI brain, dentate, and corticospinal tract involvement were the most frequent imaging findings. Bilateral hypertrophic olivary degeneration was noted in one patient and hot cross bun sign in two. Three patients underwent genetic testing and all had pathogenic variants confirming the diagnosis. Discussion: CTX is a rare treatable disorder. Apart from the usual neurological presentation with spastic-ataxia, it can present at a later age with parkinsonism. Typical patterns of imaging findings are helpful in early diagnosis which aids in the treatment to prevent the neurological sequelae of the disease.

Genetic architecture of a single cohort of 230 Indian Parkinson's Disease patients.

INTRODUCTION: Indian Parkinson's Disease (PD) patients are severely underrepresented in terms of genetic studies and little is known about the frequency of variants and their impact on motor and nonmotor symptoms (NMS). METHODS: This retrospective cross-sectional study was conducted in PD patients undergoing treatment at a tertiary care hospital from India. Patients were advised genetic testing if they had (i) age at onset (AAO) of motor symptoms at or before 50 years (EOPD), (ii) positive family history of PD, parkinsonism or dystonia. All patients underwent whole exome sequencing and potentially pathogenic variants were identified. RESULTS: Clinical and genetic data were available for 230 (163 males, 70.4 %) patients. Thirty-five pathogenic and likely pathogenic variants in various PD genes were identified in 47 patients resulting in a yield of 20.4 %. In the remaining, 82 patients had either variants of uncertain significance or had variants in genes not associated with parkinsonism and 101 patients did not have any non-benign variants. Patients with genetically mediated PD had a lower AAO and statistically greater frequency of dystonia (36.2 %), postural instability (29.8 %) and mood disorder (29.8 %) and a higher Hoehn and Yahr score (2.9). Among the 47 patients, 11 patients had PARK-PRKN, six patients had PARK-PLA2G6, and 22 patients had PARK-GBA1. CONCLUSION: Around one-fifth of early-onset PD can have an underlying monogenetic cause. PARK-GBA1, PARK-PRKN and PARK-PLA2G6 are the commoner causes of genetically mediated PD in India. Patients with genetic cause had an earlier age at onset, and more frequent dystonia, postural instability and dyskinesia.

Quantification and Clinical Correlation of Posterior Cranial Fossa Cerebrospinal Fluid Volume in Primary Hemifacial Spasm Using Magnetic Resonance Imaging.

BACKGROUND AND OBJECTIVE: Primary hemifacial spasm (HFS) is caused by neurovascular conflict (NVC) at the root entry zone of the facial nerve. Whether reduction of posterior cranial fossa (PCF) cerebrospinal fluid (CSF) volume is a risk factor for HFS is not clear. The study aims at the radiologic assessment of PCF CSF volume and its clinical correlation. METHODS: A cross-sectional, hospital-based, case-control study was conducted, in which 50 cases of primary HFS and 50 age- and sex-matched controls were recruited. PCF CSF volume was quantified in 3-T brain magnetic resonance imaging. RESULTS: The mean age at presentation of cases was 50.7 ± 10.7 years (42-69 years) and controls was 52.4 ± 8.7 years (45-68 years). The mean duration of symptoms was 3.5 ± 1.3 years (1.5-8 years). About 52% of patients had grade 2 (mild) severity of HFS. The mean PCF CSF volume of patients was 13,725.1 ± 909.5 mm 3 and controls was 14,458.5 ± 973.5 mm 3 ( P < 0.001). The mean PCF CSF volume of females with HFS was 13,714.8 ± 852.5 mm 3 and female controls was 14,521.8 ± 973.5 mm 3 ( P = 0.006). PCF CSF volume was significantly associated with the presence of HFS ( P = 0.007), the severity of HFS ( P < 0.001), and the presence of NVC ( P = 0.02). CONCLUSION: PCF CSF volume was lesser in HFS patients and was associated with the presence of HFS, the severity of HFS, and the presence of NVC. Females with HFS had smaller PCF CSF volume. Small PCF CSF volume is a risk factor for HFS, particularly in females with HFS.

Association of Insulin-like Growth Factor-1 and Neurofilament Light Chain in Patients with Progressive Supranuclear Palsy.

Background: Progressive supranuclear palsy (PSP) is the most common primary tauopathy. The definite diagnosis of PSP is established by histopathologic changes in the brain. There are no reliable blood-based biomarkers to aid the diagnosis of this fatal disease at an early stage. Also, the precise etiopathology of PSP and its variants is inadequately understood. Objective: Blood-based molecules such as neurofilament light chain (NfL) and insulin-like growth factor-1 (IGF-1) are shown as important markers of neurodegenerative and aging processes, respectively. These two biomarkers have not been analyzed simultaneously in PSP patients. Methods: To address this knowledge gap, 40 PSP patients and equal number of healthy individuals were recruited and serum levels of NfL and IGF-1 were assayed in all the study participants by enzyme-linked immunosorbent assay (ELISA). Motor and nonmotor symptoms were evaluated in PSP patients using various scales/questionnaires. Cardiac autonomic function tests were performed in a subset of patients (n = 27). Results: A significantly high serum level of NfL (P < 0.01) and a reduced level of IGF-1 (P = 0.02) were observed in PSP patients compared to healthy controls. Besides, a negative correlation (r = -0.54, P < 0.01) between NfL and IGF-1 levels was observed in PSP patients. Conclusion: The finding of this study reinforces the important role of blood NfL level as a potential biomarker of PSP. Further, the current study provides novel insights into the reciprocal correlation between NfL and IGF-1 in PSP patients. Combined analysis of blood levels of these two functionally relevant markers might be useful in the prediction and diagnosis of PSP.

Clinico-genetic profile of seven patients with PARK-PINK1: A case series from a tertiary care centre from India and review of literature.

Background: Recessive variants in the PINK1 gene is a known cause of early-onset Parkinson's disease (EOPD). Objective: To describe the clinical features and genetic profile of patients of PARK-PINK1. Methods: Retrospective chart review of demographic, clinical and genetic details of patients carrying biallelic PINK1 variants from our database. Result: Seven cases were recruited with median age at onset 33 years (Range: 20-49). All had asymmetrical onset, tremor in four, abnormal posturing in two and slowness in one patient. Parkinsonism phenotype was noted in six patients (with dystonia in four) and isolated dystonia in one. Among 6 patients with parkinsonism, five had rest tremor, all had good levodopa-response, and four had motor-fluctuation with choreiform-dyskinesia. Exome-sequencing revealed bi-allelic pathogenic/likely pathogenic variants in all of which five were novel. Conclusion: PARK-PINK1 presents as an EOPD with tremor-predominant phenotype, good levodopa-responsiveness, early motor fluctuation and dyskinesia. We describe five novel variants in PINK1 gene.