Dysregulated Cerebrospinal Fluid Proteome of Spinocerebellar Ataxia Type 2 and its Clinical Implications.

BACKGROUND: Abnormalities in ataxin-2 associated with spinocerebellar ataxia type 2 (SCA2) may lead to widespread disruptions in the proteome. This study was performed to identify dysregulated proteome in SCA2 and to explore its clinical-radiological correlations. METHODS: Cerebrospinal fluid (CSF) samples from 21 genetically confirmed SCA2 were subjected to shotgun proteome analysis using mass spectrometry (MS) and tandem mass tag (TMT)-based multiplexing. Proteins with at least 1.5-fold change in abundance were identified. Their relative abundance was measured using parallel reaction monitoring (PRM) and correlated against disease-related factors. RESULTS: Eleven proteins were significantly upregulated in SCA2. They belonged to the family of cell adhesion molecules and granins. Their fold changes showed significant clinical, genetic, and radiological correlations. CONCLUSIONS: Significant dysregulation of CSF proteome is seen in SCA2. The dysregulated protein may have potential use in clinical evaluation of patients with SCA2. © 2024 International Parkinson and Movement Disorder Society.

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.

Impact of Non-Motor Symptoms on Quality of Life in Patients with Early-Onset Parkinson's Disease.

BACKGROUND: Early-onset Parkinson's disease (EOPD) refers to patients with Parkinson's disease (PD) whose age at disease onset is less than 50 years. Literature on the non-motor symptoms (NMS) in these patients is very limited in the Indian context. We aimed to study the NMS in patients with EOPD and its impact on the quality of life (QoL). METHODS: We included 124 patients with EOPD with a mean age at disease onset between 21 and 45 years and 60 healthy controls (HC). NMS were assessed using validated scales, and the QoL domains were evaluated using the PD QoL-39 scale (PDQ-39). RESULTS: The mean age at disease onset in EOPD patients was 37.33 ± 6.36 years. Majority of the patients were male (66.12%). The average disease duration was 6.62 ± 5.3 years. EOPD patients exhibited a significantly higher number of NMS per patient (7.97 ± 4.69) compared to HC (1.3 ± 1.39; p < 0.001). The most common NMS reported were urinary dysfunction, body pain, poor sleep quality, constipation, anxiety, depression, cognitive impairment, and REM sleep behavior disorder. The total NMS burden correlated with the QoL measures. Distinctive patterns of QoL subdomain involvement were identified, with sleep/fatigue, mood/cognition, and urinary dysfunction independently influencing QoL metrics. CONCLUSIONS: Our study provides valuable insights into the NMS profile and its impact on QoL in patients with EOPD, addressing an important knowledge gap in the Indian context. By understanding the specific NMS and their influence on QoL, healthcare professionals can develop targeted interventions to address these symptoms and improve the overall QoL.

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.

Clinical characteristics, treatment and long-term prognosis in patients with anti-NMDAR encephalitis.

OBJECTIVES: We aimed to (i) analyse the clinical characteristics, treatment outcome and long-term prognosis of anti-NMDAR encephalitis and (ii) study the differences between paediatric and adult patients. METHODS: This was a chart review of all patients with anti-NMDAR encephalitis. RESULTS: There were 28 patients with 18 patients belonging to the paediatric (<18 years) age group. There was female (94%) preponderance in the paediatric age group, while in adult patients, there was no gender predilection (p=0.006). There was no significant difference in clinical feature, outcome or number of relapses between paediatric and adult population groups. MRI brain was abnormal in 53% of patients. Among the 15 patients with MRI abnormalities at the onset, 53% had poor functional outcome at 1 year, while in 12 patients with normal initial MRI brain, only 8% had poor functional outcome at 1 year (p =0.01). Nearly 53% of patients with abnormal MRI at presentation had at least one clinical relapse within 2 years while in patients with normal MRI at presentation, 15% had a clinical relapse (p=0.037). EEG abnormalities were noticed in 71% of patients; among them, 40 and 15% had poor functional outcome at 1 and 2 years respectively. In comparison, those with normal first EEG at onset, 12% had poor functional outcome at 2 years (p=0.57). CONCLUSIONS: Both paediatric and adult patients presented with similar clinical features but the paediatric population had female preponderance. The functional outcome and number of relapse were comparable in both the paediatric and adult groups. Patients with parenchymal changes on MRI and abnormal EEG showed poorer response compared to those with normal MRI and/or EEG at the onset. Patients have lesser severity of symptoms at relapse than in the first episode. An early diagnosis and treatment are essential for better long-term functional outcome.

Comparison of effectiveness of trihexyphenidyl and levodopa on motor symptoms in Parkinson's disease.

Despite anti-cholinergics being the oldest type of medication used for the treatment of Parkinson's disease (PD), the mechanism of action and exact benefit is unclear. This study compared the effectiveness of trihexyphenidyl (THP) and levodopa (LD) on motor symptoms in patients with PD. Patients with PD who are currently taking or had taken THP were recruited. UPDRS-III was done following overnight medication OFF state and 30 min, 60 min, 90 min, and 120 min after THP (4 mg). After a forty-eight-hour interval, UPDRS-III was assessed one hour after Levodopa/carbidopa (200/50 mg) in an overnight OFF state. Twenty patients with a mean age of 57.9 ± 7.8 years and mean duration of illness of 5.1 ± 3.6 years were recruited. UPDRS-III score reduction (%) with THP was maximum in the tremor sub-score (53.8 ± 22.8) and was significantly better compared to improvement in total-UPDRS-III (27.0 ± 14.7), bradykinesia-UPDRS-III (22.2 ± 27.2), rigidity-UPDRS-III (29.5 ± 28.0) and axial-UPDRS-III (8.1 ± 13.3) sub-score. In comparison, respective LD improvement was 67.1 ± 22.9 (tremor-UPDRS-III), 61.3 ± 14.4 (total-UPDRS-III), 67.9 ± 32.1 (bradykinesia-UPDRS-III), 65.3 ± 25.5 (rigidity-UPDRS-III) and 50.7 ± 16.0 (axial-UPDRS-III). Improvement (%) in tre-UPDRS-III post-THP was comparable to that of post-LD (53.8 ± 22.8 vs. 67.1 ± 22.9, p = 0.057). Those with same or better tremor response with THP had significantly milder baseline tremor severity than those who had better response with LD (tre-UPDRS-III-OFF, 10.0 ± 2.8 vs. 5.8 ± 4.0, p = 0.013). Both THP and LD showed significant improvement in UPDRS-III. With THP, the maximum degree of improvement was in the tremor sub-score and not significantly different to that obtained by LD. Those with better tremor response on THP had milder tremor severity.

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.

Generation of induced pluripotent stem cells (NIMHi015-A) from a Parkinson's Disease patient harbouring a homozygous Exon 3 deletion in the PRKN gene.

The Parkin (PRKN) gene mutation is prevalent in young-onset Parkinson's disease (PD), typically emerging before age 30, accompanied by early motor symptoms. Induced pluripotent stem cells (iPSCs) were derived from peripheral blood mononuclear cells of a PD patient with an exon 3 deletion in PRKN using Sendai-virus reprogramming. PD diagnosis was confirmed via the Unified Parkinson's Disease Rating Scale (UPDRS). Characterization of the iPSC line ensured self-renewal and pluripotency. This resource serves as a valuable platform for drug screening and elucidating the pathophysiology of this mutation, facilitating advancements in PD research.

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 mm3 and controls was 14,458.5 ± 973.5 mm3 (P < 0.001). The mean PCF CSF volume of females with HFS was 13,714.8 ± 852.5 mm3 and female controls was 14,521.8 ± 973.5 mm3 (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.