Clinical Spectrum, Radiological Correlation and Outcome of Movement Disorders in Wilson's Disease.

Introduction: Movement disorders are the commonest clinical presentation in patients with neurological Wilson's disease (NWD). There are very few studies evaluating the spectrum, severity and their correlation with magnetic resonance imaging (MRI) changes of movement disorders in NWD. Objective: To study the spectrum, topographic distribution, radiological correlate, temporal course and outcome in our cohort of NWD patients. Methods: Retrospective chart review of the NWD patients having movement disorders was performed and analyzed. Results: Sixty-nine patients (males- 47) with NWD were analysed and the mean age at the onset of neurological symptoms was 13.6 ± 6.6 years (median 13 years; range 7-37 years). The first neurological symptom was movement disorder in 55 (79.7%) patients. Tremor (43.6%) and dystonia (41.8%) was the commonest movement disorder as the first neurological symptom. Dystonia (76.8%) was the most common overall movement disorder followed by parkinsonism (52.1%) and tremors (47.8%). Chorea (10.1%), myoclonus (1.4%) and ataxia (1.4%) were the least common movement disorder. Putamen was the most common affected site (95.6%) followed by caudate nucleus (73.9%), thalamus (60.8%), midbrain (59.4%), internal capsule (49.2%), pons (46.3%). Putamen was the most common area of abnormality in dystonia (98%), tremors (85%). Caudate (75%) and putamen (75%) was the most common areas of abnormality in parkinsonism. Favourable outcome was observed in 42 patients (60.8%) following treatment. Conclusion: Dystonia is the most common movement disorder in NWD in isolation or in combination with parkinsonism and tremors. Putamen is the most common radiological site of lesions and more frequently affected in patients with dystonia and tremors. Favourable outcome does occur with appropriate medical and surgical treatment.

Spectrum and Pattern of Movement Disorders in Patients with Sporadic Creutzfeldt-Jakob Disease.

Background: Creutzfeldt-Jakob disease (CJD) is a rare neuro degenerative disease that is mainly characterized by rapidly progressive dementia along with a varying combination of myoclonus, visual, cerebellar, pyramidal/extrapyramidal and akinetic mutism. Several movement disorders phenomenologies can occurs either at onset, as presenting symptom or during the course of illness. Present study aims to characterize the clinical, radiological features and the outcome of patients with CJD with movement disorders as the forthcoming manifestation. Methods: Chart review of patients with CJD with movement disorders. Demographic, clinical and radiological details of the patients were reviewed. Results: 25 patients (13 males) of sCJD with median age at presentation of 58 years and median duration of illness of 5 months were included in the study. According to revised CDC diagnostic criteria 1 patient was classified as definite sCJD, 20 as probable and 2 as possible CJD. Myoclonus, ataxia and parkinsonism were the most common movement disorder and chorea was the least common. Magnetic resonance imaging of brain was performed in all and basal ganglia abnormality and cortical ribboning was seen in more than two-third of cases. Electroencephalographic abnormality was noted in 21 patients with triphasic waves and periodic sharp waves seen in 7 and 6 patients respectively. Cerebrospinal fluid 14-3-3 assay was abnormal in 2 out of 4 patients. Atypical presentations were noted in the form of ataxic presentation, CBS like presentation and choreiform presentation. Conclusion: Myoclonus, ataxia and parkinsonism are the most frequent movement disorders phenomenology observed in patients with sCJD.

Clinical, imaging and genetic profile of twenty-four patients with pantothenate kinase-associated neurodegeneration (PKAN)- A single centre study from India.

INTRODUCTION: Pantothenate kinase-associated neurodegeneration (PKAN) is the most common "Neurodegeneration with Brain Iron Accumulation" disorder. This study aimed to study the clinical, radiological and genetic profiling of a large cohort of patients with PKAN. METHODS: This is an ambispective hospital-based single centre study conducted at a tertiary care centre from India. After tabulating the clinical details, appropriate rating scales were applied followed by magnetic resonance imaging brain and exome sequencing. The segregation of the causal variants in the families were analysed using Sanger sequencing. RESULTS: Twenty-four patients (14 males) with a median age at initial examination of 13 years (range: 4-54 years) and age at onset of 8 years (range: 0.5-40 years) were identified. Almost two-thirds (62%) had onset before 10 years. Difficulty walking was the most common presenting symptom (41.6%) and dystonia was the most common extrapyramidal phenomenology (100%) followed by parkinsonism (54.2%). Retinitis pigmentosa was present in 37.5% patients. MRI showed hypo intensity on T2 and SWI sequences in globus pallidus (100%), substantia nigra (70.8%) and red nucleus (12.5%). Eye-of-the-tiger sign was present in 95.8%. Biallelic variants in PANK2 gene was identified in all 20 patients who underwent genetic testing. Among the 18 unique variants identified in these 20 patients 10 were novel. Sanger sequencing confirmed the segregation of the mutation in the available family members. CONCLUSIONS: Wide range of age at onset was noted. Dystonia at presentation, pathognomonic eye-of-tiger sign, and disease-causing variants in PANK2 gene were identified in nearly all patients. Ten novel variants were identified expanding the genotypic spectrum of PKAN.

Disseminated Cysticercosis in Indian Scenario - Experience from a Teaching University Hospital.

Background and Objectives: Neurocysticercosis (NCC) due to Taenia Solium is a major public health problem. Our objective was to study patients with disseminated cysticercosis (DCC) who had NCC in the brain along with an additional site in the body and assess their clinical, radiological profile, and response to therapy. Materials and Methods: A chart review of DCC with a high lesion load of NCC ≥20 (DNCC) in the brain was performed. Results: Sixteen (M:F = 13:3) patients were diagnosed with DNCC with a mean age of presentation of 35.1 ± 14.2 years. Headache was the predominant symptom, followed by seizures (93.75%), vomiting (43.75%), behavioral disturbances (31.25%), fever (12.5%), encephalopathy (12.5%), visual disturbances (6.25%), and muscle pain and limb weakness (6.25%). CT brain showed multiple active parenchymal cysts in all, and calcifications in 68.75%. MRI brain revealed involvement of cortex and subcortical structures in all, followed by cerebellum (81.25%) and brainstem (75%). Intramedullary spinal lesion was observed in 12.5% cases. Albendazole with steroids was used in 15 patients. In 93.3% patients, there was complete improvement in seizures; 12.5% subjects had persistent memory and behavioral abnormalities. One subject required decompressive craniectomy; mortality was observed in two subjects. Conclusions: We hereby report one of the largest case series on disseminated cysticercosis with a high lesion load of NCC in the brain. A comprehensive clinical, imaging, therapeutic response with repeat imaging and long-term follow-up has given us a better understanding of this difficult-to-treat neurological disorder. We suggest cautious use of anti-parasitic therapy under the cover of corticosteroids to prevent irreversible neurological sequelae.

Utility of Clinical Exome Sequencing in Dystonia: A Single-Center Study From India.

OBJECTIVE: With the use of next-generation sequencing in clinical practice, several genetic etiologies of dystonia have been identified. This study aimed to ascertain the utility of clinical exome sequencing (CES) in dystonia and factors suggestive of a genetic etiology. METHODS: This study was a retrospective chart review of patients with dystonia who had undergone CES for the evaluation of dystonia. RESULTS: Forty-eight patients (35 males, 46 families) with dystonia were studied, with a mean age at onset of 16.0 ± 14.1 (1-58) years. A pathogenic/likely pathogenic variant was found in 20 patients (41.7%) among which 14 patients (29.2%) carried a novel variant. CES was more likely to detect a genetic diagnosis in patients with an early age at onset, i.e., ≤ 20 years. CONCLUSION: CES is a useful tool in the diagnostic evaluation of dystonia, with a yield of close to 40%. Patients with an earlier age at onset have a higher likelihood of having dystonia due to a genetic cause than those with a later age at onset.

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.

Long-term Cognitive Outcomes in Tuberculous Meningitis.

OBJECTIVE: Data on cognitive changes in patients with tuberculous meningitis (TBM) are sparse. We aimed to study the cognitive profiles of patients with grade I TBM and correlate them with the cytokine values. METHODS: Prospectively, 60 patients (M:F-31:29) with grade I TBM were recruited. Clinical details were collected; CSF estimation of cytokines, neuropsychological assessment, and correlation were performed. RESULTS: Mean age at presentation was 32.2 years (32.2 ± 10.1), and the duration of symptoms was 29.9 days (29.9 ± 25.9), respectively. Definitive evidence of mycobacterial infection was observed in 28.3% of the patients. Mean levels of tumor necrosis factor-α (TNF-α), interferon (IFN-γ), and interleukin-6 (IL-6) were 11.57 ± 30.35, 197.02 ± 186.64, and 127.03 ± 88.71 pg/mL, respectively. TNF-α levels were significantly elevated in definitive TBM (p = 0.044). Neuropsychological tests revealed an impaired auditory verbal learning test (88.3%), followed by complex figure test (50%), spatial span test (50%), clock drawing test (48.3%), digit span test (35%), color trail tests 1 and 2 (30% and 33.3%, respectively), and animal naming test (28.3%). Elevated levels of IFN-γ and IL-6 in TBM directly correlated with the number of impaired neuropsychological tests. During follow-up, significant improvement was noticed in animal naming test (p = 0.005), clock drawing test (p = 0.003), color trail test 2 (0.02), spatial span test (p = 0.012), and digit span test (0.035). Verbal learning did not show any significant change. Overall, the neuropsychological tests showed better recovery of attention, working memory, and category fluency and showed minimal recovery of verbal learning. CONCLUSIONS: There is subclinical evidence of cognitive impairment in patients with TBM, and this correlated with elevated cytokines. Both the frontal and temporal lobes showed varying degrees of cognitive impairment.

The Spectrum of Movement Disorders in Cases with Osmotic Demyelination Syndrome.

BACKGROUND: Osmotic demyelination syndrome (ODS) can be a central pontine myelinolysis (CPM) and extrapontine myelinolysis (EPM) based on the regions involved even though they share the same disease process, aetiopathogenesis and time course. OBJECTIVES: Present study aims to characterize the clinical, radiological features and the outcome of patients with ODS with movement disorders as the forthcoming manifestation. METHODS: Chart review of patients with ODS with movement disorders. Demographic, clinical and radiological details of the patients were reviewed. RESULTS: Eleven patients (six females; mean age: 48.3 ± 17.6 years) were included in the study. Parkinsonism alone and parkinsonism with dystonia was noted in four patients each (36.4%) while dystonia alone was noted in the other 3 (27.3%). Five patients (45.5%) had postural tremors. While 5 patients had dystonia early in the course of illness (3-7 days), it was delayed (6-9 months) in the other 2. A triphasic course was noted in two patients. The first phase of hyponatremia induced neurological impairment was followed by a second phase of worsening due to the immediate effect of ODS and a third delayed phase of worsening due to delayed effect of ODS. MRI showed both EPM and CPM in eight patients, EPM alone in two patients and CPM alone in 1 patient. Nine patients had a good outcome with mRS < 3. CONCLUSION: Parkinsonism and dystonia are important manifestations of ODS. Triphasic course with a delayed phase of worsening of movement disorders is probably due to the maladaptive neuronal repair. The concept of triphasic ODS is first being described in our series.

Clinical and Imaging Profile of Patients with Palatal Tremor.

BACKGROUND: Palatal tremor (PT) is an uncommon movement disorder that may be classified into symptomatic (SPT) or essential (EPT). The etiology of SPT is varied, with involvement of the Guillain-Mollaret triangle (GMT) and inferior olivary hypertrophy. EPT is associated with ear clicks and normal imaging and may have a functional basis. OBJECTIVES: This study aims to explore the clinical and radiological features of a large cohort of patients with PT. METHODS: This is a retrospective chart review of patients with PT who were evaluated by the movement disorders subspeciality of the neurology department. Demographic, clinical, and imaging details of patients with PT were documented. RESULTS: A total of 22 patients with PT comprising 17 with SPT and 5 with EPT were included in this study. No patient was aware of the PT. Ear clicks were reported in 2 patients with SPT and in 3 patients with EPT. The most common etiology for SPT was vascular, followed by degenerative conditions. Patients with SPT had associated features such as tremor (70.6%), ataxia (64.7%), dystonia (52.9%), myoclonus (17.6%), and eye movement abnormalities (75%). Lesions involving the GMT were found in 82% of patients with SPT. Apart from PT, patients with EPT had no other motor symptoms, and imaging was normal. Of the patients with EPT, 2 had additional functional movement disorders. CONCLUSION: PT has significant etiological heterogeneity and can be easily missed because of the lack of awareness by patients. Involvement of the inferior olivary nucleus may not be necessarily observed. A functional etiology should be considered in cases of EPT.

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.

Myelin oligodendrocyte glycoprotein-antibody-associated disorder: a new inflammatory CNS demyelinating disorder.

BACKGROUND AND AIMS: Myelin oligodendrocyte glycoprotein (MOG) is an oligodendrocytopathy resulting in demyelination. We aimed to determine the frequency of MOG-associated disorders (MOGAD), its various clinical phenotypes, and imaging characteristics. METHODS: All patients with MOGAD were included. Description of the various clinical phenotypes, investigation profile, therapeutic response, differences between pediatric and adult-onset neurological disorders, determination of poor prognostic factors was done. RESULTS: The study population consisted of 93 (M:F = 45:48) (Pediatric:40, Adult-onset:47, Late-onset:7) patients with a median age of 21 years. Among the 263 demyelinating episodes; 45.8% were optic neuritis (ON), 22.8% were myelopathy, 17.1% were brainstem, 7.6% were acute demyelinating encephalomyelitis(ADEM), 4.2% were opticomyelopathy and 2.3% with cerebral manifestations. There was exclusive vomiting in 24.7% prior to onset of clinical syndrome, none of them had area postrema involvement. ADEM was exclusively seen in pediatric patients. Poor prognostic indicators included: (i) incomplete recovery from an acute attack, (b) brainstem syndrome, (c) ADEM with incomplete recovery, (d) MRI suggestive of leukodystrophy pattern, (e) severe ON, (f) ADEMON. CONCLUSIONS: The Spectrum of MOG-associated disorders is wider affecting the brain (grey and white matter) and the meninges. There are various clinical phenotypes and MRI patterns, recognition of which may help in the determination of therapeutic strategies, and long-term prognosis.

Flow injection ionization-tandem mass spectrometry-based estimation of a panel of lysophosphatidylcholines in dried blood spots for screening of X-linked adrenoleukodystrophy.

BACKGROUND: Elevated blood C26:0 lysophosphatidylcholine (LPC) is a diagnostic marker for X-linked adrenoleukodystrophy (X-ALD). Our aim was to develop a flow injection ionization-tandem mass spectrometry (FIA-MS/MS) method for estimating a panel of LPCs (C20:0-C26:0-LPCs) in dried blood spots (DBS) and to determine the sensitivity and specificity of this method for high-throughput screening for X-ALD. METHODS: LPCs (C20:0-C26:0) were extracted from 3.2 mm DBS in a 96-well plate, spiked with isotopically-labelled internal standard (C26:0-d4-LPC) and measured by FIA-MS/MS in electrospray ionization (ESI)-positive, multiple reaction monitoring (MRM) mode using a triple quadrupole, tandem mass spectrometer. The sensitivity and specificity of the FIA-MS/MS method for screening of X-ALD was determined. The FIA-MS/MS method was compared with the LC-MS/MS method for estimating LPC concentrations. RESULTS: Elevated C26:0 and C24:0-LPCs were 100% sensitive for identification of X-ALD. However, specificity was only 78.33% for C26:0 and 98.33% for C24:0-LPCs. Sensitivity for C22:0 and C20:0 LPCs were 89.29%, 78.33% and specificity, 67.86% and 73.33%, respectively. The FIA-MS/MS method showed good concordance with the LC-MS/MS method. CONCLUSION: The FIA-MS/MS method for estimating C26:0 and C24:0-LPCs in DBS is suitable for first-tier screening of newborns for X-ALD. Second-tier confirmatory testing is required to screen positive cases.

Liquid chromatography-tandem mass spectrometry method for estimation of a panel of lysophosphatidylcholines in dried blood spots for screening of X-linked adrenoleukodystrophy.

BACKGROUND: Elevated C26:0-lysophosphatidylcholine (LPC) is used as a biomarker to screen newborns for X-linked adrenoleukodystrophy (X-ALD), an inherited peroxisomal disorder. Our aim was to develop a liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based assay for estimating a panel of LPCs (C20:0, C22:0, C24:0 and C26:0) from dried blood spots (DBS) and to evaluate its sensitivity and specificity for identification of X-ALD in clinically suspected cases. METHODS: LPCs (C20:0 - C26:0) were extracted from 3.2 mm DBS, spiked with an isotopically labelled internal standard (C26:0-d4-LPC) in a 96-well plate, and measured by LC-MS/MS in electrospray ionization positive, multiple reaction monitoring mode. The sensitivity and specificity of the method was evaluated in 21 patients diagnosed with X-ALD and 375 healthy controls. RESULTS: Elevated C26:0 and C24:0-LPCs were 100% sensitive and specific for identification of X-ALD. The sensitivity and specificity of elevated C26:0/C20:0, C26/C22:0, C24:0/C20:0 and C24/C22:0-LPCs were > 80% and 70%, respectively. CONCLUSION: The LC-MS/MS method for estimating LPCs in DBS can be used to identify X-ALD in clinically suspected patients. Further large-scale studies to determine the pre-analytical variables and to define age- and gender-specific reference ranges in various ethnic groups are warranted before introducing this method for high-risk screening in India.

Is pruritus an indicator of aquaporin-positive neuromyelitis optica?

BACKGROUND: Recently, pruritus has been recognised as an important association with neuromyelitis optica spectrum disorders (NMOSD). OBJECTIVE: To determine the clinical and radiological characteristics of patients with NMOSD and pruritus. METHODS AND RESULTS: Among 57 consecutive patients with NMOSD, 15 (26.3% women) reported pruritus. All had aquaporin-4 (AQP4) antibodies. The mean age was 34.5 ± 9.1 years, age at onset was 31.3 ± 11.0 years and the duration of illness was 3.9 ± 3.1 years. Pruritus preceded the neurological disturbances in all the patients. Predominant patients experienced pruritus in the cervical dermatome (66.7%) followed by cervicothoracic region (13.3%), trigeminal nerve (13.3%) and lumbar region (6.7%). Lesions extending from cervicomedullary junction up to the thoracic segment was the most common site of affection (40%) followed by cervicothoracic (26.7%), cervicomedullary junction to cervical cord (13.3%), cervical cord (6.7%) and thoracic segment (6.7%). CONCLUSION: This report is one of the largest series reporting the close association of pruritus with onset of neurological symptoms in NMOSD. It highlights the importance of recognising this rare symptom which may help in making a correct diagnosis in a patient with suspected demyelinating disorder. In a patient with NMOSD, early treatment with immunomodulation during pruritus may prevent or minimise occurrence of neurological dysfunction.

Whole exome sequencing in an Indian family links Coats plus syndrome and dextrocardia with a homozygous novel CTC1 and a rare HES7 variation.

BACKGROUND: Coats plus syndrome is an autosomal recessive, pleiotropic, multisystem disorder characterized by retinal telangiectasia and exudates, intracranial calcification with leukoencephalopathy and brain cysts, osteopenia with predisposition to fractures, bone marrow suppression, gastrointestinal bleeding and portal hypertension. It is caused by compound heterozygous mutations in the CTC1 gene. CASE PRESENTATION: We encountered a case of an eight-year old boy from an Indian family with manifestations of Coats plus syndrome along with an unusual occurrence of dextrocardia and situs inversus. Targeted resequencing of the CTC1 gene as well as whole exome sequencing (WES) were conducted in this family to identify the causal variations. The identified candidate variations were screened in ethnicity matched healthy controls. The effect of CTC1 variation on telomere length was assessed using Southern blot. A novel homozygous missense mutation c.1451A > C (p.H484P) in exon 9 of the CTC1 gene and a rare 3'UTR known dbSNP variation (c.*556 T > C) in HES7 were identified as the plausible candidates associated with this complex phenotype of Coats plus and dextrocardia. This CTC1 variation was absent in the controls and we also observed a reduced telomere length in the affected individual's DNA, suggesting its likely pathogenic nature. The reported p.H484P mutation is located in the N-terminal 700 amino acid regionthat is important for the binding of CTC1 to ssDNA through its two OB domains. WES data also showed a rare homozygous missense variation in the TEK gene in the affected individual. Both HES7 and TEK are targets of the Notch signaling pathway. CONCLUSIONS: This is the first report of a genetically confirmed case of Coats plus syndrome from India. By means of WES, the genetic variations in this family with unique and rare complex phenotype could be traced effectively. We speculate the important role of Notch signaling in this complex phenotypic presentation of Coats plus syndrome and dextrocardia. The present finding will be useful for genetic diagnosis and carrier detection in the family and for other patients with similar disease manifestations.