Clinical and Genetic Heterogeneity of Nuclear Envelopathy Related Muscular Dystrophies in an Indian Cohort.

Introduction: Nuclear envelopathies occur due to structural and/or functional defects in various nuclear envelope proteins such as lamin A/C and lamin related proteins. This study is the first report on the phenotype-genotype patterns of nuclear envelopathy-related muscular dystrophies from India. Methods: In this retrospective study, we have described patients with genetically confirmed muscular dystrophy associated with nuclear envelopathy. Data on clinical, laboratory findings and muscle MRI were collected. Results: Sixteen patients were included with median age at onset of 3 years (range: 1 month - 17 years). Three genes were involved: LMNA (11, 68.75%), EMD (4, 25%) and SYNE1 (1, 6.25%). The 11 patients with LMNA variants were Congenital muscular dystrophy (MDCL)=4, Limb Girdle Muscular Dystrophy (LGMD1B)=4 and Emery-Dreifuss Muscular Dystrophy (EDMD2)=3. On muscle biopsy, one patient from each laminopathy phenotype (n = 3) revealed focal perivascular inflammatory infiltrate. Other notable features were ophthalmoparesis in one and facial weakness in one. None had cardiac involvement. Patients with EDMD1 had both upper (UL) and lower limb (LL) proximo-distal weakness. Cardiac rhythm disturbances such as sick sinus syndrome and atrial arrhythmias were noted in two patients with EDMD1. Only one patient with variant c.654_658dup (EMD) lost ambulation in the 3rd decade, 18 years after disease onset. Two had finger contractures with EMD and SYNE1 variants respectively. All patients with LMNA and SYNE1 variants were ambulant at the time of evaluation. Mean duration of illness (years) was 11.6±13 (MDCL), 3.2±1.0 (EDMD2), 10.4±12.8 (LGMD1B), 11.8±8.4 (EDMD1) and 3 (EDMD4). One patient had a novel SYNE1 mutation (c.22472dupA, exon 123) and presented with UL phenotype and prominent finger and wrist contractures. Conclusion: The salient features included ophthalmoparesis and facial weakness in LMNA, prominent finger contractures in EMD and SYNE1 and upper limb phenotype with the novel pathogenic variant in SYNE1.

Clinical, Radiological, and Genetic Profile of Spinocerebellar Ataxia 12: A Hospital-Based Cohort Analysis.

Introduction: Spinocerebellar ataxia type-12 (SCA12) is a rare form of SCA, most commonly reported from the Indian Agarwal and related families. In this study we describe the clinical, genetic, and radiological characteristics of a sizeable cohort of genetically proven SCA12. Methods: A retrospective chart-review of the genetically confirmed SCA12 patients from our centre. The demographic, clinical, and investigation findings were reviewed. Correlation of expanded repeats length with various demographic and clinical features were studied. Results: A total of 49 patients (34 males, 42 families) were included of which 79.6% belonged to Agarwal community. The mean age at onset and age at presentation were 46.38 ± 11.7 years and 53.16 ± 12.78 years respectively. The most common initial symptom was tremor (73.5%), followed by ataxia (18.4%). At presentation, 95.9% of the patients had tremor with predominant distribution in the bilateral upper limbs (85.7%). At presentation, 73.5% of patients had ataxia and 22.4% had cognitive dysfunction. The mean CAG repeat length in PPP2R2B in the expanded allele was 53.26 ± 6.10 (40-72). The lowest pathogenic expanded repeat sizes in PPP2R2B recorded in our cohort was 40 & 42 repeats from two patients with a consistent clinical phenotype. Another unusual phenotype was the presence of prominent myoclonus. There was no significant correlation between the age at onset of symptoms and the repeat size of CAG repeat. Conclusion: SCA12 is not confined to a single ethnicity. Upper limb tremor and ataxia were the most common presentation. Unusual presentation may cause diagnostic confusion especially when recorded in patients from non-Aggarwal families.

Thymic Lesions in Myasthenia Gravis: A Clinicopathological Study from India.

BACKGROUND AND OBJECTIVES: Thymic pathology is common in Myasthenia Gravis(MG) and plays a crucial role in its pathogenesis and clinical outcome. This study aims to discuss the clinicohistopathological spectrum of thymic lesions in MG. METHODS: In this retrospective study, MG patients who underwent thymectomy from 2011 to 2020 were included. Clinical, radiological, serological, and histopathological details are described. RESULTS: Of 83 patients(F = 45; M = 38), 7(8%) had ocular myasthenia, and the remaining 76(92%) had the generalized form. At onset, the median age was 36 years(M = 44; F = 31). AChR antibody was positive in 71/79 patients. RNST showed decrement response in 68/78 patients. The histopathological study demonstrated thymoma in 44(53%), thymic hyperplasias [32(38%)], involuted thymus [5(6%)], thymic cyst (1) and thymic lipoma (1). WHO grading of thymoma: B2- 48%, AB-18%, B-18%, B3-14%, A-2.3%. In these, capsular infiltration was noted in 11/44, 9 had focal and 2 had diffuse infiltration. Active germinal centers were present in 20/32 patients with thymic hyperplasia and 4/44 with thymoma. Thymomas were predominant in males and thymic hyperplasia in females. The age of onset and antibody positivity rate was higher in thymoma patients. CONCLUSION: In our cohort, there is a female preponderance. Thymoma was the commonest pathology followed by hyperplasia. We observed earlier onset of myasthenia in females. AChR antibody positivity rate was more frequent in thymomas. This study indicates that clinico-radiological evaluation adequately supported by serology and histopathology can effectively recognize the type of thymic pathology that can guide these patients' treatment planning, management, prognosis and follow-up.

Paraneoplastic neurological syndrome: growing spectrum and relevance.

Paraneoplastic neurological syndromes (PNSs) are group of disorders affecting one or multiple parts of the neuroaxis associated with underlying tumors. An antibody or autoantigen-specific cell-mediated immune response against neural antigen expressed in the tumor is the potential etiology for these rare but refractory disorders. In recent years, wide variety of neurological presentations and autoantibodies has been associated with paraneoplastic autoimmunity, leading to formulation of an updated expert consensus PNS diagnostic criteria. Recognition of these phenotypes and use of serological biomarkers may aid neurologists in early diagnosis of PNS cases encountered in the inpatient or outpatient practice. In this review article, we provide an overview of various clinical, radiological, and immunopathological characteristics of PNS. Furthermore, we discuss the updated PNS criteria and increasing recognition of neurological presentations resembling the PNS among patients receiving immune checkpoint inhibitors.

Diaphragmatic ultrasound: Prospects as a tool to assess respiratory muscle involvement in amyotrophic lateral sclerosis.

BACKGROUND: Ultrasonography (USG) of the diaphragm is a promising alternative to pulmonary function tests (PFT) for assessing respiratory function in amyotrophic lateral sclerosis/motor neuron disease (ALS/MND). METHODS: We studied 33 patients fulfilling Awaji criteria (definite = 14; probable = 12; possible = 7) and 33 age and gender-matched controls. Diaphragm thickness was measured using USG at the end of expiration (DTex) and end of inspiration (DTin). The thickness ratio (TR) was calculated as DTin/DTex. The mean age at onset and duration were 49.73 ± 12.7 years and 13.57 ± 9.7 months, respectively. Men = 25 (75.8%); Limb onset ALS/MND = 24 patients (72.7%); bulbar onset = 9 (27.3%). RESULTS: Compared to controls, ALS/MND patients had reduced mean DTex (2.22 ± 0.29 mm vs. 2.02 ± 0.32 mm, p = .012) and DTin (4.0 ± 0.71 mm vs. 3.41 ± 0.38 mm, p < .001). PFTs done in 31 patients showed restrictive abnormality in 80.6%. Significant positive correlation was seen between percentage of predicted forced vital capacity (FVC%) and DTin (p = .009) and TR (p = .037) but not with DTex (p = .852). No significant correlation was seen between diaphragmatic thickness and other PFT parameters or ALSFRS scores. CONCLUSION: The diaphragmatic thickness showed a significant decrease in ALS/MND as compared to controls. End-inspiratory diaphragmatic thickness and TR correlated well with %FVC. Thus, diaphragmatic USG could be a potential alternative to PFTs in assessing respiratory function in ALS/MND patients having the advantage of less patient participation and ease of performing in late stages of ALS/MND.

Muscle ultrasonography in detecting fasciculations: A noninvasive diagnostic tool for amyotrophic lateral sclerosis.

BACKGROUND AND OBJECTIVES: Muscle ultrasound (MUS) is an emerging noninvasive tool to identify fasciculations in amyotrophic lateral sclerosis (ALS). We assessed the utility of MUS in detecting fasciculations in suspected ALS patients. METHODS: Thirty-three patients (25 men) with possible (n = 7), probable (n = 12), or definite ALS according to Awaji criteria were studied. Electromyography was done in biceps brachii, quadriceps, and thoracic paraspinal muscles and MUS in biceps, triceps, deltoid, abductor-digiti-minimi, quadriceps, hamstrings, tibialis anterior, thoracic paraspinal, and tongue muscles. RESULTS: The age at onset and illness duration was 49.73 ± 12.7 years and 13.57 ± 9.7 months, respectively. Limb-onset = 24 patients (72.7%) and bulbar-onset = 9 (27.3%). Totally 561 muscles were examined by MUS. Fasciculations were detected in 84.3% of muscles, 98.4% with and 73% without clinical fasciculations (p < 0.001). Fasciculation detection rate (FDR) by MUS was significantly higher in muscles with wasting (95.6%) than without wasting (77.6%, p < 0.001). Compared with EMG, FDR was significantly higher with MUS in quadriceps (81.8% vs. 51.5%, p = 0.002) and thoracic paraspinal muscles (75.8% vs. 42.4%, p = 0.013). The proportion of patients with definite ALS increased from 42% by clinical examination to 70% after combining EMG and MUS findings. CONCLUSIONS: MUS is more sensitive in detecting fasciculations than electromyography (EMG) and provides a safer, faster, painless, and noninvasive alternative to EMG in detecting fasciculations in ALS.

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.

Clinical, neuroimaging and therapeutic response in AQP4-positive NMO patients from India.

BACKGROUND: Neuromyelitis Optica (NMO) is an autoimmune astrocytopathic disorder due to AQP4 antibodies. OBJECTIVES: To analyse clinical, neuroimaging features in NMO patients and assess the efficacy of various therapeutics. METHODS: AQP4+ve NMO patients were diagnosed based on consensus diagnostic criteria. RESULTS: 101 AQP4+ve NMO patients were seen with female (90) predominance. Adult population (71.3%) formed the larger group followed by pediatric (19.8%) and late-onset (8.9%). Myelopathy (36.2%) was most commonly seen followed by optic neuritis (19.1%), brainstem (17.1%), opticomyelopathy (16.1%), area postrema involvement (10.5%) and encephalopathy (1%). Encephalopathy and brainstem/cerebellar involvement were most common in pediatric population while opticomyelopathy was more common in late-onset patients. Hyperintensities of lower medulla was seen in 67.3% subjects and 49.5% had involvement of obex. Differential T2 hyperintensity of the long segment myelitis was found in 30.7%. Plasmapheresis was given in 71 subjects followed by maintenance therapy. Most of them showed significant improvement with EDSS score of 1 in 30.7%. CONCLUSIONS: Clinical manifestations in AQP4+ve NMO patients may vary depending on the age at onset of illness. MRI features affecting cervicomedullary junction, obex, differential T2 hyperintensities of the spinal cord may form a useful diagnostic clue. Plasmapheresis is helpful in achieving remission along with immunomodulation.