Novel Immunotherapies for Myasthenia Gravis.

Myasthenia gravis (MG), a prototype autoimmune neurological disease, had its therapy centred on corticosteroids, non-steroidal broad-spectrum immunotherapy and cholinesterase inhibitors for several decades. Treatment-refractory MG and long-term toxicities of the medications have been major concerns with the conventional therapies. Advances in the immunology and pathogenesis of MG have ushered in an era of newer therapies which are more specific and efficacious. Complement inhibitors and neonatal Fc receptor blockers target disease-specific pathogenic mechanisms linked to myasthenia and have proven their efficacy in pivotal clinical studies. B cell-depleting agents, specifically rituximab, have also emerged as useful for the treatment of severe MG. Many more biologicals are in the pipeline and in diverse stages of development. This review discusses the evidence for the novel therapies and the specific issues related to their clinical use.

Resting-State Functional Connectivity in Relapsing-Remitting Multiple Sclerosis with Mild Disability: A Data-Driven, Whole-Brain Multivoxel Pattern Analysis Study.

Background: Multivoxel pattern analysis (MVPA) has emerged as a powerful unbiased approach for generating seed regions of interest (ROIs) in resting-state functional connectivity (RSFC) analysis in a data-driven manner. Studies exploring RSFC in multiple sclerosis have produced diverse and often incongruent results. Objectives: The aim of the present study was to investigate RSFC differences between people with relapsing-remitting multiple sclerosis (RRMS) and healthy controls (HC). Methods: We performed a whole-brain connectome-wide MVPA in 50 RRMS patients with expanded disability status scale ≤4 and 50 age and gender-matched HCs. Results: Significant group differences were noted in RSFC in three clusters distributed in the following regions: anterior cingulate gyrus, right middle frontal gyrus, and frontal medial cortex. Whole-brain seed-to-voxel RSFC characterization of these clusters as seed ROIs revealed network-specific abnormalities, specifically in the anterior cingulate cortex and the default mode network. Conclusions: The network-wide RSFC abnormalities we report agree with the previous findings in RRMS, the cognitive and clinical implications of which are discussed herein. Impact statement This study investigated resting-state functional connectivity (RSFC) in relapsing-remitting multiple sclerosis (RRMS) people with mild disability (expanded disability status scale ≤4). Whole-brain connectome-wide multivoxel pattern analysis was used for assessing RSFC. Compared with healthy controls, we were able to identify three regions of interest for significant differences in connectivity patterns, which were then extracted as a mask for whole-brain seed-to-voxel analysis. A reduced connectivity was noted in the RRMS group, particularly in the anterior cingulate cortex and the default mode network regions, providing insights into the RSFC abnormalities in RRMS.

Clinical Spectrum of Biopsy Proven Mitochondrial Myopathy.

Objectives: Clinical spectrum of mitochondrial myopathy extends beyond chronic progressive external ophthalmoplegia (CPEO). While information on encephalomyopathies is abundant, clinical data on predominant myopathic presentation of mitochondrial disorders are lacking. Materials and Methods: Clinical, electrophysiological, biochemical, and follow-up data of patients with predominant myopathic presentation and muscle biopsy confirmed primary mitochondrial myopathy was obtained. We excluded known syndromes of mitochondrial cytopathies and encephalomyopathies. Results: Among 16 patients, 7 had CPEO, 4 had CPEO with limb-girdle muscle weakness (LGMW), and 5 had isolated LGMW. Systemic features included seizures with photosensitivity (n = 3), diabetes (n = 1), cardiomyopathy (n = 1), and sensorineural hearing loss (n = 1) and were more common in isolated LGMW. Elevated serum creatine kinase (CK) and lactate levels and electromyography (EMG) myopathic potentials were more frequent with LGMW. During follow-up, LGMW had more severe progression of weakness. Conclusion: We identified three subsets of mitochondrial myopathy with distinct clinical features and evolutionary patterns. Isolated LGMW was seen in 30% of patients and would represent severe end of the spectrum.

Genotype-phenotype correlations in valosin-containing protein disease: a retrospective muticentre study.

BACKGROUND: Valosin-containing protein (VCP) disease, caused by mutations in the VCP gene, results in myopathy, Paget's disease of bone (PBD) and frontotemporal dementia (FTD). Natural history and genotype-phenotype correlation data are limited. This study characterises patients with mutations in VCP gene and investigates genotype-phenotype correlations. METHODS: Descriptive retrospective international study collecting clinical and genetic data of patients with mutations in the VCP gene. RESULTS: Two hundred and fifty-five patients (70.0% males) were included in the study. Mean age was 56.8±9.6 years and mean age of onset 45.6±9.3 years. Mean diagnostic delay was 7.7±6 years. Symmetric lower limb weakness was reported in 50% at onset progressing to generalised muscle weakness. Other common symptoms were ventilatory insufficiency 40.3%, PDB 28.2%, dysautonomia 21.4% and FTD 14.3%. Fifty-seven genetic variants were identified, 18 of these no previously reported. c.464G>A (p.Arg155His) was the most frequent variant, identified in the 28%. Full time wheelchair users accounted for 19.1% with a median time from disease onset to been wheelchair user of 8.5 years. Variant c.463C>T (p.Arg155Cys) showed an earlier onset (37.8±7.6 year) and a higher frequency of axial and upper limb weakness, scapular winging and cognitive impairment. Forced vital capacity (FVC) below 50% was as risk factor for being full-time wheelchair user, while FVC <70% and being a full-time wheelchair user were associated with death. CONCLUSION: This study expands the knowledge on the phenotypic presentation, natural history, genotype-phenotype correlations and risk factors for disease progression of VCP disease and is useful to improve the care provided to patient with this complex disease.

A real world multi center study on efficacy and safety of natalizumab in Indian patients with multiple sclerosis.

BACKGROUND: Natalizumab (NTZ) is increasingly being used in Indian multiple sclerosis (MS) patients. There are no reports on its safety and efficacy, especially with respect to the occurrence of progressive multifocal leukoencephalopathy (PML). OBJECTIVES: To describe the patient characteristics, treatment outcomes, and adverse events, especially the occurrence of PML in NTZ-treated patients. METHODS: A multicentre ambispective study was conducted across 18 centres, from Jan 2012 to Dec 2021. Patients at and above the age of 18 years treated with NTZ were included. Descriptive and comparative statistics were applied to analyze data. RESULTS: During the study period of 9 years, 116 patients were treated with NTZ. Mean age of the cohort was 35.6 ± 9.7 years; 83/116 (71.6%) were females. Relapse rate for the entire cohort in the year before NTZ was 3.1 ± 1.51 while one year after was 0.20±0.57 (p = 0.001; CI 2.45 -3.35). EDSS of the entire cohort in the year before NTZ was 4.5 ± 1.94 and one year after was 3.8 ± 2.7 (p = 0.013; CI 0.16-1.36). At last follow up (38.3 ± 22.78 months) there were no cases of PML identified. CONCLUSIONS: Natalizumab is highly effective and safe in Indian MS patients, with no cases of PML identified at last follow up.

Impact of the COVID-19 Pandemic on the Frequency, Clinical Spectrum and Outcomes of Pediatric Guillain-Barré Syndrome in India: A Multicentric Ambispective Cohort Study.

Objective: To study impact of COVID-19 pandemic on frequency, clinical/electrophysiological profile and treatment outcomes in pediatric Guillain-Barré syndrome (GBS). Background: GBS is the most frequent cause of pediatric acute flaccid paralysis. The effect of the COVID-19 pandemic on pediatric GBS is unclear in the literature. Methods: We conducted an ambispective, multicentric, cohort study involving 12 of 27 centres in GBS Consortium, during two periods: pre-COVID-19 (March-August 2019) and during COVID-19 (March-August 2020). Children ≤12 years who satisfied National Institute of Neurological Diseases and Stroke criteria for GBS/variants were enrolled. Details pertaining to clinical/laboratory parameters, treatment and outcomes (modified Rankin Scale (mRS) at discharge, GBS Disability score at discharge and 3 months) were analysed. Results: We enrolled 33 children in 2019 and 10 in 2020. Children in 2020 were older (median 10.4 [interquartile range 6.75-11.25] years versus 5 (2.5-8.4) years; P = 0.022) and had more sensory symptoms (50% versus 18.2%; P = 0.043). The 2020 group had relatively favourable mRS at discharge (median 1 (1-3.5) versus 3 (2-4); P = 0.042) and GBS disability score at 3 months (median 0 (0-0.75) versus 2 (0-3); P = 0.009) compared to 2019. Multivariate analysis revealed bowel involvement (P = 0.000) and ventilatory support (P = 0.001) as independent predictors of disability. No child in 2020 had preceding/concurrent SARS-CoV2 infection. Conclusions: The COVID-19 pandemic led to a marked decline in pediatric GBS presenting to hospitals. Antecedent illnesses, clinical and electrophysiological profile of GBS remained largely unchanged from the pre-pandemic era.

Isolated Myelitis and Intramedullary Spinal Cord Abscess in Melioidosis-A Case Report.

Neuromelioidosis is a severe tropical infection with high morbidity and mortality. Isolated myelitis is an extremely rare manifestation of melioidosis which may evade diagnosis. We report a 69-year-old diabetic male patient who presented with acute flaccid paraplegia and longitudinally extensive myelitis and no systemic symptoms. MRI of spinal cord showed lower dorsal cord and conus T2 hyperintensity and microabscesses with dural enhancement. The diagnosis was clinched with blood culture growing Burkholderia pseudomallei. He rapidly developed colitis, septicemia and multiorgan dysfunction and succumbed to the illness in spite of antibiotics and aggressive supportive care. The case highlights that melioidosis should be considered as a differential diagnosis of infectious myelitis, especially in the tropics. Presence of a neutrophilic blood and cerebrospinal fluid picture and microabscesses in spinal cord are important diagnostic clues. The outcome is dismal unless the diagnosis is considered early in the disease course and managed expeditiously with sensitive antibiotics.

Recurrent painful ophthalmoplegic neuropathy: a cause for recurrent third nerve palsy in a child.

Recurrent painful ophthalmoplegic neuropathy (RPON), previously called ophthalmoplegic migraine, is a rare condition characterised by recurrent episodes of headache and ophthalmoplegia. We report a case of 11-year-old girl with recurrent painful ophthalmoplegia due to isolated right oculomotor nerve involvement. MR brain imaging showed enhancing lesion of cisternal segment of right oculomotor nerve. A possibility of Tolosa Hunt syndrome was considered and she was treated with glucocorticoids, followed by azathioprine due to recurrence. In the fourth episode, she developed migraine headache followed by right third nerve palsy, after which the diagnosis was revised to RPON. She was started on flunarizine along with short-term glucocorticoids. At 1-year follow-up, she remained asymptomatic. RPON should be considered in patients with recurrent third nerve palsy to avoid inadvertent long-term exposure to immunosuppressive agents.

Myoneuropathic presentation of limb girdle muscular dystrophy R8 with a novel TRIM32 mutation.

TRIM 32-related Limb Girdle Muscular Dystrophy (LGMD R8/2H) is a rare genetic muscle disease reported in fewer than 100 patients worldwide. Here, we report a male patient with progressive proximo-distal lower limb weakness with onset in the third decade who had mixed myopathic and neurogenic pattern in electrophysiology and muscle biopsy. Clinical exome sequencing revealed a homozygous pathogenic single base pair insertion in exon 2 of the TRIM32 gene confirming the diagnosis of LGMD R8. This is a novel frameshift mutation and one of the very few cases of LGMD R8 reported from India.

Impact of revascularization therapies on outcome of posterior circulation ischemic stroke: The Indo-US stroke project.

INTRODUCTION: Posterior circulation strokes (PCS) have been less extensively studied than anterior circulation strokes (ACS), especially regarding revascularization therapies. We analyzed the differences in baseline stroke characteristics, revascularization therapy and 3-month outcomes between PCS and ACS in a large prospective multicentre Indian stroke registry. METHODS: Patients with acute ischemic stroke recruited in the Indo-US collaborative stroke project from January 2012 to August 2014 were classified into PCS and ACS based on imaging-confirmed infarct location. Demographics, stroke severity, risk factors, and mechanisms were compared. We further compared these parameters in the subgroups who received revascularization therapies (RT) and no revascularization therapies (NRT). The primary outcome was 3-month modified Rankin scale (mRS). RESULTS: Of 1889 patients (1270 males), 1478 (78.2%) had ACS and 411 (21.8%) PCS. The median NIHSS was lower in PCS (7 vs 11, p < 0.001). Diabetes mellitus and hypertension were more common in PCS and rheumatic heart disease in ACS. Small artery occlusion was higher in PCS (23.8% vs 12.9%, p < 0.001). Only 28 (6.8%) PCS received RT compared to 213 (14.4%) ACS. At 90 days, a good functional outcome (mRS 0-2) was more common in PCS (56.4% vs 45.9%, p < 0.001) in NRT group, while no significant difference was noted in RT group. Stroke territory was not an independent predictor of 3-month outcome in regression analysis. In-hospital mortality was not different between the groups. CONCLUSIONS: The 3-month functional outcome and in-hospital mortality were not different between ACS and PCS. Compared to ACS, PCS received revascularization therapies less often.

Adult-onset subacute sclerosing panencephalitis.

Subacute sclerosing panencephalitis (SSPE) is a lethal slow viral disease of the central nervous system caused by a defective measles virus. The onset is mostly in childhood, manifesting clinically as decline in academic performance, behavioural changes, motor dysfunction and myoclonus. Adult-onset SSPE is rare and can present as rapidly progressive dementia. We present a young man of Indian origin with adult-onset SSPE with rapidly progressive dementia but no localising neurological signs. The diagnostic clues were parieto-occipital white matter changes on MR brain scan and history of childhood fever with rash. High titres of antimeasles antibody in cerebrospinal fluid confirmed the diagnosis. The long latency from primary measles virus infection to symptom onset can be misleading in adults. SSPE should be considered in adults with dementia, especially in tropical countries where vaccination coverage is suboptimal.

Determinants of Suboptimal Outcome Following Thymectomy in Myasthenia Gravis.

BACKGROUND: Response to thymectomy in myasthenia gravis (MG) is influenced by various patient-, disease-, and therapy-related factors. METHODS: Retrospective analysis of 128 patients with MG who underwent maximal thymectomy over 15 years was done to identify the determinants of suboptimal clinical outcome. RESULTS: Among the 128 patients, 62 (48.4%) were females with a mean age of 38.97 (12.29) years. Thymomatous MG occurred in 66 (51.6%). Overall improvement from preoperative status was noted in 88 (68.8%) patients after mean follow-up of 51.68 (33.21) months. The presence of thymoma was the major predictor of suboptimal clinical outcome (P = 0.001), whereas age, gender, preoperative disease severity, and seropositive status did not attain significance. Patients with better outcome had received higher steroid dose preoperatively (P = 0.035). CONCLUSIONS: Suboptimal response after thymectomy occurred in one-third of MG patients, more commonly with thymomatous MG. Relationship of preoperative steroid therapy to remission merits evaluation.

Quantitative susceptibility-weighted imaging in predicting disease activity in multiple sclerosis.

PURPOSE: Repeated use of Gadolinium (Gd) contrast for multiple sclerosis (MS) imaging leads to Gd deposition in brain. We aimed to study the utility of phase values by susceptibility weighted imaging (SWI) to assess the iron content in MS lesions to differentiate active and inactive lesions. METHODS: MS persons who underwent MRI were grouped into group 1 with active lesions and group 2 with inactive lesions based on the presence or absence of contrast enhancing lesions. Phase values of lesions (PL) and contralateral normal white matter (PN) were calculated using the SPIN software by drawing ROI. Subtracted phase values (PS = PL - PN) and iron content (PS/3) of the lesions were calculated in both groups. RESULTS: We analyzed 69 enhancing lesions from 22 patients (group 1) and 84 non-enhancing lesions from 29 patients (group 2). Mean-subtracted phase values and iron content corrected for voxels in ROI were significantly lower in enhancing lesions compared to non-enhancing lesions (p < 0.001). A cut-off value 2.8 µg/g for iron content showed area under the curve of 0.909 with good sensitivity. CONCLUSION: Quantification of iron content using SWI phase values holds promise as a biomarker to differentiate active from inactive lesions of MS.

Clinico-radiological correlation and surgical outcome of idiopathic spinal cord herniation: A single centre retrospective case series.

Context: Idiopathic spinal cord herniation (ISCH) remains an obscure, under recognised but potentially treatable entity among the etiologies of compressive myelopathy.Findings: Here, we present a retrospective case series of eight patients of ISCH with their clinical features, imaging findings and long-term follow up data along with a relevant review of the literature. Mean age at presentation was 36 years with the duration of symptoms ranging from two months to more than thirty years. Contrary to existing data, only two patients in our series had the classical presentation of Brown-Sequard syndrome (n = 2). The clinical spectrum of the presentation was broad with pure spastic quadriparesis (n = 3), girdle sensation (n = 1) and radiculopathy (n = 1), the latter presentation has been unreported for ISCH. The typical radiological picture was seen in all patients. All except one patient was managed conservatively. In the one patient who underwent bilateral dentate ligament excision, there was mild functional improvement on long-term follow-up despite a definite worsening of the radiological picture. Five of the patients had a long-term follow-up with no clinically or functionally significant worsening.Clinical relevance: The current study highlights the wide clinical spectrum and relatively stable natural course of ISCH and reports on hitherto undescribed presentation as radiculopathy.