Myoclonus in patients with COVID-19: Findings of autoantibodies against brain structures in cerebrospinal fluid.

BACKGROUND AND PURPOSE: COVID-19 is associated with multiple neurological manifestations. The clinical presentation, trajectory, and treatment response for three cases of myoclonus during COVID-19 infection, with no previous neurological disease, are decsribed. METODS: Analysis of cerebrospinal fluid from the cases using indirect immunohistochemistry. RESULTS: Antibodies against rodent brain tissue, and similarities in staining patterns were observed, indicating the presence of antineuronal immunoglobulin G autoantibodies targeting astrocytes in the hippocampus. CONCLUSION: Our results demontrate cerebrospinal fluid antineuronal antibodies indicating an an autoimmune involvment in the pathogenesis in COVID-19 associated myoclonus.

Clinically relevant increases in serum neurofilament light chain and glial fibrillary acidic protein in patients with Susac syndrome.

BACKGROUND AND PURPOSE: Serum levels of neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) are promising neuro-axonal damage and astrocytic activation biomarkers. Susac syndrome (SS) is an increasingly recognized neurological condition and biomarkers that can help assess and monitor disease evolution are highly needed for the adequate management of these patients. sNfL and sGFAP levels were evaluated in patients with SS and their clinical relevance in the relapse and remission phase of the disease was assessed. METHODS: As part of a multicentre study that enrolled patients diagnosed with SS from six international centres, sNfL and sGFAP levels were assessed in 22 SS patients (nine during a relapse and 13 in remission) and 59 age- and sex-matched healthy controls using SimoaTM assay Neurology 2-Plex B Kit. RESULTS: Serum NfL levels were higher than those of healthy controls (p < 0.001) in SS patients and in both subgroups of patients in relapse and in remission (p < 0.001 for both), with significantly higher levels in relapse than in remission (p = 0.008). sNfL levels showed a negative correlation with time from the last relapse (r = -0.663; p = 0.001). sGFAP levels were slightly higher in the whole group of patients than in healthy controls (p = 0.046) and were more pronounced in relapse than in remission (p = 0.013). CONCLUSION: In SS patients, both sNFL and sGFAP levels increased compared with healthy controls. Both biomarkers had higher levels during clinical relapse and much lower levels in remission. sNFL was shown to be time sensitive to clinical changes and can be useful to monitor neuro-axonal damage in SS.

White matter abnormalities in a patient with visual snow syndrome: New evidence from a diffusion tensor imaging study.

BACKGROUND: Visual snow syndrome (VSS) is a neurological condition characterized by flickering dots throughout the entire visual field. Both the pathophysiology and possible location of VSS are still under debate. White matter abnormalities were investigated using diffusion tensor imaging (DTI) in a patient with VSS. METHODS: A 28-year-old patient with VSS and 10 healthy controls were investigated with DTI. Diffusion parametric maps were calculated and reconstructed using q-space diffeomorphic reconstruction. White matter pathways of the dorsal, ventral, integrative visual streams and thalamic connectivity were tracked. Then, they were applied to each subject's parameter map, stretched to the same length, and sampled along the tracts for regional analyses of DTI parameters. RESULTS: Compared with healthy controls, our patient displayed higher axial diffusivity (AD) and radial diffusivity (RD) in the dorsal visual stream (cingulum, arcuate fasciculus, horizontal indirect anterior segment of the superior longitudinal fasciculus), in the ventral visual stream (fronto-occipital fasciculus, inferior longitudinal fasciculus) and in the integrative visual stream (indirect posterior component of the superior longitudinal fasciculus, vertical occipital fasciculus). Higher AD and RD were also detected in acoustic and optic radiations, and in thalamic radiations distal to the thalamus. CONCLUSION: This VSS patient displayed multiple, bilateral white matter changes in the temporo-parieto-occipital junction in white matter pathways related to vision. We encourage the study of white matter pathology using DTI in complex neurological syndromes including VSS.

Can diffusion tensor imaging (DTI) outperform standard magnetic resonance imaging (MRI) investigations in post-COVID-19 autoimmune encephalitis?

Background: Neurological and psychiatric manifestations related to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection are widely recognised. Standard magnetic resonance imaging (MRI) investigations are normal in 40-80% of symptomatic patients, eventually delaying appropriate treatment when MRI is unrevealing any structural changes. The aim of this study is to investigate white matter abnormalities during an early stage of post-COVID-19 (coronavirus disease 2019) encephalitis while conventional MRI was normal. Methods: A patient with post-COVID-19 autoimmune encephalitis was investigated by serial MRIs and diffusion tensor imaging (DTI). Ten healthy control individuals (HC) were utilised as a control group for the DTI analysis. Major projection, commissural and association white matter pathways were reconstructed, and multiple diffusion parameters were analysed and then compared to the HC average using a z-test for serial examinations. Results: Eleven days after the onset of neurological symptoms, DTI revealed early white matter changes, compared with HC, when standard MRI was normal. On day 68, DTI showed multiple white matter lesions compared with HC, visible at this time also by the MRI images, indicating inflammatory changes in different association and projection white matter pathways. Conclusion: We confirm a limitation in the sensitivity of conventional MRI at the acute setting of post-COVID-19 autoimmune encephalitis. A complementary DTI investigation could be a valuable diagnostic tool in early therapeutic decisions concerning COVID-19-related neurological symptoms.

Efficacy and Safety of Rituximab for New-Onset Generalized Myasthenia Gravis: The RINOMAX Randomized Clinical Trial.

Importance: Rituximab is a third-line option for refractory generalized myasthenia gravis (MG) based on empirical evidence, but its effect in new-onset disease is unknown. Objective: To investigate the efficacy and safety of rituximab compared with placebo as an add-on to standard of care for MG. Design, Setting, and Participants: This randomized, double-blind, placebo-controlled study took place throughout 48 weeks at 7 regional clinics in Sweden. Key inclusion criteria were age older than 18 years, onset of generalized symptoms within 12 months or less, and a Quantitative Myasthenia Gravis (QMG) score of 6 or more. Patients were screened from October 20, 2016, to March 2, 2020. Key exclusion criteria included pure ocular MG, suspected thymoma, previous thymectomy, and prior noncorticosteroid immunosuppressants or high doses of corticosteroids. Interventions: Participants were randomized 1:1 without stratification to a single intravenous infusion of 500 mg of rituximab or matching placebo. Main Outcomes and Measures: Minimal disease manifestations at 16 weeks defined as a QMG score of 4 or less with prednisolone, 10 mg or less daily, and no rescue treatment. Results: Of 87 potentially eligible patients, 25 were randomized to rituximab (mean [SD] age, 67.4 [13.4] years; 7 [28%] female) and 22 to placebo (mean [SD] age, 58 [18.6] years; 7 [32%] female). Compared with placebo, a greater proportion with rituximab met the primary end point; 71% (17 of 24) in the rituximab group vs 29% (6 of 21) in the placebo group (Fisher exact test P = .007; probability ratio, 2.48 [95% CI, 1.20-5.11]). Secondary end points, comparing changes in Myasthenia Gravis Activities of Daily Living and Myasthenia Gravis Quality of Life at 16 weeks with QMG at 24 weeks did not differ between groups with censoring for rescue treatment (per-protocol analysis) but were in favor of active treatment when rescue treatment was taken into account by worst rank imputation (post hoc analysis). Rescue treatments were also more frequent in the placebo arm (rituximab: 1 [4%]; placebo, 8 [36%]). One patient in the placebo arm had a myocardial infarction with cardiac arrest and 1 patient in the active arm experienced a fatal cardiac event. Conclusions and Relevance: A single dose of 500 mg of rituximab was associated with greater probability of minimal MG manifestations and reduced need of rescue medications compared with placebo. Further studies are needed to address long-term benefit-risk balance with this treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT02950155.

Patient-Reported Symptom Severity in a Nationwide Myasthenia Gravis Cohort: Cross-sectional Analysis of the Swedish GEMG Study.

OBJECTIVES: To describe Myasthenia Gravis-Activities of Daily Living (MG-ADL) in relation to clinical characteristics in a large Swedish nationwide cohort. METHODS: In a cross-sectional prevalent cohort study, the Genes and Environment in Myasthenia Gravis study (GEMG), performed November 2018 - August 2019, Myasthenia gravis (MG) patients were invited to submit an extensive 106-item life environment questionnaire, including the MG-ADL score. Patients were classified into early onset MG (EOMG, <50 years), late onset MG (LOMG, ≥50 years) or thymoma-associated MG (TAMG). Comparisons of disease-specific characteristics were made between subgroups, sex and different MG-ADL scores. RESULTS: A total of 1077 patients were included, yielding a 74% response rate: 505 (47%) were classified as EOMG, 520 (48%) LOMG and 45 (4%) TAMG. Mean age at inclusion was 64.3 years (SD 15.7) and mean disease duration was 14.6 years (SD 14.0). Complete MG-ADL scores (n=1035) ranged from 0-18p, where 26% reported a score of 0p. Higher MG-ADL scores were associated with female sex, obesity and diagnostic delay (OR=1.62, 1.72 and 1.69, P adj=0.017, 0.013 and 0.008) and inversely correlated with high educational attainment (OR=0.59, P adj=0.02), but not with age at inclusion, disease subtype nor disease duration. Almost half the population (47%) reported MG-ADL ≥3p, corresponding to an unsatisfactory symptom state. CONCLUSIONS: In this nationwide study, comprising more than 40% of the prevalent MG population in Sweden, we observe that almost half of patients report current disease symptoms associated to an unsatisfactory symptom state, indicating the need for improved treatment options.

Measurement of sCD27 in the cerebrospinal fluid identifies patients with neuroinflammatory disease.

BACKGROUND: Laboratory tests to assist in the diagnosis and monitoring of neuroinflammatory diseases are scarce. The soluble form of the CD27 molecule (sCD27) is shed in high concentrations by activated T cells and can be detected in the cerebrospinal fluid. The aim of this study was to investigate whether CSF quantitation of sCD27 could discriminate between inflammatory and non-inflammatory neurological diseases. METHODS: The concentration of sCD27 was measured using a commercially available ELISA in 803 well-defined subjects from a study cohort comprised of 338 patients with neuroinflammatory disease, 338 with non-inflammatory neurological disease and 127 controls without neurological disease. RESULTS: The median value of cerebrospinal fluid sCD27 was 64 pg/mL (IQR 0-200) in controls, 58 pg/mL (IQR 0-130) in patients with non-inflammatory disease and 740 pg/mL (IQR 230-1800) in patients with inflammatory disease. The likelihood ratio of having an inflammatory disease was 10 (sensitivity 74% and specificity 93%) if the sCD27 concentration was >250 pg/mL. In patients with a known inflammatory condition, the likelihood ratio of having an infection was 10 (sensitivity 40% and specificity 96%) if the sCD27 concentration was >2500 pg/mL. CONCLUSIONS: The likelihood of having an inflammatory neurological condition is increased with elevated concentrations of sCD27 in cerebrospinal fluid. Rapid tests of sCD27 should be developed to assist clinicians in diagnosis of neuroinflammatory disease.

Discontinuation of disease modifying treatments in middle aged multiple sclerosis patients. First line drugs vs natalizumab.

BACKGROUND: Several disease-modifying drugs (DMD) are available for the treatment of MS, and most patients with relapsing-remitting disease are currently treated. Data on when and how DMD treatment can be safely discontinued are scarce. METHODS: Fifteen MS patients, treated with natalizumab for >5 years without clinical and radiological signs of inflammatory disease activity, suspended treatment and were monitored with MRI examinations and clinical follow-up to determine recurrence of disease activity. This group was compared with a retrospectively analysed cohort comprising 55 MS patients treated with first-line DMDs discontinuing therapy in the time period of 1998-2015 after an analogous stable course. RESULTS: Natalizumab discontinuers were followed for on average 19 months, and follow-up data for 56 months were available for first-line DMD quitters. Two-thirds of natalizumab treated patients experienced recurrent inflammatory disease activity, and one third had recurrence of rebound character. In contrast, 35% of first-line DMD quitters had mild recurrent disease activity, and no one exhibited rebound. CONCLUSIONS: Withdrawal of a first-line DMD after prolonged treatment in middle-aged MS patients with stable disease appears to be relatively safe, while natalizumab withdrawal in a similar group of patients cannot be safely done without starting alternative therapy.

Recurrence of Susac Syndrome following 23 Years of Remission.

Susac syndrome is an autoimmune microangiopathy affecting the brain, retina and inner ear (cochlea and semicircular canals), leading to encephalopathy, branch retinal artery occlusions (BRAOs) and asymmetric neurosensory hearing loss, respectively. The natural history and long-term prognosis are variable as the disease has been shown to be monophasic and self-limiting, polycyclic or chronic continuous. We describe a 35-year-old woman who presented with a sudden hearing loss in the left ear in the 37th week of her second pregnancy. She subsequently developed BRAO in the right eye 2.5 months after having given birth. MRI findings included round lesions in the corpus callosum which are pathognomonic for Susac syndrome. Previous patient records documented encephalopathy, sudden deafness of the right ear and visual field defects in the left eye at the age of 12, followed by permanent hearing and visual defects. We expand on the variability in the course of Susac syndrome as recurrence may occur after as long as 23 years. Cases of monophasic self-limiting Susac syndrome may in fact turn polycyclic with an interval of more than 2 decades between the bouts of the disease. In these cases, suspecting the development of exacerbation early is important in order to start the treatment promptly.