Multiple Sclerosis Research Institute

Progressive multifocal leukoencephalopathy (PML) is a rare, often fatal demyelinating disease of the central nervous system (CNS) caused by JC virus (JCV) reactivation in the setting of impaired cellular immunity. While commonly associated with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) and immunosuppressive therapies, PML can also arise in primary immunodeficiency disorders. We report a case of PML in a young adult with autosomal recessive hyper-IgE syndrome (AR-HIES) due to DOCK8 deficiency, highlighting the importance of considering genetic immunodeficiencies in cases of JCV-PML without known iatrogenic or acquired causes.

To explore the predictive value of a variety of magnetic resonance imaging (MRI) measures of brain tissue damage on time-to-6-month confirmed ≥4-points cognitive worsening/improvement on Symbol Digit Modalities Test (SDMT; 6mCWSDMT/6mCISDMT) in siponimod-treated secondary progressive multiple sclerosis (SPMS) EXPAND study participants over short- (Core) and long-term (Core+Extension) periods (total up-to-5 years).

Tuesday, April 28April 14, 2020Free AccessCorrelations Between Four Common Measures of Cognition in Patients With Secondary Progressive Multiple Sclerosis (4000)Ralph H.B. Benedict, Xiangyi Meng, Amit Bar-Or, Bruce A.C. Cree, Robert J. Fox, Patrick Vermersch, Wendy Su, and Ludwig KapposAuthors Info & AffiliationsApril 14, 2020 issue94 (15_supplement)https://doi.org/10.1212/WNL.94.15_supplement.4000 Letters to the Editor

Alice in Wonderland syndrome (AIWS) is a paroxysmal, perceptual, visual and somesthetic disorder that can be found in patients with migraine, epilepsy, cerebrovascular disease or infections. The condition is relatively rare and unique in its hallucinatory characteristics. OBJECTIVE To discuss the potential pathways involved in AIWS. Interest in this subject arose from a patient seen at our service, in which dysmetropsia of body image was reported by the patient, when she saw it in her son. METHODS We reviewed and discussed the medical literature on reported patients with AIWS, possible anatomical pathways involved and functional imaging studies. RESULTS A complex neural network including the right temporoparietal junction, secondary somatosensory cortex, premotor cortex, right posterior insula, and primary and extrastriate visual cortical regions seem to be involved in AIWS to varying degrees. CONCLUSIONS AIWS is a very complex condition that typically has been described as isolated cases or series of cases.

Serial MRIs from 2 patients with relapsing-remitting MS displaying mild (video 1, baseline age: 42 years; disease duration: 1.2 years) and severe (video 2, baseline age: 43 years; disease duration: 1.6 years) brain atrophy with plots of brain parenchymal fraction (BPF),1 a measure of normalized brain volume, and Expanded Disability Status Scale (EDSS) are presented. Patients were scanned every 6–12 months over 14 years using standardized protocols on 3 scanners (Siemens Vision, Symphony, and Trio).2 BPF was calibrated across scanners using scan-rescan measurements. During the first year, the severe patient had 10 contrast-enhancing lesions, whereas the mild patient had none. BPF decreased by 2% (mild) compared with 10% (severe) over 14 years.

Objective: Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive, safe and efficacious technique for treating various neuropsychiatric disorders, but its underlying mechanisms are poorly understood. A newly developed H-coil allows the stimulation of deeper brain regions. This study is the first to investigate the effects of deep high-frequency rTMS on brain-derived neurotrophic factor (BDNF) serum concentrations in healthy volunteers. We aimed to evaluate the short-term effect of deep rTMS on BDNF serum concentrations. Methods: This was a double-blind, randomized deep high-frequency rTMS study using an H-coil on a cohort of 13 healthy volunteers (NCT01106365). The following stimulation protocols were applied: 18-Hz stimulation of the left dorsolateral prefrontal cortex (PFC), 5-Hz stimulation of the primary motor cortex (MC) and sham stimulation in random order. Blood samples were obtained before, 30 min after and 60 min after each treatment. Results: The BDNF serum concentration decreased significantly after MC and PFC stimulation, but not after sham stimulation. Furthermore, BDNF serum level changes were associated with changes in individual alertness. Conclusion: Although BDNF serum concentrations do not necessarily correlate with BDNF levels in the cerebrospinal fluid or the brain, these results indicate an acute biological effect of deep rTMS on BDNF release, and demonstrate that this change correlates with alertness.

The study was undertaken to determine the pathologic basis of subtle abnormalities in magnetization transfer ratio (MTR) and diffusion tensor imaging (DTI) parameters observed in normal-appearing white matter (NAWM) in multiple sclerosis brains. Brain tissues were obtained through a rapid postmortem protocol that included in situ magnetic resonance imaging (MRI). Four types of MRI-defined regions of interest (ROIs) were analyzed: (1) regions that were abnormal on all images (T2T1MTR lesions); (2) NAWM regions with slightly abnormal MTR located close to white matter lesions (sa-WM Close); (3) NAWM regions with slightly abnormal MTR located far from lesions (sa-WM Far); and (4) NAWM regions with normal MTR (NAWM). Immunohistochemical analysis for each ROI comprised immunostaining for myelin, axonal markers, activated microglia/macrophages, astrocytes, plasma proteins, and blood vessels. Forty-eight ROIs from 4 secondary progressive MS brains were analyzed. sa-WM Close ROIs were associated with significantly more axonal swellings. There were more enlarged major histocompatibility complex II(+) microglia and macrophages detected in sa-WM Far, sa-WM Close, and T2T1MTR lesions than in NAWM. Across all ROIs, MTR and DTI measures were moderately correlated with myelin density, axonal area, and axonal counts. Excluding T2T1MTR lesions from analysis revealed that MTR and DTI measures in nonlesional white matter (WM) were correlated with activated microglia, but not with axonal or myelin integrity. The pathologic substrates for MRI abnormalities in NAWM vary based on distance from focal WM lesions. Close to WM lesions, axonal pathology and microglial activation may explain subtle MRI changes. Distant from lesions, microglial activation associated with proximity to cortical lesions might underlie MRI abnormalities.

Glucocorticoids (GCs) constitute one of the oldest families of anti-inflammatory and immunosuppressive drugs. Since their first clinical use more than half a century ago, they have been employed for therapeutic invention in a variety of conditions, including atopic disorders, autoimmune diseases, and cancer. Nevertheless, their exact mechanism of action is still incompletely understood. In this review, we elaborate especially on the mechanism of GCs in experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS), and summarize our current knowledge on how therapeutic and endogenous GCs impact the pathogenesis of EAE and MS. This includes findings obtained from genetically modified mice and rats lacking or overexpressing the GC receptor (GR) in specific cell types, and the analysis of new pharmaceutical formulations and chemical GC modifications aimed at improving treatment efficacy and specificity. Stimulated by these recent developments, it can be anticipated that novel therapeutic regimens will find their way into clinical practice for the benefit of affected patients.

Copolymer I (Cop I) is being tested as a treatment for MS because it protects animals against experimental allergic encephalomyelitis, and because there is immunologic cross-reactivity reported between Cop I and myelin basic protein (MBP). From the peripheral blood mononuclear cells of four normal individuals, we isolated helper-phenotype T-cell lines that reacted in vitro with Cop I or MBP. Cop I-reactive cell lines did not respond to MBP, nor did MBP-reactive T-cell lines respond to Cop I. Antigen-specific immune tolerance was induced in MBP-reactive cell lines by exposure to MBP in vitro, but similar exposure to Cop I did not induce tolerance in the MBP-reactive cell lines. We found no evidence of immunologic cross-reactivity between Cop I and MBP.

Intracerebral inoculation of 4- to 6-week-old C57BL/6 mice with the A59 strain of mouse hepatitis virus (MHV), a murine coronavirus, produced biphasic disease. Acute hepatitis and mild meningoencephalitis were followed by subacute spastic paralysis with demyelinating lesions in the brain and spinal cord as determined by Epon-embedded toluidine-blue-stained sections and by electronmicroscopy. MHV-A59 was cultured by plaque assay from the blood, brain, spinal cord, and liver of infected mice during the acute phase, but not in the chronic stage. MHV-A59 antigen was detected by immunofluorescence (IF) until 3 months postinfection (PI). Serum anti-MHV-A59 antibodies were detected from 7 days to 5 months PI. The induction of demyelination by MHV-A59 provides a suitable system to study virus-induced demyelination further.