Objective:Multiple Sclerosis (MS) affects up to 500,000 adults in the United States, with cognitive impairment present in 45%-65% of people. Studies showed hippocampal atrophy in MS, but the underlying mechanisms remain unknown. Inflammation has been proposed to play a significant role, and associations between systemic inflammatory biomarkers and hippocampal atrophy have been shown in other neurological conditions. However, research exploring serum biomarker and volumetric associations in MS are lacking. Given that conventional imaging methods lack resolution for hippocampal internal architecture (HIA), new protocols were developed. We used the High-Resolution Multiple Image Co-Registration and Averaging (HR-MICRA) method to visualize the HIA subfields. We investigated the relationship between subfield volumes generated from HR-MICRA scans and systemic serum biomarkers in MS.Participants and Methods:Patients with MS were recruited (N= 34, mean age= 54.6, 35.3% Black) underwent Magnetic Resonance Imaging (MRI), and serum biomarkers were obtained, specifically chosen for their potential role in MS. Inflammatory biomarkers included; granulocyte colony stimulating factor (G-CSF), interleukin-10 (IL-10), matrix metalloproteinase-9 (MMP-9), tumor necrosis factor- a (TNF- a), and growth factors; vascular endothelial growth factor (VEGF); insulin-like growth factor-1 (IGF-1), and brain derived growth factor (BDNF). Imaging was performed in a Siemens Prisma 3T scanner with a 64-channel head coil using the HR-MICRA method. Hippocampal subfields were calculated using the Automated Segmentation of Hippocampal Subfields (ASHS) package. We used the Magdeburg Young Adult 7T Atlas for sub-hippocampal structures and Penn Temporal Lobe Epilepsy T1-MRI Whole Hippocampus ASHS Atlas for general hippocampal structure and segmentation. Pearson's product-moment analyses provided correlations between biomarkers and hippocampal subfield volumes for each cerebral hemisphere. A statistical significance level of p < 0.05 was used for all analyses.Results:Correlations emerged between left hemisphere Cornu Ammonis (CA) 2 and G-CSF (r = -.384; p = .025); IL-10 (r = -.342; p = .048); VEGF (r = -.371; p= .031); and CA3 with IL-10 (r = -.488, p = .003); G-CSF (r = -.386; p= .024); VEGF (r = -.352; p= .041). Dentate gyrus correlated with MMP-9 (r =.416; p=.014); IL-10 (r = -.365; p =.034). BDNF was correlated with right hemisphere CA1 (r = -.417, p = .014), CA2 (r = -.497; p= .003) and CA3 (r = -.451; p=.007).Conclusions:In our sample of persons with MS, left hemisphere hippocampal subfield volumes were negatively correlated with inflammatory biomarkers, supporting previous reports linking inflammation to reduced brain volumes in other neurological conditions. In the right hemisphere, we found negative correlations between HIA and BDNF, suggesting a neuroprotective function for BDNF in this neurodegenerative disease. These findings in a representative sample of patients with MS highlight the need for further research exploring the relationship between HIA and systemic serum biomarkers in MS.

To describe a case of cryptococcal meningoencephalitis complicated by immune reconstitution inflammatory syndrome (IRIS), vasculitis, ischemic strokes, and hydrocephalus.

Objective:To investigate the relationship between systematic inflammatory biomarkers and cognition in patients with Multiple Sclerosis (MS).Participants and Methods:We recruited 36 patients diagnosed with MS (31 with relapsing-remitting and 5 with progressive) who presented for treatment at the University of Alabama at Birmingham (UAB). Patients underwent a comprehensive neuropsychological battery, and serum blood samples were collected. Cognitive data was divided into an overall Cognitive Composite score and seven cognitive domains (i.e., Attention, Verbal Memory, Visual Memory, Visuospatial Ability, Language, Processing Speed, and Executive Function) using z-score averages. Pearson's product-moment correlations were conducted to determine the relationship between cognitive performance and 14 inflammatory biomarkers specifically chosen for their potential role in MS.Results:Granulocyte Colony Stimulating Factor (G-CSF) was significantly correlated with Executive Function (r= -.355; p=.039) and Processing Speed (r= -.528; p= .001) scores. Additionally, Interleukin-10 (IL-10) was significantly correlated with Visual Memory (r= -.346; p= .041) scores. Finally, Tumor Necrosis Factor (TNF-a) was significantly correlated with Visual Memory (r= -.347; p= .041).Conclusions:Studies investigating associations between inflammation and cognition in MS are lacking. In our sample of persons with Multiple Sclerosis, G-CSF biomarkers were negatively correlated with Executive Function as well as Processing Speed. In addition, IL-10 and TNF-a biomarkers were negatively correlated with Visual Memory scores. These findings in a representative sample of patients with MS highlight the need for further research exploring the relationship between systematic inflammatory biomarkers and cognition in MS.

Objective: To investigate the relationship between systematic inflammatory biomarkers and cognition in patients with Multiple Sclerosis (MS). Method: We recruited 36 patients diagnosed with MS (31 with relapsing-remitting and 5 with progressive) who presented for treatment at the University of Alabama at Birmingham (UAB). Patients underwent a comprehensive neuropsychological battery, and serum blood samples were collected. Cognitive data was divided into an overall Cognitive Composite score and seven cognitive domains (i.e., Attention, Verbal Memory, Visual Memory, Visuospatial Ability, Language, Processing Speed, and Executive Function) using z-score averages. Pearson's product-moment correlations were conducted to determine the relationship between cognitive performance and 14 inflammatory biomarkers specifically chosen for their potential role in MS. Results: Matrix Metalloproteinase-9 (MMP-9) was significantly correlated with Visual Memory (r= -.424; p=.01), Language (r= -.425; p= .01), and Cognitive Composite (r= -.380; p= .022) scores. Additionally, Insulin-like Growth Factor-1 (IGF-1) was significantly correlated with the overall Cognitive Composite (r= -.346; p= .039) score. Conclusions: Studies investigating associations between inflammation and cognition in MS are lacking. In our sample of persons with Multiple Sclerosis, serum IGF-1 and MMP-9 biomarkers were moderately negatively correlated with the overall Cognitive Composite scores. MMP-9 was negatively correlated with Visual Memory and Language cognitive domain scores. These findings in a representative sample of patients with MS highlight the need for further research exploring the relationship between systematic inflammatory biomarkers and cognition in MS.

Background No approved therapies exist for neuromyelitis optica spectrum disorder (NMOSD), a rare, relapsing, autoimmune, inflammatory disease of the CNS that causes blindness and paralysis. We aimed to assess the efficacy and safety of inebilizumab, an anti-CD19, B cell-depleting antibody, in reducing the risk of attacks and disability in NMOSD. Methods We did a multicentre, double-blind, randomised placebo-controlled phase 2/3 study at 99 outpatient specialty clinics or hospitals in 25 countries. Eligible participants were adults (>= 18 years old) with a diagnosis of NMOSD, an Expanded Disability Status Scale score of 8.0 or less, and a history of at least one attack requiring rescue therapy in the year before screening or at least two attacks requiring rescue therapy in the 2 years before screening. Participants were randomly allocated (3:1) to 300 mg intravenous inebilizumab or placebo with a central interactive voice response system or interactive web response system and permuted block randomisation. Inebilizumab or placebo was administered on days 1 and 15. Participants, investigators, and all clinical staff were masked to the treatments, and inebilizumab and placebo were indistinguishable in appearance. The primary endpoint was time to onset of an NMOSD attack, as determined by the adjudication committee. Efficacy endpoints were assessed in all randomly allocated patients who received at least one dose of study intervention, and safety endpoints were assessed in the as-treated population. The study is registered with ClinicalTrials.gov, number NCT02200770. Findings Between Jan 6, 2015, and Sept 24, 2018, 230 participants were randomly assigned to treatment and dosed, with 174 participants receiving inebilizumab and 56 receiving placebo. The randomised controlled period was stopped before complete enrolment, as recommended by the independent data-monitoring committee, because of a clear demonstration of efficacy. 21 (12%) of 174 participants receiving inebilizumab had an attack versus 22 (39%) of 56 participants receiving placebo (hazard ratio 0.272 [95% CI 0.150-0.496]; p<0.0001). Adverse events occurred in 125 (72%) of 174 participants receiving inebilizumab and 41 (73%) of 56 participants receiving placebo. Serious adverse events occurred in eight (5%) of 174 participants receiving inebilizumab and five (9%) of 56 participants receiving placebo. Interpretation Compared with placebo, inebilizumab reduced the risk of an NMOSD attack. Inebilizumab has potential application as an evidence-based treatment for patients with NMOSD. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

BACKGROUND:Medical decision-making capacity (MDC) refers to the ability to make informed decisions about treatment and declines in cognition are associated with declines in MDC across multiple disease entities. However, although it is well known that cognitive impairment is prevalent in multiple sclerosis (MS), little is known about MDC in the disease.METHODS:Data from 22 persons with progressive MS and 18 healthy controls were analyzed. All diagnoses were made by a board-certified neurologist with experience in MS. All study participants were administered a vignette-based measure of MDC and also a neuropsychological battery.RESULTS:Performance on three MDC consent standards (i.e., Appreciation, Reasoning, Understanding) was significantly lower for people with progressive MS as compared to healthy controls. In the progressive MS group, verbal fluency was the primary cognitive predictor for both Reasoning and Understanding consent standards. Verbal learning and memory was the primary cognitive predictor for Appreciation. MS severity was not significantly correlated with any MDC variable.CONCLUSION:MDC is a complex and cognitively mediated functional ability that is impaired in many people with progressive MS. Verbal measures of fluency and memory are strongly associated with MDC performances in the current sample of people with MS and could potentially be utilized to quickly screen for MDC impairment in MS.

ObjectiveFinancial capacity is a cognitively-complex activity of daily living that has been shown to decline in a number of neurocognitive disorders. Although it has been well established that cognitive decline is common in multiple sclerosis (MS), little is known about possible financial capacity impairment in people with MS. Thus, the objective of the current study is to investigate financial capacity and its neurocognitive correlates in MS.MethodsData from 22 people with progressive MS and a healthy comparison group composed of 18 adults were analyzed. MS diagnoses were made by a board-certified neurologist with experience in MS. Study participants were administered the Financial Capacity Instrument, a performance-based measure of financial capacity, and neuropsychological battery.ResultsOverall financial capacity and most complex financial domains were significantly poorer for people with progressive MS in relation to the healthy comparison group, and a number of cognitive variables were associated with financial capacity declines.ConclusionsFinancial capacity is a complex cognitively-mediated functional ability that was impaired in 50% of the current sample of people with progressive MS. These results indicate that people with progressive MS are at greater risk for showing impairment in complex financial tasks and should be clinically monitored for possible deficits in financial capacity.

ObjectiveThe 10/36 Spatial Recall Test is a measure of visuospatial memory and has been recommended for inclusion when administering a brief cognitive assessment to patients with multiple sclerosis by multiple groups. However, a notable limitation of the measure includes a lack of normative data with demographic corrections. Thus, the primary objective of the current study was to examine demographic influences on the 10/36 Spatial Recall Test and to introduce demographically corrected normative data for the instrument.MethodsData were collected from 116 participants over the age of 50years. All study participants were free of any neurologic disease or disorder and classified as cognitively intact by a consensus conference team that was comprised of neurologists and neuropsychologists. All study participants were administered a neuropsychological evaluation that included the 10/36 Spatial Recall Test Version A at the baseline visit.Results10/36 Spatial Recall Test scores were affected by age, education, and race. Gender effects were not observed. Given these effects, regression equations were used to correct for the effects of demographic variables. The z-scores obtained from these corrections were not significantly influenced by demographical variables.ConclusionThe demographic corrections introduced in this paper offer the possibility to enhance the clinical utility of the 10/36 Spatial Recall Test. Copyright (c) 2015 John Wiley & Sons, Ltd.

BACKGROUND:Primary and secondary progressive multiple sclerosis (MS), collectively called progressive multiple sclerosis (PMS), is characterized by gradual progression of disability. The current anti-inflammatory treatments for MS have little or no efficacy in PMS in the absence of obvious active inflammation. Optimal biomarkers for phase II PMS trials is unknown. Ibudilast is an inhibitor of macrophage migration inhibitor factor and phosphodiesterases-4 and -10 and exhibits possible neuroprotective properties. The goals of SPRINT-MS study are to evaluate the safety and efficacy of ibudilast in PMS and to directly compare several imaging metrics for utility in PMS trials.METHODS:SPRINT-MS is a randomized, placebo-controlled, phase II trial of ibudilast in patients with PMS. Eligible subjects were randomized 1:1 to receive either ibudilast (100mg/day) or placebo for 96weeks. Imaging is conducted every 24weeks for whole brain atrophy, magnetization transfer ratio, diffusion tensor imaging, cortical brain atrophy, and retinal nerve fiber layer thickness. Clinical outcomes include neurologic disability and patient reported quality of life. Safety assessments include laboratory testing, electrocardiography, and suicidality screening.RESULTS:A total of 331 subjects were enrolled, of which 255 were randomized onto active study treatment. Randomized subjects were 53.7% female and mean age 55.7 (SD 7.3) years. The last subject is projected to complete the study in May 2017.CONCLUSION:SPRINT-MS is designed to evaluate the safety and efficacy of ibudilast as a treatment for PMS while simultaneously validating five different imaging biomarkers as outcome metrics for use in future phase II proof-of-concept PMS trials.

Objective: To evaluate in a preliminary manner the feasibility, safety, and efficacy of Constraint-Induced Movement therapy (CIMT) of persons with impaired lower extremity use from multiple sclerosis (MS).Design: Clinical trial with periodic follow-up for up to 4 years.Setting: University-based rehabilitation research laboratory.Participants: A referred sample of ambulatory adults with chronic MS (N=4) with at least moderate loss of lower extremity use (average item score <= 6.5/10 on the functional performance measure of the Lower Extremity Motor Activity Log [LE-MAL]).Interventions: CIMT was administered for 52.5 hours over 3 consecutive weeks (15 consecutive weekdays) to each patient.Main Outcome Measures: The primary outcome was the LE-MAL score at posttreatment. Secondary outcomes were posttreatment scores on laboratory assessments of maximal lower extremity movement ability.Results: All the patients improved substantially at posttreatment on the LE-MAL, with smaller improvements on the laboratory motor measures. Scores on the LE-MAL continued to improve for 6 months afterward. By 1 year, patients remained on average at posttreatment levels. At 4 years, half of the patients remained above pretreatment levels. There were no adverse events, and fatigue ratings were not significantly changed by the end of treatment.Conclusions: This initial trial of lower extremity CIMT for MS indicates that the treatment can be safely administered, is well tolerated, and produces substantially improved real-world lower extremity use for as long as 4 years afterward. Further trials are needed to determine the consistency of these findings. Archives of Physical Medicine and Rehabilitation 2013;94:753-60 (C) 2013 by the American Congress of Rehabilitation Medicine

OBJECTIVE: To report a case of CD presenting solely with SFN and normal skin biopsy.

Whipple disease (WD) is usually a systemic infectious disease that can have central nervous system (CNS) involvement. WD confined to the CNS is extremely rare and difficult to diagnose, but can be fatal if not treated in a timely fashion. We present the case of a 42-year-old man with a subacute dementia accompanied by a movement disorder consisting of progressive supranuclear gaze palsy, myoclonus, and ataxia. Our patient lacked the typical magnetic resonance imaging (MRI) findings reported with isolated CNS WD and had a false-positive cerebrospinal fluid (CSF) 14-3-3 protein. The patient expired, and definitive diagnosis of isolated CNS WD was made by autopsy with characteristic macrophage accumulations found in the brain but not in the gastrointestinal tract. We examine the literature on isolated CNS WD and discuss how these previously unreported findings make a rare diagnosis even more challenging. The reported patient is the first in the literature with tissue diagnosis of isolated CNS WD in the setting of normal brain MRI and positive CSF 14-3-3 protein. Isolated CNS WD should be added to the list of considerations for a false-positive CSF 14-3-3 protein. Even in the absence of typical MRI lesions, a patient with subacute progressive dementia, supranuclear gaze palsy, and other various neurologic abnormalities should have the diagnosis of isolated CNS WD considered.