Sleep and its associations with perceived and objective cognitive impairment in individuals with multiple sclerosis.

Problems with sleep and cognitive impairment are common among people with multiple sclerosis (MS). The present study examined the relationship between self-reported sleep and both objective and perceived cognitive impairment in MS. Data were obtained from the baseline assessment of a multi-centre intervention trial (NCT00841321). Participants were 121 individuals with MS. Nearly half (49%) of participants met the criteria for objective cognitive impairment; however, cognitively impaired and unimpaired participants did not differ on any self-reported sleep measures. Nearly two-thirds (65%) of participants met the criteria for 'poor' sleep, and poorer sleep was significantly associated with greater levels of perceived cognitive impairment. Moreover, the relationships between self-reported sleep and perceived cognitive impairment were significant beyond the influence of clinical and demographic factors known to influence sleep and cognitive functioning (e.g. age, sex, education level, disability severity, type of MS, disease duration, depression and fatigue). However, self-reported sleep was not associated with any measures of objective cognitive impairment. Among different types of perceived cognitive impairment, poor self-reported sleep was most commonly related to worse perceived executive function (e.g. planning/organization) and prospective memory. Results from the present study emphasize that self-reported sleep is significantly and independently related to perceived cognitive impairment in MS. In terms of clinical implications, interventions focused on improving sleep may help improve perceived cognitive function and quality of life in this population; however, the impact of improved sleep on objective cognitive function requires further investigation.

Cognitive Impairment and Community Integration Outcomes in Individuals Living With Multiple Sclerosis.

OBJECTIVES: To determine the association between unique domains of cognitive impairment and community integration in individuals with multiple sclerosis (MS), and to determine the contributions of cognitive impairment to community integration beyond the influence of demographic and clinical variables. DESIGN: Cross-sectional analysis of objective neuropsychological assessment and self-report data. Data were collected during baseline assessment of a randomized, multisite controlled trial of ginkgo biloba for cognitive impairment in MS. Hierarchical regression analyses examined the association between subjective and objective measures of cognitive impairment and 3 domains of community integration, adjusting for relevant covariates. SETTING: Two Veterans Affairs medical center MS clinics. PARTICIPANTS: Adults (N=121; ages 24-65y) with a confirmed MS diagnosis. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Primary outcomes were scores on the Home Integration (CIQ-H), Social Integration (CIQ-S), and Productivity (CIQ-P) domains of the Community Integration Questionnaire (CIQ). RESULTS: Cognitive impairment was associated with lower scores on the CIQ-H and CIQ-S, but not the CIQ-P. Greater levels of subjective cognitive impairment were associated with lower scores on the CIQ-H and CIQ-S. Greater levels of objective cognitive impairment, specifically slower processing speed and poorer inhibitory control, were related to lower CIQ-S scores. Subjective and objective measures of cognitive impairment were significantly and independently associated with CIQ-S. CONCLUSIONS: Objective cognitive impairment may interfere with participation in social activities. Subjective cognitive impairment is also important to assess, because individuals who perceive themselves to be cognitively impaired may be less likely to participate in both home and social activities. Clinical interventions to enhance community integration in individuals with MS may benefit from addressing objective and subjective cognitive impairment by integrating cognitive rehabilitation approaches with self-efficacy-enhancing strategies.

Cytomegalovirus and varicella zoster virus coinfection-associated central hypoventilation syndrome (Ondine's Curse).

Central hypoventilation syndrome (CHS) is a rare condition resulting from damage to the respiratory centers in the central nervous system (CNS). It can be congenital or acquired and can cause hypoventilation, inadequate gas exchange, and respiratory failure, often during sleep but sometimes even while awake. CHS can lead to respiratory failure and life-threatening complications if not identified promptly. In this report, we present a rare case of a patient with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), who developed CHS likely due to an opportunistic infection by cytomegalovirus (CMV) and varicella zoster virus (VZV), manifesting as a lesion in the medullary respiratory nuclei. After treatment with ganciclovir, the patient showed clinical improvement, and his medullary lesion resolved.

The intersection of race and sex on the clinical and cognitive progression of multiple sclerosis.

OBJECTIVE: Black populations show increased incidences of diagnosis, worse disease severity, and earlier likelihood of mortality due to MS. Clinical outcomes are also linked to biological sex and as with Black individuals, MS characteristics between sexes have also shifted overtime. This study examined whether clinical disease progression differed by race and sex for patients with MS. DESIGN: "Black" (N = 47) and "White" (N = 58) participants with MS (82 % female) were recruited from a longitudinal examination of the impact of race and sex on the cognition and disease duration of patients in the gulf south region of the United States. RESULTS: Black participants had shorter disease durations [F (1,103) = 4.70, p = .03], (MDiff = [-3.96]) and were younger [F (1, 103) = 14.25, p < .001], (MDiff = [-9.04]). Despite this, Black individuals had worse SDMT t-scores [F (1, 103) = 5.22, p = .024], (MDiff = [-4.62])]. Women exhibited higher MSSS scores [F (1, 96) = 5.59, p = .02], (MDiff = [-2.15]). Specifically, Black women were younger than White women [F (1, 84) = 14.47, p < .001], (MDiff = [-9.15])] and had shorter disease durations [F (1, 84) = 6.04, p = .016], (MDiff = [-4.57])] yet scored lower on the SDMT T-scores [F (1, 84) = 6.11, p = .015], (MDiff = [-5.51])]. CONCLUSION: Findings suggest an interaction between race and sex may influence clinical progression in MS. Despite being younger and having shorter disease durations Black participants with MS, specifically Black women exhibited worse clinical outcomes. SUMMARY: For women and men, MS incidence among Black Americans has become similar to White Americans. However, Black individuals experience greater disease severity and earlier mortality. Clinical impairment often accompanies MS. We examined the influence of race and sex on clinical status using the Symbol Digit Modalities Test t-scores (SDMT T-scores) and Multiple Sclerosis Severity Scores (MSSS) in Black (N = 47) and White (N = 58) patients with MS. Women exhibited higher MSSS scores than men [F (1, 96) = 5.59, p = .02], (MDiff = [-2.15]). Black participants had shorter disease durations [F (1, 103) = 4.70, p = .03], (MDiff = [-3.96]) and were younger [F (1, 103) = 14.25, p < .001], (MDiff = [-9.04]). Despite this, Black individuals had worse SDMT T-scores [F (1, 103) = 5.22, p = .024], (MDiff = [-4.62])]. Specifically, Black women were younger than White women [F (1, 84) = 14.47, p < .001], (MDiff = [-9.15])] and had shorter disease durations [F (1, 84) = 6.04, p = .016], (MDiff = [-4.57])] yet scored lower on the SDMT T-scores [F (1, 84) = 6.11, p = .015], (MDiff = [-5.51])]. These findings suggest that an interaction between race and sex may influence clinical progression in MS.

Stress in multiple sclerosis: review of new developments and future directions.

In the experimental autoimmune encephalitis model of multiple sclerosis, the effects of stress on disease severity depend on multiple factors, including the animal's genetics and the type of stressor. The studies in humans relating stress to the risk of developing multiple sclerosis have found discordant results. The studies looking at the association of stress with relapses show a fairly consistent association, where higher stress is associated with a higher risk of relapse. Higher stress levels also appear to increase the risk of development of gadolinium-enhancing lesions. A recent randomized trial shows that reducing stress using stress management therapy (SMT), a cognitive-behavioral therapy approach, results in a statistically significant reduction in new magnetic resonance imaging lesions. The magnitude of this effect is large and comparable to the effects of existent disease-modifying therapies, but no data exist yet proving that SMT reduces relapses or clinical progression; the effect of SMT appears to be short-lived. Additional work is needed to improve the duration of this effect and make this therapy more widely accessible.

Cognitive impairment in multiple sclerosis.

Cognitive impairment (CI) is a serious complication of multiple sclerosis (MS), and the domains affected are well established, but new affected domains such as theory of mind are still being identified. The evidence that disease-modifying therapies (DMTs) improve and prevent the development of CI in MS is not solid. Recent studies on the prevalence of CI in MS among people treated with DMT, although not as solid as studies completed prior to DMT introduction, suggest that CI remains a problem even among people on DMTs and that CI occurs frequently even at the very earliest stages of MS. Functional MRI studies and studies using diffusion tractography show that the impact of lesions on cognition depends on the particular cortical networks affected and their plasticity. Cognitive rehabilitation and L-amphetamine appear promising symptomatic treatments for CI in MS, while, cholinesterase inhibitors and memantine have failed, and data on Ginkgo and exercise are limited. We need more work to understand better CI in MS and develop treatments for this serious complication of MS.

Autoimmune Myelitis and Myocarditis in a Patient With Anti-Aquaporin-4, Antinuclear, and Antiphospholipid Autoantibodies: The Neuromyelitis Optica-Systemic Lupus Erythematosus (NMO-SLE) Overlap Syndrome.

The coexistence of two or more autoimmune diseases is well-known, e.g., a person can have neuromyelitis optica (NMO) and systemic lupus erythematosus (SLE) at the same time. We report a case of NMO-SLE overlap syndrome with myelitis and myocarditis as the initial manifestations. The patient, a 64-year-old man, presented with a 15-day history of ascending sensory loss and a 10-day history of exertional dyspnea. Magnetic resonance imaging (MRI) revealed longitudinally extensive transverse myelitis (LETM) from C7 to T6. Serology showed a high anti-aquaporin-4 antibody level. We diagnosed NMO based on these findings. Echocardiography showed a hypokinetic left ventricle with a severely reduced ejection fraction. Cardiac MRI demonstrated delayed gadolinium enhancement in the myocardium consistent with active inflammation. Because the cardiac findings could not be explained on the basis of NMO, we started searching for another autoimmune disease. Serology came back positive for a variety of autoantibodies, including antinuclear, anti-dsDNA, anti-chromatin, anti-cardiolipin, anti-ß2-glycoprotein-1, and lupus anticoagulant. These findings, along with leukopenia and low serum complement C4, prompted us to diagnose SLE, in addition to NMO. He was initially treated with plasmapheresis and methylprednisolone. Maintenance therapy consisted of rituximab, hydroxychloroquine, and aspirin. One year later, he only complained of mild paresthesia in the feet. Patients with NMO should always be screened for SLE especially if they have signs and symptoms that cannot be accounted for by NMO alone, e.g., our patient had myocarditis. Conversely, patients with SLE and evidence of transverse myelitis should be screened for anti-AQP4 antibodies.

Altered mental status predicts length of stay but not death in a community-based cohort of hospitalized COVID-19 patients.

INTRODUCTION: Altered Mental Status (AMS) is a common neurological complication in patients hospitalized with the diagnosis of COVID-19 (Umapathi et al., 2020; Liotta et al., 2020). Studies show that AMS is associated with death and prolonged hospital stay. In addition to respiratory insufficiency, COVID-19 causes multi-organ failure and multiple metabolic derangements, which can cause AMS, and the multi-system involvement could account for the prolonged hospital stay and increased mortality. In this study, we built on our previous publication (Chachkhiani et al., 2020) using a new, larger cohort to investigate whether we could reproduce our previous findings while addressing some of the prior study's limitations. Most notably, we sought to determine whether AMS still predicted prolonged hospital stay and increased mortality after controlling for systemic complications such as sepsis, liver failure, kidney failure, and electrolyte abnormalities. OBJECTIVES: The primary purpose was to document the frequency of AMS in patients with COVID-19 at the time of presentation to the emergency room. Secondary aims were to determine: 1) if AMS at presentation was associated with worse outcomes as measured by prolonged hospitalization and death; and 2) if AMS remained a predictor of worse outcome after adjusting for concomitant organ failure and metabolic derangements. RESULTS: Out of 367 patients, 95 (26%) had AMS as a main or one of the presenting symptoms. Our sample has a higher representation of African Americans (53%) than the US average and a high frequency of comorbidities, such as obesity (average BMI 29.1), hypertension (53%), and diabetes (30%). Similar to our previous report, AMS was the most frequent neurological chief complaint. At their admission, out of 95 patients with AMS, 83 (88%) had organ failure or one of the systemic problems that could have caused AMS. However, a similar proportion (86%) of patients without AMS had one or more of these same problems. Age, race, and ethnicity were the main demographic predictors. African Americans had shorter hospital stay [HR1.3(1.0,1.7),p = 0.02] than Caucasians. Hispanics also had shorter hospital stay than non-Hispanics [HR1.6(1.2,2.1), p = 0.001]. Hypoxia, liver failure, hypernatremia, and kidney failure were also predictors of prolonged hospital stay. In the multivariate model, hypoxia, liver failure, and acute kidney injury were the remaining predictors of longer hospital stay, as well as people with AMS at baseline [HR0.7(0.6,0.9), p < 0.02] after adjusting for the demographic characteristics and clinical predictors. AMS at baseline predicted death, but not after adjusting for demographics and clinical variables in the multivariate model. Hypoxia and hyperglycemia at baseline were the strongest predictors of death. CONCLUSION: Altered mental status is an independent predictor of prolonged hospital stay, but not death. Further studies are needed to evaluate the causes of AMS in patients with COVID-19.

A hypothesis-generating scoping review of miRs identified in both multiple sclerosis and dementia, their protein targets, and miR signaling pathways.

Cognitive impairment (CI) is a frequent complication affecting people with multiple sclerosis (MS). The causes of CI in MS are not fully understood. Besides MRI measures, few other biomarkers exist to help us predict the development of CI and understand its biology. MicroRNAs (miRs) are relatively stable, non-coding RNA molecules about 22 nucleotides in length that can serve as biomarkers and possible therapeutic targets in several autoimmune and neurodegenerative diseases, including the dementias. In this review, we identify dysregulated miRs in MS that overlap with dysregulated miRs in cognitive disorders and dementia and explore how these overlapping miRs play a role in CI in MS. MiR-15, miR-21, miR-128, miR-132, miR-138, miR-142, miR-146a, miR-155, miR-181, miR-572, and let-7 are known to contribute to various forms of dementia and show abnormal expression in MS. These overlapping miRs are involved in pathways related to apoptosis, neuroinflammation, glutamate toxicity, astrocyte activation, microglial burst activity, synaptic dysfunction, and remyelination. The mechanisms of action suggest that these miRs may be related to CI in MS. From our review, we also delineated miRs that could be neuroprotective in MS, namely miR-23a, miR-219, miR-214, and miR-22. Further studies can help clarify if these miRs are responsible for CI in MS, leading to potential therapeutic targets.

Neurological complications of COVID19 during March 2020 at LCMC health university medical center: Dataset.

We reviewed the electronic medical records (EMR) of patients hospitalized during the peak of the pandemic, March 1st through March 31st, to document the type and frequency of neurological problems seen in patients with COVID-19 at presentation to the emergency room. Secondary aims were to determine: 1) the frequency of neurological complaints during the hospital stay; 2) whether the presence of any neurological complaint at presentation or any of the individual types of neurological complaints at admission predicted three separate outcomes: death, length of hospital stay, or the need for intubation; and 3) if the presence of any neurological complaint or any of the individual types of neurological complaints developed during hospital stay predicted the previous three outcomes. SETTING: The Louisiana Health Sciences Center - New Orleans Institutional Review Board and the University Medical Center Clinical Research Review Committee approved the study protocol. DATA ACQUISITION: We reviewed the electronic medical records (EMR) of patients hospitalized during March (March 1st through March 31st) 2020 at the University Medical Center New Orleans (UMCNO), who tested positive for SARS-CoV-2 during the same hospitalization. The EMR team generated a list of 257 patients admitted for COVID-19. We excluded seven patients because of a negative COVID-19 test result or incomplete medical record documentation. Three neurology residents (DC, MS, DB) reviewed the EMR in detail to capture the relevant medical history, clinical course, and laboratory test results and abstracted data into an electronic data collection spreadsheet.We recorded the presentation or development of the following neurological complaints: headache, syncope, altered mental status, seizure, status epilepticus, and ischemic or hemorrhagic stroke. STATISTICAL ANALYSIS: We used "R" (statistics software) and Microsoft Excel to generate summary tables. To analyze hospital length of stay or death, we fitted a competing risks proportional hazards model for time to discharge or death using the crr() function in R version 4.0.0. The competing risks model allowed the analysis of hospital stay, taking into account that the censoring of cases due to death was not random. To predict the likelihood of intubation, we used the glm() function in R to fit a logistic regression model. For each model, we determined baseline demographic variables predictive of the outcomes and generated adjusted models. For variables with less than five cases per cell, we reported the p-values for Fisher's Exact Test.The analyses and results are published in:Chachkhiani, David et al. "Neurological complications in a predominantly African American population of COVID-19 predict worse outcomes during hospitalization." Clinical Neurology and Neurosurgery (in press).These data will be useful for researchers trying to build larger datasets regarding COVID19 neurological complications for metanalysis or to answer other questions requiring larger sample sizes.

Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease Presenting as Recurrent and Migrating Focal Cortical Encephalitis.

Although pediatric myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease is increasingly well-recognized, its full clinical spectrum is still being defined. Cortical encephalitis is emerging as a distinct clinico-radiologic syndrome of adult MOG antibody-associated disease. We describe a 12-year-old girl who presented with new onset seizures and left-sided hemiparesis. Brain MRI showed edema of the right temporal-parietal-occipital cortex with associated focal leptomeningeal enhancement. Patient received high-dose corticosteroids and 21 days of acyclovir despite negative infectious work-up due to the focal nature of encephalitis. Patient remained seizure-free for 20 months before presenting with new right hemiclonic seizures with right-sided hemiparesis and edema of the left temporal-parietal cortex with associated leptomeningeal enhancement. Patient's MOG antibody titer was 1:40. She completed high-dose corticosteroids and intravenous immunoglobulin. Our patient highlights the importance of MOG antibody testing in pediatric focal cortical encephalitis to avoid unnecessary anti-viral agents and provide more appropriate immunotherapy and a more informed prognosis.

Neurological complications in a predominantly African American sample of COVID-19 predict worse outcomes during hospitalization.

People with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, COVID-19, can have neurological problems including headache, anosmia, dysgeusia, altered mental status (AMS), ischemic stroke with or without large vessel occlusion, and Guillen-Barre Syndrome. Louisiana was one of the states hit hardest by the pandemic with just over 57,000 laboratory-confirmed cases of COVID-19 by the end of June 2020. We reviewed the electronic medical records (EMR) of patients hospitalized during the peak of the pandemic, March 1st through March 31st, to document the type and frequency of neurological problems seen in patients with COVID-19 at presentation to the emergency room. Secondary aims were to determine: 1) the frequency of neurological complaints during the hospital stay; 2) whether the presence of any neurological complaint at presentation or any of the individual types of neurological complaints at admission predicted three separate outcomes: death, length of hospital stay, or the need for intubation; and 3) if the presence of any neurological complaint or any of the individual types of neurological complaints developed during hospital stay predicted the previous three outcomes. A large proportion of our sample (80 %) was African American and had hypertension (79 %). Out of 250 patients, 56 (22 %) patients died, and 72 (29 %) patients required intubation. Thirty-four (14 %) had a neurological chief complaint at presentation; the most common neurological chief complaints in the entire sample were altered mental status (AMS) (8 %), headache (2 %), and syncope (2 %). We used a competing risk model to determine whether neurological symptoms at presentation or during hospital stay were predictors of prolonged hospital stay and death. To establish whether neurological symptoms were associated with higher odds of intubation, we used logistic regression. Age was the only significant demographic predictor of death and hospital stay. The HR (95 %CI) for remaining in the hospital for a ten-year increase in age was 1.2, (1.1, 1.3, p < 0.0001), and for death was 1.3, (1.1, 1.5, p < 0.01). There were no demographic characteristics, including age or comorbidities predictive of intubation. Adjusting for age, patients who at presentation had neurological issues as their chief complaint were at significantly increased risk for remaining in the hospital, HR = 1.7, (1.1,2.5, p = 0.0001), and dying, HR = 2.1(1.1,3.8, p = 0.02), compared to patients without any neurological complaint. Of the individual admission complaints, AMS was associated with a significantly prolonged hospital stay, HR = 1.8, (1.0-3.3, p = 0.05). Patients that required dialysis or intubation or had AMS during hospitalization had more extended hospital stays. After adjusting for age, dialysis, and intubation, patients with AMS during hospital stay had a HR of 1.6, (1.1, 2.5, p = 0.01) for remaining in the hospital. Patients who had statistically significant higher odds of requiring intubation were those who presented with any neurological chief complaint, OR = 2.8 (1.3,5.8, p = 0.01), or with headaches OR = 13.3 (2.1,257.0, p = 0.008). Patients with AMS during the hospital stay, as well as those who had seizures, were more likely to need intubation. In the multivariate model, dialysis, OR = 4.9 (2.6,9.4, p < 0.0001), and AMS, OR = 8.8 (3.9,21.2, p < 0.0001), were the only independent predictors of intubation. Neurological complaints at presentation and during the hospital stay are associated with a higher risk of death, prolonged hospital stay, and intubation. More work is needed to determine whether the cause of the neurological complaints was direct CNS involvement by the virus or the other systemic complications of the virus.

Therapeutic vaccination with a trivalent T-cell receptor (TCR) peptide vaccine restores deficient FoxP3 expression and TCR recognition in subjects with multiple sclerosis.

Therapeutic vaccination using T-cell receptor (TCR) peptides from V genes commonly expressed by potentially pathogenic T cells remains an approach of interest for treatment of multiple sclerosis (MS) and other autoimmune diseases. We developed a trivalent TCR vaccine containing complementarity determining region (CDR) 2 peptides from BV5S2, BV6S5 and BV13S1 emulsified in incomplete Freund's adjuvant that reliably induced high frequencies of TCR-specific T cells. To evaluate induction of regulatory T-cell subtypes, immunological and clinical parameters were followed in 23 treatment-naïve subjects with relapsing-remitting or progressive MS who received 12 monthly injections of the trivalent peptide vaccine over 1 year in an open-label study design. Prior to vaccination, subjects had reduced expression of forkhead box (Fox) P3 message and protein, and reduced recognition of the expressed TCR repertoire by TCR-reactive cells compared with healthy control donors. After three or four injections, most vaccinated MS subjects developed high frequencies of circulating interleukin (IL)-10-secreting T cells specific for the injected TCR peptides and significantly enhanced expression of FoxP3 by regulatory T cells present in both 'native' CD4+ CD25+ and 'inducible' CD4+ CD25- peripheral blood mononuclear cells (PBMC). At the end of the trial, PBMC from vaccinated MS subjects retained or further increased FoxP3 expression levels, exhibited significantly enhanced recognition of the TCR V gene repertoire apparently generated by perturbation of the TCR network, and significantly suppressed neuroantigen but not recall antigen responses. These findings demonstrate that therapeutic vaccination using only three commonly expressed BV gene determinants can induce an expanded immunoregulatory network in vivo that may optimally control complex autoreactive responses that characterize the inflammatory phase of MS.

Cultural Adaptation, Validity, and Factor Structure of the Jalowiec Coping Scale in Iranian Women with Multiple Sclerosis: Which Coping Strategies Are Most Common and Effective?

BACKGROUND: The aims of this study were to evaluate the Jalowiec Coping Scale (JCS) psychometrically in Iranian women with multiple sclerosis (MS) and to identify the most frequent and efficacious coping strategies. METHODS: A total of 306 women with MS participated in a cross-sectional study. A demographics questionnaire, the JCS, and the Perceived Stress Scale were administered. Forward-backward translation was used to achieve a Persian version of the scale. Cronbach α and test-retest were assessed for reliability. Convergent and discriminant validity were tested using an item-scaling procedure. The association of the JCS with perceived stress was examined using multiple regression. The factor structure was also explored using rotated exploratory factor analysis. RESULTS: Participants had a mean (SD) age of 32.0 (6.6) years, and nearly half reported visual impairment as the first symptom of disease. Cronbach α for the scale was 0.898 and for the subscales ranged from 0.254 to 0.778. Relatively good convergent and discriminant validity were achieved (success rate ≥69%). Subscales assessing optimistic, fatalistic, and emotive coping predicted stress levels. A four-factor solution explained 30% of the total variance. Optimistic and supportive coping styles were the most common and effective styles, respectively, reported. CONCLUSIONS: The JCS may be useful in assessing coping strategies in Iranian women with MS. Further studies are needed to better understand how coping styles used in practice are similar to their theoretical constructs.

Low-fat, plant-based diet in multiple sclerosis: A randomized controlled trial.

BACKGROUND: The role that dietary interventions can play in multiple sclerosis (MS) management is of huge interest amongst patients and researchers but data evaluating this is limited. Possible effects of a very-low-fat, plant-based dietary intervention on MS related progression and disease activity as measured by brain imaging and MS related symptoms have not been evaluated in a randomized-controlled trial. Despite use of disease modifying therapies (DMT), poor quality of life (QOL) in MS patients can be a significant problem with fatigue being one of the common disabling symptoms. Effective treatment options for fatigue remain limited. Emerging evidence suggests diet and vascular risk factors including obesity and hyperlipidemia may influence MS disease progression and improve QOL. OBJECTIVES: To evaluate adherence, safety and effects of a very-low-fat, plant-based diet (Diet) on brain MRI, clinical [MS relapses and disability, body mass index (BMI)] and metabolic (blood lipids and insulin) outcomes, QOL [Short Form-36 (SF-36)], and fatigue [Fatigue Severity Scale (FSS) and Modified Fatigue Impact Scale (MFIS)], in relapsing-remitting MS (RRMS). METHODS: This was a randomized-controlled, assessor-blinded, one-year long study with 61 participants assigned to either Diet (N=32) or wait-listed (Control, N=29) group. RESULTS: The mean age (years) [Control-40.9±8.48; Diet-40.8±8.86] and the mean disease duration (years) [Control -5.3±3.86; Diet-5.33±3.63] were comparable between the two groups. There was a slight difference between the two study groups in the baseline mean expanded disability status scale (EDSS) score [Control-2.22±0.90; Diet-2.72±1.05]. Eight subjects withdrew (Diet, N=6; Control, N=2). Adherence to the study diet based on monthly Food Frequency Questionnaire (FFQ) was excellent with the diet group showing significant difference in the total fat caloric intake compared to the control group [total fat intake/total calories averaged ~15% (Diet) versus ~40% (Control)]. The two groups showed no differences in brain MRI outcomes, number of MS relapses or disability at 12 months. The diet group showed improvements at six months in low-density lipoprotein cholesterol (Δ=-11.99mg/dL; p=0.031), total cholesterol (Δ=-13.18mg/dL; p=0.027) and insulin (Δ=-2.82mg/dL; p=0.0067), mean monthly reductions in BMI (Rate=-1.125kg/m2 per month; p<0.001) and fatigue [FSS (Rate=-0.0639 points/month; p=0.0010); MFIS (Rate=-0.233 points/month; p=0.0011)] during the 12-month period. CONCLUSIONS: While a very-low fat, plant-based diet was well adhered to and tolerated, it resulted in no significant improvement on brain MRI, relapse rate or disability as assessed by EDSS scores in subjects with RRMS over one year. The diet group however showed significant improvements in measures of fatigue, BMI and metabolic biomarkers. The study was powered to detect only very large effects on MRI activity so smaller but clinically meaningful effects cannot be excluded. The diet intervention resulted in a beneficial effect on the self-reported outcome of fatigue but these results should be interpreted cautiously as a wait-list control group may not completely control for a placebo effect and there was a baseline imbalance on fatigue scores between the groups. If maintained, the improved lipid profile and BMI could yield long-term vascular health benefits. Longer studies with larger sample sizes are needed to better understand the long-term health benefits of this diet.

Polyphenon E, non-futile at neuroprotection in multiple sclerosis but unpredictably hepatotoxic: Phase I single group and phase II randomized placebo-controlled studies.

OBJECTIVES: Phase I (PhI): assess the safety of Polyphenon E in people with multiple sclerosis (MS) and determine the futility of Polyphenon E as a neuroprotective agent. Correlate plasma levels of EGCG with neuroprotective effects. Phase II (PhII): Further assess safety and confirm the neuroprotective effects of Polyphenon E. DESIGN: PhI: single group futility study. PhII: parallel group randomized double-blind placebo-controlled study. PARTICIPANTS: Recruitment area (both studies): LSU MS Center, New Orleans, LA and general public from surrounding areas. Inclusion criteria (both studies): 1) MS per 2005 McDonald criteria; 2) relapsing remitting or secondary progressive MS; 3) stable for six months prior to enrollment on either no therapy or glatiramer acetate (GA) for the PhI study and on either on GA or Interferon ß for the PhII study. Exclusion criteria (both studies): 1) complete bone marrow ablation or alentuzumab use at any time; 2) mitoxantrone, cyclophosphamide, natalizumab or fingolimod use in the prior nine months; 3) liver problems or significant medical problems. INTERVENTIONS: PhI: Polyphenon E, a green tea extract containing 50% of the antioxidant Epigallocatechin-gallate (EGCG), two capsules twice daily (200mg of EGCG per capsule; total daily dose 800mg) for six months. PhII: Polyphenon E or matching placebo capsules, same dose for one year. Only the research pharmacist knew treatment assignment and she randomized participants (one-to-one, stratified by GA or Interferon ß, blocks of 4 or 6). Outcome evaluators did not discuss side effects with participants. OUTCOME MEASURES: PhI: 1) adverse events (AE); 2) futility: decrease in N-acetyl aspartate (NAA) from baseline to six months of 10% or more; 3) association between EGCG plasma levels and change in NAA. PhII: 1) AEs; 2) difference in the rate of change of NAA-levels over twelve months.We measured NAA using a point resolved magnetic resonance spectroscopic imaging sequence (TE30/TR2000) on a 10cm×10cm×1cm volume of interest (VOI) located just superior to the lateral ventricles. The field of view was 16×16 resulting in 1cm(3) voxels. We quantified NAA and creatine/phosphocreatine (Cr) levels using LCModel for post-processing. RESULTS: PhI: Ten participants enrolled and completed all assessments with no serious AEs. One discontinued therapy due to grade (G) I abnormal liver function tests (LFTs). We included all participants in the analysis. NAA adjusted for creatine increased by 10% [95% CI(3.4%,16.2%), p<0.01] rejecting the futility endpoint. PhII: Thirteen participants enrolled and twelve started treatment. The DSMB stopped the study because 5/7 participants on Polyphenon E had abnormal LFTs (G I, and 1G III). Median time to onset of abnormal LFTs was 20 weeks [Inter-Quartile Range (IQR) (10,23)]. Only two participants completed the six-month visit, so we could not analyze the NAA levels. PhI participants took capsules from lot 189I1107 while 6/7 PhII participants took capsules from a new lot (L0206306). Both lots had similar levels of EGCG but differed in the levels of minor catechins. There were no significant differences between the lots on participants' median free EGCG plasma levels at either 3h or 8h as well as conjugated EGCG levels at 3h (all p>0.4, Wilcoxon exact test). Free EGCG levels at 8h correlated with changes in NAA adjusted by water content. A 1ng/ml higher EGCG plasma concentration correlated with a 0.9% increase in NAA[95% CI(0.5%,1.4%), visit*level interaction F=14.4, p<0.001]. However, EGCG plasma concentrations did not correlate with NAA adjusted by creatine (1ng/ml higher EGCG was associated with 0.02%,[95% CI(-0.27%,0.3%) change in NAA, p>0.5]). There was a trend towards an increase in creatine levels (referenced to water content) from baseline to exit (1 5% increase, [95% CI(-6%,17%), p=0.4]). The free EGCG levels at 8hours correlated significantly with change in creatine levels (1ng/ml higher EGCG level at 8h was associated with a 1.1% increase in creatine [95% CI(0.6%,1.6%)]). Thus it is possible that the discrepancy between the correlation of the EGCG 8h levels with NAA changes referenced to water and the 8h EGCG levels with NAA changes referenced to creatine was due to a change in creatine among the subjects with higher EGCG levels. Conjugated 3h and 8h levels and free 3h levels did not correlate with NAA changes (all p >0.5). CONCLUSIONS/CLASSIFICATION OF EVIDENCE: Class III evidence: Polyphenon E at a dose of 400mg of EGCG twice a day is not futile at increasing brain NAA levels. Class I evidence: some lots of Polyphenon E have a high risk of hepatotoxicity. FUNDING: National Center for Complementary and Alternative Medicine K23AT004433, National Multiple Sclerosis Society RG4816-A-1 and National Institute of General Medical Sciences 1 U54 GM104940. Mitsui Norin provided Polyphenon E and placebo and their representative reviewed the manuscript prior to publication. Mitsui Norin was not involved in other aspects of the study. The decision to submit the manuscript remained with the investigators. REGISTRATION: NCT00836719 and NCT01451723

Tumefactive multiple sclerosis and hepatitis C virus 2a/2C infection: Dual benefit of long-term interferon beta-1a therapy?

Hepatitis C virus (HCV) infection has been implicated in triggering acute disseminated encephalomyelitis but not tumefactive multiple sclerosis. We report the case of a 17-year-old female who presented with a 5-day history of left hemiparesis and hemisensory loss followed by a right third nerve palsy. Tumefactive multiple sclerosis was diagnosed based on the absence of encephalopathic signs, the presence of tumefactive brain lesions, the exclusion of neoplastic and infectious causes of the lesions by biopsy, and the occurrence of relapse after a period of remission. The patient was at risk for HCV infection due to parenteral drug abuse and multiple sexual partners. Serial HCV antibody tests and RNA polymerase chain reaction assays revealed acute HCV infection and genotyping showed HCV genotype 2a/2c. She was treated with high-dose methylprednisolone and discharged with only mild left hand weakness. Interferon beta-1a 30mcg was administered intramuscularly once a week. Remission from HCV infection was achieved in three years without standard anti-HCV therapy. This case suggests that CNS myelin is a potential target of the immune response to HCV 2a/2c infection, the HCV 2a/2c virus may be involved in triggering autoimmune tumefactive brain lesions, and interferon beta-1a is effective against HCV 2a/2c infection. We recommend serial HCV antibody testing and HCV RNA PCR assay, preferably with HCV genotyping, in all patients with acute inflammatory demyelinating diseases of the CNS.

Fatigue is associated with poor sleep in people with multiple sclerosis and cognitive impairment.

Background. Fatigue is the most common symptom in people with multiple sclerosis (MS). Poor sleep also occurs in this population. Objective. The objective of this study was to determine the relationship between fatigue and sleep quality in people with MS and cognitive impairment. Method. This cross-sectional study assessed relationships among fatigue, assessed with the Modified Fatigue Impact Scale (MFIS) and the Fatigue Severity Scale (FSS), sleep quality assessed with the Pittsburg Sleep Quality Index (PSQI), and demographics in 121 people with MS and cognitive impairment. Results. Fatigue was significantly correlated with poor sleep quality (MFIS: F = 15.60, P < 0.01; FSS: F = 12.09, P < 0.01). FSS scores were also significantly correlated with the PSQI subscore for daytime dysfunction and MFIS scores were significantly correlated with disability, age, and the PSQI subscores for sleep quality, sleep duration, and daytime dysfunction. Conclusions. This study demonstrates a relationship between fatigue and sleep quality in individuals with MS and cognitive impairment.

A randomized trial of stress management for the prevention of new brain lesions in MS.

OBJECTIVES: This trial examined the efficacy of a stress management program in reducing neuroimaging markers of multiple sclerosis (MS) disease activity. METHODS: A total of 121 patients with relapsing forms of MS were randomized to receive stress management therapy for MS (SMT-MS) or a wait-list control condition. SMT-MS provided 16 individual treatment sessions over 24 weeks, followed by a 24-week post-treatment follow-up. The primary outcome was the cumulative number of new gadolinium-enhancing (Gd+) brain lesions on MRI at weeks 8, 16, and 24. Secondary outcomes included new or enlarging T2 MRI lesions, brain volume change, clinical exacerbation, and stress. RESULTS: SMT-MS resulted in a reduction in cumulative Gd+ lesions (p = 0.04) and greater numbers of participants remained free of Gd+ lesions during the treatment (76.8% vs 54.7%, p = 0.02), compared to participants receiving the control treatment. SMT-MS also resulted in significantly reduced numbers of cumulative new T2 lesions (p = 0.005) and a greater number of participants remaining free of new T2 lesions (69.5% vs 42.7%, p = 0.006). These effects were no longer detectable during the 24-week post-treatment follow-up period. CONCLUSIONS: This trial indicates that SMT-MS may be useful in reducing the development of new MRI brain lesions while patients are in treatment. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that SMT-MS, a manualized stress management therapy program, reduced the number of Gd+ lesions in patients with MS during a 24-week treatment period. This benefit was not sustained beyond 24 weeks, and there were no clinical benefits. TRIAL REGISTRATION: ClinicalTrials.gov, number NCT00147446.