A pilot, randomized, placebo-controlled study of mindfulness meditation in treating insomnia in multiple sclerosis.

OBJECTIVE: Mindfulness is an established approach to reduce distress and stress reactivity by improving awareness and tolerability of thoughts and emotions. This study compares mindfulness training to sleep hygiene in persons with multiple sclerosis (PWMS) who report chronic insomnia, examining sleep efficiency (SE), self-reported sleep quality and quality of life. METHODS: Fifty-three PWMS were randomized (1:1) in a single-blinded, parallel group design to ten, two-hour weekly sessions of Mindfulness Based Stress Intervention for Insomnia (MBSI-I) over a span of ten weeks or a single, one hour sleep hygiene (SH) session over one day. The primary outcome measure was SE, measured by the Fitbit™ Charge 2 wrist device, at 10 and 16 weeks from the start of study interventions. Self-report outcomes included the Pittsburg Sleep Quality Rating Scale (PSQI), Insomnia Severity Index (ISI) and the Multiple Sclerosis Quality of Life Inventory (MSQLI). Nineteen participants in the MBSI-I group and 24 in the SH group completed the primary study. Subsequently, ten participants in the original SH group participated in the 10-week MSBI-I course and their data was added to the MBSI-I cohort (eMSBI-I). RESULTS: While neither SE nor the PSQI showed significant differences between MBSI-I, eMBSI-I and SH groups, ISI improved in both the MSBI-I and eMBSI-I vs SH at 10 weeks (p = 0.0014 and p = 0.0275) but not 16 weeks. However, pre and post assessments within the MBSI-I and eMBSI-I cohorts did show significant improvement in the PSQI and ISI at 10 and 16 weeks, while SH was significant in the ISI only at 16 weeks. Several quality of life measurements, including fatigue, mental health and cognitive function favored the mindfulness cohorts. CONCLUSION: This pilot study demonstrates beneficial effects of MBSR on insomnia, sleep quality and quality of life in PWMS. TRIAL REGISTRATION: NCT03949296. 14 May 2019.

Teriflunomide levels in women whose male sexual partner is on teriflunomide for relapsing multiple sclerosis.

BACKGROUND: For small molecules such as teriflunomide, used to treat relapsing multiple sclerosis (MS), that are potentially embryotoxic, there is a theoretical risk of transmission of the medication from males on the drug to female sexual partners. However, that risk has been undefined up to now. METHODS: Teriflunomide concentrations were assayed concomitantly in ten sexually active couples, not using barrier methods of contraception, in whom the male partner with MS was on treatment with teriflunomide 14 mg daily for at least two months. These results were compared by male and female age, teriflunomide concentrations and reported average number of incidences of sexual intercourse per month. The threshold level of detection of teriflunomide was 0.020 µg/ml in females. RESULTS: The average age of the cohort was 46.70 for males and 47.10 for females. Four of ten females had detectible teriflunomide concentrations (mean 0.046 µg/ml (range 0.22-0.077, standard deviation 0.025). Male age and both female teriflunomide positive threshold and female teriflunomide concentration were inversely correlated (r = 0.67, R2=0.45, p = 0.034) for the former and (r = 0.62, R2=0.39, p = 0.05, ns) for the latter. No significant correlations were observed for female age, male teriflunomide concentrations, or reported mean monthly episodes of sexual intercourse. CONCLUSION: This limited study suggests that the small risk that low levels of teriflunomide can be transmitted from male to female partners via sexual intercourse is related to male age. This supports the recommendations found in the United States Product Insert (USPI) stating that men taking teriflunomide who do not wish to father a child, and their female partners, should use reliable contraception. Men wishing to father a child should discontinue use of teriflunomide and undergo an accelerated elimination procedure to reduce the plasma concentrations of the medication to less than 0.02 mg/L (0.02 µg/ml1.

Fingolimod modulates T cell phenotype and regulatory T cell plasticity in vivo.

Fingolimod is an approved therapeutic option for patients with relapsing-remitting multiple sclerosis that primarily functions by sequestering T cells in lymph nodes inhibiting their egress to the central nervous system. However, recent data suggests that Fingolimod may also directly affect the immune cell function. Here we examined the in vivo effects of Fingolimod in modulating the phenotype and function of T cell and Foxp3 regulatory T cell populations in patients with multiple sclerosis under Fingolimod treatment. Besides decreasing the cell numbers in peripheral blood and sera levels of pro-inflammatory cytokines, Fingolimod inhibited the expression of Th1 and Th17 cytokines on CD4+ T cells and increased the expression of exhaustion markers. Furthermore, treatment increased the frequency of regulatory T cells in blood and inhibited the Th1-like phenotype that is characteristic of patients with multiple sclerosis, augmenting the expression of markers associated with increased suppressive function. Overall, our data suggest that Fingolimod performs other important immunomodulatory functions besides altering T cell migratory capacities, with consequences for other autoimmune pathologies characterized by excessive Th1/Th17 responses and Th1-like regulatory T cell effector phenotypes.

Sex differences in decreased limbic and cortical grey matter volume in cocaine dependence: a voxel-based morphometric study.

Structural neuroimaging studies have provided evidence of differences in local brain volume between cocaine-dependent and healthy control individuals. While sex differences in aetiology, course and brain dysfunction associated with chronic cocaine abuse have been previously documented, evidence of sex-specific differences in brain volume has not been examined thus far. This study examined sex-related differences in grey matter volume between cocaine-dependent and healthy control subjects using voxel-based morphometry. High-resolution T1 structural scans were obtained from 36 inpatient, treatment-engaged 3-week abstinent cocaine-dependent (CD) individuals. Fifty healthy control subjects were also scanned. Segmentation and registration were performed in SPM8, using New Segment and DARTEL, respectively. The whole-brain statistical analysis was conducted in SPM8 using random field-based cluster-size testing and family-wise error rate correction for multiple comparisons. CD patients were found to have less grey matter volume in anterior prefrontal cortex, including frontopolar and orbitofrontal cortices, and a posterior region surrounding the parietal-occipital sulcus. Female CD patients had less grey matter volume than female controls in left inferior frontal gyrus, insula, superior temporal gyrus and hippocampus. Male CD patients had less grey matter in a superior cortical region that included the precentral gyrus and the mid-cingulate. These sex differences in lower grey matter volume add to the evidence from functional neuroimaging for sex-specific differences in the neurophysiological changes associated with chronic cocaine use.

Cumulative adversity and smaller gray matter volume in medial prefrontal, anterior cingulate, and insula regions.

BACKGROUND: Cumulative adversity and stress are associated with risk of psychiatric disorders. While basic science studies show repeated and chronic stress effects on prefrontal and limbic neurons, human studies examining cumulative stress and effects on brain morphology are rare. Thus, we assessed whether cumulative adversity is associated with differences in gray matter volume, particularly in regions regulating emotion, self-control, and top-down processing in a community sample. METHODS: One hundred three healthy community participants, aged 18 to 48 and 68% male, completed interview assessment of cumulative adversity and a structural magnetic resonance imaging protocol. Whole-brain voxel-based-morphometry analysis was performed adjusting for age, gender, and total intracranial volume. RESULTS: Cumulative adversity was associated with smaller volume in medial prefrontal cortex (PFC), insular cortex, and subgenual anterior cingulate regions (familywise error corrected, p < .001). Recent stressful life events were associated with smaller volume in two clusters: the medial PFC and the right insula. Life trauma was associated with smaller volume in the medial PFC, anterior cingulate, and subgenual regions. The interaction of greater subjective chronic stress and greater cumulative life events was associated with smaller volume in the orbitofrontal cortex, insula, and anterior and subgenual cingulate regions. CONCLUSIONS: Current results demonstrate that increasing cumulative exposure to adverse life events is associated with smaller gray matter volume in key prefrontal and limbic regions involved in stress, emotion and reward regulation, and impulse control. These differences found in community participants may serve to mediate vulnerability to depression, addiction, and other stress-related psychopathology.

Association of frontal and posterior cortical gray matter volume with time to alcohol relapse: a prospective study.

OBJECTIVE: Alcoholism is associated with gray matter volume deficits in frontal and other brain regions. Whether persistent brain volume deficits in abstinence are predictive of subsequent time to alcohol relapse has not been established. The authors measured gray matter volumes in healthy volunteers and in a sample of treatment-engaged, alcohol-dependent patients after 1 month of abstinence and assessed whether smaller frontal gray matter volume was predictive of subsequent alcohol relapse outcomes. METHOD: Forty-five abstinent alcohol-dependent patients in treatment and 50 healthy comparison subjects were scanned once using high-resolution (T(1)-weighted) structural MRI, and voxel-based morphometry was used to assess regional brain volume differences between the groups. A prospective study design was used to assess alcohol relapse in the alcohol-dependent group for 90 days after discharge from 6 weeks of inpatient treatment. RESULTS: Significantly smaller gray matter volume in alcohol-dependent patients relative to comparison subjects was seen in three regions: the medial frontal cortex, the right lateral prefrontal cortex, and a posterior region surrounding the parietal-occipital sulcus. Smaller medial frontal and parietal-occipital gray matter volumes were each predictive of shorter time to any alcohol use and to heavy drinking relapse. CONCLUSIONS: These findings are the first to demonstrate that gray matter volume deficits in specific medial frontal and posterior parietal-occipital brain regions are predictive of an earlier return to alcohol use and relapse risk, suggesting a significant role for gray matter atrophy in poor clinical outcomes in alcoholism. Extent of gray matter volume deficits in these regions could serve as useful neural markers of relapse risk and alcoholism treatment outcome.

Factors that influence adherence with disease-modifying therapy in MS.

BACKGROUND: The complexity and cost of injection treatment can represent a formidable challenge for patients affected by a chronic illness, particularly those whose treatment is primarily preventative and only modestly effective on the more conspicuous symptomatic aspects of the disease process. The aim of this investigation was to identify which factors most influenced nonadherent behavior with the available disease-modifying injection therapies for multiple sclerosis (MS). METHODS: A multicenter, observational (three-wave) study using surveys was developed and administered to patients with MS through the World Wide Web. Healthcare providers at 17 neurology clinics recruited patients for the study. RESULTS: A total of 798 patients responded to the baseline wave of the study (708 responded to all three waves). The nonadherence rates for all patients (missing one or more injections) across these waves remained relatively stable at 39%, 37%, and 36%, respectively. The most common reason participants listed for missing injections was that they simply forgot to administer the medication (58%). Other factors including injection-site reactions, quality of life, patients' perceptions on the injectable medications, hope, depression, and support were also assessed in relation to adherence. CONCLUSIONS: This study characterizes factors that are associated with failure to fully adhere with disease modifying injection therapy for MS and underscores the principles associated with optimizing adherence and its implications for effective treatment of the disease process in MS.

Stiff-person syndrome with amphiphysin antibodies: distinctive features of a rare disease.

BACKGROUND: Stiff-person syndrome (SPS), formerly Stiff-man syndrome, is a rare autoimmune disease usually exhibiting severe spasms and thoracolumbar stiffness, with very elevated glutamic acid decarboxylase antibodies (GAD Ab). A paraneoplastic variant, less well characterized, is associated with amphiphysin antibodies (amphiphysin Ab). The objective of this study was to identify distinctive clinical features of amphiphysin Ab-associated SPS. METHODS: Records associated with 845 sera tested in the Yale SPS project were examined, and 621 patients with clinically suspected SPS were included in the study. Clinical characteristics were assessed with correction for multiple comparisons. RESULTS: In all, 116 patients had GAD antibodies and 11 patients had amphiphysin Ab; some clinical information was available for 112 and 11 of these patients, respectively. Patients with amphiphysin Ab-associated SPS were exclusively female; mean age was 60. All except one had breast cancer; none had diabetes. Compared to patients with GAD Ab-associated SPS, those with amphiphysin Ab were older (p = 0.02) and showed a dramatically different stiffness pattern (p < 0.0000001) with cervical involvement more likely, p < or = 0.001. Electromyography showed continuous motor unit activity or was reported positive in eight. Benzodiazepines at high dose (average 50 mg/day diazepam) were partially effective. Four patients were steroid responsive and tumor excision with chemotherapy produced marked clinical improvement in three of five patients. CONCLUSIONS: Amphiphysin Ab-associated stiff-person syndrome is strongly associated with cervical region stiffness, female sex, breast cancer, advanced age, EMG abnormalities, and benzodiazepine responsiveness. The condition may respond to steroids and can dramatically improve with cancer treatment.

Quality of life for veterans with multiple sclerosis on disease-modifying agents: Relationship to disability.

Our objective was to compare self-reported health-related quality of life (HRQOL) for U.S. veterans with multiple sclerosis (MS) on disease-modifying agents with provider reports of HRQOL from standard disability measures. We conducted a 3-year prospective observational study of 204 subjects who used interferon beta or glatiramer acetate and compared subjects' responses on the Veterans Short-Form 36 (VSF-36) (36-item short-form functional status assessment for veterans) with the Kurtzke Expanded Disability Status Scale (EDSS) and the Functional System (FS) scales, which are standard MS disability scales. EDSS and FS scores were significantly correlated with some VSF-36 domains (physical function [r = -0.57], role physical [r = -0.37], and physical component summary [r = -0.40]) and weakly correlated with other domains. HRQOL scores did not predict disability or compliance with therapy. We observed decrements in HRQOL at relatively low disability levels. HRQOL measures directly associated with physical function were correlated with standard MS disability scales. Researchers need to clarify the role of HRQOL in clinical outcomes assessment, as shown by the lack of outcome sensitivity and predictive value of the VSF-36.

IM interferon beta-1a delays definite multiple sclerosis 5 years after a first demyelinating event.

BACKGROUND: The Controlled High Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS) showed that IM interferon beta-1a (IFNbeta-1a) significantly slows the rate of development of clinically definite multiple sclerosis (CDMS) over 2 years in high-risk patients who experience a first clinical demyelinating event. This report highlights the primary results of a 5-year, open-label extension of CHAMPS (the Controlled High Risk Avonex Multiple Sclerosis Prevention Study in Ongoing Neurologic Surveillance [CHAMPIONS Study]). OBJECTIVE: To determine if the benefits of IFNbeta-1a observed in CHAMPS are sustained for up to 5 years. METHODS: CHAMPS patients at participating CHAMPIONS sites were enrolled in the study. All patients were offered, but not required to take, IFNbeta-1a 30 microg IM once weekly for up to 5 years (from CHAMPS randomization). Patients who received placebo in CHAMPS were considered the delayed treatment (DT) group, and patients who received IFNbeta-1a in CHAMPS were considered the immediate treatment (IT) group. The primary outcome measure was the rate of development of CDMS. Additional outcomes included disease state classification at 5 years, annualized relapse rates, disability level at 5 years (Expanded Disability Status Scale), and MRI measures at 5 years. RESULTS: Fifty-three percent (203/383) of patients enrolled in CHAMPIONS (n = 100, IT group; n = 103, DT group) and 64% (32/50) of CHAMPS study sites participated in CHAMPIONS. The median time to initiation of IFNbeta-1a therapy in the DT group was 29 months. The cumulative probability of development of CDMS was significantly lower in the IT group compared with the DT group (5-year incidence 36 +/- 9 vs 49 +/- 10%; p = 0.03). Multivariate analysis suggested that the only factors independently associated with an increased rate of development of CDMS were randomization to the DT group and younger age at onset of neurologic symptoms. Few patients in either group developed major disability within 5 years. CONCLUSIONS: These results support the use of IM interferon beta-1a after a first clinical demyelinating event and indicate that there may be modest beneficial effects of immediate treatment compared with delayed initiation of treatment.

Noninvasive measurement of carbon monoxide levels in ED patients with headache.

OBJECTIVES: Carbon Monoxide (CO), the third most common cause of acute poisoning death, is easily overlooked in the emergency department (ED). Nonspecific complaints such as headache, weakness, or malaise may easily result in misdiagnosis. The objectives of this study are to determine the frequency of CO poisoning in patients presenting to the ED complaining of headaches and to determine the feasibility of using noninvasive CO analyzers as a screening tool. METHODS: This prospective controlled study examined, during the winter months, adult patients presenting with a complaint of atraumatic, afebrile headaches. All subjects submitted a sample for a CO breath analyzer. Participants with elevated carboxyhemoglobin (COHb) levels (nonsmokers >2%, smokers >5%) underwent venous COHb testing. Control patients, without headaches, presenting to the ED were similarly studied. RESULTS: We enrolled 170 subjects and 98 controls. Of the 170 subjects, 12 (7.1%) had elevated COHb levels confirmed by venous COHb levels. Of the 98 controls, 1 (1.0%) had an elevated COHb level (p < 0.05). There were no differences in demographic factors between the two groups (p > 0.16). CONCLUSIONS: Noninvasive measurement of CO levels in ED patients with headaches is rapid and specific. During winter months, elevated CO levels are present in over 7% of ED patients with headaches.