Tiffany J. Braley

Sleep-disordered breathing in multiple sclerosis

Background: The objectives of this cross-sectional study were to assess the prevalence and severity of sleep apnea in patients with multiple sclerosis (MS) referred for overnight polysomnography (PSG) and to explore the radiographic and clinical features that might signal risk for undiagnosed sleep apnea. Methods: Apnea-hypopnea (AHI) and central apnea indices (CAI) from laboratory-based PSG among 48 patients with MS were compared with those of group A, 84 sleep laboratory−referred patients without MS matched for age, gender, and body mass index; and group B, a separate group of 48 randomly selected, referred patients. Results: Mean AHI was higher among patients with MS than among control groups A or B (2-way analysis of variance and multiple linear regression, p = 0.0011 and 0.0118, respectively). Median and mean CAI were also increased among patients with MS in comparison to control groups (Wilcoxon signed rank and multiple linear regression, p = 0.0064 and 0.0027, respectively). Among MS patients with available data, those with evidence of brainstem involvement, compared with groups A and B, showed particularly robust differences in AHI (p = 0.0060 and 0.0016) and CAI (p = 0.0215 and <0.0001). In contrast, MS patients without brainstem involvement, compared with groups A and B, showed diminished differences in AHI, and CAI did not significantly differ among groups. Conclusions: These data suggest a predisposition for obstructive sleep apnea and accompanying central apneas among patients with MS, particularly among those with brainstem involvement.

Fatigue, Tiredness, Lack of Energy, and Sleepiness in Multiple Sclerosis Patients Referred for Clinical Polysomnography

Objectives. To assess the relationship between nocturnal polysomnographic (PSG) findings and a group of key self-reported symptoms—fatigue, tiredness, lack of energy, and sleepiness—among sleep-laboratory referred patients with and without multiple sclerosis (MS). Methods. PSG and questionnaire data from n = 30 MS patients and n = 30 matched controls were analyzed retrospectively. Associations between symptoms of fatigue, tiredness, lack of energy, sleepiness, and PSG variables of interest were examined among MS patients and controls. Results. More MS patients than controls reported fatigue, tiredness, and lack of energy to occur often or almost always (Chi-square P < 0.0001 for each), but sleepiness was reported similarly by both groups (P = 0.3409). Among MS patients, tiredness correlated with sleepiness (Spearman correlation P = 0.005), and a trend emerged toward correlation between fatigue and sleepiness (Spearman correlation P = 0.076). Decreased sleep efficiency on PSGs correlated with fatigue, tiredness, and lack of energy in MS patients (Spearman correlation P = 0.002, 0.029, and 0.048, resp.), but not sleepiness or any symptom among controls. Conclusion. In comparison to controls, MS patients report more fatigue, tiredness, and lack energy, but not sleepiness. Fatigue and related symptoms may arise from MS itself or in relation to reduced sleep efficiency.

Obstructive Sleep Apnea and Fatigue in Patients with Multiple Sclerosis

STUDY OBJECTIVES The prevalence of obstructive sleep apnea (OSA) in persons with multiple sclerosis (MS) remains unknown, and little information exists regarding the relative contributions of OSA to symptoms of MS-related fatigue in the presence of other clinical and sleep-related confounders. The objectives of this study were to investigate the prevalence of diagnosed OSA and OSA risk among MS patients, and to assess relationships between fatigue severity, OSA, OSA risk, and sleep quality among persons with MS. METHODS N = 195 MS patients completed a questionnaire comprised of items regarding OSA diagnosis, sleep quality and quantity, daytime symptoms, and 4 validated scales: the Epworth Sleepiness Scale, Fatigue Severity Scale, Insomnia Severity Index, and STOP-Bang questionnaire. Medical records were also accessed to examine clinical characteristics that may predict fatigue or OSA risk. RESULTS N = 41 patients (21%) carried a formal diagnosis of OSA. N = 110 (56%) of all patients, and 38 (93%) of those with diagnosed OSA had STOP-Bang scores ≥ 3, indicating an elevated OSA risk. In regression models, the most significant predictors of higher FSS scores were higher STOP-Bang scores (p = 0.01), higher number of nocturnal symptoms (p < 0.0001), and higher disability level (p < 0.0001). CONCLUSIONS Sleep disturbances, and OSA in particular, may be highly prevalent yet underrecognized contributors to fatigue in persons with MS.

Sleep and Cognitive Function in Multiple Sclerosis

STUDY OBJECTIVES To examine associations between cognitive performance and polysomnographic measures of obstructive sleep apnea in patients with multiple sclerosis (MS). METHODS Participants underwent a comprehensive MS-specific cognitive testing battery (the Minimal Assessment of Cognitive Function in MS, or MACFIMS) and in-laboratory overnight PSG. RESULTS In adjusted linear regression models, the oxygen desaturation index (ODI) and minimum oxygen saturation (MinO2) were significantly associated with performance on multiple MACFIMS measures, including the Paced Auditory Serial Addition Test (PASAT; 2-sec and 3-sec versions), which assesses working memory, processing speed, and attention, and on the Brief Visuospatial Memory Test-Revised, a test of delayed visual memory. The respiratory disturbance index (RDI) was also significantly associated with PASAT-3 scores as well as the California Verbal Learning Test-II (CVLT-II) Discriminability Index, a test of verbal memory and response inhibition. Among these associations, apnea severity measures accounted for between 12% and 23% of the variance in cognitive test performance. Polysomnographic measures of sleep fragmentation (as reflected by the total arousal index) and total sleep time also showed significant associations with a component of the CVLT-II that assesses response inhibition, explaining 18% and 27% of the variance in performance. CONCLUSIONS Among patients with MS, obstructive sleep apnea and sleep disturbance are significantly associated with diminished visual memory, verbal memory, executive function (as reflected by response inhibition), attention, processing speed, and working memory. If sleep disorders degrade these cognitive functions, effective treatment could offer new opportunities to improve cognitive functioning in patients with MS. COMMENTARY A commentary on this article appears in this issue on page 1489.

Sleep Disorders in Multiple Sclerosis

Recent studies suggest that individuals with multiple sclerosis (MS) are at increased risk for sleep disturbances and that sleep disturbances contribute to fatigue and other chronic symptoms in MS. Although fatigue occurs commonly in people with MS, this symptom is often attributed to MS-specific pathology. Consequently, sleep disorders are often unrecognized and untreated in this population. Timely diagnosis and treatment of sleep problems in MS offer a new opportunity to ameliorate some of the daytime fatigue experienced by patients with MS. To increase this opportunity, the practitioner should be comfortable performing basic screening for common sleep complaints among patients with MS. The objectives of this review are to summarize the latest relevant data on sleep disorders in MS and offer a helpful approach to the identification and workup of the most common sleep problems in this population. Unexplored research avenues and opportunities to address important questions at the interface of sleep and MS are also discussed.

Hypnotic use and fatigue in multiple sclerosis

OBJECTIVES Sleep disturbances and fatigue are common in patients with multiple sclerosis (MS), but little is known about hypnotic use patterns in MS, or the relationship between these medications and fatigue. The objectives of this study were to investigate the prevalence of prescription and over-the-counter (OTC) hypnotic use among MS patients, and to assess the relationships between fatigue severity and hypnotic use among persons with MS. METHODS Data on hypnotic use frequency, hypnotic agents of choice, and clinical characteristics were extracted from medical records and a survey dataset from 190 MS patients who completed questionnaires regarding sleep quality, sleep quantity, nocturnal symptoms, sleepiness (Epworth Sleepiness Scale), obstructive sleep apnea risk (STOP-Bang questionnaire), insomnia (Insomnia Severity Index), and fatigue level (Fatigue Severity Scale - FSS). RESULTS Eighty-nine subjects (47%) endorsed hypnotic use occasionally, frequently, or always. OTC diphenhydramine-containing products accounted for the majority of utilization, reported by 47 (25%). The occurrence of occasional or more frequent hypnotic use correlated with daytime fatigue (Spearman rho = 0.28, P = 0.0002), but not sleepiness. Regression of FSS scores on hypnotic use confirmed the association [beta (SE) = 0.55 (0.21), P = 0.0092] after adjustment for clinical and sleep-related confounds. In separate, similarly adjusted models, the use of OTC hypnotics but not prescription hypnotics was independently associated with higher FSS scores [0.54 (0.22), P = 0.0159]. An analogous association was observed more specifically for the use of diphenhydramine-containing products (0.49 (0.24), P = 0.044). CONCLUSIONS Hypnotic use is highly prevalent among MS patients. Carryover effects from hypnotic agents, and in particular OTC diphenhydramine-containing products, could contribute to daytime fatigue.

Ecological Momentary Assessment of Pain, Fatigue, Depressive, and Cognitive Symptoms Reveals Significant Daily Variability in Multiple Sclerosis

OBJECTIVE To describe the daily variability and patterns of pain, fatigue, depressed mood, and cognitive function in persons with multiple sclerosis (MS). DESIGN Repeated-measures observational study of 7 consecutive days of home monitoring, including ecological momentary assessment (EMA) of symptoms. Multilevel mixed models were used to analyze data. SETTING General community. PARTICIPANTS Ambulatory adults (N=107) with MS recruited through the University of Michigan and surrounding community. INTERVENTIONS Not applicable. MAIN OUTCOME MEASURE EMA measures of pain, fatigue, depressed mood, and cognitive function rated on a 0 to 10 scale, collected 5 times a day for 7 days. RESULTS Cognitive function and depressed mood exhibited more stable within-person patterns than pain and fatigue, which varied considerably within person. All symptoms increased in intensity across the day (all P<.02), with fatigue showing the most substantial increase. Notably, this diurnal increase varied by sex and age; women showed a continuous increase from wake to bedtime, whereas fatigue plateaued after 7 pm for men (wake-bed B=1.04, P=.004). For the oldest subgroup, diurnal increases were concentrated to the middle of the day compared with younger subgroups, which showed an earlier onset of fatigue increase and sustained increases until bed time (wake-3 pm B=.04, P=.01; wake-7 pm B=.03, P=.02). Diurnal patterns of cognitive function varied by education; those with advanced college degrees showed a more stable pattern across the day, with significant differences compared with those with bachelor-level degrees in the evening (wake-7 pm B=-.47, P=.02; wake-bed B=-.45, P=.04). CONCLUSIONS Findings suggest that chronic symptoms in MS are not static, even over a short time frame; rather, symptoms-fatigue and pain in particular-vary dynamically across and within days. Incorporation of EMA methods should be considered in the assessment of these chronic MS symptoms to enhance assessment and treatment strategies.

B-Cell Targeting Agents in the Treatment of Multiple Sclerosis

Opinion statementThe aims of this article are to discuss the potential role of B lymphocytes in the pathogenesis of multiple sclerosis (MS) and in the mechanisms of action of approved and emerging disease modifying therapies. Over the last few years, significant progress has been made in the introduction of novel pharmacologic treatments that reduce the frequency of clinical exacerbations and radiological lesion formation in relapsing remitting MS. The mechanisms of action of a number of these disease modifying therapies (DMT) implicate B cells in the pathogenesis, as well as in the regulation, of MS. Further research into B-cell subset trafficking patterns, functional activities and interactions with other immune cells in the context of neuroinflammation is likely to inform the development of future generations of DMT.

Differences in diffusion tensor imaging-derived metrics in the corpus callosum of patients with multiple sclerosis without and with gadolinium-enhancing cerebral lesions.

Objective To analyze differences in corpus callosum diffusion tensor imaging metrics among patients with relapsing-remitting multiple sclerosis (MS) (RRMS) and secondary progressive MS (SPMS) with enhancing and nonenhancing cerebral lesions. Methods One-way analysis of variance and multiple linear regression models were used to assess the relationship between MS subtype, the presence of enhancing lesions, and fractional anisotropy (FA)/mean diffusivity (MD) values of the genu, body, and splenium of the corpus callosum from 22 patients with RRMS and 25 patients with SPMS. Results Analyses of variance: The subjects with SPMS with enhancing lesions had significantly lower genu and body FA values than those with nonenhancing SPMS and significantly lower genu, body, and splenium FA values than those with RRMS. Regression models: Enhancement was associated with decreased genu FA (P = 0.014). Secondary progressive MS was associated with decreased genu (P = 0.002) and splenium FA (P < 0.001) and significantly increased MD values. Conclusion Patients with SPMS with enhancing lesions may be at increased risk for neuronal damage compared to nonenhancing SPMS and RRMS subtypes.

Pain, Fatigue, and Cognitive Symptoms Are Temporally Associated Within but Not Across Days in Multiple Sclerosis

OBJECTIVE To examine the temporal associations, within day and day to day, between pain, fatigue, depressed mood, and cognitive function in multiple sclerosis (MS). DESIGN Repeated-measures study involving 7 days of ecological momentary assessment (EMA) of symptoms 5 times a day; multilevel mixed models were used to analyze data. SETTING Community. PARTICIPANTS Ambulatory adults (N=107) with MS. INTERVENTIONS Not applicable. MAIN OUTCOME MEASURE EMA of pain, fatigue, depressed mood, and cognitive function rated on a 0 to 10 scale. RESULTS Fatigue and pain were linked within day such that higher pain was associated with higher subsequent fatigue (B=.09, P=.04); likewise, higher fatigue was associated with higher pain in the following time frame (B=.05, P=.04). Poorer perceived cognitive function preceded increased subsequent pain (B=.08, P=.007) and fatigue (B=.10, P=.01) within day. Depressed mood was not temporally linked with other symptoms. In terms of day-to-day effects, a day of higher fatigue related to decreased next day fatigue (B=-.16, P=.01), and a day of higher depressed mood related to increased depressed mood the next day (B=.17, P=.01). There were no cross-symptom associations from one day to the next. CONCLUSIONS Findings provide new insights on how common symptoms in MS relate to each other and vary within and over days. Pain and fatigue show evidence of a dynamic bidirectional relation over the course of a day, and worsening of perceived cognitive function preceded worsening of both pain and fatigue. Most temporal associations between symptoms occur within the course of a day, with relatively little carryover from one day to the next.