Sexual problems in MS: Sex differences and their impact on quality of life.

BACKGROUND: Low sexual function and satisfaction are common problems among people with multiple sclerosis (PwMS), but the literature on which patient variables are associated with these issues is inconsistent. OBJECTIVE: To investigate the associations between sexual function and satisfaction in PwMS with clinical, demographic, and patient-reported quality of life (QOL) measures and determine if sex differences exist. METHODS: This analysis includes PwMS enrolled in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital (CLIMB), who completed patient-reported outcome measures: Multiple Sclerosis Quality of Life-54 (MSQOL-54), Modified Fatigue Impact Scale (MFIS), and Center for Epidemiologic Studies Depression Scale (CES-D). Regression models were used to analyze associations between patient variables and function and satisfaction. Results were stratified by sex. Cross-sectional and longitudinal data were used. RESULTS: 702 PwMS (526 females,176 males, mean age 42.2 +/-11.1, median EDSS 1.5) were included in the cross-sectional analysis. Data from 341 PwMS were used in the three-year longitudinal analysis. Increasing age, disease duration, and disability were associated with reduced sexual function and satisfaction to the same degree in males and females. However, sex differences existed in the strength of associations with QOL variables. There was no significant longitudinal change in females or males. CONCLUSIONS: Age and disease duration were associated with reduced sexual function and satisfaction in males and females. In females, function was significantly associated with disability and satisfaction with fatigue. Males had stronger associations with sexual function in domains related to emotional well-being, health perceptions, and overall QOL. Males had stronger associations with satisfaction in emotional and social functioning and physical health domains. These findings can help better understand the multidimensional problems of sexual function and satisfaction in PwMS and better guide patient care.

Identification of a predominant cognitive phenotype in patients with multiple sclerosis.

BACKGROUND AND PURPOSE: Cognitive impairment occurs frequently in multiple sclerosis (MS). However, the prevalence and clinical characteristics of cognitive MS phenotype are not well established. The aim of the study was to characterize the clinical course and neurocognitive impairment of patients with MS meeting an Expanded Disability Status Scale (EDSS)-defined cognitive phenotype. METHODS: A total of 2302 patients from the Comprehensive Longitudinal Investigation of Multiple Sclerosis at Brigham and Women's Hospital (CLIMB) study were studied. Predominant cognitive MS phenotype was defined as EDSS Cerebral Functional System (FS) subscore ≥3 and remaining EDSS FS subscores ≤2 on at least one clinical visit. Demographic/clinical characteristics, phenotype stability and neurocognitive domain impairment of these subjects were assessed. RESULTS: A total of 60 of 2302 (2.6%) patients (age 52.8 ± 10.8 years, 68% female, 82% relapsing MS) met criteria for phenotype designation. A total of 29 of 60 (48%) were designated within 10 years of their presenting MS symptom. The mean cohort annualized relapse rate was 0.38 and EDSS score at last clinical assessment was 3.2 ± 1.3. Cognitive phenotype status was poorly sustained, with only 27% of subjects maintaining Cerebral FS score ≥2 throughout all follow-up. However, predominant cognitive phenotype subjects with clinical neuropsychiatric testing [n = 39/60 (65%)] frequently had cognitive impairment (1.5 SD below mean) in ≥1 domain [n = 30/39 (77%) of subjects] affecting memory, attention/executive function and processing speed. A total of 11 of 39 (28%) patients had severe-range cognitive impairment (3.0 SD below mean). Cognitive phenotype designation was associated with low rate of employment at last clinical assessment. CONCLUSION: Predominant cognitive MS phenotype is rare, although an EDSS-based definition identifies patients with multidomain cognitive impairment and may serve as a practical screen for identification of patients who might warrant close monitoring of neurocognitive status.

Low testosterone is associated with disability in men with multiple sclerosis.

BACKGROUND: Gonadal steroids may modulate disease course in multiple sclerosis (MS). OBJECTIVE: To assess the prevalence and clinical associations of hypogonadism in men with MS. METHODS: Male patients, aged 18-65 years, with relapsing-remitting MS (RRMS) or clinically-isolated syndrome (CIS) and their first symptom < 10 years prior were selected from a longitudinal clinical study. We measured their hormones in stored morning blood samples, and collected their Expanded Disability Status Scale (EDSS) scores every 6 months and their Symbol Digit Modalities Test (SDMT) results annually. RESULTS: Our analysis included 96 men with a mean age of 40 years, EDSS of 1.1 and disease duration of 4.6 years. Of these men, 39% were hypogonadal (total testosterone < 288 ng/dL); none showed compensatory elevations in luteinizing hormone. Their low testosterone levels and testosterone:estradiol ratios were negatively correlated with body mass index (BMI) and leptin, and showed no correlation with 25-hydroxy-vitamin D levels. In our primary cross-sectional analyses, there was a negative age-adjusted correlation between total testosterone and EDSS (p = 0.044). In the age-adjusted longitudinal analyses, higher baseline testosterone levels were associated with less decline in SDMT (p = 0.012). CONCLUSIONS: Men with MS may experience hypogonadotropic hypogonadism. Low testosterone levels may be associated with worse clinical outcomes. A potential neuroprotective role for testosterone warrants further investigation.

Improving the quality of mental health care in multiple sclerosis.

OBJECTIVE: An exploratory study of mental health treatment of people with multiple sclerosis (MS) to identify hypotheses for future testing. METHODS: We mailed surveys to 8750 MS patients in four geographically distributed MS Centers; 3384 completed the survey. We used a modified version of the Experience of Care and Health Outcome Survey™ to assess mental health problems and experiences with mental health treatment and the Kessler 6 scale to identify serious mental illness. RESULTS: In the year before the survey, sixty percent of patients reported mental health problems. Less than one half of these individuals received mental health treatment, either from their MS care provider or a mental health professional in the MS Center or the community. Patients generally had good mental health treatment experiences, and felt helped by their treatment, but gave less positive reports about how long it took to be seen, receiving information about treatment options and managing their condition, and phone contact. Care experiences were more positive among those who received care from mental health professionals (compared to medical care providers) and among those receiving mental health treatment in the MS Center (compared to in the community). CONCLUSIONS: The unmet need for mental health treatment for people with MS is high. Options for MS care providers to help meet this need include hiring mental health professionals to provide on-site treatment; providing mental health treatment themselves; and referring patients to mental health professionals in the community and collaborating in integrated care. This study provided preliminary data for two related hypotheses that warrant further testing: MS patients will receive better mental health care if their mental health treatment is co-located with their MS care and if it is provided by mental health professionals.

Patients' perspectives on quality of mental health care for people with MS.

OBJECTIVE: The objective was to obtain multiple sclerosis (MS) patients' report on their experience receiving mental health care. METHODS: We convened focus groups at four MS clinical care centers to identify the aspects of mental health care that were important to people with MS. All patients (n=54) had received mental health care in the past year. Data were analyzed by coding comments under specific themes. RESULTS: Patients wanted prompt intervention after diagnosis and ongoing screening for mental health problems; they prefer providers with knowledge about MS and experience working with people with MS; they appreciated being able to access mental health services that were on-site at their MS center and noted the benefit of inclusion of family members in treatment. CONCLUSIONS: Mental health care should be provided promptly after diagnosis, with regular screening and interventions that include family members as indicated thereafter. Mental health providers should be familiar with MS, collaborate with neurologic care providers and provide services on-site at MS centers.

Identification and clinical impact of multiple sclerosis cortical lesions as assessed by routine 3T MR imaging.

BACKGROUND AND PURPOSE: Histopathologic studies have reported widespread cortical lesions in MS; however, in vivo detection by using routinely available pulse sequences is challenging. We investigated the relative frequency and subtypes of cortical lesions and their relationships to white matter lesions and cognitive and physical disability. MATERIALS AND METHODS: Cortical lesions were identified and classified on the basis of concurrent review of 3D FLAIR and 3D T1-weighted IR-SPGR 3T MR images in 26 patients with MS. Twenty-five patients completed the MACFIMS battery. White matter lesion volume, cortical lesion number, and cortical lesion volume were assessed. RESULTS: Overall, 249 cortical lesions were detected. Cortical lesions were present in 24/26 patients (92.3%) (range per patient, 0-30; mean, 9.6 ± 8.8). Most (94.4%, n = 235) cortical lesions were classified as mixed cortical-subcortical (type I); the remaining 5.6% (n = 14) were classified as purely intracortical (type II). Subpial cortical lesions (type III) were not detected. White matter lesion volume correlated with cortical lesion number and cortical lesion volume (r(S) = 0.652, r(S) = 0.705, respectively; both P < .001). After controlling for age, depression, and premorbid intelligence, we found that all MR imaging variables (cortical lesion number, cortical lesion volume, white matter lesion volume) correlated with the SDMT score (R(2) = 0.513, R(2) = 0.449, R(2) = 0.418, respectively; P < .014); cortical lesion number also correlated with the CVLT-II scores (R(2) = 0.542-0.461, P < .043). The EDSS scores correlated with cortical lesion number and cortical lesion volume (r(S) = 0.472, r(S) = 0.404, respectively; P < .05), but not with white matter lesion volume. CONCLUSIONS: Our routinely available imaging method detected many cortical lesions in patients with MS and was useful in their precise topographic characterization in the context of the gray matter-white matter junction. Routinely detectable cortical lesions were related to physical disability and cognitive impairment.

HLA (A-B-C and -DRB1) alleles and brain MRI changes in multiple sclerosis: a longitudinal study.

Several major histocompatibility complex (MHC) alleles have been postulated to influence the susceptibility to multiple sclerosis (MS), as well as its clinical/radiological course. In this longitudinal observation, we further explored the impact of human leukocyte antigen (HLA) class I/II alleles on MS outcomes, and we tested the hypothesis that HLA DRB1*1501 might uncover different strata of MS subjects harboring distinct MHC allele associations with magnetic resonance imaging (MRI) measures. Five hundred eighteen MS patients with two-digit HLA typing and at least one brain MRI were recruited for the study. T2-weighted hyperintense lesion volume (T2LV) and brain parenchymal fraction (BPF) were acquired at each time point. The association between allele count and MRI values was determined using linear regression modeling controlling for age, disease duration and gender. Analyses were also stratified by the presence/absence of HLA DRB1*1501. HLA DRB1*04 was associated with higher T2LV (P=0.006); after stratification, its significance remained only in the presence of HLA DRB1*1501 (P=0.012). The negative effect of HLA DRB1*14 on T2LV was exerted in DRB1*1501-negative group (P=0.012). Longitudinal analysis showed that HLA DRB1*10 was significantly protective on T2LV accrual in the presence of HLA DRB1*1501 (P=0.002). Although the majority of our results did not withstand multiple comparison correction, the differential impact of several HLA alleles in the presence/absence of HLA DRB1*1501 suggests that they may interact in determining the different phenotypic expressions of MS.

HLA B*44: protective effects in MS susceptibility and MRI outcome measures.

OBJECTIVE: In addition to the main multiple sclerosis (MS) major histocompatibility complex (MHC) risk allele (HLA DRB1*1501), investigations of the MHC have implicated several class I MHC loci (HLA A, HLA B, and HLA C) as potential independent MS susceptibility loci. Here, we evaluate the role of 3 putative protective alleles in MS: HLA A*02, HLA B*44, and HLA C*05. METHODS: Subjects include a clinic-based patient sample with a diagnosis of either MS or a clinically isolated syndrome (n = 532), compared to subjects in a bone marrow donor registry (n = 776). All subjects have 2-digit HLA data. Logistic regression was used to determine the independence of each allele's effect. We used linear regression and an additive model to test for correlation between an allele and MRI and clinical measures of disease course. RESULTS: After accounting for the effect of HLA DRB1*1501, both HLA A*02 and HLA B*44 are validated as susceptibility alleles (p(A*02) 0.00039 and p(B*44) 0.00092) and remain significantly associated with MS susceptibility in the presence of the other allele. Although A*02 is not associated with MS outcome measures, HLA B*44 demonstrates association with a better radiologic outcome both in terms of brain parenchymal fraction and T2 hyperintense lesion volume (p = 0.03 for each outcome). CONCLUSION: The MHC class I alleles HLA A*02 and HLA B*44 independently reduce susceptibility to MS, but only HLA B*44 appears to influence disease course, preserving brain volume and reducing the burden of T2 hyperintense lesions in subjects with MS.

Incidence and factors associated with treatment failure in the CLIMB multiple sclerosis cohort study.

OBJECTIVE: To determine the rate of treatment failure in patients outside of a controlled treatment trial and to ascertain the factors physicians used to make this decision. METHODS: One hundred and thirty four patients with the diagnosis of relapsing-remitting (RR) multiple sclerosis (MS) or clinically isolated symptom (CIS) enrolled in the CLIMB study (Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital) were treated with either interferon beta or glatiramer acetate as their initial treatment for MS. RESULTS: The probability of failing initial treatment within 3 years was 30%. Clinical activity, defined as relapses and/or progression in disability, determined treatment failure in 35.7% (n=10) of nonresponders. New T2 hyperintense or gadolinium-enhancing lesions on MRI was used to define treatment failure in 28.6% (n=8) and new MRI lesions were used in combination with clinical activity in 35.7% (n=10). Treatment failures had a higher T2 hyperintense lesion volume (p=0.015) and number of gadolinium-enhancing lesions (p=0.0001) on the enrollment MRI than responders. CONCLUSIONS: These observations demonstrate that treating physicians use both clinical and MRI parameters to define a response to treatment and initiation of a treatment change and that baseline MRI identified those with increased risk of treatment failure.

Demographics of pediatric-onset multiple sclerosis in an MS center population from the Northeastern United States.

BACKGROUND: The prevalence of pediatric-onset multiple sclerosis (MS) in the United States is unknown. OBJECTIVE: In a large cohort of MS patients, we sought to identify the proportion with first symptom-onset below the age of 18 years, and to compare their demographic and disease characteristics to a typical adult-onset MS population. METHODS: Patients seen at the Partners Multiple Sclerosis Center, Brigham and Women's Hospital, Boston, Massachusetts, with clinical histories and characteristics of first symptoms recorded in an electronic database, were included in this study. RESULTS: We found that 3.06% of patients with a recorded MS history experienced a first attack under the age of 18 years of age compared to 30.83% of patients who experienced first symptoms between the ages of 25-35 years. Gender proportions were similar in both groups, with the exception of a lower female preponderance in pre-pubertal-onset patients. There was a higher proportion of non-Caucasians in the younger cohort. Localization of first symptoms was similar in the two groups. CONCLUSION: About 3% of MS patients experience their first symptom prior to the age of 18 years. Standardized follow-up is required after a first demyelinating attack in childhood, which may lead to earlier diagnosis and treatment of pediatric-onset MS.

Cognitive dysfunction in patients with clinically isolated syndromes or newly diagnosed multiple sclerosis.

Cognitive dysfunction is common in patients with multiple sclerosis (MS), and has been associated with MRI measures of lesion burden and atrophy. Little is known about the prevalence of cognitive impairment in patients with early MS. The associations between cognitive impairment and MRI measures of disease severity early in the disease course are also unclear. This study used a brief battery of cognitive tests to determine the prevalence and pattern of cognitive impairment in patients with clinically isolated syndromes or newly diagnosed MS. The associations between cognitive impairment and MRI measures of disease severity early in the disease course were also examined. Ninety-two patients with clinically isolated syndromes or the diagnosis of MS within the last 3 years participating in the CLIMB study underwent a neurologic examination, neuropsychological evaluation and MRI at 1.5 T. Forty-nine percent of patients were impaired on one or more cognitive measures. There were no significant correlations between cognitive scores and MRI measures of disease severity including total T2 lesion volume, normal appearing white matter volume, grey matter volume, and brain parenchymal fraction. These findings suggest that cognitive impairment may predate the appearance of gross structural abnormalities on MRI and serve as an early marker of disease activity in MS.

Predicting short-term disability in multiple sclerosis.

OBJECTIVE: To develop covariate specific short-term disability curves to demonstrate the probability of progressing by Expanded Disability Status Scale (EDSS) at semiannual visits. METHODS: Semiannual EDSS scores were prospectively collected in 218 relapsing-remitting (RR) and clinically isolated syndrome (CIS) patients as part of the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital (CLIMB) study. Baseline brain parenchymal fraction (BPF) and T2 lesion volume were available on 205 patients. A partial proportional odds model determined the influence of covariates on the change in EDSS score at subsequent visits. A discrete second order Markov transitional model was fit and generated a probability matrix for each subject; the 6-month probabilities of EDSS change were graphically represented. RESULTS: The univariate analysis demonstrated the lowest baseline BPF quartile (OR 1.99; p = 0.0203) and the highest T2 lesion volume quartile (OR 2.19; p = 0.0130) were associated with progression in EDSS. Covariate specific disability curves demonstrated the effect of BPF and T2 lesion volume on short-term progression. In subjects with a 6-month EDSS of 2, the probability of a sustained progression of an EDSS of 3 within 3 years was 0.277 for a subject with low BPF and a high T2 lesion volume vs 0.055 for a subject with high BPF and a low T2 lesion volume. CONCLUSIONS: Markov transitional models allow for the comparison of covariate specific short-term disability changes among groups of patients with multiple sclerosis.

Lateralized cognitive dysfunction in patients with systemic lupus erythematosus.

This study was designed to determine whether there is a lateralized pattern of cognitive dysfunction in patients with systemic lupus erythematosus (SLE). Fifty right-handed patients with SLE, but no history of cerebrovascular disease participated in the study. Thirty right-handed healthy subjects matched for age and education served as controls. SLE and healthy control subjects underwent a three-hour neuropsychological evaluation designed to measure attention, memory, visual spatial skills, verbal skills reasoning, psychomotor speed, and motor function. A cognitive disability index was created to identify cognitive impairment. Percentile tables based on the performance of all subjects were constructed for 20 component scores. Any subject with five or more component scores below the 25th percentile was designated impaired. Using this criterion, cognitive impairment was identified in 50% of patients with SLE and 20% of healthy controls. Patients with SLE were impaired on measures of psychomotor speed/fluency, verbal speed/fluency and verbal memory. This pattern of performance on neuropsycholgical testing was consistent with left hemisphere brain dysfunction. The observed deficits were not clearly attributable to vascular lesions and suggest immune-mediated effects on specific brain regions in a subgroup of patients with SLE.

Prevalence of migraine in patients with systemic lupus erythematosus.

OBJECTIVE: To determine the prevalence of migraine in patients with systemic lupus erythematosus (SLE), and to examine the relationships between headache type and other clinical, serologic, and treatment features of the disease. BACKGROUND: Headaches are common in SLE and are a significant source of patient disability. The exact prevalence of headaches in patients with SLE is unknown. The classification of headache syndromes in SLE is also unclear. Previous studies were based on small numbers of patients and the headache types and criteria to define headache types varied widely. METHODS: Four hundred fourteen patients meeting American College of Rheumatology criteria for the diagnosis of SLE were sent the University of California, San Diego Migraine Questionnaire. Patients who completed the questionnaire had their medical records reviewed for constitutional, respiratory, cardiac, vascular, skin, musculoskeletal, other neuropsychiatric, hematologic, renal, and immunologic manifestations of the disease. Recent corticosteroid, nonsteroidal anti-inflammatory drug, antimalarial, and immunosuppressive medications were also recorded. RESULTS: One hundred eighty-six patients completed the questionnaire. Sixty-two percent of patients reported headaches: 39% met diagnostic criteria for migraine and 23% met criteria for nonmigrainous headache. Of the patients with migraine, 56% met criteria for migraine without aura and 44% met criteria for migraine with aura. There were no significant associations between headache type and other clinical, serologic, or treatment features of the disease. CONCLUSIONS: There is a high prevalence of migraine in patients with SLE, and patients should be routinely evaluated for migraine symptoms.

Lateralized EEG findings in patients with neuropsychiatric manifestations of systemic lupus erythematosus.

Routine and quantitative EEG were used to determine whether there is a lateralized pattern of electrophysiologic dysfunction in patients with diverse neuropsychiatric manifestations of SLE. Twenty consecutive patients with neuropsychiatric symptoms of SLE underwent 20-minute EEG recordings with an 18-channel polygraph. Ten 1-second intervals were randomly selected for each patient. Once selected, the intervals were analyzed for the presence of theta and delta slow activity. Mapping was done by four-point interpolation around the 18 acquired data points. On routine EEG, abnormalities were identified in 14/20 patients with SLE. In 12/14 patients, the abnormalities were localized to the left temporal region. Quantitative EEG analyses revealed theta and delta slow activity predominantly affecting the left hemisphere in 16/19 patients with SLE. Taken together, these findings suggest selective involvement of the left hemisphere in patients with diverse neuropsychiatric manifestations of SLE.

Evaluation of predictive factors for neurocognitive dysfunction in patients with inactive systemic lupus erythematosus.

OBJECTIVE: To determine predictive factors associated with the cognitive dysfunction in patients with inactive systemic lupus erythematosus (SLE). METHODS: Consecutive patients followed at the Lupus Clinic with inactive SLE (SLE Disease Activity Index, SLEDAI, = 0) underwent a battery of neuropsychological tests; Beck Depression Inventory and psychiatric assessment were also performed. Neurocognitive dysfunction was defined as 3 abnormal scores. Data were analyzed using chi-square tests, ANOVA tests, and logistic regression. RESULTS: Twenty-five of the 58 patients with SLE (43%) versus 9 of 47 healthy controls (19%) demonstrated neurocognitive dysfunction (p < 0.01). Neurocognitive dysfunction was not associated with depression or a psychiatric diagnosis, use of steroids, or previous or current evidence for fibromyalgia. SLEDAI > 10 at first presentation to the Lupus Clinic and previous vasculitis were associated with neurocognitive dysfunction, but previous central nervous system disease, renal disease, renal damage, or atherosclerotic complications were not. Neurophysiologic studies at the time of the assessment were not predictive of neurocognitive dysfunction. CONCLUSION: Patients with inactive SLE demonstrate neurocognitive dysfunction. This is associated with more disease activity at presentation, but is not associated with specific organ involvement or organ damage.

EEG abnormalities in systemic lupus erythematosus.

The medical records of 478 SLE patients were reviewed. Ninety-five patients (19.9%) with a history of seizures were identified. EEG reports were available on 62. EEGs were interpreted as normal in 8 (12.9%) and abnormal in 54 (87.1%). Abnormal EEGs were reviewed for the presence of unilateral and bilateral abnormalities. Left hemisphere abnormalities were identified in 43 (79.6%), right hemisphere abnormalities in 4 (7.4%), and bilateral abnormalities in 7 (13.0%) patients with SLE. Abnormalities included theta and delta slowing and sharp wave activity. In 32 of the 43 (74.4%) patients with left hemisphere abnormalities, the abnormalities were localized to the left temporal leads. These findings suggest selective damage to the left temporolimbic region in patients with SLE.

Pattern of neuropsychologic dysfunction in inactive systemic lupus erythematosus.

The pattern of neuropsychological dysfunction in patients with inactive systemic lupus erythematosus (SLE) was examined. Fifty-eight subjects with inactive SLE and 47 healthy controls were administered a standardized neuropsychological test battery. Summary scores reflecting 18 different cognitive processes were derived. Subjects were designated cognitively impaired if three or more summary scores differed significantly from premorbid estimates of cognitive functioning. Cognitive impairment was identified in 43% of subjects with inactive SLE and 19% of healthy controls. Subjects with inactive SLE, as a group, performed significantly worse than healthy controls on measures of auditory verbal memory, visual spatial memory, psychomotor speed, and motor functioning. A significantly greater proportion of subjects with inactive SLE than healthy controls was impaired only on a measure of visual spatial memory. Cognitive impairment in subjects with inactive SLE was associated with increasing age. There were no associations between cognitive impairment and current depressive symptoms or current corticosteroid use. These findings suggest that cognitive dysfunction occurs frequently in inactive SLE. The variability of performance of subjects with inactive SLE is consistent with the heterogeneity of CNS involvement in the disease.