William J. Culpepper

The Gulf War era multiple sclerosis cohort: age and incidence rates by race, sex and service

We characterize here a new nationwide incident cohort of multiple sclerosis from the US military-veteran population. This cohort provides an update to the only other US nationwide incidence study of multiple sclerosis performed during the 1970s. Medical records and data from the Department of Defense and Department of Veterans Affairs for cases of multiple sclerosis who served in the military between 1990, the start of the Gulf War era, and 2007 and who were service-connected for this disorder by the Department of Veterans Affairs from 1990 on, were reviewed. A total of 2691 patients were confirmed as having multiple sclerosis: 2288 definite, 190 possible, 207 clinically isolated syndrome and six neuromyelitis optica. Overall racial categories were White, Black and other, which included all Hispanics. There were 1278 White males and 556 females; 360 Black males and 296 females; and 200 others, 153 (77%) of whom were Hispanic. Mean age at onset of 30.7 years did not differ significantly by race or sex. Age at onset was 17-50 years in 99%, the same age range as 99% of the military. Average annual age specific (age 17-50 years) incidence rates per 100 000 for the entire series were 9.6 with 95% confidence interval of 9.3-10.0. Rates for Blacks were highest at 12.1 with confidence interval 11.2-13.1, Whites were 9.3 (interval 8.9-9.8) and others 6.9 (interval 6.0-7.9). For 83 Hispanics defined for 2000-07, the rate was 8.2 (interval 6.5-10.1). Much smaller numbers gave rates of 3.3 for Asian/Pacific Islanders and 3.1 for native Americans. Rates by sex for Whites were 7.3 and 25.8 male and female, respectively, for Blacks 8.4 and 26.3, and for Hispanics 6.6 and 17.0. Rates by service were high for Air Force (10.9) and Army (10.6), medium for Navy (9.1) and Coast Guard (7.9), and low for Marines (5.3). Relative risk of multiple sclerosis was 3.39 female:male and 1.27 Black:White. These new findings indicate that females of all races now have incidence rates for multiple sclerosis some three times those of their male counterparts and that among these groups, Blacks have the highest and others (probably including Hispanics) the lowest incidence rates regardless of sex or service. The low rate for Marines is unexplained. This Gulf War era multiple sclerosis cohort provides a unique resource for further study.

Time of Birth, Residential Solar Radiation and Age at Onset of Multiple Sclerosis

Backgrounds/Aim: Gestational and early life events have been suggested to contribute to multiple sclerosis (MS) susceptibility. We assessed the effects of time and place of birth on the age at onset of MS symptoms. Methods: We selected a national cohort of 967 veterans from the Multiple Sclerosis Surveillance Registry for whom month and season (time) of birth, and birthplace (city and state) were available. Multiple linear regression analyses were used to examine the association between time of birth, birthplace latitude and solar radiation, and the age at onset of MS symptoms among the study sample. Results: Patients with a relapsing form of the disease (R-MS), who were born in winter and whose birthplace was in low solar radiation areas, had disease symptom onset on average 2.8 years earlier than those born in seasons other than winter and in medium- and high-solar radiation areas (p = 0.02). Conclusions: These results suggest that exposure early in life to geographical and seasonal factors, possibly related to the protective effect of sunlight, and thus vitamin D, is associated with a delay in MS symptom onset. Other larger studies are required to examine the period-specific (from conception to adulthood) environmental factors that are associated with MS susceptibility.

Sun Exposure, Vitamin D and Age at Disease Onset in Relapsing Multiple Sclerosis

Background: Current evidence suggests that sun exposure and vitamin D intake, during childhood and adolescence, are associated with a reduced risk of multiple sclerosis (MS). However, the role of these environmental agents in the timing of disease symptom onset remains to be investigated. Methods: Using a cross-sectional study design, we recruited participants from the Veterans Health Administration – Multiple Sclerosis Surveillance Registry. Self-reported histories of residential locations, sun exposure and intake of vitamin D were used to estimate vitamin-D-related exposures. Multivariable linear regression analysis was used to examine the associations between these variables and age at MS onset. Results: Among veterans with relapsing MS who resided in low-to-medium solar radiation areas (n = 540), low sun exposure in the fall/winter during the ages of 6–15 years was significantly associated with earlier symptom onset by 2.1 years (p = 0.02). Intake of cod liver oil during the same age period was associated with later onset of MS symptoms by 4 years (p = 0.02). Conclusions: The current study provides evidence for an association between vitamin-D-related exposures during childhood and early adolescence and the timing of MS symptom onset, and supports vitamin D as a potential modulator of the clinical course of this disease.

Sun Exposure, Vitamin D Intake and Progression to Disability among Veterans with Progressive Multiple Sclerosis

Background: Early life events have been suggested to influence multiple sclerosis (MS) susceptibility, and to potentially modulate its clinical course. We assessed vitamin D-related exposures from childhood to disease onset and their associations with MS progression. Methods: Among veterans in the Multiple Sclerosis Surveillance Registry, 219 reported having the progressive form and met the inclusion criteria. Participants reported their past sun exposure, vitamin D-related intake and age at disability milestones using the Patient-Determined Disease Steps (PDDS). The Cox proportional hazards model was used to examine the association between vitamin D-related exposures and time (years) to disability. Results: Low average sun exposure in the fall/winter before disease onset was associated with an increased risk of progressing to a PDDS score of 8 (hazard ratio, HR: 2.13, 95% confidence interval, CI: 1.20–3.78), whereas use of cod liver oil during childhood and adolescence was associated with a reduced risk (HR: 0.44, 95% CI: 0.20–0.96). Conclusions: These results suggest that exposure to vitamin D before MS onset might slow disease-related neurodegeneration and thus delay progression to disability among patients with the progressive subtype.

The incidence and prevalence of comorbidity in multiple sclerosis

It is generally accepted that comorbidity, the presence of one or more co-occurring conditions or diseases, increases with age, and is common in patients with a chronic disease such as multiple sclerosis (MS). And, more importantly, that comorbidity can have many effects such as diagnostic delays, selection of treatment and their outcomes, as well as worsening quality of life, to name a few. However, it is only relatively recently that there has been a focused awareness and interest in the impact of comorbid conditions in MS patients. This is evidenced by the formation of the International Workshop on MS Comorbidities being sponsored by the International Advisory Committee on Clinical trials of the European Committee for Treatment and Research in MS (ECTRIMS) and the National MS Society (NMSS). This workshop is slated for late March, where a group of international MS researchers and clinicians will meet with the aims of better describing the types of comorbidities that commonly occur in MS patients, identifying gaps in the research and suggesting strategies for addressing these gaps. In this special issue of the Multiple Sclerosis Journal, Marrie and colleagues present six papers that provide a comprehensive review of the literature on the incidence and prevalence of a variety of comorbidities in MS. These papers provide a foundation for discussions at the upcoming MS Comorbidities workshop as well as providing the MS field with a compendium of the existing literature on the incidence and prevalence of comorbidities that occur in patients with MS.

Multiple Sclerosis in Gulf War Era Veterans. 2. Military Deployment and Risk of Multiple Sclerosis in the First Gulf War

Background: Concern has been raised that US veterans of the 1990-1991 Gulf War (GW1) may be at increased risk to develop neurologic disease. Methods: An incident cohort of multiple sclerosis (MS) and other demyelinating disease (ODD) was assembled from the US military comprising the Gulf War era (1990-2007). Cases of MS and ODD meeting standard diagnostic criteria were matched to a database of all active duty personnel from the Department of Defense. Relative risk (RR) estimates for MS and all demyelinating disease based on onset, deployment status, and exposures were calculated. Results: For GW1, a total of 1,841 incident cases of definite MS and ODD were identified, with 387 among 696,118 deployed and 1,454 among 1,786,215 nondeployed personnel. The RR for MS alone among those deployed compared to those nondeployed was 0.69 (confidence interval, CI: 0.61-0.78), with 0.72 (CI: 0.62-0.83) in men and 0.96 (CI: 0.75-1.22) in women. Deployment was also nonsignificant or protective as an MS risk factor across racial groups, all age groups, and each military service. RRs for MS by service were: Air Force 0.71 (CI: 0.53-0.96), Army 0.80 (CI: 0.67-0.96), Marines 0.96 (CI: 0.63-1.47), and Navy 0.56 (CI: 0.43-0.74). Conclusion: Military deployment to GW1 was not a risk factor for developing MS.

VHA Multiple Sclerosis Surveillance Registry and its similarities to other contemporary multiple sclerosis cohorts.

The Veterans Health Administration (VHA) has provided important contributions to our understanding of multiple sclerosis (MS); however, the characteristics of the modern VHA MS population have not been adequately characterized. Our objectives were to compare and contrast characteristics of the VHA MS population with other contemporary MS cohorts. A cross-sectional, mail-based survey of a stratified, random sample of 3,905 VHA users with MS was conducted. Detailed demographic and clinical data were collected as well as patient-reported outcomes assessing disability and quality of life. A total of 1,379 Veterans were enrolled into the MS Surveillance Registry (MSSR). Respondents did not differ from nonrespondents with regard to demographics or region. When compared to several other contemporary MS cohorts, some demographic differences were noted; however, the age of MS onset and diagnosis, subtype distribution, and most prevalent symptoms were very similar across MS cohorts. The MSSR appears to be representative of the general MS population. Combining the extensive VHA health services encounter data with the MSSR provides a rich and unique cohort for study.

Comorbidity increases the risk of hospitalizations in MS: Prevention opportunities

Comorbidity is pervasive throughout health care, affecting the health status of patients, influencing treatment decisions and the resulting outcomes. A recent review of disease multimorbidity patterns showed nonrandom associations for 3 groups: cardiovascular and metabolic diseases, mental health problems, and musculoskeletal disorders.1 Comorbid conditions are frequent in chronic conditions such as multiple sclerosis (MS). In fact, Marrie et al.2 have shown that vascular comorbidities are detectable as early as the time of diagnosis, evidenced by greater self-reported disability in patients with one or more such comorbidities. These authors have also shown that the presence of vascular comorbidities over the course of the disease are associated with a shorter time to impaired ambulation requiring gait assistance of about 6 years.3 Despite the recognized importance of comorbidity, the routine assessment of comorbidities has not been fully appreciated nor implemented in clinical practice.

A retrospective review of lithium usage in veterans with multiple sclerosis.

OBJECTIVE Lithium (Li) reduces disease activity in animal models of multiple sclerosis (MS), but has not been previously studied in human MS. While developing a clinical trial to test the effects of Li in MS, we performed a retrospective chart review to determine the safety and tolerability of Li among US veterans with MS. METHODS We identified all veterans with MS prescribed Li from 1998 to 2009 using the Department of Veterans Affairs Pharmacy Benefits Management. Charts were reviewed for Li-related adverse events and effects on the MS disease course. RESULTS Among 21,847 veterans with MS, 101 met inclusion criteria and took Li ≥6 months. Eighteen percent of subjects experienced a Li-associated adverse event. Later age of MS onset was associated with increased risk of Li-related adverse events (p=0.004). Associations between Li use and MS disease activity were mixed: Li was not associated with increased risk of enhancing MRI lesions (p=0.655), but annualized relapse rates were higher on Li (0.34 vs. 0.20, p=0.044). In contrast, change in Expanded Disability Status Scale scores was greater in the off-Li period than the on-Li period (0.8 vs. 0.3, p=0.003). CONCLUSION Adverse events occur in a minority of Li-treated MS patients. A consistent effect of Li on MS disease activity was not apparent. These findings indicate a clinical trial will be needed to ascertain Lis effects on the MS disease course.

The Gulf War era multiple sclerosis cohort: 3. Early clinical features

To present clinical features at diagnosis for a large nationwide incident cohort of multiple sclerosis (MS) among those serving in the US military during the Gulf War era (GWE).