Maria K. Houtchens

Thalamic atrophy and cognition in multiple sclerosis

Objectives: Recent studies have indicated that brain atrophy is more closely associated with cognitive impairment in multiple sclerosis (MS) than are conventional MRI lesion measures. Enlargement of the third ventricle shows a particularly strong correlation with cognitive impairment, suggesting clinical relevance of damage to surrounding structures, such as the thalamus. Previous imaging and pathology studies have demonstrated thalamic involvement in MS. In this study, we tested the hypothesis that thalamic volume is lower in MS than in normal subjects, and that thalamic atrophy in MS correlates with cognitive function. Methods: We studied 79 patients with MS and 16 normal subjects. A subgroup of 31 MS subjects underwent cognitive testing. The thalamus was segmented in whole from three-dimensional MRI scans. We also determined whole brain atrophy (brain parenchymal fraction), third ventricular width, and whole brain T2-weighted (fluid-attenuated inversion recovery) hyperintense, T1 hypointense, and gadolinium-enhanced lesion volumes. Results: Normalized thalamic volume was 16.8% lower in the MS group (p < 0.0001) vs controls. Cognitive performance in all domains was moderately to strongly related to thalamic volume in the MS group (r = 0.506 to 0.724, p < 0.005), and thalamic volume entered and remained in all regression models predicting cognitive performance. Thalamic volume showed a weak relationship to physical disability score (r = −0.316, p = 0.005). Conclusion: These findings suggest that thalamic atrophy is a clinically relevant biomarker of the neurodegenerative disease process in multiple sclerosis.

Smoking and Disease Progression in Multiple Sclerosis

BACKGROUND Although cigarette smokers are at increased risk of developing multiple sclerosis (MS), the effect of smoking on the progression of MS remains uncertain. OBJECTIVE To establish the relationship between cigarette smoking and progression of MS using clinical and magnetic resonance imaging outcomes DESIGN Cross-sectional survey and longitudinal follow-up for a mean of 3.29 years, ending January 15, 2008. SETTING Partners MS Center (Boston, Massachusetts), a referral center for patients with MS. PATIENTS Study participants included 1465 patients with clinically definite MS (25.1% men), with mean (range) age at baseline of 42.0 (16-75) years and disease duration of 9.4 (0-50.4) years. Seven hundred eighty patients (53.2%) were never-smokers, 428 (29.2%) were ex-smokers, and 257 (17.5%) were current smokers. MAIN OUTCOME MEASURES Smoking groups were compared for baseline clinical and magnetic resonance imaging characteristics as well as progression and sustained progression on the Expanded Disability Status Scale at 2 and 5 years and time to disease conversion to secondary progressive MS. In addition, the rate of on-study change in the brain parenchymal fraction and T2 hyperintense lesion volume were compared. RESULTS Current smokers had significantly worse disease at baseline than never-smokers in terms of Expanded Disability Status Scale score (adjusted P < .001), Multiple Sclerosis Severity Score (adjusted P < .001), and brain parenchymal fraction (adjusted P = .004). In addition, current smokers were significantly more likely to have primary progressive MS (adjusted odds ratio, 2.41; 95% confidence interval, 1.09-5.34). At longitudinal analyses, MS in smokers progressed from relapsing-remitting to secondary progressive disease faster than in never-smokers (hazard ratio for current smokers vs never-smokers, 2.50; 95% confidence interval, 1.42-4.41). In addition, in smokers, the T2-weighted lesion volume increased faster (P = .02), and brain parenchymal fraction decreased faster (P = .02). CONCLUSION Our data suggest that cigarette smoke has an adverse influence on the progression of MS and accelerates conversion from a relapsing-remitting to a progressive course.

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 1.5T. 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. Multiple Sclerosis 2007; 13: 1004—1010. http://msj.sagepub.com

Open label gabapentin treatment for pain in multiple sclerosis.

Pain is a frequent and distressing complaint in patients with multiple sclerosis (MS) and may present a difficult therapeutic problem. Conventional therapy is moderately effective and includes, among others, a variety of anticonvulsant medications. Gabapentin (Neurontin™) is a new generation antiepileptic drug which appears to be advantageous in treatment of intractable pain of reflex sympathetic dystrophy. This study investigates the benefits of open-label treatment with gabapentin for pain control in 25 patients with MS. Excellent to moderate pain relief was obtained in a substantial number of patients. Throbbing pains, pins and needles, and cramping pains responded best, and dull aching pains responded least to the medication. There was no significant change in distribution and type of pain as a result of this treatment Mild to moderate side effects were observed. Cautious escalation of the dose of gabapentin is advisable in MS patients. Further clinical trials with larger patient groups are recommended.

Brain MRI lesion load at 1.5T and 3T versus clinical status in multiple sclerosis.

To assess correlation between brain lesions and clinical status with 1.5T and 3T magnetic resonance imaging (MRI).

Multiple sclerosis and pregnancy: therapeutic considerations

For women with multiple sclerosis (MS) who become pregnant, the risks and benefits of ongoing therapy for the health of both the mother and the fetus must be carefully considered. Based on a literature review and our MS center’s standard practices, we provide guidance to aid clinical decision making in the absence of clear evidence-based clinical practice guidelines. Women seeking to achieve pregnancy should generally discontinue disease-modifying therapy use prior to attempting conception. For example, the immunosuppressant mitoxantrone is teratogenic and should be prescribed only with the assurance of effective contraception. Conception should be discouraged for patients on fingolimod, because of the limited information available on human pregnancy outcomes. Current evidence, including data from pregnancy registries for glatiramer acetate (GA), interferon beta-1a (IFNβ-1a), and natalizumab, has not shown specific patterns of malformations suggesting teratogenicity. Pregnancy registry data have not been published for IFNβ-1b. During breastfeeding, intravenous immunoglobulin and corticosteroids are generally safe and may be associated with a reduction in postpartum relapses; however, a washout period is recommended between corticosteroid administration and the resumption of breastfeeding. Clinical data on the use of IFNβ, GA, and natalizumab during lactation are limited. Mitoxantrone is contraindicated during breastfeeding, and fingolimod should be avoided in nursing mothers, because of a lack of data.

The relationships among MRI-defined spinal cord involvement, brain involvement, and disability in multiple sclerosis

To determine the interrelationships between MRI‐defined lesion and atrophy measures of spinal cord involvement and brain involvement and their relationships to disability in a small cohort of patients with multiple sclerosis (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 alleles 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 (pA*02 0.00039 and pB*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.

3 T MRI relaxometry detects T2 prolongation in the cerebral normal-appearing white matter in multiple sclerosis

MRI at 3 T has increased sensitivity in detecting overt multiple sclerosis (MS) brain lesions; a growing body of data suggests clinically relevant damage occurs in the normal-appearing white matter (NAWM). We tested a novel pulse sequence to determine whether 3 T MRI spin-spin relaxometry detected damage in NAWM of MS patients (n=13) vs. age-matched normal controls [(NL) (n=11)]. Baseline characteristics of the MS group were: age (mean+/-SD) 42.5+/-5.4 (range 33-51 years), disease duration 9.0+/-6.4 (range 1-22 years), Expanded Disability Status Scale score 2.5+/-1.7 (range 1-6.5). Brain MRI measures, obtained at 3 T, included global and regional NAWM transverse relaxation rate [R2 (=1/T2)], derived from 3D fast spin-echo T2 prepared images, and global white matter volume fraction derived from SPGR images. The regional NAWM areas investigated were the frontal lobe, parietal lobe, and the genu and splenium of the corpus callosum. Mean NAWM R2 was lower (indicating T2 prolongation) in MS than NL in the whole brain (p=0.00047), frontal NAWM (p=0.00015), parietal NAWM (p=0.0069) and callosal genu (p=0.0019). Similarly, R2 histogram peak position was lower in NAWM in MS than NL in the whole brain (p=0.019). However, the normalized WM volume fractions were similar in both MS and NL (p>0.1). This pilot study suggests that a novel 3D fast spin-echo pulse sequence at 3 T, used to derive R2 relaxation maps, can detect tissue damage in the global and regional cerebral NAWM of MS patients that is missed by conventional lesion and atrophy measures. Such findings may represent demyelination, inflammation, glial proliferation and axonal loss.

Management of multiple sclerosis during pregnancy and the reproductive years: a systematic review.

OBJECTIVE: To examine the evidence guiding management of multiple sclerosis (MS) in reproductive-aged women. DATA SOURCES: We conducted an electronic literature search using PubMed, ClinicalTrials.gov, and other available resources. The following keywords were used: “multiple sclerosis” and “pregnancy.” We manually searched the reference lists of identified studies. METHODS OF STUDY SELECTION: Two reviewers categorized all studies identified in the search by management topic, including effect of pregnancy on MS course, fetal risks associated with disease-modifying treatments during pregnancy, and management of patients off disease-modifying treatment. We categorized studies by strength of evidence and included prior meta-analyses and systematic studies. These studies were then summarized and discussed by an expert multidisciplinary team. TABULATION, INTEGRATION, AND RESULTS: The risk of MS relapses is decreased during pregnancy and increased postpartum. Data are lacking regarding the risks of disease-modifying treatments during pregnancy. There may be an increased risk of MS relapses after use of assisted reproductive techniques. There does not appear to be a major increase in adverse outcomes in newborns of mothers with MS. CONCLUSION: Although there are many unmet research needs, the reviewed data support the conclusion that in the majority of cases, women with MS can safely choose to become pregnant, give birth, and breastfeed children. Clinical management should be individualized to optimize both the mothers reproductive outcomes and MS course.