Bonnie I. Glanz

The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes

OBJECTIVE To develop a standardized nomenclature system for the neuropsychiatric syndromes of systemic lupus erythematosus (NPSLE). METHODS An international, multidisciplinary committee representing rheumatology, neurology, psychiatry, neuropsychology, and hematology developed case definitions, reporting standards, and diagnostic testing recommendations. Before and after the meeting, clinician committee members assigned diagnoses to sets of vignettes randomly generated from a pool of 108 NPSLE patients. To assess whether the nomenclature system improved diagnostic agreement, a consensus index was developed and pre- and postmeeting scores were compared by t-tests. RESULTS Case definitions including diagnostic criteria, important exclusions, and methods of ascertainment were developed for 19 NPSLE syndromes. Recommendations for standard reporting requirements, minimum laboratory evaluation, and imaging techniques were formulated. A short neuropsychological test battery for the diagnosis of cognitive deficits was proposed. In the postmeeting exercise, a statistically significant improvement in diagnostic agreement was observed. CONCLUSION The American College of Rheumatology (ACR) Nomenclature for NPSLE provides case definitions for 19 neuropsychiatric syndromes seen in SLE, with reporting standards and recommendations for laboratory and imaging tests. It is intended to facilitate and enhance clinical research, particularly multicenter studies, and reporting. In clinical settings, consultation with other specialists may be required. It should be useful for didactic purposes but should not be used uncritically or as a substitute for a clinical diagnosis. The complete case definitions are available on the ACR World Wide Web site: http://www.rheumatology .org/ar/ar.html.

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.

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 1.5T. 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

Deep gray matter involvement on brain MRI scans is associated with clinical progression in multiple sclerosis.

Conventional brain MRI lesion measures have unreliable associations with clinical progression in multiple sclerosis (MS). Gray matter imaging may improve clinical‐MRI correlations.

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).

The association between cognitive impairment and quality of life in patients with early multiple sclerosis

Cognitive deficits are common in patients with multiple sclerosis (MS) and may be observed early in the course of the disease. Current knowledge about the association between cognitive impairment and health-related quality of life (HQOL) in patients with early MS is limited. We used a well-established battery of cognitive tests and standardized HQOL measures to examine the associations between overall and domain-specific cognitive performance and quality of life in patients with early MS. Ninety-two patients with CIS or MS diagnosed in the previous three years participating in the CLIMB Natural History Study underwent a neurologic examination, neuropsychological evaluation and quality of life assessment. Associations between cognitive scores and HQOL measures were examined. There were no differences between cognitively impaired versus unimpaired subjects on any of the HQOL measures. After controlling for depression, scores on tests of information processing speed were significantly associated with several measures of HQOL including physical well-being, fatigue, and social support. In all cases, correlations between HQOL and cognitive measures were mild. These findings were observed in patients with limited cognitive impairment and minimal physical disability. Our results suggest that cognitive remediation programs aimed at improving cognitive skills may also improve quality of life for patients with early 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.

Cognitive deterioration in patients with early multiple sclerosis: a 5-year study

Objective The objective was to investigate changes in cognitive functioning in subjects with early multiple sclerosis (MS) over 5 years. Methodological issues associated with longitudinal cognitive research such as practice effects and drop-outs were also examined. Methods Ninety subjects with a diagnosis of clinically isolated syndrome or MS and disease duration from a first symptom of ≤6 years participated in the study. Subjects were administered the Brief Repeatable Battery of Neuropsychological Tests in MS, which includes five measures assessing four cognitive domains. As a means of stabilising practice effects, the battery was administered 1–2 weeks apart at enrolment and then annually for up to 5 years. Results Significant deterioration was found on a measure of working memory and speed of information processing. Significant deterioration was also found on measures of immediate and delayed visual spatial memory. Verbal memory was unchanged over the course of the study. Improved performance was observed on a second measure of speed of information processing and on a measure of verbal fluency. Among subjects with longitudinal follow-up, the drop-out rate was 30%, but subjects who dropped out did not differ from those who completed the study in terms of baseline cognitive performance or the change in cognitive performance from year 1 to year 2. Conclusions Subjects with early MS showed a deterioration in working memory and visual spatial memory over a period of up to 5 years. Although significant practice effects were associated with several cognitive measures, the Symbol Digit Modality Test may be useful for longitudinal evaluations of cognitive functioning in MS.

Identification and Clinical Impact of Multiple Sclerosis Cortical Lesions as Assessed by Routine 3T MR Imaging

It is possible that many if not most clinical symptoms of multiple sclerosis patients are due to plaques in the gray matter and not in the white matter as commonly believed (remember that myelinated fibers are found in cortical and deep gray matter). Could it be that because cortical plaques are not routinely seen at 1.5T we do not think about this issue? Here, the authors studied 26 patients with 3D FLAIR and inversion recovery spoiled gradient recalled sequences at 3T and found cortical plaques in 24 of them. The volume and load of these cortical plaques correlated with those seen in white matter. Cortical lesions also correlated with verbal learning test disability scale results better than white matter lesion load. Conclusion: routinely detectable cortical lesions were related to physical disability and cognitive impairment. 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 (rS = 0.652, rS = 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 (R2 = 0.513, R2 = 0.449, R2 = 0.418, respectively; P < .014); cortical lesion number also correlated with the CVLT-II scores (R2 = 0.542–0.461, P < .043). The EDSS scores correlated with cortical lesion number and cortical lesion volume (rS = 0.472, rS = 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.