Rohit Bakshi

Fatigue in multiple sclerosis and its relationship to depression and neurologic disability

We studied multiple sclerosis fatigue (MSF) and its relationship to depression and disability. Seventy-one patients [50 relapsing-remitting, 21 secondary progressive] were grouped by Fatigue Severity Scale (FSS) into MS-fatigue (MSF) (FSS55; n=46) or MS-nonfatigue (MSNF) (FSS44; n=20). Forty-one patients were grouped into MS-depression (MSD) (n=15) or MS-nondepression (MSND) (n=26) by interview. Higher expanded disability status scale (EDSS) scores were noted in MSF than MSNF patients (P=0.0003); EDSS scores correlated with FSS scores (rho=0.43, P=0.003). However, fatigue was present in 58% (n=29) of relapsing-remitting patients and in 52% (n=26) of patients with mild physical disability (EDSS53.5). Hamilton/Beck depression severity scores were higher in MSF than MSNF patients and correlated with FSS scores (P50.05). MSD had higher FSS scores than MSND patients (P=0.008). After controlling for EDSS, depression severity continued to correlate with FSS scores (rho=0.37, P=0.02). After controlling for depression, FSS scores no longer correlated with EDSS scores (rho=0.27, P=0.09). Thus, MSF is independent of physical disability, but is associated with depression, suggesting that common mechanisms play a role in MSF and MSD including psychological factors or brain lesions in specific neuroanatomic pathways. Further study is warranted to determine if antidepressant medications improve fatigue in MS.

Predicting quality of life in multiple sclerosis: accounting for physical disability, fatigue, cognition, mood disorder, personality, and behavior change.

Health-related quality of life (HQOL) is poor in multiple sclerosis (MS) but the clinical precipitants of the problem are not well understood. Previous correlative studies demonstrated relationships between various clinical parameters and diminished HQOL in MS. Unfortunately, these studies failed to account for multiple predictors in the same analysis. We endeavored to determine what clinical parameters account for most variance in predicting HQOL, and employability, while accounting for disease course, physical disability, fatigue, cognition, mood disorder, personality, and behavior disorder. In 120 MS patients, we measured HQOL (MS Quality of Life-54) and vocational status (employed vs. disabled) and then conducted detailed clinical testing. Data were analyzed by linear and logistic regression methods. MS patients reported lower HQOL (p<0.001) and were more likely to be disabled (45% of patients vs. 0 controls). Physical HQOL was predicted by fatigue, depression, and physical disability. Mental HQOL was associated with only depression and fatigue. In contrast, vocational status was predicted by three cognitive tests, conscientiousness, and disease duration (p<0.05). Thus, for the first time, we predicted HQOL in MS while accounting for measures from these many clinical domains. We conclude that self-report HQOL indices are most strongly predicted by measures of depression, whereas vocational status is predicted primarily by objective measures of cognitive function. The findings highlight core clinical problems that merit early identification and further research regarding the development of effective treatment.

Quality of life in patients with multiple sclerosis: the impact of fatigue and depression.

Quality of Life (QOL) is impaired in multiple sclerosis (MS) in part due to physical disability. MS-associated fatigue (MSF) and depression (MSD) are common and treatable features of MS, which could also impact on QOL, independent of physical disability. We prospectively studied 60 consecutive patients with MS. QOL was assessed using Multiple Sclerosis Quality of Life (MSQOL)-54. Group differences in QOL scores were assessed after adjusting for Expanded Disability Status Scale (EDSS), Fatigue Severity Scale (FSS) and Hamilton Depression Inventory scores. MS patients were grouped into relapsing-remitting (RR) or secondary-progressive (SP), MSF (FSS> or =5) or MS-nonfatigue (MSNF) (FSS< or =4), and MSD or MS-nondepression (MSND). After accounting for disability and depression, fatigue was associated with impaired QOL with respect to health perception (p=0.03) and limitations due to physical dysfunction (p=0.008). After accounting for disability and fatigue, depression was associated with lower QOL with respect to health perception (p=0.02), sexual dysfunction (p=0.03), health distress (p=0.03), mental health (p=0.006), overall QOL (p=0.006), emotional dysfunction (p=0.04), and limitations due to emotional dysfunction (p=0.03). This study demonstrates that fatigue and depression are independently associated with impaired QOL in MS, after accounting for physical disability, suggesting that their recognition and treatment can potentially improve QOL.

The measurement and clinical relevance of brain atrophy in multiple sclerosis

Brain atrophy has emerged as a clinically relevant component of disease progression in multiple sclerosis. Progressive loss of brain tissue bulk can be detected in vivo in a sensitive and reproducible manner by MRI. Clinical studies have shown that brain atrophy begins early in the disease course. The increasing amount of data linking brain atrophy to clinical impairments suggest that irreversible tissue destruction is an important determinant of disease progression to a greater extent than can be explained by conventional lesion assessments. In this review, we will summarise the proposed mechanisms contributing to brain atrophy in patients with multiple sclerosis. We will critically discuss the wide range of MRI-based methods used to quantify regional and whole-brain-volume loss. Based on a review of current information, we will summarise the rate of atrophy among phenotypes for multiple sclerosis, the clinical relevance of brain atrophy, and the effect of disease-modifying treatments on its progression.

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.

Fatigue associated with multiple sclerosis: diagnosis, impact and management.

In patients with multiple sclerosis (MS) fatigue is the most common symptom and one of the most disabling features. A s many as 40% have described it as the single most disabling symptom - a higher percentage than weakness, spasticity, motor problems, or bowel or bladder problems. The etiology and patho physiology of MS-related fatigue remain unknown. Studies have failed to demonstrate an association between MS-related fatigue and the level of disability, clinical disease subtype, or gender, although recent data show an association between MS-related fatigue and depression and quality of life. Imaging studies using positron emission tomography suggest that fatigue in MS is related to hypometabolism of specific brain areas, including the frontal and subcortical circuits. The impact of fatigue on patient functioning and quality of life clearly warrants intervention. In addition to nonpharmacologic measures, such as exercise and energy conservation strategies, several pharmacologic agents have been evaluated for their ability to reduce MS-related fatigue, including amantadine, central nervous system stimulants (pemoline), and the novel wake-promoting agent modafinil.

Gray matter involvement in multiple sclerosis

Gray matter (GM) involvement is detected even in the earliest stages of multiple sclerosis (MS), and GM atrophy occurs at a faster rate than white matter (WM) atrophy early in the disease course. Studies published to date establish that 1) GM involvement and in particular cortical demyelination can be extensive in MS; 2) GM pathology may occur in part independently of WM lesion formation; 3) a primarily GM-related process may be the earliest manifestation of MS; 4) GM involvement is associated with physical disability, fatigue, and cognitive impairment in MS; and 5) GM disease might help explain the observed dissociation between markers of inflammatory demyelination (relapses, WM gadolinium enhancement, WM lesion burden) and disease progression. It remains likely that GM damage is related to WM damage. However, continued studies of GM pathology as well as neuronal and axonal involvement in MS and related experimental models are necessary to better understand the etiology and pathogenesis of the degenerative components.

MRI in multiple sclerosis: current status and future prospects

Many promising MRI approaches for research or clinical management of multiple sclerosis (MS) have recently emerged, or are under development or refinement. Advanced MRI methods need to be assessed to determine whether they allow earlier diagnosis or better identification of phenotypes. Improved post-processing should allow more efficient and complete extraction of information from images. Magnetic resonance spectroscopy should improve in sensitivity and specificity with higher field strengths and should enable the detection of a wider array of metabolites. Diffusion imaging is moving closer to the goal of defining structural connectivity and, thereby, determining the functional significance of lesions at specific locations. Cell-specific imaging now seems feasible with new magnetic resonance contrast agents. The imaging of myelin water fraction brings the hope of providing a specific measure of myelin content. Ultra-high-field MRI increases sensitivity, but also presents new technical challenges. Here, we review these recent developments in MRI for MS, and also look forward to refinements in spinal-cord imaging, optic-nerve imaging, perfusion MRI, and functional MRI. Advances in MRI should improve our ability to diagnose, monitor, and understand the pathophysiology of MS.

Gray and white matter brain atrophy and neuropsychological impairment in multiple sclerosis

Background: The relationship of gray and white matter atrophy in multiple sclerosis (MS) to neuropsychological and neuropsychiatric impairment has not been examined. Methods: In 40 patients with MS and 15 age-/sex-matched normal controls, the authors used SPM99 to obtain whole brain normalized volumes of gray and white matter, as well as measured conventional lesion burden (total T1 hypointense and FLAIR hyperintense lesion volume). The whole brain segmentation was corrected for misclassification related to MS brain lesions. To compare the effects of gray matter, white matter, and lesion volumes with respect to brain-behavior relationships, the MS group (disease duration = 11.2 ± 8.8 years; EDSS score = 3.3 ± 1.9) underwent neuropsychological assessment, and was compared to a separate, larger group of age-/sex-matched normal controls (n = 83). Results: The MS group had smaller gray (p = 0.009) and white matter volume (p = 0.018), impaired cognitive performance (verbal memory, visual memory, processing speed, and working memory) (all p < 0.0001), and greater neuropsychiatric symptoms (depression, p < 0.0001; dysphoria, p < 0.0001; irritability, p < 0.0001; anxiety, p < 0.0001; euphoria, p = 0.006; agitation, p = 0.02; apathy, p = 0.02; and disinhibition, p = 0.11) vs controls. Hierarchical stepwise regression analysis revealed that whole gray and white matter volumes accounted for greater variance than lesion burden in explaining cognitive performance and neuropsychiatric symptoms. White matter volume was the best predictor of mental processing speed and working memory, whereas gray matter volume predicted verbal memory, euphoria, and disinhibition. Conclusion: Both gray and white brain matter atrophy contribute to neuropsychological deficits in multiple sclerosis.

Iron in chronic brain disorders: imaging and neurotherapeutic implications.

SummaryIron is important for brain oxygen transport, electron transfer, neurotransmitter synthesis, and myelin production. Though iron deposition has been observed in the brain with normal aging, increased iron has also been shown in many chronic neurological disorders including Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. In vitro studies have demonstrated that excessive iron can lead to free radical production, which can promote neurotoxicity. However, the link between observed iron deposition and pathological processes underlying various diseases of the brain is not well understood. It is not known whether excessive in vivo iron directly contributes to tissue damage or is solely an epiphenomenon. In this article, we focus on the imaging of brain iron and the underlying physiology and metabolism relating to iron deposition. We conclude with a discussion of the potential implications of iron-related toxicity to neurotherapeutic development.