# Does Losing Brain Volume Mean Worse Disability in Multiple Sclerosis? A Review of 50 Studies This systematic review pooled 50 studies to examine whether loss of brain tissue (brain volume loss, or BVL) is linked to worsening physical disability in people with multiple sclerosis (MS). Across the evidence, whole brain atrophy, ventricular atrophy, gray matter atrophy, and corpus callosum atrophy were each associated with greater physical disability progression. However, most studies found no such link for white matter atrophy. The authors conclude that whole brain atrophy is the most consistent imaging marker of disability progression, though the studies varied widely in how they measured brain volume and disability. # Does Losing Brain Volume Mean Worse Disability in Multiple Sclerosis? A Review of 50 Studies ## Table of Contents - Key Points - Background: Why This Research Matters - How the Researchers Conducted the Review - What the 50 Included Studies Looked Like - Whole Brain Volume Loss and Physical Disability - Ventricular Atrophy and Physical Disability - Gray Matter Atrophy and Physical Disability - Corpus Callosum Atrophy and Physical Disability - White Matter Atrophy and Physical Disability - Basal Ganglia and Brainstem: Too Little Data - What This Means for Patients - Limitations: What the Review Could Not Prove - Recommendations and Next Steps - Frequently Asked Questions - Source Information ## Key Points - A review of 50 studies found whole brain atrophy was linked to greater physical disability progression in MS, with 13 of 15 studies following patients five or more years reporting a significant EDSS relationship. - Ventricular atrophy (15 studies), gray matter atrophy (13 studies), and corpus callosum atrophy (4 studies) were also linked to greater physical disability progression. - Most evidence, from 6 studies, found no link between white matter atrophy and physical disability, unlike whole brain, ventricular, gray matter, and corpus callosum atrophy. - The review included only observational studies, so it can show associations but cannot prove that brain volume loss causes disability progression. - Because studies varied widely in measurement methods and populations, no single brain volume measurement should be used alone to make treatment decisions. ## Background: Why This Research Matters Multiple sclerosis (MS) is a chronic disease that damages the central nervous system, which includes the brain and spinal cord. The disease involves inflammation, loss of myelin (the protective coating around nerve fibers), and degeneration of nerve tissue. About 2.8 million people worldwide live with MS. MS mainly affects young adults. Between 70% and 80% of patients first develop symptoms between the ages of 20 and 40 years. There are three main patterns of disease course, defined by when relapses occur and how disability progresses after disease onset: - **Relapsing-remitting MS (RRMS)** — most patients start with this pattern, which often later evolves into secondary progressive MS - **Secondary progressive MS (SPMS)** — a later phase with steady disability worsening - **Primary progressive MS (PPMS)** — disability worsens steadily from the start, without distinct relapses Brain volume loss is a sign of neurodegeneration (loss of nerve tissue). People with MS lose brain volume faster than healthy adults, and this loss begins at the earliest stage of the disease. It continues throughout the disease course. The numbers here are striking. Among patients with RRMS, the yearly rate of brain volume loss ranges from **0.5% to 1.35% per year**. In healthy individuals, normal age-related brain shrinkage is only **0.1% to 0.3% per year**. This means patients with RRMS may lose brain volume several times faster than expected from normal aging. Many observational studies and clinical trials have suggested a strong link between brain volume loss and the buildup of disability in MS. One important example comes from the INFORMS trial. Among 487 patients with PPMS in the placebo group, a lower baseline normalized brain volume (NBV) predicted disease progression. The relative risk of confirmed disability worsening at 12 weeks was reduced by **36%** in patients with high baseline NBV compared with those with low baseline NBV. Long-term cohort studies support this pattern. In one study, 480 patients with RRMS were followed for 10 years. The three groups with the lowest quartiles of adjusted baseline brain volume had a significantly increased risk of disease progression, with odds ratios ranging from **4.13 to 6.12**, compared with the highest quartile. Importantly, this link held true regardless of whether patients had clinical relapses. However, the studies differ greatly in their designs and in how they measure brain volume loss. This variation raises questions about whether the findings apply broadly to all patients. The researchers therefore conducted this systematic review to describe the relationship between brain volume loss and physical disability in MS. ## How the Researchers Conducted the Review The researchers followed the PRISMA guidelines, a standard set of rules for conducting and reporting systematic reviews. They used a protocol that defined the study designs, populations, and outcomes of interest in advance. They searched two major medical databases: MEDLINE and Embase. The searches were run on June 20, 2021. Conference abstracts were excluded. The team also searched the reference lists of systematic reviews and narrative reviews published in the previous three years. They also searched Google and Google Scholar for gray literature (research not published in traditional journals). To be included, a study had to meet specific criteria: - It assessed brain volume loss in MS using defined outcomes - It measured physical disability using the EDSS, MSSS, or MSFC scales (or specific components of the MSFC, such as the 9-Hole Peg Test or the Timed 25-Foot Walk Test) - It used one of these study designs: prospective cohort, retrospective cohort, cross-sectional, or case-control - It was published in English from 2010 onward Randomized and other controlled trials were excluded, including single-arm trials. There were no restrictions on MS subtype, age, or ethnicity. Two reviewers screened titles and abstracts, then screened full-text copies of potentially relevant publications. They assessed study quality using the Newcastle-Ottawa Scale (NOS) for observational studies. The NOS score ranges from 0 to 9, where 0 is the poorest quality and 9 is the highest quality. The reviewers extracted data into a predefined Excel-based grid. Any disagreements were resolved by a third reviewer. ## What the 50 Included Studies Looked Like The structured searches retrieved 1,620 citations. Of these, 50 publications met the screening criteria and were included in the final data set. The mix of study designs was nearly even. There were 24 retrospective cohort studies and 26 prospective cohort studies. Follow-up duration varied. About 43% of the cohort studies (21 studies) followed patients for five years or more. About 53% (27 studies) followed patients for less than five years. Two studies did not report follow-up duration. Sample sizes also varied widely: - About 25% of studies (13 studies) had fewer than 50 patients - About 20% (9 studies) had between 51 and 100 patients - About 55% (28 studies) had more than 100 patients Most studies were conducted in Europe (70%, 34 studies), followed by North America (21%, 10 studies), the Pacific region (4%, 2 studies), and Asia and South America (2%, 1 study each). About 63% of studies (31 studies) were published between 2015 and 2021. The remaining studies (about 37%, 19 studies) were published between 2010 and 2014. The studies also differed in which MS subtypes they included: - About 20% (9 studies) included only patients with RRMS - About 15% (8 studies) included only patients with clinically isolated syndrome (CIS), an early episode of symptoms that may or may not become MS - About 5% (2 studies) included only patients with PPMS - About 60% (30 studies) included a combination of different MS subtypes Average EDSS scores at baseline were not reported in about 43% of studies (21 studies). Among the remaining studies, baseline EDSS scores varied considerably: 2.0 or lower in about 20% (10 studies), above 2.0 to 3.0 in about 15% (8 studies), above 3.0 to 4.0 in about 20% (10 studies), and above 4.0 in one study (2%). The most common measure of association was the correlation coefficient (26%, 13 studies), followed by the regression coefficient (22%, 11 studies). More than one measure was used in 14 studies (28%). About half of the studies (24 studies) reported multivariable analyses, which adjust for other factors. About 30% (16 studies) reported univariable analyses, and about 20% (10 studies) reported both types. ## Whole Brain Volume Loss and Physical Disability Thirty-six primary studies examined the link between whole brain volume loss and physical disability in MS. This was the largest body of evidence in the review. Of these 36 studies, 19 were prospective cohorts and 17 were retrospective cohorts. Follow-up ranged from one year to 15 years. Sample sizes ranged from 20 to 1,651 patients. The average age of patients across the studies ranged from 30 to 51 years. The EDSS was the most commonly used disability measure, reported in 20 of the 36 studies, with baseline scores ranging from 1.0 to 6.0 points. The researchers grouped the studies by follow-up duration: 15 studies followed patients for five years or more, and 21 studies followed patients for less than five years. **Findings from studies with five or more years of follow-up (15 studies):** - Of the 15 studies examining whole brain volume change and EDSS, **13 found a significant relationship**. Greater whole brain volume loss during observation was linked to physical disability progression. - Of the three studies examining whole brain volume change and MSSS, **two found that greater brain volume loss was significantly linked to a higher (worse) MSSS score**. - Of the three studies examining whole brain volume change and MSFC or its component performance measures, **none reported a significant link**. - One study looked at conversion from CIS to clinically definite MS (CDMS). It found that greater brain volume loss was linked to a greater risk of conversion. In addition, the risk of being diagnosed with MS was significantly reduced in patients with lower brain atrophy rates. **Findings from studies with less than five years of follow-up (21 studies):** - Of the 20 studies examining whole brain volume change and EDSS, **13 found a significant relationship**. Greater whole brain volume loss was linked to worsening EDSS scores. One notable long-term study was the 2019 study by Cree and colleagues, which followed 480 patients (88 with CIS and 392 with RRMS) for 10.7 years. The average age was 41.6 years, and the median EDSS at baseline was 1.5. The researchers classified patients as having disease progression or remaining stable. In patients whose physical disability worsened without relapse, there was a significant annual relative brain volume loss of 0.00018%. This was compared with patients whose EDSS stayed stable and who had no prior relapses. The statistical result was a linear mixed model beta of −0.00018 with a P value of 0.0094. In patients whose physical disability worsened with relapse, there was a significant annual relative brain volume loss of 0.00013%. This was compared with patients whose EDSS stayed stable and who had no prior relapses. The statistical result was a linear mixed model beta of −0.00013 with a P value of 0.0470. The analysis adjusted for age, sex, disease duration at baseline, and HLA-DRB1*15:01 (a genetic variant that influences certain clinical features of MS). The authors concluded that long-term worsening of physical disability was common in relapsing MS patients and was linked to accelerated brain atrophy. Another important study was the 2019 study by Dekker and colleagues from the Netherlands. This retrospective cohort followed patients for 6 and 12 years. The 6-year follow-up group included 115 patients (36 with CIS, 68 with RRMS, and 11 with PPMS), with an average age of 35.3 years. The 12-year follow-up group included 79 patients (27 with CIS, 50 with RRMS, and 2 with PPMS), with an average age of 34.9 years. The median EDSS at baseline was 2.0. In the 6-year follow-up group, every 1 standard deviation increase in annualized percentage brain volume (aPBV) loss over 2 years was significantly linked to a higher EDSS score. That EDSS score was 0.143 standard deviation higher (worse) at 6-year follow-up. The statistical result was a standardized beta of −0.143 with a P value of 0.026. In the 12-year follow-up group, every 1 standard deviation increase in aPBV loss over 2 years was linked to a 0.037 standard deviation higher (worse) EDSS score at 12-year follow-up. However, this link was not statistically significant, with a standardized beta of −0.037 and a P value of 0.743. The analysis adjusted for baseline EDSS and disease-modifying therapy use during follow-up. The authors concluded that MS patients with early signs of neurodegeneration, or early whole brain atrophy, were more prone to develop physical disability progression. The 2019 study by Genovese and colleagues was a retrospective cohort of 1,465 patients (124 with CIS, 1,089 with RRMS, 217 with SPMS, and 35 with PPMS) followed for 5 years. The average age was 47.6 years for disease progression converters and 44.3 years for non-converters. The median EDSS at baseline was not reported. This study found that every 1% increase in aPBV loss was significantly linked to a **12% higher risk of physical disability progression at 5 years of follow-up**. The statistical result was a logistic odds ratio of 0.89 with a P value of 0.006. The analysis adjusted for all significant MRI outcomes found in the univariate regression analysis. The authors concluded that percentage brain volume loss represents a viable predictive MRI marker of physical disability development in MS patients. Not all studies found a link. The 2018 study by Dwyer and colleagues was a retrospective cohort of 192 patients (18 with CIS, 126 with RRMS, and 48 with SPMS or PPMS) followed for 5 years. The average age was 44.8 years for CIS patients, 43.8 years for RRMS patients, and 55.5 years for SPMS/PPMS patients. Median EDSS at baseline was not reported. This study found no significant link between brain volume loss and physical disability. Brain volume loss at 5-year follow-up was not linked to a change in EDSS between baseline and 5-year follow-up. The hierarchical regression result was an R-squared of 0.045 with a P value of 0.061. Brain volume loss at 5-year follow-up was also not linked to the 9-Hole Peg Test or the Timed 25-Foot Walk Test at 5 years. The analysis adjusted for age, sex, new lesion volume, and enlarging lesion volume. The 2018 study by Ghione and colleagues was a retrospective cohort of 1,651 patients (137 with CIS, 1,219 with RRMS, 255 with PPMS, and 40 with SPMS) followed for 5 years. The average age was 45.6 years overall, 39.5 years for CIS patients. The median EDSS at baseline was 2.5, and the median MSSS at baseline was 3.7. This study found that every one-point increase in EDSS score annually was significantly linked to a 2.187 ml increase in brain volume loss at 5-year follow-up. The statistical result was a linear mixed-effect model beta of −2.187 with a P value of 0.0001. Similarly, every one-point increase in MSSS score (worsening) annually was significantly linked to brain volume loss. The statistical result was a linear mixed-effect model beta of −2.001 with a P value of 0.0001. The authors concluded that increased brain volume loss was linked to physical disability progression in MS patients. ## Ventricular Atrophy and Physical Disability Fifteen primary studies examined the link between ventricular atrophy (enlargement of the fluid-filled spaces in the brain) and physical disability in MS. The evidence suggests that ventricular atrophy is linked to greater physical disability progression in MS patients. The review reported data on different ventricular measures: - Total ventricle volume: 4 studies using EDSS, 1 study using MSSS - Lateral ventricle volume: 10 studies using EDSS, 2 studies using MSSS, 1 study using MSFC or its components - Third ventricle volume: 2 studies using EDSS, 1 study using MSSS As the ventricles enlarge, brain tissue around them shrinks. This makes ventricular size an indirect marker of brain tissue loss. ## Gray Matter Atrophy and Physical Disability Thirteen primary studies examined the link between gray matter atrophy and physical disability in MS. Gray matter is the brain tissue that contains the main bodies of nerve cells. The existing evidence suggests that gray matter atrophy is linked to greater physical disability progression in MS patients. The review reported data on several gray matter measures: - Total gray matter volume: 9 studies using EDSS, 1 study using MSSS - Cortical gray matter volume: 6 studies using EDSS, 1 study using MSSS - Deep gray matter volume: 3 studies using EDSS - Cortical thickness: 3 studies using EDSS In addition, six studies examined limbic structures, which include the amygdala, hippocampus, bilateral cingulate gyrus, and thalamus. These studies used EDSS, MSSS, and MSFC measures. ## Corpus Callosum Atrophy and Physical Disability Four primary studies examined the link between corpus callosum atrophy and physical disability in MS. The corpus callosum is the bundle of nerve fibers that connects the two halves of the brain. The evidence suggests that corpus callosum atrophy is linked to greater physical disability progression in MS patients. All four studies used the EDSS as the disability measure. ## White Matter Atrophy and Physical Disability Six primary studies examined the link between white matter atrophy and physical disability in MS. White matter contains the nerve fibers that connect different brain regions. The majority of the existing evidence, from 6 primary studies, suggests **no link** between white matter atrophy and physical disability in MS. This finding stands out because it differs from the results for whole brain, ventricular, gray matter, and corpus callosum atrophy. All six studies used the EDSS as the disability measure. ## Basal Ganglia and Brainstem: Too Little Data The review found it difficult to define a relationship between basal ganglia volume loss and physical disability. The basal ganglia are deep brain structures involved in movement control. Only three studies examined this link using EDSS and one study using MSSS. Similarly, the review found it difficult to define a relationship between medulla oblongata width and physical disability. The medulla oblongata is the lower part of the brainstem. Only one study examined this measure, using EDSS. With so few studies, the researchers could not draw firm conclusions about these brain regions. ## What This Means for Patients The main message of this review is that whole brain atrophy is linked to greater physical disability progression in MS patients. This finding comes from 36 primary studies, the largest body of evidence in the review. The review also found links between physical disability progression and atrophy in several specific brain regions: - **Ventricular atrophy** — supported by 15 primary studies - **Gray matter atrophy** — supported by 13 primary studies - **Corpus callosum atrophy** — supported by 4 primary studies In contrast, most evidence (6 primary studies) found no link between white matter atrophy and physical disability. These findings matter because they point to brain volume loss as a potential imaging biomarker. A biomarker is a measurable indicator of disease activity or progression. If brain volume loss reliably tracks with disability progression, doctors could use MRI measurements to monitor how well treatments are working. The authors state that their review can help define future imaging biomarkers for physical disability progression and treatment monitoring in MS. However, the review also shows that the evidence is very heterogeneous. This means the studies differed greatly in their patient populations, their definitions of brain volume loss, their image analysis methods, their disability measures, and their statistical approaches. Because of this variation, patients and doctors should interpret any single study's findings with caution. ## Limitations: What the Review Could Not Prove The review has several important limitations that patients should understand. First, the studies were highly heterogeneous. They differed in the underlying study population, the definitions of brain volume loss, the image analysis methodologies, and the physical disability measure used. They also differed in the measures of association reported and whether the analysis was univariable or multivariable. This makes it hard to combine results into one clear conclusion. Second, measuring brain volume is technically challenging. Changes in brain volume are generally small. Most changes cannot be assessed quantitatively with computational tools that detect differences or changes using a range of algorithms. Third, different measurement methods can give different results. Cross-sectional methods, such as BPF (brain parenchymal fraction) and SIENAX, measure brain volume at one time point using a single MRI scan. Longitudinal methods, such as SIENA, measure change in brain volume over time by comparing two MRI scans taken at different times. BPF and SIENA are the most frequently used methods. Even measures determined with the same algorithm can be strongly influenced by technical factors. These include differences in image acquisition between sites, across MRI machines, and between imaging protocols. They also include tissue artifacts arising from differences in patient position within scanners or from patient movement. Fourth, the review excluded randomized and other controlled trials. It included only observational study designs: prospective cohort, retrospective cohort, cross-sectional, and case-control. This means the review can show associations but cannot prove that brain volume loss causes disability progression. Fifth, only English language articles published from 2010 onward were included. Studies published in other languages or before 2010 were not part of the final data set. Sixth, some brain regions had very limited data. The review could not define a relationship between basal ganglia volume loss and physical disability, or between medulla oblongata width and physical disability, because too few studies examined these measures. ## Recommendations and Next Steps The authors conclude that the evidence gathered from this systematic review, although very heterogeneous, suggests that whole brain atrophy is linked to greater physical disability progression in MS patients. Based on the review, several points are clear for patients and their care teams: 1. Brain volume loss is a meaningful marker in MS. It is linked to physical disability progression across many studies. 1. Whole brain atrophy has the strongest and most consistent evidence base, drawn from 36 primary studies. 1. Ventricular, gray matter, and corpus callosum atrophy also show links to disability progression, but with fewer supporting studies. 1. White matter atrophy does not appear to show the same link, based on the majority of existing evidence. 1. More research is needed on the basal ganglia and brainstem regions, where data are very limited. The authors state that their review can help define future imaging biomarkers for physical disability progression and treatment monitoring in MS. This means future studies may use brain volume measurements to track how patients respond to treatment. For patients, the practical message is that MRI measurements of brain volume may become an increasingly important part of monitoring MS. However, because measurement methods vary and the evidence is heterogeneous, no single measurement should be used alone to make treatment decisions. Patients should discuss the role of MRI monitoring with their neurologist. ## Frequently Asked Questions ### What is brain volume loss in multiple sclerosis? Brain volume loss, or BVL, is shrinkage of brain tissue from neurodegeneration. People with MS lose brain volume faster than healthy adults, starting at the earliest disease stage and continuing throughout the disease course. In relapsing-remitting MS, yearly loss ranges from 0.5% to 1.35%, compared with only 0.1% to 0.3% per year from normal aging. ### Does losing brain volume mean my disability will get worse? A review of 50 studies found whole brain atrophy was linked to greater physical disability progression, with 13 of 15 studies following patients five or more years reporting a significant relationship with EDSS. However, studies varied widely in measurement methods, and the review could show associations only, not that brain volume loss causes disability progression. ### Which brain measurements were linked to disability progression? Whole brain atrophy had the largest evidence base, from 36 primary studies. Ventricular atrophy was supported by 15 studies, gray matter atrophy by 13 studies, and corpus callosum atrophy by 4 studies. Most evidence, from 6 studies, found no link between white matter atrophy and physical disability. Basal ganglia and brainstem had too little data for conclusions. ### How is brain volume measured on MRI? Cross-sectional methods such as BPF and SIENAX measure brain volume from a single MRI scan. Longitudinal methods such as SIENA compare two scans taken at different times to measure change. BPF and SIENA are the most frequently used. Results can be influenced by differences between MRI machines, imaging protocols, patient positioning, and movement. ### Could brain volume loss be used to monitor my treatment? The review authors state their findings can help define future imaging biomarkers for physical disability progression and treatment monitoring in MS. This means future studies may use brain volume measurements to track treatment response. However, because measurement methods vary and evidence is heterogeneous, no single measurement should be used alone to make treatment decisions. ### What were the limitations of this review? The 50 studies were highly heterogeneous, differing in populations, definitions of brain volume loss, image analysis methods, disability measures, and statistical approaches. The review excluded randomized and other controlled trials, so it can show associations but cannot prove causation. Only English-language articles published from 2010 onward were included, and some brain regions had very limited data. ### What should I discuss with my neurologist about MRI monitoring? Patients should discuss the role of MRI monitoring with their neurologist. Brain volume loss is linked to physical disability progression across many studies, and MRI measurements of brain volume may become an increasingly important part of monitoring MS. However, because measurement methods vary and evidence is heterogeneous, no single measurement should be used alone to make treatment decisions. ### If my MRI shows brain volume loss and my MS treatment is being decided, when should I get a second opinion? Brain volume loss is linked to physical disability progression in MS, and whole brain atrophy has the most consistent evidence, drawn from 36 studies. Ventricular, gray matter, and corpus callosum atrophy also show links, while most evidence finds no link for white matter atrophy. Because studies varied widely in how they measured brain volume and disability, no single measurement should be used alone to make treatment decisions. A second opinion can help interpret your MRI findings and treatment options. Diagnostic Detectives Network provides independent expert second opinions. ## Source Information **Original article title:** The association between brain volume loss and disability in multiple sclerosis **Authors:** Paul M. Matthews, Digant Gupta, Deepali Mittal, Wenjia Bai, Antonio Scalfari, Kevin G. Pollock, Vishal Sharma, Nathan Hill **Author affiliations:** Department of Brain Sciences and UK Dementia Research Institute at Imperial College London (London, UK); Bridge Medical Consulting Limited (Richmond, London, UK); Department of Computing, Imperial College London (London, UK); Imperial College Healthcare Trust, Centre of Neuroscience, Department of Medicine, Charing Cross Hospital (London, UK); Bristol-Myers Squibb (Uxbridge, UK) **Journal:** Multiple Sclerosis and Related Disorders, volume 74 (2023), article 104714 **Publication details:** Received 19 December 2022; revised 23 March 2023; accepted 8 April 2023; available online 9 April 2023 **DOI:** https://doi.org/10.1016/j.msard.2023.104714 **Note:** This patient-friendly article is based on peer-reviewed research. The original article is an open access article published under the CCBY license. --- Publisher: Diagnostic Detectives Network (https://diagnosticdetectives.com) — independent multi-expert medical second opinions, worldwide, private-pay. Author byline: Anton Titov, MD, PhD. Contact: https://diagnosticdetectives.com/pages/contact Canonical page: https://diagnosticdetectives.com/products/does-losing-brain-volume-mean-worse-disability-in-multiple-sclerosis-a-review-of-50-studies