Brain Shrinkage and Disability in Multiple Sclerosis: What 58 Studies Reveal About the Link

Table of Contents

• Key Points
• Background: Understanding Brain Atrophy and Multiple Sclerosis
• How the Research Was Conducted
• Key Findings: What the Studies Showed
• Longitudinal Studies: Brain Volume Loss Over Time and Disability
• Cross-sectional Studies: Brain Volume and Disability at a Single Time Point
• Baseline Brain Volume as a Predictor of Future Disability
• What This Means for Patients
• Limitations of the Research
• Recommendations for Patients
• Frequently Asked Questions
• Source Information

Key Points

• Global brain atrophy is strongly linked to disability progression in people with MS, with about 1% brain volume loss per year associated with worsening disability.
• A single baseline brain volume measurement is less reliable for predicting future disability; most follow-up studies found no association.
• Monitoring brain volume changes over time may help track disease progression and guide treatment decisions.
• The review included 58 studies, mostly in people with CIS or RRMS; findings may not apply to primary or secondary progressive MS.
• Regular MRI monitoring, understanding your EDSS score, and discussing treatment targets with your neurologist are recommended.

Background: Understanding Brain Atrophy and Multiple Sclerosis

Multiple sclerosis (MS) is a neuroinflammatory disease (causing inflammation in the brain and spinal cord) that leads to progressive neurodegeneration (gradual loss of nerve cells). It typically starts at a young age. Symptoms include altered sensation such as numbness, tingling, itching or pins and needles, impaired coordination and balance, weakness, muscle spasms or cramps, fatigue, pain, and visual disturbances.

Brain atrophy (BA) means loss of brain tissue volume. It was first observed in people with MS in the early 1960s. By the mid-1990s, magnetic resonance imaging (MRI) was being used to quantify BA and its association with physical disability. Early studies used two-dimensional scans, but more recent studies use three-dimensional scans with software called Structural Image Evaluation Using Normalization of Atrophy (SIENA).

People with MS lose about 0.5% to 1.35% of brain volume per year. In contrast, an average person without MS loses only 0.1% to 0.3% of brain volume per year due to normal aging. Measurements of BA are thought to represent the net effect of all degenerative processes in MS. They seem to be better predictors of clinical outcomes than other MRI measures. For example, BA is a better marker of clinical disability than conventional lesion measures. People with higher levels of BA are more likely to progress from clinically isolated syndrome (CIS, a first episode of neurological symptoms that may lead to MS) to MS. BA has also been associated with increased disability, worsening cognition, poorer quality of life, increased fatigue, and poorer economic outcomes.

The most widely used instrument to assess disability progression (DP) in people with MS is the Expanded Disability Status Scale (EDSS). The EDSS is an ordinal rating system ranging from 0 to 10, where higher scores indicate worse disability. A frequent criticism of the EDSS is the unequal interval distances between points. For example, the difference between scores 1 and 2 has a different relevance than the difference between scores 6 and 7. This is because the lower end of the scale (0–4) measures neurological impairments, 4–6 indicates impacts on walking ability, 6–7 indicates loss of walking other than a few metres, and 7–7.5 indicates wheelchair dependency. Furthermore, EDSS is only weakly correlated with neuropsychological impairment or patient-reported outcomes.

The MAGNIMS (Magnetic Resonance Imaging in Multiple Sclerosis) group is an expert consensus group. The MAGNIMS group recently recommended that global brain volume loss (BVL) is used to define and predict MS severity. The MAGNIMS group also recommended that global brain volume loss (BVL) is included as a secondary outcome in therapeutic clinical trials. An earlier review looked at associations between BA and physical disability using studies published prior to 2013. This new review builds on that by systematically reviewing the associations between global BA and physical disability measured by EDSS in people with MS. The review focuses particularly on CIS and relapsing-remitting MS (RRMS), from 2013 onwards.

How the Research Was Conducted

This was a systematic review. The protocol was designed according to the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) 2015 statement and finalized in January 2022 before the final literature search.

Researchers searched Medline, Embase, Cochrane Library, Cochrane Clinical Register of Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews (CDSR), and Cumulative Index to Nursing and Allied Health Literature (CINAHL). The search terms included combinations of "multiple sclerosis," "brain volume loss," and "Expanded Disability Status Scale."

Inclusion criteria:

• People aged 18 or over, diagnosed with CIS or MS.
• Longitudinal observational studies, clinical trials, and modelling studies measuring the association between change in whole brain volume (BV) and EDSS score or DP defined by EDSS score. Confirmed or non-confirmed DP was included.
• Cross-sectional studies measuring the association between normalized brain volume (NBV), or fraction, and EDSS score or DP defined by EDSS score.
• Original article written in English and published between 1 January 2013 and 3 February 2022 in a peer-reviewed journal.

Exclusion criteria:

• Study population includes 20% or more people with primary progressive multiple sclerosis (PPMS). A pragmatic decision was made to keep the review focus on CIS/RRMS.
• Studies measuring the association with cord or regional atrophy only.
• Studies where EDSS was only reported as a composite of 'No Evidence of Disease Progression' (NEDA-3 or NEDA-4).
• Studies where the association was not reported separately for people with MS and healthy controls.

The screening process started with 3,114 abstracts. After initial screening, 715 papers and abstracts went to full screening. The review was then limited to full-text articles published from 2013 onwards, resulting in 320 articles for full-text screening. In total, 164 articles published before 2013 and 231 conference abstracts published from 2016 onwards were not considered further. The full-text screening resulted in 197 articles measuring BA; 131 of which also focused on disability outcomes. Studies only addressing regional BA, or not reporting on the associations with EDSS or DP, or where the study population included more than 20% PPMS diagnoses were excluded. The remaining 58 studies were included in this review.

Data were extracted using a standardized Excel spreadsheet. Studies were grouped first according to study design: longitudinal or cross-sectional. Longitudinal studies were then grouped according to the way EDSS was used to describe increase in disability. The increase in disability was described either as change in BV (percentage of brain volume loss, PBVL) or as DP. Cross-sectional studies were further grouped into those comparing baseline BA with baseline EDSS and those comparing baseline BA with follow-up EDSS. Within these groups, studies were described and compared qualitatively.

Key Findings: What the Studies Showed

The review included 58 studies. Twenty-three were longitudinal analyses, 29 were cross-sectional, and 15 were follow-up studies (some studies had both cross-sectional and longitudinal components). The longitudinal studies had slightly larger study populations and included slightly younger people with MS with slightly shorter disease duration compared to cross-sectional and follow-up studies.

Key characteristics of the study populations are summarized below (median values with ranges):

• Longitudinal studies (n=23): Median study size 180 people (range 16–3635). Median follow-up 4 years (range 1–12). Median age 37 years (range 29–48). 70% female. Median EDSS score 2 (range 1.3–6). Median disease duration 7.5 years (range 1–14).
• Cross-sectional studies (n=29): Median study size 80 people (range 20–3635). Median age 41 years (range 31–61). 68% female. Median EDSS score 2.5 (range 1.2–6.5). Median disease duration 9.5 years (range 0.5–27).
• Follow-up studies (n=15): Median study size 102 people (range 23–1214). Median follow-up 5 years (range 1–30). Median age 40 years (range 31–61). 68% female. Median EDSS score 2.5 (range 1.2–5). Median disease duration 8.5 years (range 4–30).

Most longitudinal studies (19 out of 23) observed a significant association between global BVL and change in EDSS score or DP. Similarly, the majority of cross-sectional studies (26 out of 29) observed an association between baseline BV measures and EDSS. However, most studies investigating the association between baseline brain volume measures and follow-up EDSS did not find an association (only 4 out of 15 observed an association).

Overall, around a 1% decrease in global BV per year was associated with DP, but the range across studies was 0.4% to 1.3%. The authors recommend caution in comparing studies due to variations in the definition of DP.

Longitudinal Studies: Brain Volume Loss Over Time and Disability

All longitudinal studies measured BA as PBVL, but one study categorized PBVL for analysis. Eight studies investigated the association between PBVL and change in EDSS; 6 of these observed a significant association (p < 0.05). Two small studies were inconclusive: one observed a non-significant association (n=38) and another observed no change in EDSS (n=16).

Fifteen studies investigated the association between PBVL and DP defined by changes in EDSS score. Of these, 13 reported a significant association between PBVL and DP. One study observed a non-significant association (n=62), and one study observed no difference in NBV (n=82). There were six different definitions of DP used across the studies.

Three longitudinal studies were prospective. Two of these observed a significant association between PBVL and DP. One observed a significant association between PBVL and EDSS with Icobrain software but not with SIENA software. All except one of the longitudinal studies used SIENA software (one used FreeSurfer), but two used other software in addition to SIENA (Icobrain and SPM12).

Eighteen studies used regression or survival models adjusted for various combinations of sex, age, education, disease phenotype, disease duration, study cohort, lesion volume, field strength, and other baseline variables. The majority of the study populations were treated with disease-modifying therapies (DMTs), and just one study included mostly untreated patients. Many studies also reported measures of regional BA (14 out of 23, 61%), and regional atrophy was the main focus for many studies. A few studies reported additional measures of physical disability, specifically the 9-Hole Peg Test (9HPT) and Timed 25-Foot Walk (T25FW) (4 out of 23, 17%).

Most studies did not report an annualized PBVL, tending to report the PBVL over the observation period or by categories. For the 5 studies that did report annualized PBVL, the range was −0.48% ± 0.93 to −0.9% ± 1.0, with observation periods ranging from 2 to 7.5 years.

Specific examples from the review include:

• A large retrospective study by Uher et al. (2022) with 2,306 participants found a significant association between PBVL and EDSS change (p<0.05) using mixed models adjusted for sex, age, baseline NBV, T2 lesion volume, cohort, proportion of time on DMTs, and other factors. The mean PBVL was −0.48% ± 0.93 over 4.3 years.
• A study by De Stefano et al. (2019) with 1,517 participants found an association between EDSS score at 6 years and PBVL (p<0.05). The mean PBVL was −0.45% ± 0.55 over 6 years.
• A study by Ghione et al. (2018) with 1,561 participants found that PBVL was an independent predictor of EDSS change (p<0.001). The mean PBVL was −0.9% ± 1.0 over 4.7 years.

Cross-sectional Studies: Brain Volume and Disability at a Single Time Point

Twenty-nine studies investigated cross-sectional associations between baseline BA measured by NBV, normalized brain parenchymal volume (NBPV), or whole brain volume (WBV) and baseline EDSS. Of these 29 studies, 26 observed a significant association between baseline BV measures and EDSS. Three studies did not find an association.

The median study size for cross-sectional studies was 80 people (range 20–3635). The median age was 41 years (range 31–61), 68% were female, median EDSS was 2.5 (range 1.2–6.5), and median disease duration was 9.5 years (range 0.5–27).

Most cross-sectional studies used software such as SIENAX to measure normalized brain volume. The measurements were then compared with EDSS scores or between groups such as people with MS with or without disability progression.

Baseline Brain Volume as a Predictor of Future Disability

Fifteen follow-up studies investigated whether baseline brain volume measures could predict future EDSS score or disability progression. Most of these studies (11 out of 15) did not find an association. Only 4 out of 15 observed an association between baseline BV and future EDSS or DP.

This suggests that a single measurement of brain volume at one point in time may not be a reliable predictor of future disability. In contrast, changes in brain volume over time (longitudinal measurements) appear to be more strongly associated with disability progression.

What This Means for Patients

This review confirms that global brain atrophy is a useful marker of disability progression in people with MS. Around a 1% decrease in global brain volume per year is associated with worsening disability. This means that monitoring brain volume changes over time could help patients and their doctors track disease progression and make treatment decisions.

The MAGNIMS group recommends that global brain volume loss should be included as a secondary outcome in therapeutic clinical trials. This means that new treatments for MS should be evaluated not only on their ability to reduce relapses and lesions but also on their ability to slow brain atrophy.

For patients, this research highlights the importance of regular MRI monitoring. If brain volume loss is detected, it may indicate that the disease is progressing, even if other symptoms are not obvious. This could prompt a discussion about changing or intensifying treatment.

However, it is important to note that brain atrophy is only one measure of disease. EDSS scores, relapse rates, and lesion counts also provide valuable information. Patients should discuss all these factors with their neurologist.

Limitations of the Research

The review has several limitations. First, there were six different definitions of disability progression used across the studies. This makes it difficult to compare results directly. The authors recommend caution in comparing studies due to these variations.

Second, the studies were heterogeneous in design, population, and software used to measure brain volume. Most longitudinal studies used SIENA software, but some used other software such as FreeSurfer, Icobrain, and SPM12. Different software may produce slightly different measurements.

Third, the review focused on people with clinically isolated syndrome (CIS) and relapsing-remitting MS (RRMS). Studies with more than 20% of people with primary progressive MS (PPMS) were excluded. This means the findings may not apply to people with PPMS or secondary progressive MS (SPMS).

Fourth, most studies were retrospective analyses of existing cohorts or clinical studies. Only three longitudinal studies were prospective. Retrospective studies can have biases.

Fifth, the EDSS itself has limitations. It has unequal interval distances and is only weakly correlated with cognitive impairment and patient-reported outcomes. Therefore, EDSS may not capture all aspects of disability.

Finally, most patients in the studies were treated with disease-modifying therapies (DMTs). This may affect the rate of brain atrophy and the association with disability.

Recommendations for Patients

Based on this review, here are some recommendations for people with MS:

1. Regular MRI monitoring: Discuss with your neurologist how often you should have MRI scans to monitor brain volume. Brain atrophy can occur even without new symptoms or lesions.
2. Understand your EDSS score: The EDSS is a common measure of disability, but it has limitations. Ask your doctor to explain your score and how it relates to your overall health.
3. Consider brain volume as a treatment target: When evaluating treatments, ask your neurologist whether the treatment has been shown to slow brain atrophy.
4. Adhere to your treatment plan: Disease-modifying therapies can reduce relapses and may slow brain volume loss. Take your medications as prescribed.
5. Participate in clinical trials: If you are eligible, consider joining clinical trials that include brain volume loss as an outcome. This helps advance research.
6. Maintain a healthy lifestyle: While not directly studied here, healthy habits like regular exercise, a balanced diet, and not smoking may support overall brain health.
7. Discuss any changes: If you notice new or worsening symptoms, tell your neurologist. They may recommend additional MRI scans to check for brain volume changes.

Frequently Asked Questions

What does brain atrophy mean for someone with MS?

Brain atrophy means loss of brain tissue volume. In MS, it is thought to reflect the net effect of all degenerative processes. People with MS lose about 0.5% to 1.35% of brain volume per year, compared with 0.1% to 0.3% from normal aging. Higher brain atrophy has been linked to increased disability, worsening cognition, more fatigue, and poorer quality of life.

How fast does brain volume loss happen in MS?

People with MS lose about 0.5% to 1.35% of brain volume per year. In contrast, an average person without MS loses only 0.1% to 0.3% per year due to normal aging. In the reviewed studies, around a 1% decrease in global brain volume per year was associated with disability progression, though the range across studies was 0.4% to 1.3%.

Can a single MRI predict my future disability?

Probably not reliably. In 15 follow-up studies, most (11 out of 15) did not find an association between a single baseline brain volume measurement and future EDSS score or disability progression. Only 4 out of 15 observed such an association. Changes in brain volume over time appear more strongly linked to disability progression than one measurement at a single point.

What is the EDSS score and what do the numbers mean?

The Expanded Disability Status Scale (EDSS) rates disability from 0 to 10, with higher scores meaning worse disability. Scores 0–4 measure neurological impairments, 4–6 reflect walking ability, 6–7 indicate loss of walking other than a few metres, and 7–7.5 indicate wheelchair dependency. The EDSS has unequal intervals and is only weakly correlated with cognitive impairment and patient-reported outcomes.

Does this research apply to progressive forms of MS?

The review focused on people with clinically isolated syndrome (CIS) and relapsing-remitting MS (RRMS). Studies where more than 20% of participants had primary progressive MS (PPMS) were excluded. Therefore, the findings may not apply to people with primary progressive MS or secondary progressive MS. Discuss your specific MS type with your neurologist.

What are the limitations of this research?

The review has several limitations. Six different definitions of disability progression were used, making comparisons difficult. Studies varied in design, population, and software for measuring brain volume. Most were retrospective, and only three longitudinal studies were prospective. Most patients were treated with disease-modifying therapies, which may affect brain atrophy rates and the association with disability.

When should someone with multiple sclerosis seek a second opinion about brain atrophy monitoring and treatment?

A second opinion can be useful when MRI monitoring of brain volume is being considered or when treatment decisions rest on it. Around a 1% decrease in global brain volume per year is associated with worsening disability. Monitoring changes over time is more informative than a single baseline measurement. A single baseline measurement is often not a reliable predictor of future disability. Because EDSS scores, relapse rates, and lesion counts also matter, an independent review can help clarify how these measures apply to your situation. Diagnostic Detectives Network provides independent expert second opinions.

Source Information

Original article title: association between global brain atrophy and the Expanded Disability Status Scale score in people with multiple sclerosis

Authors: Robert Zivadinov, Hoa H. Le, Alexander Keenan, and Susan Jill Stocks

Publication details: Therapeutic Advances in Neurological Disorders, 2025, Vol. 18: 1–34. DOI: 10.1177/17562864241303681

Note: This patient-friendly article is based on peer-reviewed research. The original article is a systematic review of 58 studies. For full details, including all tables and references, please consult the original publication.