Brain Atrophy, Pseudoatrophy, and Multiple Sclerosis

Patient Expert

Multiple sclerosis is a demyelinating disease of the central nervous system that is often marked by changes in the brain. Using magnetic resonance imaging (MRI), these changes can appear as lesions, “black holes," or brain atrophy.

What are lesions?

In MS, the fatty, protective covering that surrounds nerves, called myelin, becomes damaged due to inflammation in the central nervous system. The result of this inflammatory damage is demyelination. Lesions are the hardened areas (scars) or plaques where myelin has been damaged. Multiple sclerosis literally means "many scars."

Where inflammation damages the blood-brain barrier, lesions can develop. This inflammation and active lesions appear on MRI scans as white spots when gadolinium, a contrast agent, is injected into a vein beforehand. Lesions can also affect the spinal cord or optic nerves.

What are black holes?

When so much of the protective myelin has been damaged that nerves die, the resulting lesions appear as dark spots on MRI scan. These dark spots are often referred to as “black holes.” Although the body can work hard to repair myelin, once the nerves have died they do not grow back. The damage is permanent.

What is brain atrophy?

Brain atrophy, also called cerebral atrophy, is a common feature of many diseases that affect the brain. Atrophy means the wasting away of cells. In brain tissue, atrophy indicates a loss of neurons and their connections. In other words, brain atrophy means that part of the brain has shrunk. Many diseases, including MS, are associated with brain atrophy.

Disease-modifying therapies and the brain

Disease-modifying therapies (DMTs) used to treat MS are designed to slow down the disease process, including abnormal changes in the brain. When drugs are in the testing stage, their effectiveness is measured in various ways, including assessment of brain lesions and brain atrophy,  in people diagnosed with MS. Many of these DMTs reduce inflammation in the central nervous system.

A recent systematic review and meta-analysis of clinical trials of DMTs found that some of the drugs appeared to be more effective in the second year of the trial than in the first, based on changes in brain volume. In some of these trials, it appeared that the brain shrunk in the first year, despite other measures that demonstrated the neuroprotective qualities of DMTs as evidenced by fewer new or worsening lesions (Koudriavtseva and Mainero 2016). Researchers have called this phenomenon “pseudoatrophy.”

What is pseudoatrophy?

Researchers believe that untreated inflammation in MS might affect brain volume. Many of the DMTs for MS have anti-inflammatory properties. Pseudoatrophy is a phenomenon seen during the first 6-12 months of DMT treatment where researchers noticed that brain volume might appear to get smaller, which makes it harder to compare the effectiveness of one treatment versus placebo or another treatment. Researchers hypothesize that this pseudoatrophy reflects resolution of edema and shifts in fluid in the brain, rather than true tissue loss.

In clinical trials, the effect of pseudoatrophy was greater in patients who showed more inflammatory disease at baseline. It was also more apparent with treatments that have stronger anti-inflammatory properties. Researchers suggest that clinical trials should measure baseline brain volume at six months after the start of treatment to avoid the confounding effects of pseudoatrophy.

Do I need to worry about pseudoatrophy?

When patients are in the process of being diagnosed, MRIs are used to measure the likelihood of MS; they are not specific to MS. After diagnosis, MRIs are used to measure disease progression and to determine the effectiveness of DMT treatment, usually after a patient has been on treatment for a year, or sooner if indicated by a major relapse. It is not likely that the pseudoatrophy phenomenon would be detected outside of a clinical trial.

Pseudoatrophy is not an indication that anything detrimental is going on in the brain. It is a phenomenon of interest to researchers that highlights the need to improve the way clinical trials are conducted and the ways that treatment effectiveness is measured.

See More Helpful Articles:

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Koudriavtseva T, Mainero C. Brain Atrophy as a Measure of Neuroprotective Drug Effects in Multiple Sclerosis: Influence of Inflammation. Frontiers in Human Neuroscience. 2016;10:226. doi:10.3389/fnhum.2016.00226.