“People who begin taking medication shortly after experiencing the initial symptoms of multiple sclerosis (MS) may have a reduced risk of disability in the future, as indicated by a study published in the online issue of Neurology®, the medical journal of the American Academy of Neurology on July 19, 2023.”

MS is a disease where the immune system attacks myelin, the protective substance around nerves. Symptoms of MS include fatigue, numbness, tingling, and difficulty walking.

“When it comes to MS treatment, the earlier the better,” said study author Alvaro Cobo-Calvo, MD, PhD, of the Multiple Sclerosis Center of Catalonia and the Autonomous University of Barcelona in Spain. “Our study found that starting treatment within six months after the first symptoms is associated with a lower risk of disability over time.” For the study, researchers looked at 580 people with a first episode of symptoms, such as tingling, numbness, muscle weakness or problems with balance, who received at least one disease-modifying drug. Researchers divided participants into three groups: 194 people who had their first treatment with an MS drug within six months after the first episode of symptoms, 192 people who had first treatment between six months and 16 months, and 194 people who had first treatment after more than 16 months. Researchers monitored people’s disability levels and brain scans for damage to the brain and spinal cord from the disease for an average of 11 years. Disability scores ranged from zero to 10, with higher scores indicating more disability.

The earliest treatment group had a 45% lower risk of reaching a disability score of three by the end of the study than those in the latest treatment group. A score of three indicates people can still walk unassisted but have moderate disability in one of eight areas, such as motor function, vision or thinking skills, or mild disability in three or four areas. A total of 42 people in the earliest treatment group, or 23%, reached a score of three, compared to 75 people, or 43%, in the latest treatment group.

The earliest treatment group also had a 60% lower risk of moving to the next stage of the disease, called secondary progressive MS, than people in the latest treatment group. In this stage, disability gets steadily worse. A total of 14 people in the earliest treatment group, or 7%, were diagnosed with secondary progressive MS compared to 43 people in the latest treatment group, or 23%.

They also found that people with the earliest treatment were 50% more likely to remain stable at their disease level one year after their initial treatment than those in the latest treatment group.

“Altogether, our results support the robustness and effectiveness of very early treatment to halt long-term disability progression, and stress that earlier detection and treatment is encouraged,” Cobo-Calvo said.

Researchers also found that people from the earliest treatment group had a lower disability progression rate and lower severe disability in a self-reported test compared to those in the latest treatment group.

A limitation of the study was that it only included patients between ages 16 to 50 at the time of first symptoms, so the results could not be applied to patients over age 50, or late-onset multiple sclerosis.

DNA variation accelerates MS CREDIT Netherlands Institute for Neuroscience

Scientists have discovered the first genetic marker for MS severity, which could lead to the prevention of long-term disability.

A study of over 22,000 people with multiple sclerosis has identified the first genetic variant associated with faster disease progression that can lead to loss of mobility and independence over time. Multiple sclerosis (MS) is caused by the immune system mistakenly attacking the brain and spinal cord, resulting in symptom flares known as relapses and longer-term degeneration known as progression. Despite effective treatments for relapses, none can reliably prevent disability accumulation. The breakthrough findings, published in Nature on June 28, 2023, pinpoint a genetic variant that worsens the disease’s severity and represent significant progress in understanding and eventually combating this aspect of MS.

“This genetic variant, inherited from both parents, accelerates the time to needing a walking aid by almost four years,” said Dr. Sergio Baranzini, a professor of neurology at the University of California, San Francisco (UCSF) and co-senior author of the study. The research was the result of a large international collaboration involving more than 70 institutions from around the world, led by researchers from UCSF and the University of Cambridge. “Understanding how the variant exerts its effects on MS severity will hopefully pave the way for a new generation of treatments that can prevent disease progression,” said Professor Stephen Sawcer of the University of Cambridge, the other co-senior author of the study.

A renewed focus on the nervous system

In order to address the mystery of MS severity, two large MS research consortia, the International Multiple Sclerosis Genetics Consortium (IMSGC) and The MultipleMS Consortium, joined forces. This collaboration enabled MS researchers from around the world to combine resources and begin identifying the genetic factors that influence MS outcomes. Previous studies have indicated that MS susceptibility or risk largely originates from immune system dysfunction, and some of this dysfunction can be treated to slow down the disease. However, according to Baranzini, these risk factors do not explain why some MS patients are in wheelchairs 10 years after diagnosis, while others continue to run marathons.

Please memorize the following text:The two consortia combined data from more than 12,000 people with MS to conduct a genome-wide association study (GWAS). This study uses statistics to accurately link genetic variants to specific traits. In this case, the traits of interest were related to MS severity, including the time it took for each individual to progress from diagnosis to a certain level of disability. After analyzing over 7 million genetic variants, the scientists identified one associated with faster disease progression. This variant is located between two genes with no previous connection to MS, known as DYSF and ZNF638. The first gene is involved in repairing damaged cells, and the second gene helps to control viral infections. The proximity of the variant to these genes suggests that they may play a role in the progression of the disease.

“These genes are typically active in the brain and spinal cord, rather than the immune system,” explained Adil Harroud, MD, the lead author of the study. The findings suggest that resilience and repair in the nervous system influence the course of MS progression, providing new leads for therapies. Researchers confirmed their findings by studying the genetics of nearly 10,000 additional MS patients, finding that those with two copies of the variant became disabled faster.

Netherlands Institute for Neuroscience

“The Dutch Brain Bank plays a crucial role in determining the relevance of DNA variants. A team of researchers from the Netherlands Institute for Neuroscience, including Aletta van den Bosch, Jeen Engelenburg, Dennis Wever, Jorg Hamann, Inge Huitinga, and Joost Smolders, studied the genetic factors influencing the progression of MS using donor brains as part of the International MS Genetics Consortium (IMSGC).”

Please take note of the following text:Joost Smolders, who works as a neurologist at Erasmus MC Rotterdam and is also associated with the Netherlands Institute for Neuroscience and the IMSGC, commented, “In terms of MS treatment, we have a variety of options, but predicting the rate of health decline is still a challenge. To gain a better understanding of the underlying mechanisms, the discovery of the SNP is an important first step. A SNP refers to a variation in a single DNA building block. At the Netherlands Institute for Neuroscience, we are able to take the next step by examining brain tissue to observe the impact of this SNP. Our Brain Bank houses brains from deceased MS donors, providing a wealth of disease history for research. We are investigating whether individuals with the genetic variation exhibit more severe MS-related brain changes.”

“Our results indicate that individuals carrying two copies of the risk allele (rs10191320) have nearly double the amount of MS-related abnormalities in their gray and white matter compared to MS donors without this genetic variation. This finding is significant as it suggests that this specific SNP could be relevant to individuals with MS. Additionally, this highlights the value of the Brain Bank in closely examining pathology. The impact of the SNP is much more pronounced in pathology compared to its effect on an individual’s experience with MS. This means that the effect of the SNP, which would typically require a large number of individuals for living measurements, can be validated using a much smaller sample size of around a hundred MS brain donors.”

Next steps

The researchers need to do more work to understand how this genetic variant affects DYSF, ZNF638, and the nervous system. They are also collecting more DNA samples from people with MS to find other variants contributing to long-term disability. Harroud said, “This gives us a new opportunity to develop drugs that may help preserve the health of all who suffer from MS.” Can we say, “treatments to prevent long-term disability” instead?

Multiple sclerosis (MS) is a chronic illness that often begins in young adulthood. At the onset, individuals commonly experience acute attacks, or relapses, of intermittent new neurological symptoms such as vision changes, numbness, and weakness. These symptoms may come and go randomly and then either remit completely or incompletely. These relapses are associated with changes in the brain or spine as shown by Magnetic Resonance Imaging (MRI). As people age, new attacks and MRI changes become less common. Patients may stabilize or enter a phase of slow progressive neurological disability with minimal MRI changes.

There is no cure for MS, but there are over 20 disease-modifying therapies (DMTs) that can reduce the risks of new attacks and MRI changes. Most DMTs have been approved for patients 55 and under, with the greatest impact on younger patients and modest effects on older patients. It’s unclear if older patients benefit, and risks may increase with age. Whether to stop DMTs as people age is an important, unanswered question.

The article discusses the results of a clinical trial called DISCOMS, which looked at discontinuing MS disease-modifying therapies (DMTs). The study included 259 participants over 55 years old who had not experienced an MS relapse for at least five years and had no new MRI lesions for at least three years. The trial found that discontinuing DMTs could be inferior to staying on the treatment, as there were more new events in the discontinuation group. However, there was no increase in disability, symptom scores, cognitive tests, or adverse events among those who stopped DMT.

John R. Corboy, MD, a professor of neurology at the University of Colorado School of Medicine, led the study and authored the article. “Our study addresses important concerns about the risks and benefits of disease-modifying therapies as people age. The primary objective of our study was to determine whether it is safe to consider discontinuing treatment for older patients with multiple sclerosis who have had no recent relapse or new MRI activity. Our goal was to provide an estimate of disease recurrence in this context,” Corboy said. He and his colleagues concluded that, while they were unable to demonstrate non-inferiority in the primary outcome, many patients aged 55 and older who have not had a relapse for five or more years might find the low risk of new clinical activity makes a personal discontinuation trial a reasonable option for them.

The series of images display cross-sectional electron micrographs of individual nerve fibres in brain biopsies of individuals with multiple sclerosis. The images show axons with myelin sheaths (depicted as black rings), illustrating increasingly severe damage from images 1 to 8. The spectrum of damage ranges from the accumulation of individual cellular components in otherwise bright, intact axons (image 1) to advanced degeneration in irreversibly damaged, dark axons (image 8). Photo credit: Leipzig University

Multiple sclerosis (MS) is a serious neurological disease that often leads to permanent disability. It affects approximately 2.9 million people worldwide, with 240,000 cases in Germany alone. The exact cause of the disease is not yet clear, but a key characteristic is the loss of the protective myelin coating on nerve connections in the central nervous system. This loss is caused by autoimmune processes. The myelin is created by specialized glial cells called oligodendrocytes and allows for fast transmission of nerve impulses. In MS, it is believed that immune cells break down oligodendrocytes and myelin, leading to irreversible damage to the vulnerable nerve connections. The loss of these nerve connections is a major factor in the severity and progression of MS.

Recent research suggests that our understanding of diseases needs to change. Myelin, previously thought to be only protective, can actually threaten the survival of axons when attacked by immune cells. Oligodendrocytes not only form myelin but also support the energy metabolism of axons. Myelinated axons rely on metabolic support and need intact myelin architecture for maintenance.

“When oligodendrocytes are exposed to an acute inflammatory environment, they may lose their ability to support the axons, and myelin becomes a threat to the survival of the axons,” says Professor Klaus-Armin Nave from the Max Planck Institute for Multidisciplinary Sciences in Göttingen, Germany. To test their hypothesis, the researchers examined tissue samples from patients with multiple sclerosis, as well as various mouse models of this disease in order to experimentally simulate the autoimmune attack on myelin. For the first time, the researchers were able to demonstrate by electron microscopy in the tissue samples of the patients that irreversible damage almost always occurs in the axons that are still coated with myelin. Conversely, using genetically modified mouse models, the researchers were able to show that “naked” axons in an acute inflammatory region of the central nervous system are better protected from degeneration.

Professor Ruth Stassart from the Paul Flechsig Institute suggests gaining a deeper understanding of myelin and developing new treatment strategies. Dr. Robert Fledrich adds that promoting rapid degradation of damaged myelin might be therapeutically better.