Multiple sclerosis (MS) is a neurodegenerative disease that, despite its relatively low occurrence worldwide (only 2-3 million people), most of us have heard of. It’s a disease whose course I am familiar with due to my grandma developing symptoms in her 30s, that went on to affect the rest of her life. However, my knowledge of MS never went far beyond racing her in her electric wheelchair and I always harbored the thought growing up that it wouldn’t be too long before a cure would be found. Yet here we are, 20 years of progress later, and although the scene has changed enormously in the 50 years since my grandma’s diagnosis, are we really any closer to treating MS?
For those like myself who don’t know much about nervous system diseases, MS is the name for the disease characterized by the inflammation and demyelination of nerves in the central nervous system. “Demyelination” is the process through which the lipid (fat-based) sheaths around nerve cell axons, called myelin, are stripped away, leading to detrimental impacts on the function of the affected cells. The disease does not stop there though, as the demyelination and inflammation coincides with the loss of axons in CNS nerves and the atrophy of white and grey brain matter over time. The “over time” is key here because MS presents as one of three subtypes: primary progressive, secondary progressive and relapse. Of these, relapse is the most common, with only ~10-15% of MS patients experiencing progressive subtypes. In relapse, episodes of neurological symptoms appear and recover periodically. This can sometimes progress to secondary progressive, where the symptoms continue to worsen over time, without any remission. Lastly, in the primary subtype, symptoms do not worsen in episodes but immediately begin to progress, at an unpredictable rate.
Irrespective of type, MS symptoms present not only physically, as most people are aware, in the form of loss of limb function over time, but also cognitively. The detrimental impacts on the brain over the course of an MS patient’s life are difficult to predict because the neuroplasticity inherent in the brain means that some patients experience significant loss of cognitive processing speed (the speed with which one handles tasks), visual memory (recalling pictures/visual memories) and executive function (such as attention), while others never experience any of this throughout their whole lives.
MS is three times more common in females than males, but in all sexes, it presents most often in a patient’s early 30s with a first episode of neurological dysfunction, i.e. the nervous system behaving abnormally. In all episodes throughout a patient’s life, the dysfunction can occur immediately over the course of hours, slowly over the course of days, or even occur without the person’s awareness for years. The name “relapse” derives from the insidious nature of the disease, as the symptoms naturally pass into remission, again either slowly or quickly, and can return at any time. Episodes continue to return over the course of the MS patient’s life, however the relapses decrease in frequency over time.
To treat such a disease, one needs to understand it, yet it’s at this stage that MS escapes us. Substantial progress has been made in modeling how the disease might arise and progress in individuals, however the exact pathology of MS remains unknown. What we do know is that the immune system plays a significant role in the development and worsening of the disease. Immune cells attack tissue in the CNS, leading to the demyelination process and atrophy of brain matter. The cells of greatest interest in the immune system are B-cells and T-cells, which appear to play a critical role in relapses. Drugs targeting T-cells have been ineffective at managing symptoms of MS, but those targeting B-cells have reduced the frequency and intensity of relapses in this MS subtype. The question remains, though, why do these immune system cells start to attack our own central nervous system so insidiously?
The leading theory has to do with a virus that you and I likely both have already. In fact, over 90% of the adult population worldwide already has Epstein-Barr virus (EBV) lying latent in their bodies. How this became the focus of MS researchers had a lot to do with processes of elimination and looking for any similarities between patients, thus population-based studies were required. The most in-depth and long-lasting of these was a study of 10 million US army personnel who were followed for over 20 years, until a small percentage of them developed MS. Looking at all the factors that matched between these varying individuals, the conclusion was that all of them had EBV. Indeed, it has been demonstrated that everyone with MS has been infected with EBV. Nevertheless, if nearly everyone has EBV, then why do more people not develop MS? Thus, we arrive at the crux of the MS problem. EBV appears to be a trigger for developing relapse MS, but the exact mechanism behind why is poorly understood, thanks in large part to just how complicated EBV infection is (Editing note: there has been an update since time of writing, https://www.sciencedaily.com/releases/2024/05/240523153711.htm ).
EBV is so ubiquitous in the world because it is incredibly good at infecting us. It can enter our bodies either by invading B-cells or epithelial cells (the walls of skin and organs), or in rare cases it can even invade T-cells. When it gets to a B-cell, it begins reprogramming and influencing genes in these immune system cells such that it can remain dormant and un-targeted. EBV is also thought to mimic our local cells, which helps it to stay below the immune system’s radar, however it is because of this that the immune system likely begins targeting the CNS. There are proteins on the surface of the EBV that look identical to proteins in the tissue of CNS cells, thus it would not be hard to imagine a confused and hyperactive immune system accidentally nuking the wrong cells in an attempt to keep us safe, as seen in immune system disorders.
Given how little we do know about exactly how the disease occurs and relapses, how do we treat it and what can be done to improve treatment? The most commonly prescribed first response to a relapse is to use corticosteroids to dampen the immune system. This has proven to be effective at controlling the symptoms of an episode, but such drugs cannot be used over the long-term because they impact the entire immune system, leaving us more vulnerable to all infections. Another popular line of treatment is the use of so-called “disease-modifying treatments” (DMTs), the most effective of which target certain B-cell types in the immune system, to substantial effect.
Nevertheless, available treatments, though incredibly helpful, only treat the symptoms and not the overall problem. Consequently, future research will likely continue to follow the EBV pathway to understand how it triggers MS later in a patient’s life. Advancement toward a cure for MS will generate substantial progress in not just neurodegenerative disease research but also virology, genetics, antibody and cognitive research that will go beyond benefiting patients alone.
Author: Thomas von Rein
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