Every five minutes, someone in the world is diagnosed with multiple sclerosis (MS). This disease affects more than 2.8 million people worldwide, including 55,000 in Spain. It usually appears between the ages of 20 and 40 (being the second leading cause of disability among young people) and three out of every four sufferers are women.

MS is an neurodegenerative disease of autoimmune origin that affects the brain and spinal cord. It occurs when the immune system mistakenly attacks the protective layer of neurons (called the myelin) and their axons (the part that connects them to other nerve cells). When this insulating layer and part of the neurons are damaged, communication between the brain and the rest of the body is interrupted, leading to progressive disability.

The symptoms vary greatly and can include fatigue, vision problems, cognitive changes, pain, balance and bladder control disorders and difficulty in walking or speaking. This variability complicates the diagnosis and means that the impact on quality of life varies greatly from one patient to another.

The exact cause of MS remains unknown but experts believe it’s a disease in which both genetic and environmental factors are involved. Moreover, risk factors have been identified such as low vitamin D levels, smoking, a sedentary lifestyle and the composition of the gut microbiota. There’s still no definitive cure but current treatments can modify the course of multiple sclerosis, slow its progression and reduce the frequency of flare-ups.

Led by three experts on the disease, Pablo Villoslada, Pablo Arroyo-Pereiro and Mar Tintoré Subirana, the latest Health Research Debate, held on 10 December, explored the current situation of multiple sclerosis, the advances being made in its diagnosis, the study of its causes and the effectiveness of current treatments and others in the pipeline.

• Pablo Villoslada is head of the Neurology Department at Hospital del Mar and director of the Neuroscience Programme at the Hospital del Mar Research Institute (IMIM).
• Pablo Arroyo-Pereiro is a neurologist at the Multiple Sclerosis Unit, Department of Neurology at Bellvitge University Hospital (HUB).
• Mar Tintoré Subirana is clinical head of the Multiple Sclerosis Centre of Catalonia (Cemcat) and of the Neurology/Neuroimmunology Department at Vall d’Hebron University Hospital (VHIR), and professor of Neurology at the University of Vic – Central University of Catalonia (UVic-UCC).

Below, we review the main ideas addressed by these three experts during the Debate, chaired by Jessica Mouzo, a journalist at El País newspaper specialising in health.

Jessica Mouzo

 

Genetic and environmental factors

What is multiple sclerosis?

“Multiple sclerosis is a disease of the central nervous system, which means that it affects our brain and spinal cord. Neurons have a head and a very long tail, which transmits the nerve signal generated by the neuron and is covered, like an electrical cable, by a sheath called the myelin. In multiple sclerosis, instead of protecting us our own defences attack us and the myelin becomes inflamed, affecting the transmission of information. This can lead to loss in vision, sensitivity or strength, depending on the cable affected. In short, multiple sclerosis is an autoimmune and demyelinating disease” – Mar Tintoré Subirana

How does it differ from amyotrophic lateral sclerosis (ALS)?

“They are two completely different diseases. ‘Sclerosis’ means scarring but, in MS, there’s scarring due to inflammation whilst in ALS the scarring is due to degenerative damage to the brain. Multiple sclerosis usually appears in young people whilst ALS tends to appear in people over 50” – Pablo Villoslada

What are the causes of multiple sclerosis?

“We know that, in general, autoimmune diseases involve a failure of the mechanisms of immunotolerance, which is the immune system’s ability to identify and respect the body’s own structures. Why do these mechanisms fail in MS? There are genetic factors that can affect a person’s risk or predisposition to developing the disease but there are also environmental factors that can cause the immune system to malfunction. In recent years, the Epstein-Barr virus has come to the fore among the environmental factors, as it’s probably one of the main triggers of multiple sclerosis” – Pablo Arroyo-Pereiro

What other risk factors are there?

“When it comes to factors that increase the risk of developing the disease, the most significant ones are infectious in nature, such as the Epstein-Barr virus. In fact, one relatively important study has indicated that this virus appears to be a necessary condition for the disease to develop. Additionally, other risk factors have been identified that influence the development of MS, such as smoking, a lack of vitamin D and exposure to the sun, obesity and even other viruses from the herpes family” – Pablo Arroyo-Pereiro

How important are genetic factors?

“Multiple sclerosis isn’t hereditary but it does have a genetic basis. In other words, there’s a genetic predisposition to developing it but that doesn’t mean you’ll necessarily suffer from it if your parents have it. More than 250 genes have been found that facilitate the development of multiple sclerosis, though not all of them carry the same weight. These genetic factors cause our immune system, when faced with the slightest provocation, to respond by becoming excessively inflamed and having difficulty in controlling itself, thereby facilitating the onset of multiple sclerosis” – Pablo Villoslada

How do the genetic and environmental factors fit together?

“It would go something like this: there are genetically predisposed people with a higher number of the 250 genes involved. A virus, such as the Epstein-Barr, comes along and their defences get rid of it but these defences also encounter bits of the myelin that resemble the virus and they get confused, attacking it. If our vitamin D levels are low, if we smoke or eat a diet rich in polyunsaturated fats, our defences make more mistakes. On the other hand, if, for example, we exercise, our defences make fewer mistakes. Consequently, in genetically predisposed individuals an autoimmune response is triggered that attacks the myelin, and this response can be increased or decreased depending on all these other environmental factors” – Mar Tintoré Subirana

 

The disease with a thousand faces

Why are the manifestations of multiple sclerosis so variable?

“It’s a disease in which inflammation can affect any part of the brain, the torso, the spinal cord or the optic nerve. And that means the symptoms can vary greatly, because each part of these structures has a specific function in terms of strength, sight, hearing or involuntary functions such as continence, among other things. That’s why it’s known as the disease with a thousand faces, but that doesn’t mean the symptoms are infinite. In fact, most episodes follow predetermined patterns” – Pablo Arroyo-Pereiro

How does the disease develop?

“When our defences mistakenly attack an area of the central nervous system, there’s a loss in function that normally lasts two or three weeks. Afterwards, our body manages to repair the myelin and recovers. This is what we call a flare-up or relapse. However, our defences can also attack areas that don’t cause symptoms: it’s been estimated that ten times more things happen in each flare-up that we can’t see. On the other hand, it should be remembered that the body’s ability to repair itself is limited so, if the disease is left untreated, it ends up leaving sequelae and causing chronic inflammation” – Mar Tintoré Subirana

Which cognitive functions are most affected?

“What we normally see is that the deterioration is gradual and slow and that, in the long run, it tends to affect frontotemporal functions more, especially the attention, verbal fluency and working memory – the ability to remember where I left something or that I left the stove on. These symptoms gradually develop over the years” – Pablo Arroyo-Pereiro

Can multiple sclerosis contribute to the onset of other mental health disorders?

“The disease has been linked to a higher incidence of certain mood disorders, anxiety and depression. But it’s unclear whether this is a direct consequence of the disease or whether they are reactive mood-related symptoms. On the other hand, some studies have also shown that there are a number of symptoms that precede the disease, non-specific symptoms like anxiety or fatigue” – Pablo Arroyo-Pereiro

 

The diagnosis of multiple sclerosis

What is the prevalence of the disease?

“It affects around two and a half million people worldwide and more than 50,000 in Spain. It’s more prevalent in white populations and in advanced, industrialised societies. What’s more, as people in Africa and Asia have adopted Western lifestyles, the incidence has increased. Finally, it’s also more common in women, as are all inflammatory diseases” – Pablo Villoslada

“The prevalence of inflammatory diseases, and multiple sclerosis in particular, has increased in recent years due to several factors. On the one hand, it’s much better diagnosed thanks to greater access to MRI scans. This also means that it’s not only severe cases that are diagnosed: today, even patients who haven’t had any symptoms can be diagnosed. Moreover, we’ve greatly refined the diagnosis, also in people over 60 and under 16, groups in which it used to be more difficult to obtain an effective diagnosis. On the other hand, the prevalence has also increased due to lifestyle factors” – Pablo Villoslada

Why does it affect women more?

“Gender plays a very important role in all autoimmune diseases but we’re not sure why. Hormones certainly play a crucial role. In fact, this disease often first appears in adolescence. However, it’s not clear whether oestrogen is really a differentiating factor or whether there are other contributing factors” – Mar Tintoré Subirana

And how does it affect young people?

“Diagnosis in children is more complicated because there are other diseases we have recently identified, such as the disease associated with MOC (Myositis Ossificans Circumscripta), which can confuse us. In addition, young people’s defence systems are very active: they’re very effective against infections but that also makes them more prone to mistakes. This causes children to have a particularly aggressive form of MS, although they also have a very good ability to repair lesions” – Mar Tintoré Subirana

Is it easy to detect multiple sclerosis?

“The diagnostic criteria, which have been updated this year, enable us to make an increasingly early diagnosis, which in turn is crucial for starting treatment as soon as possible. Today, we can even identify the disease in its pre-symptomatic stages in some patients. We also have biomarkers that help us to confirm our suspicions and act more quickly and confidently. In addition, the general public’s knowledge of the disease has improved, which also means that those with MS are more likely to see a doctor sooner” – Mar Tintoré Subirana

How can diagnosis be improved and what progress has been made?

“The area where we have the most problems is in predicting the disease. We can see flare-ups and acute inflammation very clearly on MRI scans and our treatments are also increasingly effective. However, the progression of the disease is more difficult for us to detect and predict” – Pablo Arroyo-Pereiro

“With Dr. Pablo Naval, a radiologist at Bellvitge Hospital, we’re carrying out a project to use artificial intelligence in the diagnosis of multiple sclerosis, as it allows us to use a lot of data simultaneously to try to improve the accuracy with which we can predict the disease’s behaviour. However, although AI can help us, we’ll most likely need to develop new markers to extract more information about the disease” – Pablo Arroyo-Pereiro

 

The treatment of multiple sclerosis: towards a possible cure?

What therapies are available to treat the disease?

“Having MS today is nothing like it was 25 years ago. We have a large number of tools to help patients live a normal life. We have drugs that enable us to eliminate flare-ups, eliminate new lesions and eliminate acute inflammation, and we’ve greatly improved the prognosis. It’s true there are still things that need to be improved: today we’ve got a fabulous therapeutic arsenal, with 14 or 15 approved drugs, but we still have problems treating the chronic inflammation that appears in the long term” – Mar Tintoré Subirana

What side effects do these treatments cause?

“We’ve also made significant improvements in this area. The first treatments had to be administered every other day and were quite unpleasant, causing what we called ‘flu-like’ symptoms which were difficult to tolerate. Today, there are several strategies available to try to make a patient’s defences less aggressive. This can take its toll because, sometimes, in the long run patients are more exposed to infections or have a poorer response to vaccines, but work is being carried out to reduce these adverse effects. On a day-to-day basis, most treatments enable patients to lead a normal life” – Mar Tintoré Subirana

What role does neuromodulation play in these treatments?

“Neuromodulation consists of using energy to change how the brain works. In the case of multiple sclerosis, we’re particularly interested in focused ultrasound. Ultrasound enables us to focus the energy on very specific areas of the brain, which is why it’s already commonly used to treat certain lesions, for example in Parkinson’s. So far, we’ve seen that, by using low-intensity ultrasound, we can change the functioning of the neurons and the cells that help neurons produce myelin. This helps us to reduce inflammation, promote myelin formation and prolong the life of the nerves, slowing the progression of the disease” – Pablo Villoslada

What new drugs are in the pipeline?

“Treatments have improved greatly but we still need to resolve chronic inflammation. In this respect, there are several interesting drugs being tested that could begin to be used in the short to medium term. We’re hopeful that the so-called BTK drugs can act on chronic encapsulated inflammation at a central level. Another drug that gives us hope and in whose clinical trial we’re participating is FrexalimAB. There are also interesting immunotherapies that are beginning to be tested, such as CAR-T therapies, which consist of extracting defence cells from the patient and training them to attack a specific target (in the case of MS, the idea is that they can attack the defence cells that are attacking the patient’s nervous system). Finally, another very interesting development is that of shuttles, which enable the drugs we use today to penetrate more effectively the skull and meninges, i.e. the central nervous system, to treat encapsulated inflammation” – Pablo Arroyo-Pereiro

Are there any vaccines that can prevent the disease?

“There’s a lot of expectation regarding the development of a vaccine against the Epstein-Barr virus, as current evidence suggests that infection with this virus is almost a necessary requirement for the development of multiple sclerosis. The hypothesis is that, if we could vaccinate future generations and eliminate this triggering factor, we could imagine a world without MS. There’s still a lot of work to be done before we can confirm whether this is the case, but clinical trials of Epstein-Barr vaccines are now underway” – Mar Tintoré Subirana

Could there ever be a cure for multiple sclerosis?

“I believe so. Perhaps not a complete eradication of the disease but, if we manage to control the risk factors such as the Epstein-Barr virus, and if we manage to locate the specific proteins that trigger the immune system attack, we’ll be able to develop much more effective treatments and could have the disease under complete control and inactive” – Pablo Villoslada

“Currently, the Epstein-Barr virus vaccine is a good bet for preventing future cases. Drugs to treat chronic inflammation are also important. I don’t know if we’ll be able to completely halt the disease but we’re on the right track. I think it would also be important to improve treatments that reinforce myelin regeneration because, so far, we haven’t been able to find anything that works well” – Pablo Arroyo-Pereiro

“Last year, we took part in an international group of scientists that attempted to define the path towards curing multiple sclerosis. I think it was one of the first initiatives in which we dared to use that word: cure. We concluded that three things were needed: managing to slow down the disease, which is where we’re currently most successful, to repair what’s been lost, and to prevent the disease” – Mar Tintoré Subirana