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Causes and prevention of MS

What is multiple sclerosis?

This is the first of a series of basic lessons to help you understand multiple sclerosis (MS).

Key points

  • MS is an autoimmune disease in which the immune system attacks the central nervous system.
  • Its exact cause is unknown; some contributory environmental factors are outlined.
  • Common manifestations of MS include lesions, relapses and intermittent symptoms, which often worsen with fatigue.
  • Early treatment is important to help prevent the damage that occurs with MS.

Multiple sclerosis (MS) is an organ-specific autoimmune disease. Autoimmune simply means that the immune system, whose primary role is to fight infections and cancers, goes awry and attacks itself. Organ-specific means that a disease is limited to one organ. So, in the case of MS, the immune system attacks the central nervous system (CNS), which consists of the brain, spinal cord and optic nerves.

Every organ in the body has its specific autoimmune disease. For example:

  • joints: rheumatoid arthritis
  • skin: psoriasis 
  • insulin-producing cells of the pancreas: type 1 diabetes
  • intestines: inflammatory bowel disease
  • kidneys: autoimmune nephritis (interstitial or glomerulonephritis).

The cause of MS

At present, the exact cause of MS is unproven. MS is a complex disease that occurs due to the environment’s interaction with inherited or genetic factors.1 Some of the main environmental factors are:

  • low vitamin D levels or a lack of sunshine
  • smoking 
  • Epstein–Barr virus (EBV), the virus that causes infectious mononucleosis (glandular fever) 
  • obesity, particularly in adolescence.

What we don’t know is how these genetic and environmental factors interact to cause MS. There are many genetic variants that predispose someone to get MS, but only a minority of people who have these variants will get the disease. Similarly, only a minority of people exposed to environmental risk factors get the disease.

Mechanisms that underlie the common manifestations of MS

Lesions

MS is characterised by inflammatory lesions – areas of damage or scarring (sclerosis) in the CNS – that come and go. The clinical manifestations of MS depend on where these inflammatory lesions occur. If, for example, a lesion involves the optic nerve, it will cause impaired vision; if it involves the brain stem, it causes double vision, vertigo or unsteadiness of gait; a spinal cord lesion leads to loss of feeling, limb weakness or bladder and bowel problems.  

Relapses

A new MS lesion in a site that is eloquent will cause symptoms and neurological signs; if these last for at least a day, they are called an attack or a relapse. If a lesion occurs in a site not associated with overt symptoms, this is often referred to as a subclinical or asymptomatic relapse. Subclinical relapses can be detected using magnetic resonance imaging (MRI). It is said that for every clinical attack there are 10 or more sub-clinical attacks (new MRI lesions).2 

Damage frequently occurs at the site of MS lesions. The inflammation strips the myelin covering the nerve processes and may cut through axons. Axons are the nerve processes that transmit electrical impulses or signals. When the axons are stripped of their myelin sheath, and/or are cut, they can’t transmit electrical signals. This causes loss of function, which manifests with specific symptoms.

Demyelination: loss of the myelin sheath that insulates nerves, leading to disruption of electrical signals. Image courtesy of Timonina/shutterstock.com. 

Intermittent symptoms

Surviving axons that pass through the lesion are able to recover function, by synthesising and distributing so-called ion channels across the demyelinated segment or by being remyelinated. Both these processes are not perfect. For example, the new sodium channels may not function normally, so they sometimes fire spontaneously. The spontaneous firing of axons may cause positive symptoms, for example, pins and needles, pain or spasms. The new myelin is typically thinner and shorter than normal and is temperature, fatigue and stretch sensitive. 

Stretch sensitivity

If someone with MS has a lesion in their spinal cord, electric shock-like sensations may occur when they stretch the spinal cord by bending or flexing their neck; this is known as Lhermitte’s sign.  

Temperature sensitivity

Recurrent symptoms may occur when body temperature rises, for example following fever, exercise or a hot bath. The MS symptoms (which may vary among individuals) disappear when the fever resolves or the body cools down. The temperature sensitivity is often referred to as Uhtoff’s phenomenon. 

Fatigue

Symptoms tend to worsen with physical and/or mental fatigue; for example, someone with MS may begin dragging a leg or dropping their foot after 20–30 minutes of walking. This is because the transmission in the functioning nerves, which have been previously damaged, begins to fail. This failure may be related to a lack of energy and/or to temperature changes that occur with exercise. 

Worsening MS (also called progressive MS)

If the axons, or nerve processes, above and below an MS lesion die off, the surviving axons may sprout to take over the function of the axons below the lesion. This puts an unnecessary strain on the surviving axons, which makes them vulnerable to die off in the future. A reduction in the number of nerves in a neuronal system reduces the neurological reserve of that system, making it more vulnerable to future attacks. In other words, the ability to recover from future attacks is reduced, and the neuronal pathway is susceptible to delayed degeneration and premature ageing. Clearly, if no treatment is given and focal inflammatory lesions continue to come and go, this will cause worsening of the disease. If enough damage is allowed to accrue, even switching off new inflammatory lesions may not prevent the so-called delayed neurodegeneration. This is why one of the primary principles of managing MS is early treatment to prevent damage from occurring in the first place. We have also discovered that the neuronal systems with the longest nerve fibres, in particular the bladder and legs, are much more susceptible to damage. We think this is simply because the longest pathways provide the greatest scope to be hit by multiple MS lesions.

Ageing and MS

As we get older our nervous systems degenerate. If we live long enough, we will all develop age-related neurological problems, such as unsteadiness of gait, loss of memory, reduced vision, loss of hearing, and poor coordination. 

What protects people with MS from becoming disabled and developing age-related neurodegeneration are brain reserve and cognitive reserve. Brain reserve is simply the size of your brain or the number of nerve cells you have. Cognitive reserve, in comparison, relates to how well these nerves function; it is associated with your level of education and how well you enrich your life by using your brain. From about 35 years of age, our brains start to shrink. In MS, this brain shrinkage is in general much greater than normal, and the resulting reduction in brain and cognitive reserve almost certainly primes the nervous system to age earlier. This is one of the reasons why people with MS continue to develop worsening disability later in the course of their disease. This insight is one of the main reasons why we promote early effective treatment of MS to protect and maintain brain and cognitive reserves.  

References

  1. Olsson T, et al. Interactions between genetic, lifestyle and environmental risk factors for multiple sclerosis. Nat Rev Neurol 2017;13:25–36.
  2. Gafson A, et al. The diagnostic criteria for multiple sclerosis: From Charcot to McDonald. Mult Scler Relat Disord 2012;1:9–14

Diagnosis

Am I sure that I have MS?

The multiple sclerosis misdiagnosis rate is around 5% and this has major implications for individuals and the treatment of MS.

Key points

  • A wrong diagnosis of MS may have financial, social and psychological consequences for the individuals concerned, affecting major life decisions.
  • Some MS treatments have life-threatening complications and should only be prescribed for people with a clear diagnosis of MS.
  • Some of the diseases that mimic MS can be made worse by disease-modifying treatments for MS.
  • Diagnostic criteria for MS have evolved and now take account of clinical, electrical, laboratory and magnetic resonance imaging findings.

A case study

She had been diagnosed with multiple sclerosis 8 years ago and had been taking interferon-beta since her diagnosis. I told her that I didn’t think she had MS and that her diagnosis was almost certainly complicated migraine with aura. The lesions on her magnetic resonance imaging (MRI) scan were non-specific white matter lesions and not inflammatory. Her neurological examination, spinal fluid analysis and evoked potentials (EPs) were normal. What clinched the non-MS diagnosis for me was the history of neurological events, which were too short-lived and migratory to be MS attacks. The final piece of the jigsaw was that a special MRI sequence showed none of her white matter lesions had a central vein, which told me that none of her white matter lesions was an MS lesion.  Her anger was palpable. She was angry because she had decided not to start a family and had changed her career because of the fear of becoming disabled in the future and not being able to work or look after a child.  This case illustrates why I always try to review the diagnosis of patients referred to me with MS and why it is important to answer this question before starting a disease-modifying therapy (DMT).   

Making a diagnosis of MS

Unfortunately, there is no single test to diagnose MS. Rather, MS is diagnosed by combining a set of clinical and MRI findings, electrical or neurophysiological investigations and laboratory tests. If these tests fulfil a set of so-called MS diagnostic criteria, the healthcare professional (HCP) or neurologist makes a diagnosis of MS. 

The underlying principles of diagnosing MS are to show the dissemination of lesions in space and time and exclude possible mimics of MS. The diagnostic criteria have evolved over time from 1) being based purely on clinical attacks,1 to 2) include electrical and spinal fluid tests as well as clinical attacks,2 and 3) to add on the use of MRI to help confirm dissemination in time and space.3–6  

Dissemination in time 

This means that two attacks or MS lesions must occur at least 30 days apart or that oligoclonal bands (OCBs) of immunoglobulins can be detected in the spinal fluid.

Dissemination in space 

This requires MS lesions to occur in different locations, for example, the optic nerve and the spinal cord. 

Electrical tests

The electrical or neurophysiological tests are called evoked potential (EPs) and test electrical conduction in a particular pathway. They can show lesions in nerve pathways that are not evident on the neurological examination or seen on MRI. The EPs can also show slow electrical conduction, which is one of the hallmarks of diseases that affect myelin, the insulation around nerves that is responsible for speeding up the electrical conduction of nerve impulses.

Laboratory tests

The laboratory tests are typically done to exclude other diseases that can mimic MS. Examining the spinal fluid for the presence of OCBs is useful in helping to make an MS diagnosis. OCBs are the fingerprint of a specific type of immune activation within the central nervous system (CNS). The OCB fingerprint is relatively specific for the diagnosis of MS in the correct clinical context. (OCBs are also found in CNS infections and other autoimmune diseases, but these are relatively easy to differentiate from MS.)

Please be aware that you may have MS according to the latest diagnostic criteria when you could not be diagnosed with MS using past criteria.

Why is a correct diagnosis important?

Neurologists get the diagnosis wrong in approximately 5% of people with MS. In other words, one in 20 people who have a diagnosis of MS in life does not have MS when their brain is studied post mortem. This data is based on a large study in a region of Denmark.7 More recently, a study from a specialist MS centre in the United States reported a misdiagnosis rate of approximately 15% in patients with presumed MS referred to their centre for treatment.8 

Why is getting the diagnosis of MS correct so important? Firstly, some MS treatments have life-threatening complications; you don’t want to expose people without MS to these complications. More concerning is that some of the diseases that mimic MS can be made worse by MS DMTs. Finally, a diagnosis of MS has many psychological, social, financial and economic implications. Even if you turn out to have ‘benign disease’, just having a diagnosis of MS, has implications for your life choices and may impact your ability to get insurance cover, to name obvious examples. I, therefore, advise you to make sure you have MS and not an MS mimic.

Common MS mimics

References

  1. Schumacher GA, et al. Problems of experimental trials of therapy in multiple sclerosis: Report by the Panel on the Evaluation of Experimental Trials of Therapy in Multiple Sclerosis. Ann N Y Acad Sci 1965;122:552–68.
  2. Poser CM, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13:227–31.
  3. McDonald WI, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50:121–7.
  4. Polman CH, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann Neurol 2005;58:840–6.
  5. Polman CH, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011;69:292–302.
  6. Thompson AJ, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol 2018;17:162–73.
  7. Engell T. A clinico-pathoanatomical study of multiple sclerosis diagnosis. Acta Neurol Scand 1988;78:39–44.
  8. Kaisey M, et al. Incidence of multiple sclerosis misdiagnosis in referrals to two academic centers. Mult Scler Relat Disord 2019;30:51–6.
Brain health and holistic management of MS, Treatment strategy

What are the consequences of not treating MS?

Are there valid reasons not to treat MS with a disease-modifying therapy? What are the consequences of not treating MS? Is watchful waiting justified?

Key points

  • Untreated MS will, given time, result in physical disability, impaired quality of life and ‘hidden’ problems such as cognitive impairment, anxiety and depression.
  • Brain atrophy, or shrinkage, occurs at a faster rate in people with MS than in healthy individuals.
  • Optic neuritis, inflammation or destruction of nerve fibres in the brain and spinal cord, and extensive damage to the cerebral cortex (grey matter) are some consequences of MS lesion development.
  • Quality of life impacts may include reduced mobility, relationship difficulties, increased likelihood of unemployment and memory impairment.
  • Without treatment, the life expectancy of people with MS is reduced by about 6 ̶ 8 years.
  • There are, however, several valid reasons why some people with MS prefer not to receive disease-modifying treatments.

Risks from no disease-modifying treatment

Many patients ask me what will happen to their MS if they don’t take a disease-modifying treatment (DMT) and how effectively DMTs prevent these outcomes. Here I try and address questions you need to ask yourself before starting a DMT.

If you are an individual with MS, predicting your disease course is difficult. However, many studies monitoring groups of people with MS show patterns in relation to the progression of the disease and its outcome, with various data sets being consistent.

Given sufficient time, most people with MS who are not treated will become disabled. Most people focus on physical disability, but MS causes many hidden problems, such as cognitive impairment, anxiety and depression.

How untreated MS can progress – headline results

The slides below summarise some of the outcomes of untreated MS; these include brain changes (atrophy), further MS lesion development, reduced health-related quality of life, long-term impact on physical and mental health and shorter life expectancy. (To enlarge an individual slide, click on the arrow at the top right.)

Brain changes
MS lesion development
Quality of life impact
Long-term outlook

DMTs have changed the landscape

It is important to note that these outcomes are from the pre-DMT era and don’t apply to populations of people with MS treated with DMTs. New real-life data indicate that DMTs, particularly high-efficacy DMTs, are preventing many of these problems. By not being on a DMT, if you have active MS, you are at risk of acquiring damage from focal inflammatory lesions. Early in the disease course, you may not be aware of this damage because of the remarkable capacity of the nervous system to compensate for damage (neurological reserve). However, once the compensatory mechanisms have been exhausted, further damage results in overt disability. It is important to regard DMTs as preventive treatments, i.e. their aim is to delay, and hopefully prevent, future disability.

Possible reasons for not receiving a DMT

Many people with MS will not be on a DMT, for a variety of reasons. The list below is probably not extensive; if you know of other reasons why someone who qualifies is not taking a DMT, please let me know.

Inactive MS

Someone with inactive MS will not be eligible for a DMT. There is no standard definition of active MS. To me, active MS is recent evidence of focal inflammatory disease activity, defined as:

  • clinical relapse(s) in the last 2 years
  • OR magnetic resonance imaging (MRI) activity in the last 12 ̶ 36 months (new or enlarging T2 lesions or T1 Gd-enhancing lesions)
  • OR a raised cerebrospinal fluid (CSF) neurofilament light chain level in the last 12 months.

Worsening disability in MS without focal inflammatory disease activity is not active disease. It can be due to damage caused by past inflammation, smouldering MS or the effects of premature ageing; anti-inflammatory DMTs can’t address this problem. We need different types of DMTs to address these mechanisms – for example, neuroprotective and/or remyelination therapies and anti-ageing therapies.

Watchful waiting

In many situations, some neurologists think someone with MS will end up having benign disease, so they are not prepared to start treatment until the patient develops some overt disability. I abhor this practice and it is one of the reasons I spend so much of my time disseminating knowledge and getting involved with health politics. Watchful waiting, in terms of treating MS, is not supported by data. The earlier and more effectively you treat MS, the better the outcome. The only situation I could condone watchful waiting in someone with active MS is when the diagnosis of MS is in question. Sometimes in neurology, time is the best diagnostician. If the person has MS, it will declare itself with further disease activity, and this would be the trigger to start a DMT.

Family planning

Trying to fall pregnant, pregnancy or breastfeeding are common reasons to interrupt or stop DMTs. Please note that most neurologists now have options to treat MS during pregnancy and while breastfeeding, so this is becoming a less common reason for not taking a DMT.

Risk aversion

Some people with MS are not prepared to take the potential risks associated with DMTs.

Personal reasons

Some people with MS don’t believe in having their MS treated, preferring to try alternative medicines and turn down traditional DMTs. If you are one of these people, I would recommend you continue to interact with your MS team and have regular monitoring of your MS (clinical, MRI, patient-related outcome measures [PROMS] and possibly CSF analyses). Then, if these alternative strategies don’t work, you will keep open the option of treatment with a ‘traditional DMT‘. Most alternative treatment strategies for MS are compatible with DMTs and hence should be viewed as complementary. Understanding the difference between complementary and alternative treatments is important. Complementary treatment strategies are part of the holistic management of MS.

Financial constraints

In some parts of the world, MS treatment is not covered by a national health service or medical insurance scheme and some people with MS simply can’t afford DMTs. Even in rich countries, people with MS who are disenfranchised don’t have access to treatment; these may include illegal immigrants, refugees and asylum seekers waiting for their applications to be processed.

Progressive or more advanced MS

In most countries, neurologists don’t initiate treatment in patients with more advanced MS. This approach is based on a lack of evidence of the effectiveness of DMTs in this population. However, we are increasingly offering ocrelizumab (for active primary progressive MS), siponimod (for active secondary progressive MS) or off-label therapies on a compassionate basis to people with more advanced MS. In addition, there is also the potential to participate in clinical trials of new treatments for more advanced MS.

Ageism

Some healthcare systems and some neurologists are reluctant to start DMTs in people with MS who are over a certain age. This is based on a lack of evidence of the effectiveness of DMTs in this population, and it is why we need to do clinical trials in older people with MS.

Comorbidities

Many people have other medical problems for which the treatment takes priority over the treatment of MS. For example, a patient of mine was diagnosed with stage four bowel cancer. After her surgery, she started an intensive period of chemotherapy during which we stopped her DMT.

References

  1. Fisher E, et al. Gray matter atrophy in multiple sclerosis: a longitudinal study. Ann Neurol 2008;64:255–65.
  2. Barkhof F, et al. Imaging outcomes for neuroprotection and repair in multiple sclerosis trials. Nat Rev Neurol 2009;5:256–66.
  3. Simon JH. Brain atrophy in multiple sclerosis: what we know and would like to know. Mult Scler 2006;12:679–87.
  4. Ziemssen T, et al. Optimizing treatment success in multiple sclerosis. J Neurol 2016;263:1053–65.
  5. Hickman SJ, et al. Detection of optic nerve atrophy following a single episode of unilateral optic neuritis by MRI using a fat-saturated short-echo fast FLAIR sequence. Neuroradiology 2001;43:123–8.
  6. Trapp BD, et al. Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998;338:278–85.
  7. Peterson JW, et al. Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol 2001;50:389–400.
  8. Orme M, et al. The effect of disease, functional status, and relapses on the utility of people with multiple sclerosis in the UK. Value Health 2007;10:54–60.
  9. Pfleger CC et al. Social consequences of multiple sclerosis (1): early pension and temporary unemployment – a historical prospective cohort study. Mult Scler 2010;16:121–6.
  10. Kobelt G, et al. Costs and quality of life of patients with multiple sclerosis in Europe. J Neurol Neurosurg Psychiatry 2006;77:918–26.
  11. Feuillet L, et al. Early cognitive impairment in patients with clinically isolated syndrome suggestive of multiple sclerosis. Mult Scler 2007;13:124–7. 
  12. Confavreux C and Compston A. Chapter 4. The natural history of multiple sclerosis. In: McAlpine’s Multiple Sclerosis, Fourth Edition, 2006; 183 ̶ 272. Churchill Livingstone.
  13. Weinshenker BG et al. The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability. Brain 1989;112:133 ̶ 46.
  14. Torkildsen GN, et al. Survival and cause of death in multiple sclerosis: results from a 50-year follow-up in Western Norway. Mult Scler 2008;14:1191–8.
  15. Kingwell E, et al. Relative mortality and survival in multiple sclerosis: findings from British Columbia, Canada. J Neurol Neurosurg Psychiatry 2012;83:61–6.
  16. Sadovnick AD, et al. Cause of death in patients attending multiple sclerosis clinics. Neurology 1991;41:1193–6.
  17. Brenner P, et al. Multiple sclerosis and risk of attempted and completed suicide – a cohort study. Eur J Neurol 2016;23:1329–36.