Tag Archives: comorbidity

DMTsSafety, Monitoring MS

How can I reduce my chances of adverse events on specific DMTs?

The complications associated with immunosuppression vary from DMT to DMT. You will find it helpful to understand what investigations to expect before and during treatment and how these may vary depending on the DMT(s) you are considering.

Key points

  • Numerous tests are carried out at the start of your treatment (baseline); these include blood, urine and tests for a range of infections.
  • Some patients will need tests or procedures specific to their DMT that are inappropriate for everyone with MS – for example, vaccination against some infections; pregnancy and/or genetic counselling; prevention of cardiovascular complications; and management of infusion reactions.
  • Ongoing monitoring is required for many but not all of the above factors.
  • All licensed MS DMTs have had a thorough risk ̶ benefit assessment, and their benefits are considered to outweigh the potential risks.

Standard tests … and why we do them

If you have read the article on immunosuppression, you will know that immunosuppressive DMTs may reduce white blood cell counts and antibody responses to vaccines and increase the likelihood of some infections and cancers. However, we can reduce the risk of many complications associated with long-term immunosuppression (we use the shorthand ‘de-risk’). This article explains what needs to be done at the start of DMT administration (baseline) and during subsequent monitoring. The specifics, however, vary from DMT to DMT.

Baseline tests

Tests at baseline (before starting DMT administration) include full blood count, platelets, liver, kidney and thyroid function tests, and a urine screen. Recording baseline immunoglobulin levels is particularly important if you are about to start an anti-CD20 therapy (ocrelizumab, ofatumumab or rituximab) so that we have a reference level for future comparisons. 

Serum protein electrophoresis is done for patients considering starting interferon-beta; having a so-called monoclonal gammopathy (an abnormal immunoglobulin) is a contraindication to starting an interferon-beta formulation in people with MS. The drug has been associated with a form of capillary leak syndrome, leading in rare cases to death from an adult respiratory distress syndrome.

The table below summarises the routine investigations required at baseline; subsequent sections provide further detail.

Tests routinely carried out at the start of treatment (baseline).
AHSCT, autologous haematopoietic stem cell transplantation; CMV, cytomegalovirus; CSF, cerebrospinal fluid; DMT, disease-modifying therapy; EBV, Epstein ̶ Barr virus; ECG, electrocardiogram; FBC, full blood count; HIV, human immunodeficiency virus; HPV, human papillomavirus; JCV, JC virus; LFTs, liver function tests; MMR, measles/mumps/rubella; MRI, magnetic resonance imaging; PCP, pneumocystis pneumonia; PML, progressive multifocal leukoencephalopathy; TB ELISpot, tuberculosis enzyme-linked immune absorbent spot; TFTs, thyroid function tests; U&E, urea and electrolytes; VZV, varicella zoster virus.

Infection screening

At our centre, we screen for a relatively large number of infectious diseases so that we can treat any subclinical infection before starting a DMT. This is particularly relevant for HIV-1 and 2, hepatitis B and C, syphilis and tuberculosis (TB).  

Screening for the JC virus (JCV), which causes progressive multifocal leukoencephalopathy (PML), is only really needed for people with MS considering starting natalizumab. Even if you are JCV positive, you can be treated with natalizumab for 6 ̶ 12 months and sometimes longer if you are prepared to take on the risk and the extra monitoring required to detect PML early. 

We only check measles/mumps/rubella (MMR) status in patients without documentation of full vaccination as children. We check varicella zoster virus (VZV) status before starting immunosuppression and vaccinate seronegative individuals. Currently, we are still using the live VZV vaccine. This will change, and we will likely be offering all people with MS in the UK the component inactive VZV vaccine (Shingrix, that has had its licence extended) to reduce the chances of zoster reactivation in all adults starting immunosuppression. This new Shingrix indication is similar to the pneumococcal vaccine (Pneumovax). Our centre is only recommending Pneumovax in patients about to start an anti-CD20. However, when Shingrix becomes available on the NHS, it will make sense to bundle this with the Pneumovax and make it routine for all people with MS before starting immunosuppressive therapy. Please check with your healthcare team which products are available locally.

Routine tests and monitoring for Epstein-Barr virus (EBV) and cytomegalovirus (CMV) are only needed for subjects undergoing autologous haematopoietic stem cell transplantation (AHSCT), which causes profound short-term immunosuppression that can result in CMV and EBV reactivation. CMV reactivation also occurs with alemtuzumab, so this needs to be considered when investigating patients who develop complications after receiving alemtuzumab (please see Opportunistic infection in MS). 

For patients starting long-term immunosuppression, it is advisable to screen for active human papillomavirus (HPV) infection (by cervical smear or vaginal swab) and for warts or active infection with molluscum contagiosum. Warts are caused by HPV skin infection; molluscum contagiosum is due to a relatively benign pox virus that typically affects young children but occasionally affects adults. Warts and molluscum contagiosum can spread rapidly in patients receiving alemtuzumab, so I recommend treating these skin infections before starting immunosuppression for MS. 

Vaccinations

We encourage all patients to be vaccinated against COVID-19 and seasonal flu; outside the flu vaccine season, we remind people to get vaccinated during the next vaccine season. 

Hepatitis B, meningococcal and Haemophilus influenzae vaccines are considered only for people with MS who are at high risk of infection and have not had these vaccines as part of a national vaccine programme, i.e. healthcare and laboratory workers for hepatitis B, school and university students and military recruits for meningococcal vaccine and paediatric patients for Haemophilus influenzae. 

The issue around having the HPV vaccine as an adult is more complex. For example, in the UK, the NHS does not cover the cost of the vaccine for people over 25. In addition, most people have only had the quadrivalent vaccine (Gardasil-4), which covers about two-thirds of the strains that cause cancer. Some people with MS may want to upgrade their immunity with the polyvalent vaccine (Gardasil-9) that covers over 95% of the cancer-causing strains of HPV. For more information on HPV vaccination, please see Case study: cervical intraepithelial neoplasia (CIN) and ocrelizumab.

MMR is a live vaccine given in childhood (see MMR vaccine: to vaccinate or not? ). Owing to vaccine hesitancy, however, many people do not receive this vaccine as children. Therefore, if an adult with MS is about to start immunosuppressive therapy and has not been vaccinated against MMR, we advise them to do so. This is particularly important for people about to start natalizumab because these viruses are neurotropic and can infect the brain. Natalizumab blocks immune response within the brain; hence, exposure to a neurotropic virus could cause serious infection, similar to what we see with the JC virus – which causes PML.

Travel vaccines for people who travel as part of their work or plan to travel shortly need to be considered. In particular, the yellow fever vaccine is a live vaccine (made from a weakened yellow fever virus strain) and it should ideally be given before someone starts on immunosuppressive therapy. 

Cardiovascular screening

You may need an ECG (electrocardiogram), to rule out an abnormal heart rhythm or electrical conduction abnormality and to check your left ventricular function (ejection fraction). These abnormalities are a relative contraindication to using the S1P modulators (fingolimod, siponimod, ozanimod, ponesimod), which may affect the conduction of the heart. In patients treated with mitoxantrone, the left ventricular ejection fraction (LVEF) must be done at baseline and regularly monitored because mitoxantrone is toxic to the heart. If the LVEF drops significantly, further dosing of mitoxantrone is contraindicated. 

Pregnancy, family planning and genetic testing

Many chemotherapy agents used in AHSCT for ablating (extracting) the bone marrow are toxic to the ovaries and testes. Therefore, patients receive counselling before treatment and can have eggs (oocytes) or sperm banked for future use. Egg banking is also an issue for women with MS being treated with mitoxantrone. Men receiving mitoxantrone do not need to bank sperm, however, because mitoxantrone does not cross the testes ̶ blood barrier. 

Genetic testing is only required at present if you wish to receive siponimod. Siponimod is metabolised by a specific liver enzyme (biological catalyst) with two functional variants – slow metabolising and fast metabolising. People who carry two slow-metabolising variants of the enzyme cannot receive siponimod. Intermediate metabolisers (those that carry one slow- and one fast-metabolising version of the enzyme) receive low-dose siponimod, while those with two fast-metabolising enzymes receive high-dose siponimod. 

Protecting against progressive multifocal leukoencephalopathy

I have included magnetic resonance imaging (MRI) and lumbar puncture with cerebrospinal fluid (CSF) testing for JCV among the baseline tests. This is specific to patients at high risk of developing PML who are switching from natalizumab to a depleting immune reconstitution therapy such as alemtuzumab or another therapy that depletes their immune system (e.g. cladribine or an anti-CD20 therapy). These tests are done to exclude asymptomatic PML, which will otherwise be carried over to the new treatment. The effects of these immunosuppressive therapies on your immune system cannot be rapidly reversed, which is a problem because immune reconstitution is needed to clear PML. Most MS centres do not mandate CSF testing in this situation because it does not always reveal the presence of PML. However, I still request this test on my patients to gain as much information as possible on which to base potentially life-changing decisions.

Prophylactic antivirals and antibiotics

Patients in our centre undergoing AHSCT or receiving alemtuzumab will be given antivirals and antibiotics to reduce the likelihood of certain infections. This is particularly relevant for listeriosis, which is a rare infection transmitted via food. We also encourage all our patients to start and maintain a specific diet to reduce the chances of listeriosis. The risk of listeriosis is only present for a short period when both the adaptive and innate immune systems are compromised, that is, for 4 weeks after receiving alemtuzumab, so we recommend antibiotic prophylaxis for 4 weeks. Our online resource provides more information about listeriosis. If you live in the UK, you can order our free listeriosis prevention kit, which contains a booklet (also downloadable) and various practical items to help keep you safe.

Strategies for limiting the risks from immune reconstitution therapies and infusion DMTs.

Infusion reactions

When you use agents that cause cell lysis (breakdown), such as alemtuzumab and intravenous anti-CD20 therapies, the contents of cells cause infusion reactions. To prevent such reactions or reduce their severity, we pretreat patients with corticosteroids, antihistamines and antipyretics. The exact protocols for each DMT differ; for example, ocrelizumab infusion reactions are generally only a problem with the first and second doses; therefore, many centres don’t give steroids with the third and subsequent infusions. The latter was particularly important during the COVID-19 pandemic when it was shown that the recent administration of high-dose steroids increased your chances of severe COVID-19. 

Ongoing monitoring

Once someone has been treated with a DMT, ongoing monitoring is required. What gets monitored and how frequently depends on the individual DMT. For a list of DMTs associated with important adverse events, please see our summary Table in ‘De-risking’ guide: monitoring requirements of individual DMTs.

The regulatory authorities usually put in place specific monitoring requirements, which can differ worldwide. It is important that you also enrol in your national cancer screening programmes. Being on chronic immunosuppression increases your chances of developing secondary malignancies, so please remain vigilant. 

Tests carried out regularly as part of ongoing monitoring.
FBC, full blood count; LFTs, liver function tests; MRI, magnetic resonance imaging; PML, progressive multifocal leukoencephalopathy; TFTs, thyroid function tests; U&E, urea and electrolytes.

I want to reassure you that all licensed MS DMTs have undergone a thorough risk ̶ benefit assessment by the drug regulators, and the benefits of these treatments are considered to outweigh the potential risks. On balance, the level of immunosuppression associated with MS DMTs is typically mild to moderate; hence, the complications are relatively uncommon. MS is a bad disease and, if left to run its natural course, would result in most patients becoming disabled. To learn more about the natural course of MS, please read the section entitled What are the consequences of not treating MS?

DMTs, Treatment strategy

How immunosuppressed am I?

Do you understand the difference between short-term intermittent and long-term continuous immunosuppression? Here we address another of the key questions to consider before deciding on a specific disease-modifying therapy (DMT).

Key points

  • Immunosuppressive disease-modifying therapies (DMTs) reduce the immune system’s effectiveness.
  • It is important to weigh up the benefits and risks of short-term versus continuous immunosuppression.
  • Non-selective DMTs suppress the adaptive and innate immune systems; selective DMTs do not affect the innate immune system and are thus associated with a low risk of bacterial infections.
  • The implications of immunosuppression need to be considered within the context of other health and lifestyle factors.

Which DMTs cause immunosuppression?

A useful way of thinking about DMTs is based on whether they are immunosuppressive. Broadly speaking, an immunosuppressive is any DMT that reduces the immune system’s activation or effectiveness. 

From a regulatory perspective, for a drug to be classified as immunosuppressive, it should: 

  • cause significant lymphopaenia or leukopenia (reduced white cell counts)
  • be associated with opportunistic infections (infections that don’t occur in people with a normal, healthy immune system)
  • reduce antibody and/or T-cell responses to vaccines 
  • increase the risk of secondary malignancies. 

Based on the above criteria, the interferon-beta preparations and glatiramer acetate are immunomodulatory rather than immunosuppressive. Teriflunomide is also an immunomodulatory therapy with the potential, albeit small, to cause immunosuppression. In real life, however, very few people with MS treated with teriflunomide develop significant lymphopaenia or leukopenia; if they do, we tend to stop the drug. The other licensed DMTs are immunosuppressive to a greater or lesser degree. 

Short-term versus continuous immunosuppression

The duration and intensity of immunosuppression further determine the risks. Short-term or intermittent immunosuppression associated with an immune reconstitution therapy (IRT) front-loads the risks, which decrease substantially once the immune system has reconstituted itself. In comparison, long-term continuous or persistent immunosuppression, which occurs with most maintenance DMTs, accumulates problems over time, particularly opportunistic infections and secondary malignancies.

Live vaccines are, in general, contraindicated in patients on continuous immunosuppressive therapies. However, someone with MS on an IRT who has reconstituted their immune system can tolerate and respond to live vaccines. The benefits of administering live vaccines always need to be balanced against the risks of the vaccine.

How immunosuppressed are you table

The main characteristics of continuous persistent and short-term (intermittent) immunosuppression. Modified from Giovannoni, Curr Opin Neurol.1
AHSCT, autologous haematopoietic stem cell transplantation; PML, progressive multifocal leukoencephalopathy.

Selective versus non-selective immunosuppression

Immunosuppression that accompanies DMTs may be selective or non-selective. Non-selective therapies deplete and/or suppress both the adaptive immune system (T cells and B cells) and the innate immune system (monocytes, neutrophils and natural killer [NK] cells). Alemtuzumab, AHSCT (autologous haematopoietic stem cell transplantation) and mitoxantrone are non-selective and are therefore associated with acute bacterial infections such as listeriosis, nocardiosis and cytomegalovirus reactivation. In comparison, anti-CD20 agents (ocrelizumab and ofatumumab) and cladribine are selective, do not affect the innate immune system and are therefore associated with a low risk of acute bacterial infections. 

How immunosuppressed are you_MET vs IRT_6 Sept 2022

Classification of disease-modifying therapies for relapsing forms of MS. Modified from Giovannoni, Curr Opin Neurol.1
AHSCT, autologous haematopoietic stem cell transplantation.

Other considerations

Please note that the implications of immunosuppression are not black and white but interact with other factors such as:

These factors have been highlighted during the COVID-19 pandemic, particularly in relation to the risk of severe COVID-19 and the variations in vaccine responses among people with MS (including waning of the immune response).

It is important to realise that we can derisk (reduce the risk of) some complications associated with long-term immunosuppression and the use of DMTs. Please see the post entitled How can I reduce my chances of adverse events on specific DMTs?

References

  1. Giovannoni G. Disease-modifying treatments for early and advanced multiple sclerosis: a new treatment paradigm. Curr Opin Neurol 2018;31:233 ̶ 43.
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. 

Brain health and holistic management of MS, Causes and prevention of MS

What prognostic group do I fall into?

Having some idea of how bad your MS is, or not, will allow you to discuss important issues with your neurologist so that you can make an informed decision about your MS treatment.

Key points

  • It is hard to predict the disease course of MS accurately for an individual.
  • Population data allow us to define three broad prognostic MS categories: good, indeterminate or poor.
  • Given sufficient time, most people with MS will do badly without treatment.
  • Factors linked to poor prognosis in untreated people with MS are listed.
  • The wide use of disease-modifying therapies is changing the natural history of MS for the better.
  • Adopting a healthy lifestyle, in parallel with appropriate treatment, can help to improve outcomes.  

Predicting MS outcomes: an imperfect science

We can’t predict the prognosis of an individual person with MS very accurately. So don’t let your neurologist mislead you if he or she says you are likely to have benign MS. ‘Benign MS’ is a relative term and can only be used retrospectively once you have had MS for many years or decades. In the era before disease-modifying treatments (DMTs), most people with MS would eventually become disabled, which is why I prefer not to use the term benign MS to predict outcomes. I now use it as a treatment aim, because we want all people with MS to have benign disease.

Three broad prognostic categories

Applying population data to place an individual into a broad prognostic group is often helpful. It allows you to frame your disease in terms of potential outcomes and may help you balance the risks of some treatments against the potential impact of MS later in your life. Predicting outcomes in MS is comparable to an actuary working in the insurance industry; we try to give you an average prognosis with a wide range of possibilities or errors. For this reason, I try to keep it simple and classify people with MS into three prognostic categories: poor, indeterminate, or good. Poor in this context means that if you leave MS to its own devices and let it run its natural course, the average person in this category will do badly.

Most people with a predicted poor prognosis will do badly without treatment for their MS.

Given sufficient time, most people with MS will do badly without treatment. This is why I actively promote treatment based on the scientific rationale that preventing damage now will protect your brain reserve and cognitive reserve and improve your long-term outcome. This is the philosophy behind the MS Brain Health initiative and the report Brain health: time matters in multiple sclerosis,1 which everyone with MS should take time to read. 

Below is a list of factors that have been linked to poor prognosis in people who have not received a DMT. If you have fewer than five of these factors, you are likely to have a good outcome. In comparison, people with ten or more of these factors fall into the poor prognostic group. Most people with MS fall into the intermediate (indeterminate) prognostic group, with 5–10 of these factors. Some of these baseline factors are modifiable,2,3 so you can make the effort to help improve your own prognosis. 

Factors linked to poor prognosis

Please note that the factors listed here only apply to people with MS who are untreated.  It is clear that DMTs are changing the outcome of MS.

  1. Older age of onset (greater than 40 years).
  2. Male sex.
  3. Multifocal onset – more than one site in the nervous system involved with the initial attack.
  4. Efferent or effector system is affected early – that is, the motor (power), cerebellar (balance and coordination) or bladder and bowel functions.  
  5. Partial or no recovery from initial relapses – do you have residual deficits from your initial attacks?
  6. A high relapse rate in the first 2 years – that is, more than two relapses. 
  7. Early disability – an Expanded Disability Status Scale (EDSS) score > 3.0 within 5 years of symptom onset indicates a poor prognosis. You can calculate your EDSS using an online calculator (web-EDSS calculator).
  8. Abnormal magnetic resonance imaging (MRI) scan with large lesion load – more than nine T2 lesions (white blobs) on the baseline MRI.
  9. Active or enhancing lesions on your baseline (initial) MRI – enhancing lesions imply that the lesions are new and actively inflamed.
  10. Posterior fossa lesions on the MRI – these refer to lesions in the back of the brain that involve the brainstem and cerebellum.
  11. Lesions in the spinal cord on MRI.
  12. Obvious early brain atrophy on MRI – brain atrophy refers to premature shrinkage of the brain over and above what you would expect for your age. This information is unlikely to be available to you because neuroradiologists often do not measure or comment on it. 
  13. Retinal thinning on optic coherence tomography (OCT) – people with MS who have lost a lot of retinal nerve fibres do worse than people with a normal retina. Yes, the eye is truly a window into what is happening in the brain of someone with MS. 
  14. Abnormal cerebrospinal fluid – positive immunoglobulin (Ig) bands (known as oligoclonal bands, OCBs) in the spinal fluid.
  15. Raised neurofilament levels in your spinal fluid – this test may not be part of routine care at your neurology centre. Neurofilaments are proteins that are released from damaged nerve fibres, and high neurofilament levels indicate greater damage and poorer outcome than low levels.
  16. Low vitamin D levels – this is controversial, but several studies have shown that people with MS with low vitamin D levels do worse than those with higher levels. These observations do not necessarily imply that by taking vitamin D you will do better. The observation may be related to reverse causation, in that the MS-associated inflammation uses up vitamin D; more inflammation indicates worse MS and is therefore linked with greater depletion of vitamin D levels.
  17. Smoking – smokers with MS do worse than non-smokers. This is modifiable and it is one of many reasons why you should try and give up smoking. 
  18. Comorbidities – people with MS who are obese, have diabetes, prediabetes, hypertension or raised cholesterol do worse than people with MS without these comorbidities.4
  19. Cognitive impairment – people with MS with poor cognitive function do worse than people with MS with good cognition. You can’t really assess your own cognition at present; you need to have it tested by a neuropsychologist.

‘It won’t happen to me’

Humans have interesting psychology in that they tend to consider themselves to be the exception to the rule. Gamblers don’t enter a casino to lose; they always believe they will win. A person with lung cancer who starts chemotherapy believes they will be one of the 10% who is cured. When someone is diagnosed with MS, they believe they will be one of the 30% with benign disease. (The current dogma is that 30% of untreated people with MS will have benign disease.) 

This definition of ‘benign MS’ is based on having no or little disability at 15 years since onset, i.e., an EDSS score of 3.0 or less (no visible disability). However, when you interrogate people with so-called benign MS you find that more than 50% of them have hidden symptoms of depression, anxiety or cognitive impairment. Can we really justify this definition of benign MS? What is more, when you follow people with benign MS past 15 years, only 15% remain benign at 25 years and 5% at 30 years. If you get to 40 years of follow-up, half of these with benign MS will become disabled over the next 10 years.

Moving towards a more favourable outcome

Many will state that these figures are now out of date and there are newer and better figures, which show MS is a more benign disease. You are right, and there are several very good reasons for this. In population-based studies, the proportion of subjects with benign MS is greater than in hospital- or clinic-based studies; for example, in the Olmsted Mayo Clinic MS population, about 45% have benign disease at 15 years. The reason for this is that people with MS with benign disease often drop out of hospital follow-up, but still show up in population-based studies. 

The earlier diagnosis of MS, that is, identification of those who would not have been diagnosed in the past, is changing the definition of MS. For example, most people with a clinically isolated syndrome (CIS) are now being diagnosed as having MS. The wide use of DMTs is beginning to change the natural history of MS for the better; making sure that people with MS adopt a healthy lifestyle is another strategy that can be done in parallel. 

With currently available high-efficacy DMTs and the prospect of effective combination treatments in the future, the proportion of people with MS who experience normal ageing is set to increase. The blue areas illustrate the likely number of people with MS in each prognostic category.
With currently available high-efficacy DMTs and the prospect of effective combination treatments in the future, the proportion of people with MS who experience normal ageing is set to increase. The blue areas illustrate the likely number of people with MS in each prognostic category.
With currently available high-efficacy DMTs and the prospect of effective combination treatments in the future, the proportion of people with MS who experience normal ageing is set to increase. The blue areas illustrate the likely number of people with MS in each prognostic category.
With currently available high-efficacy DMTs and the prospect of effective combination treatments in the future, the proportion of people with MS who experience normal ageing is set to increase. The blue areas illustrate the likely number of people with MS in each prognostic category.

With currently available high-efficacy DMTs and the prospect of effective combination treatments in the future, the proportion of people with MS who experience normal ageing is set to increase. The blue areas illustrate the likely number of people with MS in each prognostic category.

The above figures illustrate what we aim to do with DMTs. We are simply trying to move you to the right, into a more favourable prognostic group. In other words, we want to make sure your MS is benign and that you reach old age with as healthy a brain as possible. Your brain reserve and cognitive reserve protect you from developing age-related cognitive impairment and dementia. MS reduces both of these reserves, which is why it is so important to protect them. 

References

  1. Giovannoni G, et al. Brain health: time matters in multiple sclerosis. 2015, Oxford Health Policy Forum CIC.
  2. Miller DH, et al. Clinically isolated syndromes. Lancet Neurol 2012: 11:157–69.
  3. Weld-Blundell IV, et al. Lifestyle and complementary therapies in multiple sclerosis guidelines: Systematic review. Acta Neurol Scand 2022;145:379–92.
  4. Kappus N, et al. Cardiovascular risk factors are associated with increased lesion burden and brain atrophy in multiple sclerosis. J Neurol Neurosurg Psychiatry 2016;87:181–7.