Tag Archives: study

Pregnancy and childbirth, Women's health

Concerns about parenting

Being disabled or unemployed because of MS does not mean you cannot be a good parent. Here I cover some of these practical considerations as well as the steps you can take to reduce the potential risk of your child developing MS.

Can I be a good parent if I become disabled from my MS?

This is difficult to answer and depends on how disabled you are, the nature of your disabilities and whether you have support. For example, some patients who are wheelchair users, or close to being wheelchair users, when they give birth manage to nurse and look after their children. On the other hand, some patients with cerebellar problems find it very difficult to bathe, change and feed their babies due to poor coordination and tremor. If you have advanced MS, the decision to start or extend your family needs to be discussed with your partner. If necessary, ask an occupational therapist to assess you and discuss all the issues relevant to you becoming a parent. Disability per se is not a reason not to have children, but it does raise important issues that need careful consideration. The decision to have children needs to be taken by you and not by your HCP.

If I become disabled or unemployed because of MS, will I be able to support my children?

This is another difficult question, and the answer depends on your circumstances. In the modern era having children and supporting them is expensive, but most high-income countries have social safety nets to protect you and your family in times of adversity. We now have effective DMTs that prevent or delay disability, so deciding to have children is easier than it was in the pre-DMT era.

What is the risk of my children getting MS?

MS is not a genetic disease in the Mendelian sense that you pass on to your children with a well-defined inheritance pattern. However, there are genetic factors that increase your risk of getting MS. In high-prevalence countries such as the UK, the lifetime chances of a woman developing MS is about 1 in 375 ̶ 400; for a man, it is close to 1 in 750 ̶ 800. However, for a daughter whose mother has MS, the risk is close to 1 in 40, and for a son, it is lower than 1 in 80. In some studies, the latter risk is no higher than the background rate. If the father has MS, the risk of his daughter developing MS is about half the risk of mother ̶ daughter pairing, i.e. 1 in 70. For a son of a father with MS, the risk is likely lower than this, but the results across studies are inconsistent.  

Can I prevent my children from getting MS?

Based on the known and modifiable risk factors for MS, you should try and keep your children vitamin D replete. To do this, you will likely need to supplement your children’s vitamin D intake as follows:

  • for children less than 2 years of age, 600 IU per day
  • for children 2 ̶ 10 years of age 2,000 IU per day
  • for children above 10 years of age, 4,000 IU vitamin D3 per day (the same dose we recommend for adults).

Other modifiable risk factors are childhood and adolescent obesity and smoking. We estimate that about 15 ̶ 20% of new or incident new cases could potentially be prevented by eliminating obesity and smoking in the general population. I must stress that these suggested interventions are based on studies that show associations between the risk factors and MS but may not necessarily be cause and effect. I should also point out that most people with all the risk factors for MS will not get the disease. This implies that the development of MS involves other random factors, or bad luck, that can’t necessarily be modified.

The issues raised above show you how complex the management of MS has become, which is why there is a push for people with MS to be managed in specialist MS units.

References

Krysko KM et al. Treatment of women with multiple sclerosis planning pregnancy. Curr Treat Options Neurol 2021;23:11.

Other articles in this series on Pregnancy and childbirth
Planning for pregnancy
Managing MS during pregnancy
Preparing to give birth
Breastfeeding if you are on a DMT

Pregnancy and childbirth, Women's health

Planning for pregnancy

This article discusses the effects of MS on fertility, decisions about starting or stopping a DMT, the use and safety of oral contraceptives and the possible impact of in vitro fertilisation on MS disease course.

Does MS affect my fertility?

No, MS does not affect fertility. Women and men with MS are as fertile as people without MS. However, MS does not protect women and men from other causes of infertility. Fertility treatment may impact MS (see below). Please be aware that mitoxantrone, AHSCT (autologous haemopoietic stem cell treatment) and other chemotherapy treatments, such as cyclophosphamide used off-label to treat MS, may be toxic to ovarian and testicular function and require egg and sperm banking before treatment.

Should I go onto a DMT and get my MS under control before starting a family or first start my family?

In general, I recommend that women with active MS delay pregnancy until their disease is under control, optimise their general health and prepare properly for becoming a parent. There is no point in having active MS, not starting a DMT and having a catastrophic relapse in the period during which you are trying to fall pregnant.

However, a desire to start or extend your family should not change the way you want your MS managed. Early effective treatment, treating to a target of NEIDA, potentially flipping the pyramid, preventing end-organ damage and the holistic management of MS are all compatible with pregnancy. There are no rules for implementing this strategy in pregnancy because all decisions should be personalised. For example, a woman with rapidly evolving severe MS may choose natalizumab and stay on it throughout pregnancy and while breastfeeding because her MS was so active and potentially devastating. Another woman who is young, risk adverse and with a very good prognosis may choose to delay starting a DMT until she has had a child. Yet another woman, diagnosed at 40, may not want to delay falling pregnant and may opt for a DMT that is safe during pregnancy.

It is up to the person with MS, their partner and sometimes their extended family to make the final decisions about how to manage their MS during pregnancy. The healthcare professional (HCP) is there to provide information and guidance in this process.

Are oral contraceptives safe in people with MS?

To my knowledge, contraceptives are safe and effective in women with MS. The same contraindications and relative contraindications to specific contraceptives apply to women with MS as to the general population. Hormonal contraceptives are associated with an increased risk of thrombosis; women with MS who are immobile thus have a higher risk of deep vein thrombosis than those who are mobile.

Which contraceptive would you recommend?

MS should not be the deciding factor around the choice of contraceptive unless the degree of MS-related disability makes managing menstrual hygiene difficult. In this case, contraceptives that suppress menstruation have advantages, for example, continuous hormonal contraceptives or the progestin-tipped intrauterine contraceptive device (Mirena).

Inclusion criteria for participation in specific drug trials sometimes mandate double contraception, for example, a hormonal contraceptive and a barrier method. This is to try and avoid accidental pregnancies while taking an investigational compound without a safety track record in humans.

How long before I fall pregnant must I stop my DMT?

It depends on which DMT you are taking. Only the DMTs that are teratogenic or potentially teratogenic (i.e., may cause foetal malformations) need to be stopped before you fall pregnant. It is essential to allow sufficient time for these agents to be eliminated from the body.

Teriflunomide

Teriflunomide has a very long half-life because it is reabsorbed in the intestine and is eliminated slowly from the plasma. Without an accelerated elimination procedure, it takes up to 8 months to reach plasma concentrations of less than 0.02 mg/l, which are considered safe. Remarkably, due to individual variations in teriflunomide clearance, it may take up to 2 years to fall to acceptable levels. An accelerated elimination procedure with cholestyramine or activated charcoal can be used at any time after the discontinuation of teriflunomide.

Teriflunomide accelerated elimination procedure

After stopping treatment with teriflunomide:

• Cholestyramine 8 g is administered three times daily for 11 days, or cholestyramine 4 g three times a day can be used if cholestyramine 8 g three times a day is not well tolerated.

• Alternatively, 50 g of activated powdered charcoal is administered every 12 hours for 11 days.

Following either of the accelerated elimination procedures, it is recommended to verify elimination by checking teriflunomide blood levels and allow a waiting period of 1.5 months between the first occurrence of a plasma concentration below 0.02 mg/l and planned fertilisation.

S1P modulators

S1P modulators are contraindicated during pregnancy, owing to the risk to the foetus. Before starting treatment in women of childbearing potential, we do a urine pregnancy test. Women taking an S1P modulator must use effective contraception during treatment and then continue for:

  • 2 months after stopping treatment with fingolimod (Gilenya)
  • 10 days after stopping treatment with siponimod (Mayzent)
  • 3 months after stopping treatment with ozanimod (Zeposia)
  • 7 days after stopping treatment with ponesimod (Ponvory).

Stopping the S1P modulators brings the potential for rebound disease activity, so most neurologists now prefer to transition women on one of these therapies to another class of DMT that is considered safer in pregnancy.

Safer options

Safer options during pregnancy include an injectable (interferon-beta or glatiramer acetate), a fumarate, an anti-CD20 therapy, natalizumab or an immune reconstitution therapy (cladribine or alemtuzumab). I cover some of the issues related to anti-CD20 therapies in the MS-Selfie case study ‘Wait to fall pregnant or start a DMT now?’.

The good news is that several DMT options are now available to women with MS wanting to fall pregnant.

Can I have IVF, and what will IVF do to my MS?

There is no reason why a person with MS cannot have IVF (in vitro fertilisation). However, there appears to be a slightly increased risk of relapse after IVF and egg harvesting. Whether this is due to stopping DMTs before undergoing IVF or due to the drugs used to stimulate ovulation is unknown. Studies reporting an increase in disease activity after IVF are more likely to be published than studies not showing such an increase so that publication bias may affect the findings. I recommend viewing IVF as a planned pregnancy and giving women with MS the option of receiving a DMT that is relatively safe in pregnancy or treating their MS with immune reconstitution therapy before IVF.

References

Krysko KM et al. Treatment of women with multiple sclerosis planning pregnancy. Curr Treat Options Neurol 2021;23:11.

Other articles in this series on Pregnancy and childbirth:
Managing MS during pregnancy
Preparing to give birth
Breastfeeding if you are on a DMT
Concerns about parenting

DMTs, Treatment strategy

How do I want my MS to be treated?

What is the difference between a maintenance ̶ escalation DMT and an immune reconstitution therapy (IRT)? Why is it important to understand the distinction?

Key points

  • Maintenance–escalation and immune reconstitution therapy (IRT) are two approaches to MS treatment currently favoured.
  • IRT is a one-off, short course which acts on immune system cells in three stages: reduction, repopulation and reconstitution.
  • Maintenance–escalation is given continuously without interruption. Suboptimal response to the maintenance treatment typically results in a treatment switch (escalation).
  • Additional future approaches are likely to include induction ̶ maintenance and/or combination therapy.

If I had MS, how would I want to be treated? This is a difficult question, and one that many of my patients ask me. The answer depends on your life stage, what risks you are prepared to take, personal factors such as family planning considerations and the extent of your understanding of MS and how we approach its treatment.

Currently, there are two main philosophies regarding the treatment of MS with DMTs: maintenance/escalation versus immune reconstitution therapies (IRTs). 

What is an immune reconstitution therapy?

By definition, an IRT is given as a short course, i.e. as a one-off treatment in the case of autologous haematopoietic stem cell transplantation (AHSCT) or intermittently in the case of alemtuzumab, cladribine or mitoxantrone. IRTs are not given continuously, and additional courses of the therapy are given only if there is a recurrence of MS inflammatory activity. IRTs can induce long-term remission and, arguably, in some cases a potential cure.

IRTs have three phases to their mode of action, which I refer to as the ‘three Rs’.

  1. Reduction, or depletion, when we try to kill the autoimmune cells that cause MS.
  2. Repopulation, when the immune system recovers from stem cells and, hopefully, the autoimmune cells don’t return.
  3. Reconstitution, when the immune system is recovered and fully competent. The recovered immune system following treatment with an IRT is different from what was there before. Some people like to think of an IRT as a reboot of the immune system, but without MS.
Slide1

The three Rs of immune reconstitution therapy: reduction, repopulation and reconstitution. From Giovannoni, Curr Opin Neurol.1 

What is an MS ’cure’?

One attempt defines an MS cure as no evidence of disease activity (NEDA) 15 years after the administration of an IRT. I justify using 15 years because it is the time-point most accepted for defining ‘benign MS’ and is also beyond the average time to onset of secondary progressive MS in natural history studies.

What is a maintenance therapy?

A maintenance therapy is given continuously without an interruption in dosing. Although maintenance therapies can induce long-term remission (i.e. NEDA), they cannot result in a cure. The recurrence or continuation of inflammatory disease activity with maintenance therapies is an indication of a suboptimal response to treatment and typically results in a treatment switch. Ideally, this switch should be to a more effective class of DMTs – hence the term ‘escalation’. 

What would I recommend?

I can’t choose for you. The debate is complex and depends on many factors. One important consideration is vaccine readiness: will I be able to mount an adequate immune response to a vaccine? IRTs have the advantage that they allow reconstitution of the immune system; once it recovers, vaccine responses are restored, and even live vaccines can be given.

The table below highlights key differentiators. Further, detailed information about most of the products listed in the Table can be accessed through the DMT comparison tool available at ClinicSpeak or via the Multiple Sclerosis Trust MS Decisions aid.

Slide2

Similarities and differences between maintenance treatments and immune reconstitution therapies. Registered trade names (UK market) of the generic drugs listed are shown in brackets. *How to define a ‘cure’ in MS is controversial. Modified from Giovannoni, Curr Opin Neurol.1
DMT, disease-modifying therapy; HSCT, haematopoietic stem cell transplant; IRT, immune reconstitution therapy.

The future

I envisage two more treatment strategies emerging.

  • The diagram below illustrates the scheduling of the four approaches discussed in this section. You may like to try out the DMT comparison tool to find out how some of the drugs listed in the comparison Table above align with your personal life choices and priorities.
Slide5

Four approaches discussed in this section. The white panels illustrate the two approaches currently available; the shaded panels illustrate two strategies that may emerge in the future. Modified from Giovannoni, Curr Opin Neurol.1

References

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

Am I eligible for an MS disease-modifying therapy?

Key points

Do you know the eligibility criteria for MS disease-modifying therapies? And who decides what drugs can be prescribed for your MS?

  • Disease-modifying treatments (DMTs) change the long-term trajectory of MS and protect the central nervous system.
  • Regulators such as the European Medicines Agency (EMA) and the Federal Drug Administration (FDA) decide in which group(s) of patients a particular drug can be used, based on the results of clinical trials.
  • Once a drug has been licensed in your region, local payers decide whether to make it available within your country, based on cost-effective assessments.
  • If you have active MS, your level of disease activity, its severity and speed of development will determine which DMTs you can be offered.
  • In recent years, ocrelizumab and siponimod have been approved for the treatment of active primary progressive MS (PPMS) and active secondary progressive MS (SPMS), respectively, in some countries.
  • Protecting upper limb function has been a neglected area; studies are now ongoing, however, with a view to finding DMTs that limit the progression of upper limb disability.

What do disease-modifying drugs do?

Disease-modifying therapies (DMTs) are treatments that change the natural history – that is, the long-term trajectory – of the disease. They reduce the rate of disability worsening and so protect the end-organ (in the case of MS, this is the central nervous system). To simplify, let’s say that a person with MS on no treatment may manage for an average of 18-20 years before needing to use a walking stick (corresponding to Expanded Disability Status Scale [EDSS] 6.0), while someone on treatment might manage without aid for 24 years, i.e. a 4-6-year delay, then the treatment can be called disease-modifying. (Please note, the treatment effect or 4-6-year delay in reaching EDSS 6.0 is an average and some people with MS will do better than others. Conversely, some will do worse than average.) 

Is interferon a DMT?

In the early days of interferon therapy, there was debate about whether simply reducing the relapse rate by 30% relative to placebo treatment, without slowing down the worsening of the disease over 2 years, was disease-modification. However, subsequent trials and follow-up of people with MS treated with interferon-beta showed a slowing down of disease worsening, delays in developing secondary progressive MS and a favourable impact on survival.1 

Do symptomatic treatments modify the disease?

Symptomatic treatments improve the symptoms associated with MS without affecting the natural history. Treatments are classified as symptomatic in relation to their mode of action; but some classes of treatment may yet prove to be disease-modifying. For example, we often use sodium channel blocking agents, such as phenytoin, carbamazepine, oxcarbazepine and lamotrigine, for MS-related neuralgia and other pain syndromes. However, there is evidence that this class of therapy may be neuroprotective and hence disease-modifying. 

Who decides on eligibility for a licensed DMT?

Regulators decide in which group of people with MS the DMT can be used, and they grant a licence for its use. Regulators include the EMA, the FDA and the Medicines and Healthcare products Regulatory Agency (MHRA in the UK).

Payers hold the purse strings and decide which licensed drugs to make available. They makecost-effective assessments to try and optimise the use of the drug in clinical practice. Payers include medical insurance companies and the NHS in the UK. 

Guidelines are formulated to help healthcare professionals use DMTs in the most appropriate way within a particular healthcare system. Guidelines often go much further than the regulators and payers, in that they try to address potential ambiguities in the prescribing of DMTs. National, regional or local guidelines that provide expert clinical guidance include the UK NICE (National Institute for Health and Care Excellence) MS management guidelines and the Association of British Neurologists guidelines. 

In the NHS in England, we must abide by NHS England’s algorithm that is predominantly based on NICE technology appraisals, NICE standards of care and the Association of British Neurologists guidelines. To navigate the specifics of the eligibility criteria is quite complex. However, a simpler way of looking at this is to start by defining how active your MS is. 

How does disease activity affect my treatment options?

To be eligible for DMTs, you must have active MS. A summary of the four categories of disease activity is given below. Further details can be found in the section entitled Do I have active MS?

  1. Inactive MS – you are not currently eligible for DMTs.
  2. Active MS – you should be eligible for a so-called platform therapy (interferon-beta, glatiramer acetate, teriflunomide, dimethyl fumarate or ponesimod) and ocrelizumab or ofatumumab.
  3. Highly active MS – you are eligible for all therapies except natalizumab. Please note in England fingolimod can only be used as a second-line therapy (after another DMT has failed).
  4. Rapidly evolving severe MS – you should be eligible for all DMTs.

Advanced or progressive MS

Ocrelizumab and siponimod are now approved in several countries for the treatment of active PPMS and active SPMS, respectively. A classification of active PPMS requires recent MRI evidence of disease activity, that is, the formation of new T2 lesions and/or the presence of gadolinium-enhancing lesions in the last 3 years. Active SPMS is confirmed by the occurrence of superimposed relapses and/or the presence of new T2 lesions and/or gadolinium-enhancing lesions in the last 2 years. Based on these very narrow definitions, most patients with PPMS and SPMS will not be eligible for ocrelizumab or siponimod, respectively. The differences between the MRI criteria for active PPMS and active SPMS reflect the reality that people with PPMS are less likely to be having regular monitoring MRI scans.

Stages of MS currently not eligible for treatment

In the UK, people with MS who are wheelchair users are not eligible for DMTs. The reason for this is that patients with more advanced MS have generally been excluded from phase 3 clinical trials; hence there are no data to show whether licensed DMTs are effective in this group.

There is a long-held view that inflammation is reduced or absent in advanced MS. However, clinical, imaging and pathological data show that inflammation still plays a large, and possibly a major, role in advanced MS. Therefore, not targeting more advanced MS with an anti-inflammatory is counterintuitive.

The importance of upper limb function

In 2016, the #ThinkHand campaign was launched to raise awareness of the importance of hand and arm function in people with MS and the need for clinical trials in this population. Studies currently ongoing that focus on limiting upper limb disability progression include ChariotMS (oral cladribine)2 in people with advanced MS (UK only) and the global, multicentre O’HAND trial  (ocrelizumab)3 in participants with PPMS. 

Once someone with MS becomes a wheelchair user, they still have neuronal systems that are potentially modifiable – for example, upper limb, bulbar (speech and swallowing), cognition and visual function. There is an extensive evidence base showing that several licensed DMTs can slow the worsening of upper limb function despite subjects having advanced MS. Now that ocrelizumab and siponimod have been licensed for active primary and secondary progressive MS, respectively, these DMTs may form the platform for future add-on trials. 

References

  1. Goodin DS, et al. Survival in MS: a randomized cohort study 21 years after the start of the pivotal IFNβ-1b trial. Neurology 2012;78:1315 ̶ 22.
  2. National Institute for Health and Care Research (NIHR). MS clinical trial to focus on people who can’t walk. November 2020. Available at https://www.nihr.ac.uk/news/ms-clinical-trial-to-focus-on-people-who-cant-walk/26227 (accessed June 2022).
  3. US National Library of Medicine. A Study to Evaluate the Efficacy and Safety of Ocrelizumab in Adults With Primary Progressive Multiple Sclerosis (O’HAND). First posted July 2019. Available at https://clinicaltrials.gov/ct2/show/NCT04035005 (accessed June 2022).
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.