Tag Archives: disability

Clinical decisions, Legal matters, Talking about dying

Suicide and end-of-life choices: readers’ responses

The article on Suicidal ideation and suicide in MS prompted many responses from newsletter readers. Their comments provide a deep and arguably multifaceted look at how people with MS view suicidal ideation, mental health and assisted dying. I have summarised the key arguments below.

Suicide: a rational decision or a mental health disorder? 

A significant thread throughout the comments is the belief that contemplating suicide is a logical, rational response to the relentless physical decline caused by MS, rather than a psychiatric illness.

Slide1

Conversely, there is pushback against dismissing the clinical reality of mental health disorders in MS.

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Arguments for and against assisted suicide 

Those advocating for the right to assisted dying focus primarily on bodily autonomy and the prevention of extreme suffering.

Arguments against legalising assisted dying focus on fears of systemic healthcare degradation, coercion and procedural concerns.

Defining the role of the healthcare system

The medical literature focuses entirely on preventing suicide by identifying and treating underlying distress, rather than providing policies to guide people with MS toward assisted suicide. Most articles state that suicide in MS is not inevitable and emphasise aggressive treatment of the drivers of suicidal ideation.

However, the patient community, or at least part of it, has highlighted a desperate need for policies that allow for open, non-judgmental dialogue about end-of-life fears without people with MS immediately losing their autonomy. Therefore, learnings and policies could be implemented to identify and support these individuals.

Policies for systematic screening and identification

To accurately identify who is experiencing suicidal ideation, healthcare professionals (HCPs) must stop relying on people with MS to volunteer this information spontaneously.

  • Mandatory routine screening. Clinics must embed a validated screening tool, such as the Patient Health Questionnaire-9 (PHQ-9), into routine MS reviews.
  • Targeted screening at critical junctures. Screenings should occur at least annually and, crucially, at major transition points. These include diagnosis, relapses, major disability milestones (like losing the ability to walk or drive), or when transitioning to secondary progressive MS.
  • Structured follow-up questions. If someone with MS screens positive for suicidal ideation, policies must dictate specific follow-up questions to assess imminent risk. Clinicians must ask whether the individual has a plan, access to the means, or has made any preparations for suicide.
  • Immediate action protocols. The presence of a plan, access to means, or preparatory behaviour must trigger an urgent, ideally same-day, psychiatric referral.

Policies for intervention and support

Once identified, the healthcare system must have pathways to address the physical, psychological and social drivers of the patient’s distress.

  • Aggressive treatment of comorbidities. Depression is not just a ‘normal’ reaction to having MS. Clinic policies should encourage the proactive use of antidepressant drug treatments, talking therapies, mindfulness and cognitive behavioural therapy, which have a good evidence base in MS.
  • Holistic symptom management. Physical symptoms directly drive suicidal ideation; therefore, treating pain, fatigue, sleep disturbances and intimate issues (bladder, bowel or sexual dysfunction) must be viewed as an active suicide prevention strategy.
  • Mandatory safety planning. For at-risk people with MS, HCPs must collaboratively develop a written safety plan (such as the Stanley-Brown Safety Plan) that outlines warning signs, coping strategies and crisis contacts.
  • Embedded mental health professionals. At a systemic level, it should be a minimum standard – not a luxury – to have a clinical psychologist or neuropsychologist embedded directly within the MS care service.

Policies for managing ‘rational’ end-of-life discussions

While the clinical framework aims to prevent suicide, some people with MS may advocate for policies that allow them to discuss the realities of severe disability safely.

  • Destigmatising the conversation. HCPs should be trained to initiate calm, kind and reassuring discussions about general mental health shortly after a diagnosis of MS. They should normalise the fact that people with MS may experience fears about mortality or even abstract thoughts of suicide when facing severe disability.
  • Protecting patient ‘agency’. Policies should ensure that when people with MS express fears about their future or end-of-life scenarios, the medical system does not immediately ‘swoop in’ with aggressive interventions that strip them of their voice.
  • Facilitating frank discussions. MS support services should facilitate open discussions about life in the later stages of MS, including the associated problems, rather than treating it as a taboo subject. The latter must not be rose-tinted, but realistic.

Implementing these policies requires significant investment and a shift in how chronic illness is managed, ensuring mental health is treated with the same urgency as physical health.

Cognition and mental health

Suicidal ideation and suicide in MS

Mental health problems and suicide are the underbelly of MS, the elephant in the consulting room. I have attempted to discuss these topics in a way that is not too dark, based on data from a 2026 systematic review. Please be aware, however, that the content may still be upsetting.

Key points

  • The suicide rate among people with MS is roughly twice that of the general population.
  • Several biological, psychological and social factors contribute to suicide risk:
    • depression and anxiety: a biological basis for these comorbidities exists in MS
    • MS disease-related factors: increased disability, disease duration and progression; life-changing symptoms
    • socio-demographic factors: age, male sex, living alone, education level
    • social and existential factors: loneliness, social exclusion and low perceived social support; loss of purpose and meaning; financial strain; fear of stigma.
  • Thoughts of ending one’s life – ‘suicidal ideation’ – precede suicide attempts; effective screening tools exist, are quick to complete and can identify patients at risk of suicide.
  • Systematic screening is not optional but should be part of the basic standard of care.
  • Suicide prevention in MS requires participation by the clinic, the patient (and their family) and the health system.
  • If you or someone you know is having thoughts of suicide, please reach out for help. Support groups are available.

The problem we avoid talking about …

MS is a chronic, unpredictable and often disabling neurological condition. People with MS know this, and as a result they carry a psychological burden that is usually overlooked in a 15-minute annual outpatient appointment. Mental health problems and suicide are the elephant in the MS consulting room. They sit quietly alongside the disability progression conversation, the drug treatment switch discussion, and the “How are things at home?” question that healthcare professionals (HCPs) often forget to ask.

How common are suicidal ideation and suicide in MS?

Suicidal ideation – thoughts of ending one’s life, with or without a plan – is the single most important precursor to suicide attempts, and death by suicide among people with MS is far more common than most HCPs appreciate. A landmark Canadian study in 1991 found that suicide was the third most common cause of death reported in MS clinics.1 The proportion of deaths due to suicide among people with MS (15%) was 7.5 times the proportion in an age-matched general population (2%).

More recent work suggests that the suicide rate among people with MS is roughly twice that of the general population.2 A 2026 systematic review and meta-analysis of suicidal ideation in MS draws on 18 studies and more than 8,000 people with MS to provide a picture of how common it is, what drives it and where the gaps are in MS care.2 From these combined data, the authors estimate that one in five people (20%) in an MS clinic waiting room has considered suicide. This is higher than the 13% figure from a 2020 meta-analysis,3 and the authors suggest two plausible explanations:

  • an expanding evidence base that now includes more diverse settings
  • a real rise in suicidal ideation rates – perhaps linked to the COVID-19 pandemic, growing geopolitical instability and reduced stigma around reporting mental health symptoms.

Individual study prevalence ranged dramatically, from 8% in a Canadian cohort to 36% in an Iranian cohort. This is probably telling us something important about how context, culture, income level and healthcare infrastructure shape suicide risk.

In most high-income countries, lifetime suicidal ideation prevalence in the general population is around 9–10%. The recent 20% figure in people with MS2 is therefore roughly double that seen in the background population – a finding echoed by many independent studies.

Regional and temporal patterns

In the 2026 review, subgroup analysis based on country income level reported a pooled suicidal ideation prevalence of 17% among the 14 high-income countries compared with 32% in the countries with ‘upper-middle’ incomes (three studies from Iran and one from Brazil).2 This aligns with what we know about mental health inequities more broadly – poverty, housing insecurity, financial strain, limited access to psychiatric services, and stigma all worsen outcomes in lower-resource settings. (Please note, the ‘upper-middle income’ data in this review came from just two countries; therefore, we should be cautious about extrapolating to sub-Saharan Africa, South Asia or Latin America as a whole.)

Suicidal ideation prevalence figures published between 19911 and 20262 from many studies conducted across different regions of the world vary widely and may appear inconsistent. The 2026 figure of 20% still means, however, that roughly one in five people with MS has active suicidal thoughts, and global crises in the last five years may be masking an underlying deterioration that will only become visible in the next generation of studies.

Limitations of study data

The 2026 review has limitations that need to be acknowledged. Study methodologies vary widely: suicidal ideation is measured with different instruments and at different time points; diagnostic criteria for MS are inconsistently reported; variability between studies is high. The ‘20% prevalence’ figure from 2026 is therefore an estimate with uncertainty. What is not uncertain is that suicidal ideation is substantially more common in MS than in the general population, and that it is driven by modifiable factors and hence is preventable. 

Who is at risk of suicidal ideation among people with MS

No single risk factor predicts suicidal ideation in isolation. Suicide is the final common pathway of several biological, psychological and social factors. Consistent drivers can be grouped into four domains.2

1. Psychiatric comorbidity: depression and anxiety

Depression and anxiety are the most consistently reported risk factors for suicidal ideation in MS.2 Depression affects up to 50% of people with MS at some point, far exceeding the 14–21% figure in the general population. This matters because depression in MS is both more common and more severe than in the general population, and it is driven by a mixture of:

  • neuroinflammation and hormonal factors (depression in MS is not simply a ‘reaction’ to having MS – it has a biological basis)
  • lesion location, particularly in limbic and frontal lobe/cortex pathways
  • disease-modifying therapy (DMT) side effects (particularly with interferon therapy)
  • the psychological burden of uncertainty, disability and loss of role.

Anxiety, which is often under-recognised and under-treated in MS, frequently coexists with depression and independently elevates suicidal ideation risk.

2. Disease-related factors

Several disease features align with suicidal ideation across studies.

  • Greater disability – measured both by clinician-rated EDSS (Expanded Disability Status Scale) scores and by self-reported physical impairment. The latter may be a stronger predictor than EDSS scores, because it captures the subjective experience of living with impairment.
  • Longer disease duration – though this relationship is complex. Study results vary, suggesting that some patients adapt psychologically over time, probably depending how well they adjust to living with MS.
  • Progressive MS – higher suicidal ideation rates are found in people with more advanced MS when compared with the earlier relapsing–remitting phase. Many HCPs and healthcare systems think that once someone with MS becomes disabled, the disease is not modifiable. I hope landmark studies like ocrelizumab in PPMS (O’HAND study), siponimod in SPMS (EXPAND study) and tolebrutinib in non-relapsing SPMS (HERCULES study) change this perspective. 
  • Specific symptoms – fatigue, sleep disturbance, spasms, bladder and bowel difficulties, and speech and swallowing problems also correlate with suicidal ideation. Together, these symptoms erode quality of life.

3. Sociodemographic factors

The evidence here is more mixed.

  • Age – findings are inconsistent. Some studies identify older patients (≥ 65 years) as higher risk; others find younger people with MS more vulnerable. Both extremes carry risk for different reasons; younger recently diagnosed patients face a challenge to their identity and loss of envisioned future; older patients face accumulated disability and social isolation.
  • Male sex – some (but not all) studies find men at higher risk, consistent with general population data on completed suicide.
  • Unmarried status and living alone are both associated with increased suicidal ideation in multiple studies.
  • Education level – most studies suggest that higher educational attainment is protective (better health literacy, coping strategies, economic resources); one Iranian study found the opposite, perhaps reflecting unmet expectations or awareness of prognosis.

4. Social and existential factors

This domain is the easiest to miss in a busy MS clinic but most important to address.

  • Low perceived social support, from family, friends and significant others, is a consistent risk factor.
  • Loneliness and social exclusion – ‘feeling socially excluded’ strongly correlates with suicidal ideation.
  • Hopelessness and loss of purpose – perceived loss of control, loss of masculinity/femininity and failure to achieve an expected role contribute psychologically to suicidal ideation.
  • Challenges to faith or spiritual meaning – having a sense of purpose, comfort in faith, and church membership can all be helpful and protective (in those for whom they are important).  
  • Financial strain and anticipated stigma are particularly important in lower-resource settings.

Screening for suicidal ideation in the clinic

If 20% of people with MS experience suicidal ideation but only a small fraction volunteer it spontaneously, systematic screening is not optional but should be part of the basic standard of care. Effective screening tools exist, and they are quick to complete.

The Patient Health Questionnaire-9 (PHQ-9)

The PHQ-9 is the most practical and widely validated mental health tool for neurological conditions, including MS; it is particularly suited to detecting suicidal ideation. Item 9 of this 9-item self-report depression screen specifically asks about thoughts of self-harm or being better off dead. It takes under 3 minutes to complete and can be done in the waiting room or electronically before the clinic. Scores above 10 indicate clinically significant depression warranting action. A positive response to item 9 should trigger a suicide risk assessment. It could be argued that every MS clinic should administer the PHQ-9 at least annually, and at every unscheduled visit where there has been a relapse, a significant disability progression, a DMT change or a major life event.

The Beck Scale for Suicide Ideation (BSI)

The BSI is a 20-item instrument designed specifically for suicide risk. It is more detailed than the PHQ-9 and is better suited to psychiatric follow-up than to first-line screening.

The Beck Depression Inventory-II (BDI-II)

The BDI-II is a broader 21-item depression measure that includes a suicide item. This is often used in research settings but takes longer to complete than the PHQ-9 in a clinic.

The Hospital Anxiety and Depression Scale (HADS)

The HADS is my favoured option that captures both anxiety and depression domains. It does not, however, include a direct suicide item, so a ‘positive’ (i.e. high: 11−21) HADS score should always prompt a follow-up suicide-specific question.

What should you be asked if a screen is positive?

Clinicians often feel awkward asking directly about suicide. Evidence is unambiguous that asking about suicide does not increase the risk. A graded approach works well:

  1. ‘Have you had thoughts that life isn’t worth living, or that you’d be better off dead?’
  2. ‘Have you had thoughts of harming yourself?’
  3. ‘Have you thought about how you might do it?’ (plan)
  4. ‘Do you have access to the means?’ (access)
  5. ‘Have you taken any steps or made any preparations?’ (intent)

Presence of a plan, access to means, or preparatory behaviour indicates a high imminent risk and demands urgent psychiatric referral – ideally, the same day.

Suicide prevention: what can we do?

Suicide prevention in MS operates at three levels: the clinic, the patient and the system.

At the clinical level

  • Screen systematically. A good MS service should embed PHQ-9 into routine MS review and not rely on patients volunteering suicidal ideation. If I were setting up an MS clinic now, I would include PHQ-9 in routine screening and add it to the annual questionnaire that patients must complete before each clinic visit. 
  • Treat depression and anxiety aggressively. Depression and anxiety are the dominant modifiable risk factors. Selective serotonin reuptake inhibitors (SSRIs: sertraline, citalopram, escitalopram) are first-line, well-tolerated drugs and have no meaningful interaction with current DMTs. Cognitive behavioural therapy (CBT) – including web-based models – has a good evidence base in MS. We should reject the dogma that ‘of course they’re depressed, they have MS’ as a reason not to proactively manage depression.
  • Address symptom burden. Fatigue, pain, sleep disturbance, bladder dysfunction and spasticity are not just quality-of-life issues – they are suicide risk factors that need to be treated. Please make sure that your MS care team provides relevant support. 
  • Be alert at transition points. Diagnosis, relapse, disability milestones (losing the ability to walk, work or drive), DMT failure, and being labelled as having secondary progressive MS are all periods of elevated risk. 
  • Assess social support explicitly. Who do you live with? Who helps you? Who would you call at 3 am? Treat loneliness and social isolation as vital potential danger signs.
  • Restrict means where appropriate. Safe storage of medications, particularly in patients with large quantities of prescribed opioids, benzodiazepines or anticholinergics, can save lives. This conversation needs to be had with the patient, their partner and their family. 
  • Document and communicate risk. A named crisis contact, a safety plan, and timely communication with the GP or primary care physician should be standard practice.

At the patient and family level

  • Psychoeducation. Many people with MS don’t know that depression is a common and treatable part of MS – they assume sadness and hopelessness are inevitable. Naming and confronting depression and suicidal ideation helps.
  • Normalise help-seeking. The stigma of psychiatric care in MS remains real. Framing mental health as part of MS care, not something separate, reduces that barrier.
  • Involve family. Family members are often the first to notice a change – withdrawal, giving away possessions, changes in sleep. They need to be taught about what to watch for.
  • Build purpose and connection. Peer support groups (e.g. MS Society, Shift.ms, MS Trust, MS International Federation resources, National MS Society [US]), vocational rehabilitation, social prescribing, church attendance, volunteering and hobbies all buffer against hopelessness. Having a purpose in life and being productive reduce the likelihood of suicidal ideation.
  • Safety planning. A written safety plan – warning signs, coping strategies, people to call, reasons for living, means restriction – is a simple but evidence-based self-administered intervention. The Stanley-Brown Safety Plan is freely available online.

At the system level

  • Integrate mental health into MS services. A neuropsychologist or clinical psychologist embedded in an MS service should not be a luxury; it is the minimum standard for a condition where one in two patients develops depression. That said, most NHS MS clinics don’t employ a neuropsychologist, and referring people with MS for assessment and management takes time.
  • Address inequity. The doubled suicidal ideation prevalence in upper-middle-income countries2 is not inevitable. It reflects under-resourced mental health services, stigma, and financial barriers to care – all modifiable at a policy level.
  • Research under-represented populations. The Bazmi review2 of 14 high-income and three upper-middle-income countries openly discusses its limitations: it includes no data from low-income countries and none from most of Asia, Africa or Latin America, beyond a single Brazilian study. MS care cannot be evidence-based at a global level if the evidence is dominated by findings from high-income countries. More research is needed. 

The bottom line

If you are an HCP and are reading this, please remember that roughly one in five of your MS patients has had thoughts of suicide. Most of them have not told you. The dominant drivers – depression, anxiety, disability, symptom burden, loneliness, hopelessness – are either treatable or modifiable, and the screening tools are simple, brief and validated. Although suicidal ideation is common in people with MS, it is driven by modifiable factors and hence is preventable. Suicide in MS is not inevitable. It is, however, easy to miss. Every person with MS deserves a clinician who asks directly, listens without flinching, and acts on what they hear.

If you or someone you know is having thoughts of suicide, please reach out for help.

In the UK, Samaritans are available 24/7 on 116 123.

In the US, the 988 Suicide and Crisis Lifeline is available by call or text.

In other countries, the International Association for Suicide Prevention (IASP) maintains a directory of crisis services at iasp.info/crisis-centres-helplines/

You are not alone, and help is available.

References

  1. Sadovnick AD, et al. Cause of death in patients attending multiple sclerosis clinics. Neurology 1991;41:1193. doi.org/10.1212/WNL.41.8.1193.
  2. Bazmi E, et al. Global prevalence and risk factors of suicidal ideation in multiple sclerosis: a systematic review and meta-analysis. Health Sci Rep 2026;9:e72331. doi: 10.1002/hsr2.72331.
  3. Kouchaki E, et al. Prevalence of suicidal ideation in multiple sclerosis patients: meta‐analysis of international studies. Soc Work Pub Health 2020;35:655–63.

Detail, DMTsDetail, Treatment strategy

What are the attributes of the specific DMTs?

Multiple sclerosis (MS) treatment has evolved rapidly, with 11 classes of disease-modifying therapy (DMT) now available in the UK. I will summarise them briefly and explain how they fit within a treatment paradigm for effective and safe use.

Maintenance therapies versus immune reconstitution: what’s the difference?

There is a divide between the two main treatment philosophies: maintenance ̶ escalation versus immune reconstitution therapies (IRTs).

An IRT is given as a short course – a one-off treatment in the case of autologous haematopoietic stem cell transplantation (AHSCT) or intermittently for alemtuzumab, cladribine or mitoxantrone. IRTs are not given continuously, and additional courses are given only if inflammatory activity recurs. IRTs can induce long-term remission and, in some cases, potentially a cure.

Maintenance therapies, by comparison, are given continuously without an interruption in dosing (‘continuous’ administration may be daily, one or more times weekly, monthly or even once every few months). Although maintenance therapies can induce long-term remission, they cannot, by definition, result in a cure. The recurrence or continuation of inflammatory activity indicates a suboptimal response to treatment and typically requires a treatment switch. Ideally, this switch should be an escalation to a more effective class of DMT.

An article in our list of key questions, entitled How do I want my MS to be treated?, provides a more detailed comparison of maintenance and IRT therapies, including frequency of administration, efficacy, risks, use in pregnancy, vaccine response and potential for a cure.

The DMTs currently licensed in the UK (in August 2024) are listed in the table under the relevant category.

Disease-modifying therapies for MS licensed in the UK. *Please note, Bonspri is available in other markets but not the UK.

How effective are the different DMTs?

The measures used to assess the effectiveness of a DMT include its ability to reduce or prevent relapses, focal inflammatory activity (that is, new or enlarging lesions) on magnetic resonance imaging (MRI), and disability progression. Additional factors that can help to assess the relative efficacy of DMTs include the proportion of clinical trial subjects who experience improvement in disability and the impact of the treatment on brain volume loss.

The MS-Selfie InfoCards are an easy-to-use resource to help people with MS compare the key features of each DMT. They contain bite-sized information designed to aid treatment choices and an overview of the key aspects of each DMT.

Efficacy of the licensed DMTs for MS can be visualised as pyramid, with the moderately effective treatments at the bottom and the more effective approaches at the top. What determines the most appropriate DMT efficacy level for an individual depends on several factors, such as baseline prognostic profile, family planning requirements, local or national treatment guidelines, socioeconomic factors, consideration of any co-existing illnesses, cognitive impairment, risk aversion and lifestyle issues.

Pyramid format updated 180625 SS

UK licensed DMTs for MS, in ascending order of efficacy.
HSCT/AHSCT, haematopoietic stem cell transplantation/autologous haematopoietic stem cell transplantation.

What is the goal of treatment? Introducing NEIDA as a target

In the past, we used no evident disease activity (NEDA) as a treatment target. ‘Disease activity’ included progression or disease worsening independent of relapse activity (termed smouldering MS). Although some of the more effective DMTs may modify this stage of the disease, many neurologists feel uncomfortable switching or stopping a DMT based simply on smouldering MS disease activity. 

Relapses and ongoing focal MRI activity are associated with a worse short-term to intermediate-term prognosis. These observations have led to the increasing adoption of ‘no evident inflammatory disease activity’ (NEIDA) as a new treatment target. For more information about treatment targets, please see the article in our key questions, Do I understand the concepts of treat-2-target and NEDA?

Many healthcare professionals (HCPs) remain sceptical of using NEIDA as a treatment target, fearing that this could lead to more people with MS being on ‘riskier’ high-efficacy therapies. However, achieving long-term remission, or NEIDA, is a well-established treatment target in other autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease. People with MS treated-to-target of NEIDA from the outset do better than those whose treatment is escalated following breakthrough disease (at a clinical or subclinical/MRI level)1. I would, therefore, strongly encourage people with MS and their HCPs to adopt NEIDA as an initial treatment target.

Flipping the pyramid

The effectiveness, or relative effectiveness, of individual DMTs becomes less critical in the context of a treatment target of NEIDA. Choosing a DMT with a lower efficacy rate simply means that a greater proportion of treated people with MS will need to be switched to higher efficacy therapies over time to achieve NEIDA. We refer to the latter of these three approaches – starting with high-efficacy treatment – as flipping the pyramid. In recent trials of alemtuzumab, ocrelizumab, ofatumumab and ublituximab, people with MS randomised to 2 years of lower efficacy DMTs (interferon-beta-1a or teriflunomide) had poorer outcomes than those receiving highly active therapy from the outset. Real-world data from registries also support this; groups of people with MS with delayed access to high-efficacy DMTs did worse than those who received high-efficacy treatments early.1,2

Horizontal versus vertical switching

If we consider the conventional step care paradigm, people with MS who switch horizontally from interferon-beta to glatiramer acetate, or vice-versa (i.e. from one moderate efficacy DMT to another moderate efficacy DMT) do less well than those who switch vertically to fingolimod, a highly effective DMT. Similarly, people with MS escalating to natalizumab, a very high-efficacy DMT, do better than those being escalated to the less effective, but still high-efficacy, DMT fingolimod. 

Continuous and intermittent immunosuppression

Another useful way of classifying DMTs is whether they are immunosuppressive, that is, they reduce the activation, or effectiveness, of the immune system. Drug regulators stipulate that a drug may be classified as immunosuppressive if it (1) causes significant lymphopaenia (low lymphocyte count) or leukopenia (low white blood cell count), (2) is associated with opportunistic infections, (3) reduces the antibody and immune response to vaccines and (4) increases the risk of secondary malignancies.

The duration and intensity of immunosuppression further determine the risks. For example, short-term or intermittent immunosuppression associated with IRTs front-loads the risks, which are substantially lower once the immune system has reconstituted itself. In comparison, long-term continuous or persistent immunosuppression, which occurs with some of the maintenance DMTs, accumulates problems over time, particularly opportunistic infections and secondary malignancies. You can read more detail on this topic in the key question How immunosuppressed am I? The following table summarises the main attributes of intermittent and persistent immunosuppression.

How immunosuppressed are you table updated format 180625 SS

The main characteristics of continuous (persistent) and short-term (intermittent) immunosuppression. Modified from Giovannoni, Curr Opin Neurol.2
AHSCT, autologous haematopoietic stem cell transplantation; PML, progressive multifocal leukoencephalopathy.

Adverse effects, monitoring and risk reduction

The complications associated with immunosuppression vary from DMT to DMT. Each individual drug summary in the DMTs section of MS-Selfie contains detailed information about the main adverse events, key monitoring requirements, use (or contraindication) during pregnancy and breastfeeding, and response to vaccines. The MS-Selfie InfoCards provide bite-sized summaries of several practical aspects, including side effects, to enable easy comparison of any treatments you are considering; some of this information is collated below for easy reference.

Short-term versus long-term adverse effects

Each drug has been given scores from 1 to 10 based on published analyses of its short-term and long-term side effects. Short-term refers to side effects that emerge when a treatment is started and decrease in severity or disappear within days or weeks. A well-known example of short-term side effects on starting interferon-beta is flu-like symptoms that typically abate within 4 ̶ 8 weeks.

A long-term side effect persists for months or doesn’t disappear on continuing the DMT. Examples include intermittent but persistent flushing after taking dimethyl fumarate, or low B lymphocyte counts with anti-CD20 therapies that may lead to low antibody or immunoglobulin levels (hypogammaglobulinaemia).

A low score denotes few or rare side effects; a high score denotes many or frequent side effects. The score does not correlate to a percentage. More information can be found in each drug summary and the manufacturer’s Summary of Product Characteristics.

Scores for short-term and long-term side effects assigned to the individual DMTs summarised in the MS-Selfie InfoCards, based on a published network meta-analysis.3
Alem, alemtuzumab; GA, glatiramer acetate; HSCT, haematopoietic stem cell transplantation; IFN-beta; interferon-beta; Nat, natalizumab.

Monitoring and risk reduction

Numerous tests are carried out at the start of treatment, and ongoing monitoring is required for many factors, to reduce the risk from adverse events. The key question, How can I reduce my chances of adverse events on specific DMTs?, explains what needs to be done at the start of DMT administration (baseline) and during subsequent monitoring. The specifics vary from DMT to DMT; please refer to the individual summaries for details such as baseline tests, follow-up, infection prevention, cancer risk, pregnancy, breastfeeding and vaccination. It is important to remember that all licensed MS DMTs have had a thorough risk ̶ benefit assessment, and their benefits are considered to outweigh the potential risks.

Administration and other practical considerations

Routes and frequency of administration

The MS-Selfie InfoCards contain a symbol for each DMT, showing how it is administered. Some DMTs are available in more than one formulation (e.g. tablets and injection). The frequency of administration varies greatly from DMT to DMT; please consult the relevant summary in the DMTs section and discuss your preferences and priorities with your MS HCP.

The route of administration for each drug in the MS-Selfie InfoCards is clearly identified by the relevant symbol. (If a DMT is available in more than one formulation, there is a separate card for each delivery route.)

Number of clinic visits

It may be important for you to consider the frequency of clinic visits. This will depend on factors such as the delivery route of your DMT, the monitoring requirements of the drug regulators and the risk of specific side effects. The table below summarises the assessments from the MS-Selfie InfoCards. This is another factor to consider in discussions with your MS HCPs about the most appropriate DMT for you.

Conclusions

People with MS must understand the objectives of MS treatments and the different treatment strategies currently available to achieve these objectives. Although the MS therapeutic landscape is complex and hence may seem overwhelming, framing the choices using a relatively simple construct should help each individual to make informed decisions about managing their MS. MS-Selfie aims to guide you in the process of deciding on the most appropriate therapeutic strategy and specific DMT for treating your disease.

References

  1. Rotstein D, et al. Association of No Evidence of Disease Activity with no long-term disability progression in multiple sclerosis: a systematic review and meta-analysis. Neurology 2022;99:e209̶ ̶ 20.
  2. Giovannoni G. Disease-modifying treatments for early and advanced multiple sclerosis: a new treatment paradigm. Curr Opin Neurol 2018;31:233 ̶ 43.
  3. Samjoo IA, et al. Efficacy classification of modern therapies in multiple sclerosis. J Comp Eff Res 2021;10:495–507.
Pregnancy and childbirth, Women's health

Preparing to give birth

Some of the concerns that people with MS raise about giving birth are covered here, such as the possible need for assisted delivery, the likelihood of a normal vaginal delivery and the use of pain-relieving measures.

Am I more likely to need an assisted delivery because I have MS?

In people with MS who are not disabled, the answer is no. However, the more disabled you are, the more likely you are to have an assisted delivery or caesarean section. The latter may be due to fatigue and a lower threshold for the obstetric team to intervene in labour if a woman is significantly disabled. Please discuss the type of delivery you would like with your midwife and/or obstetrician.

Will I be able to have a normal vaginal delivery?

Yes, you should be able to have a normal vaginal delivery. The exception is women with MS with significant disabilities (see above), but even then, a normal vaginal delivery is possible. Providing there are no contraindications, you might consider having a trial of labour and if it fails you can have an intervention such as a caesarean section. Please discuss this with your midwife and/or obstetrician who are best placed to advise and to help you plan.

Will I be able to have an epidural during labour?

Yes, you can have an epidural and other standard pain-relieving measures during labour. There have in the past been cases of people with advanced MS not tolerating spinal anaesthesia well, with some reported to have a slow and incomplete recovery of function. The anaesthetist should be aware of this because an epidural occasionally needs to be converted to a spinal anaesthetic if the epidural needle pierces the dura surrounding the nerve roots at the base of the spine.

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
Breastfeeding if you are on a DMT
Concerns about parenting

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

What impact does MS have on pregnancy and having children?

MS affects mainly women during their childbearing years and, as a result, impacts pregnancy, family planning and decisions about starting or extending a family. Opinion on this subject is based largely on data that predate the current era of active treatment and the newer generation of disease-modifying therapies (DMTs). I have addressed the many issues around this subject by answering several questions that have arisen in my MS practice over the years. Please see below for details of topics that you can find in the section on Pregnancy and childbirth.

Planning for pregnancy

Here I discuss 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.

Read more

Managing MS during pregnancy

Some important topics discussed in this section include:

  • the effect of pregnancy on the course of MS
  • how to manage relapse during pregnancy
  • the role of naturally occurring interferon-beta, and its possible implications for women with MS taking therapeutic interferon-beta
  • management of MS symptoms and morning sickness during pregnancy
  • the crucial issue of DMT safety and possible teratogenic effects on the developing foetus.

Read more

Preparing to give birth

Some of the concerns that people with MS raise about giving birth are covered here, such as the possible need for assisted delivery, the likelihood of a normal vaginal delivery and the use of pain-relieving measures.

Read more

Breastfeeding if you are on a DMT

This section explains how relapse is managed during breastfeeding and provides detailed guidance on which DMTs are safe (or not safe) to use while breastfeeding.

Read more

Concerns about parenting

Being disabled or unemployed because of MS does not mean you cannot be a good parent. In this section, I consider some important issues to explore with your partner and/or family before deciding. I also discuss the anxiety many of you may have about your children getting MS and the steps you can take to reduce this potential risk.

Read more

You may find the following review of managing pregnancy in women with MS helpful:

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

Treatment strategy

Do I understand the concepts of treat-2-target and NEDA?

Has anyone discussed a treatment target with you, including the need to rebaseline your disease activity? Have the concepts of preventing end-organ damage to the central nervous system (the ‘end-organ’ in MS) and brain volume loss or atrophy been broached?

Key points

  • Achieving long-term remission is a well-established treatment target in MS and several other autoimmune diseases.
  • Key measures of MS disease activity are used to define composite treatment targets; they provide objective means for monitoring and decision-making.
  • To demonstrate a target of no evident disease activity (NEDA) requires a minimum of three criteria to be met: no relapses, no MRI activity and no disability progression.
  • More stringent definitions of NEDA targets have evolved and will continue to do so as new predictors of treatment response are developed.

If you are on a disease-modifying therapy (DMT), what is the objective or treatment target for your MS? This is another question to be answered before committing yourself to a specific treatment strategy.

Treat-2-target

Relapses and ongoing focal inflammatory activity on MRI (new or enlarging T2 lesions and T1 gadolinium-enhancing lesions [Gd-enhancing]) are associated with poor outcomes. This has led to the adoption of ‘no evident disease activity’ (NEDA) as a treatment target in MS. NEDA, or NEDA-3, is a composite of three related measures of MS disease activity: (i) no relapses, (ii) no MRI activity (new or enlarging T2 lesions or Gd-enhancing lesions) and (iii) no disability progression. NEDA is an important goal for treating individuals with MS.

When to rebaseline

To use NEDA as a treatment target in day-to-day clinical practice, it is advisable to be ‘rebaselined’ after the onset of action of the DMT you have been started on. The timing of the MRI to provide a new baseline depends on the DMT concerned. The recommendations for immune reconstitution therapies (IRTs) are very different from those for maintenance therapies. In the case of an IRT (for example alemtuzumab or cladribine, which are given as short courses), breakthrough disease activity can be used as an indicator to retreat rather than necessarily to switch therapy. Therefore, a rebaselining MRI should be delayed until after the final course of therapy, e.g. 2 years, or close enough to the time when a third, or subsequent course, can be administered.

Determining treatment failure: IRTs

Questions remain of how many treatment cycles need to be given before considering that a specific IRT has not been effective.

  • For alemtuzumab, the threshold is three cycles under NHS England’s treatment algorithm (based on their cost-effectiveness analysis). Alemtuzumab is a biological or protein-based treatment, so the risk of developing neutralising anti-drug antibodies increases with each infusion.
  • Cladribine on the other hand is a small molecule, so neutralising antibodies are not a problem and there is no real limit on the number of courses that can be given.
  • Although HSCT tends to be a one-off treatment, there are rare reports of people with MS receiving more than one cycle.

Please note there are potentially cumulative risks associated with multiple cycles of an IRT: secondary malignancies in the case of HSCT and persistent lymphopaenia with cladribine. 

Determining treatment failure: maintenance therapies

In comparison to IRTs, if you have disease activity on a particular maintenance DMT, and provided you have been adherent to your treatment, this is usually interpreted as a suboptimal response or non-response and it should trigger a switch to another class of DMT. 

A criticism of NEDA is the omission of so-called ‘non-relapse-associated disease worsening’ as a component of the treatment target (in addition to evidence of incomplete recovery from relapses). I refer to this disease worsening as smouldering MS. Worsening disability in the absence of relapses may have little to do with ongoing focal inflammatory activity. It may simply represent a delayed dying-off of axons and nerve fibres following earlier focal inflammatory lesions. As a result, many neurologists feel uncomfortable switching, or stopping a DMT, based simply on non-relapse-associated worsening disability. For more information, please see Getting worse – smouldering MS.

Beyond NEDA-3

The definition of NEDA is evolving with clinical practice. Some centres are now testing for brain volume loss (that is, brain atrophy) and/or increased neurofilament light chain (NFL) in cerebrospinal fluid (CSF) as part of the NEDA-3 treatment target. NEDA-4 builds on NEDA-3, by including the target of normalising brain atrophy rates to within the normal range. The problem we have found with this is that the measurement of brain atrophy in an individual with MS level is very unreliable. For example, dehydration, excessive alcohol consumption and some symptomatic medications can cause the brain to shrink temporarily. We, therefore, think that CSF NFL levels are a better treatment target, less prone to misinterpretation. Neurofilaments are proteins that are found in nerves and axons (nerve fibres) and are released in proportion to the amount of nerve fibre damage that occurs in MS. Normalising CSF NFL levels, which would indicate that nerve damage is stopped, is referred to as NEDA-5. From a scientific perspective, including a more objective end-organ biomarker makes sense and will almost certainly be incorporated into our treatment target in the future.  

The components of NEDA-recommended targets are expanding as our ability to measure predictors of treatment response grows.
CSF, cerebrospinal fluid; MRI, Magnetic resonance imaging; NEDA, no evident disease activity; NEIDA, no evident inflammatory disease activity; NFL, neurofilament light; PROMS, patient-related outcome measures.

End-organ damage

The combination of relapses, the development of new MRI lesions and brain volume loss over 2 years in clinical trials predicts quite accurately who will become disabled over the same time period. From a treatment perspective, it is important to stop relapses, new MRI lesions and brain volume loss if we are to prevent or slow down worsening disability. Therefore, we must go beyond NEIDA (no evident inflammatory activity), which refers to relapses and focal MRI activity, and normalise brain volume loss if we can. 

Alternatives to NEDA?

Many neurologists are critical of using NEDA as a treatment target in clinical practice, fearing that it encourages people with MS to take highly effective DMTs that they consider may be ‘more risky’ (see short summaries of the available DMTs for information about individual drugs). Such neurologists, therefore, promote a less proactive approach and allow for some residual MS disease activity, but at a lower level. This treatment target is referred to as minimal evidence of disease activity, or MEDA.

In my opinion, MEDA flies in the face of the science of focal inflammatory lesions being ‘bad’ and it is associated with poor short-term, intermediate and long-term outcomes. If most people with MS end up receiving so-called high-efficacy therapies because of breakthrough disease activity, then this is what they probably need, that is, to have their MS treated adequately. Compelling evidence has emerged from trials, large registries and real-world data that people with MS treated early with highly effective DMTs (flipping the pyramid) do better than those who have delayed access to more effective DMTs.1,2,3 You can find a short summary of some key findings on the MS Brain Health website.

Implementing NEDA in clinical practice

Please note that achieving long-term remission, or NEDA, is a well-established treatment target in other autoimmune diseases, such as rheumatoid arthritis, autoimmune kidney disease and inflammatory bowel disease. People with MS treated to a target of NEDA do better than those with breakthrough disease activity. I would therefore strongly encourage you to discuss this treatment target with your own MS neurologist. 

The flowchart below illustrates how we implement a treat-2-target of NEDA strategy. The important take-home message is that the treatment targets in MS have moved; goal-setting and the active monitoring of outcomes is now required to achieve these goals. 

Treat to target NEDA algorithm

Recommended approaches to implementing a treat-2-target of NEDA strategy, using maintenance ̶ escalation or immune reconstitution therapy (IRT). The dotted lines indicate that if treatment fails you can either switch within the class (maintenance or IRT) or reassess the strategy. From Giovannoni, Curr Opin Neurol.4
Alem, alemtuzumab; Clad, cladribine; DMF, dimethyl fumarate; Fingo, fingolimod; GA, glatiramer acetate; HSCT, haematopoietic stem cell transplantation; IFNβ, interferon-beta; Mitox, mitoxantrone; NEDA, no evident disease activity; Nz, natalizumab; Ocre, ocrelizumab; Ofat, ofatumumab; Teri, teriflunomide.

There is also a clear need to update the definition of NEDA regularly as new technologies become available and are validated as predictors of treatment response. I therefore envisage the definition of NEDA changing still further in future to include more objective measures, particularly ones measuring end-organ damage and the inclusion of patient-related outcome measures.

References

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.

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_2 Dec 2024

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.
Causes and prevention of MS

What is multiple sclerosis?

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

Key points

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

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

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

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

The cause of MS

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

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

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

Mechanisms that underlie the common manifestations of MS

Lesions

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

Relapses

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

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

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

Intermittent symptoms

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

Stretch sensitivity

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

Temperature sensitivity

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

Fatigue

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

Worsening MS (also called progressive MS)

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

Ageing and MS

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

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

References

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

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 from further damage.
  • 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 some countries, ocrelizumab has been approved for the treatment of active primary progressive MS (PPMS) and siponimod has been approved for the treatment of active secondary progressive MS.
  • 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-effectiveness 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).
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