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Fatigue and insomnia, Sleep disorders

Understanding and managing insomnia in MS

Insomnia is the most common sleep disorder I encounter in my MS practice. It often goes untreated because people with MS accept it as part of living with the disease or because healthcare professionals (HCPs) prioritise other MS-related problems.

Key points

  • Insomnia is more common in people with MS than in the general population and is associated with poor mental health and other medical problems.
  • Factors that contribute to insomnia include anxiety, frequent visits to the bathroom, pain, leg spasms, restless legs, inability to roll over in bed, menopausal symptoms (hot flushes and night sweats) and poor sleep hygiene; they need to be managed appropriately.
  • Several online tools and questionnaires exist that can help you assess the nature and severity of insomnia.
  • Sleep aids (drugs) available over the counter or on prescription may be helpful.
  • Cognitive and digital approaches to insomnia management also have a role but are not widely available or suitable for everyone.
  • Complementary and alternative therapies are a valuable aid to self-management of insomnia.

Sleep, glorious sleep!

Sleep is the most essential performance-enhancing agent we know. You know what it is like if you wake in the morning and have had a good night’s sleep; you feel energised, your mood is good and you are ready to face the day. In contrast, when you wake from a night of tossing and turning, or not being able to turn, legs jerking, getting up several times to go to the toilet, maybe with a hangover from too much alcohol the night before, then you are irritable, your mood is low and it is challenging to get through the day. 

Most studies on sleep in MS show that over 70% of people with MS have a sleep disorder. In an MS-Selfie survey on sleep, a minority (33%) of 173 respondents described their sleep as good, very good or excellent, with 49% formally diagnosed with one or more sleep disorder and over 80% not having undergone formal sleep studies. Insomnia is the most common sleep disorder I encounter in my MS practice. Insomnia is defined as difficulty initiating or maintaining sleep, which can be a symptom or a disorder. If a disorder, insomnia is associated with a feeling of distress about poor sleep, and it disrupts social or occupational functioning.

Causes and impact of insomnia

In the general population, ~10% of adults have insomnia disorder and another 15 ̶ 20% report occasional insomnia, i.e. the symptom. In comparison, 40 ̶ 50% of people with MS have insomnia. Insomnia is more common in women than in men and is associated with poor mental health and other medical problems. Common MS-associated symptoms linked to insomnia (and resulting in fatigue) include pain, lack of bladder control, spasticity, restless legs, periodic limb movements and discomfort from being unable to turn in bed; other factors that contribute to insomnia – not just in people with MS but also more widely –  include alcohol and stimulant misuse, menopausal symptoms, poor sleep hygiene (daytime napping), deconditioning (lack of exercise), anxiety and depression. All these problems can interfere with sleep initiation, maintenance or perception in people with MS.

Insomnia can be episodic (with symptoms lasting 1 ̶ 3 months) or situational (of short duration, in response to a specific event of circumstance) and tends to follow a persistent course. Episodic insomnia refers to insomnia for a defined period, for example lasting several months linked to anxiety. In comparison, situational insomnia refers to insomnia triggered by a specific stimulus or event, such as sleeping away from home or after alcohol consumption. Chronic insomnia can cause depression and is associated in the general population with the development of hypertension and dementia. Insomnia assessment, diagnosis and management require a careful history to document its course, concomitant comorbidities and potential contributing factors. 

Several studies show that approximately 40% of people with MS have obstructive sleep apnoea and that it is not necessarily associated with obesity and a large neck. Sleep apnoea in MS may be due to brain stem pathology from MS affecting pharyngeal (throat) muscle function. If you know or think you are a snorer and you have periods when you stop breathing, you can download one of the many smartphone sleep apps that can assess this.

Approaches to managing insomnia

Any MS-related symptoms that can affect sleep need to be managed appropriately. How can you treat insomnia if your sleep is interrupted by anxiety-related rumination, nocturia, pain, leg spasms, restless legs, inability to roll over in bed, menopausal symptoms of hot flushes and night sweats and poor sleep hygiene? 

Recording your sleep patterns

A 24-hour history of sleep ̶ wake behaviours can help to identify additional behavioural and environmental factors for intervention. Patient-reported outcome measures (PROMS) and sleep diaries provide valuable information about the nature and severity of insomnia. They can help screen for other sleep disorders and monitor treatment progress.

A sleep diary should collect information on your sleep cycle (bedtime, arising time, napping) and estimates of your sleep ̶ wake characteristics, i.e. sleep latency (how long it takes to fall asleep), number and duration of awakenings, and an estimated overall sleep time. Useful PROMS include the Insomnia Severity Index, the Pittsburgh Sleep Quality Index, the STOP-BANG Sleep Apnea Questionnaire (for evaluating the risk of sleep apnoea) and the Restless Legs Syndrome Rating Scale. 

Sleep hygiene

I suggest you start with a simple self-help guide to improve your sleep hygiene.

  1. Ensure you spend an appropriate amount of time asleep, at least 6 hours in bed. Some people need more than this to feel refreshed. 
  2. Limit daytime naps to 30 minutes. Please note that napping does not make up for inadequate nighttime sleep. 
  3. Avoid stimulants such as caffeine, modafinil and nicotine close to bedtime. 
  4. Only drink alcohol in moderation. Alcohol is known to help you fall asleep faster, but too much disrupts sleep.
  5. Exercise helps improve sleep quality. As little as 10 minutes of aerobic exercise daily can enhance the quality of sleep. 
  6. Don’t eat before going to bed. Heavy foods and fizzy drinks can trigger indigestion or heartburn/reflux that disrupts sleep.
  7. Ensure you get adequate exposure to natural light; exposure to sunlight during the day and darkness at night help to maintain a regular sleep ̶ wake cycle. 
  8. Establish a regular relaxing bedtime routine, which helps the body recognise it is bedtime. This could include taking a shower or bath or reading. However, avoid reading or watching emotionally upsetting content before attempting to sleep.
  9. Make sure that your sleep environment is pleasant. Your mattress and pillows should be comfortable. The bedroom should be cool for optimal sleep (16 ̶ 20°C). The bright light from lamps, smartphones and television screens can make it difficult to fall asleep, so turn those lights off or adjust them when possible. Use the blue filter mode on your smartphone and other devices to reduce the inhibition of melatonin from light. Consider using blackout curtains, eyeshades, earplugs, white noise machines and other devices to make the bedroom more relaxing.
  10. If you have pain, nocturia, restless legs, sleep apnoea or other causes of discomfort, get these adequately managed via your HCP.

If these self-help measures fail, other current treatment options include prescription-only and over-the-counter (OTC) medications, cognitive behavioural therapy for insomnia (CBTI) and complementary and alternative therapies. 

Over-the-counter sleep aids

Over-the-counter sedatives tend to be first-generation antihistamines with potent centrally acting anticholinergic effects that impair cognitive function and long-term brain health. I recommend you avoid them (see newsletter entitled ‘Your anticholinergic burden’). 

Some people with MS self-medicate with OTC melatonin, cannabidiol (CBD) or tetrahydrocannabinol (THC) preparations. Melatonin has a U-shaped dose ̶ response curve for some individuals; therefore, lower doses may be better than higher doses. In general, I cannot recommend the use of CBD or THC for insomnia. CBD is a drug and is associated with liver toxicity; it may also interact with your other medications. However, if you do decide to buy CBD and/or THC, please use a reputable supplier and pharmaceutical-grade products. Medicinal cannabis cannot be prescribed on the NHS but can be obtained via private clinics. Many patients purchase it online; as a doctor, I cannot recommend buying it this way. 

Prescription-only sleep aids

If you raise the issue of insomnia with your HCP, they may reach for the prescription pad. Before accepting a sedative, please be aware of its limitations and ensure you have optimised all the above guidance. Sedatives are only a short-term solution; they work well for about 4 ̶ 5 days before you develop tachyphylaxis and need higher doses. Tachyphylaxis refers to the rapidly diminishing response to successive doses of a drug, rendering it less and less effective. Once you develop tachyphylaxis and stop taking sedatives, you may experience rebound insomnia. Benzodiazepines (e.g. diazepam) are addictive and doctors generally avoid prescribing them for insomnia. However, they still have a role when insomnia is part of acute anxiety. The sedatives most often used are the so-called Z-drugs (zolpidem, zopiclone, zaleplon and eszopiclone). Zopiclone and eszopiclone have a longer half-life than the other two drugs (5 ̶ 6 hours). In comparison, zolpidem and zaleplon act for a much shorter period (1 ̶ 3 hours). 

The older, tricyclic antidepressants, such as amitriptyline, are commonly used as sedatives. I have largely stopped prescribing them unless there is another reason for using a tricyclic, e.g. to help with pain management (please read my newsletter ‘Amitriptyline: the neurologist‘s dirty little secret’. I mostly use duloxetine in my clinical practice for pain management. It is not as sedating as tricyclic antidepressants, but some patients find it helps with sleep. Duloxetine is a serotonin ̶ noradrenaline reuptake inhibitor and has fewer anticholinergic side effects than tricyclics.

Antispasticity agents such as baclofen and gabapentinoids (gabapentin and pregabalin) also help sleep, but they should only be used for insomnia if you have spasticity or, in the case of the gabapentinoids, spasticity and/or pain that needs to be managed.  

Psychiatrists and some neurologists use sedating antipsychotics to help with insomnia. Sadly, as a neurologist, I have seen too many severe adverse events resulting from the liberal use of antipsychotics as sedatives. There needs to be a good reason for prescribing an antipsychotic, and insomnia in isolation is not one of them; however, there is a role for them in patients with cognitive issues or significant psychiatric problems. The older generation antipsychotics (e.g. haloperidol) have now been replaced by safer drugs such as quetiapine and olanzapine.

A new class of sedatives is now available in some countries; these are the dual orexin receptor antagonists suvorexant, lemborexant and daridorexant. Daridorexant is NICE approved for use by the NHS; it is recommended for treating insomnia in adults with symptoms lasting for 3 nights or more per week for at least 3 months and whose daytime functioning is considerably affected, but only if CBTI has been tried and not worked, or if CBTI is not available or is unsuitable.

Cognitive approaches to managing insomnia

Cognitive Behavioural Therapy for Insomnia (CBTI)

Only some patients receive CBTI, owing to a lack of adequately trained therapists. CBTI aims to change the behaviour and psychological factors that contribute to insomnia (e.g. anxieties and unhelpful beliefs about sleep). At the core of CBTI are behavioural and sleep-scheduling strategies (sleep restriction and stimulus control instructions), relaxation methods, psychological and/or cognitive interventions to change unhelpful beliefs or excessive worrying about insomnia, and sleep hygiene education. 

CBTI is focused on sleep and oriented toward problem-solving. A psychologist typically guides the process over roughly six consultations. Several variants in the methods for implementing CBTI include shorter formats, group therapy, using other providers such as counsellors and specialist nurses, and the use of telehealth digital platforms, including smartphone applications. 

Brief behavioural treatment for insomnia

This abbreviated version of CBTI emphasises behavioural components and is typically implemented in fewer sessions. It involves education about sleep regulation, factors that promote or interfere with sleep, and a tailored behavioural prescription based on stimulus control and sleep restriction therapy.

eCBTI

Digital CBTI (eCBTI) is becoming increasingly popular. The Sleepio application, which is recommended and covered by the NHS, has a positive effect on several sleep outcomes and is said to be as effective as medication. NICE recommends Sleepio as a cost-saving option for treating insomnia and insomnia symptoms in primary care for people who would otherwise be offered sleep hygiene or sleeping pills. A medical assessment should be done before referral to Sleepio for people who may be at higher risk of other sleep disorder conditions, such as during pregnancy or in people with comorbidities.

Complementary and alternative therapies

Sleep restriction

Limit the time you spend in bed to match your sleep time as closely as possible. After the initial restriction, the sleep window can be gradually adjusted upward or downward on a weekly basis as a function of sleep efficiency (time asleep÷time spent in bed×100) until an appropriate sleep duration is established.

Stimulus control

You need to follow a set of instructions designed to reinforce the association between bedtime and bedroom stimuli with sleep and to re-establish a consistent sleep ̶ wake schedule.

  • Go to bed only when you feel sleepy.
  • Get out of bed when you are unable to sleep.
  • Use the bed and bedroom for sleep and sex only; do not use your bed for reading, watching television, etc.
  • Try and get up at the same time every morning.
  • Avoid napping.

Relaxation training

Try using different procedures such as progressive muscle relaxation and imagery training to reduce arousal, muscle tension and intrusive thoughts that interfere with sleep. Relaxation procedures need to be practised daily over a few weeks. 

Cognitive therapy

This is a psychological approach to revising many common misconceptions about sleep and reframing unhelpful beliefs about insomnia and its daytime consequences. This method also reduces excessive worrying about sleep difficulties and their daytime consequences. Additional cognitive strategies include paradoxical intention (willingly trying to stay awake rather than trying to fall asleep) to alleviate the performance anxiety triggered by attempting to force sleep.

Sleep hygiene education

These general guidelines include advice about a healthy diet, exercise, substance use, and optimising environmental factors such as light level, noise and excessive temperature that may promote or interfere with sleep (see above). 

Acceptance and commitment therapy (ACT)

ACT is a form of psychotherapy that aims to educate people to stay focused on the present moment and accept life experiences, thoughts, and feelings (even negative ones) without trying to change them. ACT uses different methods and processes (e.g. acceptance, defusion, mindfulness, and committed action) to increase psychological flexibility.

Mindfulness

This meditation method involves observing one’s thoughts and feelings and letting go of the need to change or ruminate. Originally designed to reduce stress and anxiety, mindfulness has been adapted for the management of insomnia and can be included as one component of ACT.

Conclusion

Poor sleep, be it due to a comorbid sleep disorder, MS-related symptoms or poor sleep hygiene, is a very common problem in people with MS. It contributes to daytime fatigue and hypersomnolence and impacts physical and cognitive function. As a result, poor sleep reduces quality of life and can exacerbate other MS-related problems such as poor cognition, anxiety and depression. It is essential that poor sleep is documented, investigated appropriately and treated accordingly to improve the functioning and quality of life of people with MS.

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.

table format updated 180625 SS

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

Managing MS during pregnancy

Opinion on how MS impacts pregnancy is based largely on data that predate the current era of active treatment and the newer generation of disease-modifying therapies (DMTs). In this section I have therefore addressed many of the important issues that women who are considering pregnancy need to understand, including:

  • 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.

Will pregnancy affect the course of my MS?

Yes, pregnancy effects on MS have been observed at a group level, though it is difficult to notice changes in individuals. It is well known that MS attack rates drop during the second and third trimesters of pregnancy and relapses rebound again in the first 6 months after delivery. However, only a minority of women with MS have post-partum relapses. Breastfeeding may blunt the post-partum rebound, but this is not absolute. Therefore, most neurologists now recommend starting or restarting DMTs soon after delivery to try and prevent post-partum relapses.

At a population level, the more children you have, the better your overall prognosis. This effect is small and is based on studies done in the pre-DMT era. It may be due to the immunological effects of pregnancy that work like a DMT in MS. Immunologists have tried to understand this phenomenon in the hope of developing treatments for MS that mimic the pregnancy state.

How is a relapse managed during pregnancy?

In the event of having a relapse during pregnancy, a short course of high-dose corticosteroids can be considered. However, I limit using steroids to disabling and/or severe relapses, especially early in the first trimester, as there is a small risk of orofacial abnormalities (cleft lip and palate) and reduced birth weight from exposure of the developing foetus to high-dose steroids. There is also a risk of precipitating gestational diabetes in women receiving high doses of steroids during pregnancy. In the rare situation of a severe relapse unresponsive to high-dose steroids, plasma exchange may need to be considered.

Could neutralising antibodies to therapeutic interferon-beta affect my baby?

Naturally occurring interferon-beta is a cytokine (cell-signalling agent) produced by the body to help fight infections. As there is only one human interferon-beta, antibodies to therapeutic interferon-beta (IFN-beta) will neutralise the body’s own natural interferon-beta. If you are taking IFN-beta for your MS, there is thus a theoretical risk that neutralising antibodies (NABs) to the DMT might cross the placenta and affect the role of human interferon-beta in foetal development.

Interferon-beta is important for innate immunity and neutralising your own interferon-beta may put you at risk of getting viral infections. Interferon-beta also plays a role in foetal bone development, but the placenta does not mature in relation to immunoglobulin transfer until near the end of the second trimester of pregnancy, so it is unlikely that sufficient NABs cross the blood ̶ placental barrier to affect foetal bone development. However, in the third trimester, NABs will cross over the placenta into the foetal circulation and may impact the baby’s innate immunity. Despite these theoretical concerns, there is no indication from published data to support these potential adverse effects of NABs on IFN-beta.

If I fall pregnant while on a DMT, will this affect the baby?

This depends on which DMT you are taking and what you mean by ‘affecting the baby’. We worry most about teratogenic effects, which describe congenital malformations. Teriflunomide, S1P modulators and cladribine are generally classified as drugs that may be teratogenic, and hence precautions need to be taken so as not to fall pregnant on these agents. Foetal malformations usually occur very early in foetal development, often before the woman knows she is pregnant; therefore, it is difficult to do anything about it once foetal exposure occurs. Despite this, even for women who are on these agents and fall pregnant, we don’t automatically recommend termination of pregnancy. We refer them to the high-risk pregnancy clinic to discuss the options with an obstetrician. Many women continue their pregnancies with an uneventful outcome and a normal baby. On the other hand, some women choose the option of terminating their pregnancy.

A large amount of data from MS pregnancy registries and post-marketing surveillance indicates no increased risk of major congenital anomalies or spontaneous abortions (miscarriages) after exposure to interferon-beta or glatiramer acetate. Most neurologists are, therefore, comfortable with their female patients falling pregnant on these agents, continuing the treatment through pregnancy and then breastfeeding their babies.

Fumarates (dimethyl fumarate [Tecfidera], diroximel fumarate [Vumerity]) are not teratogenic and are unlikely to have a negative impact on pregnancy outcomes. We need more data from registries and post-marketing surveillance before we can be confident that the fumarates are safe during pregnancy. However, these agents are prodrugs and converted to monomethyl fumarate, which is part of our metabolism, so it is very unlikely that the fumarates will cause problems. I don’t have an issue with women falling pregnant on the fumarates and continuing them through pregnancy, but there is conflicting advice about this.

Should I continue taking drugs for my MS symptoms during pregnancy?

Yes and no. It depends on what the medications are for and whether they are safe during pregnancy. Ideally, you should wean off any symptomatic therapies or at least change to alternative medications that are safe to take during pregnancy. It is important to try and plan your pregnancy and if necessary be referred to a special medical pregnancy clinic so that these issues can be addressed. Many women with MS find that their MS-related symptoms improve during pregnancy, and they can do without symptomatic therapies. However, unless you are prepared to wean yourself off symptomatic therapies you won’t know.

Physical therapies should be continued during pregnancy. One could argue that everyone with MS should be physically active and do pelvic floor exercises. Pregnancy and childbirth may impact bladder and bowel function, so it is important to see a pelvic floor therapist to start pelvic floor exercises. The latter are taught to women in antenatal classes.

How do you treat morning sickness or hyperemesis gravidarum during pregnancy?

Treating morning sickness or hyperemesis gravidarum is no different in women with MS than in the general population. It involves hydration, vitamin supplements (in particular, thiamine) and the judicious use of antiemetics (for example, cyclizine, prochlorperazine, promethazine, chlorpromazine, metoclopramide and domperidone). If the vomiting extends into the second trimester, ondansetron can be used. In very severe cases of morning sickness, steroids may be required; for example, hydrocortisone 100 mg twice daily can be converted to prednisolone 40 ̶ 50 mg daily by mouth, which can then be tapered to the lowest level that still controls symptoms. For patients taking a fumarate, try and take your medication later in the morning when you are less likely to vomit.

What dose of vitamin D do you advise during pregnancy?

During pregnancy vitamin D requirements are increased and I recommend doubling the dose for supplementation from 4,000 IU of vitamin D3 to 8,000 IU per day. At the same time, women who are pregnant should be on iron and folate supplements that should ideally be started before falling pregnant.

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
Preparing to give birth
Breastfeeding if you are on a DMT
Concerns about parenting

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 the potential to cause birth defects; therefore, patients must have effective contraception whilst on this treatment. It 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

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.

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 effective DMTs are at preventing negative 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

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  2. Barkhof F, et al. Imaging outcomes for neuroprotection and repair in multiple sclerosis trials. Nat Rev Neurol 2009;5:256–66.
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  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.
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  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.
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