Tag Archives: prognosis

Bladder and bowel, Intimate issues

Intimate issues: bladder dysfunction

Bladder dysfunction in people with MS is a sign of early damage, particularly to the spinal cord, and an early indication of a poor prognosis. Why do people with MS who develop bladder dysfunction do worse than those with no bladder symptoms? Here, I explain why I take bladder problems seriously and their implications for MS management.

Key points

  • Urinary hesitancy, urgency, frequency and incontinence, including at night, are bladder problems that affect many people with MS and cause significant frustration and anxiety.
  • A range of drug-based treatments, behavioural techniques and specialist physical interventions can help people with MS to manage bladder dysfunction and achieve adequate control.
  • However, the bladder pathways will probably continue to be affected in the long term due to the development of new lesions or the expansion of old lesions.
  • Frequent and severe urinary tract infections (UTIs) increase the likelihood that MS will progress.
  • I recommend regular dipstick testing at home, as part of your MS self-management, to increase the chances of early detection and treatment of a UTI.
  • Lifestyle approaches, such as avoiding smoking and reducing alcohol and caffeine consumption, should help to reduce bladder symptoms. Pelvic floor exercises are also important.
  • Dehydration is not a good way to control your bladder symptoms. Chronic dehydration can have a significant impact on your overall health and well-being and can exacerbate many of your MS symptoms.

Causes and significance of bladder dysfunction

Bladder dysfunction is the most common symptomatic problem I encounter in an MS clinic, affecting more than 50% of people with MS. It is one of the signs of early damage, particularly spinal cord damage, and an early indication of a poor prognosis. It therefore has important implications for treatment: if you have early bladder symptoms, you may want to take a more effective therapy early on rather than starting on a less effective DMT and waiting to see how you respond. It is best to maximise your chances of responding to treatment by opting for a highly efficacious therapy first-line. I call this ‘flipping the pyramid’.

Infections, both viral and bacterial, are a known trigger of relapse in MS. Frequent and severe urinary tract infections (UTIs) increase the likelihood that your MS will progress. This is why it is important to improve the management of bladder problems in people with MS to prevent or reduce UTIs. You can read more about managing  UTIs here.

Why do people with MS who develop bladder dysfunction do worse than those with no bladder symptoms? The bladder is a complicated organ with several neurological components that need to be coordinated. The descending nerve fibres that travel from the brain to the lower segments of the spinal cord are very long and have the greatest chance of being damaged by MS lesions in their path down to the bladder centre in the sacral area of the lower spinal cord. Therefore, any progressive or worsening MS damage is likely to manifest with bladder dysfunction early on.

The detrusor (or balloon) muscles and the sphincter (or valve) need to coordinate their action to enable normal bladder function. When the bladder is filling, the detrusor muscle relaxes to allow the bladder to expand and the sphincter contracts to keep the urine in the bladder. The opposite occurs when you pass urine; the sphincter opens and the detrusor contracts to empty the bladder.

Common MS-related bladder problems

Hesitancy

Urinary hesitancy occurs when the function of the detrusor and sphincter muscles is not coordinated: you try to pass urine, but the bladder sphincter won’t open. Hesitancy may be intermittent; if you try again later, the bladder will open, allowing you to pass urine. Conversely, the sphincter may close as you pass urine, which breaks up the urine stream or prevents complete bladder emptying; this can cause dribbling. The medical term for incoordination of the bladder muscles is dyssynergia or, more correctly, detrusor-sphincter-dyssynergia (DSD). People with MS find urinary hesitancy and its unpredictability very frustrating.

The drug treatment for DSD includes alpha-blockers (prazosin, indoramin, tamsulosin, alfuzosin, doxazosin and terazosin). Other strategies include small bladder stimulators or vibrators that are placed over the pubic area and work by blocking signals that inhibit the sphincters. The vibrators work in some people with MS and may help relax the sphincter.

Trying to relax when passing urine can help to improve hesitancy. The sound of running water, for example from a tap, may trigger the relaxation of the sphincter. Simulating this in public toilets may not be possible. Some people with MS find pressing on the lower abdomen helps. If all else fails, intermittent self-catheterisation (ISC) may be the only option to manage urinary hesitancy (see below).

Frequency and urgency

In MS the commonest bladder problem is spasticity, or irritability, of the detrusor muscle. The detrusor can’t relax, which prevents the bladder from filling to its maximum capacity. Frequent spasms of the detrusor muscle tell the brain that the bladder is full and you need to pass urine. This causes frequency, i.e. the need to use the toilet many times during the day and night. Frequency often accompanies the symptom of urgency, the need to get to the toilet as quickly as possible to prevent incontinence. 

When urgency is a problem, distraction techniques such as breathing exercises and mental tricks (e.g. counting) may be helpful. If urinary frequency is your main problem, you might try to retrain your bladder by holding on for as long as you can each time before passing urine. The aim is to train the detrusor muscle to expand more to hold on for longer when you need the toilet. These behavioural techniques rarely work for long; MS is a relapsing and/or progressive disease, and the bladder pathways will likely continue to be affected due to the development of new lesions or the expansion of old lesions.

Incontinence

Incontinence occurs when you lose the ability to suppress or ignore the signals from the detrusor muscle with the result that the sphincter relaxes or opens as part of a spinal cord reflex. We typically treat this problem with anticholinergic drugs, e.g. oxybutynin, solifenacin or tolterodine. The older generation anticholinergics such as oxybutynin cross the blood ̶ brain barrier and enter the brain, where they can exacerbate cognitive problems in people with MS. The commonest side effect of anticholinergics is dryness of the mouth; they can also worsen constipation. People with MS must be warned about the risk that anticholinergics will relax the bladder too much and precipitate urinary retention; the solution to urinary retention is ISC. 

The good news is that we now have a relatively new muscle relaxant, mirabegron (Betmiga), which activates the β3 adrenergic receptor in the detrusor muscle. I am increasingly using mirabegron to avoid the side effects (particularly cognitive issues) associated with anticholinergics. The main side effect of mirabegron is that it tends to increase your blood pressure.

Nocturia

Nocturia means you need to get up frequently at night to pass urine. If nocturia is your main bladder problem, using agents to concentrate the urine at night might help. A hormone called DDAVP works on the kidneys to reduce urine production; it is available as a nasal spray or tablets (Desmotabs or Desmospray). DDAVP should only be taken once a day, to avoid continuous water retention by the kidneys; this presents as swelling of the feet and reduces the salt or sodium levels in your blood, which can be dangerous. You therefore need to have your sodium levels checked about 4 ̶ 6 weeks after starting DDAVP therapy. 

Second-line treatments for bladder problems

If you fail to respond to anticholinergics, mirabegron and/or behavioural techniques, you need a bladder scan to see if you have a raised residual volume (the amount of urine left after you have emptied your bladder). If the residual volume is greater than 80 ̶ 100mL you may need to consider intermittent self-catheterisation (ISC). Some continence advisors act at the 80 mL threshold, and others at the 100 mL threshold, when recommending ISC.

Intermittent self-catheterisation

ISC serves two purposes. It increases your functional residual bladder volume, allowing more storage space for urine, which reduces frequency and urgency. This can help if you need to travel some distance or to join in a social activity without having to pass urine. It also helps to reduce nocturia, which in turn improves sleep and possibly MS-related daytime fatigue.

ISC also removes urine from the bladder. The residual urine acts as a culture medium for bacteria; by clearing your bladder you can prevent bladder infections. Conversely, if you don’t do the ISC technique correctly you can introduce bacteria into the bladder that then cause infections.

Botox

Botox injection into the detrusor muscle is increasingly used as a treatment for bladder dysfunction, in conjunction with ISC. Botox paralyses the muscle, turning it into a flaccid bag for urine storage. The surgical techniques that were previously used to remove the nerve supply to the bladder (which had the same effect as Botox) are now rarely used.

Percutaneous tibial nerve stimulation 

Percutaneous (or posterior) tibial nerve stimulation is a form of neuromodulation that can help with impaired bladder function and may improve urinary urgency, urinary frequency and urge incontinence. It is offered as a treatment in specialist neuro-urology units.

Permanent catheterisation

If all else fails, some people with MS may need to be permanently catheterised. This can be done via the urethra or the lower abdominal wall; the latter is called a suprapubic catheter. Being permanently catheterised sounds drastic, but this significantly improves the quality of life in some people with MS. Allowing bladder dysfunction to control your life can result in social isolation and constant anxiety about being incontinent in public. With the above-mentioned strategies, adequate bladder control should be the norm in MS.

In my experience, the biggest hurdle to achieving adequate bladder control is when people with MS assume their bladder symptoms are part of the disease and resign themselves to living with them. Such patients may start using continence pads as if this is normal or inevitable for someone living with MS. This is not normal; incontinence can lead to skin rashes and pressure sores. Please don’t accept this as the norm or something you must live with. If you have problems, tell your MS nurse or neurologist; they can help you.

Anatomy of the human urinary bladder; reproduced from Wikipedia, created by U.S. National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) Program.

Lifestyle factors that impact your bladder

Smoking, alcohol and caffeine

Nicotine irritates the bladder. If you are a smoker, then stopping smoking may significantly improve your bladder symptoms. Similarly, reducing alcohol and caffeine consumption may help; these agents are diuretics and cause the kidneys to make more urine.

Pelvic floor exercises

One of the treatments recommended to all patients with bladder problems is pelvic floor exercises. These are also important for managing bowel and/or sexual problems. For detailed guidance on incorporating these into your daily life, please see pelvic floor training post.

Avoiding dehydration

Try to anticipate times when urinary frequency and urgency will be most inconvenient; reducing the amount you drink beforehand may help. For example, don’t drink too much for 2 ̶ 3 hours before you go out. After you have finished passing urine, go back to the toilet again after a few minutes to try to pass some more urine. This is called the double micturition technique, which aims to ensure the bladder is emptied completely. However, do not reduce your total fluid intake to less than 1.5 litres each day.

Dehydration is not a good way to control your bladder symptoms. The issue of people with MS dehydrating themselves to manage their bladder problems was highlighted as early as the 1960s by Professor Bryan Matthews, a neurologist in Oxford, in his textbook on MS.

When researching the topic in the 1990s, it became clear to me that people with MS with severe disability were most likely to have bladder dysfunction and were chronically dehydrating themselves to manage urinary frequency, urgency and nocturia. Studies showed that a high urinary concentration of creatinine, a waste product that the kidneys filter out of the blood through the urine, correlated with increased disability levels. Urine containing myelin basic protein-like material (MBPLM), an indicator of myelin damage in MS, was also shown to correlate with disability. It is dehydration that causes higher levels of MBPLM and creatinine in the urine, indicating that dehydration is associated with disability.1 

A more recent paper from researchers in the Southampton group described the same findings, that urinary tract symptoms are very common in people with progressive MS and are associated with inadequate hydration.2

Despite highlighting the issue of chronic dehydration in MS over the years, it remains a persistent problem. My message is clear: don’t use dehydration to manage your bladder symptoms. Chronic dehydration can have a significant impact on your overall health and well-being and can exacerbate many of your MS symptoms. Some potential effects of chronic dehydration are listed in the box below.

  1. Physical performance: Dehydration can decrease physical endurance, cause muscle cramps and exacerbate or cause fatigue. This can affect overall physical performance and make everyday tasks more challenging.
  2. Cognitive function: Dehydration has been linked to cognitive impairment, including issues with concentration, alertness and short-term memory. Prolonged dehydration may even contribute to long-term cognitive decline.
  3. Mood and mental health: Studies have shown that dehydration can affect mood and contribute to increased feelings of anxiety and irritability. In severe cases, it can even lead to symptoms resembling depression.
  4. Kidney function: Chronic dehydration can put a strain on the kidneys, potentially leading to the formation of kidney stones and urinary tract infections. It can impair the kidneys’ ability to effectively filter waste from the blood. It also makes you more susceptible to the side effects of non-steroidal anti-inflammatory medications.
  5. Digestive problems: Dehydration can lead to constipation and other digestive issues. It may also contribute to an increased risk of developing peptic ulcers and acid reflux.
  6. Skin health: Inadequate hydration can lead to dry, flaky skin and exacerbate conditions such as eczema and psoriasis. Proper hydration is essential for maintaining overall skin health and elasticity.
  7. Heat-related illnesses: Dehydration reduces your body’s ability to regulate temperature, increasing the risk of heat exhaustion and heat stroke, particularly in hot and humid conditions. Please remember that people with MS, particularly those with more advanced MS, may already have a problem with thermoregulation.

In conclusion

I advise using a holistic approach to managing urinary symptoms, in addition to medication or other aids where recommended. Please review the questions below to check whether you are optimising your self-management.

  • Have you deconditioned your bladder because you are not training yourself to resist emptying it whenever you get the urge to pass urine? The bladder is a muscle that needs to be trained.
  • Have you tried peripherally acting anticholinergics or mirabegron?
  • Have you had a post-micturition bladder scan to see if you are emptying your bladder?
  • Do you need to use intermittent self-catheterisation to increase your functional bladder volume?
  • Do you have a chronic low-grade urinary tract infection? Are you performing regular urine dipstick testing (see post on UTIs and dipstick testing)?
  • Do you have bladder stones?
  • Have you tried DDAVP (Desmotabs or Desmospray) to help concentrate your urine without dehydrating yourself?
  • Are you avoiding bladder irritants or stimulants such as caffeine and nicotine?
  • Are you doing your pelvic floor exercises? If you are a post-menopausal woman, have you tried HRT (hormone replacement therapy)? Pelvic floor tone and bladder function often improve on HRT. 

References

  1. Giovannoni G, et al. Urinary myelin basic protein-like material as a correlate of the progression of multiple sclerosis. Ann Neurol 1996;40:128 ̶ 9.
  2. Kaninia S, et al. Dehydration associates with lower urinary tract symptoms in progressive multiple sclerosis. Eur J Neurol 2024;31: e16175.
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

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

What prognostic group do I fall into?

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

Key points

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

Predicting MS outcomes: an imperfect science

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

Three broad prognostic categories

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

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

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

Factors linked to poor prognosis

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

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

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

‘It won’t happen to me’

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

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

Moving towards a more favourable outcome

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

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

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

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

The above figures illustrate what we aim to do with currently available high-efficacy DMTs (compared with older, lower efficacy treatments). We are simply trying to move you to the right, into a more favourable prognostic group. In other words, we want to make sure your MS is benign and that you reach old age with as healthy a brain as possible. Your brain reserve and cognitive reserve protect you from developing age-related cognitive impairment and dementia. MS reduces both of these reserves, which is why it is so important to protect them. With the prospect of effective combination treatments in the future, the proportion of people with MS who experience normal ageing is set to increase.

References

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