Tag Archives: bowel

Bladder and bowel, Intimate issues

Intimate issues: bowel disorders

Here I discuss why people with MS develop problems with their bowel function and I offer straightforward advice on how to manage constipation, diarrhoea and other MS-related bowel problems.

Key points

  • Many people with MS experience a bowel disorder as a result of changes within the central nervous system that may affect the rectal and anal muscles.
  • Agents that increase the muscular action of the bowel can help to treat constipation.
  • Medications for some MS symptoms can increase constipation and may need to be reviewed.
  • Faecal impaction associated with constipation is a serious problem that may need hospital treatment.
  • Small intestinal bacterial overgrowth (SIBO) from faecal impaction may occur if the bacteria of the small intestine increase above normal values, producing harmful toxins.
  • SIBO is associated with unpleasant symptoms including abdominal bloating, pain, anaemia, irritable bowel syndrome, constipation, diarrhoea and faecal impaction.
  • Bowel hypomobility and any faecal impaction underlying SIBO need to be addressed, and antibiotics may be required to reduce the abnormal bacteria in the bowel. A gut health programme and dietary review are important for long-term management.
  • Being incontinent of faeces in public is highly embarrassing and may lead to severe anxiety and social isolation.
  • Faecal urgency or incontinence are best treated by developing a bowel routine and trying to evacuate your bowels in a controlled environment and at a regular time of day.
  • Regular rectal or transanal irrigation can significantly improve the quality of life in such cases.
  • MS should be treated early with effective DMTs, to avoid or delay damage to the neuronal pathways that control bowel function.

Many people with MS experience bowel disorders, including constipation, faecal hesitancy (difficult initiating a bowel action), incomplete emptying, faecal urgency, urgency incontinence, overflow diarrhoea, excessive bloating and excessive flatus. Understanding the causes of rectal and anal dysfunction in patients with MS can help us to select the most relevant therapies to target specific symptoms.

People with MS who experience constipation generally have a loss of sphincter tone (strength) at rest and during contraction compared with non-MS patients. In faecal incontinence, rectal sensitivity threshold is reduced, meaning that when faeces enter the rectum the threshold at which the defaecation reflex is triggered is lower than normal. There is also evidence that the coordination of the pelvic floor following contraction of the anal sphincter is abnormal in people MS. Pelvic floor exercises may help with this.

Management of constipation

Bowel dysfunction, particularly constipation, is common in MS. Constipation occurs because the MS bowel is sluggish due to reduced motility (i.e. the muscles or nerves do not work as they should). The management aim is usually to encourage regular bowel action, either daily or at least every two days.

Prokinetic agents that increase the muscular action of the bowel can help to treat constipation. The prokinetic agent I prescribe most often is senna. If this fails, other options include bisacodyl, co-danthrusate, sodium picosulfate or prucalopride; these agents work by stimulating the nervous system in the bowels. Prokinetic agents often need to be taken with bulking (fibre) and loosening (liquid) agents. Bulking agents include methylcellulose, psyllium or ispaghula husks, and sterculia granules. Loosening agents keep liquid in the bowel, causing water to be retained with the stool; examples include lactulose, polyethylene glycol (Movicol), magnesium hydroxide and magnesium sulphate (Epsom salts).

Cyclical use of laxatives can contribute to ongoing constipation: you use laxatives to treat your constipation, the laxatives cause diarrhoea, so you stop taking them. You then become constipated again, and the cycle repeats itself. 

If you experience bladder incontinence, dehydrating yourself to control your bladder problems can make constipation worse; you must drink adequate quantities of water throughout the day. Similarly, anticholinergic drugs used for treating urinary frequency and urgency and treatments for pain and spasticity may all make constipation worse. Therefore, if you are constipated your medications for other symptoms of MS need to be reviewed. 

Faecal impaction

Over time, the bowels may become impacted with faeces, and a hard, stony mass of compacted faeces forms (known as a faecolith). The gut bacteria may then overgrow and liquefy the stool above this impacted faecolith, bypass the impaction and cause diarrhoea. A typical history of faecal impaction includes periods of constipation punctuated by episodes of diarrhoea. If you suffer from chronic constipation and intermittent diarrhoea, you should contact your health team for help. Faecal impaction is a serious problem and often warrants treatment in hospital.

Below are some tips for managing MS-related constipation.

  1. Optimise your diet by eating lots of fibre.
  2. Don’t dehydrate yourself. Drink plenty of water; be aware that caffeine and alcoholic beverages are not hydrating. Both cause the kidneys to make more urine (diuresis) and are dehydrating.
  3. Try to eliminate the concurrent use of medications that exacerbate constipation (anticholinergics and opioids).
  4. Exercise regularly; the anticipation of exercise and exercise itself stimulate a defaecation reflex.
  5. If you need to use laxatives, start with a prokinetic agent that stimulates the bowel to move, such as senna; then add in bulking agents (e.g. psyllium husks or other fibre substitutes) followed by liquifying agents (lactulose or polyethylene glycol).
  6. Don’t suppress the need to go to the toilet; many people with chronic constipation have learnt bad habits (such as not using toilets that are unfamiliar to them).
  7. Try to develop a daily bowel routine, for example, by having a bowel movement at a particular time (ideally in the morning). This may require you to stimulate a bowel movement, perhaps by eating something, drinking a caffeine-containing drink, anal stimulation (anal plug), using glycerine suppositories, mini-enemas or (if necessary) an anal irrigation system. An anal plug is used to stimulate the colonic emptying reflex and is removed before you have bowel action.

These final recommendations may sound extreme, but they are essential steps to prevent faecal impaction. They may also give you the confidence to go out knowing that you can avoid faecal urgency and incontinence.

Small intestinal bacterial overgrowth (SIBO)

People with MS with bowel dysfunction may develop small intestinal bacterial overgrowth (SIBO), which is defined as an increase in the bacterial content of the small intestine above normal values. Some studies show that four in every 10 people with MS have SIBO; it is also detected in approximately one-third of patients with gastroenterological complaints who undergo a breath test. Proton pump inhibitors (omeprazole and related drugs) and smoking are risk factors for developing SIBO. The risk of SIBO increases with age and does not depend on gender or race.

SIBO is associated with dyspepsia, abdominal bloating, abdominal pain, anaemia, irritable bowel syndrome, functional constipation, diarrhoea and faecal impaction. A slowdown in your bowel transit time with SIBO decreases the normal clearance of bacteria from the small intestine. This slowdown is due to changes in the motility of the intestine, which is almost universal in people with MS.

Risks from SIBO

SIBO may damage the intestinal surface or mucosa of the bowel, because the bacteria can produce harmful toxins. This can result in leaky gut syndrome and acquired lactose intolerance. The leaky gut syndrome is controversial and associated with many symptoms that may overlap with MS-related symptoms. Leaky gut syndrome is not medically defined, and no specific tests or treatments are available. In comparison, acquired lactose intolerance occurs when someone loses the ability to digest lactose, the main sugar in milk, which causes them to develop diarrhoea, gas and bloating after eating or drinking dairy products. If you have lactose intolerance, you quickly learn to avoid lactose-containing products or use lactase preparations that help digest lactose. Please note that cheeses and yoghurt are generally tolerated because the bacteria used in the culturing process to produce these dairy products break down the lactose.

We know that many bacterial overgrowth products can impact human metabolism and behaviour. For example, people with liver dysfunction can’t metabolise these bacterial toxins and they develop hepatic encephalopathy. People with neurological disorders with reduced brain and cognitive reserve tend to be more susceptible to the effects of these bacterial metabolites, which are thought to upregulate innate immunity in the nervous system. This is why I try to stress to my patients that they should manage their constipation to prevent this from happening. Severe constipation and faecal impaction should be viewed as a chronic infection and managed and treated.

Diagnosis of SIBO

A breath test is most commonly used to diagnose SIBO. This noninvasive test measures the amount of hydrogen or methane you breathe out after drinking a mixture of glucose and water. A rapid rise in exhaled hydrogen or methane indicates bacterial overgrowth in the small intestine. Although widely available, breath testing is less specific than other tests for diagnosing bacterial overgrowth.

The gold standard for diagnosing SIBO is a small intestine aspirate and fluid culture. The fluid sample is obtained as part of a small bowel endoscopy. Other tests can include abdominal X-rays or CT scans. Faecal impaction resulting from constipation can also be diagnosed from spinal MRI scans of people with MS.

Management of SIBO

The initial way to treat bacterial overgrowth is to manage the underlying bowel hypomobility problem and clear any faecal impaction. In parallel, a course of antibiotics may be needed to reduce the number of abnormal bacteria in the bowel. However, unless you deal with the underlying problems, the bacteria will repopulate the bowel when the antibiotics are discontinued. This is why some people with SIBO may require long-term antibiotics. Switching between different antibiotics helps prevent bacterial antibiotic resistance from emerging. Please be aware that antibiotics wipe out most intestinal bacteria, both normal and abnormal; hence, they are not an ideal long-term solution to SIBO.

Starting a gut health programme is an essential part of treating SIBO. You will need a nutritional review, possibly with a dietitian, and you may need to change your diet to prevent constipation and/or faecal impaction. In some cases, you may require supplements. particularly if you are vegan.

Management of faecal incontinence

Being incontinent in public is one of the most embarrassing things that can happen to someone with MS, and it may result in social isolation to avoid experiencing the embarrassment again. Many patients with MS describe their experience of being incontinent of faeces and/or urine in public as the worst thing that has happened to them. It doesn’t have to happen; there are many ways to prevent it.

Faecal urgency needs attention (as does urgency incontinence – see section on bladder disorders). It is best treated by developing a bowel routine and trying to evacuate your bowels at a regular time of day, typically in the morning. This can be aided by using something to stimulate the bowels. I usually start by prescribing glycerine suppositories or mini-enemas. If the latter fails, I may elect to use transanal irrigation.

Transanal irrigation may sound drastic, but it often makes a massive difference to the quality of life in people with MS who need it and helps them to tackle a problem that can otherwise leave them stranded at home. I regularly refer patients for assessment to use the commercial rectal irrigation system, Peristeen, mainly because of the psychological benefits they derive from it.

The biggest problem with poor rectal compliance and faecal urgency is the odd occasion when you have diarrhoea due to gastroenteritis. With diarrhoea, whatever the cause, your rectum fills multiple times during the day and hence you are more likely to be incontinent. In this situation, you may need to use incontinence pads.

Faecal incontinence is not necessarily linked to disability. Why not? The reason is that a strategically placed MS lesion in the spinal cord can impact bowel function without causing other disabilities. I have patients who have had spinal cord relapses that leave them with faecal urgency and episodes of faecal incontinence, but very little other disability.

Case example

One patient of mine developed a severe anxiety disorder following an episode of faecal incontinence in public. She had intrusive thoughts and unpleasant flashbacks, reliving the episode repeatedly. After referral to a psychiatrist, she was diagnosed as having post-traumatic stress disorder. It took several years of counselling for her to overcome the social phobia associated with her anxiety and start going out again.

She now ventures out only after having an enema to clear her lower colon and rectum; she never eats when she is out, so as not to stimulate the reflex urge to defaecate that follows eating. She wears pads and carries a change of clothing. Her faecal incontinence emergency pack contains wet wipes, clean underwear, spare continence pads and poo bags to dispose discreetly of any used items – the same items I packed when I went out with my daughters before they were potty trained.

The importance of managing bowel dysfunction

Bowel dysfunction is one of the hidden symptoms of MS. To assess whether or not you have a bowel problem, and its severity, you can complete the Wexner Incontinence Score. Over the lifetime of the disease, most people with MS develop bowel problems, so it is important to realise that much can be done to help you. Please discuss these symptoms with your neurologist or MS clinical nurse specialist. 

On the positive side, if MS is treated early and effectively before the neuronal pathways that control bowel function are damaged, these issues can usually be avoided or delayed. Preventing disability, such as bowel dysfunction, is better than treating it. This is another critical reason to manage your MS actively with DMTs.

Bladder and bowel

Pelvic floor training

Do you have bowel, bladder and/or sexual problems? Here, I discuss pelvic floor exercises, which may help alleviate all these symptoms.

Pelvic floor exercises are one of the treatments recommended for all patients with bladder problems.1 However, when I ask patients if their continence advisors have formally instructed them on how to do these exercises, most say they were given an instruction sheet, referred to the pelvic floor exercise NHS site or other online resources. What is clear is that few people have been adhering to the pelvic floor exercise regimen; I estimate this to be less than 20% or even 10% of patients. 

  • Who should do pelvic floor exercises? 
  • Do you know how to do them and at what intensity? 
  • Have you adhered to doing them? 

Pelvic floor structure and function

The pelvic floor consists of muscles and other tissues at the bottom of the pelvis. The muscles attach to the pelvic bones and sacrum. The pelvic floor supports the lower abdominal organs and is essential for maintaining bowel, bladder and sexual function. The pelvic floor muscles have a constant tone at rest, i.e. they are tonically contracted. Voluntary and involuntary contraction and relaxation of the pelvic floor allow for normal bowel, bladder and sexual function; for example, reflex muscle contraction in response to sudden increases in intra-abdominal pressure, such as coughing or sneezing, maintains continence. Pelvic floor dysfunction causes symptoms such as urinary incontinence, voiding difficulty, pelvic organ prolapse, anal incontinence, evacuation difficulty, sexual dysfunction and pain. 

Pelvic floor muscle training

Like all muscle training programmes, pelvic floor muscle training (PFMT) is designed to improve pelvic floor muscle strength, endurance, power, relaxation or a combination of these. PFMT is typically unsupervised and self-administered. On the NHS, PFMT can be supervised by an HCP, typically a physiotherapist or a continence nurse. The National Institute for Health and Care Excellence (NICE), recommends PFMT to manage symptoms of pelvic floor dysfunction in women. NICE also recommends encouraging all women aged 12 and over to perform preventive exercises. This makes sense; the pelvic floor is just another muscle, and strengthening it should help prevent pelvic floor dysfunction in the future. Therefore, I have added PFMT to my list of exercises for my MS prehabilitation programme. 

PFMT is indicated mainly for urinary incontinence, pelvic organ prolapse and faecal incontinence. These are all problems associated with MS; in many cases MS either causes or contributes to these symptoms. 

PFMT for women

A self-administered programme should include basic voluntary contractions, which aim to improve pelvic floor muscle reaction to activities such as coughing, sneezing, exercise, and lifting, as well as sustained voluntary contractions that enhance endurance.

  • Sit comfortably with your knees slightly apart and contract the pelvic floor by lifting and tightening the muscles around the anus and vagina—as if to prevent the passage of gas and stop your urine flow.
  • Once you can achieve PFMT seated, you can perform the exercises in a standing position and during activity.
  • If you experience stress urinary incontinence (e.g. when sneezing), you can contract the pelvic floor in preparation for a leakage-provoking event; this is called the “knack”.
  • A basic voluntary contraction involves a hold of 1 ̶ 2 seconds, with the same rest time; a sustained voluntary contraction should last for 6 ̶ 10 seconds, with the same rest time. Once you establish a baseline sustained contraction, gradually increase the length of the contraction (to a maximum of 10 seconds). 

Approximately one-quarter of women cannot perform a pelvic floor contraction on their first attempt with just verbal instruction. Digital assessment of the pelvic floor – using biofeedback devices, electrical stimulation, or vaginal cones – is therefore useful to help them know when they are contracting effectively. If your progress is minimal, please ask your MS team for a referral to a suitable HCP for clinical assessment and a personalised, supervised PFMT programme.

Other resources providing useful instructions are available, e.g. a patient education leaflet from the International Urogynecological Association and smartphone applications such as the Squeezy NHS pelvic floor app. 

PFMT for men

Pelvic floor dysfunction can also occur in men, and PFMT is a recommended first-line conservative treatment. The following is an extract from the Pelvic Obstetric & Gynaecology Physiotherapy ‘Pelvic floor muscle exercises and advice for men’. 

Sit comfortably with your thighs, buttocks and tummy relaxed. Squeeze and lift the muscles from the front by either imagining you are trying to stop yourself from passing urine or trying to shorten or draw your penis up and inwards. Now try lifting the muscles from the back as if stopping the escape of wind. When you feel you have the hang of it, try lifting the front and back together. Don’t worry if you find it too difficult; after some practice, you will find the easiest and most comfortable method. This is a pelvic floor muscle contraction. To check that your pelvic floor muscles are working correctly: 

  • Place your fingers on your perineum. You should feel the perineum lift upwards as you contract your muscles.
  • Stand in front of a mirror; when you do a pelvic floor muscle contraction, you should see the base of your penis draw inwards and your testicles/ scrotum lift. 

Try not to hold your breath while you contract your pelvic floor. You are more likely to breathe easily if you lift your pelvic floor on your out-breath. Do not actively clench your buttocks, but don’t be concerned if you simultaneously feel a tightening in your buttocks and/or lower abdomen. This is normal. If you cannot feel a definite tightening in the pelvic floor muscles, you should seek professional advice.

Reference

  1. Kajbafvala M et al. Pelvic floor muscle training in multiple sclerosis patients with lower urinary tract dysfunction: A systematic review and meta-analysis. Mult Scler Relat Disord 2022;59:103559. 

Fatigue and insomnia, Sleep disorders

Fatigue in MS – a disabling symptom

Fatigue in MS is common, but it is often not investigated or managed properly. This post highlights the complexity of MS-related fatigue and explains why and how to manage it holistically. 

Key points

  • The different mechanisms underlying MS-related fatigue are explained.
  • The MS disease process, the burden of living with MS, and other factors such as drug side effects, comorbidities and lifestyle choices may all contribute to fatigue in MS.
  • Practical guidance is provided on managing many aspects of MS-related fatigue, using a holistic and systematic approach.
  • Not all fatigue is MS-related; it is important to ascertain if your fatigue could be due to another disease process.

Fatigue is one of the most disabling of all the symptoms of MS. It is the symptom that over 50% of people with MS would most like to be rid of. MS-related fatigue has several underlying mechanisms.

Fatigue caused by MS disease processes

Inflammation in the brain

Inflammatory mediators or cytokines associated with MS – in particular, interleukin-1 (IL-1) and TNF-alpha – trigger ‘sickness behaviour’. This is the response to inflammation that forces us to rest and sleep so that our body can recover. Sickness behaviour is also the body’s response to a viral infection such as flu; in fact, many people with MS describe their fatigue as being like the fatigue they experience with flu. 

Sickness behaviour from an evolutionary perspective is well conserved and occurs in most animals. This type of fatigue needs to be managed by switching off ongoing inflammation in the brain. Many people with MS who take a highly effective DMT report feeling much better and free from fatigue and/or brain fog. This is why recent-onset fatigue that cannot be explained by other factors (see below) may indicate MS disease activity. At present, fatigue on its own does not constitute a relapse.

Many patients with MS who have had COVID-19 tell me that MS-related cog-fog and fatigue feel like the cog-fog and fatigue of COVID-19 and long-COVID. As many as one in four people with long-COVID experience cog-fog, which includes problems in attention, language fluency, processing speed, executive function, and memory: these are the same problems that affect people with MS. 

Cog-fog related to MS and to COVID-19 could be linked to the same inflammatory mechanisms. This syndrome of systemic inflammation causing profound fatigue and cog-fog is not new. Some people with MS who have a systemic infection take weeks or months to return to normal; some patients with more advanced MS never return to their original baseline. This is why, as part of the holistic management of MS, we need to treat and prevent systemic infections as best we can.

The overlap between COVID-19 and MS-related cog-fog raises the question whether both are due to viral infections. There is some evidence of recent Epstein-Barr virus (EBV) reactivation in patients with long-COVID,1 suggesting that the EBV rather than the SARS-CoV-2 may be causing long-COVID symptoms. This is important because chronic EBV infection has been associated with chronic fatigue syndrome. It has also been suggested that chemo-brain is due to similar mechanisms, i.e. chemotherapy triggers CNS inflammation, which causes cog-fog.

Neural plasticity

When parts of the brain are damaged by MS, other areas are co-opted to help take over, or supplement, the function of the damaged area. In other words, people with MS use more brain power than people without MS to complete the same task. This usually manifests as mental fatigue and is why people with MS have difficulty concentrating for prolonged periods and multitasking. At present we have no specific treatment for this type of fatigue, but some patients find amantadine or modafinil helpful. There is also some emerging evidence that fampridine may help with cognitive fatigue. However, preventing damage in the first place should prevent this type of fatigue.

Exercise-related conduction block

Damage to axons that conduct electrical impulses is the reason why people with MS notice their legs getting weaker or another neurological symptom getting worse with exercise. We think this is due to demyelinated or remyelinated axons failing to conduct electrical impulses when they become exhausted. Exercise-induced fatigue is probably the same as temperature-related fatigue; a rise in body temperature also causes vulnerable axons to block and stop conducting. To deal with this type of fatigue we need therapies to promote remyelination and to increase conduction. These types of fatigue are treated by rest, cooling and possibly drugs such as fampridine that improve conduction. At the heart of this type of fatigue is localised energy failure.

Fatigue from living with MS symptoms

Temperature sensitivity

Many people with MS are temperature sensitive. Typically, high temperatures worsen fatigue, but low temperatures also affect some patients. Many people with MS manipulate their behaviour to avoid hot or cold environments. Some find it helpful to use cooling suits, but these are costly and are not covered by NHS funding. Cold or ice baths, swimming and air conditioning can all help with temperature-related fatigue.

Case example

One of my patients had a walk-in butcher’s fridge installed in her house, and she spends 30 minutes there 4 ̶ 5 times a day to manage her fatigue. She is a wheelchair user, and she sits in her wheelchair in the fridge.

Menstrual and menopausal fatigue

Menstrual (or catamenial) fatigue is a form of temperature-related fatigue that occurs in women during the second half of the menstrual cycle when their body temperature increases. It responds to paracetamol and to non-steroidal anti-inflammatory drugs such as ibuprofen and naproxen. Fatigue is a common symptom of menopause too; some women with MS who are menopausal and have fatigue find hormone replacement therapy helpful. 

Whether or not men go through a ‘menopause’ is a moot point. Testosterone levels do drop with age, however, and some male patients find that testosterone replacement therapy helps their MS-related fatigue. In the UK, the indications for testosterone replacement therapy are very well defined and do not include MS-related fatigue, so most people with MS who want to try this therapy need to pay for a private prescription.

Bladder problems

Intermittent waking due to bladder problems may result in fatigue from disrupted sleep. Bladder problems may also contribute to insomnia, with the affected individual needing to visit the bathroom frequently and unable to relax into sleep. For detailed guidance on managing bladder problems, particularly at night, please see the bladder and bowel section of the website, particularly the article on nocturia.  

Insomnia due to pain and discomfort

Other disease-related factors that contribute to fatigue include insomnia from pain, discomfort of being unable to turn in bed and restless legs syndrome (RLS). RLS is common in people with MS, affects sleep quality and is associated with poor cognition. For detailed guidance on managing these MS symptoms, please see the post entitled Sleep disrupted by pain and discomfort.  

A case scenario

“A 28-year-old woman with early relapsing ̶ remitting MS, on glatiramer acetate, and little overt neurological impairment suffers from severe fatigue, which is worse during the latter half of her menstrual cycle. She has recently split up with her long-term partner because of the impact her symptoms have had on her relationship. She has also had to stop working as a bank clerk because of her fatigue.”

Prof G’s response
This patient needs to be examined and will need an MRI and a lumbar puncture to measure her spinal fluid neurofilament levels. If she has evident inflammatory disease activity, her DMT will need to be switched. She needs a full medical assessment, which includes a screen for comorbidities.

The patient complains of cognitive fatigue and, despite not having much physical disability, she was found to have a high brain MS lesion load and noticeable brain volume loss. A formal neuropsychological assessment to establish if she has cognitive impairment would allow her to be referred to a cognitive rehabilitation programme; this can target specific areas to help her cope with her cognitive deficits.

To combat fatigue during her menstrual cycle, this patient did well on naproxen, which is longer acting than ibuprofen and paracetamol. Naproxen only needs to be taken during the second half of her cycle. She was screened for poor sleep hygiene, and she volunteered intermittent early morning waking due to bladder problems and anxiety. Both would need to be addressed as part of her fatigue management programme.

It was clear that the patient had both depression and anxiety, which were related to the impact of MS on her occupational and social functioning. This must be managed with cognitive behavioural therapy (CBT), mindfulness and an exercise programme. If this approach is not helpful, then I would suggest the judicious use of an antidepressant and, failing this, a referral to a psychiatrist and/or psychologist.

Fatigue resulting from other factors

Comorbidities and other diseases

Comorbidities and other diseases related to MS can cause fatigue and should be screened for. These include infections (see above). In people with more advanced MS, the urinary tract is most often affected, but other sites of infection include the sinuses, teeth, lungs, skin (intertrigo and pressure sores) and bowels.

Fatigue is common with thyroid disease; an underactive thyroid gland (hypothyroidism) and an overactive gland (hyperthyroidism, or thyrotoxicosis) cause fatigue. Diabetes, other endocrine (hormonal) problems, anaemia and heart, kidney, liver or lung diseases all cause fatigue.

Side effects of drugs

Fatigue is a common side effect of many medications, particularly drugs that cause sedation and some DMTs. Flu-like side effects from interferon-beta, for example, may make fatigue worse. Anticholinergics and antispasticity drugs are sedating, blunt cognition and may worsen MS-related fatigue. If you have fatigue, therefore, it is important to review your medications. MS is associated with polypharmacy, but some of the medications that cause or exacerbate fatigue can be reduced in dose, stopped or potentially replaced with alternatives that don’t exacerbate fatigue.

Lack of sleep and/or sleep disorders

Poor sleep means you feel tired in the morning. Most people with MS have poor sleep hygiene and almost half have an actual sleep disorder. A clue to this is how you feel in the morning and whether you have excessive daytime sleepiness. If you wake up in the morning and don’t feel refreshed and/or you fall asleep frequently during the day, you need a formal sleep assessment. You can complete the Epworth Sleepiness Scale online to see if you have a problem.

Depression and anxiety

Fatigue is a common symptom of depression and anxiety. Of the many online screening tools for depression and anxiety, the best one to use if you have MS is probably the Hospital Anxiety and Depression Scale (HADS). 

Obesity

Being overweight requires additional energy to perform physical tasks, and obesity itself causes fatigue. Recently an association has been found between obesity and depression. Obesity also predisposes you to sleep disorders; obese people with MS are more likely to have obstructive sleep apnoea. For all these reasons you should engage with lifestyle and wellness programmes to manage obesity and fatigue. 

Deconditioning

Deconditioning is simply the term we use for being unfit. If you are unfit, performing a demanding physical task makes you tired. Deconditioning is treated with exercise, which paradoxically can reduce fatigue. Patients may claim that exercising makes their fatigue worse. Yes, that does happen, but if you persevere and get fitter your fatigue often improves. The important thing is to start a graded exercise programme and build up slowly. Exercise does some incredible things to the brain, many of which explain why it is effective at treating not only fatigue but also depression and anxiety. Exercise is a form of ‘disease-modifying therapy’ and hence everyone with MS should be participating in an exercise programme. 

Poor nutrition and ‘food coma’

Some people with MS are anorexic and eat very poorly; as a result, they have little energy. Although this is quite rare, I have had a few such patients over the years. Similarly, overnutrition may have the same effect. Some of the hormones your gut produces cause you to feel tired and want to sleep; this is the so-called siesta effect (also referred to as food coma or postprandial hypersomnolence). Reducing the size of your meals and changing your eating behaviour may improve this. Postprandial hypersomnolence has two components.

  1. A state of perceived low energy related to activation of the parasympathetic nervous system (which is part of the autonomic nervous system) in response to expansion of the stomach and duodenum from a meal. In general, the parasympathetic nervous system slows everything down. 
  2. A specific state of sleepiness triggered by the hormone cholecystokinin that helps digest food and regulate appetite. It is released in response to eating and to changes in the firing and activation of specific brain regions. The coupling, or interaction, of digestion and the brain is referred to as ‘neurohormonal modulation of sleep’ and it underlies the reflexes responsible for postprandial hypersomnolence. There is therefore a well-studied biological reason why we feel sleepy after eating a meal. 

Managing food coma – practical tips

The first patient who alerted me to the problem of food coma in MS was so affected by postprandial hypersomnolence that she now eats only one meal a day, late in the evening. She can then ‘crash’ and go to sleep about an hour after eating. She needs to be functional during the day but cannot do her professional work if she eats anything substantial during working hours because of her overwhelming desire to sleep. She has tried caffeine, modafinil and amantadine to counteract postprandial hypersomnolence, but all these substances had only a small effect.

Other patients reporting postprandial hypersomnolence derive some benefit from the judicious use of stimulants. You can start by self-medicating with caffeine, but this may have the drawback of worsening your bladder function. Please note, however, that it is not advisable to take stimulants later than about 3 pm or 4 pm because they have a long half-life and can cause insomnia.

Some patients find carbohydrate-rich foods particularly potent at inducing ‘food coma’. Indeed, glucose-induced insulin secretion is one of the drivers of this behavioural response. This may be why people who fast or eat very low-carbohydrate or ketogenic diets describe heightened alertness and an ability to concentrate for long periods. Another option is to reduce your meal size: instead of large meals, try eating multiple small snacks during the day.

Exercise has helped some patients deal with postprandial hypersomnolence. I am not sure exactly how exercise works – possibly by lowering glucose and insulin levels and improving insulin sensitivity. The latter will reduce hyperinsulinaemia, which not only causes postprandial hypersomnolence but is an important driver and component of metabolic syndrome and obesity.

Postprandial hypersomnolence will be worse if you already suffer from a sleep disorder and excessive daytime sleepiness. Most people with MS have a sleep disorder, so there is little point in focusing on postprandial hypersomnolence and ignoring the elephant in the room.

Using your energy effectively

One strategy to manage MS-related fatigue is to imagine your energy levels as a battery, i.e. you have only so much energy in the day. People with MS have smaller batteries than people without MS and therefore need to plan their day and activities to maximise their use of energy. For example, if you do something tiring in the morning, you should rest in the afternoon to conserve energy for evening activities. Similarly, if you find some activities very tiring, such as taking a hot shower or bath, plan to do this in the evening before bed.

Conclusion

It is apparent from this discussion that fatigue in MS is more complex than we realise. So be careful, or at least wary, if your neurologist simply wants to reach for the prescription pad to get you out of the consultation room. Any MS-related symptoms that can affect sleep need to be managed accordingly. Like other MS-related problems, a holistic and systematic approach is needed to manage and treat MS-related fatigue correctly. Not all fatigue is MS-related. This is why it is important to take a step backwards and ask yourself if your fatigue could be due to another disease process.

Reference

  1. Gold JE et al. Investigation of long COVID prevalence and its relationship to Epstein-Barr virus reactivation. Pathogens 2021;10:763.
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

Treatment strategy

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

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

Key points

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

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

Treat-2-target

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

When to rebaseline

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

Determining treatment failure: IRTs

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

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

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

Determining treatment failure: maintenance therapies

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

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

Beyond NEDA-3

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

Table format updated 180625 SS

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

End-organ damage

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

Alternatives to NEDA?

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

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

Implementing NEDA in clinical practice

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

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

Treat to target NEDA algorithm

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

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

References

Causes and prevention of MS

What is multiple sclerosis?

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

Key points

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

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

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

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

The cause of MS

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

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

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

Mechanisms that underlie the common manifestations of MS

Lesions

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

Relapses

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

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

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

Intermittent symptoms

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

Stretch sensitivity

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

Temperature sensitivity

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

Fatigue

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

Worsening MS (also called progressive MS)

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

Ageing and MS

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

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

References

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

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

  1. Fisher E, et al. Gray matter atrophy in multiple sclerosis: a longitudinal study. Ann Neurol 2008;64:255–65.
  2. Barkhof F, et al. Imaging outcomes for neuroprotection and repair in multiple sclerosis trials. Nat Rev Neurol 2009;5:256–66.
  3. Simon JH. Brain atrophy in multiple sclerosis: what we know and would like to know. Mult Scler 2006;12:679–87.
  4. Ziemssen T, et al. Optimizing treatment success in multiple sclerosis. J Neurol 2016;263:1053–65.
  5. Hickman SJ, et al. Detection of optic nerve atrophy following a single episode of unilateral optic neuritis by MRI using a fat-saturated short-echo fast FLAIR sequence. Neuroradiology 2001;43:123–8.
  6. Trapp BD, et al. Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998;338:278–85.
  7. Peterson JW, et al. Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol 2001;50:389–400.
  8. Orme M, et al. The effect of disease, functional status, and relapses on the utility of people with multiple sclerosis in the UK. Value Health 2007;10:54–60.
  9. Pfleger CC, et al. Social consequences of multiple sclerosis (1): early pension and temporary unemployment – a historical prospective cohort study. Mult Scler 2010;16:121–6.
  10. Kobelt G, et al. Costs and quality of life of patients with multiple sclerosis in Europe. J Neurol Neurosurg Psychiatry 2006;77:918–26.
  11. Feuillet L, et al. Early cognitive impairment in patients with clinically isolated syndrome suggestive of multiple sclerosis. Mult Scler 2007;13:124–7. 
  12. Confavreux C and Compston A. Chapter 4. The natural history of multiple sclerosis. In: McAlpine’s Multiple Sclerosis, Fourth Edition, 2006; 183 ̶ 272. Churchill Livingstone.
  13. Weinshenker BG et al. The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability. Brain 1989;112:133 ̶ 46.
  14. Torkildsen GN, et al. Survival and cause of death in multiple sclerosis: results from a 50-year follow-up in Western Norway. Mult Scler 2008;14:1191–8.
  15. Kingwell E, et al. Relative mortality and survival in multiple sclerosis: findings from British Columbia, Canada. J Neurol Neurosurg Psychiatry 2012;83:61–6.
  16. Sadovnick AD, et al. Cause of death in patients attending multiple sclerosis clinics. Neurology 1991;41:1193–6.
  17. Brenner P, et al. Multiple sclerosis and risk of attempted and completed suicide – a cohort study. Eur J Neurol 2016;23:1329–36. 

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

What prognostic group do I fall into?

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

Key points

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

Predicting MS outcomes: an imperfect science

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

Three broad prognostic categories

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

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

Given sufficient time, most people with MS will 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.