Tag Archives: limb

Understanding and managing insomnia in MS

26/03/2025 Gavin Giovannoni

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

Key points

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

Sleep, glorious sleep!

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

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

Causes and impact of insomnia

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

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

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

Approaches to managing insomnia

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

Recording your sleep patterns

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

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

Sleep hygiene

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

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

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

Over-the-counter sleep aids

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

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

Prescription-only sleep aids

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

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

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

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

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

Cognitive approaches to managing insomnia

Cognitive Behavioural Therapy for Insomnia (CBTI)

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

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

Brief behavioural treatment for insomnia

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

eCBTI

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

Complementary and alternative therapies

Sleep restriction

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

Stimulus control

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

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

Relaxation training

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

Cognitive therapy

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

Sleep hygiene education

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

Acceptance and commitment therapy (ACT)

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

Mindfulness

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

Conclusion

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

Causes and prevention of MS

What is multiple sclerosis?

15/08/2022 Gavin Giovannoni

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

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

DMTs, Treatment strategy

Am I eligible for an MS disease-modifying therapy?

28/06/2022 Gavin Giovannoni

Key points

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

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

What do disease-modifying drugs do?

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

Is interferon a DMT?

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

Do symptomatic treatments modify the disease?

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

Who decides on eligibility for a licensed DMT?

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

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

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

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

How does disease activity affect my treatment options?

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

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

Advanced or progressive MS

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

Stages of MS currently not eligible for treatment

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

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

The importance of upper limb function

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

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

References

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