Multiple sclerosis (MS) is a cell-mediated autoimmune condition characterised by repeated episodes of inflammation of the nervous tissue in the brain and spinal cord, causing loss of the insulating myelin sheath.
Multiple areas of scar tissue (sclerosis) form along the neurons. This slows or blocks the transmission of signals to and from the brain and spinal cord. In this way movement and sensation may be impaired.
The causes of MS are not completely understood but the autoimmune process appears to be caused both by genetic and environmental factors - eg, viral infections in early life. Minor viral infections frequently precipitate relapses.
There are different patterns of MS:
- Relapsing-remitting MS: symptoms come and go. Periods of good health or remission are followed by sudden symptoms or relapses (80% of people at onset).
- Secondary progressive MS: follows on from relaxing-remitting MS. There are gradually more or worsening symptoms with fewer remissions (about 50% of those with relapsing-remitting MS develop secondary progressive MS during the first ten years of their illness).
- Primary progressive MS: from the beginning, symptoms gradually develop and worsen over time (10-15% of people at onset).
Acute attacks are followed by periods of remission when there is remyelination but, with advancing disease, this process begins to fail and periods of remission are less frequent.
Clinically isolated syndrome (CIS) corresponds to the typical first MS episode, especially when associated with other asymptomatic demyelinating lesions, without clinical, radiological and immunological sign of any differential diagnosis. After a CIS, the delay before a relapse, which corresponds to the conversion to clinically definite MS, varies from several months to more than 10 years. 10-15% of patients have benign relaxing-remitting MS or 'benign MS'. Benign MS is a variation of relapsing-remitting MS where relapses are very mild, there are very long periods between relapses and/or only a few relapses ever occur.
Radiologically isolated syndrome (RIS) was defined in 2009 for asymptomatic patients who presented incidentally identified white matter anomalies within the central nervous system suggestive of MS. Approximately one third of people with RIS will develop a clinical demyelinating event within five years of the identification of their abnormal MR[2, 3].
- MS estimated prevalence is 190 cases per 100,000 population.
- MS is more than twice as common in females than males.
The highest prevalence for MS occurs in the 60 to 69 years age group for both sexes.
- The MS estimated incidence in England is between 8 and 11 new cases per 100,000 population.
- The highest proportion of new female cases occurs in the 30 to 34 years and 40 to 44 years age groups. The highest proportion of new recorded diagnoses in males is in the 45 to 49 years age group.
- Family history - about 2% of people with a first-degree relative with MS will develop the condition.
- There is no evidence that pregnancy influences the overall course of the condition over time. Women with MS who wish to become pregnant should be advised that the risk of relapse decreases during pregnancy and increases transiently postpartum.
- There is no single specific diagnostic test available. The diagnosis can be made clinically (by a consultant neurologist) in most people and an MRI scan should not be used in isolation to make the diagnosis.
- If there is doubt about the diagnosis, further investigation should be used to exclude an alternative diagnosis or find evidence that supports the diagnosis of MS.
- Dissemination in space should be confirmed, if necessary, using an MRI scan, interpreted by a neuroradiologist, using agreed criteria - eg, the revised McDonald criteria.
Two or more relapses, and either:
- Objective clinical evidence of two or more lesions; or
- Objective clinical evidence of one lesion together with reasonable historical evidence of a previous relapse.
Two or more relapses; objective clinical evidence of one lesion (dissemination in time), plus dissemination in space shown by:
- One or more MRI detected lesions typical of MS; or
- A further relapse showing damage to another part of the CNS.
One relapse; objective clinical evidence of two or more lesions (dissemination in space), plus dissemination in time shown by:
- Oligoclonal bands; or
- MRI evidence of a new lesion since a previous scan; or
- A further relapse.
One attack/relapse; objective clinical evidence of one lesion (clinically isolated syndrome), plus:
- Dissemination in space shown by:
- One or more MRI detected lesions typical of MS; or
- A further relapse showing activity in another part of the CNS.
- Dissemination in time shown by:
- Oligoclonal bands; or
- MRI showing new lesions since a previous scan; or
- A further relapse.
Insidious neurological progression suggestive of MS (typical for primary progressive MS), plus any two of:
- One or more MRI detected lesions in the brain typical of MS.
- Two or more MRI detected lesions in the spinal cord.
- Oligoclonal bands in the spinal fluid.
There is a wide range of symptoms and signs. The most common features are:
- Very common, usually due to demyelination of the optic nerve.
- Can cause sight impairment or hemianopia.
- Optic neuritis is an acute, sometimes painful, reduction or loss of vision in one eye and is a relatively common presenting symptom of MS.
- Eye movements:
- Very common - may cause double vision.
- The most frequent sign is symmetrical horizontal jerking nystagmus.
- Also common is lateral rectus weakness. See the separate Diplopia and III, IV and VI Cranial Nerve Lesions article.
- Facial weakness:
- Bell's palsy can occur alone or with other indications of brainstem disorder.
- Other features may include one or more of trigeminal neuralgia, paroxysmal dysarthria and ataxia (with a clumsy arm, disturbed sensation and painful tetanic posturing of the limb, lasting 1-2 minutes).
- There may be other paroxysmal symptoms, which may include one or more of the following: bursts of pain, bursts of paraesthesia, itching, cough, hiccup, painful spasm and complex gaze palsies.
- Hearing and balance:
- Deafness can occur and feelings of unsteadiness are common.
- Acute demyelination in the brainstem causes severe positional vertigo, vomiting, ataxia and headache.
- Cognitive symptoms:
- Visual and auditory attention may be affected, occasionally in the early stages.
- Effects on intelligence increase with duration of the disease and onset of the progressive phase, causing loss of memory more than language skills.
- Psychological symptoms:
- Psychotic symptoms are rare but depression is common.
- Taste and smell:
- Frequently found if specifically looked for.
- Unpleasant sensations:
- Tightness, burning, twisting, tearing and pulling sensations may be reported due to damage to the posterior columns in the cervical cord.
- When the spinothalamic tract is involved this causes loss of thermal and pain sensation.
- Nonspecific tingling is common.
- Paraesthesiae and numbness:
- Loss of sensation in the legs ascending to the trunk is caused when spinal nerves of the dorsal or lumbar segments are affected.
- May be sacral sparing but a characteristic feature in MS is numbness of the perineum and genitalia with altered sphincter function.
- Transverse myelitis:
- An acute episode of weakness or paralysis of both legs, with sensory loss and loss of control of bowels and bladder; requires urgent hospital admission.
- Autonomic system:
- Bladder symptoms: loss of inhibition of reflex bladder emptying causes urgency and frequency with incontinence when there is associated immobility. May alternatively be impaired bladder emptying. Faecal incontinence due to impaired rectal sphincter is less common.
- Sexual problems: impotence is common in men; there may also be problems of spasticity, altered sensation and problems with indwelling catheters.
- Loss of thermoregulation: excess sweating, pyrexia or hypothermia.
- Other symptoms:
- These include Horner's syndrome, abnormal cardiac rhythm, abnormal vascular responses (with acute pulmonary oedema), weight loss, and inappropriate antidiuretic hormone (ADH) secretion.
- Hereditary spastic paraplegia: mimics familial MS; other inherited diseases can also appear as MS.
- Cerebral variant of systemic lupus erythematosus (SLE) can present with features of MS without other clinical manifestations of SLE.
- In patients of African or Asian origin, alternative diagnoses should be considered - eg, AIDS, tropical spastic paraplegia or neuromyelitis optica.
- Before referring to a neurologist, exclude differential diagnoses by checking FBC, inflammatory markers, U&E, LFT, TFT, glucose, HIV serology, calcium and B12 levels.
- Electrophysiology: can detect demyelination in apparently unaffected pathways with characteristic delays. Visual evoked potential studies should be the first choice.
- MRI scan: 95% of patients have periventricular lesions and over 90% show discrete white matter abnormalities. Areas of focal demyelination can also be seen as plaques in the optic nerve, brainstem and spinal cord. By using a contrast agent, active inflammatory plaques can be distinguished from inactive ones. The number and size of lesions do not correlate well with disease activity or progress. It also excludes other lesions producing the symptoms.
- Cerebrospinal fluid: rise in total protein with increase in immunoglobulin concentration with presence of oligoclonal cases.
The management of people with MS should include:
- Good communication with patients and their carers.
- Provision of written information regarding the disease, treatments and available help and support.
- Informing them of their legal obligation to notify the DVLA of their condition.
- Ensuring all available help and support with rehabilitation, employment and mobility.
- Encouraging autonomy/self-management.
- Support to the family and carers, including respite care.
- Close co-operation and communication between all health professionals involved in caring for the person (including their GP, nurse specialists and specialists).
- Any episode of sudden increase (ie over 12-24 hours) in distressing symptoms or an increased limitation on activities should be assessed promptly. Symptoms should be discussed with a clinician with expertise in MS to decide whether oral or intravenous (IV) methylprednisolone treatment is required. A urinary tract infection should be excluded as the cause of the exacerbation of symptoms before steroids are considered. The course should be started as soon as possible after onset of the relapse:
- The usual dose is 500 mg/day methylprednisolone for five days. This is given as a day-case treatment but admission may be arranged if required by the patient.
- IV infusion is given over four hours. Oral medication (as 5 x 100 mg tablets) is also available.
- Patients often notice an unpleasant metallic taste with this treatment.
- It is no longer considered necessary to taper doses down after this course.
- Gastric protection should be provided by ranitidine 150 mg bd, or omeprazole 20 mg daily.
- The use of steroids on more than three occasions per year, or for longer than three weeks on any one occasion, should be avoided.
NB. Any woman receiving disease-modifying therapy (eg, interferon) must stop treatment for at least 12 months before trying to conceive.
Disease-modifying drugs are the recommended treatment for active relapsing-remitting multiple sclerosis. Interferon beta and glatiramer acetate may be preferred because of their established safety profile, and long-term clinical experience associated. Peginterferon beta-1a requires less frequent administration. Teriflunomide and dimethyl fumarate are also treatment options for patients with active disease. More active disease may be treated with natalizumab or alemtuzumab. In May 2019, the MHRA published restrictions on the use of alemtuzumab due to reports of serious cardiovascular and immune-mediated reactions. Natalizumab may be preferred due to the complex safety profile associated with alemtuzumab. Natalizumab is only recommended for the treatment of rapidly-evolving severe relaxing-remitting MS. Fingolimod is the recommended treatment for patients with highly active disease.
- Interferon beta:
- This is licensed for use in patients with relacing-remitting MS (characterised by at least two attacks of neurological dysfunction over the previous two or three years, followed by complete or incomplete recovery) who are able to walk 100 m unaided. Not all patients respond and a deterioration in the bouts has been observed in some.
- Interferon beta-1b is also licensed for use in patients with secondary progressive MS. However immunomodulatory strategies used for relaxing-remitting MS, such as beta interferon, have not proven effective when extended into secondary progressive MS.
- Interferon beta-1a is recommended by the National Institute for Health and Care Excellence (NICE) as an option for treating MS, only for relaxing-remitting MS. Interferon beta-1b (Extavia®) is recommended by NICE as an option for treating MS, only for relapsing-remitting MS with two or more relapses within the previous two years, or for secondary progressive MS with continuing relapses.
- This is licensed for reducing the frequency of relapses in ambulatory patients with relapsing-remitting MS who have had at least two clinical relapses in the previous two years.
- It is given daily by subcutaneous injection. Injection site reactions are common, as are flu-like symptoms. These decrease over time.
- Glatiramer acetate is recommended by NICE as an option for treating MS, only for relapsing-remitting MS.
- Dimethyl fumarate:
- Dimethyl fumarate is recommended by NICE as an option for treating adults with active relapsing‑remitting MS (two clinically significant relapses in the previous two years) but only if they do not have highly active or rapidly evolving severe relapsing‑remitting MS.
- Teriflunomide is recommended by NICE as an option for treating adults with active relapsing-remitting MS (normally defined as two clinically significant relapses in the previous two years), only if they do not have highly active or rapidly evolving severe relapsing-remitting MS.
- Also recommended by NICE as an option for treating adults with active relapsing-remitting MS.
- This is a recombinant humanised monoclonal antibody, produced in murine myeloma cells. NICE approval was granted in August 2007. It is given monthly by IV infusion.
- The first oral therapy for MS. Approved by NICE in April 2012.
- There is a great deal of anecdotal evidence for the therapeutic benefits of cannabis for a variety of MS symptoms, including spasticity, tremor, bladder problems and pain.
- Sativex® oromucosal spray is now licensed in the UK on a named patient basis.
- NICE recommends that THC:CBD spray (Sativex®) can be offered as a four-week trial to treat moderate to severe spasticity in adults with MS if other pharmacological treatments for spasticity are not effective. After the four-week trial, THC:CBD spray can be continued if the person has had at least a 20% reduction in spasticity-related symptoms on a 0 to 10 patient-reported numeric rating scale.
- First consider and treat any underlying causes - eg, depression, disturbed sleep, chronic pain and poor nutrition.
- Advise fatigue may become worse with heat and stress.
- Medication should also be reviewed; some medications (eg, interferon beta) have fatigue as a side-effect.
- Advise that aerobic exercise or yoga may be beneficial.
- Offer amantadine for fatigue but also consider mindfulness-based training or cognitive behavioural therapy (CBT).
- This may be of neuropathic origin or from musculoskeletal problems, secondary to reduced mobility.
- It may need suitable analgesia and, if still a problem, transcutaneous electrical nerve stimulation (TENS) or antidepressant medication.
- Cognitive behavioural and imagery treatment methods may also be beneficial.
- Neuropathic pain should be treated using anticonvulsants such as carbamazepine or gabapentin, or using antidepressants such as amitriptyline.
Visual and communication
- Difficulty in reading or seeing television is not uncommon and the usual reason (other than the lack of glasses) is that the control over eye movement is poor.
- Actual loss of visual function due to optic neuritis is rare.
- Visual disturbance associated with MS requires an ophthalmological opinion.
- The patient should be assessed for glasses by an optometrist and, if necessary, at a specialist ophthalmology clinic.
- If nystagmus is causing reduced visual acuity or other visual symptoms, offer a trial of treatment with oral gabapentin (initiated and monitored in a specialist clinic).
- May need low-vision equipment and adaptive technology and require to be registered as sight impaired.
- Dysarthria may cause great difficulty. This should be assessed and advice given by a specialist speech and language therapist.
- May need alternative non-verbal means of assisting with or replacing speech.
- Weakness and cardiorespiratory fitness:
- Exercises and techniques to maximise strength and endurance appropriate to their circumstances, including aerobic training.
- Motor weakness may require equipment - eg, orthoses or specialist supportive equipment for postural difficulties.
- Spasticity and spasms:
- Consider and explore possible aggravating factors - eg, pain, infection.
- Advice on physical techniques - eg, passive stretching, to reduce spasticity and avoid the development of contractures.
- Baclofen or gabapentin are the drugs of choice if required.
- Tizanidine and dantrolene are recommended second-line treatments if treatment with baclofen or gabapentin is unsuccessful or the side-effects are intolerable. Benzodiazepines may be used as third-line agents. There are only poor-quality data regarding the comparative efficacy and tolerability of anti-spasticity agents and a Cochrane review concluded that no recommendations could be made to guide prescribing.
- Troublesome spasticity and spasms should be assessed by a specialist team. Intramuscular botulinum toxin can be considered for relatively localised hypertonia or spasticity that is not responding to other treatments.
- THC:CBD spray (Sativex®) can be offered as a four-week trial to treat moderate to severe spasticity in adults with MS if other pharmacological treatments for spasticity are not effective (see above).
- Contractures at joints: specific treatments include prolonged stretching - eg, with serial plaster casts.
- Ataxia and tremor:
- Should be assessed by a specialist rehabilitation team.
- If problems remain severe and intractable, the person should also be assessed by a neurosurgical team for suitability for operative intervention.
- Pressure ulcers:
- Many people with MS are at high risk of developing pressure ulcers because of, for example, limited mobility, impairment of sensory functioning and reduced cognitive function.
- Most pressure ulcers can be avoided.
- Bladder symptoms: check for underlying urinary tract infection and assess postmicturition residual bladder volume by ultrasound.
- Urgency or urge incontinence:
- Offer convene drain (for men) or pads (for women); consider toilet arrangements (eg, a commode downstairs) and intermittent self-catheterisation if there is a high residual volume.
- Consider anticholinergics (eg, oxybutynin, tolterodine).
- Desmopressin may be used for night problems or to control urinary frequency during the day but should never be used more than once in 24 hours.
- Continued incontinence, despite treatment, can be treated by a course of pelvic floor exercises preceded by a course of electrical stimulation of the pelvic floor muscles.
- Continued bladder symptoms may require intermittent self-catheterisation or longer-term urethral catheterisation. Suprapubic catheterisation is useful if active sexual function is wanted.
- Urgency, pain, constipation or incontinence may occur.
- Faecal incontinence may be due to constipation with overflow, possibly exacerbated by laxative use.
- Constipation may require the routine use of suppositories or enemas.
- Swallowing difficulties:
- Dysphagia may lead to choking and aspiration of food or liquid, leading to chest infections.
- Assessment is advised if there are any symptoms or chest infections.
- Should be assessed by a specialist speech and language therapist and given advice on specific swallowing techniques and on adapting food consistencies and dietary intake.
- May need further assessment (eg, by videofluoroscopy), possibly short-term nutritional support via nasogastric tube or percutaneous endoscopic gastrostomy (PEG) tubes.
- Cognitive losses:
- About half of all people with MS may have impaired ability to learn and remember, to plan, to concentrate and to handle information quickly.
- If such problems occur, review medication and assess for depression.
- A formal neuropsychological assessment by a specialist clinical psychologist (and speech and language therapist if appropriate).
- May cry or laugh with minimal provocation and with little control.
- A full assessment of their emotional state may be required and antidepressant medication and/or advice on behavioural management strategies may be beneficial.
- Assessment should include all contributory factors (eg, chronic pain or social isolation) and consideration of interventions to ameliorate these.
- Antidepressant medication or CBT should be considered as part of an overall programme.
- Anxiety: may require psychologically based treatment or medication such as antidepressants or very short-term benzodiazepines.
- May disturb the normal sexual physiology and it may result in other impairments (such as spasms) that make normal sexual behaviour difficult.
- If sexual dysfunction is persistent, specific treatments (eg, sildenafil) should be offered and discussed.
- Male sexual dysfunction: erectile dysfunction needs full assessment of possible causes such as anxiety and, possibly, medication.
- Female sexual dysfunction: full assessment of general and specific underlying factors that might cause or worsen sexual dysfunction and that are amenable to treatment.
- Infections may be associated with a worsening of disability and may trigger a relapse. People with MS should be offered immunisation against influenza. People with relapsing-remitting MS should be warned that vaccination may trigger a relapse.
- Complementary therapies: there is some evidence to suggest possible benefit from some complementary therapies - eg, reflexology and massage.
- People with MS should be advised that linoleic acid 17-23 g/day may reduce progression of disability.
- Fish oils may also be beneficial.
- Patients may spend many years in each of these phases or quickly progress to one of fixed progressive disability. Approximately 25% of patients have a non-disabling form of MS. 5% of patients have frequently recurring relapses without recovery, rapidly causing disability and early death. Up to 15% of patients are severely disabled within a short period.
- Episodes occur initially at approximately 1.5/year with recovery being slower than onset of symptoms (and may be incomplete). Secondary progressive MS tends to affect those systems previously involved in a relapsing-remitting stage.
- 20% of cases are progressive from onset (primary progressive) - this is mainly in older patients and these have a poorer prognosis.
- Relapse rate is reduced during pregnancy but increases again after delivery.
Further reading and references
Multiple sclerosis; NICE Quality Standard (January 2016)
Filippini G, Del Giovane C, Clerico M, et al; Treatment with disease-modifying drugs for people with a first clinical attack suggestive of multiple sclerosis. Cochrane Database Syst Rev. 2017 Apr 254:CD012200. doi: 10.1002/14651858.CD012200.pub2.
Thouvenot E; Update on clinically isolated syndrome. Presse Med. 2015 Apr44(4 Pt 2):e121-36. doi: 10.1016/j.lpm.2015.03.002. Epub 2015 Mar 23.
Yamout B, Al Khawajah M; Radiologically isolated syndrome and multiple sclerosis. Mult Scler Relat Disord. 2017 Oct17:234-237. doi: 10.1016/j.msard.2017.08.016. Epub 2017 Aug 31.
Lebrun C, Kantarci OH, Siva A, et al; Anomalies Characteristic of Central Nervous System Demyelination: Radiologically Isolated Syndrome. Neurol Clin. 2018 Feb36(1):59-68. doi: 10.1016/j.ncl.2017.08.004.
Multiple sclerosis: prevalence, incidence and smoking status; Public Health England. February 2020.
Multiple sclerosis: management of multiple sclerosis in primary and secondary care; NICE clinical guideline (October 2014 - last updated November 2019)
Thompson AJ, Banwell BL, Barkhof F, et al; Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018 Feb17(2):162-173. doi: 10.1016/S1474-4422(17)30470-2. Epub 2017 Dec 21.
British National Formulary (BNF); NICE Evidence Services (UK access only)
Beta interferon and glatiramer acetate for treating multiple sclerosis; NICE Technology Appraisal Guidance (TA527), June 2018
Dimethyl fumarate for treating relapsing‑remitting multiple sclerosis; NICE Technology Appraisal Guidance, August 2014
Teriflunomide for treating relapsing–remitting multiple sclerosis; NICE Technology Appraisal Guidance, January 2014
Alemtuzumab for treating relapsing‑remitting multiple sclerosis; NICE Technology Appraisal Guidance, May 2014
Natalizumab for the treatment of adults with highly active relapsing-remitting multiple sclerosis; NICE Technology Appraisal Guidance, August 2007
Fingolimod for the treatment of highly active relapsing–remitting multiple sclerosis; NICE Technology Appraisal Guidance, April 2012
Cannabis-based medicinal products; NICE Guidance (November 2019)
Shakespeare DT, Boggild M, Young C; Anti-spasticity agents for multiple sclerosis. Cochrane Database Syst Rev. 2003(4):CD001332.