Multiple Sclerosis

Definition

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.


Pathogenesis

Multiple areas of scar tissue (sclerosis) form along the neurones. 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 by both genetic and environmental factors, e.g. viral infections in early life. Minor viral infections frequently precipitate relapses.

There are different patterns of multiple sclerosis (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 relapsing/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 10 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.


Epidemiology

The global distribution of multiple sclerosis (MS) can be generalised as increasing with distance north or south of the equator, but that summary conceals many places with disproportionately high or low frequencies.


  • MS usually starts in early adult life.
  • About 1 in 1,000 population have MS.
  • Female to male ratio is 3:2.
  • Caucasians have the highest risk.

Risk factors

  • Family history, 4% of people with a first-degree relative with MS will develop the condition. 20% of MS patients have an affected relative.
  • 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.

Diagnosis

  • There is no single specific diagnostic test available.1 The diagnosis can be made clinically 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 multiple sclerosis (MS).
  • Dissemination in space should be confirmed, if necessary, using an MRI scan, interpreted by a neuroradiologist, using agreed criteria, e.g. those described by McDonald et al:2
    • Objective evidence of dissemination in time and space of lesions typical of MS is mandatory, as is the exclusion of other, better explanations for the clinical features.
    • Historical reports of symptoms may suggest previous episodes of demyelination, but cannot be used without objective evidence to satisfy the requirement of lesions disseminated in time and space.
    • MS can be diagnosed on purely clinical evidence of lesions separated in time and space.
    • MRI and laboratory evidence are desirable and may be essential where clinical evidence is insufficient for a secure diagnosis.
    • The choice of investigation will be determined by the clinical situation, e.g. a delayed visual evoked potential is of value in a person with a spinal cord lesion but is of little value in a person with optic neuritis.
    • MRI scanning is less useful in older people and in other inflammatory conditions, e.g. acute encephalomyelitis where its specificity is lower.
  • Dissemination in space may also be confirmed using evoked potential studies; visual evoked potential studies should be the first choice.

Presentation

There is a wide range of symptoms and signs. The most common features are:

  • Visual:
    • Very common, usually due to demyelination of the optic nerve.
    • Can cause blindness 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 multiple sclerosis (MS).
  • Eye movements:
  • Facial weakness:
    • Bell's palsy can occur alone or with other indications of brainstem disorder.
    • There may also be trigeminal neuralgia, or 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, including bursts of pain and paraesthesia, itching, cough and 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.
  • Paraesthesias 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 ADH secretion.

Differential diagnosis

  • Hereditary spastic paraplegia: mimics familial multiple sclerosis (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.
  • Sarcoidosis.
  • In patients of African or Asian origin, alternative diagnoses should be considered, e.g. AIDs, tropical spastic paraplegia or neuromyelitis optica.

Investigations

  • 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. Can also see areas of focal demyelination as plaques in the optic nerve, brainstem and spinal cord. Can distinguish active inflammatory plaque from inactive ones by using contrast. The number and size of lesions does not correlate well with disease activity or progress. Also excludes other lesions producing the symptoms.
  • Cerebrospinal fluid: rise in total protein with increase in immunoglobulin concentration with presence of oligoclonal cases.

Management

General measures

The management of people with multiple sclerosis (MS) should include:1

  • Good communication with patients and their carers.
  • Provision of all information regarding the disease, treatments and available help and support.
  • 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).

Pharmacological

  • Relapses:
    • Any episode of sudden increase (ie over 12-24 hours) in distressing symptoms or an increased limitation on activities should be assessed promptly and referred for oral or intravenous (IV) methylprednisolone treatment. 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:[1]
      • 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.[1]
    • There is some evidence that azathioprine is beneficial in reducing relapses and progression of MS, and is therefore an appropriate maintenance treatment for patients with MS who frequently relapse and require steroids.[3]
  • Disease-modifying therapy:
    • Interferon beta:
      • This is licensed for use in patients with relapsing, 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 but its role in this condition has not been confirmed.
      • It is given by subcutaneous (Rebif® and Betaferon®) or intramuscular (Avonex®) injection. Preparations vary but can be alternate days (Betaferon®), three times per week (Rebif®) or weekly (Avonex®).
      • The most commonly reported side-effect is a flu-like ague for 24 hours after the injection, which is effectively treated with ibuprofen. This lessens over time. Injection site reactions also occur, but can be minimised with good technique and rotation of sites.
      • 10 years of clinical experience show a 30-40% relapse reduction.[4][5] There is some evidence for greater efficacy with Betaferon® and Rebif®, compared with Avonex®.[6]
    • Glatiramer (Copaxone®):
      • 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 designed to mimic the effects of the main proteins in myelin.
      • Eight years of clinical experience show a 30% relapse reduction rate.[7]
      • It is given daily by subcutaneous injection.
      • Injection site reactions are common, as are flu-like symptoms. These decrease over time.
      • Sporadic, short-lived chest tightness and shortness of breath have been reported.
    • Any woman receiving disease-modifying therapy, eg interferon, must stop treatment for at least twelve months before trying to conceive.
    • The National Institute for Health and Clinical Excellence (NICE) does not recommend either interferon beta or glatiramer acetate[8] but the Department of Health, the National Assembly for Wales, the Scottish Executive, the Northern Ireland Department of Health, Social Services and Public Safety, and the manufacturers have reached agreement on a risk-sharing scheme for the NHS supply of interferon beta and glatiramer acetate for MS.[9]
  • Second-line therapies:
    • Natalizumab (Tysabri®):
      • 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.
      • There is 68% relapse reduction.[10]
      • It is well-tolerated, but there have been several cases of progressive multifocal leukoencephalopathy (PML) in treated patients. Risk is currently estimated to be 1 in 600 cases, increasing with the number of treatments received. PML is thought to be caused by the John Cunningham (JC) virus.[11][12]
    • Fingolimod (Gilenya®):
      • The first oral therapy for MS. Approved by NICE April 2012.[13]
      • It works by preventing lymphocyte movement across the blood-brain barrier and causes a reversible lymphopenia.
      • It reduces the rate of relapses by 50% compared to placebo.[14]
      • The dose is 0.5 mg/day. Possible side-effects include first dose bradycardia, macular oedema and increased risk of infection.
    • Campath-1H®:
      • This works by destroying T cells. Is also used in leukaemia and treatment of organ rejection. It is given as IV infusion - daily for five days, once a year.
      • There is 90% reduction in agressive MS.[15]
      • There is no reduction in long-term disability in secondary progressive MS.
      • There is risk of rebound autoimmune problems, eg thyroid or idiopathic thrombocytopenic purpura.
      • There is a possible long-term risk of lymphopenia.
    • Mitoxantrone:
      • This is a cytotoxic immunosuppressant.
      • It is given by monthly infusion.
      • There is 70-90% reduction in very active MS relapses.[16]
      • There is a possible risk of cumulative cardiotoxicity after 2-3 years.
      • There is a 1 in 400 risk of late leukaemia.
  • Other treatments:
    • Cannabinoids:
      • 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.
      • However, convincing evidence that cannabinoids are effective in MS is still lacking.[17]
      • Sativex® oromucosal spray is now licensed in the UK on a named patient basis.
    • Percutaneous venoplasty:
      • Venoplasty (with or without stenting) is being used in some (non-NHS) centres. The theory is based on the premise that MS is partly caused by chronic insufficiency in the venous drainage of the brain.
      • This treatment is yet unproven and further research is required. See Internet and further reading, below.

General problems

  • Fatigue:
    • First consider and treat any underlying causes, e.g. depression, disturbed sleep, chronic pain and poor nutrition.
    • Medication should also be reviewed; some medications, e.g. beta interferon, have fatigue as a side-effect.
    • General advice, including aerobic exercise.
    • Several studies have shown some benefit with amantadine,15 although a recent Cochrane review was equivocal about its benefit and tolerability.16 It is an alternative for patients who do not respond to or cannot tolerate modafinil.15 Modafinil has been shown to be effective in some studies.
  • Pain:
    • 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

  • Visual problems:
    • 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 partially sighted.
  • Speech difficulties:
    • Dysarthria may cause great difficulty. Should be assessed and given advice by a specialist speech and language therapist.
    • May need alternative nonverbal means of assisting with or replacing speech.

Motor problems

  • Weakness and cardiorespiratory fitness:
    • Exercises and techniques to maximise strength and endurance appropriate to their circumstances, including aerobic training.
    • Motor weakness may require equipment, e.g. orthoses, or specialist supportive equipment for postural difficulties.
  • Spasticity and spasms:
    • Consider and explore possible aggravating factors, e.g. pain, infection.
    • Advice on physical techniques, e.g. passive stretching, to reduce spasticity and avoid the development of contractures.
    • Baclofen or gabapentin are the drugs of choice if required.
    • Other drugs, including tizanidine, clonazepam, or dantrolene should only be used if treatment with baclofen or gabapentin is unsuccessful or the side-effects are intolerable. 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.17
    • 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.
  • Contractures at joints: specific treatments include prolonged stretching, e.g. 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.

Urological

  • Bladder symptoms: check for underlying urinary tract infection and assess postmicturition residual bladder volume by ultrasound.18
  • Urgency or urge incontinence:
    • Offer convene drain (for men) or pads (for women), consider toilet arrangements (e.g. commode downstairs), intermittent self-catheterisation if there is a high residual volume, anticholinergics (e.g. 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.

Gastroenterological

  • 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, e.g. by videofluoroscopy, possibly short-term nutritional support via nasogastric tube or percutaneous endoscopic gastrostomy (PEG) tubes.

Higher functions

  • 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).
  • Emotionalism:
    • 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.
  • Depression:
    • Assessment should include all contributory factors, e.g. chronic pain or social isolation, and consideration of interventions to ameliorate these.
    • Antidepressant medication or cognitive behavioural therapy 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.

Sexual dysfunction

  • 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, e.g. 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.

Other considerations

  • Infections may be associated with a worsening of disability and may trigger a relapse. People with MS should be offered immunisation against influenza.
  • Complementary therapies: there is some evidence to suggest possible benefit from some complementary therapies, e.g. 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.

Prognosis

  • 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 multiple sclerosis (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 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 & references

  1. Multiple Sclerosis - Management of multiple sclerosis in primary and secondary care, NICE Guidance (November 2003)
  2. Compston A, Coles A; Multiple sclerosis. Lancet. 2008 Oct 25;372(9648):1502-17. [abstract]
  3. Casetta I, Iuliano G, Filippini G; Azathioprine for multiple sclerosis. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD003982. [abstract]
  4. Portaccio E, Zipoli V, Siracusa G, et al; Response to interferon-beta therapy in relapsing-remitting multiple sclerosis: a comparison of different clinical criteria. Mult Scler. 2006 Jun;12(3):281-6. [abstract]
  5. Embrey N. Beta interferon therapy in multiple sclerosis: an audit of patients in North Staffordshire Hospital Trust; 2002
  6. Etemadifar M, Janghorbani M, Shaygannejad V; Comparison of Betaferon, Avonex, and Rebif in treatment of relapsing-remitting multiple sclerosis. Acta Neurol Scand. 2006 May;113(5):283-7. [abstract]
  7. Achiron A, Fredrikson S; Lessons from randomised direct comparative trials. J Neurol Sci. 2009 Feb 1;277 Suppl 1:S19-24. [abstract]
  8. Multiple sclerosis - beta interferon and glatiramer acetate, NICE Technology Appraisal Guidance (January 2002)
  9. Cost Effective Provision of Disease Modifying Therapies for People with Multiple Sclerosis, Department of Health Service Circular, 2002
  10. Klawiter EC, Cross AH, Naismith RT; The present efficacy of multiple sclerosis therapeutics: Is the new 66% just the Neurology. 2009 Sep 22;73(12):984-90. [abstract]
  11. Fox R; Advances in the management of PML: focus on natalizumab. Cleve Clin J Med. 2011 Nov;78 Suppl 2:S33-7. [abstract]
  12. Bloomgren G, Richman S, Hotermans C, et al; Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med. 2012 May 17;366(20):1870-80. [abstract]
  13. Multiple sclerosis (relapsing-remitting) - fingolimod, NICE Technology Appraisal Guideline (April 2012)
  14. Tsang BK, Macdonell R; Multiple sclerosis- diagnosis, management and prognosis. Aust Fam Physician. 2011 Dec;40(12):948-55. [abstract]
  15. Coles AJ, Cox A, Le Page E, et al; The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy. J Neurol. 2006 Jan;253(1):98-108. Epub 2005 Jul 27. [abstract]
  16. Fox EJ; Management of worsening multiple sclerosis with mitoxantrone: a review. Clin Ther. 2006 Apr;28(4):461-74. [abstract]
  17. Iannaccone ST; Modern management of spinal muscular atrophy. J Child Neurol. 2007 Aug;22(8):974-8. [abstract]
  18. Zifko UA; Management of fatigue in patients with multiple sclerosis. Drugs. 2004;64(12):1295-304. [abstract]
  19. Pucci E, Branas P, D'Amico R, et al; Amantadine for fatigue in multiple sclerosis. Cochrane Database Syst Rev. 2007 Jan 24;(1):CD002818. [abstract]
  20. Shakespeare DT, Boggild M, Young C; Anti-spasticity agents for multiple sclerosis. Cochrane Database Syst Rev. 2003;(4):CD001332. [abstract]
  21. DasGupta R, Fowler CJ; Bladder, bowel and sexual dysfunction in multiple sclerosis: management strategies. Drugs. 2003;63(2):153-66. [abstract]

Internet and further reading

Acknowledgements

EMIS is grateful to Dr Hayley Willacy for writing this article and to Dr Colin Tidy for earlier versions. The final copy has passed scrutiny by the independent Mentor GP reviewing team. ©EMIS 2010.
Document ID: 2474
Document Version: 23
Document Reference: bgp779
Last Updated: 12 Mar 2010
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