Multiple sclerosis

Contributed by Dr Kathryn Brennan, SpR in neurology and Dr James Overell, consultant neurologist at the Southern General Hospital, Glasgow.

Nerve demyelination (white) in MS
Nerve demyelination (white) in MS

Section 1: Epidemiology and aetiology
Multiple sclerosis (MS) is the most common disabling neurological condition affecting young adults in the UK. It is a major cause of non-traumatic disability in young adults, and results in considerable social and economic costs.

It affects one million people aged from 17 to 65 years worldwide. The estimated prevalence of MS in Europe is 83 per 100,000, with higher rates in northern countries.1

MS is the result of auto-immune damage to myelin and myelin-producing cells of the CNS. It is a chronic inflammatory disease characterised by multiple focal areas of white matter inflammation, demyelination and gliosis.

Lesions appear in different areas of the brain and spinal cord, in particular in sites such as the periventricular white matter. New lesions appear throughout the course of the disease.

Genetic factors
Development of MS depends on both genetic susceptibility and environmental factors.2-4 How these complex factors interact is largely unknown.

The importance of genetic factors is suggested by the familial aggregation of disease (see box). The high prevalence of MS in specific ethnic populations, and the absence of increased MS in adopted relatives of those with MS also indicate a genetic component. Work suggests that genetic susceptibility in MS is polygenic and may involve 20 different genes.

Environmental factors
The influence of environmental factors on MS risk is suggested by a variation in disease incidence. There is a higher incidence in temperate climates further away from the equator.

Epidemiological data from migrant populations suggest early life environment is important. Those emigrating before the age of 15 from a high-risk zone to a low-risk zone carry at least part of the high risk of their country of origin.3,4 Exposure to common childhood/adolescent viral infections (and vaccinations) has occurred by this age.

Hard evidence for specific viral agents contributing to the MS pathogenesis is lacking, but a number of viral agents have been postulated as causative agents in its pathogenesis. A great deal of recent interest centres on Epstein-Barr virus.

Familial risk of developing MS
Relative with MSRisk of developing MSIncrease in risk above
baseline of 0.2%
Monozygotic twin 25-30%125-150 fold
First degree relative 2-4%10-20 fold
Both parents with MS30.5%150 fold

Section 2: Diagnosis
MS should be considered when young adults present with episodes of focal neurological dysfunction. MS is classified according to the clinical course at onset (see box).

Forms of MS
The most common subtype is relapsing remitting MS (RRMS). It is diagnosed when there have been two or more episodes of exacerbation lasting over 24 hours, separated by one month or more. Relapses last for a number of days or weeks.

Primary progressive MS (PPMS) should be considered when adults present with progressive neurological decline. It is more common in older patients. Other subtypes of MS are secondary progressive MS (SPMS) and progressive relapsing MS (PRMS).

Symptoms attributable to MS are generally indicative of damage to CNS white matter. These include painful partial loss of vision secondary to optic neuritis and gait and coordination problems secondary to cerebellar disease.

Attacks may be monofocal or multifocal. Multifocal episodes are predictive of a more severe outcome.

Investigations
There are no pathognomic tests for the diagnosis of MS. Diagnosis is established by demonstrating evidence of lesion dissemination in time and space using clinical findings and subsequent investigations. MRI can enable a diagnosis to be reached earlier.

Clinical information from MRI, cerebrospinal fluid (CSF) tests and evoked potential findings are incorporated into a diagnostic scheme known as the McDonald criteria.5 Using these criteria, a patient with clinically isolated demyelinating syndrome (CIS) who has suffered a single event can be followed up with repeat MRI scanning. If the repeat scan shows new lesions, the diagnosis of MS is established.

MRI markers of MS
Only a fraction of lesions identified through MRI are manifest clinically by symptoms. Acute lesions can be demonstrated with the administration of the contrast agent, gadolinium, especially in the relapsing remitting group.

Independent immunoglobulin synthesis within the CSF, typically detected as oligoclonal bands via electrophoresis, is present in over 90 per cent of MS patients (see image). However, this is not a specific finding.

Referral
Patients suspected of having MS should be referred to specialist care. They should be seen by either a consultant or senior specialist registrar for the diagnosis.

The patient should be given information about the disease and information about its social impact.

When to refer

  • When the diagnosis is suspected.
  • Acute relapse.
  • Consideration of DMT.
  • Management of symptoms.
  • If patient is not known to MS team


Clinical subtypes of MS
RRMS

  • Relapses followed by either recovery or residual deficit.
  • Lack of progression between relapses.
  • Female to male ratio of 2:1
  • Progression to SPMS in 80%.

SPMS

  • Gradual accumulation of disability with relapses less evident.

PRMS

  • Progressive accumulation of disability from onset with superimposed relapses.

PPMS

  • Progressive accumulation of disability from onset.
  • Possible minor fluctuations in disability, but no clear history of relapses.

Section 3 Management
Treatments used in MS can be divided into three groups. There are treatments used for acute relapses, disease modifying therapies (DMTs) that have a direct effect on the disease process, and symptomatic therapies.

When a patient presents with relapse symptoms, the first step is to confirm that the history and examination findings are also suggestive of an MS relapse.

Steroids
Corticosteroids shorten the duration of relapse by accelerating recovery, but there is no convincing evidence that they have any effect on long-term disability. Often no treatment is warranted for those with mild relapses.

For disabling or functionally limiting relapses a short course of high-dose methylprednisolone 1g IV for three days or, if the patient is ambulant, oral methylprednisolone 500mg for five days can be given.

Disease modifying agents
The commonly used DMTs are glatiramer acetate, interferon beta-1b, and interferon beta-1a. Randomised, placebo-controlled trials support the use of these agents. They reduce relapses by about one-third in patients with RRMS.6

The Association of British Neurologists recommends DMT for patients with CIS and MRI evidence confirming the diagnosis of MS, patients with RRMS and significant relapses, and patients with SPMS and significant relapses.6 Patient choice is an important factor in deciding which of them to use.

These drugs have a modest effect on disability. Their long- term effects are not known because data are only available from trials lasting two to three years. No appreciable benefit is seen in patients with non-relapsing forms of MS.

Treating advanced disease
Other treatment options exist for patients with highly active disease. These include mitoxantrone and natalizumab.

Mitoxantrone is an anthrecenedione used to treat malignant disorders. It is very effective but dose-related cardiotoxicity limits its use. It is currently used by neurologists in the UK off-licence.

Natalizumab is a new treatment for patients with rapidly evolving severe (RES) RRMS. It has recently been approved by NICE and the Scottish Medicines Consortium for this indication.

It is a humanised monoclonal antibody that prevents leucocytes crossing the blood-brain barrier.

Randomised trials demonstrate a relapse-rate reduction that is double that of the interferons (68 per cent). Subgroup analysis suggests it could be even more effective in the group of patients with RES disease.7

It also has a significant effect on the accumulation of relapse-related sustained worsening of disability.

Symptom management
Symptomatic treatments are often the mainstay of MS management. There are many symptoms associated with MS that are notoriously difficult to treat.

Common MS symptoms and their treatment

  • Fatigue - exercise is often the best intervention. Amantadine and modafinil may be helpful.
  • Pain - amitriptyline, gabapentin, pregabalin, carbamazepine.
  • Bladder problems - referral to a continence centre. Small capacity spastic bladder with urinary urgency, frequency and incontinence may respond to an anticholinergic. Large flaccid bladder with overflow incontinence may require intermittent self- catheterisation.
  • Constipation - change in diet advised. May need treatment with stool softeners.
  • Spasticity - muscle relaxants such as baclofen or tizanidine when spasticity impairs mobility.
  • Sexual health - sexual therapy and/or pharmacological treatment.
  • Cognitive impairment - referral to neuropsychology. Cognitive rehabilitation techniques may be helpful.
  • Depression - cognitive behavioural therapy and/or antidepressants.

Section 4: Prognosis
A recent review of 27 studies found that the best predictors of poor prognosis were sphincter symptoms at onset, incomplete recovery from the first episode of demyelination, a short interval between the first and second attacks and early accumulation of disability.8 Factors believed to be strong predictors of poor prognosis in MS such as older age of onset and cerebellar symptoms at onset demonstrated weak effects on prognosis.

Disability
Kurtzke's expanded disability status scale (EDSS) is commonly quoted in letters from neurologists to GPs about MS patients. It is not without faults and places a heavy reliance on gait, but disregards the impact that cognition has on disability. However, the EDSS is the standard scale used to assess disability objectively in MS (see box).

An EDSS of less than two indicates minimal disability. A score of greater than 6.5 indicates significant disability, such as in the case of a patient who requires constant bilateral assistance to walk 100 metres.

A population-based study found a 90 per cent chance that MS patients would remain stable if their EDSS scores were two or lower for 10 years or longer. This 'benign' group constituted 17 per cent of MS patients.9

Earlier treatment

Recent guidelines allow earlier diagnosis of MS and earlier treatment. What long-term effect this will have is unclear, but some data suggest that early DMT may have positive effects.

The more disabling secondary progressive phase of MS remains resistant to immunomodulatory treatment. Research into neuroprotective and neuroregenerative techniques, such as stem cell therapy, is under way.

Referral patterns should reflect the more active treatment approach that is currently being practised in specialist centres.

Expanded Disability Status Scale (EDSS) Score

  • 1.0 No disability, minimal signs in one functional system (FS).
  • 1.5 No disability, minimal signs in more than one FS.
  • 2.0 Minimal disability in one FS.
  • 2.5 Mild disability in one FS or minimal disability in two FS.
  • 3.0 Moderate disability in one FS, or mild disability in three or four FS. No impairment to walking.
  • 3.5 Moderate disability in one FS and more than minimal disability in several others. No impairment to walking.
  • 4.0 Significant disability but self-sufficient. Able to walk 500m.
  • 4.5 Significant disability but able to work a full day, may otherwise have some limitation of full activity or require minimal assistance. Able to walk without aid or rest for 300m.
  • 5.0 Disability severe enough to impair full daily activities and ability to work a full day without special provisions. Able to walk for 200m.
  • 5.5 Disability severe enough to preclude full daily activities. Able to walk without aid or rest for 100m.
  • 6.0 Requires a walking aid to walk about 100m.
  • 6.5 Requires two walking aids to walk about 20m without resting.
  • 7.0 Unable to walk beyond approximately 5m even with aid. Essentially restricted to wheelchair; although wheels self in standard wheelchair and transfers alone. Up and about in wheelchair some 12 hours a day.
  • 7.5 Unable to take more than a few steps. Restricted to wheelchair and may need aid in transferring. Can wheel self but cannot carry on in standard wheelchair for a full day and may require a motorised wheelchair.
  • 8.0 Essentially restricted to bed or chair or pushed in wheelchair. May be out of bed itself much of the day. Retains many self-care functions. Generally has effective use of arms.
  • 8.5 Essentially restricted to bed much of day. Has some effective use of arms retains some self care functions.
  • 9.0 Confined to bed. Can still communicate and eat.
  • 9.5 Confined to bed and totally dependent. Unable to communicate effectively or eat/swallow.

Resources

Websites

References

1. Pugliatti M, Rosati G, Carton H et al. The epidemiology of multiple sclerosis in Europe. Eur J Neurol 2006; 13: 700-22.

2. Poser C. The multiple sclerosis trait and the development of multiple sclerosis: genetic vulnerability and environmental effect. Clin Neurol Neurosurg 2006; 108: 227-33.

3. Poser C. The pathogensis of multiple sclerosis: a commentary. Clin Neurol Neurosurg 2000; 102: 191-4.

4. Poser C, Brinar V. The nature of multiple sclerosis. Clin Neurol Neurosurg 2004; 106: 159-71.

5. Polman C, Reingold S, Edan G et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria". Ann Neurol 2005; 58: 840-6.

6. Association of British Neurologists guidelines for the treatment of multiple sclerosis with beta interferon and glatirmer acetate. March 2007. http://theabn.org/downloads/ABN-MS-Guidelines-2007.pdf

7. Polman C, O'Connor P, Havrdova E et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006 2; 354: 899-910.

8. Langer-Gould A, Popat R, Huang S et al. Clinical and demographic predictors of long-term disability in patients with relapsing-remitting multiple sclerosis: a systematic review. Arch Neurol 2006; 63: 1,686-91.

9. Pittock S, McClelland R, Mayr W et al. Clinical implications of benign multiple sclerosis: a 20 year population-based follow-up study. Ann Neurol 2004; 56: 303-6.

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