Clinical Review: Multiple sclerosis

Contributed by Dr Oliver Lily, consultant neurologist, Leeds General Infirmary

MRI showing demyelination spreading outwards from the ventricles (Photograph: Dr O Lily)
MRI showing demyelination spreading outwards from the ventricles (Photograph: Dr O Lily)

1 Epidemiology and risk factors
Multiple sclerosis (MS) is the most common cause of progressive neurological disability in young people in the UK. It currently affects up to one in 800 people and there is estimated to be at least 50,000 MS patients in the UK. Despite this, very little is known about its aetiology or pathogenesis.

MS is thought to be an autoimmune illness and its epidemiology does mirror other autoimmune diseases. It is three times more common in women and is most likely to occur around age 30. It is rare before puberty.

Although MS has a worldwide distribution, it has become more common in temperate countries in the northern and southern hemispheres. It is rare in equatorial countries.

Environmental cause
Early epidemiological studies suggested that people who migrate before their early teenage years adopt the risk of their new country, while those who migrate after this age keep the risk of their birthplace.1 This effect is born out of studies of second-generation immigrants in the UK from countries such as Pakistan, who have a typical UK incidence while their parents tend to retain a very low risk from their place of birth.2

All this strongly suggests an environmental cause and the Epstein-Barr virus (EBV) has been proposed as a possible culprit.

Currently there is only circumstantial evidence that EBV is involved, including almost universal seropositivity in MS patients compared with about 90% seropositivity in age-matched controls.3

Genetic influence seems to be comparatively weak and so far the only significant link is to antigens HLADR15 and DQ6.4 Many studies have suggested the illness is becoming progressively more common, especially in women.5

Pathology can be confusingly heterogenous.6 However, the hallmark is a sharp-edged demyelinated plaque associated with a non-specific lymphocytic infiltrate. It is always entirely confined to the CNS.

Section 2: Making the diagnosis
MS is a clinical diagnosis and should be made by a neurologist with experience of the condition. There are as yet no diagnostic tests. Diagnosis is also complicated by the fact that MS can run one of several different disease courses (see box below).

The Common Clinical Phenotypes of MS

1. Relapsing-remitting (80% at onset)

  • Inflammatory attacks separated by remissions.
  • Diagnosis made by at least two attacks separated in time and place.
  • A single attack may be called clinically isolated syndrome (CIS); 30-70% of CIS patients go on to develop MS.
  • Relapse rate responds to immunomodulation.

2. Primary progressive (10%)

  • Insidious and progressive deterioration from onset (usually paraparesis).
  • No attacks.
  • No response to immunomodulation.
  • Diagnosis relies on oligoclonal bands in the CSF.
  • Onset age usually >50 years.

3. Secondary progressive (65% at some point)

  • Insidious progression of disability (usually mobility) approximately 10 to 30 years after diagnosis of relapsing-remitting MS.
  • Attacks may occur (although frequently stop).
  • Fluctuation of symptoms with exertion, heat or illness (Uhthoff's phenomenon).
  • No response to immunomodulation.

4. Rapidly progressive (5% or less)

  • Rapid accumulation of disability in a young patient shortly after diagnosis.
  • May respond to aggressive immunosuppression.
  • Poor prognosis without treatment.

Relapsing-remitting
Most patients present with a relapsing-remitting course. Attacks tend to affect the optic nerve (optic neuritis), spinal cord (myelitis) or brainstem. The attacks can be mild and the prognosis for recovery is usually good.

However, the majority of patients will eventually go on to develop secondary progressive MS, with the accumulation of gradually worsening deficits and disability without remission. This stage of the illness tends to occur when the patient is in their fifties and causes the majority of the disability burden.

The current UK diagnostic criteria are called McDonald criteria.7 They build on the long-held logic of inflammatory lesions confined to the CNS, disseminated in time and place, in the absence of any other known cause.

In MS sufferers, the MRI scan often shows high-signal T2 demyelinating lesions radiating out from the ventricles. They are said to be flame-shaped and are sometimes called Dawson's fingers (see image above).

It should be noted that similar lesions are found in healthy individuals, while many people presenting with MS will have an entirely normal scan. The sensitivity and specificity of MRI for MS may be much less than generally thought and it should be used as a supporting investigation only.8

Another useful supporting investigation is the use of oligoclonal bands in the cerebrospinal fluid but not in the serum.

This denotes the production of antibodies inside the CNS. Approximately 90% of MS patients are positive for this test but unfortunately it is also positive in other inflammatory CNS diseases.

Spastic paraparesis
The diagnosis of primary progressive MS is more difficult as this most commonly presents with an insidious symmetrical spastic paraparesis. MRI scans may not show lesions.

In order to be sure about the diagnosis, progression over at least 12 months should be documented, and oligoclonal bands should be positive. Fortunately, other conditions causing CNS inflammatory lesions are fairly rare.

The differential diagnosis of MS includes neuromyelitis optica (Devic's disease), cerebral lymphoma, neurosarcoid, Lyme disease, inherited leucodystrophies and other rarities.

Section 3: Managing the condition
The management of MS is challenging given the unique natural history of the illness. While there is excellent evidence that the initial relapsing stage of the illness responds to immunosuppressants or immunomodulation, the secondary progressive stage does not seem to respond to any drug treatment at all. NICE recommends that MS treatment is started and monitored at a specialist MS centre.


Physiotherapy is vital to reduce spasticity and help maintain mobility (Photograph: SPL)

Suppression of relapses
Current management is based on fairly aggressive suppression of relapses in the first part of the illness with the assumption that this may prevent patients entering the progressive stage and accumulating significant disability later in the illness (see table below). In fact, evidence for this is lacking and there is still a debate about the role of aggressive immunosuppression.

Disease-modifying therapies
Drug Percentage reduction in relapses Side-effects
Beta-interferon Approximately 30% Leukopenia
Mild hepatitis
Injection site reactions
Glatiramer acetate 29% Injection site reactions
Natalizumab 68% Risk of progressive multifocal leukoencephalopathy limits duration of treatment
Mitoxantrone Approximately 80% Risk of leukaemia and cardiomyopathy limits duration of treatment
Fingolimod 60% Disseminated infection
Macular oedema
Heart conduction defects

One of the challenges for the future management of MS is to establish the relationship between the early relapses and the later progression of disability, and perhaps come up with neuroprotective strategies effective in the later stages.

In the UK, NICE has dictated a pragmatic approach with injectable disease modifying therapy (interferon9 or glatiramer10) recommended for patients with relapsing-remitting MS who have more than two significant attacks in two years. For more severe cases with two or more disabling attacks in the same 12-month period, natalizumab therapy is recommended.11

Patients with even more aggressive MS causing the rapid accumulation of disability may be treated with mitoxantrone chemotherapy.12 Other cytotoxics, such as azathioprine, are occasionally used but detailed evidence is lacking. Fingolimod has just been licensed but is not funded.13

Methylprednisolone is often given to treat acute relapses. Low doses are of no benefit, and the usual regimen is either IV 1g daily for three days or oral 500mg daily for five days. Osteoporosis is a significant risk and more than three courses a year are not recommended.

Relapse clinics
A specialist review prior to treatment is recommended, as not all MS symptoms are due to a relapse. Many centres now provide 'relapse clinics' with self-referral or open access.

In patients with secondary progressive MS, management is primarily symptomatic. Physiotherapy is important, particularly to reduce spasticity and help maintain mobility. Muscle relaxants, such as baclofen or tizanidine, are often recommended.

Anticholinergics or intermittent self-catheterisation may be necessary for bladder problems. Neuropathic pain may require treatment with amitriptyline, gabapentin or pregabalin.

Depression is common at all stages of the illness and can often mimic MS symptoms, particularly fatigue or forgetfulness.

A multidisciplinary approach is needed, often with many specialists being involved (see box below).

A multidisciplinary approach to MS

Recommended members of MS specialist team

  • Neurologists.
  • MS specialist nurses.
  • MS specialist physiotherapists.
  • Occupational therapists.
  • Speech and language therapists.
  • Neuropsychologists.
  • Social workers.

Close links needed to:

  • Dietetics.
  • Liaison psychiatry.
  • Continence advisory and management services.
  • Pain management services.
  • Chiropody and podiatry.
  • Ophthalmology services.
  • Rehabilitation specialists.
  • GP

Section 4: Prognosis
Long-term prognosis of MS is unpredictable. Historical cohorts suggest that while up to 20% of patients will never accumulate significant disability, the majority will need some sort of walking aid after approximately 15 years and a wheelchair after a median of 30 years.14

It is hoped that new immunosuppressive agents given as soon as possible after the diagnosis will reduce the disability levels, although even with interferon it is difficult to collect data and too early to be sure.

In the UK, the risk-sharing scheme that provides access to disease-modifying therapy has captured a cohort of 10,000 patients and should provide more up-to-date prognostic information. The initial 10-year results have been confusing and the statistical methods have been criticised.15 A re-analysis and more up-to-date data are expected soon.

Section 5: Case study
An 18-year-old medical student presents with painless visual loss in the left eye. Her visual acuity had faded over 48 hours. Ophthalmological examination was normal, as was a routine CT brain scan. Visual evoked potentials showed delayed conduction on the left. A diagnosis of optic neuritis was made and the patient was counselled appropriately. Her vision returned to normal without treatment over the next six weeks.

Five years later, just before her medical finals, she presented with ascending numbness evolving over a week to reach her upper chest.

She described a squeezing feeling like a tight band at this level. When she walked she could not feel the floor and felt unsteady. Neurological examination was normal except for some difficulty appreciating the tuning fork at the knees or ankles.

Clinically definite MS
An MRI scan showed myelitis at T2, while the brain scan showed multiple inflammatory periventricular white matter lesions. A diagnosis of clinically definite MS was made and she was started on subcutaneous interferon three times a week.

At five-year follow-up she was well and symptom free.

Fifteen years later, she began to notice her right leg dragging when she walked any distance. Over the next few years the distance she could walk reduced to about 200 yards. She began to have urinary urgency.

Neurological examination showed bilaterally increased tone with sustained clonus on the left and upgoing plantar on the left. The diagnosis of secondary progressive MS was made. Her interferon treatment was stopped and she began physiotherapy.

Over the next five years her mobility gradually deteriorated so that she needed a walking stick or a wheelchair for long distances. She complained of forgetfulness and had to take early retirement from the NHS at the age of 48 years.

Section 6: Evidence base
Clinical trials

Guidelines

Key text

  • Compston A, Confavreux C, Lassmann H et al. McAlpine's Multiple Sclerosis (fourth edition). Churchill-Livingstone, 2006.

This is a comprehensive key text book.

Curriculum

This topic is covered in the GP curriculum in statement 15.7: Neurological problems

Online

Useful online resources are provided by the MS society (www.mssociety.org.uk) and MS Trust (www.mstrust.org.uk), including downloadable free guides for primary care.

Click here to take a test on this article and claim a certificate on MIMS Learning

CPD IMPACT: EARN MORE CREDITS

These further action points may allow you to earn more credits by increasing the time spent and the impact achieved.

  • In a practice meeting, role play breaking bad news to a patient with possible MS and critique your performance.
  • Find out about local MS support groups in your area to help your patients.
  • Review your cases of MS and discuss with colleagues how the patients presented. Would you have done anything differently?

References
1. McLeod JG, Hammond SR, Kurtzke JF. J Neurol 2011; 258(6): 1140-9.

2. Elian M, Nightingale S, Dean G. J Neurol Neurosurg Psychiatry 1990; 53(10): 906-11.

3. Lucas RM, Hughes AM, Lay ML et al. J Neurol Neurosurg Psychiatry 2011; 82(10): 1142-8.

4. McElroy JP, Oksenberg JR. Neurol Clin 2011; 29(2): 219-31.

5. Hirst C, Ingram G, Pickersgill T et al. J Neurol Neurosurg Psychiatry 2009; 80(4): 386-91.

6. Lassmann H, Bruck W, Lucchinetti C. Trends Mol Med 2001; 7(3): 115-21.

7. Polman CH, Reingold SC, Banwell B et al. Ann Neurol 2011; 69(2): 292-302.

8. Schaffler N, Kopke S, Winkler L et al. Acta Neurol Scand 2011; 124(3): 151-64.

9. Rice GP, Incorvaia B, Munari L et al. Cochrane Database Syst Rev 2001; (4): CD002002.

10. Johnson KP, Brooks BR, Cohen JA et al. Neurology 1995; 45(7): 1268-76.

11. Polman CH, O'Connor PW, Havrdova E et al. N Engl J Med 2006; 354 (9): 899-910.

12. Hartung HP, Gonsette R, Konig N et al. Lancet 2002; 360(9350): 2018-25.

13. Cohen JA, Barkhof F, Comi G et al. N Engl J Med 2010; 362 (5): 402-15.

14. Weinshenker BG, Bass B, Rice GP et al. Brain 1989; 112 (Pt 1): 133-46.

15. Boggild M, Palace J, Barton P et al. BMJ 2009; 339: b4677.

Visit the GP Curriculum Centre for hundreds of articles linked to key topics in the RCGP curriculum

Have you registered with us yet?

Register now to enjoy more articles and free email bulletins

Register

Already registered?

Sign in

Before commenting please read our rules for commenting on articles.

If you see a comment you find offensive, you can flag it as inappropriate. In the top right-hand corner of an individual comment, you will see 'flag as inappropriate'. Clicking this prompts us to review the comment. For further information see our rules for commenting on articles.

comments powered by Disqus