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Introduction

Multiple Sclerosis (MS) is a chronic inflammatory condition of the CNS. It results from demyelination and axonal loss of nerves in the CNS. Peripheral nerves are not affected. It is one of the most common neurodegenerative conditions. It results in many and varied neurological deficits which don’t always fit an obvious pattern.

The typical age of onset for MS is 20-40, and is 3x more common in women. It is considered an auto-immune disease, whereby a combination of environmental factors can precipitate the disease in a genetically susceptible individual. These environmental factors can ‘prime’ the immune system to attack myelin. The prevalence is directly correlated to the distance from the equator at which the patient has lived in pre adult years – the highest incidences are in cooler climates, the age at which the patient contracted Epstein-Barr virus (older age = greater risk), and a history of smoking.

Typically cases can be relapsing and remitting (more common and better prognosis) or progressive. Pregnancy is thought to be preventative against relapses.

A single episode is known as Clinically isolated syndrome (CIS). This refers to a set of neurological symptoms that last >24 hours before resolution, caused by inflammation or demyelination in the brain, optic nerves, or spinal cord. A patient needs to have two or more episodes to be diagnosed with MS. Between 35-50% of those who have a CIS will go on to develop MS.

Epidemiology & Aetiology

  • More common the further away from the equator you are
  • More common in those who contract Epstein-Barr virus (EBV) at a later age (glandular fever)
    • Rare in those who are seronegative for EBV)
  • Some genetic factors involved
    • HLA-DRB1 is associated with an increased risk
  • 2-3x more common in women
  • Mean age of onset 20-45
  • Presentation before puberty and after 65 is rare
  • A combination of genetic and environmental factors.
    • Living near the equator in the first 10 years of life. Prevalence:
    • Latitude 50-65: 100 per 100 000
    • Latitude<30 – <10 per 100 000
    • Those who move from a low incidence areas to a high incidence area before the age of 10 will aquire the incidence of the region they are moving to.
  • For those in the UK, the lifetime risk of developing MS is 1 in 400.
  • Genetic factors:
    • Siblings – 5%
    • Dyzygotic tiwns – 5%
    • Monozygotic twins – 30%

Pathology

Multiple sclerosis is a demyelinating condition, but there is also always axonal loss. This process is caused by some sort of autoimmune reaction against myelin and oligodendrocites – the mechanism of which is not exactly known. CD4 T cells mediate an attack on white matter, specifically on the oligodendrocites – which produce myelin, and on myelin itself.
There is destruction of myelin, and axonal loss. Antibodies to Myelin basic protein seen early on in the disease. Normally, macrophages cannot easily cross BBB, but in Multiple Sclerosis, they exhibit glycoprotein α4 β1, allowing them to adhere to and cross the endothelium.
At the active lesions – called plaques – there are increased numbers of inflammatory cells, and it is thought that essentially Macrophages digest the myelin sheath. As well as this, the macrophages produce nitric oxide which directly damages the axon.
Active lesions (plaques) are sites of inflammation, and show up on MRI as white blobs, roughly 2-10mm in size.

Plaques can be found anywhere in the CNS, but particularly in the :

  • Optic nerves
  • Periventricular region
  • Corpus callosum
  • Brainstem and cerebellar connections
  • Cervical spinal cord:
    • Posterior columns
    • Corticospinal tracts
They can be seen as white areas on MRI scan:
 Multiple sclerosis lesions on MRI
These are essentially due to conduction block / axonal loss at the site of the plaques. Most probably, conductional loss is to blame for the symptoms – and this is why steroid treatment can quickly reverse symptoms – as it rapidly reduces the inflammation, and allows the oligodendrocites time to recover. Axonal loss generally occurs in the latter stages of the disease, and results in progressive and persistent disability.

Patterns of Disease progression

It is often said that it is a relapsing / remitting disease, but in actual fact there are several patterns of MS.

Note that in all the below instances, the disease progressively gets worse. However! – some people may only have 1 (or a very small number of) attacks of the disease – which we could call benign MS. Essentially, this does not progressively deteriorate, although there is now some evidence that after several decades, there is actually a gradual decline in function, but not on the same scale as other varieties of the disease.

Multiple Sclerosis progression patterns

Multiple Sclerosis progression patterns

In a:
  • Relapse – there is focal inflammation, damage to myelin and oligodendrocites, and conduction block
  • Remission – the inflammation subsides, and there is remyleination of damaged areas – and much of the damaged function may return to normal.
In severe cases of inflammation, then permanent axonal damage can occur.

Clinical features

Almost any neurological sign can be present in multiple sclerosis, but some are more common than others. Common examples are below. Usually for motor function, the signs are UMN signs, but there may also be LMN signs. Episodes are typically separated by months or years – and often involve a different selection of signs and symptoms in each episode.
  • Optic Nerve:
    • Optic Neuropathy – there is typically blurring of vision in one eye that develops over a period of days. It can vary from ‘frosted glass’ sensation, to severe visual loss, but there is rarely blindness. There might also be some slight eye pain. It is almost always unilateral, and full recovery occurs within 2 months.
    • Optic disc swelling can occur if this area of the nerve is affected, but if the lesion is higher up the nerve than this, there are unlikely to be any ophthalmoscopic abnormalities – ‘When the patient sees nothing the doctor sees nothing’ – this type of lesion is known as retrobulbar neuritis.
      • Disc swelling in optic neuritis causes early and gradual visual loss, which can help you differentiate it from disc swelling due to raised intracranial pressure – which causes sudden late, visual loss.  
    • Uthoff’s phenomenonworsening of neurological symptoms (particularly vision), after a period of exercise and/or increase body heat (e.g. on a hot day, or after taking a hot bath). This is because conduction is slowed by an increased temperature. Another common finding with this is that the patient may be able to get into a hot bath, but cannot get out!
    • Relative afferent pupillary defect – this is often seen, and will usually persist even after recovery from the episode.
    • Late signs – often the vision fully resolves, and there are no lasting defects. But in some cases there may be:
      • Scotoma – a dark spot in the centre of the vision
      • Colour vision problems
      • Disc pallor
    • Diplopia
    • Nystagmus
    • Loss of colour vision – especially the colour red – which may appear grey
  • Spinal cord:
    • Motor – UMN lesions – weakness, spacticity, brisk reflexes. Generally develops over a period of days or weeks, gradually getting worse. Usually the result of demyelination in the spinal cord. May have:
      • L’Hermitte signon voluntary flexing of the head, there is an electric shock sensation travelling down the spine and into the limbs. Sometimes called the barber chair phenomenon. Due to a lesion in the posterior columns.
    • Sensory – numbeness, parasthesia (pins + needles, neuropathic pain). Typically in an ascending pattern over a period of days
    • Autonomic – incontinence (urine)/constipation (bowel), sexual dysfunction (erection problems, reduced sensation)
  • Brain stem – ophthalmaplegia (INO), neuralgia, hearing loss, vertigo, dysphagia, dysphonia
    • INO – Internucelar ophthalmoplegia – a condition affecting the movement of the eyes that is characteristic of MS. When covering one eye, unilateral movements will be normal. But when together, the adducting eye will not move past the midline. It may affect one or both of the eyes, and the patient may complain of horizontal diplopia. It is due to a lesion in the medial longitudinal fasciculus – which is a heavily myelinated tract, which connects optic brainstem nuclei on either side of the brainstem. Thus, conjugate movements, but not unilateral movement, is affected.
Multiple Sclerosis eye signs - internuclear ophthalmoplegia
    • Facial numbness / weakness
    • Vertigo
    • Dysarthria
    • Dysphagia
  • Cerebellum – ataxia
  • Cerebral hemispheres – anything! Rarely there can be:
    • Epilepsy
    • Trigeminal neuralgia
    • Tonic spasms – a brief spasm of the limbs.
  • Fatigue!important to exclude other causes:
Basically, there can be a combination of pretty much any neurological signs! Including both UMN and LMN, however, UMN are probably more common.

End-stage Multiple Sclerosis

  • Spastic tetraparesis
  • Ataxia
  • Optic atrophy
  • Brainstem signs
  • Psuedobulbar palsy
  • Urinary incontinence
  • Dementia
Death usually results from bronchopneumonia or renal failure.
Devic’s disease – Neuromyelitis optica
Considered a subtype of MS. Causes:
  • Optic neuritis
  • Acute myelitis (especially in spinal cord)

Examination

A targeted neurological examination design to elicit features specific to MS may be useful in suspect patients:

  • Eyes
    • Visual acuity
    • Eye movements (INO, pain, nystagmus)
    • Colour vision (may be reduced, especially red)
    • Fundoscopy – may show optic disc swelling
  • Limbs
    • Tone, reflexes, power and co-ordination
    • Cerebellar sings – ataxia, hypotonia
    • Sensory impairment of face or limbs
  • Cognitive function – may be reduced

Investigations

  • MRI – this is THE definitive investigation.
    • Will show plaques in 85% of clinical presentations
    • Multiple plaques are usually present in MS – a typically flare up will have about 10 plaques.
    • The correlation of MRI plaques and clinical disease is poor.
    • CT scan is not helpful
  • Bloods
    • May be useful to exclude differentials. Consider:
      • FBC
      • CRP
      • TSH
      • B12
      • LFTs
      • CMP
  • Visual evoked potentials – can detect lesions in visual pathway. The patient has EEG probes placed on the skull to measure brain response to visual stimuli. They are then given a visual stimulus, and the time between the visual stimulus and the brain response (on EEG) is measured. If the response is delayed this is evidence of some sort of optic nerve lesion.
  • Lumbar puncture – Oligoclonal bands in CSF
    • Similar to monoclonal bands seen in Lymphoma. However, where monoclonal bands represent massive proliferation of one type of plasma cell (and thus 1 antibody), oligoclonal bands represent massive proliferation of a small number of type of plasma cell.
    • Usually only necessary when MRI cannot confirm the diagnosis.
    • Actually not that useful! – in 80% of cases there will be oligoclonal bands, but these just show that there is a lot of antibody to something  in the CSF.
Peripheral nerve tests, blood/urine samples, and normal EEG are not helpful in the diagnosis.

Differentials

  • Migraine
  • Cerebral neoplasms (primary and secondary)
  • Nutritional deficiencies – particularly B12 or copper
  • Infections – e.g. syphilis, HIV
  • Motor neurone disease
  • Psychiatric disease / functional
  • Vascular Causes – tend to present suddenly
  • Other progressive diseases – tend to follow a progressive, rather than relapsing/remitting pattern.
  • MRI lesions – several other conditions can mimic the MRI lesions seen:

Diagnosis

  • At least 1 ‘attack’ – typically several months apart
  • Multiple plaques on MRI
  • OR
  • A single attack / progressive disease MS
  • Multiple plaques on MRI
  • Other evidence, e.g.
    • Oligoncloncal bands in CSF
    • Visual evoked potentials

Progression / Prognosis

  • Relapses may be induced by stress
  • Some patients will develop no disability
  • For others, disability gets gradually worse with each relapse
  • Patient may also experience a pseudo-relapse. It is important to differentiate between true relapses and pseudo-relapses.
    • Pseudo-relapse – typically <24 hours, symptoms may fluctuate and then completely resolve, symptoms may be identical to previous relapses. May be triggered by heat, stress, infection, surgery, new medications, fatigue. Pseudo-relapses are NOT caused by new lesions
    • True relapse – symptoms typically >24 hours duration, are present in the absence of obvious triggers (as above), and are often involve different symptoms to previous relapses.
  • Good prognostic factors
    • Optic neuritis or isolated sensory symptoms only at diagnosis
    • Relapsing remitting initial course
    • Long-interval to second relapse
    • No disability at 5 years
    • Normal initial MRI
    • Younger age at onset
    • Complete recovery from the first episode
  • Poor prognostic factors
    • Multi-focal initial presentation
    • High lesion load on MRI at initial presentation
    • Substantial disability at 5 years
    • High relapse rate in first 5 years
  • Prognosis
    • <5% have significant disability at 5 years
    • Up to 20% of patients have significant disability at 20 years
    • Without prognosis altering treatment, median time:
      • To requiring walking assistance – 15 years
      • To bed bound – 26 years
      • Death – 41 years
    • The exact extent to which medication alters this prognosis is not known
    • Life expectancy is typically 5-10 years less than the general population – but the disability burden is much greater
    • MS also effective cognitive function – particularly processing speed, memory and executive skills – and can significantly affect employment

Management

There is no cure. Management aims at reducing the risk and frequency of relapse and preserving function as long as possible. 
The course is very variable, but a particularly bad prognosis is associated with widespread plaques on MRI at first presentation.
The severity is also variable. Some patients may be able to live normally for many years, whilst other will becomes severely disabled.
  • You should advise patients about the widespread variability, and reassure that many cases do not cause severe disability (benign MS).
  • Smoking cessation should be advised in all MS patients who are smokers
Acute relapse:
  • Try to work out if true relapse vs pseudo-relapse (see Progression / Prognosis above)
  • If pseudo-relapse  – treat the underlying cause
  • If true relapse:
    • Short course of steroids – e.g. methylprednisolone, 1g/day for 3-5 days IV or PO
      • Can induce remission, and reduce the severity of the relapse – do not alter long-term outcome.
    • Urgent neurology referral – if acutely disabling symptoms consider same-day neurology review (either via Emergency Department or by liaising with patient’s previously known specialist)
    • Avoid using steroids in patients whose symptoms involve only fatigue or sensory loss, or induce only very minimal disability as the benefit is very limited
Preventing Relapse and disability
Once a second episode has been confirmed patients might typically start on a Disease modifying drug (DMD). Traditionally interferon-beta was used first-line, however, this has generally been superseded by glatiramer. They have both been shown to have similar efficacy (reduce relapse rate by about 30%) but glatiramer typically has fewer side effects.
Typically, DMDs are only initiated by neurologists.
  • Glatiramer acetate – a synthetic polypeptide, structurally similar to myelin-basic-protein. It is thought that because of this similar structure, it can bind to T-lymphocytes, and block the presentation of myelin antigens to the T-cells. Given IV. It can reduce the number of relapses, but may not alter long term outcome.
    • Administed SC 20mg daily – patients usually taught to self-administer
    • Unwanted effects – flushing, chest pain, palpitations, dyspnoea (immediately after administration)
  • Mitoxantrone – a cytotoxic antibiotic. May improve long term outcome when given at 3 monthly intervals.
  • Natalizumab – monoclonal antibody, that inhibits adhesion, thus reduces the number of inflammatory cells that are able to cross the blood-brain barrier. Reduces the relapse rate. Given IV 300mg once a month.
    • It has been shown to be more effective than both glatiramer and B-interferon – however 1 in 600 patients will suffer from progressive multifocal leukocephelopathy as a result of taking natalizumab – which is caused by infection with the JC virus. The risk is greater the longer that natalizumab is used. This is a devastating illness. As such, natalizumab is generally used second line, in patients who have not responded to other DMDs or in whom there is particularly aggressive disease.
  • Cyclophosphamide – has a cyclonic effect on lymphocytes
  • Fingolidmod – Spinhosine 1-phosphate receptor modulator
  • Β-interferon – in relapsing and remitting disease, this can be given by self-injection in trained patients.
    • The criteria for giving this, are that the patient’s disease must – have had two attacks in the last 3 years, followed by reasonable recovery.
    • This drug helps to reduce the relapse rate (by about 30%)and reduce the occurrence of plaques on MRI.
    • Again, it DOES NOT alter long term outcome.
    • Only really used in relapsing/remitting, and not very good for secondary and primary progressive.
    • It may also be given IV/IM at the first presentation of Multiple Sclerosis – and in such cases, it can reduce the risk of ‘full blown’ MS being present at 2 years.
    • Mechanism- Causes down-regulation of interferon-γ and increases the activity of suppressor T cells.
    • Unwanted Effects. Soreness at injection site – may progress to ulceration in some cases.Flu-like symptoms
  • Symptomatic management
    • Baclofen – is a GABA agonist – can reduce spasticity
    • Diazepam – may also reduce spasticity and tremor
    • Carbamazepine – may reduce fatigue, weakness and ataxia, as well as tremor
    • Propranolol – may reduce tremor
    • Oxybutynin or amitriptyline – can be used to treat urinary urgency and incontinence
    • Sildenafil (viagra) – can be used to treat erectile dysfunction
    • Amantadine – can be useful to treat fatigue

Pregnancy

  • Most of the drugs used are not safe in pregnancy, except glatiramer and natalizumab. Relapse rate during pregnancy is typically much lower than the year preceding pregnancy, but high in the postpartum period
  • Decisions on when to cease and when to re-start treatments should be discussed with patients on an individual basis

Rehabilitation

Many practical changes can be made in a person’s living environment to make life easier; e.g. modifications to cars, walking frames, hand rails etc. Patients may also need counselling over fears of disease progression and sexual dysfunction.
  • VERY IMPORTANT – treat all infections promptly – particularly UTI’s – as these are known to exacerbate symptoms.
  • Urinary incontinence – when residual volume is >100ml, manage with oxybutinin, or self-catheterisation.
  • Physiotherapy – reduces pain in spasticity, particularly in flexor spasms of the lower limb. This can also be relieved with botox injections and other agents such as baclofen, diazepam, tizanidine. With these other agents, you should start at a low dose, and increase gradually as necessary.
  • Cannabis – is used by many patients for symptom relief. There are trials currently ongoing of cannabis extracts (e.g. Sativea).
  • Pressure sores – should be prevented at all costs!
  • Depression and anxiety are common in MS patients. Management is typically similar to non-MS patients – including psychology and use of antidepressant medication.

References

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