Summary

MS is an inflammatory condition that affects the oligodendrocites of the CNS. Peripheral nerves are not affected.

Epidemiology & Aetiology

  • More common the further away from the equator you are
  • Some genetic factors involved
  • Twice as common in women
  • Mean age of onset 20-45

Pathology

An autoimmune reaction against myelin and oligodendrocites (CNS equivalent of Schwann cells). 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 MS, they exhibit glycoprotein α4 β1, allowing them to adhere to and cross the endothelium.
Active lesions (plaques) are sites of inflammation, and show up on MRI as white blobs, roughly 2-10mm in size, and can occur anywhere in the CNS, although most commonly occur at the optic nerves, periventricular lesion, brainstem and cerebellar connections.
Conduction loss is probably to blame for most of the symptoms of MS.

Patterns of Disease progression

Progression is extremely variable. Some patients may only ever have one episode (benign MS), whilst other may rapidly get worse with no periods of remission.

Clinical features

Almost any neurological sign can be present in MS, 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.
  • Optic Nueropathy
  • Optic disc swelling
  • Uthoff’s phenomenon – signs worse on hot day or after exercise – heat slows conduction in nerve fibres
  • Relative afferent pupillary defect
  • UMN signs – spasticity, weakness, brisk reflexes
  • Lehrmitte signon voluntary flexing of the head, there is an electric shock sensation travelling down the spine and into the limbs.
  • Sensory Signs – numbness and parasthesia
  • Autonomic defects – urinary incontinencem constipation, sexual dysfunction
  • Cerebellar defects – ataxia
  • Fatigue

End-stage Multiple Sclerosis

  • Spastic tetraparesis
  • Ataxia
  • Optic atrophy
  • Brainstem signs
  • Psuedobulbar palsy
  • Urinary incontinence
  • Dementia

Investigations

  • MRI – definitive test. 85% of cases will show plaques on MRI.
  • VEP – visual evoked potentials – can detect lesions in visual pathway. The patient has EEG probes on the skull the 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.
  • 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. 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.

Diagnosis

  • At least 1 ‘attack’
  • 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

Management

There is no cure.
Acute relapse:
  • Short course of steroids – e.g. methylprednisolone, 1g/day for 3 days, OR, high dose oral steroids.
    • Can induce remission, and reduce the severity of the relapse – do not alter long-term outcome.
    • You should not use steroids more than 2x/year!
Preventing Relapse and disability
  • Β-interferon –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.
  • Glatiramer acetate – a synthetic polypeptide, structurally similar to myelin-basic-protein. Given IV. It can reduce the number of relapses, but does not alter long term outcome.
    • Unwanted effects – flushing, chest pain, palpitations, dyspnoea (immediately after administration)
  • Mitoxantrone – a cytotoxic antibiotic. Experimental – 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.
  • Baclofen – often used as symptomatic treatment. It is an antagonist of GABA receptors.

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 incontinencewhen 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!

 

More Information

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.

Epidemiology

  • Prevalence depends on distance from the equator. At the equator, the disease is very rare, and becomes more common the further away you go.
  • M:F – 1:2
  • Onset is usually between ages of 20-45. Presentation before puberty and after 65 is rare.

Aetiology

  • 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

MS is a demyelinating condition, but there is also always axonal loss. This process is caused by some sort of autoimmune reaction – the mechanism of which we are not entirely sure of. CD4 T cells mediate an attack on white matter, specifically on the oligodendrocites – which produce myelin, and on myelin itself.
  • Oligodendrocties are the CNS equivalent of Schwann cells. However, unlike Schwann cells, which are very small, and there are several for each axon, oligodendrocites are much larger, and one cell may insulate a small portion of each of 50 axons. This portion can be up to 1mm long.
 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.
  • Normally, these cells cannot easily cross the blood/brain barrier. In MS, they start exhibiting glycoprotein α4 β1which allows them to adhere to endothelial cells, and get into the CNS.
  • Antibodies to myelin basic protein can be found early on in the disease.
It is thought that like many autoimmune disease, an infection of some kind may initially trigger off the disease.  Many patients with MS produces excess/abnormal antibodies to viral infections, particularly measles. However, there is no known link between a particular infective agent and MS.
Plaques – are the main feature. They are usually 2-10mm in size, and can be found anywhere in the CNS, but particularly in the :
  • Optic nerves
  • Periventricular region
  • Brainstem and cerebellar connections
  • Cervical spinal cord:
    • Posterior columns
    • Corticospinal tracts
They can be seen as white areas on MRI scan:
 
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.

The course of the disease

It is often said that it is a relapsing / remitting disease, but in actual fact there are several pattern of MS:
  • Note that in all the above 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.
 
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.

Signs and symptoms

  • 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 sever 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). This is because conduction is slowed by an increased temperature. Another common finding with this is that – the patient can 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
  • 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:
      • Lehrmitte 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)
    • 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.
  • 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)

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.
  • Visual evoked potentials – can detect lesions in visual pathway. The patient has EEG probes on the skull the 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.
  • 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

  • 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

The diagnosis cannot usually be made on a single episode of the disease, because we cannot tell if it relapsing/remitting or pregressive. To diagnose MS you basically need to have:
  • At least 1 ‘attack’
  • 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

Management

There is no cure. Often you will need to discuss practical plans for the patient, such as living arrangements (do they need any modifications to help them get around the house), job, and general future plans, even if these might be a long way in the future.
The course is obviously very variable, but a particularly bad prognosis is associated with widespread plaques on MRI at first presentation.
The severity is also very 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).
Acute relapse:
  • Short course of steroids – e.g. methylprednisolone, 1g/day for 3 days, OR, high dose oral steroids.
    • Can induce remission, and reduce the severity of the relapse – do not alter long-term outcome.
    • You should not use steroids more than 2x/year!
  • Try to avoid infection and stress
  • Initiate a long term treatment (below)
Preventing Relapse and disability
  • Β-interferon – in relapsing and remitting disease, this can be given by self-injection by 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 MS – 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
  • Glatiramer acetate – a synthetic polypeptide, structurally similar to myelin-basic-protein. Given IV. It can reduce the number of relapses, but does not alter long term outcome.
    • Unwanted effects – flushing, chest pain, palpitations, dyspnoea (immediately after administration)
  • Mitoxantrone – a cytotoxic antibiotic. Experimental – 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.
  • Baclofen – often used as symptomatic treatment. It is an antagonist of GABA receptors.

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 this is common in the later stages of the disease, and once the residual volume is >100ml, should be managed 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!

 

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