Multiple Sclerosis

Epidemiology

Prevalence: ~ 1/2000 in the UK

Risk factors:

  • Age: onset is generally in the 20s
  • Female (2:1)
  • Smoking
  • EBV exposure
  • Low vitamin D
  • Childhood obesity
  • Genetics: HLA-DRB1 allele 1*15 carries the greatest risk.

Pathogenesis

MS is an autoimmune inflammatory disorder of the CNS which is characterised by widespread areas of focal inflammatory demyelination throughout the brain and spinal cord, as well as diffuse neuronal loss similar to that seen in neurodegenerative disorders.

The pathogenesis is not fully understood. The most widely-held theory is that self-reactive T and B lymphocytes gain entry to the CNS due to disruption of the blood-brain barrier, promoting CNS inflammation, degeneration of oligodendrocytes (the cells responsible for myelination of CNS axons), and consequent neuronal and axonal degeneration. Acute episodes of inflammation are superimposed onto a background of chronic, progressive neurodegeneration.

Presentation

MS can be categorised into two main forms:

  • Relapse-onset (95%)
  • Progressive-onset (5%)

Relapse-onset MS presents with an episode of acute new neurological symptoms and signs attributable to an episode of focal inflammatory demyelination. In the initial phase of the disease, these symptoms and signs resolve at least partially. Further episodes (relapses) usually occur.

Progressive-onset MS presents with progressive accumulation of neurological disability from disease onset without identifiable transient deteriorations in neurological function (relapses).

MS lesions can affect anywhere in the CNS. However, the following are the most characteristic syndromes seen at initial presentation and relapse:

  • Optic neuritis
  • Transverse myelitis
  • Sensory disturbance
  • UMN weakness
  • Cerebellar syndrome
  • Brainstem syndromes, e.g internuclear ophthalmoplegia

There are some specific features of demyelinating lesions in the history:

  • Lhermitte’s sign: paroxysmal shock-like sensations down the back and the limbs on neck flexion
  • Uhtoff’s phenomenon: paroxysmal worsening of symptoms on heat exposure

In relapsing disease it is reasonably common for people with MS to regain full function after a relapse. For many people, as the disease progresses, there is a gradual accrual of neurological disability due to chronic neurodegeneration and incomplete recovery from acute relapses. Over time a variety of symptoms and signs may develop, including:

  • Urinary incontinence
  • Faecal incontinence
  • Depression
  • Fatigue
  • Cognitive impairment
  • Spasticity
  • Visual loss
  • Gait impairment
  • Loss of hand function

Investigation

The diagnosis of MS is usually made based on clinical and MRI findings using the revised 2010 MacDonald criteria. After a first clinical episode suggestive of MS, the MacDonald criteria require evidence of dissemination in time and space to make a diagnosis of MS. This can now be done on the basis of clinical evidence (i.e. a relapse suggesting a new lesion) or radiological evidence (i.e. MRI findings of multiple lesions which have been present for different lengths of time).

Macdonald 2010 criteria:

  • Dissemination in space:
    • Relapse
    • Radiological
  • Dissemination in time:
    • Clinical
    • Radiological

The work-up for MS depends upon the mode of presentation. For most people it is useful to carry out at least the following:

  • Bloods: depending on clinical context special tests may include…
    • Vasculitis screen
    • Infectious screen: Lyme serology, HIV serology, syphilis test, HTLV-1 testing
    • Aquaporin-4 antibodies
  • MRI brain and spinal cord (essential):
    • T2-weighted
    • T1 with gadolinium
  • Lumbar puncture:
    • Oligoclonal bands

Management

The management of MS is divided into the management of acute relapses and disease-modifying therapy.

Acute relapses

Definition:

  • An acute relapse is defined as a transient worsening of neurological function typical for a demyelinating CNS lesion which evolves over at least 24 hours and is not associated with fever or infection, and is preceded by 30 days of clinical stability
  • Intercurrent illness can cause an apparent worsening of symptoms

Diagnosis:

  • Search for an alternative explanation:
    • Electrolyte disturbance
    • Fever
    • Infection
  • Confirm the diagnosis of relapse with brain and spinal cord MRI (T1 with Gadolinium + T2-weighted)

Treatment

  • Steroids are the mainstay of treatment:
    • Indications: any proven MS relapse which impairs function
    • Formulations: no evidence to choose between oral or IV
    • Benefits:
      • Shortens duration of relapse
      • DOES NOT improve longer-term outcome
    • Plasma exchange: rarely used
      • Indications: severe relapses unresponsive to steroid therapy

Disease-modifying therapy

Following a diagnosis of MS most people should be offered disease-modifying therapy. Unfortunately these have no proven benefit in progressive MS.

DMT Mechanism Route Adverse effects Monitoring
Interferon-beta Anti-inflammatory S/C

IM

 

Flu-like symptoms

Nausea

Injection site reactions

Fever

Headache

Depression

Bone marrow suppression

Hepatotoxicity

Loss of effect due to neutralising antibodies

FBC

LFT

Glatiramer acetate Myelin basic protein analogue S/C Injection site reactions

Infusion reactions

None
Daclizumab IL-2R antagonist S/C Severe infection

Hepatotoxicity

LFT
Natalizumab Alpha-4 integrin antagonist IV Progressive multifocal leukoencephalopathy

Severe infection

Infusion reactions

Anti-JC virus antibodies
Alemtuzumab Anti-CD52 IV Infusion reactions

Infections

Autoimmune disorders (e.g. thyroiditis)

ITP

Loss of effect due to neutralising antibodies

FBC

 

Ocrelizumab Anti-CD20 antibody IV Exacerbation of underlying HepB

Infusion reactions

HBV serology
Dimethyl fumarate Immunomodulator Oral Flushing

GI upset

Hepatotoxicity

FBC

LFTs

Teriflunomide Inhibitor of pyrimidine synthesis Oral Diarrhoea

Nausea

Hepatotoxicity

Hair loss

LFT
Fingolimod Sphingosine-1-phosphate receptor moduator Oral Infection

Flu-like symptoms

Hepatotoxicity

Headache

Cardiac arrhythmias

Increased cancer risk

Maculae oedema

FBC

LFT

VZV serology

ECG

Eye exam

Cladribine Purine nucleoside analogue Oral Infection

Cytopaenias

GI upset

Flu-like symptoms

Hepatotoxicity

FBC

U&E

LFT

 

The only proven treatments for progressive-onset MS are ocrelizumab and haematopoietic stem cell transplantation.

Symptomatic treatment

Control of symptoms is an important aspect of treating people with MS. Common symptoms and their treatments are detailed below:

Symptom Treatment
Nociceptive Pain NSAIDs

TENS

Physio

Neuropathic Pain Anticonvulsants (gabapentin)

Antidepressants (amitryptilline)

TENS

Trigeminal neuralgia Carbamazepine 300mg daily

Lamotrigine

Baclofen

Tizanidine

Paroxysmal positive symptoms Carbamazepine low dose (100mg daily)
Cerebellar tremor Isoniazid 800mg/day, builinding up weekly to 1200mg/day

Clonazepam

Propranolol

Stereotactic thalamotomy if unilateral

Fatigue Pulsed steroids

Amantadine

Modafinil

Bladder dysfunction

–          Detrusor hyperreflexia >> urgency

–          Detrusor-sphincter dyssynergia >> hesitancy & incomplete emptying

Oxybutynin 5mg 2-3 times/day

Imipramine 75-150mg nocte

Self-catheterisation

Desmopressin intranasal (ADH analogue)

Intravesical botulinum toxin (requires self-catherisation as it paralyses the bladder)

Long-term suprapubic catheter

Spasticity Baclofen

Dantrolene

Diazepam

Intrathecal baclofen

Botulinum toxin