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