Multiple sclerosis (MS) is an inflammatory demyelinating disease, clinically defined by two episodes of neurological dysfunction (brain, spinal cord or optic nerves) separated in space and time. Thought to be an autoimmune disease and multifactorial origin, MS is the most common cause of neurological disability in those younger than 40 years old and affects ~ 190 per 100,000 population. The female to male ratio is around 3:1 with increasing frequency of MS in women, which suggests an environmental factor working in a sex-specific manner.


In 2014, the International Advisory Committee on Clinical Trials of MS in collaboration with the European Committee for Treatment and Research in MS (ECTRMS) and National MS Society, redefined the original clinical phenotypes first set out in 1996. Clinical descriptive terminology in relation to MS was further defined:

Dissemination in space (DIS)
  • Development of lesions in different anatomical locations within the CNS
  • Demonstrated on MRI by
    • ≥1 T2 hyperintense lesion characteristic of MS
    • In 2 or more of: periventricular, cortical or juxtacortical and infratentorial brain regions or the spinal cord

Dissemination in time (DIT)
  • Development of new CNS lesions appearing over time
  • Demonstrated on MRI by
    • Simultaneous gadolinium (Gd) enhancing and non enhancing lesions at any time or
    • New T2 hyperintense or Gd enhancing lesions compared to a baseline MRI

  • Reported symptoms or objective findings suggestive of focal or multifocal MS pathology
  • Lasting at least 24 hours
  • Developed acutely or subacutely
  • With or without recovery
  • In the absence of fever or infection
  • Preceded by a stable neurological state of at least 30 days.
  • Attack, exacerbation and (when it is the first episode) clinically isolated syndrome are synonyms

  • Clinical relapses and/or radiological evidence of new lesions on MRI

  • An MS course characterised by steadily worsening neurological disability (objectively documented)
  • Stability and superimposed relapses can occur
  • Can be further classified as primary progressive or secondary progressive (see below)

Worsening disease
  • Increase in neurological disability secondary to relapses and/or progressive disease

The 3 main patterns of the disease are based on disease activity and progression:

Relapsing-remitting MS (RRMS) (~85% of cases):
  • Relapses are followed by periods of neurological stability between episodes.
  • Relapse symptoms can last anywhere from a few days to months, however, they usually resolve after 4-6 weeks.
  • Periods of stability can then occur for months, even years before another relapse
  • Multiple relapses can result in irreversible CNS damage leading to partial recovery during remissions

Secondary progressive MS (SPMS):
  • A progressive neurological disability after an initial RRMS course.
  • ~50% of RRMS progress to SPMS within 15 years of disease onset
  • ~66% by 30 years of disease onset

Primary progressive MS (PPMS) (~10-15% of cases):
  • Steady progressive worsening of neurological symptoms from onset

Clinically isolated syndrome (CIS):
  • A separate entity to MS, but can subsequently lead to a diagnosis of the condition
  • This is similar to relapse, but in a patient not known to have MS
  • Typical presentation include optic neuritis, focal supratentorial, brainstem or cerebellar syndrome
  • If the patient is subsequently diagnosed with MS, the CIS is defined as their first attack


  • Incidence: 10.00 cases per 100,000 person-years
  • Peak incidence: 40-50 years
  • Sex ratio: more common in females 3:1
Condition Relative
Multiple sclerosis1
Transverse myelitis0.05
<1 1-5 6+ 16+ 30+ 40+ 50+ 60+ 70+ 80+


The underlying cause for this autoimmune response appears to be multifactorial in nature, associated with environmental factors in those with genetic susceptibility:

  • 15-20% of MS patients report a family history of the disease
  • Concordance rate in monozygotic twins is ~ 25% and dizygotic/1st degree relatives are 2-5%
  • Genes in the HLA and IL region have been implicated

  • EBV
    • People with EBV antibody-positive serology have a 5.5 times greater risk of MS than those without
    • Hypothesised that primary EBV infection increases blood-brain barrier permeability to lymphocytes
  • Smoking
    • Increased odds or rate ratio of 1.22 to 1.51 of MS in smokers
    • Nitric oxide and carbon monoxide can cause neuronal damage
  • Vitamin D
    • A prospective case-control study of 7 million military personnel found the risk of MS decreased with higher Vitamin D levels
    • Role in gene expression and immunity regulation
  • Latitude
    • The prevalence of MS appears to increase with higher geographic latitudes
    • Also associated with earlier onset of MS
    • This appears to be linked with exposure to sunlight (and therefore vitamin D)

  • Since MS has a higher predilection in females of childbearing age, knowledge of managing MS in pregnancy is important to prevent delay of treatment and safety to mother and baby
  • In 2018 Association of British Neurologists devised a consensus on pregnancy in MS. In summary:
    • Prepregnancy counselling should inform women who have MS to involve their MS specialist
    • MS does not affect conception or increase the risk of miscarriage
    • Treatment should not be deferred because they wish to have children in the future
    • Having MS does not necessarily make a pregnancy high risk and should not limit birthing options
    • During pregnancy many find their symptoms improve and experience fewer relapses. However, ~25% of women will relapse within 3 months postpartum
    • If a relapse occurs women should be treated with corticosteroids
    • MRI is not contraindicated in pregnancy, however Gd contrast should be avoided
    • 1st line therapies for MS in pregnancy include interferon beta or glatiramer acetate


The exact pathogenesis of MS is still unknown, however it is thought to be an autoimmune mediated (mostly T cell activated) response, that results in 2 distinct phases:

  • T-lymphocyte activation and interaction with CNS endothelial cells, leading to inflammatory cytokine and macrophage induced demyelination

  • Demyelination leads to affects axonal support and membrane potentials
  • Eventual degeneration and loss over time

Histopathologically MS is characterised by:
  • Multifocal demyelination
  • Loss of oligodendroctyes
  • Astrogliosis and loss of axons in mostly white matter

Clinical features

Since MS affects the CNS, its presentation of symptoms and signs can differ greatly between individuals day to day.

Some of the most common symptoms are:

Vision problems (~85%)
  • Around 1 in 4 cases of MS present with optic neuritis
  • This can present as temporary vision loss (including a scotoma), colour blindness and painful eye movements
    • Examination may reveal internuclear ophthalmoplegia or a pale optic disc on fundoscopy

Fatigue (~80%)
  • Exhaustion disproportionate to the activity being carried out
  • Causes of fatigue are in MS are thought to be due to the disease process (primary) and as a consequence of living with it (secondary) e.g. pain affecting sleep

Pain (neuropathic and nociceptive) and altered sensation (~80%)
  • Trigeminal neuralgia
  • Optic neuritis
  • Chest tightness (or banding)
  • Lhermitte's phenomenon
    • A shock-like sensation radiating down the spine induced by neck flexion)

Muscle spasticity, stiffness and weakness (~80%)
  • Spasticity usually affects legs more than arms.
  • Can be associated with spasms that may disturb sleep and lead to falls and issues with mobility
  • Weakness usually affects both lower limbs>one lower limb>upper and lower limb same side>an upper limb

Mobility issues (~75%)
  • Demyelination of cerebellar pathways can lead to ataxia
  • Upper limb intention tremor is common due to thalamus and basal ganglia involvement

Bladder and bowel dysfunction (~75-90%)
  • Increased frequency and urgency
  • Urinary retention
  • Recurrent UTIs
  • Constipation is the most common bowel complaint

Sexual dysfunction (40-90%)
  • Erectile dysfunction is the most common complaint in men
  • Loss of libido and anorgasmia have been documented in both sexes

Depression and anxiety (~40-60%)
  • Most common mood disorder in MS
  • No clear correlation with severity, type of MS or symptom duration
  • Often associated with cognitive impairment, fatigue and pain

Cognitive impairment (~43%)
  • Problems with learning and short term memory common
  • Executive functions (e.g. problem solving and planning) affected

Speech and swallowing issues (~40%)
  • Bulbar muscle problems causing dysarthria or dysphagia


The 2019 NICE Guidelines recommend the following 1st line blood tests in those suspected of MS prior to referring to neurology:

  • Rule out evidence of anaemia (macrocytic in B12 deficiency) and malignancy (thrombocytopenia in lymphoma)
Inflammatory markers (e.g. CRP and ESR)
  • Elevated in infections of the CNS or vasculitides
  • Chronic liver disease can cause polyneuropathy and hepatic encephalopathy

  • Hypocalcaemia classically presents with paraesthesia and tetany
  • Peripheral neuropathy secondary to poor diabetic control
  • Hypothyroidism can present with fatigue, muscle weakness, constipation, slowed movement and thought processing
Vitamin B12
  • Severe deficiency leading to subacute combined degeneration of spinal cord
HIV serology
  • Progressive multifocal leukoencephalopathy due to reactivation of the JC virus
  • Lesions occur anywhere in the CNS mimicking MS

In the absence of abnormal blood tests and high clinical suspicion of MS, referral to a consultant neurologist is recommended.

Investigations carried out in secondary care to confirm diagnosis of MS as recommended in the 2017 McDonald Criteria include:

  • MRI brain in all suspected MS patients

  • MRI spine if:
    • Suggestion of spinal cord lesion
    • Primary progressive pattern
    • MS in atypical demographic
    • To confirm diagnostic confidence of MRI brain

  • CSF examination recommended when:
    • Insufficient clinical of MRI evidence to diagnose MS
    • Any presentation other than CIS
    • Atypical clinical, imaging or lab findings of MS
    • MS in atypical demographic


The McDonald criteria devised in 2001, has undergone a number iterations, most recently revised in 2017 by the International Panel on Diagnosis of MS. This combines clinical, radiological and lab-based findings for diagnosis.

Their position paper describes the following diagnostic criteria for MS:

Clinical PresentationAdditional Data Needed for Diagnosis
≥ 2 clinical attacks and objective clinical evidence of ≥ 2 lesionsNone
≥ 2 clinical attacks and objective clinical evidence of 1 lesionDIS: a further attack indicating a different CNS site or by MRI
1 clinical attack and objective clinical evidence of ≥ 2 lesionsDIT: a further attack or by MRI
OR CSF-specific oligoclonal bands
1 attack and objective clinical evidence of 1 lesionDIS: a further attack indicating a different CNS site or by MRI
DIT: further clinical attack or by MRI
CSF-specific oligoclonal bands

Specifically when assigning a specific MS clinical phenotype the following diagnostic criteria apply:

  • Requires evidence of:
    • Dissemination in space on MRI
    • Gadolinium enhancing and hypointense T2 lesions and/or
    • Subsequent clinical or radiological relapse

  • ≥ 1 year of disability progression (determined prospectively or retrospectively) irrespective of relapses
  • With two of the following:
    • ≥1 T2 hyperintense lesions characteristic of MS in one or more of the following regions: periventricular, cortical or juxtacortical, or infratentorial
    • ≥2 T2 hyperintense spinal cord lesions
    • Presence of CSF-specific oligoclonal bands

  • Currently, there are no clearly defined clinical, imaging or biochemical diagnostic criteria that define SPMS
  • Diagnosis is frequently retrospective
  • A definition based on the Expanded Disability Status Scale (EDSS) is currently being explored

Differential diagnosis

MS can present with a wide range of symptoms including visual disturbance, muscle weakness and sensory disturbance. The following conditions below represent the most common differentials:

Differential diagnosisHistoryExamInvestigations
  • Headache lasting between 4 to 72 hours
  • Aura
  • Photophobia
  • Nausea and vomiting
  • Risk factors
  • Neurological examination normal
  • Clinical diagnosis
  • Further investigations to rule out plausible alternative diagnoses e.g. bloods, LP, MRI
  • TIA/stroke
    • Sudden onset of symptoms (weakness, visual loss, aphasia, ataxia)
    • Risk factors
  • Neurological exam in keeping with single neurological lesion rather than multiple
  • CT head shows ischaemic/haemorrhagic changes
  • Giant Cell Arteritis
    • Usually >50 years old
    • F>M
    • Headache
    • Visual disturbance
    • Jaw claudication
    • Scalp tenderness
    • Fever
    • Malaise
    • Myalgia
  • Absent temporal pulses
  • Pale optic disc on fundoscopy
  • Raised ESR
  • Positive temporal artery biopsy
  • Fibromyalgia
    • Chronic multi-focal pain
    • Generalised weakness
    • Non-specific fatigue
    • Sleep and mood disturbance
    • Family history
  • Neurological examination normal
  • No biochemical abnormalities
  • MRI may show non-specific white matter changes not indicative of MS
  • Myelopathy secondary to cervical pathology
    • Previous neck trauma, surgery or history of cancer
    • Usually painless
    • Reports of hand weakness and reduced coordination
    • Rarely loss of proximal muscle function
    • Symptoms involving a single nerve root
  • Upper motor neurone signs on examination
  • Cervical MRI demonstrating spinal cord or nerve root compression, bony lesions or degenerative changes
    Neuromyelitis optica (NMO) and NMO Spectrum Disorders (NMOSD)
    • Primary presentation is visual disturbance, usually bilateral and more severe than MS
    • May also present with motor or sensory dysfunction
  • As for MS
  • Positive anti-aquaporin-4 antibody and/or +ve anti myelin oligodendrocyte glycoprotein
  • Transverse myelitis
    • Bimodal age presentation: 10-19 or 30-39 years old
    • Muscle weakness and sensory loss
    • Bladder and bowel dysfunction also common
    • Can be a precursor to MS or post infectious (EBV, HSV, CMW and VZV are common)
  • Upper motor neurone signs (hyperreflexia, Babinski sign and spasticity)
  • Hyperintense T2 and Gd enhancing lesions in the spinal cord, but no evidence of brain involvement (if positive likely MS)
  • Increased white cell count on CSF analysis
  • Autoimmune conditions (Lupus, Sjogren's, Antiphospholipid Syndrome (APS)
    • Fever
    • Fatigue
    • Rash
    • Arthralgia/myalgia
    • Thromboembolic events
  • Neurological exam usually normal
  • Raised autoantibodies (anti-Ro/anti-La in Sjogren's, anti-nuclear/anti-DS DNA antibodies in lupus and anticardiolipin in APS)
  • SACD
    • Sensory loss
    • Fatigue
    • Memory loss
  • Decreased vibration sense
  • Gait abnormalities
  • Peripheral neuropathy
  • Low B12 levels
  • Macrocytic anaemia
  • Management

    The 2019 NICE guidelines on MS in adults, suggests a coordinated MDT approach involving professionals from both primary and secondary care including:
    • Doctors
    • Specialist nurses
    • Physiotherapists
    • Occupational therapists
    • Speech and language therapy
    • Dietitians
    • Psychologists
    • Social care
    • Continence specialists

    There is no cure for MS and the mainstay of treatment in patients with MS is symptom control. The main scale to monitor this is the Expanded Disability Status Scale (EDSS). This is based on 8 functional systems:
    • Pyramidal
    • Cerebellar
    • Brainstem
    • Sensory
    • Bowel and bladder
    • Vision
    • Cerebral
    • Other

    The NICE guidelines suggest the majority of complications arising from MS will be managed by a specialist MDT in secondary care, however, depending on local arrangements, the following symptoms may be managed in primary care:

    Acute relapse
    • Discussion should occur with MS specialist prior to instituting treatment in primary care
    • 1st line: oral methylprednisolone 0.5g daily for 5 days
    • If failed or not tolerated on severe relapse: admission for IV methylprednisolone

    • Rule out any other potential medical cause
    • Reassurance and explanation
    • Non-drug-based therapies: mindfulness, CBT, exercise programmes

    Spasticity/mobility issues
    • Treat aggravating factors: skin irritation, constipation, infections, pain
    • 1st line: consider baclofen or gabapentin (off label)
      • Gabapentin is now a Class C controlled drug due to risk of addiction and respiratory depression (especially in existing opioid users)
      • Also useful in MS neuropathic pain
    • 2nd line: consider tizanidine or dantrolene
    • 3rd line: consider a benzodiazepine

    • No recommended treatment. Consider physio or OT referral

    Mental health problems
    • 1st line for emotional lability: Amitriptyline
      • Additional benefit for managing neuropathic pain
    • Offer CBT to patients having issues coping with MS (depression more common in these patients)

    • Musculoskeletal: follow WHO pain ladder
    • Neuropathic: as mentioned before

    Sexual dysfunction
    • PDE-5 inhibitors for erectile dysfunction in men
    • Referral to counselling services

    Alongside the above treatments, secondary care can also institute disease-modifying therapies (DMTs). An algorithm (recently updated in 2019) by NHS England in accordance with NICE guidance, provides a guide to starting these treatments.

    Treatment criteria:
    • EDSS score <7.0
    • No evidence of non-relapsing progressive MS
    None recommendedInterferon beta 1aInterferon beta 1bGlatiramer acetateDimethyl fumarateTeriflunomideAlemtuzumabOcrelizumabCladribineNatalizumab
    1 episode and diagnostic of RRMSYesYesNoYesNoNoYes if evidence of rapidly developing permanent disabilityYes if evidence of rapidly developing permanent disabilityNoNo
    RRMS (2 relapses in 2 years)NoYesYesYesYesYesYesYesNoNo
    RRMS (1 relapse in last 2 years and evidence of radiological activityNoYesNoYesNoNoYesYesNoNo
    Rapidly evolving RRMS:
    • 2 or more relapses in 1 year
    • 1 T1 Gd enhancing lesion
    • Non-responsive to previous DMTs
    Relapsing SPMS:
    • 2 relapses in 2 years
    • EDSS <7.0
    • Minimal change in disability due to progression over the last 2 years
    • >18 years old
    • No contraindications


    The main complications arise largely from worsening of their existing symptoms as described before:
    • Recurrent UTIs
    • Osteopenia and osteoporosis
    • Depression
    • Visual impairment
    • Cognitive impairment
    • Impaired mobility


    It is difficult to prognosticate in MS patients as some may follow a very benign course whilst others will develop rapid onset disability within years of diagnosis. This can be influenced by:

    MS phenotype
    • A study of 220 MS patients, showed after 15 years: RRMS patients had a survival rate of ~95% (PPMS, ~90%), those without a wheelchair (EDSS <7.0) ~84% (PPMS, ~42%) and ~71% (PPMS, ~9%) walking without an aid.

    Severity and frequency of relapses
    • RRMS prognosis more favourable in those with less frequent initial relapses and if there is more than 2-3 years between 1st and 2nd relapse.
    • Newer studies show higher lesion burden at onset=poorer prognosis.

    Responsiveness to treatment
    • Steroids reduces length and severity of relapse, but no long term effect on disease course or prognosis.
    • DMTs may reduce the number and severity of relapses.
    • A 2013 Cochrane review found they can prevent disability progression, but longer-term studies needed.