Multiple sclerosis

Definition

    • An inflammatory demyelinating disease

    • Characterised by the presence of episodic neurological dysfunction in at least 2 areas of the CNS (brain, spinal cord, and optic nerves) separated in time and space

Risk Factors

    • Strong

      • Female sex

      • Northern latitude

    • Weak

      • Genetic factors

      • Smoking

      • Vitamin D deficiency

      • Autoimmune disease

Differential diagnosis

  • Myelopathy due to cervical spondylosis

      • The patient's symptoms and signs are all below the neck (although they may have dizziness and headache).

  • Fibromyalgia

      • Symptoms are vague, with generalised weakness and non-specific fatigue common.

      • Neurological examination is normal apart from possible functional overlay.

      • Postural orthostatic tachycardia syndrome with or without cervicogenic migraine

      • History is significant for headaches and dizziness, particularly with change of head position or standing.

      • Examination is normal.

  • Sleep disorders

      • Patient describes nonrestful sleep with variable features of snoring, restless legs, and apnoea.

      • Memory changes and mood disturbances may be prominent.

      • Neurological examination is normal.

    • Sjogren's syndrome

      • Symptoms of dry eyes and dry mouth as well as joint stiffness and pain.

      • Neurological examination is usually normal

    • Vitamin B12 deficiency

      • Numbness, fatigue, and possible memory loss.

      • Posterior column loss of sensation (vibration and proprioception) in the presence of increased reflexes on examination

    • Ischaemic stroke

      • History indicates sudden onset of symptoms.

      • Signs and symptoms usually explainable on the basis of a single neurological lesion, rather than multiple

      • Peripheral neuropathy

      • Loss of sensation and reflexes in the feet and hands

    • Lymphoma

      • Patient has gradual onset of severe disability

      • Inherited disorders such as mitochondrial diseases and leukodystrophies

      • Patient has gradual onset of memory or cognitive problems, sometimes in the setting of neuropathy.

  • Guillain-Barre syndrome

      • Loss of reflexes with predominantly motor symptoms.

      • Dangerous respiratory complications are more common.

  • Amyotrophic lateral sclerosis (ALS)

      • Mixed upper and lower motor neuron signs are present:

        • increased reflexes (upper motor neuron)

        • atrophy and fasciculations (lower motor neuron).

      • Visual changes are absent.

      • ALS may involve dysphagia and pulmonary function abnormalities, but the dysphagia, unlike in MS, is usually accompanied by tongue fasiculations and dysphonia

  • Systemic lupus erythematosus (SLE)

      • Patient may have fevers, joint pain and swelling, muscle tenderness, (malar) rash.

Epidemiology

    • MS is most commonly diagnosed between 20 to 40 years old.

      • However, it can occur in the paediatric age group to as young as 2 years, where it may be confused for acute disseminated encephalomyelitis.

      • It is occasionally diagnosed in individuals in their sixth or seventh decade who may have been asymptomatic for years.

    • There is a significantly skewed sex ratio, with a female to male ratio of around 3:1, and the disparity appears to be increasing. [8]

    • MS is the most common cause of neurological disability among young adults.

      • In Europe and North America the estimated prevalence of MS is 1 in 800, and the annual incidence is between 2 and 10 cases per 100,000 population. [9]

    • Within the US the incidence of MS is most common in white women who were raised in northern US. [10]

      • Estimates of prevalence range from over 400,000 in the US population as a whole, to 250,000 to 350,000 in the white population. [10]

    • Both the incidence and the ascertainment (i.e., diagnosis using more sensitive and specific investigations) of MS are felt to be rising in the US and globally.

    • A geographic gradient, with higher incidence at latitudes closer to the poles, has been linked with MS. [11]

    • Individuals of European decent are most commonly affected

      • However, affected black Americans may have more aggressive courses due to a combination of socioeconomic and genetic factors, as well as later diagnosis. [12]

Aetiology

    • While classically viewed as a disease of CNS white matter, there is now substantial evidence supporting both grey and white matter involvement. [13]

    • It appears to have both inflammatory and degenerative components that may be triggered by an environmental factor or factors in persons who are genetically susceptible.

      • MS is 20 to 40 times more common in first-degree relatives. [10]

      • While the genetics of this condition are multifactorial, genes in the human leukocyte antigen (HLA) region and interleukin region are likely to be involved. [14]

    • Environmental factors that have been postulated to be involved in MS include:

      • toxins

      • viral exposures

      • sunlight exposures (and its effect on vitamin D metabolism). [15]

    • While some researchers have proposed that MS is caused by a virus, none of the nearly 20 viruses that have been candidates over the last 20 years have proved to be causative.

      • Epstein-Barr virus (EBV) is currently the virus shown to have the greatest link to increased risk of MS.

    • Relapses are often triggered by infections or postpartum hormonal changes.

    • Surgical procedures may also trigger relapses, and some literature suggests that acute trauma or stressful events may be precipitants, although this is controversial.

Clinical features

    • Visual disturbance in one eye (common)

      • Graying or blurring of vision in 1 eye (can be described as looking through petroleum jelly).

      • May have pain in moving that eye and describe loss of colour discrimination, particularly reds.

    • Peculiar sensory phenomena (common)

      • Patients often describe odd sensations of a patch of wetness or burning, or hemibody sensory loss or tingling.

      • In particular, banding or hemibanding is associated with spinal cord lesions.

      • Lhermitte’s sign (electric shock-like sensations extending down the cervical spine radiating to the limbs) and trigeminal neuropathy or neuralgia are other possible sensory findings in MS.

    • Female (common)

      • Incidence in females to males is around 3 to 4:1. [8]

    • Age 20 to 40 (common)

      • Most commonly diagnosed from age 20 to 40 years old.

    • Foot dragging or slapping (common)

      • Patient will often describe gradual onset of weakness after walking several streets or several miles such that the foot slaps the ground.

      • This weakness resolves with rest.

    • Leg cramping (common)

      • Patient describes involuntary movement in the lower leg with cramping or jerking in the calves, particularly at night or while driving.

    • Fatigue (common)

      • May be related to MS primarily, but often worsened dramatically by such multifactorial causes as poor sleep hygiene, depression, restless legs, urinary frequency, or underlying sleep apnoea.

    • Urinary frequency (common)

      • Multifactorial causes including damage to CNS resulting in urinary retention and detrusor instability.

      • UTIs are more frequent in patients with urinary retention.

    • Bowel dysfunction (common)

      • Constipation is commonly seen in MS.

      • Bowel urgency and incontinence are almost always symptoms of constipation and should be managed as such.

    • Spasticity/increased muscle tone (common)

      • Damage to the CNS resulting in increased muscle tone.

      • Commonly affects the legs and can be very unpleasant and painful, disturbing sleep as well as ambulation.

    • Increased deep tendon reflexes (common)

      • Particularly clonus at the ankles and often asymmetrical.

    • Imbalance/incoordination (common)

      • Wide-based gait and/or limb ataxia indicate cerebellar dysfunction, which occurs frequently in MS.

    • Pale optic disc or noncorrectable visual loss (uncommon)

      • Suggestive of optic neuritis.

    • Incorrect responses to Ishihara colour blindness test plates (uncommon)

      • Damage to optic nerve, may be accompanied by decrease in ability to see reds, which are seen as less intense or orange.

    • Abnormal eye movements (uncommon)

      • Intranuclear ophthalmoplegia (nystagmus of the abducting eye with absent adduction of the other eye), or isolated nystagmus may be present.

Pathophysiology

    • The precise pathogenesis of MS is unknown.

    • There is no specific or sensitive antigen or antibody, and there is some debate if MS represents a single disease or a syndrome of pathogenically heterogeneous patient subgroups.

    • Recent conceptualisations of MS immunopathology involve 2 distinct but overlapping and connected phases, inflammatory and degenerative.

      • During the initial stage of the inflammatory phase, lymphocytes with encephalitogenic potential are activated in the periphery by factors such as infection or other metabolic stress.

        • These activated T cells seek entry into the CNS via attachment to a receptor on endothelial cells.

        • This interaction, mediated by production of matrix metalloproteinases, allows a breach in the blood-brain barrier

          • Leads to further upregulation of endothelial adhesion molecules and additional influx of inflammatory cells.

        • The T cells produce inflammatory cytokines that cause direct toxicity and also attract macrophages that contribute to demyelination.

      • The degenerative component of MS is believed to reflect axonal degeneration and loss.

        • Demyelination disrupts axonal support and leads to destabilisation of axonal membrane potentials, which causes distal and retrograde degeneration over time.

        • There is also suggestion that inflammatory cells, antibodies, and complement may contribute to axonal injury.

        • Axonal damage has been identified in regions of active inflammation indicating that it begins early in the disease process. [17]

    • Pathologically, MS is characterised by multifocal areas of demyelination, loss of oligodendrocytes, and astrogliosis with loss of axons primarily in the white matter of the CNS

      • Although cortical lesions may also play a significant role.

    • Both the clinical heterogeneity and studies of biopsy and autopsy specimens have suggested that the mechanisms leading to tissue damage differ from patient to patient.

      • Relapsing-remitting MS (RRMS) shows the most inflammatory activity

        • Followed by relapsing-progressive MS (RPMS) and early secondary-progressive MS (SPMS).

      • Primary-progressive MS (PPMS) shows a primarily degenerative process.

    • Disease-modifying therapies in MS are most active against inflammation.

    • Acute relapses of MS with disturbance of CNS function such as vision or mobility are thought to be periods of increased inflammatory activity of the immune system and treated accordingly.

    • Clinical progression is believed to be a manifestation of combined on-going chronic low-level inflammation with degenerative processes.

      • Gradual loss of ability to ambulate over several years

      • Poorer recovery from relapses

    • Brain and spinal MRI manifestations of inflammation show contrast-enhancing lesions with limited oedema

    • MRI manifestations of the progressive process show atrophy and T1 hypointensity (or black holes).

    • Management of MS attempts to reduce the potential for triggering the bursts of inflammatory activity known as relapses, as well as limiting the extent of the relapses.

Investigations

    • MRI - brain

      • Hyperintensities in the periventricular white matter, most sensitive images are sagittal FLAIR

    • MRI - spinal cord

      • Many MS patients will have cervical spinal cord lesions and the specificity of this finding is very high

    • FBC

      • Indicated to exclude alternative diagnoses or concomitant illnesses

    • Comprehensive metabolic panel

      • Indicated to exclude alternative diagnoses or concomitant illnesses

    • Thyroid-stimulating hormone (TSH)

      • Indicated to exclude alternative diagnoses or concomitant illnesses

    • Vitamin B12

      • Indicated to exclude alternative diagnoses or concomitant illnesses

    • anti-NMO antibody

      • Present in neuromyelitis optica (Devic's syndrome)

      • Anti-NMO (anti-aquaporin 4 (AQP4)) antibody testing is recommended in:

        • patients with long segments of spinal cord demyelination, with or without optic neuritis

        • patients with recurrent optic neuritis with normal brain imaging

    • CSF evaluation

      • Due to the invasive nature of the testing, all other non-invasive tests should be pursued first.

      • Note that the CSF is normal in 10% to 20% of MS cases

      • Glucose, protein, and cell count should be normal

      • Oligoclonal bands and elevated CSF immunoglobulin G (IgG) and IgG synthesis rates are present in 80% of MS cases

    • Evoked potentials

      • Prolongation of conduction, particularly asymmetrical prolongation in the visual evoked potentials

        • Visual evoked potentials are most commonly abnormal, with somatosensory and auditory evoked potentials less so.

        • Somatosensory evoked potentials can be painful for the patient, as well as technically difficult

Management

a) conservative

    • lifestyle assessment ± medication

    • physiotherapy

b) medical

    • immunomodulators

    • methylprednisolone

    • intravenous immunoglobulin (IVIG)

    • plasma exchange

    • low-dose anticonvulsants

  • dalfampridine

    • fatugue medication

      • amantadine, modafinil, or armodafinil

    • Oxybutynin and other agents such as solifenacin, darifenacin, fesoterodine, and tolterodine may be used for symptoms of urinary frequency if retention is not present.

c) surgical

    • n/a

Prognosis

    • It is very difficult to prognosticate effectively for MS patients.

    • Some individuals have a very benign course and/or respond well to treatment, whereas others become rapidly disabled within several years of diagnosis.

    • Various factors favouring better prognosis have been supported by older demographic studies done in the pre-treatment era

      • Include female sex, sensory symptoms, or optic neuritis at onset.

    • Poorer prognostic factors include frequent relapses and motor or cerebellar onset.

    • Newer studies have looked at lesion burden on MRI at onset, indicating that a higher lesion burden at onset portends a poorer prognosis