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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
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