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).
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.
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.
Symptoms of dry eyes and dry mouth as well as joint stiffness and pain.
Neurological examination is usually normal
Numbness, fatigue, and possible memory loss.
Posterior column loss of sensation (vibration and proprioception) in the presence of increased reflexes on examination
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
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.
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.
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
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