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Subject: Multiple Sclerosis
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An autoinflammatory disease causing demyelination, neuronal loss, and scarring within the white matter of the brain and spinal cord
Four recognized forms of multiple sclerosis (MS) 1:
Most patients experience lower exacerbation rates during pregnancy. Following delivery, the immune system reverts and MS flares become more likely.
Breastfeeding does not affect the risk of MS relapse.
Relapse during postpartum can be safely treated by IVIG and corticosteroids 2[C].
Age: peak incidence ages 15 to 45 years, mean age 28 to 31 years (slightly earlier in women than men)
Gender: Studies suggest F:M between 1.4:1 and 3:1.
Latitude: Prevalence tends to rise with increasing distance from the equator, although newer data reveals this latitude gradient may be declining 3,4.
Women (worldwide): 3.6 cases/100,000 person-years
Men (worldwide): 2.0 cases/100,000 person-years
United States: ∽350,000 MS patients
Worldwide: ∽2,500,000 MS patients
MS lesions: Inflammatory cells, mainly T lymphocytes and macrophages, surround vasculature within the CNS, creating sites of inflammation. These cells then disrupt the blood-brain barrier and infiltrate the surrounding white matter, meanwhile preserving the vessel wall. B lymphocytes, as well as myelin-specific autoantibodies, also infiltrate the CNS and cause degeneration of the myelin sheaths.
Following demyelination, faster salutatory nerve conduction velocities (impulses jumping between nodes of Ranvier) are replaced with considerably slower continuous nerve velocities.
Astrocytes begin to proliferate and cause gliosis.
Oligodendrocytes, which have survived, or ones formed from precursor cells, are able to partially remyelinate stripped axons, producing irreversible scars.
In each MS lesion, axonal damage may occur, but it is the cumulative axonal loss over time that is responsible for the progressive and irreversible neurologic disability seen in MS patients.
Most axons are typically lost from the lateral corticospinal (motor) tracts of the spinal cord.
Strong predisposition: HLA DRB1 5
Proposed predisposition: IL2RA and IL7RA
Race: Caucasian > Africans or Asians
Genetic: DRB1 locus on chromosome 6 has strongest MS risk association; DRB1*15 and *16 produce major histocompatibility complexes (MHC) with high binding affinity to myelin basic proteins (MBPs) 3,5.
Geographic: Previously, distance from equator showed association with increased risk, though now declining. However, sun exposure (ultraviolet B [UVB] radiation necessary for endogenous vitamin D production) appears to have inverse relation to MS incidence 3.
Infectious: viral infections (especially EBV, HHV) 3,5
Race: Caucasian > African, Asian, Native American, although this is decreasing 5
Others: tobacco smoking 6
Internuclear ophthalmoplegia (INO): Injury to the medial longitudinal fasciculus (MLF) causes impaired adduction to the affected eye.
Optic neuritis: inflammation of optic nerve resulting in loss of vision
Uhthoff phenomenon: Symptoms worsen with exposure to higher than usual temperature.
Lhermitte sign: electric-like shocks extending down the spine caused by neck movement, especially flexion
A person with MS can present with a number of neurologic signs and symptoms depending on the locations of the lesions within the CNS 5[C].
Clinical diagnosis: ≥2 attacks; objective clinical evidence of ≥2 lesions or objective clinical evidence of 1 lesion with history of a previous episode. Flare-up duration must be at least >24 hours. Relapses must be separated by ≥1 month. ≥1 out of 2 neurologic signs must be present. The second clinical sign may be obtained through an abnormal paraclinical exam such as MRI or evoked potentials (EPs) or may be supported by an abnormal paraclinical exam 5,7[C].
For patients with steady decline of neurologic function for ≥6 months without flares, intrathecal IgG may be used to support the diagnosis 5[C].
Optic disc swelling or pallor
Nystagmus in abducting eye
Hypesthesia or paresthesia
Cerebellar dysarthria (scanning speech)
Spasticity (especially in lower extremities)
Systemic lupus erythematosus (SLE)
Antiphospholipid antibody syndrome
Progressive multifocal leukoencephalopathy (PML)
Cobalamin (vitamin B12) deficiency
Acute disseminated encephalomyelitis (ADEM)
Normal pressure hydrocephalus
CSF: increased monocyte cell count and intrathecally formed IgG levels. Total protein within CSF may be normal or increased. The presence of oligoclonal bands (OCB) is used to determine amount of IgG intrathecally synthesized. ≥2 OCBs is diagnostic 5[B].
Tests used for exclusion of alternative diagnoses: antinuclear antibodies (ANAs), serum cobalamin level, erythrocyte sedimentation rate (ESR), and testing for syphilis
MRI of head/spine (more sensitive than CT):
McDonald criteria 5:
Three main categories currently exist for MS treatment: treatment for acute relapses, treatment for reducing MS-related activity using disease-modifying agents and symptomatic therapy 2,5[B]
For apparent acute relapse, rule out infectious etiology prior to treatment.
Acute relapses 2[B]
Reduction of MS biologic activity, interferon-β (IFN-β) 1,5,8
Symptomatic therapies 5[B]:
Cognitive behavioral therapy
Physical and occupational therapy
Water therapy: Swimming, in cool water, is typically well-tolerated.
Strenuous physical activity appears to confer protective benefit and slow the disease progression in pediatric patients.
1.0—no disability, minimal signs in 1 FS
2.0—minimal disability in 1 FS
3.0—moderate disability in 1 FS or mild disability in 3 to 4 FS, but fully ambulatory
4.0—ambulatory without aid or rest for ∽500 m
5.0—ambulatory without aid or rest for ∽200 m
6.0—intermittent/constant unilateral assistance (cane, crutch, or brace) must be able to walk 100 m
7.0—unable to walk beyond 5 m even with aid; essentially restricted to wheelchair, wheels self and transfers alone; active in wheelchair for ∽12 hr/day
8.0—essentially restricted to bed, chair, or wheelchair; may be out of bed most of the day; retains self-care functions, generally effective use of arms
9.0—helpless, bed-bound; but patient can communicate, eat
10.0—death due to MS
Differs in each individual; depends on the form of MS, the individual's sex and age, the initial presentation of the disease, and the amount of disability
Average life expectancy is 5 to 10 years less than unaffected people.
Specific clinical features suggesting more favorable course: early onset, RRMS form, female sex, ≪2 relapses within first year of diagnosis, and minimal functional decline after 5 years 5.
Mortality secondary to MS relapse is unusual; death more commonly associated with a complication of MS such as infection in a person with more disability.
24700007 Multiple sclerosis (disorder)
428700003 Primary progressive multiple sclerosis
425500002 secondary progressive multiple sclerosis (disorder)
426373005 relapsing remitting multiple sclerosis (disorder)
Immune-mediated inflammatory disease causing demyelination, neuronal loss, and scarring within the white matter of the CNS
Charcot classical MS triad: nystagmus, intention tremor, and dysarthria
Acute relapses are treated with steroids; disease-modifying medications are used for chronic treatment; currently, there is no treatment for promoting remyelination or neuronal repair.
Based on limited clinical data, IVIG is not thought to be effective therapy for relapsing remitting MS (10).
Autologous stem cell transplantation for MS shows promise, but more rigorous research is needed (11,12).