An autoimmune CNS disorder with discrete brain lesions and lesions throughout the CNS.
And most characteristic lesions are focal demyelination in the white matter, as identified on MRI.
In MS grey matter and cortical lesions are also common on pathological tissue analysis but not reliably visualized with current imaging.
MS lesions may enter a chronic phase where can include remyelinization, inflammation resolution without repair, or a smoldering state in which inflammation and myelin degeneration coexist.
T cells have a role in the development of information and demyelination.
B cell deleting therapies support a pathogenic role through regulation of T cells.
MS is an inflammatory demyelinating disease of the central nervous system (CNS) that develops in genetically susceptible individuals after exposure to unknown environmental trigger(s).
The bases for MS are unknown but are strongly suspected to involve immune reactions against autoantigens, particularly myelin proteins.
The most accepted hypothesis is that dialogue between T-cell receptors and myelin antigens leads to an immune attack on the myelin-oligodendrocyte complex.
These interactions between active T cells and myelin antigens provoke a massive destructive inflammatory response and promote continuing proliferation of T and B cells and macrophage activation, which sustains secretion of inflammatory mediators.
Relapsing and often progressive disorder of the white matter of the CNS characterized by injury to oligodendrocytes and axonal demyelination that is generally believed to be immune mediated.
Relaxing-remitting MS starts with clinical relapses with near or complete recovery, but overtime recovery may be incomplete, and disability can accumulate.
Approximately 20% of patients with relapsing-remitting MS developed progressive neurologic decline later in the disease and transition to secondary progressive MS.
Small proportion of patients, 15%, have progression of disease from onset.
Life expectancy in MS patients is 5 to 10 years lower than unaffected people.
Patients with relapsing remitting MS and progressive MS report the median time from onset requiring a walking aid of 20 and seven years, respectively.
Idiopathic, autoimmune, chronic inflammatory demyelinating CNS disease with genetic and environmental effects.
Etiology is unknown, but environmental, lifestyle, and genetic factors may contribute to development and outcomes.
A Neurodegenerative autoimmune disease that results in the formation of lesions in the protective layer around the nerves in the brain and spinal cord.
It is associated with adverse events affecting communication among various areas within the nervous system, resulting in a wide range of symptoms, such as mental changes and psychiatric complications.
The activity and interactions of B cells, T cells, and myeloid Cells are mvolved in the immuno-pathological features of the disease.
Regulatory T cells are defective in many autoimmune diseases, including multiple sclerosis.
Multiple sclerosis is a neurodegenerative disease in which T-cells attack the important myelin sheath in brain neurons.
It is a failure of myelin generating cells and the immune system.
B cells are mediators of both aspects of MS: inflammation and neurodegeneration.
Anti-CD20 monoclonal antibodies that induce B cell depletion such as rituximab and ocrelizumab are effective disease modifying therapies.
The most common autoimmune demyelinating disease of the CNS.
An inflammatory disease of the CNS that shares several genetic variants with other autoimmune diseases.
Antigen-activated B cells influence functions through antigen presentation and production of cytokines and antibodies.
Peripheral B cells are responsible for relapses, while sequestered the cells within the CNS contribute to progression.
Macrophages and microglia are evident in multiple sclerosis lesions and contribute tissue damage and repair.
Characteristic periventricular white matter lesions the hallmark of MS.
Most cases begin as inflammatory relapsing remitting disease.
Relapse onset MS encompassing relapse-onset and secondary progressive multiple sclerosis is the most frequent form.
Within two decades of onset, 80% of untreated patients with relapsing-remitting MS convert to a phase of sustained disability accrual term secondary progressive multiple sclerosis.
Secondary progressive multiple sclerosis is responsible for much of the diseases negative physical, psychological, and societal affects.
10-15% of patients have progressive disability from onset with no, or very very infrequent, relapses and remissions.
The classic presentation includes: unilateral optic neuritis with blurred vision and associated pain, partial myelitis with extremity and torso impaired sensation, weakness, and/or ataxia, focal sensory disturbances with limb paresthesias, abdominal or chest banding, or brainstem syndromes with internuclear ophthalmoplegia, vertigo, hearing loss, facial sensory disturbance.
Objective findings that may be present to neurologic examination include afferent pupillary defect, impaired sensation, motor weakness, ataxia, and gait impairment, often with hyperreflexia.
White matter of the cerebral hemispheres, infratentorial and spinal cord are affected with plaques.
Common in the optic nerves and optic tracts, in the supratentorial and infratentorial white matter, along the myelinated aspects of the spinal cord and may occur in the corpus callosum, cerebeller white matter and corticospinal tracts.
White matter CNS lesions include loss of myelin, neuronal axons, and myelin producing oligodendrocytes characterized the multifocal pathology.
Sharply demarcated white matter lesions with marked disruption of the myelin sheath is the hallmark of MS.
Associated with a complex immune response whereby the adaptive immune system drives pathology in the early stages of disease.
Eventually immune system reaction wanes to be overtaken by other disease processes such as innate immune system reactions, mitochondrial dysfunction, glutamate toxicity, and reducd compensatory ability leading to gradual disability accumulation in older age.
Serum neurofilament light chain (NFL) levels, represent axonal breakdown, correlates with disease activity.
Neurofilament levels tend to agree with MRI findings and may become a useful biomarker of MS disease activity.
Many patients, even if asymptomatic, have ongoing MS disease activity that can be detected by periodic MRI scans.
Activated leukocytes promote acute inflammation in CNS lesions and enter into the central nervous system through a breach in the blood brain barrier.Correlated with the acute inflammatory lesions are a clinical attack consisting of subacute neurologic symptoms that worsen over a few days to a few weeks, and early in the disease, often recover spontaneously and completely.
Involvement with gray matter, may be relevant to irreversible disability.
Majority of patients enter a secondary progressive phase of disease for which there is no efficacious therapy.
Prevalence of up to 400,000 cases in the U.S. annually.
Childhood obesity is associated with increased risk.
150 people per 100,000 prevalence.
Estimated worldwide 2.5-3.5 million have this disease.
Average annual cost $47,000 per patient in the US.
Prevalence approximately 1 case per 1000 persons in white populations, and female to male ratio 2:1.
Mean age of diagnosis 28-31 years.
May present from the first to the seventh decades of life.
Increased female risk develops around age 11 years, and patients with earlier menarche correlates with earlier MS onset.
Occurs much less frequently in tropical and semitropical areas than in cold parts of the world.
Multiple sclerosis is associated with decreased risk of cancer overall but an increased risk of central nervous system cancer, primarily in the brain.
Prevalence increases the further one moves from the equator, thought to be related to differences in genetic background, infection exposure and vitamin D levels.
Clinical onset often insidious.
The free radicals, cyanate and carbon monoxide found in cigarettes are directly neurotoxic, explaining that smoking with MS may be associated with higher disease activity, faster brain atrophy and greater disabilities.
Cigarette smoking and Epstein-Barr virus infection are associated with increased risk.
Quality of life affected by physical symptoms, including fatigue, pain, impaired mobility, and social dysfunction along with impaired mood and affect.
Physical activity is associated with improved symptoms and anti-inflammatory effects and may be associated with larger brain volume.
50% of patients are unable to continue employment 10 years after diagnosis, require ambulation assistance by 15 years, or cannot walk by 25.years.
First neurological episode of central nervous system dysfunction suggestive of multiple sclerosis is known as a clinically isolated syndrome, and it is difficult to predict an individuals risk of multiple sclerosis.
The McArdle’s sign, defined as greater than 10% neck flexion and is associated with a reduction in strength is specific and 65% sensitive for a diagnosis of MS.
Occurrence before age 10 and after age 50 years is rare, but has been documented to have occurred from ages 2-74 years.
Median age of clinical onset is approximately 29 years.
Female:male approaches 3:1.
Usually appears between late teenage years and the fourth decade, with peak at approximately 35 years of age.
Affects 1 in 1,000 people in Western countries.
Most prevalent in whites of northern European descent.
Prevalence in northern Europe 2 per 1000 population.
More common in temperate climates.
Japanese Americans have a prevalence of one fourth of white Americans, while African-Americans have approximately one third the prevalence of white Americans.
Highest prevalence among individuals in the Orkney Islands of Scotland with 250 cases per 100,000 population.
In many countries with a high prevalence such as US, northern Europe, Russia, Canada, and New Zealand there is a Latitude gradient of risk.
In regions with lower prevalence this gradient relationship does not always hold.
Individuals that move from low to higher prevalence regions after age 15 maintain the lower risk of the area they migrated from, whereas patients migrating before this age assume the risk of the region they move to.
Most common chronic disabling CNS disease in young adults.
Involvement of the auditory system with hearing loss is rare.
More than 80% of patients have genitourinary symptoms, ranging from urging incontinence to urinary retention.
Early-onset multiple sclerosis occurs in 2.7-5% of all cases.
Vasculitis is peripheral in the retina, and is associated with cellular infiltration of the peripheral vitreous.
Older age at clinical onset is frequently associated with a poor prognosis.
Patients with MS and comorbidities such as psychiatric and cardiovascular diseases and health behavior abnormalities such as tobacco use are associated with increase disability, MRI changes with lower brain volumes, increased mortality, and decreased quality of life.
Psychiatric disorders of depression and anxiety are more common in patients with MS with a range of 21 to 50%, and prevalence estimates or 2 to 3 times higher than the general population.
Vascular abnormalities including hyperlipidemia, hypertension, heart disease, diabetes, and peripheral artery disease can lead to worse outcomes in MS.
Viral etiology suggested by the fact that several viruses are associated with encephalomyelitis, demyelination can be induced in animal studies through viral infections, axonal damage can be seen with viral infections of the CNS, and such infections may precede demyelination in multiple sclerosis, CD8+ Tcells involved in viral immunity predominate and expand an active MS plaques, gray matter lesions and axle damage are commonly seen in multiple sclerosis, and some viruses including human herpes virus 6 (HHV-6), have latency and periodic reactivation, similar to the behavior of relapsing-remitting MS 9 Voumourakis, K et al).
Part of the Epstein-Barr virus mimics a protein made in the brain and spinal cord, leading the immune system to mistakenly attack the body’s nerve cells.
Approximately 85% have a relapsing form of the disease at onset.
Highest frequency of relapse-onset MS occurs in women.
Multiple sclerosis (MS) occurs more frequently in women, often during childbearing years.
Estimated female to male incidence ratio of 2.3:1.
Patient’s with primary progressive MS are generally about 10 years older at diagnosis than those with relapsing MS.
Mean age of onset for primary progressive MS is about 40 years and 30 years for relapse-onset MS.
The second most common cause of disability in young adults.
More than half of patients have increasing and sustained disability between acute attacks and transition to secondary progressive MS within 10-20 years after diagnosis.
Life expectancy reduced from 4 to 12 years.
Diagnosis is based on a combination of clinical findings, imaging, and laboratory data using McDonald criteria.
Diagnosis is defined by a demonstration of dissemination of disease characteristics in space and time.
Dissemination in space refers to the presence of lesions in distinct CNS anatomical locations.
These lesions can be identified by clinical events implicated in different areas of the CNS, or multiple T2-hyperintense lesions on MRI or both.
Dissemination in time can be defined by multiple distinct clinical attacks, and spinal fluid oligoclonal band presence.
MRI the most sensitive imaging technique to detect lesions.
High-powered MRI scanners can identify smoldering chronic active lesions which were previously only detected at autopsy.
MRI enhancement of lesions tend to be transient, often at their initial presentation.
Inflammatory component on gadolinium MRI is less prominent in primary progressive MS than in relapse onset multiple sclerosis.
Corpus callosum often disproportionately involved.
Relapses are not induced by vaccinations.
Most common cause of severe neurologic disability in adults of north European origin.
Multiple areas of focal loss of myelin with relative preservation of axons, a variable amount of inflammation and astrocytic gliosis.
Axonal damage is an early event in the evolution of multiple sclerosis.
In areas of inflammation the blood-brain barrier breaks down and perivascular lymphocytic and monocytic infiltration occur with focal destruction of myelin, axonal damage, gliosis with plaque formation.
Pathophysiology relates to an autoimmune process in which lymphocytes migrate from lymph nodes into the circulation and cross the blood brain barrier targeting myelin antigens in the CNS, causing inflammation, demyelination, neuroaxonal injury, astrogliosis and neuronal degeneration eventually (Hafler DA et al).
Lymphocyte migration from lymph nodes is dependent on G protein-coupled receptor, S1P1 present on the surface of the lymphocyte.
G protein-coupled receptor ligand for this receptor is the lipid sphingosine S1P, found predominantly in the serum and lymph, and a gradient in its concentration induces lymphocyte migration from lymph nodes into the circulation.
As damage occurs the brain there is significant loss of white matter and reduction in brain volume.
About 85% present with a relapsing stage; the relapses are associated with periventricular foci of inflammation in the white matter.
First clinical demyelinating event in 15-20% of patients is optic neuritis with 50% experiencing this problem some time during the course of the disease.
Increased risk of MS among patients with isolated syndrome and antibodies to recombinant myelin oligodendrocyte glycoprotein (MOG) and purified myelin basic protein (MBP).
MOG makes up 0.01-005% of central myelin protein and is found exclusively in the CNS, with its N-terminal domain expressed on the myelin surface accessible to antibodies.
MPG makes up about 30% of the central myelin protein and is localized on the cytoplasmic side of the myelin sheath.
Serum neurofilament light is associated with multiple sclerosis (MS) disability, brain atrophy, and disease activity.
Typically begins in the second and third decades with a female preponderance of about 2:1.
Most patients have relapsing-remitting form characterized by episodes of neurologic impairment followed by complete or nearly complete recovery: Later neurologic impairment becomes progressive.
Characteristically starts with sensory and visual changes, extremity weakness, ataxia, bowel and bladder complaints.
After relapsing-remitting phase, most patients enter a secondary progressive phase and accumulate irreversible neurological deficits.
Most patients have sensory and motor dysfunction, and visual loss from optic neuritis is not uncommon.
Worsening of vision with exertion or exposure to heat seen in this disease is referred to a the Uhthoff phenomenon.
Estimated that 50% of patients will require ambulation assistance after 15 years of disease process.
Cognition is impaired in approximately in 43% of patients (Rao).
More than 80/% develop genitourinary tract dysfunction ranging from urethral and bladder dysfunction and impotence.
Acute relapses associated with focal inflammatory demyelination resulting in nerve-conduction blocks with production of nitric oxide by macrophages.
Remissions associated with reduction in inflammation and conduction restoration and variable remyelination.
15% of patients have a primary progressive form.
Not associated with Hepatitis B vaccine administration.
MacDonald’s diagnostic criteria:
2 or more attacks-no additional data needed
2 or more objective clinical lesions-no additional data needed
2 or more attacks or 1 objective clinical lesion-plus dissemination in space demonstrated by MRI, CSF abnormality and 2 or more MRI lesions consistent with diagnosis, or a further clinical attack involving a different site
1 attack and 2 or more objective clinical lesions-plus dissemination in time demonstrated by MRI, or second clinical attack
1 attack and 1 objective clinical lesion (monosymptomatic presentation)-plus dissemination in space demonstrated by MRI, or positive CSF and 2 or more MRI lesions consistent with multiple sclerosis and dissemination in time demonstrated by MRI or second clinical attack
Insidious neurological progression suggestive of multiple sclerosis (primary progressive MS)-positive CSF and dissemination in space demonstrated by MRI evidence of 9 or more T2 brain lesions or 2 or more spinal cord lesions, or 4-8 brain and 1 spinal cord lesion, or positive visual evoked potential wit 4-8 MRI lesions or positive visual evoked potential with < 4 brain lesions plus 1 spinal cord lesion and disseminated in time demonstrated by MRI or continued progression for 1 year.
Current treatment for MS consists of multidisciplinary approach including disease modifying therapies, symptomatic treatment, lifestyle modifications, psychological support, and rehabilitation interventions.
Management of symptoms includes: spasticity, pain, fatigue, cognitive impairment, bladder and bowel issues, gait dysfunction, mood dysregulation, and sleep disturbances.
Spasticity is common and is defined as velocity dependent increase in muscle tone.
Chronic pain associated with MS includes dysesthesia‘s, back pain, tonic spasms, L’hermitte syndrome, visceral pain, and trigeminal neuralgia.
Pain pathophysiology reflects sensual pain from corticospinal disinhibition, activation of nociceptor afferents and the consequence of spasticity.
fatigue and cognitive dysfunction may be secondary to depression, and sleep disorders.
Fatigue is often the most to debilitating symptom.
Cognitive dysfunction often affects verbal memory, recall and abstract reasoning and linguistic function.
Disease modifying treatments decrease the frequency of relapse and reduce short-term disability.
Presently there are nine classes of disease modifying therapies including: interferons, glatitamer acetate, teriflunomide, sphingosine1-phosphate receptive modulators, fumarates, cladribine, natalizumab, ocreelizumab, alemtuxumab, and ofatumumab.
All disease modifying agents modulate the immune system through mechanisms that include sequestration of lymphocytes, T cell shifts, interference with DNA synthesis in lymphocytes, depletion of immune cells, and or changes in cytokines secretion pattern.
The primary mechanism of action of all disease modifying therapies is thought to be diminishing neuroinflammation.
Some disease modifying therapies may also slow the underlying neurodegenerative process of brain atrophy.
All disease modifying therapies approved for relapsing and recurrent MS or active secondary MS are thought to have more inflammatory disease activity.
Disease modifying therapy )DMT) is a lifelong process to prevent relapses and future disabilities.
None of the DMTs suppress all relapses.
Some all the patients who have been clinically stable clinically and radiographically stable for extended period of time of greater than four years have a low recurrence of disease activity and may benefit from treatment discontinuation.
Interferon beta-1a slows the progression of physical disability and brain atrophy and reduces the frequency of symptomatic relapses.
Interferon beta-1a reduces greatly the extent of active MRI lesions.
Interferon beta-1a mechanism of action is predominantly anti-inflammatory.
Interferon beta-1a treatment at an early stage has significant positive effects on clinical and MRI outcomes.
Higher levels of vitamin D in persons with multiple sclerosis are associated with lower degree of MS activity, magnetic resonance imaging lesion load, brain atrophy, and disease progression in patients treated with Betaseron (Ascherio A et al).
In a phase II randomized ,blinded trial involving untreated, early relapsing MS to receive subcutaneous interferon beta 1a or alemtuzumab: alemtuzumab was more effective with a reduced rate of sustained accumulation of disability compared to beta-1a interferon (CAMMS223 Trial Investigators).
Beta-interferons and glatimer acetate reduce annualized relapse rate by 30-35%.
Alemtuzumab compared to interferon beta-1a reduced risk of sustained accumulation of disability by 71% and risk of relapse by 74%, and efficacy remained over 36 months (CAMMS223 Trial Investigators).
Traditionally the diagnosis is made when a patient has at least two attacks consistent with demyelination that occur at least a month apart and affect two or more areas of the central nervous system.
The identification of CSF specific oligoclonal bands can fulfill the criterion of dissemination in time, as it indicates the intrathecal antibody synthesis and is associated with a higher risk of a multiple attacks.
For patients suffering their first demyelinating event, interferon beta-1a taken immediately afterward can often delay the onset of multiple sclerosis.
MRI is the best predictor of a second attack after an initial clinically isolated syndrome.
MRI provides prognostic about future disabilities and subclinical changes in MRI.
Studies reveal elevations in Epstein Barr virus antibodies in patients with MS.
There is a near 100% seropositivity for Epstein-Barr virus in MS patients, and in pediatric onset’s disease there is an unexpectedly high rate of asymptomatic Epstein-Barr virus seropositivity.
Significant age related increase in antibody titer correlates with age at onset of MS.
Highly active lesions can demonstrate a mass effect and rarely can lead to midline shift, herniation, infarcts and even death.
It is a demyelinating disease of the CNS consisting of two distinct but overlapping components, early relapse is mediated by inflammation, and late progression due to neurodegeneration.
Fulminant disease is known as malignant multiple sclerosis or Marburg variant of disease.
Patients treated with natalizumab have an estimated risk of developing progressive multifocal leukoencephalopathy (PML)with a risk of 1 in 1000 patients.
Patients treated with natalizumab have an increased CD34+ cells in their circulation and also upregulation of genes involved in B cell maturation.(Zohren F).
Natalizumab use associated with a 70% reduction in the annualized relapse rate.
Fingolimod Is structurally similar to S1P and when phosphorylated after ingestion can engage 4 of the 51P receptors, acting as an agonist of the S1P1 receptor, becoming a potent functional antagonist leading to internalization of S1P1 receptors on lymph node T cells: as a result the remaining sequestered lymphocytes in lymph nodes.
In multiple sclerosis it has been shown Fingolimod can suppress inflammatory activity for up to five years (Kappos L).
Fingolimod use associated with a 55% reduction in annualized relapse rate.
Fingolimod In MS associated with a decrease in the total mean lymphocyte count and blocks the exit of naïve and central memory lymphocytes, but not effector memory T cells from the lymph node.
Naïve T cells and central memory cells, but not effector memory cells, express the chemokine receptor CCR7, which induces homing to the lymph nodes.
Alemtuzumab use is associated with a 55% reduction in the annualized relapse rate, teriflunomide 30%, laquinimod 20-25%, daclizumab 55%, and fumarate 30%.
In a phase 3 study involving patients with relapsing-remitting multiple sclerosis utilizing Fingolimod, the relapse rate and disease activity was reduced as measured by MRI, compared to beta-1 A. interferon (Cohen JA).
In a randomized study of 1326 patients treated with 2 dosages of cladribine vs. placebo: a lowered rate of annualized relapse, a higher rate of relapse free rate, a lowered risk of disability progression, and a significant reduction in MRI brain lesion count with cladribine compared to placebo (CLARITY Study Group).
CLARITY (Cladribine Tablets Treating Multiple Sclerosis Orally) study revealed that lymphocytopenia was the most common adverse event, and there was an increased incidence of herpes zoster.
Ocrelizumab an anti- CD 20 monoclonal antibody that resulted in an 89-96% reduction in the number of gadolinium enhancing MRI lesions compared with placebo, and they send the-80% reduction in annualized relapse rate (Kappos L et al).
Among MS patients with relapsing-remitting disease nonmyeloablative hematopoietic stem cell transplant is associated with improvement in neurological disability compared to disease modifying therapy. (Burt RK et al).
Disease modifying aging should not be used in pregnancy or breast-feeding.
A Cochrane review of 39 clinical randomized trials the comparisons of: beta interferons, glairamer acetate, natalizumab, mitoxantrone, Fingolimod, teriflunomide, dimethylfumarate, alemtuzumab, pegylated interferon beta-1a, daclizumab, laquinimod, azothioprine and immunoglobulins-alemtuzumab, natalizumab and Fingolimod were associated with the greatest benefit card to relapse prevention in relapsing-remitting multiple sclerosis (Tramacere I et al).
Disease modifying therapy treating patients that have no evidence of disease activity is 30-50% after 2 years of treatment in approximately 18% after four years of treatment.
Among patients with relapsing-remitting MS, initial treatment with single fingolimod, alemtuzumab,or natalizumab was associated with a lower risk of conversion to secondary progressive MS versus initial treatment with glatiramer or interferon beta.
The majority of patients with relapsing remitting MS eventually enter an axonal degenerative phase of irreversible progressive disability for which there is no significant efficacious treatments and during which there is an increase in disease related mortality.
In the above analysis the association with Fingolimod was associated with a high risk of treatment discontinuation due to adverse events.
No treatment has been shown to change the disease course in primary progressive MS.
Daclizumab is a once monthly self administered subcutaneously injection indicated for the treatment of adult patients with relapsing forms of multiple sclerosis.
Cladribine tablets approved for treatment of adults with relapsing multiple sclerosis (MS) and active secondary progressive disease who have had insufficient response to other agents.
Among patients with multiple sclerosis, ofatumumab is associated with lower annualized relapse rate than teriflunomide.
Among patients with relapsing MS, Ublituximab resulted in lower annualized relapse rates and fewer brain MRI lesions than teriflunomide over 96 weeks but did not result in a significant lower risk of worsening of disability: it is associated with infusion related reactions.