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Multiple Sclerosis N.Beladimoghadam.MD Shahid Beheshti University of Medical Science MS is a leading cause of disability in young adults PATHOPHYSIOLOGY • Demyelination interrupts current flow by removing the insulator of internodal axon current flow. • For short segments (one or two internodes) demyelination is usually not critical because of a high safety factor for transmission. • However, longer segments of demyelination can result in interruption of current flow, because current must flow by continuous propagation. • Persistent neurological deficits or negative symptoms of MS are caused by regions in which conduction block persists, such as in regions of large plaques, whereas transient worsening of function reflects a drop below the safety threshold for conduction because of physiological changes involving the partially demyelinated axon (Uhthoff's phenomenon, worsening with increased body temperature). PATHOLOGY • The pathological hallmark of MS is the cerebral or spinal plaque, which consists of a discrete region of demyelination with relative preservation of axons, although spectroscopic and pathological studies suggest some axonal loss may be an integral part of the disease process. • Gross examination of the brain in MS often reveals variable degrees of atrophy and ventricular dilatation. Plaques develop in a perivenular distribution and are seen most frequently in the periventricular white matter, brain stem, and spinal cord. • However, large numbers of small plaques, often detected only by microscopy, are found in cortical regions affecting intracortical myelinated fibers. PATHOLOGY • Histological examination of active plaques reveals perivascular infiltration of lymphocytes (predominantly T cells) and macrophages with occasional plasma cells. • In the plaque, myelin is disrupted, resulting in myelin debris found in clumps or within lipid-laden macrophages. Macrophages, most prominent in the plaque center, appear to have an integral role in stripping myelin lamellae from axons. • Reactive astrocytes are prominent in plaques. Immunohistochemical studies have found increased levels of cytokines in active plaques, indicative of ongoing immunoreactivity. In pathologic specimens, the demyelinating lesions of MS, called plaques), appear as indurated areas; hence the term sclerosis. Inflammation in multiple sclerosis Perivascular infiltration of inflammatory cells. These infiltrates are composed of activated T cells, B cells, and macrophages Mechanism of demyelination in MS • May be activation of myelin-reactive T cells in the periphery, which then express adhesion molecules, allowing their entry through the blood-brain barrier (BBB). • T cells are activated following antigen presentation by antigen-presenting cells such as macrophages and microglia, or B cells. Perivascular T cells can secrete proinflammatory cytokines, including interferon gamma and tumor necrosis factor alpha. • Antibodies against myelin also may be generated in the periphery or intrathecally. • may be activation of myelin-reactive T cells in the periphery, which then express adhesion molecules, allowing their entry through the blood-brain barrier (BBB). T cells are activated following antigen presentation by antigen-presenting cells such as macrophages and microglia, or B cells. Perivascular T cells can secrete proinflammatory cytokines, including interferon gamma and tumor necrosis factor alpha. Antibodies against myelin also may be generated in the periphery or intrathecally. Ongoing inflammation leads to epitope spread and recruitment of other inflammatory cells (ie, bystander activation). The T cell receptor recognizes antigen in the context of human leukocyte antigen molecule presentation and also requires a second event (ie, costimulatory signal via the B7-CD28 pathway, not shown) for T cell activation to occur. Activated microglia may release free radicals, nitric oxide, and proteases that may contribute to tissue damage. Immune cells in MS • Molecular studies of the white matter plaque tissue have shown that :interleukin (IL)-12, a potent promoter of inflammation, is expressed at high levels in lesions that form early. A molecule required to stimulate lymphocytes to release proinflammatory cytokines, B7-1, is also expressed at high levels in early MS plaques. • Evidence exists of higher frequencies of activated myelin-reactive T-cell clones in the circulation of patients with RRMS and higher IL-12 production in immune cells of patients with progressive MS, when compared with healthy controls. critical immune cells in the pathogenesis of MS. *CD4+ CD25+ T cells :regulatory role (Tregs) Decreased function ( due to cytokine IL-23 role? ) *proinflammatory cytokine IL-17 ( TH 17 cells) *Immune cells such as microglia (resident macrophages of the CNS), dendritic cells, natural killer (NK) cells, and B cells. *nonimmune cells (ie, endothelial cells) Etiology • The cause of MS is unknown • multiple factors (not a single identifiable agent or event act in concert to trigger or perpetuate the disease. • These factors are in part environmental and in part hereditary • The concordance rate for MS among monozygotic twins is only 20-35%, suggesting that genetic factors have only a modest effect. • The presence of predisposing non-Mendelian factors (ie, epigenetic modification in 1 twin), along with environmental effects, plays an important role. For first-degree family members (children or siblings) of people affected with MS, the risk of developing the disorder is only 3-5%. It has been hypothesized that MS results when an environmental agent or event (eg, virus, bacteria, chemicals, lack of sun exposure) acts in concert with a genetic predisposition to immune dysfunction. . HLA-DRB1 is the only chromosomal locus that has been consistently associated with MS susceptibility.Possibility that peripheral blood T cells may become activated to attack a foreign antigen and then erroneously direct their attack toward brain proteins that share similar protein epitopes Etiology • Genetic and molecular • A virus that infects cells of the immune and nervous systems can factors possibly be reactivated periodically • Viruses and thus lead to acute exacerbations in • Environmental factors MS. The Epstein-Barr virus (EBV)? • Vitamin D levels • one early study showed 47% of MS • Chronic cerebrospinal brains were positive for HHV-6, and venous insufficiency 80% showed elevation of antibodies in • Hepatitis B vaccine the serum • Geography is clearly an important factor . • Must exert its effect in early childhood. • Eskimos do not have a high frequency of MS. Etiology • Genetic and molecular factors • Viruses • Environmental factors • Vitamin D levels • Chronic cerebrospinal venous insufficiency • Hepatitis B vaccine • Vitamin D has a role in regulating immune response, by decreasing production of proinflammatory cytokines and increasing production of antiinflammatory cytokines; also, high circulating levels of vitamin D appear to be associated with a reduced risk of MS. • May be one reason for the geographic variations in MS incidence, and the protective effect of traditional diets high in vitamin D could help explain why certain areas (eg, Norway) have a lower incidence of MS despite having limited sunlight. Etiology • Genetic and molecular factors • Viruses • Environmental factors • Vitamin D levels • Chronic cerebrospinal venous insufficiency • Hepatitis B vaccine • Paolo Zamboni described an association between MS and chronic cerebrospinal venous insufficiency (CCSVI ). Hepatitis B vaccine: Multiple Sclerosis Society expert panel states: “People with MS should not be denied access to health-preserving and potentially-life saving vaccines because of their MS, Preliminary data from Zivadinov (president of the International Society for Neurovascular Disease) et al, from the MS research group Buffalo:at the State University of New York • presented findings in the first 500 participants studied with venous Doppler looking at the prevalence of CCSVI in MS patients and controls. Using the requirement that ≥2 CCSVI Doppler criteria be met, CCSVI was found in 62.5% of MS patients, 25.9% of healthy controls and 45% of other neurological disorders. • The study also found the prevalence of CCSVI was different depending on a patient’s stage of the disease. About 38 per cent of patients in the early stage of MS presented with CCSVI, while 80 to 90 percent of patients in progressive stages had the condition • At least preliminarily, these results are different from the 100% sensitivity and specificity found by Zamboni and colleagues. the University of Buffalo study neither proves nor disproves the CCSVI theory • Dr. Zivadinov said. "Our findings are consistent with an increased prevalence of CCSVI in MS but with modest sensitivity/specificity. Our findings point against CCSVI having a primary causative role in the development of MS," he added. "We are showing that CCSVI is connected to the progression of disease, but whether it is a cause of the progression or a consequence, we don't know at this time." • Dr, Zivadinov added. "The currently ongoing placebocontrolled study in Buffalo, in collaboration with Department of Neurosurgery at the University of Buffalo, is aiming to answer this question and data should be available by the second part of 2011," he said. "We are against performing open-label endovascular treatment in patients with MS." Stress? Stress does not appear to play a major role in the • development of multiple sclerosis from the University of Bergen, Norway June, 2011 • Epidemiology • Prevalence estimates for MS in the United States vary from 58 to 95 per 100,000 population . • MS is more common in women. • Worldwide, approximately 2.1 million people are affected by MS. • low rates among Chinese, Japanese, and African blacks; high rates among Sardinians, Parsis, and Palestinians), Classic MS symptoms are as follows: • Sensory loss (ie, paresthesias) - Usually an early complaint • Spinal cord symptoms (motor) - Muscle cramping secondary to spasticity • Spinal cord symptoms (autonomic) - Bladder, bowel, and sexual dysfunction • Cerebellar symptoms - Charcot triad of dysarthria, ataxia, tremor • Constitutional symptoms - especially fatigue (which occurs in 70% of cases) and dizziness; fatigue must be differentiated from depression (which may, however, coexist), lack of sleep, and exertional exhaustion due to disability • Pain - Occurs in 30-50% of patients at some point in their illness • Optic neuritis • Subjective difficulties - With regard to attention span, concentration, memory, and judgment MS symptoms • Depression - A common symptom • Euphoria - Less common than depression • Bipolar disorder or frank dementia - May appear late in the disease course but is sometimes found at the time of initial diagnosis. • Trigeminal neuralgia - Bilateral facial weakness or trigeminal neuralgia • Facial myokymia (irregular twitching of the facial muscles) - May also be a presenting symptom • Partial acute transverse myelitis • Eye symptoms - Including diplopia on lateral gaze; these occur in 33% of patients • Heat intolerance MS Symptoms • Fatigue • • • • • is one of the most commonly reported symptoms of MS, being experienced in up to 90% of patients with the disease. Estimates of the prevalence of cognitive dysfunction in MS range from 40-70%. No correlation exists with the degree of physical disability, and cognitive dysfunction. may occur early in the course of disease. . Areas of cognition affected include comprehension and use of speech, attention, memory, visual perception, planning, problem solving, and abstract reasoning. is a common occurrence in MS, with 30-50% of patients experiencing it .( primary or secondary) Attack • An attack is defined as a neurologic disturbance of the kind seen in MS. It can be documented by subjective report or by objective observation, but it must last for at least 24 hours. Pseudoattacks and single paroxysmal episodes must be excluded. To be considered separate attacks, at least 30 days must elapse between onset of one event and onset of another event. • It is important to recognize that the progression of physical and cognitive disability in MS may occur in the absence of clinical exacerbations Optic Neuritis • Approximately 20% of patients with MS present with optic neuritis (ON) as a first demyelinating event, and 40% of patients may present with ON during the course of their disease. • Sequential episodes of optic nerve involvement and a longitudinally extensive myelopathy (ie, neuromyelitis optica [NMO], or Devic disease. • Optic neuritis (ON), which involves the afferent visual pathway, typically causes acute to subacute unilateral loss of visual acuity, color and contrast sensitivity, visual field changes, and pain. Onset of ON typically occurs over minutes or hours, rarely days; however, loss of visual acuity may progress over days to weeks. • Only 3% of patients had no light perception (NLP). Given the rarity of NLP in ON, other potential etiologies for vision loss (eg, inflammatory, infiltrative, neoplastic) might need to be considered in such patients. Optic Neuritis • Most cases of ON are retrobulbar. • A relative afferent pupillary defect is present in unilateral cases and in bilateral-but-asymmetrical cases but may be absent in bilateral and symmetrical cases. • The visual field defect: central scotoma-AltitudinalThree-quadrant -One-quadrant -Hemianopic Peripheral rim –Arcuate-Enlarged blind spot • fundus findings:anterior uveitis, vitreitis, vascular sheathing, and disc and papillary hemorrhages, as well as compromise of the central arterial and venous circulations, are uncommon. • In the ONTT, mild to severe pain was present in 92.2% of patients Visual disorders that may occur in MS: • Diplopia due to an internuclear ophthalmoplegia (INO), ocular motor cranial neuropathy ( 6TH>3 & 4) , The oneand-a-half syndrome , Horizontal or vertical gaze palsies • Oscillopsia, Oscillopsia can occur secondary to various types of nystagmus . • Nystagmus:. A new-onset, acquired pendular nystagmus is relatively common, but upbeat, downbeat, convergence-retraction, and other forms of nystagmus may develop in MS, depending on the location of the demyelinating lesion Neuromyelitis optica (NMO) • An inflammatory disease of the central nervous system (CNS) characterized by severe attacks of optic neuritis and myelitis, and which, unlike multiple sclerosis (MS), commonly spares the brain in the early stages. • NMO used to be considered as a special form of MS. During the past 10 years, however, the two diseases have been shown to be clearly different. • NMO is a B-cell-mediated disease associated with antiaquaporin-4 antibodies in many cases and its pathophysiology seems to be near the acute lesion of necrotizing vasculitis. • Assessment of prevalence shows that NMO is far less frequent than MS, which explains the absence of randomized clinical trials and NMO treatment strategies validated by evidence-based medicine. • Recently, many data have been published that suggest that the therapeutic option in NMO should be immunosuppressive rather than immunomodulatory drugs Neuromyelitis optica (NMO) • An inflammatory disease of the central nervous system (CNS) characterized by severe attacks of optic neuritis and myelitis, and which, unlike multiple sclerosis (MS), commonly spares the brain in the early stages. NMO • The disease can be monophasic, i.e. a single episode with permanent remission. However, at least 85% of patients have a relapsing form of the disease. • . Relapses usually occur early with about 55% of patients having a relapse in the first year. • In some patients (33% in one study), transverse myelitis in the cervical spinal cord resulted in respiratory failure and subsequent death. However, the spectrum of Devic's disease has widened due to improved diagnostic criteria, and the options for treatment have improved; as a result, researchers believe that these estimates will be lowered • . In 2006, revised criteria for NMO were proposed including, in addition to the two major symptoms (myelitis and optic neuritis), any two [Bonnet et al. 1999] of the following three criteria: extended myelitis on spinal cord MRI, normal brain MRI at onset and positive anti-AQP4 antibodies [Wingerchuk et al. 2006]. • Limited forms of Devic's disease, such as single or recurrent events of longitudinally extensive myelitis, and bilateral simultaneous or recurrent optic neuritis • Asian optic-spinal MS. This variant can present CNS involvement like MS[ • Longitudinally extensive myelitis or optic neuritis associated with systemic auto-immune disease • Optic neuritis or myelitis associated with lesions in specific brain areas such as the hypothalamus, periventricular nucleus, and brainstem Clinical Rating Scales • The most widely accepted of these is the 10-point Kurtzke Expanded Disability Status Scale (EDSS) :1955 -has been revised over the years. • Evaluate dysfunction in 8 neurologic systems, including pyramidal, cerebellar, brainstem, sensory, bladder and bowel, vision, cerebral, and "other." EDSS grades . • 0 - Normal neurologic examination • 5.5 - Ambulatory without aid or rest for approximately 100 m • 6.0 - Intermittent or unilateral constant assistance • 9.5 - Totally helpless bed patient; unable to communicate effectively or eat/swallow Categorizing MS • MS is divided into the following categories on the basis of clinical and radiologic criteria, including the frequency of clinical relapses, time to disease progression, and lesion development on MRI : • Relapsing-remitting MS (RRMS) :approximately 85% of MS cases • Secondary progressive MS (SPMS):Approximately 50% of patients with RRMS convert to a secondary progressive pattern within 10 years after disease onset • Primary progressive MS (PPMS):approximately 10% of MS cases • Progressive-relapsing MS (PRMS):(< 5% of patients with MS) have occasional relapses superimposed on progressive disease Diagnostic Considerations • A common misconception is that any attack of demyelination means a diagnosis of acute MS. When a patient has a first attack of demyelination, the physician should not rush to diagnose MS, because the differential diagnosis includes a number of other diseases. • commonly see patients referred for multiple, ill-defined, vague complaints who had recent head or spinal MRI scans in which T2 hyperintense lesions have been demonstrated. Careful questioning in these cases reveals that symptoms have been stereotyped and vague or do not truly qualify as exacerbations • These nonspecific lesions are relatively common in the general adult population, and clinical correlation (ie, a high degree of suspicion based on clinical evidence) becomes important in the diagnosis. To confirm MS in these cases, the physician should look for sites of involvement that are rare for UBOs but frequent for MS (eg, the corpus callosum or throughout the spinal cord). • MRI shows brain abnormalities in 90-95% of MS patients and spinal cord lesions in up to 75%, especially in elderly patients. T2-weighted images show edema and more chronic lesions, whereas T1-weighted images demonstrate cerebral atrophy and "black holes." These black holes represent areas of axonal death. One of the limitations of using MRI in patients with MS is the discordance between lesion location and the clinical presentation. In addition, depending on the number and location of findings, MRI can vary greatly in terms of sensitivity and specificity in the diagnosis of MS. A clinician presented with an MRI report that details a few "nonspecific white matter lesions" that are "compatible with MS" is often frustrated with the lack of sensitivity and specificity of such a description. For this reason, described in detail imaging findings need to be Diagnostic criteria • in 1965 Schumaker criteria • In 1983 , Poser et al • In 2001, the International Panel on the Diagnosis of Multiple Sclerosis, headed by Dr. W. Ian McDonald, published a new set of criteria . • In 2005, the International Panel reconvened to review the effectiveness of the criteria (Polman et al., 2005) • In2007, Swanton et al. published a study of patients who had Clinically Isolated Syndrome (CIS), in which a patient has a single incident of a neurological symptom similar to early MS, and objective evidence of a CNS abnormality (for example, from MRI, CSF, or VEP results). • If the diagnostic criteria can predict which patients will develop CDMS, the criteria are established as sensitive and accurate 2010 McDonald MRI Criteria for Demonstration of DIS • DIS Can Be Demonstrated by 1 T2 Lesiona in at • Least 2 of 4 Areas of the CNS: • • • • Periventricular Juxtacortical Infratentorial Spinal cordb 2010 McDonald MRI Criteria for Demonstration of DIT • DIT Can Be Demonstrated by: • 1. A new T2 and/or gadolinium-enhancing lesion(s) on follow-up MRI, with reference to a baseline scan, irrespective of the timing of the baseline MRI • 2. Simultaneous presence of asymptomatic gadolinium-enhancing and nonenhancing lesions at any time 2010 McDonald Criteria for Diagnosis of MS in Disease with Progression from Onset • 1. One year of disease progression (retrospectively • or prospectively determined) • 2. Plus 2 of the 3 following criteriaa: • A. Evidence for DIS in the brain based on 1 T2b • lesions in at least 1 area characteristic for MS • (periventricular, juxtacortical, or infratentorial) • B. Evidence for DIS in the spinal cord based • on 2 T2b lesions in the cord • C. Positive CSF (isoelectric focusing evidence of • oligoclonal bands and/or elevated IgG index) • MR spectroscopy appears to be capable of depicting changes in white matter that are not detected with routine pulse sequences. Because the findings are correlated with disability scores, the use of MR spectroscopy may prove valuable in monitoring patients after treatment and in formulating their prognosis. • CT has had a limited role in the diagnosis of MS. CT scans can help in assessing the degree of cerebral atrophy associated with advanced MS. • . Angiography also has a limited role in the diagnosis and management of MS, but when CNS vasculitis is considered in a patient with undifferentiated findings, angiography may occasionally be considered. Evoked Potentials • These tests, are used to identify subclinical lesions but are nonspecific for MS : • Visual evoked potentials (VEPs): VEPs are not typically necessary for patients with clear clinical evidence of optic neuritis (ON). • Somatosensory evoked potentials (SSEPs) • Brainstem auditory evoked potentials (BAEPs) Lab Studies to exclude • Perform blood work collagen vascular disease, infections (ie, Lyme disease, syphilis), endocrine abnormalities, vitamin B-12 deficiency, sarcoidosis, and vasculitis. Copper studies may also be useful in MS patients. • NMO,, can be confirmed by the presence of serum antibodies against aquaporin 4, a water channel expressed at major fluid-tissue barriers across the CNS. (The NMO-IgG test) Lumbar Puncture • Lumbar puncture with CSF analysis is no longer routine in the investigation of MS, but this test may be of use when MRI is unavailable or MRI findings are nondiagnostic. CSF is evaluated for oligoclonal bands (OCBs) and intrathecal immunoglobulin G (IgG) production, as well as for signs of infection. OCBs are found in 9095% of patients with MS and intrathecal IgG production is found in 70-90% of patients. OCB • Detection of oligoclonal IgG bands in CSF is the test with the highest sensitivity to predict conversion from CIS to MS. • In patients suspected of having MS, but without oligoclonal bands in CSF, alternative diagnoses should always be thoroughly investigated. • The correlation between presence of oligoclonal IgG bands and disability progression is uncertain. •The reported frequencies of oligoclonal IgG bands differ in different parts of the word. THE VALUE OF CEREBROSPINAL FLUID FINDINGS IN DIAGNOSIS • The McDonald Criteria ofthe International Panel on Diagnosis of MS reaffirmed that positive cerebrospinal fluid (CSF) findings (elevated immunoglobulin G [IgG] index or 2 or more oligoclonal bands) can be important to support the inflammatory demyelinating nature of the underlying condition, to evaluate alternative diagnoses, and to predict CDMS. MS & Pregnancy • Investigators found that infants born to mothers with MS did not have a significantly different mean gestational age or birth weight compared with infants born to mothers without the disease. MS was also not significantly associated with assisted vaginal delivery or caesarean section. • Ann Neurol. Published online June 27, 2011 • In general, relapse rates drop over the nine months of pregnancy and rise significantly in the three-six months post partum. • The more active a woman’s disease was during pregnancy and the year prior, the higher her risk of post partum relapse. Postpartum steroid dose reduces Multiple Sclerosis relapses A single dose of methylprednisolone given to new mothers with multiple sclerosis immediately after delivery reduced the risk of relapse for up to three months, researchers found. During the first postpartum trimester, relapses occurred in 18% of new mothers who received 1 g of intravenous methylprednisolone compared with 46% of those not receiving treatment. . An alternative treatment, intravenous immunoglobulin, is significantly more expensive and more complex to administer than IV methylprednisolone Prognosis • If left untreated, more than 30% of patients with MS will develop significant physical disability within 20-25 years from onset . • Less than 5-10% of patients have a clinically milder MS phenotype, in which no significant physical disability accumulates despite several decades passing since onset (sometimes in spite of multiple new lesions seen on MRI). Detailed examination of these patients in many instances reveals some degree of cognitive deterioration. • Male patients with primary progressive MS have the worst prognosis. • Life expectancy is shortened only slightly in persons with MS, and the survival rate is linked to disability. Death usually results from secondary complications (50-66%), such as pulmonary or renal causes, but can also occur due to primary complications, suicide, and causes unrelated to MS. Marburg variant of MS is an acute and clinically fulminant form of the disease that can lead to coma or death within days