Epidemiology and Clinical Features of Multiple Sclerosis in Adults Uptodate3

31/5/2014 Epidemiology and clinical features of multiple sclerosis in adults
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Official reprint from UpToDate
www.uptodate.com 2014 UpToDate
Author
Michael J Olek, DO
Section Editor
Francisco Gonzalez-Scarano, MD
Deputy Editor
John F Dashe, MD, PhD
Di scl osures: Michael J Olek, DO Nothing to disclose. Francisco Gonzalez-Scarano, MD Employement: University of Texas Health Science Center, San Antonio; University of Pennsylvania. Equity Ownership/Stock
Options: Multiple, but traded by advisors without my input (Pharmaceutical). Other Financial Interests: NeuroLink (Venture Capital). John F Dashe, MD, PhD Employee of UpToDate, Inc.
Contributor disclosures are reviewed f or conf licts of interest by the editorial group. When f ound, these are addressed by vetting through a multi-level review process, and through requirements f or ref erences to be
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Epidemiology and clinical features of multiple sclerosis in adults
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Apr 2014. | This topic last updated: May 09, 2014.
INTRODUCTION Diseases that affect central nervous system myelin can be categorized as demyelinating (acquired, inflammatory) and dysmyelinating (abnormal formation of myelin,
usually genetic basis) (table 1). The most common autoimmune inflammatory demyelinating disease of the central nervous system is multiple sclerosis (MS).
The epidemiology, risk factors, clinical features, and disease course of MS will be reviewed here. Comorbid problems associated with MS, and the diagnosis and treatment of MS are
discussed separately. (See "Comorbid problems associated with multiple sclerosis in adults" and "Diagnosis of multiple sclerosis in adults" and "Treatment of relapsing-remitting multiple
sclerosis in adults" and "Treatment of progressive multiple sclerosis in adults".)
PATHOGENESIS Multiple sclerosis is a heterogeneous disorder with variable clinical and pathologic features reflecting different pathways to tissue injury [1]. Inflammation,
demyelination, and axon degeneration are the major pathologic mechanisms that cause the clinical manifestations [2]. However, the cause of MS remains unknown. The most widely
accepted theory is that MS begins as an inflammatory autoimmune disorder mediated by autoreactive lymphocytes [1,3]. Later, the disease is dominated by microglial activation and
chronic neurodegeneration [2]. Supporting evidence includes the following observations:
However, direct proof of an autoimmune cause of MS is lacking, as no specific autoantibody or autoreactive T-cell directed against a self-antigen in the nervous system can passively
transfer MS to experimental animals. EAE itself is an imperfect model of MS, as it does not exactly parallel the clinical or pathological features of MS [1,3,13]. In addition, EAE is
responsive to many drugs directed against T-cells (eg, azathioprine, cyclosporine, and monoclonal antibodies directed at CD4 cells). These same drugs have failed to demonstrate
consistent effectiveness as therapy for MS.
In addition to loss of myelin and oligodendrocytes, axonal injury is a prominent pathologic feature of the MS plaque [14-17]. Disease progression involves a degenerative phase of cerebral
atrophy and axonal loss that is not clearly related to immune mechanisms or inflammation.
Alternate theories of MS pathogenesis include the following [3,13]:
Neuropathologic evidence suggests that oligodendrocyte apoptosis, perhaps triggered by viral or glutamate excitotoxicity, may be the primary event preceding inflammation in at least
some newly forming lesions in patients with relapsing-remitting MS [18,19]. However, the importance of oligodendrocyte apoptosis in the pathogenesis of MS remains to be established
[17].
EPIDEMIOLOGY AND RISK FACTORS Multiple sclerosis affects more women than men. A systematic review of 28 epidemiologic studies found that, from 1955 to 2000, the estimated
female to male ratio of MS incidence increased from 1.4 to 2.3 [20]. A later systematic review and meta-analysis also found evidence suggesting that the incidence of MS is increasing in
females [21]. The reason for this is unknown [22]. A case-control study from Crete found that an increase in the incidence of MS in females since 1980 was concurrent with a population
shift from rural to urban areas, and speculated that environmental factors accompanying urbanization may trigger the development of MS [23].
The incidence and prevalence of MS varies geographically, as discussed below. (See 'Geographic factors' below.)
The median and mean ages of MS onset are 23.5 and 30 years of age, respectively. The peak age of onset is about five years earlier for women than for men. Relapsing-remitting MS tends
to have an earlier onset, averaging 25 to 29 years; this may convert to progressive MS at a mean age of 40 to 44 years. Primary-progressive MS has a mean age of onset of 35 to 39 years.
Onset of MS can rarely occur as late as the seventh decade.
In support of a possible autoimmune basis for MS, some [24,25] but not all [26] studies have observed that patients with MS are more likely than controls to have other autoimmune
disorders, such as autoimmune thyroid disease. In addition, patients with other autoimmune disorders are more likely to have MS. As an example, a large Danish study found that patients
with type 1 diabetes mellitus had an increased risk for developing MS compared with the general population [27]. Another large, well-designed cohort study found that patients with
inflammatory bowel disease have an increased risk for demyelinating diseases, including MS [28].
Role of immune system stimuli Because the pathogenesis of MS is thought to involve the immune system, it has been hypothesized that a stimulus of the immune system (eg, a
vaccine) may trigger the disease. However, substantial evidence exists that there is no association between vaccines and MS.
Inflammation in conjunction with blood-brain-barrier disruption, characterized by gadolinium enhancement on MRI, is seen in the early stages of most demyelinating lesions in patients
with relapsing-remitting and secondary progressive MS. (See "Diagnosis of multiple sclerosis in adults", section on 'Magnetic resonance imaging'.)
Inflammatory T cells, B cells, and macrophages are typically seen on histopathologic examination of MS lesions at biopsy and autopsy [4]. At least four histopathologic subtypes of
MS demyelinating lesions have been described.
Increased oligoclonal IgM and IgG levels are found in the cerebrospinal fluid (CSF) of patients with MS. (See "Diagnosis of multiple sclerosis in adults".)
Approximately one-half of patients with MS have a specific serum IgG autoantibody directed against the inwardly rectifying potassium channel Kir4.1, which is expressed by
oligodendrocyte cell bodies and perivascular astrocyte processes in the central nervous system [5]. This finding suggests that Kir4.1 is a target of the immune response involved in
MS pathogenesis, at least in a subset of patients with the disease.
Myelin reactive T cells are found in MS plaques and in the CSF and peripheral circulation of patients with MS [6,7].
T helper 17-type immune activation, mediated in part by interleukin 23 expression, is associated with active MS lesions [8-10]
The risk of developing MS is associated with certain class I and class II alleles of the major histocompatibility complex (MHC), loci that are involved in T-cell activation and regulation.
(See 'Genetic factors' below.)
Reduction in MS disease activity has been demonstrated with immunomodulatory drugs that reduce the Th1 immune response (ie, interferon beta), increase the Th2 and Th3
responses (ie, glatiramer acetate), or block T-cell movement from the blood into the central nervous system (ie, natalizumab). (See "Treatment of relapsing-remitting multiple sclerosis
in adults".)
An animal model of MS (experimental allergic encephalomyelitis or EAE) can be induced by myelin antigens [11], including myelin basic protein (MBP), proteolipid protein (PLP),
myelin associated glycoprotein (MAG), and myelin oligodendrocyte glycoprotein (MOG) [12].
A possible immune (but not autoimmune) etiology due to a chronic viral infection
A nonimmune noninflammatory etiology due to a genetically determined neuroglial degenerative process
Two well-designed studies seemingly refuted the possible link: one finding no association between hepatitis B vaccination and the development of MS [29], and the other finding no
association between several different vaccines and disease relapse in patients with MS [30].

Although a later, well-designed, case-control study found an increased risk of MS in patients who had received hepatitis B vaccination [34], the indisputable large benefit of this vaccine far
outweighs the possible and still unproven risk of developing MS that the vaccine may carry [34,35].
Viral infections A possible infectious stimulus of the immune system has received more support than vaccines in the literature [36,37]. Although many viruses have been
associated with MS [38], no specific evidence linking viruses directly to the development of MS has been reported. It should be noted that there is no evidence linking hepatitis B infection
with the risk of developing or worsening MS, despite the possible but unproven link with the hepatitis B vaccine.
Increasing attention has centered on the Epstein Barr Virus (EBV), which causes infectious mononucleosis, as a possible cause or trigger of MS [39,40].
One difficulty in proving a link between EBV and MS is that serological evidence of EBV can be found in 83 to 90 percent of adults in the Western hemisphere [42,48,49]. On the other
hand, EBV seropositivity among adult MS patients is near 100 percent, significantly higher than healthy controls [49-53], and children with MS are significantly more likely than healthy
peers to have serological evidence for prior EBV infection, at an age when EBV seropositivity is much less common than in adults [54].
While these findings do not confirm that EBV is an etiologic agent, they are suggestive and warrant further study.
Varicella zoster virus (VZV) has also been linked to MS in some studies [55-57]. A case-control study found viral particles identical to VZV, and DNA from VZV, in cerebrospinal fluid (CSF)
samples from patients with acute relapses of MS [56]. Viral particles were not seen in CSF samples from cases of MS in remission or in samples from control subjects, and DNA from
VZV was not seen in most patients in remission. These findings suggest that VZV participates in MS exacerbations, but require confirmation in additional studies.
Another hypothesis proposes that early life infections may attenuate the response that leads to autoimmune disorders such as MS [58]. In support of this theory, a population-based case-
control study found that higher exposure to infant siblings during the first six years of life was inversely associated with the risk of MS [59]. The proposed explanation was that greater infant
sibling exposure leads to increased early life infection exposure or reexposure; this in turn confers protection against autoimmunity later in life.
Geographic factors The incidence and prevalence of MS varies geographically [60,61]. High frequency areas of the world (prevalence of 60 per 100,000 or more) include all of Europe
(including Russia), southern Canada, northern United States, New Zealand, and southeast Australia. In many of these areas the prevalence is more than 100 per 100,000; the highest
reported rate of 300 per 100,000 is in the Orkney Islands. In the United States, the prevalence is 100 per 100,000 (0.1 percent), for a total of 250,000 persons with MS. This geographic
variance may be explained in part by racial differences; white populations, especially those from Northern Europe, appear to be most susceptible; people of Asian, African, or American
Indian origin have the lowest risk, with other groups intermediate.
There is also a widely held belief of an association between latitude and MS, with the risk of MS increasing from south to north [20]. In an analysis from the Nurses' Health Study, for
example, the adjusted rate ratios were 3.5 for the northern United States and 2.7 for the middle tiers relative to the southern tier [62]. Persons migrating from a high to low-risk area after
the age of puberty are thought to carry their former high risk with them, while those that migrate during childhood seem to have the risk associated with the new area to which they
migrated.
However, the universal association between latitude and risk of MS has been challenged by findings from a 2010 systematic review and meta-analysis of epidemiologic studies of MS [21].
The results showed that, while the prevalence of MS increased with geographic latitude in Western Europe, North America, and Australia/New Zealand, the incidence of MS increased with
latitude only in Australia/New Zealand, and not in Western Europe or North America. Thus, there was no latitudinal gradient for MS incidence in the northern hemisphere. In the absence of
association with incidence, the observed latitudinal gradient of MS prevalence could be explained by other factors, such as survival time, diagnostic accuracy, and ascertainment
probability.
Sunlight and vitamin D One proposed explanation for the possible association of MS with latitude is that exposure to sunlight may be protective, either because of an effect of
ultraviolet radiation or of vitamin D [63]. A number of studies have found an inverse relationship between sun exposure, ultraviolet radiation exposure, or serum vitamin D levels, and the risk
or prevalence of MS [64-69], while others have shown that serum vitamin D levels are inversely related to MS disease activity [70,71]. The following observations are examples:
Other environmental factors Environmental triggers unrelated to geography may be involved in the development of MS [72]. A number of studies have suggested an association
between smoking and MS [72]. As examples, a cross-sectional study of 22,312 people in Norway found a higher risk of MS in ever-smokers than in never-smokers (relative risk 1.81, 95%
CI 1.13-2.92) [73], and a case-control study in the United Kingdom found similar results [74]. Smoking may also be a risk factor for disease progression [63,74-77].
Month of birth has been implicated as a possible risk factor for MS, though the literature is conflicting. A 2013 meta-analysis and systematic review found that the risk of MS was increased
for those born in April and May and decreased for those born in October and November [78], suggesting that the gestational or neonatal environment influences the risk of MS later in life.
However, it is possible that studies finding a month of birth effect are actually false positive results that result from confounding caused by seasonal variation in birth rates, with data from
Europe and North America showing excess births in March, April, or May, and reduced births in November, December, and January [79].
Genetic factors The risk of developing MS is associated with certain class I and class II alleles of the major histocompatibility complex (MHC), particularly the HLA-DRB1 locus [80-
85]. Mounting evidence suggests that the risk of MS is associated with multiple non-MHC susceptibility genes of modest effect (eg, CD6, CLEC16A, IL2RA, IL7R, IRF8, and TNFRSF1A)
[83,84,86,87]. In addition, polymorphisms in the IL-7R gene may slightly increase the risk of MS [81,88,89]. (See 'Pathogenesis' above.)
The presence of a vitamin D response (VDRE) element located in the promotor region of many but not all HLA-DRB1 alleles suggests that environmental differences in vitamin D might
interact with HLA-DRB1 to influence the risk of MS [90]. The VDRE enhances gene expression when stimulated by vitamin D. However, other factors related to HLA variation may have
more impact on MS risk than vitamin D regulation of HLA-DR expression. In one study of Caucasian subjects from Australia that compared 466 MS cases and 498 controls, the risk of
developing MS varied more than 10-fold according to HLA-DRB1 allele type and associated sequence variation in the promotor region, with odds ratios ranging from 0.28 to 3.06 [91]. A
protective effect was associated with HLA-DRB1*04, *07, and *09 (DR53 group) alleles, while an elevated risk was associated with DRB1*15 and *16 (DR51 group) and *08 (DR8 group)
alleles. However, VDRE sequence variation itself was not independently associated with MS risk. Most of the Caucasian HLA-DRB1 alleles expressed a functional VDRE sequence,
including alleles that had no apparent effect on MS risk.
In twin studies, the risk of developing MS for dizygotic twin pairs is the same as that for siblings (3 to 5 percent); however, the risk for monozygotic twins is at least 20 percent and may
reach close to 39 percent [92].
The frequency of familial MS varies from 3 percent to 23 percent in different studies. One well-designed population study of 8205 Danish patients with MS found that relative lifetime risk of
MS was increased sevenfold (95% CI 5.8-8.8) among first-degree relatives (n = 19,615) [93]. The excess familial lifetime risk for first-degree relatives was 2.5 percent (95% CI 2.0-3.2)
A systematic review of nine case-control studies found a negative association between tetanus vaccination and the risk of MS (odds ratio 0.67; 95% CI 0.55-0.81) [31].
A summary of published evidence (through January 2001) supported the safety of vaccination in patients with MS [32], and a subsequent case-control study found no association
between several different vaccines and the development of MS and/or optic neuritis [33].
In a meta-analysis of 14 case-control and cohort studies, the risk of MS was increased after infectious mononucleosis (relative risk 2.3, 95% CI 1.7-3.0) [41].
A prospective nested case-control study of women found significant elevations in anti-EBV antibody titers before the onset of MS, particularly antibody to the EBV nuclear antigen 2
(EBNA-2) [42]. Another nested case-control study found that higher antibody titers to EBNA complex and EBV viral capsid antigen were associated with an increased risk of MS [43].
There is conflicting evidence concerning whether EBV infection is present in brain tissue of patients with MS [44-47].
An analysis of data from the Nurses' Health Study and Nurses' Health Study II observed that the risk of developing MS was significantly reduced for women taking 400 international
units/day of vitamin D (relative risk 0.59, 95% CI 0.38-0.91) [69].
A longitudinal cohort study of 469 subjects with MS found that vitamin D levels were inversely associated with the risk of new T2-weighted or gadolinium-enhancing T1-weighted
lesions on brain MRI [70].
A prospective report of over 450 patients with a clinically isolated syndrome suggestive of MS showed that serum 25-hydroxyvitamin D levels, measured in the first 12 months, were
inversely associated over the subsequent four years with the risks of conversion to clinically definite MS, the presence of new active MS brain lesions on MRI, and MS progression
[71].

added to the sporadic absolute risk of MS in Danish women and men of 0.5 and 0.3 percent. These sporadic rates from the Danish population are among the highest in the world.
For purposes of genetic counseling, the sibling risk of MS is 3 to 5 percent. Studies of unaffected family members that have noted abnormalities on MRI scanning suggest that the risk may
be even higher.
Accumulating data suggest that transmission of MS is influenced by the sex of the affected parent [94-100]. Most studies have found a maternal parent-of-origin effect, with an excess of
maternal transmission observed when examining half-sibling pairs with MS and unaffected parents, patients with MS in extended pedigrees, or avuncular pairs of patients with MS
[94,98,99]. In contrast, studies of parent-child pairs with MS have found that paternal transmission is equal to or greater than maternal transmission [95-97]. The explanation for this
discrepancy is unclear, but epigenetic mechanisms (eg, DNA modifications such as histone acetylation and DNA methylation that do not modify the DNA sequence) transmitted through
cell division may be involved in direct transmission from an affected parent [100].
Results from a meta-analysis and a large population-based study suggest that apolipoprotein epsilon (APOE) variation plays no role in MS disease severity or susceptibility [101,102].
Chronic cerebrospinal venous insufficiency Chronic cerebrospinal venous insufficiency (CCSVI) is largely disproven as having a role in the pathogenesis of MS but remains
controversial. It is characterized by purported anomalies of cerebrospinal veins that interfere with venous drainage from the brain [103]. Proposed diagnostic ultrasound criteria for CCSVI
require two or more of the following five parameters:
In the original report, CCSVI was present in all 65 patients with MS and in none of 235 controls, yielding a sensitivity and specificity of 100 percent, which is unusual for any diagnostic
study [103]. However, the high sensitivity and specificity of CCSVI for MS have not been consistently replicated by subsequent reports. Rather, numerous studies have found no
association of CCSVI with MS [104-112], though a few have found either an uncertain relationship [113] or a strong association [114,115]. One of the highest-quality studies was an
assessor-blinded case-control study of 177 adults (79 subjects with MS, 55 of their unaffected siblings, and 43 unrelated healthy controls) [112]. The following observations were made:
These findings strongly suggest that CCSVI is unlikely to be a primary cause of MS [116].
One proposed mechanism linking CCSVI and MS is that insufficient venous drainage in the brain might lead to extravasation of blood products and perivenular iron deposition thus
overloading the brain and thereby promoting oxidative stress, inflammation and lesion formation [117]. However, this hypothesis is speculative, and is discordant with the following
observations:
CLINICAL SYMPTOMS AND SIGNS There are no clinical findings that are unique to MS, but some are highly characteristic of the disease (table 2). Common symptoms of MS are
listed in Table 3 (table 3). The typical patient presents as a young adult with two or more clinically distinct episodes of CNS dysfunction with at least partial resolution.
Optic neuritis Optic neuritis (ON) is the most common type of involvement of the visual pathways. It usually presents as acute or subacute unilateral eye pain that is accentuated by
ocular movements [126]. This is followed by a variable degree of visual loss (scotoma) affecting mainly central vision. Bilateral simultaneous ON is rare in MS; its occurrence in isolation
may suggest another diagnosis such as Leber hereditary optic atrophy or toxic optic neuropathy. When ON does occur bilaterally in patients with MS, the impairment begins
asymmetrically and is usually more severe in one eye.
Bitemporal hemianopia is rare in MS and, if present, should raise the suspicion of a mass lesion compressing the visual pathways. Homonymous field defects are uncommon but can be
seen in MS due to involvement of the optic radiations.
Physical examination of patients with ON reveals a relative afferent pupillary defect (Marcus Gunn pupil). Disc edema may be observed on fundus examination when the acute ON lesion
involves the head of the optic nerve, a finding more common in children than in adults. Most often the lesion of the optic nerve is retrobulbar, and fundus examination is normal in the acute
stage. Later the optic disc becomes pale as a result of axonal loss and resultant gliosis. This pallor predominates in the temporal segment of the disc (temporal pallor).
The clinical features and diagnosis of optic neuritis is discussed in detail separately. (See "Optic neuritis: Pathophysiology, clinical features, and diagnosis".)
Ninety percent of patients regain normal vision over a period of two to six months after an acute episode of ON. Desaturation of bright colors, particularly red, is often reported by recovered
patients; some also report a mild nonspecific dimming. (See "Optic neuritis: Prognosis and treatment", section on 'Prognosis'.)
Progression to MS after optic neuritis The reported risk of progression to clinically diagnosed MS after an episode of ON ranges from 15 to 75 percent. MRI can help differentiate
groups of patients with ON who are likely or unlikely to develop MS. This topic is discussed in greater detail separately. (See "Optic neuritis: Prognosis and treatment", section on 'Risk of
multiple sclerosis'.)
Internuclear ophthalmoplegia Internuclear ophthalmoplegia (INO) refers to abnormal horizontal ocular movements with lost or delayed adduction and horizontal nystagmus of the
abducting eye. It is caused by a lesion of the medial longitudinal fasciculus on the side of diminished adduction. Convergence is preserved. When present bilaterally, it is usually coupled
with vertical nystagmus on upward gaze. A bilateral INO is most suggestive of MS but also can be observed with other intraaxial brainstem lesions, including brainstem glioma, vascular
lesions, Arnold-Chiari malformations, and Wernicke encephalopathy. (See "Internuclear ophthalmoplegia".)
Sensory symptoms Sensory symptoms are a common initial feature of MS (table 3) and are present in almost every patient at some time during the course of disease. The sensory
features can reflect spinothalamic, posterior column, or dorsal root entry zone lesions. Symptoms are commonly described as numbness, tingling, pins-and-needles, tightness, coldness,
or swelling of the limbs or trunk. Radicular pains also can be present, particularly in the low thoracic and abdominal regions. An intensely itching sensation, especially in the cervical
dermatomes and usually unilateral, is suggestive of MS.
The most common sensory abnormalities on clinical examination include:
Patients also frequently report that the feeling of pinprick is increased or feels like a mild electric shock or that the stimulus spreads in a ripple fashion from the point at which it is applied.
A bilateral sensory level is more common than a hemisensory (Brown-Squard) syndrome.
Reflux constantly present in internal jugular veins and/or vertebral veins with the head at supine (0) and sitting (90) positions
Reflux in the deep cerebral veins
High resolution B-mode evidence of proximal internal jugular vein stenosis
Flow not Doppler detectable in the internal jugular veins and/or vertebral veins despite numerous deep inspirations with the head at 0 and 90
Negative change in cross-sectional area of the internal jugular vein with the head at 0 and 90, denoting the loss of normal postural control
The prevalence of CCSVI by catheter venography criteria was low and similar for subjects with MS, their siblings, and controls (2, 2, and 3 percent, respectively)
Greater than 50 percent narrowing of any major vein by catheter venography was common among subjects with MS, their siblings, and controls (74, 66, and 70 percent, respectively)
The prevalence of CCSVI by ultrasound criteria was not significantly different for subjects with MS, their siblings, and controls (44, 31, and 45 percent, respectively)
Ultrasound criteria for the detection of >50 percent narrowing on catheter venography had a poor sensitivity and specificity (0.41 and 0.64)
Brain iron deposition is a nonspecific finding that is seen in neurodegenerative disorders without demyelination such as Parkinson disease and Alzheimer disease [118,119].
In MS, brain iron accumulation may be a result of inflammation rather than the cause [120].
Other conditions characterized by increased venous pressure, such as cerebral venous thrombosis, are not associated with a risk of developing MS [118].
CCSVI may be a secondary phenomenon in some patients with MS [121], perhaps caused by reduced arterial blood flow and globally decreased cerebral perfusion noted in a number
of studies [120,122-125].
Varying degrees of impairment of vibration and joint position sense

Decreased pain and light touch perception in a distal distribution in the four extremities
Patchy areas of reduced pain and light touch perception in the limbs and trunk
Impairment of facial sensation, subjective or objective, is a relatively common finding in MS. Trigeminal neuralgia in a young adult may be an early sign of MS. Facial myokymia, a fine
undulating wave-like facial twitching, and hemifacial spasm also can be due to MS, but other causes of a focal brainstem lesion must be excluded. Unilateral facial paresis can occur, but
taste sensation is almost never affected.
Lhermitte phenomenon Lhermitte phenomenon is a transient sensory symptom described as an electric shock radiating down the spine or into the limbs with flexion of the neck
[127]. It may be infrequent or occur with the least movement of the head or neck. Although most frequently encountered in MS, this symptom also can be seen with other lesions of the
cervical cord, including tumors, cervical disc herniation, postradiation myelopathy, and following trauma. (See "Complications of peripheral nerve irradiation".)
Pain Pain is a common symptom in patients with MS. A multicenter cross-sectional study assessed pain in 1672 patients with MS [128]. Overall, 43 percent of the patients reported
one or more painful symptoms. Types of pain and their frequencies in this population were as follows:
Vertigo Vertigo is a reported symptom in 30 to 50 percent of patients with MS. It is commonly associated with symptoms reflecting dysfunction of adjacent cranial nerves such as
hyper- or hypoacusis, facial numbness, and diplopia.
Nystagmus Approximately 2 to 4 percent of patients with MS develop acquired pendular nystagmus [129,130]; most patients with this form of nystagmus have MS [131]. It is seldom a
presenting sign of MS, more typically developing later in the course of disease and persisting indefinitely, resolving in only 5 percent. (See "Pendular nystagmus".)
Acquired pendular nystagmus is characterized by rapid, small-amplitude pendular oscillations of the eyes in the primary position resembling quivering jelly. Patients frequently complain of
oscillopsia (subjective oscillation of objects in the field of vision), which impairs visual performance. Marked impairment of visual acuity may also be present, due in part to blurring from
constant eye motion and perhaps also to concurrent optic neuropathy [130].
Motor symptoms Paraparesis or paraplegia is more common than significant upper extremity weakness in patients with MS due to the frequent occurrence of lesions in the descending
motor tracts of the spinal cord. Severe spasticity can occur, such that extensor spasms of the legs and sometimes the trunk may be provoked by active or passive attempts to rise from a
bed or wheelchair.
Physical findings include spasticity, usually more marked in the legs than in the arms. The deep tendon reflexes are exaggerated, sustained clonus may be elicited, and extensor plantar
responses are observed. All of these manifestations are commonly asymmetrical.
Occasionally, deep tendon reflexes are decreased due to lesions interrupting the reflex arc at a segmental level, and an inverted triceps reflex may be observed where the triceps
contraction is lost and the efferent component is represented by a contraction of the biceps muscle. The Achilles reflex can be absent due to lesions of the sacral segments of the spinal
cord, with or without concomitant sphincter and sexual problems. Occasionally, reduced reflexes reflect hypotonia resulting from cerebellar pathway lesions.
Amyotrophy can occur and is usually of the disuse type, most frequently affecting the small muscles of the hand. Less commonly, lesions of the motor root exit zones cause muscle
denervation due to axon loss. Secondary entrapment neuropathies are also a cause of muscle atrophy in MS.
Coordination Gait imbalance, difficulty in performing coordinated actions with the arms, and slurred speech may occur as a result of impairment of cerebellar pathways. Physical
examination typically reveals dysmetria, decomposition of complex movements, and hypotonia, most often observed in the upper extremities. An intention tremor may be noted in the limbs
and in the head. Walking is impaired by truncal ataxia. Ocular findings of nystagmus, ocular dysmetria, and failure of fixation suppression (square wave jerks) suggest cerebellar or
cerebello-vestibular connection dysfunction. Speech can be scanning or explosive in character. In severe cases there is complete astasia (inability to stand), inability to use the arms due
to a violent intention tremor, and virtually incomprehensible speech. Cerebellar signs are usually mixed with pyramidal (corticospinal) tract signs.
Bowel/bladder/sexual function Bowel, bladder, and sexual dysfunction are common in MS. The extent of sphincter and sexual dysfunction often parallels the degree of motor
impairment in the lower extremities. The most common urinary complaint is urgency. Urinary incontinence becomes more common as the disease progresses, and an atonic dilated
bladder that empties by overflow can be the end result.
Other causes of urinary urgency and incontinence need to be considered in patients with MS. (See "Approach to women with urinary incontinence".) Urinary tract infections are common in
MS, particularly in women, and may increase the extent of bladder dysfunction.
Constipation is more common than fecal incontinence. These problems may be a result of both upper and lower motor neuron impairment in addition to decreased general mobility.
Sexual dysfunction is common in patients with MS. About 50 percent of patients become completely sexually inactive secondary to their disease, and an additional 20 percent become
sexually less active. Men experience various degrees of erectile dysfunction. Most women preserve their orgasmic capabilities, sometimes even in the presence of complete loss of bladder
and bowel function.
Sphincter and sexual dysfunction associated with MS are discussed in greater detail separately. (See "Comorbid problems associated with multiple sclerosis in adults".)
Heat sensitivity Heat sensitivity (Uhthoff phenomenon) is a well known occurrence in MS; small increases in the body temperature can temporarily worsen current or preexisting signs
and symptoms [132]. This phenomenon is presumably the result of conduction block developing in central pathways as the body temperature increases [133]. Normally, the nerve
conduction safety factor decreases with increasing temperature until a point is reached at which conduction block occurs; this point of conduction block is reached at a much lower
temperature in demyelinated nerves.
Paroxysmal symptoms Paroxysmal attacks of motor or sensory phenomena can occur with demyelinating lesions. Within the brainstem, lesions may cause paroxysmal diplopia,
facial paresthesia, trigeminal neuralgia, ataxia, and dysarthria. Motor system involvement results in painful tonic contractions of muscles of one or two (homolateral) limbs, trunk, and
occasionally the face, but these only rarely occur in all four limbs or the trunk. These paroxysmal attacks typically respond to low doses of carbamazepine and frequently remit after
several weeks to months, usually without recurrence. These symptoms and their management are discussed in greater detail separately. (See "Comorbid problems associated with
multiple sclerosis in adults".)
Fatigue Fatigue is a characteristic finding in MS, usually described as physical exhaustion that is unrelated to the amount of activity performed. Many patients complain of feeling
exhausted on waking, even if they have slept soundly. Fatigue can also occur during the day but may be partially or completely relieved by rest. In addition, there appears to be a
correlation between fatigue and disrupted sleep in MS patients. Fatigue is often seen in association with an acute attack and may precede the focal neurologic features of the attack and
persist long after the attack has subsided. There is a poor correlation between fatigue and the overall severity of disease or with the presence of any particular symptom or sign. Fatigue
associated with MS is discussed in greater detail separately. (See "Comorbid problems associated with multiple sclerosis in adults".)
Depression Affective disturbance occurs in up to two-thirds of patients with MS, and depression is the most common manifestation. Depression may be more common in patients with
MS than in others with chronic medical conditions. It is not known whether depression in MS patients reflects a comorbid association with bipolar illness or an effect of frontal or subcortical
white matter disease. Early trials suggested that treatment with interferon beta may contribute to the development of depression, but subsequent studies have not found such an
association.
Euphoria is usually associated with moderate or severe mental impairment. Patients may also manifest a dysphoric state with swings from depression to elation. Mood disturbance in MS
is discussed separately. (See "Comorbid problems associated with multiple sclerosis in adults".)
Cognitive dysfunction Frank dementia is an uncommon feature of MS, occurring in less than 5 percent of patients. It is usually only encountered in severely affected individuals.
However, 34 to 65 percent of patients have cognitive impairment on the basis of neuropsychological testing, and cognitive impairment may be common even at the onset of MS. The most
Trigeminal neuralgia in 2 percent
Lhermitte sign in 9 percent
Dysesthetic pain in 18 percent
Back pain in 16 percent
Visceral pain in 3 percent
Painful tonic spasms in 11 percent
frequent abnormalities are with abstract conceptualization, recent memory, attention, and speed of information processing.
The degree of cognitive decline in patients with MS correlates with the severity of cerebral pathology on MRI, and cortical atrophy on MRI (image 1) correlates with cognitive impairment.
Acute cerebral lesions occasionally manifest as a confusional state associated with progressive focal paralysis. Cognitive dysfunction in MS is discussed separately. (See "Comorbid
problems associated with multiple sclerosis in adults".)
Epilepsy Epilepsy is more common in patients with MS than in the general population, occurring in 2 to 3 percent of patients. Convulsions may be either tonic-clonic in nature or partial
complex. They generally are benign and transient and respond well to antiepileptic drug therapy or require no therapy, although up to 11 percent of patients with MS and epilepsy may
develop intractable seizures. This topic is discussed in greater detail separately. (See "Comorbid problems associated with multiple sclerosis in adults".)
RELAPSES Multiple sclerosis is most commonly characterized by relapse, which is defined as the acute or subacute onset of clinical dysfunction that usually reaches its peak from
days to several weeks, followed by a remission during which the symptoms and signs resolve to a variable extent. The minimum duration for a relapse has been arbitrarily established at 24
hours. Clinical symptoms of shorter duration are less likely to represent new lesion formation or extension of previous lesion size.
Analysis of prospectively collected data from a cohort of 195 patients suggests that symptomatic demyelinating events in early RRMS have a tendency to recur in the same location (eg,
spinal cord, optic nerve, brainstem) [134]. However, relapses can present with any of the typical clinical symptoms of MS, and there are no specific clinical features that can reliably
distinguish the initial clinical attack of MS from a relapse, other than history. (See 'Clinical symptoms and signs' above.)
The frequency of relapses is highly variable and depends upon the population studied and the closeness of observation and recording by patients and physicians. Summaries of many
studies provide an average figure of 0.4 to 0.6 relapses per year. Relapses tend to be more frequent during the first years of the disease and wane in later years.
In a single center study that analyzed data from 2587 relapses occurring in 1078 patients during an average follow-up of 7.4 years, relapses causing permanent disability were rare [135].
Relapses were not associated with starting or stopping interferon treatment.
In the absence of a new demyelinating event, worsening of previous clinical dysfunction can occur in the setting of fever, physical activity, or metabolic upset, and may last for hours to a
day or more. Such worsening is thought to reflect conduction block in previously demyelinated axons.
DISEASE PATTERN The pattern and course of MS is categorized as follows [136]:
Relapsing remitting Relapsing-remitting multiple sclerosis (RRMS) is characterized by clearly defined relapses (see 'Relapses' above) with full recovery or with sequelae and residual
deficit upon recovery. There is no disease progression during the periods between disease relapses. This type of MS accounts for approximately 85 to 90 percent of MS cases at onset.
However, most patients with RRMS will eventually enter a secondary progressive phase as discussed below.
Secondary progressive Secondary progressive multiple sclerosis (SPMS) is characterized by an initial RRMS disease course followed by progression with or without occasional
relapses, minor remissions, and plateaus. Some studies suggest that SPMS ultimately develops in most patients with RRMS and causes the greatest amount of neurological disability.
Primary progressive Primary progressive multiple sclerosis (PPMS) is characterized by disease progression from onset with occasional plateaus and temporary minor improvements
allowed. This type represents about 10 percent of cases at disease onset [137]. In PPMS, patients experience a steady decline in function from the beginning and never have acute
attacks. The most common clinical presentation is a spinal cord syndrome with spastic paraparesis and no clear sensory level [138]. These patients have a more even sex distribution,
tend to have a later age of onset, and may have a worse prognosis for ultimate disability compared to patients with RRMS.
Progressive relapsing Progressive relapsing multiple sclerosis (PRMS) is characterized by progressive disease from onset, with clear acute relapses, with or without full recovery.
Progression continues during the periods between disease relapses.
Clinicopathologic correlation The pathogenesis of brain injury may be different between relapsing and progressive forms of MS. In a neuropathologic study, tissue from 52 patients
with MS was compared with 30 controls, and the following observations were made [139]:
These data suggest that MS begins as a focal inflammatory disease but that longer disease duration is associated with accumulation of diffuse brain inflammation, cortical demyelination,
and slowly progressive axonal injury in the NAWM [139]. However, other studies have found that inflammatory cortical demyelination is present even in the early stages of MS, at least in
some patients [140-143].
DISEASE SEVERITY A clinic-based study of 1100 patients found that 66 percent had relapsing-remitting MS (RRMS) disease at onset, 15 percent progressive relapsing (PRMS), and
19 percent primary progressive (PPMS) [144]. The clinical course can evolve from relapsing to secondary progressive (SPMS); 85 percent of patients begin with a relapsing course, but the
proportion remaining as relapsing falls steadily, so that only one-half are still relapsing by nine years from onset. The course of MS with onset after the age of 40 years is progressive in
over 60 percent of patients [144].
Progression of disability due to MS is highly variable (see 'Rate of disability progression' below). At the extreme ends of the severity spectrum, there are benign and malignant forms of MS
(see 'Benign MS' below and 'Malignant MS' below).
Measures of disease progression The Kurtzke disability scale (table 4), or DSS, and the expanded version (expanded disability status scale (table 5), or EDSS) are commonly used
indices of clinical disability in MS [145,146]. These indices use numbers ranging from 0 for normal examination and function to 10 for death due to MS. The scales are nonlinear, with great
emphasis on ambulation capabilities with scores above 4.
Most MS cohort studies have found bimodal distributions of EDSS scores, with peaks at values of 1 (no disability with minimal neurologic signs) and 6 (cane needed for walking). The time
spent by a patient at a given level of disability varies with the score. The median time spent with a DSS score of 4 or 5 is 1.2 years, while the median time spent at DSS 1 is four years and
at DSS 6 three years [144]. These results have powerful implications for the conduct of clinical studies with respect to patient selection, stratification, and duration of follow-up: if many
patients of DSS 1 or 6 are included, little movement will be seen in a group followed for a year or two.
The EDSS is universally used in clinical trials, but it has a number of serious limitations. Inter- and intra-rater variations in scoring are common. EDSS scores of 4 and higher depend
almost entirely on the ability to walk. Problems such as the development of dementia, visual loss, or hand weakness may pass undetected by the scoring. Thus, other outcome measures
should be also be used, and minor changes in the EDSS alone should not be over-interpreted.
Rate of disability progression Progression of disability due to MS is highly variable [147], but accumulating evidence suggests that progression in most patients with MS is slow
[137,148-152]. One of the largest longitudinal studies followed 2319 patients from British Columbia for 22,723 patient years [150]. Disability scores were prospectively assigned in greater
than 95 percent of the patients.
The following observations were reported [150]:
Active focal inflammatory demyelinating lesions in the white matter were present mainly in patients with acute and RRMS, while inactive or slowly expanding white matter plaques
were found in SPMS and PPMS.
Global inflammation of the brain and meninges was characteristic of SPMS and PPMS.
Cortical demyelination mainly affecting the subpial layers of the cerebral cortex was a characteristic feature of PPMS and SPMS, but it was rare or absent in acute MS and RRMS.
Diffuse injury in normal appearing white matter (NAWM) was prominent in SPMS and PPMS, but it was rare or absent in acute MS and RRMS.
The median time from disease onset to EDSS 6 (cane needed for walking) was 27.9 years; the median age from birth to EDSS 6 was 59 years
A primary progressive course was associated with more rapid disease progression than a relapsing course, and was a risk factor in multivariate analysis for time to use of a cane
(EDSS 6) from both MS onset (hazard ratio [HR] 2.90, 95% CI 2.39-3.52) and from birth (HR 2.68, 95% CI 2.20-3.26)
Although men progressed more quickly than women from onset, both men and women required a cane at similar ages (58.8 and 60.1 years), and male sex was not associated with a
Some earlier studies suggested that MS progressed more rapidly. As an example, a 25-year follow-up study of 308 patients with MS found that 50 percent of the patients reached EDSS 6
within 16 years of onset [154].
Mortality Mortality due to MS is difficult to determine because of poor data collection and reporting. A review of large MS cohort registries assessing mortality found that, compared with
the general healthy population, life expectancy in patients with MS was reduced by 7 to 14 years [155]. One-half or more of the deaths among patients with MS were directly related to
complications of MS.
Benign MS Benign MS refers to disease in which the patient remains fully functional in all neurologic systems 15 years after the disease onset, and is usually a retrospective
diagnosis. Approximately 15 percent of patients will never experience a second relapse, although the exact frequency of this benign form of disease is unknown since many of these
individuals never come to medical attention. Among patients in a population-based cohort study who had MS for 10 or more years, about 17 percent had minimal or no disability [149].
Autopsy studies have found a significant number of cases with CNS pathology consistent with MS but no documented clinical evidence of disease. MRI studies of asymptomatic relatives
of MS patients have discovered lesions consistent with demyelination in up to 15 percent of these relatives [156]. The use of MRI may expand the spectrum of MS by detecting milder
cases that previously were not included in prognosis studies. Prospective MRI studies are needed to determine if there are reliable imaging features that can distinguish benign MS from
RRMS and progressive types of MS [157].
In our experience and that of most others, patients who have had a known benign course for 15 years will only rarely develop a more severe course [149,154]. However, evidence is
conflicting, and some have found that patients with benign MS for 10 years still have a substantial risk of disease progression and increased disability [158]. The range of evidence is
illustrated by the following reports:
Malignant MS Malignant MS refers to disease with a rapid progressive course, leading to significant disability in multiple neurologic systems or death in a relatively short time after
disease onset. In a single center study of 487 patients with MS that defined malignant MS by the need for assistance with ambulation (ie, an EDSS score 6) within five years from
symptom onset, the number of patients with a malignant course was 59 (12 percent) [159]. Malignant status was transient for 17 (3.5 percent) and sustained for 42 (8.6 percent).
Predictors for malignant MS were older age at onset, motor symptoms at onset, and progressive disease onset.
PROGNOSTIC FACTORS A variety of factors have been identified as possible prognostic indicators in MS that may modify the disease course or predict exacerbations.
Demographic and racial factors As already noted (see 'Geographic factors' above), white populations, especially those originally from Northern Europe, appear to have the highest
risk for developing MS, while people of Asian, African, or American Indian origin have the lowest risk.
Racial differences may also exist for the clinical features and prognosis of MS, although this is less well established than for differences in the risk of developing MS. A retrospective study
found that black Americans who develop MS have a later age of disease onset than white Americans (age 33.7 versus 31.1 years, respectively) and are more likely to develop ambulatory
disability than white Americans with MS [160]. Since the median time to both MS diagnosis and MS onset to treatment was significantly shorter for blacks compared with the whites in this
study population, it is likely that the increased risk of disability for blacks is independent of health care access.
The same study noted that black Americans with MS were more likely to present with multifocal signs and symptoms, were more likely to have clinical involvement restricted to the optic
nerves and spinal cord (opticospinal MS), and were more likely to develop transverse myelitis compared with white Americans with MS [160]. It should be noted that while 63 black
Americans in the study had opticospinal MS (defined as relapses or clinical signs restricted to the optic nerves and spinal cord), only three met the criteria for neuromyelitis optica (NMO or
Devic syndrome) [161]. (See "Diagnosis of multiple sclerosis in adults", section on 'Neuromyelitis optica and optic-spinal MS'.)
Earlier data suggested that MS followed a more benign course in women than men and that onset at an early age has a favorable prognosis compared with onset at older ages [144].
These notions have been challenged by subsequent data showing that sex and age of onset are not independent prognostic factors [150]. (See 'Rate of disability progression' above.)
Relapsing versus progressive phase of disease The relapsing form of MS is generally associated with a better prognosis than progressive disease [144,150]. An observational
natural history study found that irreversible disability occurred sooner in patients in whom the disease was progressive from the onset than in those in whom the onset was relapsing-
remitting [148]. Once irreversible disability occurred, however, the time course of progressive disability was similar in the two groups.
Although not firmly established by the existing evidence, there are data suggesting that most patients with relapsing MS will eventually enter a progressive phase of disease [144,162]
where neurologic disability gradually worsens regardless of the presence or absence of superimposed attacks. The development of a progressive course may be the single most adverse
factor influencing prognosis [154,162-168]. One study found that the progressive phase of MS appeared to be independent of relapses that occurred before or after the onset of relapse-free
progression [162]. In addition, disability in MS may be more dependent on patient age than on the initial course, whether relapsing or progressive from onset [153,169].
Early disease Certain types of MS symptoms at disease onset were once thought to predict a favorable (sensory symptoms, optic neuritis) or unfavorable (pyramidal, brainstem, and
cerebellar symptoms) prognosis [144]. However, subsequent data suggested that none of these onset symptoms were independent prognostic factors [150,170].
In a systematic review of 27 eligible studies published by May 2005 that evaluated patients with RRMS, bowel and/or bladder symptoms at onset were the only symptoms that had strong
and consistent associations with poor prognosis. Additional factors that predicted long-term disability in those with RRMS were incomplete recovery from the first attack, a short interval
between the first and second attack, and early accumulation of disability [170].
An observational study found that early clinical variables predicted time to disability defined as an EDSS of 4 (ie, limited walking but without aid) but not the subsequent progression of
disease [171].
A long-term observational study of patients with progressive types of MS found that polysymptomatic compared with monosymptomatic onset of MS was associated with a significantly
shorter time to the development of progressive disease [162]. (See 'Rate of disability progression' above.)
Lesion load A serial MRI study in 71 patients followed for a mean of 14 years found that lesion volume at five years and the change in volume during the first five years of illness
correlated more strongly with disability scores at 14 years than measures of volume at earlier or later times, suggesting that the development of lesions in the early years may have an
important influence on long-term disability [172].
However, there is only weak correlation between MRI lesion load and age at disease onset, disease duration, and progression, as shown in an analysis of 1312 placebo subjects with MS
in pooled data from 11 randomized controlled trials [173]. The correlation appears to plateau at higher levels of disability, suggesting that MRI lesion burden is a poor measure of disease
progression in patients with advanced disease.
Furthermore, the extent of cranial MRI abnormalities in individual patients does not necessarily correlate with the degree of clinical disability. Patients with small numbers of lesions may be
quite disabled, while others can function well despite a large burden of disease detected by MRI. There are several possible explanations for this observation: lesions may occur in areas
that are clinically silent; small lesions in the spinal cord can cause major disability in the absence of cerebral lesions; MRI may miss or underestimate lesions that are clinically relevant
worse outcome after controlling for other factors
The type of onset symptoms (eg, motor, sensory, optic neuritis, cerebellar, ataxia, or brainstem) did not predict disease progression after controlling for other factors
A younger age at onset was associated with slower progression, but patients older at onset were consistently older when they progressed to EDSS 6 than patients younger at onset
(figure 1). Similar results were found in a large epidemiology study from France [153].
In one long-term cohort, only 8 percent of patients with mild disease (EDSS score 0 to 3) five years after diagnosis progressed to severe disease (EDSS score 6) by 10 years, and
only 12 percent by 15 years [154].
Similar results were noted in a second cohort, 17 percent of whom had minimal or no disability (EDSS score of 2 or lower) at study onset despite a 10-year or longer history of MS
[149]. The longer the duration of MS and the lower the disability, the more likely the patient was to remain stable and not progress.
In contrast, a cohort study of 169 patients with EDSS scores 3 at 10 years from MS onset found progression to EDSS scores of 6 at 20 years after onset in 21 percent [158]. The
EDSS score at 10 years was the only independent predictor of score at 20 years.

such as those in cortex, basal ganglia, and brainstem; and large plaques detected by MRI may not have functional correlates but reflect increased tissue water without impairment of neural
function.
The amount of ongoing MRI activity (new or enlarging lesions and/or gadolinium-enhancing lesions) exceeds the observed clinical activity by a factor of 2 to 10 [174]. This may reflect not
only the factors discussed above, but also may be due in part to underreporting of minor symptoms and under recognition of minor signs in MS patients. It does, however, suggest that MS
is a much more dynamic and active disease than is clinically apparent.
Pregnancy Since MS is a disease that predominantly affects women and has a maximum incidence during child-bearing years, the course and prognosis of MS with pregnancy has
been studied. Some studies have noted a reduction in relapses late in pregnancy and an increase in the three-month postpartum period [175], but these findings are not universal. It is
generally agreed that there is no difference in overall prognosis between women who have been pregnant compared with those who have not. Furthermore, women with MS do not have an
increased number of stillbirths, ectopic pregnancies, or spontaneous abortions [176]. (See "Neurologic disorders complicating pregnancy", section on 'Multiple sclerosis'.)
These data suggest that pregnancy has no ill effect on MS and that MS has no negative effect on the fetus or the course of pregnancy. However, pregnancy may affect the choice of
therapy since some drugs used to treat MS are known teratogens (table 6).
Psychosocial stress Relapses of MS may be more common after stressful life events [177-179]. Perhaps the strongest evidence comes from a meta-analysis of 14 observational
studies that found a significant association between stress and MS exacerbations [177]. The authors cautioned that the study does not offer absolute evidence of a causal association.
The potential biological mechanisms that might link stress to MS exacerbations remain unproven. Proposed mechanisms include proinflammatory responses mediated by:
Other factors
INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. The Basics patient education pieces are written in
plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who
want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are
written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a
variety of subjects by searching on patient info and the keyword(s) of interest.)
SUMMARY
Increased T cell production [180] of gamma interferon [178]
Increased cortisol concentrations enhancing sensitivity of T cells to proinflammatory cytokines and peptides [181]
Increased cortisol altering glucocorticoid receptors on immune cells [182]
Increased permeability of the blood brain barrier via activation of endothelial mast cells [183]
Physical trauma does not appear to be related to disease induction or relapse [178]
Neurologic diagnostic procedures such as myelography and lumbar puncture have not been linked with aggravation of the disease course, nor has administration of local or general
anesthetics
th th
th th
Basics topics (see "Patient information: Multiple sclerosis in adults (The Basics)")
Multiple sclerosis (MS) is a heterogeneous disorder with variable clinical and pathologic features reflecting different pathways to tissue injury. Inflammation, demyelination, and axon
degeneration are the major pathologic mechanisms that cause the clinical manifestations. However, the cause of MS remains unknown. The most widely accepted theory is that MS
begins as an inflammatory autoimmune disorder mediated by autoreactive lymphocytes. Later, the disease is dominated by microglial activation and chronic neurodegeneration. (See
'Pathogenesis' above.)
Multiple sclerosis affects more women than men. The median and mean ages of MS onset are 23.5 and 30 years of age, respectively. The peak age of onset is about five years earlier
for women than for men. Onset of MS can rarely occur as late as the seventh decade. (See 'Epidemiology and risk factors' above.)
The incidence and prevalence of MS varies geographically. (See 'Geographic factors' above.)
There is no association between vaccines and MS. Although many viruses, and particularly the Epstein Barr virus, have been associated with MS, there is no specific evidence
linking viruses directly to the development of MS. (See 'Role of immune system stimuli' above.)
Genetic factors appear to contribute to the pathogenesis of MS, particularly variation involving the HLA-DRB1 locus. (See 'Genetic factors' above.)
Chronic cerebrospinal venous insufficiency has been reported in some patients with MS but its relationship to MS is controversial (See 'Chronic cerebrospinal venous
insufficiency' above.)
There are no clinical findings that are unique to MS, but some are highly characteristic of the disease (table 2). Common symptoms of MS (table 3) include sensory symptoms in
limbs or face, visual loss, acute or subacute motor weakness, diplopia, gait disturbance and balance problems, Lhermitte sign (electric shock-like sensations that run down the back
and/or limbs upon flexion of the neck), vertigo, bladder problems, limb ataxia, acute transverse myelopathy, and pain. The onset is often polysymptomatic. The typical patient
presents as a young adult with two or more clinically distinct episodes of CNS dysfunction with at least partial resolution. (See 'Clinical symptoms and signs' above.)
Multiple sclerosis is most commonly characterized by relapse, which is defined as the acute or subacute onset of clinical dysfunction that usually reaches its peak from days to
several weeks, followed by a remission during which the symptoms and signs resolve to a variable extent. The common patterns of MS are categorized as follows (See 'Relapses'
above and 'Disease pattern' above.):
Relapsing-remitting multiple sclerosis (RRMS) is characterized by clearly defined relapses with full recovery or with sequelae and residual deficit upon recovery. There is no
disease progression during the periods between disease relapses. This type of MS accounts for approximately 85 to 90 percent of MS cases at onset. However, most patients
with RRMS will eventually enter a secondary progressive phase.
Secondary progressive multiple sclerosis (SPMS) is characterized by an initial RRMS disease course followed by progression with or without occasional relapses, minor
remissions, and plateaus. Some studies suggest that SPMS ultimately develops in most patients with RRMS and causes the greatest amount of neurological disability.
Primary progressive multiple sclerosis (PPMS) is characterized by disease progression from onset with occasional plateaus and temporary minor improvements allowed. This
type represents about 10 percent of cases at disease onset. In PPMS, patients experience a steady decline in function from the beginning and never have acute attacks.
Progressive relapsing multiple sclerosis (PRMS) is characterized by progressive disease from onset, with clear acute relapses, with or without full recovery. Progression
continues during the periods between disease relapses.
Progression of disability due to MS is highly variable, but accumulating evidence suggests that progression in most patients with MS is slow. At the extreme ends of the severity
spectrum, there are benign and malignant forms of MS. Benign MS refers to disease in which the patient remains fully functional in all neurologic systems 15 years after the disease
onset. Malignant MS refers to disease with a rapid progressive course, leading to significant disability in multiple neurologic systems or death in a relatively short time after disease
onset. (See 'Disease severity' above.)
A variety of factors have been identified as possible prognostic indicators in MS that may modify the disease course or predict exacerbations. White populations, especially those
originally from Northern Europe, appear to have the highest risk for developing MS, while people of Asian, African, or American Indian origin have the lowest risk. The relapsing form of
MS is generally associated with a better prognosis than progressive disease. (See 'Prognostic factors' above.)

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