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p. 1217

Multiple sclerosis (MS) is a chronic inflammatory and degenerative

disease of the central nervous system in which demyelination and

axonal damage occur. MS can take one of several forms: relapsingremitting, secondary-progressive, or primary-progressive are the most

common forms.

Case 57-1 (Questions 1, 5),

Figure 57-1

The diagnosis of MS is based on clinicalsymptoms and is supported by

magnetic resonance imaging (MRI) and laboratory testing

(cerebrospinal fluid oligoclonal bands and immunoglobulin G synthesis

rate; evoked potential testing). In an individual patient, dissemination in

space and time must be demonstrated before the diagnosis of MS is

made.

Case 57-1 (Questions 1, 5)

Glucocorticoids are the agents of choice for treatment of acute

MS relapses.

Case 57-1 (Question 7)

Clinically isolated syndrome (CIS) is a term used to describe a first

demyelinating neurologic event before the diagnosis of MS has been

made. When a patient presents with CIS and MRI abnormalities,

progression to clinically definite MS is likely, and therapy with interferon

β, glatiramer acetate, or teriflunomide helps to prevent this progression.

Case 57-1 (Questions 1, 2)

Dimethyl fumarate, glatiramer acetate, interferon β-1a, interferon β-1b,

and teriflunomide are potential first-line therapies for relapsing forms of

MS. The choice of treatment is often based on provider or patient

preference.

Case 57-1 (Questions 3, 5–8)

Case 57-2 (Question 1),

Table 57-3

Adherence to self-injection therapy with interferon β-1a, interferon β-1b,

and

glatiramer acetate is low.

Case 57-1 (Question 4),

Table 57-7

Alemtuzumab, fingolimod, mitoxantrone, and natalizumab therapy is

generally reserved for patients with worsening relapsing forms of MS

because of adverse effect concerns.

Case 57-1 (Question 7)

Case 57-2 (Question 3)

Patients with MS can experience many symptoms, such as walking

problems or impaired ambulation, sexual dysfunction, pain, bladder

dysfunction, fatigue, cognitive dysfunction, spasticity, bowel dysfunction,

dysphagia or dysarthria, and pseudobulbar affect. These symptoms may

require both nonpharmacologic and pharmacologic therapy.

Case 57-1 (Question 10),

Case 57-2 (Question 4),

Table 57-2 and 57-4

EPIDEMIOLOGY, NATURAL COURSE OF THE

DISEASE, AND PROGNOSIS

Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease of the

central nervous system (CNS) in which demyelination and axonal damage occur.

1

The disease has a mean age at onset of 30 years, with diagnoses typically occurring

between the ages of 20 and 50 years.

2

,

3 Because of the young age at onset, MS has a

dramatic effect on employment and, in fact, is the most common cause of disability in

young adults.

4 Overall life expectancy is decreased by about 6 years compared with

age- and sex-matched control subjects,

5 and patients are three more likely to die than

the general population when matched for age and sex.

5

Infection and cardiac causes

of death are the most commonly reported, similar to a control population, but

occurring in higher frequencies in patients with MS.

5

,

6 Health-related quality of life

p. 1218

p. 1219

is lower in patients with MS than in the general population, and this decrease is

related to the severity of MS.

7

MS affects approximately 0.1% of the US population (400,000 people) and about

2.5 million people worldwide.

3

,

4 Women are 2 to 3 times more likely to have MS

than men.

3 Many environmental and genetic factors have been associated with MS

(Table 57-1); however, the causal nature of any of these factors has yet to be

established.

8–18 Current thought is that an environmental trigger acting in a genetically

susceptible individual is the probable cause of MS.

19

MS is most frequently encountered between 40 and 60 degrees north or south

latitude. Regions with a high prevalence include Western and Northern Europe,

Canada, Russia, Israel, Northern United States, New Zealand, and Southeast

Australia.

20 Additionally, relapse rates may also vary seasonally with latitude.

21 This

finding has spurred many research studies and hypotheses. One hypothesis is that

development of MS is related to sunlight exposure or vitamin D. Higher serum

concentrations of 25-hydroxyvitamin D (the major circulating form and the one that is

measured by clinical laboratory testing) are associated with reduced hazard of an MS

relapse, and lower concentrations are associated with higher rates of MS

diagnoses.

22

,

23 Genetically, lack of the vitamin D receptor (VDR) and CYP27B1

(encodes the enzyme responsible for vitamin D activation converting 25-hydroxylvitamin D to 1,25-hydroxyl-vitamin D) is associated with impaired immune system.

24

Some investigators have found links between season of birth and development of MS,

suggesting that maternal vitamin D status may be important.

24 Relapses also follow a

seasonal pattern, with peaks in the early spring and troughs in the autumn in both

hemispheres, further suggesting a role of vitamin D in relapses.

21

Epstein–Barr virus is a ubiquitous infection; however, high EBV titers and a

history of infectious mononucleosis both increase risk of developing MS. Smoking is

a risk factor, with higher levels of smoking conferring greater risk.

17

,

24 Dietary salt

intake may be associated with higher relapse rates and increased numbers of brain

lesions.

18

There is likely a genetic predisposition to development of MS. First-degree

relatives of people with MS have a risk of MS that is 10 to 25 times greater than the

general population; the concordance rate in identical twins is 35%.

11

,

13 There are

probably several genetic factors that increase risk for MS, including HLA type and

various single-nucleotide polymorphisms that control T-cell receptors, vitamin D

receptors, and estrogen receptors.

23

,

25

,

26 A specific major histocompatibility complex

(MHC) associated with MS is HLA-DRB1*1501 class II, but over 100 different

genetic variations have been associated with MS.

24 No genetic association has been

found for a particular clinical course or rate of progression.

24

Although MS is more prevalent in Caucasian populations in the United States,

there is evidence that African-American patients may be more likely to have primaryprogressive forms and may have a more severe disease course.

27–29

Table 57-1

Factors Associated with Multiple Sclerosis (MS)

Female sex

3,8 Low sun exposure

9,10

Caucasians

11 Low serum concentrations of vitamin D (25-

hydroxyvitamin D)

10

Higher latitudes of residence

12 Northern European heritage

13

High serum antibody titers to the Epstein–Barr virus

nuclear antigens

14,15

Tobacco smoking

14,16

Infectious mononucleosis

17 Dietary salt

18

MS is generally characterized as one of three main types according to the

presentation and clinical course of the disease: relapsing-remitting MS, secondaryprogressive MS, and primary-progressive MS. These three types of MS are

distinguished by their natural histories. Relapsing-remitting MS was named for the

relapses (also called exacerbations or attacks) of clinical disease activity that

alternate with periods of symptom remission. Recovery during the remission periods

can be complete, or the patient may continue to have some clinical deficits.

30

Between 80% and 90% of patients have relapsing-remitting MS when they are first

diagnosed.

1

,

31 Patient registry data provide insight regarding the prognosis of those

with relapsing-remitting MS. Patients diagnosed with relapsing-remitting MS at onset

have slower progression to disability than patients with primary-progressive MS;

patients having complete or near-complete recovery from the first attack of MS have

a longer time to disability compared with those with significant persistent deficits

after the first attack.

1

,

31

Approximately 80% of patients initially diagnosed with relapsing-remitting MS

experience a secondary-progressive form in which fewer relapses occur, but

disability continues to progress.

1

,

2 The cause of the conversion from relapsingremitting MS to secondary-progressive MS is unknown, but it has been hypothesized

that the change occurs when axonal loss in the CNS reaches a critical threshold.

32

The time to development of secondary-progressive MS is quite variable. The usual

time to conversion is 20 to 25 years after diagnosis, with a median patient age at the

time of conversion of 43 years; however, it may occur much sooner.

1

,

30

,

33

It is not

known how treatment affects this process. In one study, the number of early relapses

(within 2 years of diagnosis) was associated with a shorter time to development of

secondary-progressive MS.

34 Therefore, early treatment with a therapy that reduces

relapses might be expected to delay development of secondary-progressive MS.

Approximately 10% to 15% of patients have primary-progressive MS.

1

,

35 This

type of MS is progressive from onset with occasional minor improvements or

periods of stabilization.

30 Primary-progressive MS is more common in patients who

are older than 50 years at diagnosis.

1 Select studies have found this form to be more

common in men, but others have found no association with sex.

1

,

35 Mean time from

diagnosis to requiring a cane to walk is approximately 9 years for patients with

primary-progressive MS.

36

In the absence of treatment, patients who initially present with relapsing-remitting

MS develop average Expanded Disability Status Scale (EDSS) scores of 4.0 or

higher (indicating significant disability) by 7 years after diagnosis.

20 The EDSS is a

scale commonly used in MS to measure level of disability and progression of the

disease.

37 Some predictors of a more progressive disease course include male

gender, multisystem symptoms, incomplete recovery from the initial episode,

progressive disease from the time of diagnosis, older age at onset, and abnormal

baseline magnetic resonance imaging (MRI) results.

30