with different types of MS, once progression begins, all forms of progressive MS
follow a similar time course for subsequent progression.
A new classification system has been proposed which denotes disease activity and
39 Patients with new, active MRI lesions or with clinical relapses within
a specified time frame are classified as active, whereas those without new lesions or
relapses are classified as inactive. In a similar way, patients are categorized as
progressing if they have steadily increasing objectively documented neurologic
dysfunction without recovery or non-progressing. For example, a patient with
relapsing-remitting MS who has had a clinical relapse in the last year, but who had
full recovery, would be classified as relapsing-remitting MS-active and not
39 Because MS begins during young-to-middle adulthood, there is a large
economic burden associated with the disease. One study in
which newly diagnosed patients were matched to healthy control subjects found
that patients with MS were 3.5 times as likely to be hospitalized, twice as likely to
have at least one emergency department visit, and 2.4 times as likely to have at least
one visit for physical, occupational, or speech therapy during the course of a year.
These additional services were associated with higher mean annual all-cause
healthcare costs ($32,051 vs. $4,732 for MS patients and control subjects,
41 These estimates do not consider the loss of employment or loss of
caregiver employment. When these factors are taken into consideration, the cost of
Ten years after diagnosis, 50% to 80% of patients with MS are unemployed.
Surprisingly, only 15% of unemployment is related to physical restrictions.
factors most often cited as leading to unemployment, only decreased walking ability
relates to physical disability. The other common factors are increased age, decreased
verbal fluency, and loss of memory.
Many aspects of the pathophysiology of MS remain unclear, although research in this
area is progressing rapidly. Foremost in unresolved issues is the identity of the actual
initiating factor for the autoimmune and inflammatory processes that characterize MS.
Through the years, several dozen triggers have been proposed. Current thinking is
that a genetically susceptible individual has an environmental factor which triggers
the immune system to cause MS.
There are two pathologic processes that occur during MS. The first is
inflammatory. During this process, the body mounts an autoimmune attack on the
myelin covering of nerve fibers of the white matter in the CNS. These areas of
demyelination are visualized as plaques or lesions and are seen on brain tissue
directly (e.g., on autopsy) or on MRI with contrast agents (Fig. 57-1).
inflammation that causes the relapses that are seen clinically, and it is the resolution
of these relapses that is seen as remission.
Figure 57-1 Myelin destruction in multiple sclerosis.
The second process is neurodegenerative, during which the axons of nerves in
brain white matter are damaged, some irrevocably. This neurodegeneration causes a
progressive disability when transmission through the nerve cell is slowed or fails
completely. It is cumulative with time and may be irreversible. It is not known
whether the inflammatory or neurodegenerative process occurs first in MS or
whether they are simultaneous.
The inflammatory cascade in MS is complex. Various types of T cells play a role
4 The unknown antigen couples with MHC molecules.
These antigen–MHC pairs encounter antigen-presenting cells (APC) such as
dendrites, macrophages, and microglia.
20 T cells recognize this antigen–MHC–APC
complex, become activated, and initiate the immunologic cascade.
Under normal circumstances, regulatory T cells (Treg
autoimmune T-cell formation in the periphery. It has been hypothesized that Treg cells
malfunction in people with MS.
The activated T cells then retreat to the lymphatic tissues in the body, such as the
spleen and lymph nodes, to expand.
4 At the appropriate time, the T cells exit the
lymphatic tissues and rejoin the circulation. Sphingosine-1-phosphate (S1P), a small,
circulating lipid molecule, is important in this process. For the T cells to exit the
lymphatic tissues, the S1P receptor 1 must be expressed on their surface.
cells follow an S1P concentration gradient to exit the lymphatic tissues and join the
The activated T cells must cross the blood–brain barrier to attack myelin in the
CNS. An adhesion molecule, α4β1
-integrin (VLA4), is found on the surface of T
25 When the T cells approach the blood–brain barrier, they slow and bind to the
-integrin and p-selectin glycoprotein ligand 1. This bonding allows the T cells to
transmigrate through the endothelial cells of the blood vessel.
Now in the perivascular space, the T cells must be reactivated by new APC.
Through the action of matrix metalloproteinases 2 and 9, the activated T cells invade
46 Once ensconced in the brain, the T cells begin to
secrete various proinflammatory cytokines that further stimulate the inflammatory
cascade, including stimulation of microglia.
The microglia produce proteolytic enzymes, lipolytic enzymes, reactive oxygen
species, reactive nitrogen species, excitotoxins, and more proinflammatory cytokines.
Activated microglia can also serve as APCs for activation of additional T cells.
Nitric oxide, a reactive nitrogen species, is increased during inflammation and can
inhibit mitochondrial respiration, inhibit the sodium–potassium adenosine
triphosphatase pump, and cause the intracellular release of calcium. The excess
calcium leads to degenerative processes within the cell.
Although the role of T cells is central to MS pathology, the role of B and NK cells
is much less clear. B cells may be involved in antigen presentation and the
production of the immunoglobulin found in the CSF of patients with MS.
have been postulated to have both helpful and deleterious effects.
At some point, the resolution of inflammation begins. During the inflammatory
cascade, myelin is broken down, and this myelin debris inhibits remyelination. The
microglia use phagocytosis to clear myelin structures, axons, apoptotic cells, and
myelin debris from the area of inflammation.
47 After this process, the microglia begin
to produce immunomodulatory cytokines.
47 Helper T type 2 cells become more
prominent and begin secreting immunomodulatory cytokines as well.
Remyelination then begins; however, some evidence suggests that the ability of the
body to remyelinate decreases with age.
Microglia produce more cytokines and some growth factors that cause
oligodendrocyte progenitor cells to migrate to the area. Remyelination occurs when
oligodendrocyte progenitor cells differentiate into new oligodendrocytes.
receptors 1 and 5 present on oligodendrocytes appear to help with differentiation.
Remyelination may not be complete and, in some cases, does not occur at all. The
myelin also may be thinner and shorter than the original myelin.
Axonal injury can occur throughout the course of the disease and may even occur
Inside chronic MS lesions, there are 60% to 70%
fewer axons compared with other white matter in the same patient.
producing myelin, oligodendrocytes support axons through production of insulin-like
growth factor type I and neuregulin; thus, axons can die without the support of the
oligodendrocytes. However, axonal loss has been demonstrated at sites separate
from MS lesions, particularly the thalamus.
50 Although oligodendrocytes provide
trophic support for the axons, they also inhibit new growth to prevent random neurite
sprouting. Three myelin-associated inhibitor factors, myelin-associated glycoprotein,
Nogo-A, and oligodendrocyte myelin glycoprotein, lie in the sheath of myelin closest
to the axon, where they prevent this sprouting.
Microtubules are also important for neurite growth. The assembly of microtubules
is controlled by collapsin response mediator protein 2 (CRMP-2).
phosphorylated, neurite growth is inhibited.
3 Ras homolog gene family, member A
(RhoA)–guanosine triphosphate (GTP), has action on both the myelin-associated
inhibitory factors and CRMP-2. The myelin-associated inhibitory factors signal
RhoA–GTP to neurite retraction rather than growth.
Myelin normally allows saltatory, fast conduction (i.e., conduction via leaps) at
the nodes of Ranvier; thus, loss of myelin slows or prevents transmission of nerve
In the demyelinated state, sodium channels under the myelin sheath may become
functional to allow improved nerve conduction.
32 The activation of sodium channels
results in sodium entry into the cell. The excess sodium activates the sodium–calcium
exchanger to export sodium and import calcium, fueling the degenerative processes
demyelinated axons. Activation of these receptors results in increased levels of
intracellular sodium and calcium, further contributing to neurodegeneration.
Because the demyelination associated with MS can occur in any part of the CNS,
many different symptoms are associated with the disease. At first presentation, the
most common clinical symptoms are sensory disturbances, particularly of the
extremities, partial or complete visual loss, motor dysfunction of the limbs, diplopia,
20 Two demyelinating syndromes are so distinct and they have
been recognized, named, and deserve particular mention: optic neuritis and
transverse myelitis. Optic neuritis is the acute demyelination of the optic nerve.
Symptoms may include ocular pain, blurred vision, or changes in color perception.
Transverse myelitis is impairment of motor control or sensory function, or control
over bladder, bowel, and sexual functions that are consistent with a lesion at a
specific point in the spinal cord, but without a structural cause such as a herniated
Common Symptoms in Chronic Multiple Sclerosis
Walking problems or impaired ambulation
As concern has developed about neurodegenerative changes that occur early in the
course of MS, there has been more interest in very early treatment after the
emergence of symptoms to delay or decrease the development of MS. The term
clinically isolated syndrome (CIS) describes a first demyelinating neurologic event
involving the optic nerve, cerebrum, cerebellum, brainstem, or spinal cord.
85% of people with MS may first present with CIS.
52 Of those who present with CIS,
63% will develop MS during the ensuing 20 years.
Patients younger than 40 years old are more likely to convert from CIS to
clinically definite MS than those ≥40 years.
53 Patients with optic neuritis as the
presenting diagnosis are less likely than those with other symptoms to develop
clinically definite MS. The presence of oligoclonal bands in the CSF, low serum
concentrations of vitamin D, and multiple lesions on MRI are associated with a
particularly high risk of development of MS.
Occasionally, MS-type lesions will be visible on an MRI scan performed for other
55 About 30% of these patients have a clinical episode within 5
years of the detection of their MRI abnormality.
56 Younger patients, males, and those
with lesions on the spinal cord were more likely to develop a CIS.
suggested for patients with these findings at this time.
With time and with neurodegeneration, many other symptoms can develop in
people with MS. The most common symptoms are listed in Table 57-2.
When patients first present for medical care with symptoms of MS, diseases as
diverse as infections, cancers, vascular disease, or other inflammatory demyelinating
diseases are commonly part of the differential diagnosis. Thus, the addition of MRI
and other laboratory findings can help with the diagnosis. At other times, the
diagnosis is not apparent until the occurrence of a second attack.
Various diagnostic criteria have been proposed in an effort to standardize
diagnoses of MS and to promote earlier treatment. The initial criteria stated that the
patient must have experienced at least two demyelination-related episodes separated
and space (i.e., at least two episodes involving distinct regions of the CNS).
Guidelines proposed in 2001 and revised in 2005 and 2010 allow for the use of MRI
and CSF findings to fulfill these criteria after an initial clinical attack.
68–70 Primaryprogressive MS is diagnosed when there is continuous progression of neurologic
symptoms during a 1-year period with characteristic MRI and CSF findings.
Although the mechanisms of action of MS pharmacotherapies are diverse, they all
can be generally categorized as immunomodulating agents. To date, all therapies for
MS have targeted the inflammatory response rather than the accompanying
neurodegeneration features of the disease.
Corticosteroids are used in the treatment of MS to control inflammation during acute
relapses. Although most patients respond to treatment with corticosteroids, some do
not. These agents have several actions that contribute to their acute anti-inflammatory
effects. Corticosteroids increase the activity of Treg cells, reduce the activity of T and
B cells, reduce adhesion molecule production, and reduce proinflammatory
Treatment of Relapsing-Remitting Multiple Sclerosis
and it has an important inflammatory aspect. The agents that are currently US Food
and Drug Administration (FDA)-approved for MS include alemtuzumab, beta
interferons, dimethyl fumarate, fingolimod, glatiramer acetate, mitoxantrone,
natalizumab, and teriflunomide.
Alemtuzumab is a monoclonal antibody aimed at CD52. It reduces the population of
circulating B and T cells. The peripheral circulating lymphocytes are undetectable
74 These cells repopulate, but fairly slowly; B cells have a
median recovery time of 8 months, CD8
months. However, some patients took as long as 12 years to reach baseline levels.
Alemtuzumab reduced relapses and MRI lesions compared to interferon β-1a
subcutaneously, but had similar rates of disability progression; 77% of patients
taking alemtuzumab were completely relapse-free at 2 years.
saw benefits sustained from alemtuzumab over 5 years.
Beta interferons are thought to work by suppressing T-cell activity, downregulating
antigen presentation by MHC class II molecules, decreasing adhesion molecules and
matrix metalloproteinase 9, and increasing anti-inflammatory cytokines while
decreasing proinflammatory cytokines.
78 There are two types of interferon β
(interferon β-1a and interferon β-1b) and a total of four preparations available to
79–82 Placebo-controlled trials of each of the interferon β
agents have shown a reduced number of relapses and decreased disease progression
measured on the EDSS in patients treated with interferon versus those who were
Interferon β Preparations Used in the Treatment of Multiple Sclerosis
Interferon Type Route of Administration Frequency of Injection
Interferon β-1a Intramuscular Weekly
Interferon β-1a Subcutaneous 3 times weekly
Interferon β-1b Subcutaneous Every other day
Peginterferon β-1a Subcutaneous Every 2 weeks
Data are available for patients who have been treated with interferon β-1b for up
to 16 years. A sustained reduction in relapse rate of 40% was seen in patients who
received the drug continuously, an improved response compared with those who
received placebo or interferon only for a short time. Patients who received
continuous interferon therapy also had slower rates of disease progression.
87 Eightyear follow-up data for interferon β-1a given intramuscularly did not show this
sustained reduction in relapse rate, but did show that those who began treatment
earlier had better long-term outcomes.
Dimethyl fumarate is rapidly cleaved in the intestine to form its active form,
monomethyl fumarate. The medicine causes a shift in cytokine production from
interferon γ and tumor necrosis factor α to interleukin-4 and -5.
also activates the antioxidant effects of nuclear 1 factor (erythroid-related 2)-like 2
(Nrf2) transcriptional pathway which may assist with the neurodegeneration in
88 Dimethyl fumarate reduces the relapse rate by about half and
new lesion development on MRI scan compared to placebo.
Fingolimod is an S1P receptor modulator.
It binds to the S1P receptor 1 expressed
49 This binding causes the receptor to be internalized in the T cell, where it
is unresponsive to the normal signal to exit the lymphoid tissues and recirculate.
Without the T cells circulating, they are not activated and this disrupts the
inflammatory cycle. Fingolimod has been shown to decrease the relapse rate by about
half compared with placebo as well as to reduce disability progression.
Glatiramer acetate decreases type 1 helper T (TH1) cells while increasing type 2
helper T (TH2) cells. Additionally, it increases production of nerve growth
78 The short-term and long-term efficacy of glatiramer acetate is similar to
93 Regimens of 20 mg subcutaneously daily and 40 mg
subcutaneously 3 times weekly are effective compared to placebo.
Mitoxantrone works as a general immunomodulator. It decreases monocytes and
macrophages and inhibits T and B cells.
4 Compared with placebo, mitoxantrone
decreased the number of exacerbations and improved MRI in treated patients.
Natalizumab is a humanized monoclonal IgG4 antibody. It blocks T-cell entry into the
-integrin located on the lymphocyte to keep it from binding to
adhesion molecule-1 on the endothelial cell.
In clinical trials, natalizumab was
very effective, reducing the 1-year relapse rate by 68%, the risk of progression of
disability in 2 years by 42%, and new lesions on MRI by 83%.
Teriflunomide is the active metabolite of leflunomide. It is thought to act in MS by
blocking de novo pyrimidine synthesis, inhibiting B- and T-cell division, and
blocking the inflammatory pathway prominent in MS.
It may also inhibit the pairing
of T cells and APC to prevent T-cell activation. Teriflunomide reduces the
annualized relapse rate by about 20% to 30% and reduces the risk of new MRI
lesions by 60% to 80% compared to placebo in clinical trials.
Treatment of Progressive Forms of Multiple Sclerosis
Patients with both secondary-progressive and primary-progressive MS may
experience relapses. In these cases, all of the agents used for relapsing-remitting MS
may be useful to reduce the number of relapses.
103–106 Some evidence suggests that
therapies (specifically, interferon β-1a) are less effective for secondary- progressive
MS than for relapsing-remitting MS.
106 This finding is consistent with the known
mechanisms of action for the currently available agents, which are directed at the
inflammatory processes. Treatment of progressive forms of MS is an area in urgent
need of scientific investigation. Recently (March 2017), the FDA approved Ocrevus
(ocrelizumab), that is the first agent for primary-progressive MS.
As disability increases, many patients with MS exhibit other associated symptoms
that require targeted treatment (Table 57-2).
BLADDER, BOWEL, AND SEXUAL DYSFUNCTION
Bladder, bowel, and sexual dysfunction are very common in patients with MS. Up to
75% of patients have bladder symptoms; constipation or bowel incontinence occur in
approximately 50% of patients; and sexual dysfunction occurs in 84% of men and
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