Download multiple sclerosis: a comprehensive review

MULTIPLE SCLEROSIS: A COMPREHENSIVE REVIEW
INTRODUCTION
Multiple sclerosis (MS) is a chronic, debilitating neurodegenerative disease. The basic
disease process of multiple sclerosis is characterized by inflammation and then
destruction of the myelin sheaths and axons in the central nervous system, e.g., the brain,
brain stem, spinal cord, and optic nerve. Patients typically experience phases of
remissions and phases of relapses, although there can be variations in the clinical
presentation. The exact cause of MS is not known, but MS is most likely caused by an
environmental trigger in a susceptible individual. There is no cure for MS.
OBJECTIVES
When the student has finished this module, he/she will be able to:
1. Identify a basic definition of MS.
2. Identify the basic disease process of MS.
3. Identify the basic pathophysiological process that causes the neurological damage of
MS.
4. Identify the correct definition of myelin.
5. Identify the three basic causes of MS.
6. Identify three environmental causes of MS.
7. Identify the three requirements for making a diagnosis of MS.
8. Identify the correct definition of clinically isolated syndrome.
9. Identify the two most common forms of MS.
10. Identify three common signs and symptoms of MS.
11. Identify the pattern of presentation of the most common form of MS.
12. Identify the class of drug that is used to treat MS relapses.
13. Identify three drugs that are used to modify the course of MS.
14. Identify two psychosocial problems commonly associated with MS.
15. Identify two non-pharmacological interventions that can help patients with MS.
EPIDEMIOLOGY
There are approximately 400,000 people in the United States with MS, and
approximately 10,000 new cases are diagnosed each year.1 Multiple sclerosis primarily
affects women (3:1 ratio) and Caucasians.2 The disease is also far more common in
northern latitudes, and MS is almost unknown near the equator.3 The disease most often
develops in people aged 18 to 50 years of age, but it can happen it develop at any time of
life.4
PATHOPHYSIOLOGY
The pathophysiological process that causes the signs and symptoms of MS is not
completely understood. It probably begins when pro-inflammatory T lymphocytes are
activated by an antigen. (Note: A T lymphocyte is a type white blood cell that is involved
in cell-mediated immunity. There are various types of T lymphocytes, all with a different
action they perform once they are activated. The T stands for thymus; T cells mature in
the thymus). The activated T lymphocytes cross the blood-brain barrier and secrete proinflammatory cytokines that in turn activate B cells, macrophages, and other T cells.5
These cells initiate and sustain an inflammatory process that damages the myelin
sheaths and the axons. The name of the disease – multiple sclerosis – is derived from
the multiple sclerotic lesions that result from this process.
Learning Break: Myelin is an insulating material that surrounds the axon of a neuron.
Myelin increases the speed at which nerve impulses travel along the nerve fiber, and it
also prevents the nerve impulse from leaving the nerve fiber. A crude but somewhat
accurate way of picturing myelin is to imagine it as the insulation around an electrical
wire. Because the wire is surrounded by insulation, the electrical current does not “leak”
into the surrounding area and the current moves more quickly and efficiently down the
wire.
THE CAUSES OF MULTIPLE SCLEROSIS
Multiple sclerosis is most likely caused by a complex and poorly understood interplay
between environmental “triggers” and genetic factors that confer susceptibility. There is
also evidence that MS is in part an autoimmune disease or the disease process is mediated
by an autoimmune response: an environmental trigger initiates and sustains an
autoimmune response. in someone with a genetic susceptibility to MS. 6,7
Environmental Causes of Multiple Sclerosis

Cigarette smoking: People who smoke cigarettes have an increased risk of
developing MS when compared to people who have never smoked.8 The risk of
developing MS increases as the duration and intensity of the smoking habit
increases, and exposure to second-hand smoke may increase an individual’s risk
for developing MS.9,10 Smoking may also cause MS to progress. Cigarette smoke
contains toxins that can compromise the blood-brain barrier, may cause
demyelination, and can cause damage to axons. These toxins may also affect the
immune system and predispose the smoker to autoimmune diseases such as MS
and rheumatoid arthritis. Also, people who smoke have more respiratory
infections and these infections have been linked to an increased risk for the
development of MS.11

Vitamin D: Vitamin D is needed for the absorption of calcium. There are dietary
sources of vitamin D, but approximately 90% of the vitamin D we require is
synthesized by liver, the kidneys, and the two innermost layers of the epidermis.
There is a large body of evidence that strongly suggests that a lack of vitamin D is
an environmental risk factor for the development of MS.12 The lack of vitamin D
may affect the immune system, e.g., by allowing/increasing harmful activities of
lymphocytes and cytokines that can cause the inflammatory process that damages
myelin. Epidemiological studies have shown that a low serum level of vitamin D,
living in northern latitudes, and exposure to the sun appear to influence the risk of
developing MS. Providing vitamin D supplements as a preventative measure
would seem to make intuitive sense. Clinical trials using this approach have
produced promising results, but there are very few of these studies and they have
been small and not well designed.13

Epstein-Barr virus: The Epstein-Barr virus is a virus of the herpes family.
Epstein-Barr virus causes mononucleosis, certain cancers, and has been strongly
implicated as a cause of autoimmune diseases such as MS.14 Epstein-Barr virus
causes a life-long infection, continuous virus production, and has a modulating
effect on the immune system. Several studies indicated that the risk of developing
MS increased as the level of Epstein-Barr antibody titers increased.15,16
Genetic Causes of Multiple Sclerosis
Genetics influences the incidence of MS, but the exact nature and scope of the
contribution of inheritance to the development of the disease is not known. Caucasians
are at a higher risk for developing MS even when living in the same environmental
conditions as Africans and Asians.17 Multiple sclerosis clusters in families; the risk of
developing MS is 1 in 3 if an identical twin has MS, and 1 in 1000 if no one in the family
has MS. Determining the genetic basis of MS has proved to be difficult. The
susceptibility to the disease is polygenic, and there are perhaps 100 common genetic
variants that are likely to be involved in expression of MS.18
DIAGNOSING MULTIPLE SCLEROSIS
There is no definitive test that can be used to diagnose MS. A diagnosis of MS requires
a) documentation of two or more episodes (with signs and symptoms lasting > 24 hours)
of signs and symptoms that clearly indicate white matter pathology; these episodes, b)
must be distinct and separated by a month or more; and in addition, c) the diagnosis
requires that an MRI exam reveal two separate areas of damage to the CNS.19

Cerebrospinal fluid examination: The cerebrospinal fluid (CSF) of someone with
MS will often have elevations of IgG and an elevated IgG index. The IgG index
reflects the IgG and albumin levels of the CSF in relation to the IgG and albumin
levels in the serum.20 The CSF will also have oligoclonal IgG bands. These are
bands of immunoglobulins that are seen in CSF that is examined using protein
electrophoresis or isoelectric staining. The result is rather like an x-ray; the patient
with MS will have a characteristic “picture” that shows bands of the
immunoglobulins.
Learning Break: The value of CSF examination is of particular value in predicting the
development of MS in patients who have clinically isolated syndrome (this will be
discussed in a following section).

Imaging studies: A magnetic resonance imaging (MRI) exam will typically show
characteristic white matter lesions.21
Learning Break: The MRI exam can show characteristic lesions, but there can also be
non-specific findings that may indicate the presence of MS, but may be cause by other
pathological processes. In order to make a diagnosis of MS, MRI and examination of the
CSF must be used together,
CLINICAL PRESENTATION OF MULTIPLE SCLEROSIS
Multiple sclerosis is a complex disease, and there are four distinct patterns of clinical
presentation.22

Relapsing/remitting MS: Relapsing/remitting MS (RRMS) is the most common
form of MS; approximately 80% of all patients with MS have RRMS. Patients
have periods of remission and periods of relapse. Many (up to 80%) of patients
with RRMS will gradually suffer from irreversible neurological damage and
develop secondary progressive MS (SPMS).23,24

Primary progressive MS: Primary progressive MS (PPMS) accounts for
approximately 15% of all cases of MS. In PPMS, the patient suffers a steady,
progressive deterioration that begins at the onset of the disease.25

Secondary progressive MS: As mentioned earlier, the great majority of people
with RRMS eventually develop SPMS: the rate of conversion of one to the other
is approximately 2.5% per year.26 People with SPMS experience a steady decline
in functional ability that is not associated with attacks. The damage suffered is
usually greater than that suffered by patients with RRMS.

Progressive/relapsing MS: Progressive/relapsing MS (PRMS) appears to be a
variant of the disease that is uncommon (it accounts for ~ 5% of all MS patients).
People with PRMS have a steady decrease in functional ability between attacks,
but unlike SPMS, the attacks are superimposed on the progressive course of the
disease.27
Learning Break: Clinically isolated syndrome (CIS) is a term for a neurological
episode caused by inflammation or demyelination that is consistent with the
pathophysiological process of MS. Clinically isolated syndrome can often be a harbringer
of MS. Approximately 60% to 80% of patients with CIS and a documented brain lesion
will develop MS, and approximately 20% of patient with CIS and no documented brain
lesion will develop MS.28
CLINICAL PRESENTATION OF MULTIPLE SCLEROSIS
The onset of the MS can be sudden and dramatic, or slow and subtle. The clinical
presentation is very varied and unpredictable, and it will depend on the severity and
location of the lesions. The patients have sensory, motor, visual, brainstem, and
psychological signs and symptoms. Sensory loss (37%), optic neuritis (36%), weakness
(35%) and paresthesias (24%) are often reported.29 Many patients experience fatigue,
bladder dysfunction (incontinence), constipation, pain, and weakness. Depression is very
common, and suicide is 7.5-fold more common among people with MS.30
Learning Break: Optic neuritis characterized by pain, decreased visual acuity, and
reduced color and contrast acuity.
The relapses that occur and these signs and symptoms seen during a relapse are caused
by inflammation and myelin damage. In order to be considered a “true” relapse, the signs
and symptoms must last more than 24 hours, and they must be separated from a previous
relapse by a month. A relapse can be confirmed with a MRI exam that uses gadolinium
contrast.
PROGNOSIS OF MULTIPLE SCLEROSIS
There is no cure for MS. The relationship between relapses and prognosis and longterm disability is not clear.31 The majority of patients with MS will eventually develop a
neurological disability. Fifteen years after the onset of the disease, only 20% of all
patients with MS will not have a functional disability, and 25 years after onset ~ 80% will
need assistance in walking.32 Patients with MS rarely die as a direct result of the disease;
complications such as pneumonia are far more common, as is suicide.
TREATMENT OF MULTIPLE SCLEROSIS
Multiple sclerosis treatment focuses on treating relapses (acute care), trying to alter the
progressive course of the disease (disease-modifying therapy), and providing
symptomatic relief
Treating Relapses
Acute relapses of MS are treated with high-dose, short-term IV corticosteroids. These
drugs will decrease the severity and shorten the duration of the signs and symptoms.
However, they will not affect the degree of recovery, they do not decrease the rate of
occurrence of relapses, and they do not modify the course of the disease.33,34 There is
some evidence that oral corticosteroids can be effective.35,36
Methylprednisolone is the drug of choice. The dose is 500-1000 mg. The drug is mixed
with 120-200 mL of IV solution, and the mixture is administered over one to two hours,
once a day for three to five days.37 After the IV infusions, the physician will often
prescribe oral prednisone, 60 mg to 80 mg, one a day, tapering the dose over the course
of two weeks.
Learning Break: It is important to distinguish between a true relapse and
pseudoexacerbation that may be caused by infection, fatigue, or a change in ambient
temperature before using corticosteroids.
Disease-Modifying Therapy
The disease-modifying drugs are used for patients with CIS, RMMS, and SPMS.38
They are not used for patients with PPMS. They work by modifying the immune
response. These drugs have been shown to have multiple benefits:39






Lower relapse rates
Milder relapses
Longer interval between relapses
Improved quality of life
Decreased lesion development as seen by MRI
Decreased development of disabilities
Drugs that are commonly used as disease-modifying agents in MS include:

Interferon beta-1a: Interferon beta-1a (Avonex®, Rebif®) has been shown to be
effective in modifying the course of MS.40,41,42 The drug appears to work by
altering the immune process via several mechanisms, e.g., decreasing T-cell
activity, increasing the activity of anti-inflammatory mediators, or decreasing the
activity of pro-inflammatory cytokines. As a result, patients have fewer relapses
and fewer severe relapses, and there is MRI evidence of fewer lesions.43
Interferon beta-1a can also decrease the incidence of progression from CIS to
MS.44 Common side effects include flu-like symptoms, depression, hepatic
laboratory abnormalities, thyroid function abnormalities, neutropenia, anemia,
and pain at the injection site.

Interferon beta-1b: Interferon beta-1b (Betaferon®, Betaseron®) decreases the
rate of relapses, decrease the number of patients who will suffer from a relapse,
decreases the incidence of severe relapses, and decreases the number of brain
lesions seen by MRI.45 (Note: Interferon beta-1b differs from interferon beta-1a
only in dosing schedule [every other day versus once a week] and in the basic
structure of the drug).
Learning Break: Interferon is a naturally occurring substance. It is a glycoprotein, and it
helps to regulate immune function and is involved in anti-viral activity. Interferon beta-1a
and beta-1b are both given as subcutaneous or intramuscular injections.

Glatiramer acetate: Glatiramer acetate (Copaxone®) is a mix of amino acids that
are found in myelin basic protein. Glatiramer acetate appears to work by affecting
the immune response that causes myelin damage. It may do so by mimicking
myelin proteins that act as antigens; components of the immune system that attack
and damage normal myelin would attach to glatiramer acetate, instead.46 Several
clinical trials have shown that glatiramer actetate reduces the frequency of
relapses and decreases brain lesions detected by MRI.47,48 The drug is given
subcutaneously, once a day. Chest tightness, palpitations, shortness of breath,
palpitations, and flushing are relatively common, but these signs and symptoms
do not cause harm and are transient.

Natalizumab: Natalizumab (Tysabri®) is a recombinant monoclonal antibody. It
appears to work by blocking T-cell activation and by interfering with the
migration of leukocytes in to CNS tissue. Natalizumab was removed from the
market in 2005 because it was felt that the risk of developing progressive
multifocal leukoencephalopathy (PML) was too great. It was subsequently reintroduced, but it can only be prescribed, dispensed, and taken if the patient is
enrolled in a special program. It can dramatically reduce the incidence of relapses.
The drug is indicated for use in patients who have not responded to other drugs,
have relapsing MS, and should be used with other immune modulating drugs; it is
intended to be used as a monotherapy.49 The drug is given once a month as an IV
infusion.
Learning Break: PML is a very serious, progressive neuromuscular disease caused by
an opportunistic infection of the white matter in various locations in the brain.

Mitoxantrone: Mitoxantrone (Novantrone®) is an antineoplastic drug that targets
T-cells, B-cells, and macrophages. It is considered to be a second-line drug
because significant side effects (e.g., severe bone marrow depression and
cardiomyopathy) are possible, and it is used when first-line agents have failed.50
Mitoxantrone is given as an IV infusion, every three months.

Cyclophosphamide: Cyclophosphamide (Cytoxan®, Neosar®) is an alkylating
chemotherapy drug. It has strong immunosuppressant activity, and has been used
to treat RRMS and SPMS for many years as a second-line agent when patients do
not respond to interferon or glatiramer and cannot receive natalizumab.51 It seems
to be most useful for treating MS in younger (ages 18 to 40 years) patient with a
reltively short duration of the disease. Numerous studies have shown that it is
effective in preventing relapses and improving the quality of life.52
Cyclophosphamide is given as an IV infusion; dosing regimens are
individualized. Infertility and bladder cancer are possible.

Azathioprine: Azathioprine (Imuran®) is an immunosuppressive drug that is
commonly used to treat MS. It has been shown to be effective at reducing relapses
and preventing new lesions. The side effects (nausea, vomiting, bone marrow
suppression, hepatic toxicity) can be easily manages, and the risk of malignancies
can be minimized by using doses less than 600 mg.53 Azathioprine is given orally,
once or twice a day.54

Methotrexate: Methotrexate (Rheumatrex®) is an immunosuppressive drug that is
used to treat leukemia, psoriasis, and rheumatoid arthritis. It has been used with
some limited success to treat SPMS.55
Learning Break: Cyclophosphamide, azathioprine, and methotrexate are considered to
be off-label treatments for MS.
The drugs used as disease-modifying agents have been proven to be very useful.
However, there are still important issues about the use of these drugs that have not been
answered. There are a limited number of studies that have directly compared drugs are
limited. It is not clear when to start patients on these drugs, and the role of combination
therapy – or if there is a role for it – is not known.
Symptomatic Treatment
The following drugs have been used to provide symptomatic relief:56

Weakness: Dalafampridine (Ampyra®) is a potassium channel blocker that can be
used for weakness and heat-related symptoms.

Ataxia/tremor: Clonazepam, mysoline (Primidone®), propranolol, or ondansetron
(Zofran®) can help alleviate ataxia and tremor.

Spasticity: There are many medications that have been used to alleviate spasticity,
e.g., baclofen (Lioresal®), diazepam, and dantrolene.

Pain: Carbamazapine, phenytoin, tricyclic antidepressants, gabapaentin
(Neurontin®) and pregabalin (Lyrica®) can be used to treat pain.

Bladder dysfunction: Drugs with an anticholinergic effect (e.g., oxybutinin,
hyoscyamine) can be useful if the patient with MS is incontinent.
LIFESTYLE ISSUES
Psychiatric Issues
Multiple sclerosis cannot be cured. Relapses and disabilities can be managed, but they
are painful, unpredictable, and affect quality of life. People with MS are twice as likely to
suffer from a major depressive disorder or anxiety. Substance abuse and suicide are far
more likely in this patient population.57 These issues obviously have profound impact on
patients (and the families of patients) personally, socially, and professionally. The
treatment for relapses, IV corticosteroids, can also cause psychiatric dysfunction. The
incidence and etiology of depression have been closely studied, and there is some
completed research on treatment. Much less is known about anxiety and substance abuse
in the population that as MS.
Depression in the population with MS appears to be underdetected and undertreated.58
Antidepressants can be used, and there is evidence that they can be effective, but the
amount of literature that supports their use is small.59 There is much more evidence for
the effectiveness of cognitive behavioral therapy (CBT) in treating depression in patients
with MS.60
Learning Break: Approximately 10% of all patients with MS suffer from pseudobulbar
affect (PBA). People with PBA have mood swings are noted to laugh or cry to a degree
that is out of proportion to the situation or the stimulus.
Fatigue
Fatigue affects a large percentage of patients with MS. Approximately 75% to 95% of
patients with MS report fatigue and large number (50% to 60%) of them feel that fatigue
is the most incapacitating aspect of the disease and a major disruption to their social and
professional lives.61 fatigue in patients with MS appears to be more common in the
afternoon and aggravated by high ambient temperatures. The cause of fatigue is not
known, and it doesn’t appear to be associated with to disability levels or the progress of
the disease. Amantadine (Symmetrel®) is an antiviral drug used to prevent and treat
influenza A. It can be effective in relieving fatigue, but the evidence for its use has only
reached Level II.62 Modafanil (Provigil®) is an analeptic that works (probably) by
increasing the level of monoamines such as noradrenaline and dopamine. It has been used
off-label to treat fatigue in patients with MS, and there is some evidence for, and some
against, its effectiveness.63,64
Exercise and Exercise Tolerance
At one time it was thought that patients with MS should not exercise. But research
during the last ten years has shown that resistance and endurance exercise can improve
the physical condition of patients with MS and the improvement of physical condition
improves the quality of life.65 Patients are now advised to exercise after consulting with a
physician. Two to three days a week is a reasonable schedule. Patients must be counseled
that exacerbations of the signs and symptoms of MS caused by exercise are temporary,
and they need to pay close attention and make sure they are not exercising too vigorously
if the ambient temperature is high.
NURSING ISSUES
Multiple sclerosis can have a profound impact on physical and psychological health.
Nursing care of the patient with MS should focus on the needs of the patient in those two
areas.
The status of the physical health of the patient with MS can vary from day to day and
change over time, as well. It is important to ascertain, with the patient’s input, what the
patient wants/needs to do in terms of physical activity. This information should be
balanced with information about the patient’s capabilities for physical activity. It is
important to stress that these are capabilities, not limitations. Certainly, the patient with
MS may not be able to do everything he/she wants to do; the disease can put limits on
physical activity. But with careful planning and assistance, the patient should be able to
maintain a level of activity that is satisfying and allows for good health. Help the patient
see the possibilities, not just the limitations. Help the patient see these issues as
challenges that can be solved, not just as problems to be endured. Specific issues that
patients may need advice/assistance with include: ambulation, bowel/bladder issues, skin
integrity, fatigue, energy expenditure and conservation, and exercise.
The psychological health of the patient with MS can be fragile – and understandably
so. The patient has a disease that cannot be cured, progresses, and can cause physical pain
and disabilities and serious emotional issues. There is no easy way for providing
emotional/psychological support for the patient with MS. It is not the role of the nurse to
substitute as a professional counselor. But the nurse can help by encouraging the patient
with MS to verbalize his/her feelings and to encourage the patient to seek help.
INFORMATION FOR PATIENTS
Multiple sclerosis is a disease that must be managed on a day-to-day basis. Patient
education and active participation by the patient in his/her own care is very important.

Patients need to have the ability to recognize a relapse and have a plan if one
occurs.

Patients must be aware that there are many, many treatment options that can help
them cope with the disease. No one has to suffer.

Patients must be aware that MS causes physical signs and symptoms, but also
causes emotional and social problems.

There are medical issues associated with MS, but also issues of managing the
challenges to day-to-day living, e.g., nutrition, exercise, ambulation,
transportation, etc. MS. Patients need to know that there are a lot of resources
available to help them with these challenges of living with MS. One good source
of help is the National Multiple Sclerosis Society, www.nationalmssociety.org,
1-800-344-4867
REFERENCES
1. Dangond F. Mutiple Sclerosis. eMedicine. April 14, 2010.
http://emedicine.medscape.com/article/1146199. Accessed August 7, 2010.
2. Noonan CW, Williamson DM, Henry JP, Indian R, Lynch SG, Neuberger JS, et al. The
prevalence of multiple sclerosis in 3 US communities. Preventing Chronic Disease.
2010;7: 1-8.
3. Lünemaann JD, Kamradt T, Martin R, Münz C. Epstein-Barr virus: Environmental
trigger of multiple sclerosis? Journal of Virology. 2007;81:6777-6784.
4. Dangond F. Mutiple Sclerosis. eMedicine. April 14, 2010.
http://emedicine.medscape.com/article/1146199. Accessed August 7, 2010.
5. Lipsy RJ, Schapiro RT, Prostko CR. Current and future directions in MS management:
key considerations for managed care pharmacists. Journal of Managed Care Pharmacy.
2009;15:S1-S17.
6. McFarland HF, Martin R. Multiple sclerosis: a complicated picture of autoimmunity.
Nature Immunology. 2007;8:913-919.
7. Goverman J. Autoimmune T cell responses in the central nervous system. Nature
Reviews Immunology. 2009;9:393-407.
8. Healy BC, Ali E, Guttmann CRG, Chitnis T, Glanz BI, Buckle G, et al. Smoking and
disease progression in multiple sclerosis. Archives of Neurology. 2009;66:858-864.
9. Hernán MA, Olek MJ, Ascherio A. Cigarette smoking and incidence of multiple
sclerosis. American Journal of Epidemiology. 2001;154:69-74.
10. Mikaeloff Y, Caridade G, Tardieu M, Suissa S. Parental smoking at home and the risk
of childhood-onset multiple sclerosis in children. Brain. 2007;130;2589-2595.
11. Healy BC, Ali E, Guttmann CRG, Chitnis T, Glanz BI, Buckle G, et al. Smoking and
disease progression in multiple sclerosis. Archives of Neurology. 2009;66:858-864.
12. Pierrot-Deseilligny C. Clinical implications of possible role of vitamin D in multiple
sclerosis. Journal of Neurology. 2009;256:1468-1479.
13. Pierrot-Deseilligny C. Clinical implications of possible role of vitamin D in multiple
sclerosis. Journal of Neurology. 2009;256:1468-1479.
14. Lünemaann JD, Kamradt T, Martin R, Münz C. Epstein-Barr virus: Environmental
trigger of multiple sclerosis? Journal of Virology. 2007;81:6777-6784.
15. DeLorenze GN, Munger KL, Lennette ET, Orentreich N, Vogelman JH, Ascherio A.
Epstein-Barr virus and multiple sclerosis: evidence of association from a prospective
study with long-term follow-up. Archives of Neurology. 2006;63:839-844.
16. Levin LI, Munger KL, Rubertone MV, Peck CA, Lennette ET, Speigelman D,
Ascherio A. Temporal relationship between elevation of Epstein-Barr virus antibody
titers and initial onset of neurological symptoms in multiple sclerosis. Journal of the
American Medical Association. 2005;293:2496-2500.
17. Hauser SL, Goodin DS. Multiple sclerosis and other demyelinating diseases. In: Fauci
AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J, eds.
Harrison’s Principles of Internal Medicine. 17th ed. New York, New York. McGrawHill;2008:2611-2620.
18. Sawcer S. The genetic aspects of multiple sclerosis. Annals of the Indian Academy of
Neurology. 2009;12:206-214.
19. Hauser SL, Goodin DS. Multiple sclerosis and other demyelinating diseases. In: Fauci
AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J, eds.
Harrison’s Principles of Internal Medicine. 17th ed. New York, New York. McGrawHill;2008:2611-2620.
20. Dangond F. Mutiple Sclerosis. eMedicine. April 14, 2010.
http://emedicine.medscape.com/article/1146199. Accessed August 7, 2010.
21. Dangond F. Mutiple Sclerosis. eMedicine. April 14, 2010.
http://emedicine.medscape.com/article/1146199. Accessed August 7, 2010.
22. Hauser SL, Goodin DS. Multiple sclerosis and other demyelinating diseases. In: Fauci
AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J, eds.
Harrison’s Principles of Internal Medicine. 17th ed. New York, New York. McGrawHill;2008:2611-2620.
23. Scalfari A, Neuhaus A, Degenhardt A, Rice GP, Muraro PA, Daumer M, et al. The
natural history of multiple sclerosis, a geographically based study 10: relapses and longterm disability. Brain. 2010;133:1914-1929.
24. Spain RI, Cameron MH, Bourdette D. Recent developments in multiple sclerosis
therapeutics. BMC Medicine. 2009;7:74
25. Spain RI, Cameron MH, Bourdette D. Recent developments in multiple sclerosis
therapeutics. BMC Medicine. 2009;7:74
26. Hauser SL, Goodin DS. Multiple sclerosis and other demyelinating diseases. In: Fauci
AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J, eds.
Harrison’s Principles of Internal Medicine. 17th ed. New York, New York.McGrawHill;2008:2611-2620.
27. Hauser SL, Goodin DS. Multiple sclerosis and other demyelinating diseases. In: Fauci
AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J, eds.
Harrison’s Principles of Internal Medicine. 17th ed. New York, New York. McGrawHill;2008:2611-2620.
28. Lipsy RJ, Schapiro RT, Prostko CR. Current and future directions in MS
management: key considerations for managed care pharmacists. Journal of Managed
Care Pharmacy. 2009;15:S1-S17.
29. Hauser SL, Goodin DS. Multiple sclerosis and other demyelinating diseases. In: Fauci
AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J, eds.
Harrison’s Principles of Internal Medicine. 17th ed. New York, New York. McGrawHill;2008:2611-2620.
30. Scalfari A, Neuhaus A, Degenhardt A, Rice GP, Muraro PA, Daumer M, et al. The
natural history of multiple sclerosis, a geographically based study 10: relapses and longterm disability. Brain. 2010;133:1914-1929.
31. Hauser SL, Goodin DS. Multiple sclerosis and other demyelinating diseases. In: Fauci
AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J, eds.
Harrison’s Principles of Internal Medicine. 17th ed. New York, New York. McGrawHill;2008:2611-2620.
32. Hauser SL, Goodin DS. Multiple sclerosis and other demyelinating diseases. In: Fauci
AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J, eds.
Harrison’s Principles of Internal Medicine. 17th ed. New York, New York. McGrawHill;2008:2611-2620.
33. Spain RI, Cameron MH, Bourdette D. Recent developments in multiple sclerosis
therapeutics. BMC Medicine. 2009;7:74
34. Myhr KM, Mellgren SI. Corticosteroids in the treatment of multiple sclerosis. Acta
Neurologica Scandinavia. Supplement. 2009;189:73-80.
35. Martinelli V, Rocca MA, Annovazzi P, Pulizzi A, Rodegher M, Boseschi FM, et al. A
short-term randomized MRI study of high-dose oral versus intravenous
methylprednisolone in MS. Neurology. 2009;73:1842-1848.
36.Burton JM, O’Connor PW, Hohol M, Beyene J. Oral versus intravenous steroids for
treatment of relapses in multiple sclerosis. Cochrane Database of Systematic Reviews.
2009. Jul 8 (3); CD006921.
37. Dangond F. Mutiple Sclerosis. eMedicine. April 14, 2010.
http://emedicine.medscape.com/article/1146199. Accessed August 7, 2010.
38. Coyle PK. Disease-modifying agents in multiple sclerosis. Annals of the Indian
Academy of Neurology. 2009;12:273-282.
39. Coyle PK. Disease-modifying agents in multiple sclerosis. Annals of the Indian
Academy of Neurology. 2009;12:273-282.
40. Applebee A. Panitch H. Early stage and long-term treatment of multiple sclerosis
with interferon beta. Biologics. 2009;3:257-271.
41. Jacobs LD, Beck RW, Simon JH, Kinkel RP, Brownscheidle CM, Murray TJ, et al.
Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in
multiple sclerosis. CHAMPS Study Group. New England Journal of Medicine.
2000;343:898-904.
42. Jacobs LD, Cookfair DL, Ruddick RA, Herndon RM, Richert JR, Salazar AM, et al.
Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis:
The Multiple Sclerosis Collaborative Research Group (MSCRG). Annals of Neurology.
1996;39:285-294.
43. Applebee A. Panitch H. Early stage and long-term treatment of multiple sclerosis
with interferon beta. Biologics. 2009;3:257-271.
44. Kappos L, Polman CH, Freedman MS, Edan G, Hartung HP, Miller DH, et al.
Treatment with interferon beta-1b delays conversion to clinically definite and McDonald
MS in patients with clinically isolated syndromes. Neurology. 2006a;67:1242-249.
45. Coyle PK. Disease-modifying agents in multiple sclerosis. Annals of the Indian
Academy of Neurology. 2009;12:273-282.
46. Dangond F. Mutiple Sclerosis. eMedicine. April 14, 2010.
http://emedicine.medscape.com/article/1146199. Accessed August 7, 2010.
47. Johnson KP, Brooks BR, Cohen JA, Ford CC, Goldstein J, Lisak RP, et al.
Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple
sclerosis: results of a Phase III multi-center, double-blind, placebo-controlled trial.
Neurology. 1995;45:1268-1276.
48. Comi G, Fillipi M, Wolinsky JS. European/Canadian multi-center, double-blind,
randomized, placebo-controlled study of the effects of glatiramer acetate on magneticresonance imaging-measure disease activity and burden in patients with relapsing
multiple sclerosis. European/Canadian Glatiramer Acetate Study Group. Annals of
Neurology. 2001;49:290-297.
49. Dangond F. Mutiple Sclerosis. eMedicine. April 14, 2010.
http://emedicine.medscape.com/article/1146199. Accessed August 7, 2010.
50. Dangond F. Mutiple Sclerosis. eMedicine. April 14, 2010.
http://emedicine.medscape.com/article/1146199. Accessed August 7, 2010.
51. Elkhalifa AS, Weiner HL. Cyclophosphamide treatment of MS: Current therapeutic
approaches and treatment regimens. The International Multiple Sclerosis Journal.
2010;17:12-18
52. Elkhalifa AS, Weiner HL. Cyclophosphamide treatment of MS: Current therapeutic
approaches and treatment regimens. The International Multiple Sclerosis Journal.
2010;17:12-18
53. Casetta I, Iuliano G, Filipinni G. Azathioprine for multiple sclerosis. Cochrane
Database of Systematic Reviews. 2007Oct 17 (4);CD003982.
54. Invernizzi P, Benedetti MD, Poli S, Monaco S. Azathioprine in Multiple Sclerosis.
Mini- Reviews in Medicinal Chemistry. 2008;9:919-926.
55. Hauser SL, Goodin DS. Multiple sclerosis and other demyelinating diseases. In: Fauci
AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J, eds.
Harrison’s Principles of Internal Medicine. 17th ed. New York, New York. McGrawHill;2008:2611-2620.
56. Hauser SL, Goodin DS. Multiple sclerosis and other demyelinating diseases. In: Fauci
AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J, eds.
Harrison’s Principles of Internal Medicine. 17th ed. New York, New York. McGrawHill;2008:2611-2620.
57. Chwastiak LA, Ehde DM. Psychiatric issues in multiple sclerosis. Psychiatric Clinics
of North America. 20027;30:803-817.
58. Mohr DC, Hart SL, Fonareva I, Tasch ES. Treatment of depression for patients with
multiple sclerosis in neurology clinics. Multiple Sclerosis. 2006;12:20-208.
59. Chwastiak LA, Ehde DM. Psychiatric issues in multiple sclerosis. Psychiatric Clinics
of North America. 20027;30:803-817.
60. Mohr, DC, Boudewyn AC, Goodkin DE, et al. Comparative outcomes for individual
cognitive-behavioral, supportive expressive group psychotherapy and sertraline for the
treatment of depression in multiple sclerosis. Journal of Consulting Clinical Psychology.
2001;69:942-949.
61. Penner IK Calabrese P. Managing fatigue: Clinical correlates, assessment procedures
and therapeutic strategies. International Multiple Sclerosis Journal. 2010;17:28-34.
62. Penner IK Calabrese P. Managing fatigue: Clinical correlates, assessment procedures
and therapeutic strategies. International Multiple Sclerosis Journal. 2010;17:28-34.
63. Lange R, Volkmer M, Heesen C, Lipert J. Modafinil effects in multiple sclerosis
patients with fatigue. Journal of Neurology. 2009;256:645-650.
64. Rammohan KW, Rosenberg JH, Lynn DJ, Blumenfeld, AM, Pollak CP, Nagaraja
HN. Efficacy and safety of modafanil (Provigil®) for the treatment of fatigue in multiple
sclerosis: a two centre phase 2 study. Journal of Neurology, Neurosurgery & Psychiatry.
2002;72:179-183.
65. Dalgas U, Ingemann-Hansen T, Stenager E. Physical exercise and MS –
Recommendations. International Multiple Sclerosis Journal. 2009;16:5-11.