Mammalian Physiology

Dr. Deen
March 18, 2016
Multiple Sclerosis

Multiple Sclerosis (MS) means many hardenings. The name of the

disease refers to the multiple scars that form on the brain and spinal cord.
There is no cure for the disease and it requires medical diagnosis to be
identified. It is primarily, but is not limited to, young adults. MS is rare, with
fewer than 200,000 cases reported each year in the United States. The
disease can last for years or even a lifetime. MS is a disease of unknown
cause that manifests as multiple hard plaques of degeneration of the
insulating layer of nerve fibers in the central nervous system. The loss of
insulation causes a short circuiting of nerve impulses. Multiple sclerosis is
a chronic inflammatory disease of the central nervous system. Various
symptoms are manifested over the course of time in the progression of the
disease due to multiple sites of neurological damage throughout the central
nervous system. Heidi J. Crayton states, in Managing the symptoms of
multiple sclerosis: A multimodal approach, that patients with multiple
sclerosis may experience numerous symptoms that include spasticity,
fatigue, cognitive dysfunction, depression, bladder dysfunction, bowel
dysfunction, sexual dysfunction, and pain. Less common are depression,

bowel dysfunction and paroxysmal symptoms

According to Multiple Sclerosis: Diagnosis and Therapy by Howard L
Weiner, spasticity is seen in more than 60% of patients with MS. It may not
cause pain but can contribute directly and indirectly to other symptoms such
as bladder and bowel dysfunction. The increased muscle tone, hypertonia,
results from injury to the corticospinal system and unmodulated activity of
local spinal neurons and sensory afferent pathways. This can lead to pain,
spasms, reduced mobility, a limited range of movement and contractures if
not managed well. Spasticity can also have positive effects, such as aiding
in ambulation by compensating for muscle weakness or decreased strength.
Many patients with MS report fatigue as being their most disabling symptom
of the disease. Fatigue in patients suffering with multiple sclerosis differs
from healthy individuals in that it interferes with routine physical and
cognitive functioning and is worsened by heat. Fatigue can worsen the
morbidity of MS by limiting a patients energy and endurance and negatively
affecting mood and the ability to cope with accompanying symptoms
(Crayton, 2006). Fatigue is worsened by depression; sleep disturbances and
physical disabilities that accompany the disease.
Many patients with MS show some deficits in neuropsychological
testing. In the early stages of the disease, cognitive deficits may be present
even in the absence of physical disabilities and may become more apparent
as the disease progresses. Cognitive impairment does not progress linearly

and there is no consensus regarding the long-term prognosis in patients.

Patients who suffer from this impairment participate in fewer social activities,
are less likely to be employed, have more sexual dysfunction, and are more
likely to require assistance with personal and household duties. Patients with
multiple sclerosis suffering from depression, is a result of the disease as well
as an adverse side effect of treatment for the disease. Bladder dysfunction
occurs in as many as 80% of patients with a new diagnosis of MS, and the
prevalence increases to 96% in those who have had the disease for > 10
years. (Crayton, 2006) The bladder problems associated with the disease
include hyperreflexia, sudden need to urinate, inability to initiate urination,
not completely emptying the bladder when urinating, and nighttime
incontinence. Constipation in patients may be caused by slow colonic transit
or abnormal rectal function. Bowel incontinence can result from reduced
sensation, poor pelvic muscle control or reduced compliance or weakness of
the anal sphincter.
Men and women with multiple sclerosis may suffer from sexual
dysfunction as the disease progresses. Reports of pain are difficult to assess
due to the use of different classifications, such as symptom related or
disease oriented. Trigeminal neuralgia, chronic pain affecting the trigeminal
nerve in the face, is estimated to be in ~1% of patients. It arises from the
fifth cranial nerve and may be caused by a demyelinating plaque at the
nerve root entry zone or in the pontine tegmental pathway (Crayton, 2006).
Lhermitts sign is a symptom of MS that occurs when the neck is flexed. It is

an electric-shock-like sensation that radiates down the spine and into to the
legs. Paroxysmal dystonia is a movement disorder associated with painful,
unilateral dystonic posture triggered by movement, sensation, a startling
noise or hyperventilation in patients of Multiple Sclerosis.
The pathology of MS lesion is defined by the presence of large
multifocal, demyelinated plaques, oligodendrocyte loss and axonal
degeneration (Weiner, 2012). In the early development of MS lesions, the
stability of the blood-brain barrier is compromised. This results in the
invasion of monocytes and T cells to the brain parenchyma. Mononuclear
cells, activated microglia and peripheral monocytes, are the primary cells
involved in the demyelination of Multiple sclerosis lesions. These lesions are
classified into three groups- active, chronic active, and chronic inactive.
Active and chronic active lesions are distinguished by the presence of evenly
distributed MHC class II positive cells. Chronic active plaques are
characterized by the presence of MHC class II and myelin lipid positive cells
that are distributed perivascularly, whereas, chronic inactive lesions have
few MHC class II positive cells (Weiner, 2012). A classification based on a
broad spectrum of immunological and neurological markers in a large set of
pathological samples of MS, characterized four different patterns. Patterns 1
and 2 are characterized by the T cell and macrophage-mediated
inflammation. Pattern 2 showed antibody and complement dependent
demyelination. Pattern 3 lesions contained T cells and macrophages and are
also defined by distal oligodendrogliopathy. The fourth pattern is showed the

complete loss of oligodendrocyte in addition to the presence of inflammatory

infiltrates mostly dominated by macrophages as well as T cells. It is
generally believed that the acute MS lesions are initiated by a myelin
reactive CD4+ T cell that is stimulated in the periphery and enters the brain
and spinal cord (Weiner, 2012).
The etiology of multiple sclerosis is still debatable but current data
suggest that environmental factors in genetically susceptible background
can predispose an individual to the disease. Family studies assessing the risk
of relatives suggests that first degree relatives are 10-25 times at greater
risk of developing MS than the general population.(Weiner, 2012) Gender
and ethnicity are other contributors in susceptibility to the disease with
women being at higher risk than males. Caucasians are more susceptible
than African Americans. Environmental factors have the potential to increase
the risk of developing MS such as infection, vaccination, climate and a
persons diet. Infections are considered the most common risk factor for MS
as many infections and antibodies generated in response to these infections
are present in sera or the cerebrospinal fluid (CSF) of MS patients at higher
titers than controls (Weiner, 2012). Smoking, herpes virus 6, retroviruses and
Chlamydia are other potential risks linked to Multiple Sclerosis.
Understanding of Multiple Sclerosis pathology and the immune system
helps to design various treatments for the disease. The primary function of
the immune system is to protect the body against pathogens. The immune

system falls into two categories- innate immune system and adaptive
immune system. It is not known the degree that both systems interact with
MS. There are various cures related to the treatment of MS- halting the
progression of the disease, reversing the neurological deficits, and
developing a strategy to prevent Multiple sclerosis. Progress is being made in
slowing the progression of MS and approaches have been made that may
help reverse neurological deficit. Strategies to prevent MS are beginning to
develop as well. Expectations are that over the next 4 years no fewer than
five new drugs may receive regulatory approval for MS, which holds further
promise for patients (Weiner, 2012). Pharmacological treatment of Multiple
Sclerosis is essential in the management of the symptoms of the disease,
helping to improve a patients quality of life, ease of care and help to ensure
their independence. Symptoms of the disease can change over the course of
time as the disease progresses, so serial monitoring helps to optimize
interventions. The management of the individual symptoms is grouped
based on a wide range of symptoms, beginning with the mobility-related
symptoms- spasticity, ataxia and impaired ambulation. Another group is
comprised of bladder, bowel and sexual dysfunction. A group of symptoms
that is typically over looked is comprised of fatigue, cognitive dysfunction
and mood disturbance.
At the onset of multiple sclerosis, several factors need to be considered
in the general management of spasticity. If the spasticity is localized or
generalized, possible features that could affect the patients function, the

potential of spasticity masking underlying muscle weakness and ataxia,

possible aggravating factors, which drug treatments are appropriate, and if
physiotherapy and nursing interventions necessary. Management of
spasticity may include an exercise regime consisting of stretching, range-ofmotion and aerobic exercises and relaxation techniques (Crayton, 2006).
Baclofen, benzodiazepines (ie, diazepam and clonazepam), and tizanidine
seem to have similar effects in reduction of stiffness and spasms, but
tizandine seems to be the best and diazepam the worst tolerated as
explained in Pharmacological management of symptoms in multiple
sclerosis: current approaches and future directions by Alan J. Thompson.
Baclofen is recommended first for patients, especially those with spinal cordrelated spasticity. Tizandine can also be used in first-line treatment but side
effects are dose-dependent. Clonazepam can help reduce spams and
stiffness but due to drowsiness caused by the drug, it is prescribed for
nighttime use. Patients with severe spasticity are recommended intrathecal
when it is difficult to manage the symptoms with oral drugs. It is given
through a catheter that releases the drug directly into the intrathecal space
from a programmable pump in the abdominal wall (Thompson, 2010). This
way, very high concentrations of the drug within a body can be reached
without systemic side-effects. Morphine can be added when severe pain
remains despite treatment with intrathecal baclofen. There is little evidence
available for the treatment of ataxia and tremor, symptoms that are very
difficult to manage.

The fatigue experienced by patients with Multiple sclerosis may be a

result of the disease of a side effect of treatments of MS. Treating underlying
factors that exacerbate fatigue can help the patient better manage the
fatigue. Improving physical fitness, improving mobility with physical and
occupation therapy as well as mobility aid and techniques, learning energy
conservation and cooling techniques call all help patients manage the
fatigue they experience.
Cognitive impairment is common (40-70%) in patients with MS and
occurs in all phenotypes (Thompson, 2010). Several domains, such as
memory, speed of information processing, mental flexibility and executive
functions are affected by the disease. Currently, no medications have been
approved by the US Food and Drug Administration for the treatment of the
symptoms of MS-associated cognitive impairment (Crayton, 2006). Ginkgo
Biloba has been used by some patients with MS and may warrant evaluation.
Treatment of MS-related fatigue and depression can be important for
cognitive functions in patients.
The rate of depression in patients suffering with Multiple Sclerosis
reaches 50% by the age of 59 years. In evaluations of patients symptoms, it
is important to distinguish between major depression, adjustment disorder
with depressed mood and dysthymic disorder. It is also important to
recognize any physical and cognitive features of Multiple Sclerosis. Treatment
of depression in patients with MS is the same in patients not suffering from

the disease- it should include psychotherapy and pharmacologic

intervention. It is important to treat depressive symptoms in patients with MS
who are receiving disease-modifying agents for several reasons: depressive
symptoms are unlikely to remit spontaneously; depression has a negative
impact on cognitive function, which may already be compromised in patients
with MS; and depressed patients with MS are less likely than those without
depression to adhere to long-term disease modifying therapy (Crayton,
2006).
As MS progresses, dysfunction of the bladder will typically worsen in
association of the continued impairment of muscle control, immobility,
spasticity, and cognitive impairment. Urinary tract infections are associated
with MS-related urinary incontinence. Before treatment for urinary
incontinence begins, patients should be evaluated for the presence of a
urinary tract infection. Nonpharmacologic methods for the management of
bladder symptoms may include timed voiding, regulating fluid intake, and a
restriction on consumption of bladder irritants like caffeine and aspartame.
Surgical approaches to incomplete bladder emptying include augmentation
cystoplasty and sacral nerve stimulation (Crayton, 2006). Overactive
bladders respond to treatment with anticholinergic medications. Incomplete
bladder emptying can be treated mechanically with the use of intermittent
self-catheterization.
Bowel dysfunction may be associated with the process of Multiple

Sclerosis and/or compounded by the adverse effects of medications used to

treat symptoms of the disease. Constipation may be caused by either slow
colonic transit of abnormal rectal functioning. Prevention of constipation
involves the use of laxatives, stool softeners, an increase in fiber intake and
adequate hydration. Bowel training and maintenance of physical activity may
also be helpful. Laxatives and enemas are useful in relieving constipation.
Bowel incontinence can be a result of reduced sensation, poor pelvic muscle
control or reduced compliance or weakness of the anal sphincter. The first
step in treating bowel incontinence in MS patients is to look for contributory
factors that can be modified, such as dietary intolerances. When medical
therapy fails to relieve bowel incontinence, a surgical procedure (eg, anterior
sphincter repair, artificial sphincter implantation) may be beneficial.
Sexual dysfunction occurs in many patients suffering from Multiple
Sclerosis. The main complaints in males with MS are reduced libido, erectile
impotence, and premature ejaculation (Thompson 2010). The main
complaints are reduced libido, difficulties reaching orgasms, and a
decreasing in vaginal lubrication. Men and women suffering with one these
symptoms also suffered from the affects it had on their quality of life. Men
suffering from erectile dysfunction can be treated with oral
phosphodiesterase-5 inhibitors. Attention to relationship factors and
symptomatic measures may relieve some of the sexual problems
experienced by patients.

Pain occurs frequently, even in the early stages of Multiple Sclerosis

and is often severe. Studies have reported a prevalence ranging from 2590%. Treatment recommendations are derived from the results of research
in other disorders due to a rarity in randomized controlled trials in MS.
Recommendations for pain management include carbamazepine or
oxcarbazepine for first-line treatments. Surgical procedures include
radiofrequency treatment of the Gasserian ganglion or microvascular
decompression. Lhrmittes sigh is treated with general antiepileptic drugs.
Painful tonic spasm can be treated with gabapentin, tiagabine, and
botulinum toxin A. Gamma-knife radiosurgery has been reported to
effectively control pain in some patients for up to 5 years. Management
recommendations for persistent pain in MS are similar to those for general
causes of neuropathic pain. Recent guidelines from the UK National Institute
for Health and Clinical Excellence suggest that treatment should start with
amitriptyline or pregabalin for neuropathic pain (Thompson, 2010).
Cannabinoids provide no definitive benefits on spasticity but patients
reported significant improvement in pain. Evidence for non-pharmacological
treatments is weak and based on small open-label trails and case-reports. In
MS, intrathecal infusions of baclofen and morphine or both might be
beneficial in severe cases of pain. Trigeminal neuralgia can initially be
managed with anticonvulsant carbamazepine but over time, response to this
drug decreases and add-on therapy with other medications, such as
baclofen, gabapentin or lamotrigine, are necessary.

Multiple sclerosis can be comprised of a wide range of symptoms. For

optimum management of the symptoms of the disease requires
multidisciplinary approaches and focus on the needs of each individual
patient. Due to an interrelation within symptoms of MS: one symptom may
cause another or treatment can even cause another symptom.
Pharmacological and nonpharmacological methods are recommended with
the goal of improving or maintaining body functions and preserving each
patients quality of life.

Work Cited
1. 1.

Heidi, Crayton J., and Howard S. Rossman. Managing the

symptoms of multiple sclerosis: A multimodal approach. Clinical

Therapeutics- Volume 28, Issue 4, April 2006, Pages 445-460
2. 2.

Alan J. Thompson, et al. Pharmacological management of

symptoms in multiple sclerosis: current approaches and future

directions.The Lancet Neurology- Volume 9, Issue 12, December 2010,
Pages 1182-1199.
3. 3.

Howard L. Weiner, and James M. Stankiewicz. Multiple Sclerosis.

Wiley- Blackwell February 2012.