• Multiple sclerosis (MS) is a chronic disease characterized
3. gliosis (plaques or scarring),
4. neuronal loss.
• MS plaques typically occur at different times and in
different CNS locations.
• MS is said to be disseminated in time and space.
• 5 million individuals worldwide.
• Manifestations of MS vary from a benign illness to a rapidly
evolving and incapacitating disease requiring profound
Epidemiology and causes
• MS is approximately threefold more common in women than men.
• The age of onset is typically between 20 and 40 years
• Prevalence of MS is 0.1–0.2%.
• The cause of MS is unknown; however, it is believed to occur as a result of some
combination of genetic and environmental factors such as infectious agents.
• Risk factors:-
1. Geographicly the highest known prevalence for MS in north of Scotland. In other
temperate zone areas
• Moving at an early age from one location in the world to another alters a person's subsequent
risk of MS.
2. Vitamin D deficiency is associated with an increase in MS risk .
• ongoing deficiency may increase the relapse rate in established MS.
3. a protective effect of sun exposure.
4. any microbes have been proposed as triggers of MS, but none have been
5. Smoking has been shown to be an independent risk factor for MS.
6. Stress may be a risk factor although the evidence to support this is weak.
1- Stage of inflammation:-
• Perivenular cuffing with inflammatory mononuclear
cells (T cells & macrophages) with infiltration of
surrounding white matter
• Disruption of blood brain barrier (but vessel wall is
preserved, a contrast to vasculitis syndromes where
vessel wall is damaged)
2- Stage of demyelination:-
• Demyelination is the hallmark of the pathology
• Cell-mediated immunity
• T-lymphocytes against Myelin Basic Protein (MBP)
• Humoral immunity
• Myelin specific antibodies
• presence of elevated levels of locally synthesized
immunoglobulins and oligoclonal antibodies, derived
from clonally restricted CNS B cells and plasma cells, in
the CSF are also characteristic of MS.
3- Stage of Gliosis/Scarring:-
• Astrocytic proliferation (gliosis)
• Relative sparing of axons is typical of MS
• Partial or total axonal destruction can also occur,
especially within highly inflammatory lesions
• MS Plaques
- Oligodendrocyte precursor cells survive and in many
lesions are present in even greater numbers than in
normal tissue but fail to differentiate into mature
myelin- producing cells
- Partial remyelination of surviving naked axons by
surviving oligodendrocytes appearing as ‘shadow
Multiple sclerosis types
1.Relapsing remitting MS
2.Primary progressive MS
3.2nd progressive MS
4.Progressive relapsing MS
1- Relapsing Remitting MS
• It occurs more than 85% of the cases
• is characterized by discrete attacks
of neurological dysfunction that
generally evolve over days to weeks
(rarely over hours).
• There is often complete recovery
over the ensuing weeks to months.
• Approximately half will fail to
• Between attacks, patients are
2- Primary Progressive MS
• accounts for ∼ 15% of cases.
• These patients do not experience
attacks but only a steady
functional decline from disease
• The sex distribution is more even,
• The disease begins later in life
(mean age ∼ 40 years),
• Disability develops faster (relative
to the onset of the first clinical
3- Secondary Progressive MS
• SPMS always begins as RRMS.
• At some point, however, the clinical course
changes so that the patient experiences a
steady deterioration in function unassociated
with acute attacks (which may continue or
cease during the progressive phase).
• SPMS produces a greater amount of fixed
neurologic disability than RMS.
• For a patient with RMS, the risk of developing
SPMS is ~2% each year, meaning that the
great majority of RMS ultimately evolves into
• As such, SPMS appears to represent a late
stage of the same underlying illness as RMS.
4- Progressive/relapsing MS
• (PRMS) overlaps PPMS and SPMS
• accounts for ∼ 5% of MS patients
• Like patients with PPMS, these
patients experience a steady
deterioration in their condition
from disease onset.
• However, like SPMS patients, they
experience occasional attacks
superimposed upon their
• The onset of MS may be abrupt or insidious.
• Symptoms may be severe or seem so trivial that a patient
may not seek medical attention for months or years.
• Symptoms of MS are extremely varied and depend on the
location and severity of lesions within the CNS
Ataxia and vertigo
1- Motor symptoms
• Weakness of the limbs may manifest as
loss of strength, , speed, or dexterity, as fatigue
a disturbance of gait
• Exercise-induced weakness is a characteristic symptom of
• The weakness is of the upper motor neuron type.
• Usually accompanied by other pyramidal signs such as
spasticity, hyperreflexia, and Babinski signs.
• A tendon reflex may be lost (simulating a lower motor
neuron lesion) if an MS lesion disrupts the afferent reflex
fibers in the spinal cord.
• Is commonly associated with spontaneous and movement-
induced muscle spasms.
• More than 30% of MS patients have moderate to severe
spasticity, especially in the legs.
• This is often accompanied by painful spasms interfering
with ambulation, work, or self-care.
• Occasionally, spasticity provides support for the body
weight during ambulation, and in these cases, treatment of
spasticity may actually do more harm than good.
3- Facial weakness
• Due to a lesion in the pons.
• May resemble idiopathic Bell’s palsy.
• Unlike Bell’s palsy, facial weakness in MS is usually
NOT associated with :
- Ipsilateral loss of taste sensation
- Retroauricular pain.
4- Sensory symptoms
• Include both
1. Paresthesias (e.g., tingling, prickling sensations, formications,
“pins and needles,” or painful burning)
2. Hypesthesia (e.g., reduced sensation, numbness, or a “dead”
• Unpleasant sensations (e.g., feelings that body parts are
swollen, wet, raw, or tightly wrapped) are also common.
• Sensory impairment of the trunk and legs below a horizontal
line on the torso (a sensory level) indicates that the spinal
cord is the origin of the sensory disturbance.
• It is often accompanied by a band-like sensation of tightness
around the torso.
• Pain is a common symptom of MS:-
• experienced by >50% of patients.
• Pain can occur anywhere on the body and can change locations
5- Optic neuritis (ON)
• Periorbital pain (aggravated by eye movement) often precedes or
accompanies the visual loss.
• Diminished visual acuity,
• Decreased color perception (desaturation) in the central field of
• These symptoms can be mild or may progress to severe visual loss.
• Rarely, there is complete loss of light perception.
• Central visual loss (central scotoma)
• Visual symptoms are generally monocular but may be bilateral.
• An afferent pupillary defect is usually present.
• Funduscopic examination:-
• may be normal
• optic disc swelling (papillitis).
• Pallor of the optic disc (optic atrophy) commonly follows ON.
• Uveitis is uncommon and should raise the possibility of alternative
6- Visual blurring
• May result from
1. Optic neuritis (ON)
2. Diplopia – if the symptom resolves when either eye is covered,
the cause is diplopia.
• Diplopia may result from
Internuclear ophthalmoplegia (INO)
OR from palsy of the 6th cranial nerve (rarely the 3rd or 4th).
• An INO is an impairment in horizontal eye movement
o impaired adduction of affected eye
o abduction nystagmus of the contralateral eye
o due to a lesion in the ipsilateral medial longitudinal fasciculus.
• A bilateral INO is particularly suggestive of MS.
• Other common gaze disturbances in MS include
1. a horizontal gaze palsy,
2. a “one and a half” syndrome (horizontal gaze palsy plus an INO),
3. acquired pendular nystagmus.
• During horizontal eye movement
• The paramedian pontine reticular
formation (PPRF) sends a signal to
the abducens nucleus, which
contains 2 sets of neurons
1. neuronal axons that innervate
the ipsilateral rectus muscle
and cause abduction
2. abducens interneurons
decussate to form the medial
longitudinal fasciculus (MLF)
and innervate the medial rectus
• axons from the medial rectus
subnucleus innervate the
ipsilateral medial rectus
• usually manifests as cerebellar tremors.
• Ataxia may also involve
- the head
- the voice – producing a characteristic cerebellar
dysarthria (scanning speech).
8- Vertigo and Hearing loss
• may appear suddenly from a brainstem lesion,
superficially resembling acute labyrinthitis.
• Hearing loss may also occur in MS but is
• is an electric shock–like sensation
• that radiates down the back into the legs.
• Rarely, it radiates into the arms.
• Typically induced by flexion or other movements of the
• It is generally self-limited but may persist for years.
• Lhermitte’s symptom can also occur with other disorders
of the cervical spinal cord (e.g., cervical spondylosis).
• Refers to neurologic symptoms produced by an
elevation of the body’s core temperature.
• For example, unilateral visual blurring may occur during
a hot shower or with physical exercise (Uhthoff’s
• It is also common for MS symptoms to worsen
transiently, sometimes dramatically, during febrile
• Such heat-related symptoms probably result from
transient conduction block.
• can occur when the demyelinating lesion involves the
root entry (or exit) zone of the fifth, seventh, and ninth
cranial nerve, respectively.
• Trigeminal neuralgia (tic douloureux) is a very brief
lancinating facial pain often triggered by an afferent
input from the face or teeth.
• Most cases of trigeminal neuralgia are not MS related;
• Atypical features that should raise the possibility that
1. onset before age 50 years,
2. bilateral symptoms,
3. objective sensory loss
4. Nonparoxysmal pain
• Consists of either persistent rapid flickering
contractions of the facial musculature (especially
the lower portion of the orbicularis oculus)
• or a contraction that slowly spreads across the face.
• It results from lesions of
1. the corticobulbar tracts
2. or brainstem course of the facial nerve.
• Bladder dysfunction
is present in >90% of MS patients,
in a third of patients, dysfunction results in weekly or more frequent
episodes of incontinence
• Cognitive dysfunction
• can include memory loss, impaired attention, difficulties in executive
functioning, memory, problem solving, slowed information processing,
and problems shifting between cognitive tasks
• Depression , experienced by approximately half of patients
• Fatigue is experienced by 90% of patients; this symptom is the
most common reason for work-related disability in MS.
• Sexual dysfunction may manifest as decreased libido, impaired
genital sensation, impotence in men, and diminished vaginal
lubrication or adductor spasms in women.
• Constipation occurs in >30% of patients.
• Fecal urgency or bowel incontinence is less common (<15%) but
can be socially debilitating.
• There is no definitive diagnostic test for MS.
• Diagnostic criteria for clinically definite MS require
documentation of two or more episodes of symptoms and
two or more signs that reflect pathology in anatomically
noncontiguous white matter tracts of the CNS.
• Symptoms must
1. last for >24 h
2. occur as distinct episodes
3. that are separated by a month or more.
• In patients who have only one of the two required signs
on neurologic examination, the second may be
documented by abnormal tests such as MRI or evoked
1- DIAGNOSTIC TESTS- MRI
• Characteristic abnormalities are found in >95% of patients,
although more than 90% of the lesions visualized by MRI are
T1 C+ (gadolinium): active lesions show enhancement.
• MS a breakdown of the BBB increase in vascular permeability
leakage of IV (Gd) into the parenchyma.
• Such leakage occurs early in the development of an MS
• a useful marker of inflammation.
• Gd enhancement typically persists for <1 month, and the residual MS
plaque remains visible indefinitely as a focal area of hyperintensity (a
lesion) on T2-weighted images.
• Older lesions show no enhancement
T1 : lesions are typically iso- to hypointense (T1 black holes).
• Black holes may be a marker of irreversible demyelination and axonal loss.
T2 : lesions are typically hyperintense
resonance imaging in
particularly in the
on T2 image.
In T1 image with
• lesions (A arrows)
for 4 weeks);
• older lesions (B
arrows) show no
enhancement but low
Axial first-echo image
abnormalities in white
matter, typical for MS.
recovery (FLAIR) image in
which the high signal of
fluid (CSF) has been
CSF appears dark,
whereas areas of brain
edema or demyelination
appear high in signal, as
shown here in the corpus
Lesions in the anterior
corpus callosum are
frequent in MS and rare
in vascular disease.
Sagittal T2-weighted fast
spin echo image of the
demonstrates a fusiform
lesion in the midthoracic
image obtained after
reveals focal areas of
2- DIAGNOSTIC TESTS- Evoked potentials
• Visual evoked potentials (VEP) about 85% of people with
definite MS have an abnormal VEP.
• Somatosensory evoked potential (SSEP) about 77% of
people with definite MS have an abnormal SSEP.
• Brain stem Auditory evoked potential (BAEP) about 60%
of people with definite MS have an abnormal BAEP.
3- DIAGNOSTIC TESTS- CSF
- Suggestive of MS:
1. Normal opening pressure.
2. Normal sugar.
3. Total CSF protein is usually normal or slightly elevated
(less than 100 mg/dL).
4. Mononuclear pleocytosis.
5. Oligoclonal band.
6. Increase level of intrathecally synthesized IgG.
- The followings raise the concern that MS is not the diagnosis:
- A pleocytosis of >75 cells/μL,
- the presence of polymorphonuclear leukocytes,
- a protein concentration >1 g/L (>100 mg/dL) in CSF
• The specific tests required to exclude alternative
diagnoses will vary with each clinical situation;
• The followings should probably be obtained in all
patients with suspected MS:-
2. serum B12 level,
3. anti-nuclear antibodies,
4. treponemal antibody
DISORDERS THAT CAN MIMIC MS
• Acute disseminated encephalomyelitis (ADEM)
• Neuro myelitis optica
• Antiphospholipid antibody syndrome
• Behçet’s disease
• Neoplasms (e.g., lymphoma, glioma, meningioma)
• Stroke and ischemic cerebrovascular disease
Treatment of Multiple Sclerosis
• Therapy for MS can be divided into several categories:
1. treatment of acute attacks
2. Treatment with disease-modifying agents that reduce the
biological activity of MS,
3. Symptomatic therapy
ACUTE ATTACKS OR INITIAL
• When patients experience acute deterioration, it is
important to consider whether this change reflects
new disease activity or a “pseudoexacerbation”
resulting from an increase in ambient temperature,
fever, or an infection.
• When the clinical change is thought to reflect a
pseudoexacerbation, glucocorticoid treatment is
ACUTE ATTACKS OR INITIAL
• Glucocorticoids are used to manage:-
1. first attacks
2. acute exacerbations.
• When patients experience an acute deterioration,
glucocorticoid treatment is administered as IV
methylprednisolone 500 to 1000 mg/d for 3 to 5
days followed by a course of oral prednisone
beginning at a dose of 60 to 80mg/d and gradually
tapered over 2 weeks.
• IV immunoglobulin and plasma exchange when
1. relapses are sever (Acute MS)
2. when corticosteroids are contraindicated.
DISEASE-MODIFYING THERAPIES FOR
RELAPSING FORMS OF MS
(RRMS, SPMS WITH EXACERBATIONS)
• In relapsing-remitting and relapsing secondary
progressive MS these disease modifying drugs
reduce the relapse rate by about 30%.
• IFN-B is a class 1 interferon.
• Efficacy in MS, however probably results from
immunomodulatory properties (reduce inflammatory
• There is one 1b (Betaferon/Betaseron) and two 1a
(Avonex and Rebif) formulation of interferon-beta.
• Common side effects of INF-B therapy :
• Flu-like-symtom ,
• lymphopenia ,
• elevated liver function tests.
• Hypothyrodism ,
• depression ,
• increased spasticity .
• Cognitive change have been reported.
• Is asynthetic , random polypeptide composed of four
amino acid .
• 20 mg is administered by subcutaneous injection
• Side effects include: flushing, chest tightness,
• Safe in pregnancy
• Prevent 50% of MS
• this once daily medication can reduce relapse rate.
• SEs: hair loss and liver damage.
• Its administered as IV infusion every 4 weeks.
• Side effects include: hypersensitivity and
• Its antineoplastic drug, Its administered by IV
infusion every every 3 months
• Side effects include: bone marrow suppression and
• Other immunomodulatory agents: like
azathioprine, methotrexate, cyclophosphamide,
intravenous immunogiobuline are occasionally used
in aggressive secondary progressive MS.
• Potassium channel blockers e.g. 4- aminopyridine 10 to 40 mg/d may be
• Ataxia and tremor Clonazepam.
• Spasticity spasm improve by Baclofen, tizanidine, and
• Pain treated by anticonvulsant (carbamazepine, gabapentin)
• Bladder dysfunction
• urinary incontinence by oxybutynin
• urinary retention by bethanecol.
• Depression SSRI (e.g. fluoxitine)
• Fatigue improve with modafenil or pemoline Or amantadine
• Sexual dysfunction helped by Sildenafil.
CLINICAL VARIANTS OF MS
• Neuromyelitis optica (NMO), or Devic’s syndrome, is an
aggressive inflammatory disorder consisting most typically of
attacks of acute ON and myelitis
• Attacks of ON can be bilateral (rare in MS) or unilateral
• myelitis can be severe and transverse (rare in MS) and is
typically longitudinally extensive, involving three or more
contiguous vertebral segments
• The brain MRI was classically thought to be normal at the
onset of NMO
• Up to 40% of patients have a systemic autoimmune disorder,
often systemic lupus erythematosus, Sjögren’s syndrome,
myasthenia gravis, Hashimoto’s thyroiditis
• highly specific autoantibody directed against the water
channel protein aquaporin-4 is present in the sera of 60–70%
of patients who have a clinical diagnosis of NMO
Nerve conduction in myelinated and demyelinated axons. A. Saltatory nerve conduction in myelinated axons occurs with the nerve impulse jumping from one node of Ranvier to the next. Sodium channels (shown as breaks in the solid black line) are concentrated at the nodes where axonal depolarization occurs. B. Following demyelination, additional sodium channels are redistributed along the axon itself, thereby allowing continuous propagation of the nerve action potential despite the absence of myelin.
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