1. Multiple Sclerosis
Name : Vihari Vichakshana Rajaguru
Group No : 32
4th year 1st semester (2016)
Kursk State Medical University
2. Introduction
Transmission of action potentials along myelinated
axons.
An action potential “jumps” from node to node.
Voltage-gated Na+ channels are present only at the
nodes of Ranvier.
3. What is MS ?
a chronic, typically progressive disease
involving damage to the sheaths of nerve
cells in the brain and spinal cord.
The immune system attacks the protective
sheath (myelin) that covers nerve fibers
and causes communication problems
between your brain and the rest of your
body. Eventually, the disease can cause
the nerves themselves to deteriorate or
become permanently damaged
6. Etiology
Cause of MS is still not known,
scientists believe that the interaction
of several different factors may be
involved.
Immunologic Factors
Environmental Factors
Infectious Factors
Genetic Factors
7. Path physiology
Blood-brain barrier
breakdown
The BBB prevent entrance of T cells into the nervous system.
The blood–brain barrier is normally not permeable to these types of
cells, unless triggered by infection or a virus, which decreases the
integrity of the tight junctions.
When the blood–brain barrier regains its integrity, usually after
infection or virus has cleared, the T cells are trapped inside the
brain.
Autoimmunology The immune system attacks the nervous system, forming plaques
or lesions.
Commonly involves white matter.
Destroys oligodendrocytes- causing demyelination
Remyelination occurs in early phase but not completely.
Repeated attacks lead to fewer remyelination.
Inflammation T-cells attacks on myelin triggers inflammatory processes,
stimulating other immune cells and soluble factors like cytokines
and antibodies.
Leaks form in the BBB cause swelling, activation of macrophages,
and more activation of cytokines and other destructive proteins
8.
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12. CLASSIFICATION OF MULTIPLE SCLEROS
PRMS Progressive Relapsing MS
SPMS Secondary Progressive MS
PPMS Primary Progressive MS
RRMS Relapsing/ Remitting MS
Gradual progression of the disease from its
onset with no relapses or remissions
Unpredictable attacks which may or may not leave
permanent deficits followed by periods of remission
Initial RRMS that suddenly begins to decline without
periods of remission and relapses.
Steady decline since onset with super-imposed
attacks.
13. Progressive Relapsing
Mild infrequent sensory exacerbations
with full recovery.
Secondary Progressive
Condition of patients with
relapsing/remitting disease begins to
gradually worsen over time with
resulting accumulation of neurological
signs and symptoms. In this form of the
disease, relapses become more severe
while remissions are less complete,
shorter in duration, and eventually non-
existent. The course of MS becomes
steadily progressive.
14. Primary Progressive
There is no history of relapse in these
patients. Disease begins with a slow
progression of neurologic deficits.
Problems appear and gradually worsen
over time. Common problems include
spastic paraparesis, cerebellar ataxia,
urinary incontinence.
Relapsing Remitting Multiple Sclerosis
Episodes of exacerbations and
remissions during which not all
symptoms resolve completely. The
patient may be left with permanent
disability which may vary in severity.
Relapses are often more severe than in
the previous group. Relapses also
become more severe with time.
15. The most common
initial symptoms
• changes in sensation
in the arms, legs or
face : numbness
(33%)
• Optic neuritis (20%)
• weakness (13%)
• double vision-
internuclear
opthalmoplegia (7%)
• unsteadiness when
walking (5%)
• and balance
16. sensory exam
◦ - ascending numbness starting in the
feet;
◦ - bilateral hand numbness;
◦ - hemiparesthesia;
◦ - dysesthesia in one of the above
distributions;
◦ - generalized heat intolerance
Objectively the most common sensory
findings in the"numb" areas are dorsal
column signs, such as reduction of
vibration, proprioception and stereognosis,
rather than problems with spinothalamic
tract.
17. Right internuclear
ophthalmoplegia in a
patient with multiple
sclerosis. In the initial
phase of leftward gaze
(upper photograph), only
the left eye is abducted.
The right eye follows,
after a delay (lower
photograph).
18. Lhermitte's
sign (25-40%)
is an electrical
sensation that
runs down the
back and into the
limbs and is
produced by
bending the neck
forwards. The
sign suggests a
lesion of the
dorsal columns of
the cervical cord
or of the caudal
Uhthoff's
phenomenon
is the worsening of
neurologic
symptoms in
multiple sclerosis
and other
neurological,
demyelinating
conditions when the
body gets
overheated from
hot weather,
19. Ongoing Symptoms and
Signs
Motor system:
◦ -weakness (variable severity mono-
and paraparesis, hemiparesis,
quadriparesis)
◦ -increased spasticity resulting in
spastic gait
◦ -pathologic signs (Babinski's,
Chaddock's, Hoffmann, Oppenheim's,
etc.) -dysarthria
Cerebellar signs:
◦ -incoordination (dysdiadochokinesia,
problems with heel-to-shin test)
◦ -slowing of rapid repeating movements
◦ -cerebellar ataxia (ataxic gait)
◦ -scanning speech
20. INVESTIGATION
CSF oligoclonal bands, abnormal colloidal gold curve, elevated γ-
globulin IgG, mild mononuclear pleocytosis (<40 cells/mL),
myelin debris, normal or slightly elevated protein. (Myelin basic
Protein)
Blood
test
•B-12 and folate levels or antinuclear antibody (ANA) titers.
•Antiphospholipid antibody syndrome must be undertaken in
patients with evidence of blood dyscrasia and in women with
unexplained miscarriages or history of deep venous thrombosis.
•elevated erythrocyte sedimentation rate (ESR) and positive
titers of rheumatoid factor (RF) should help identify the presence
of a vasculitic disorder that may be mimicking MS.
MRI MRI of the head and spine (more sensitive than CT): May show
many plaques.
MRI reveals multiple lesions with high T2 signal intensity and
one large white matter lesion. These demyelinating lesions may
sometimes mimic brain tumors because of the associated
edema and inflammation.
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25. Diagnostic Criteria
Clinical Presentation Additional Data Needed
* 2 or more attacks (relapses)
* 2 or more objective clinical
lesions
None; clinical evidence will
suffice (additional evidence
desirable but must be consistent
with MS)
* 2 or more attacks
* 1 objective clinical lesion
Dissemination in space,
demonstrated by:
* MRI
* or a positive (cerebrospinal
fluid) CSF and 2 or more MRI
lesions consistent with MS
* or further clinical attack
involving different site
Diagnosis is based on McDonald’s Criteria (Revised
2010)
26. * 1 attack
* 2 or more objective clinical lesions
Dissemination in time, demonstrated
by:
* MRI
* or second clinical attack
* 1 attack
* 1 objective clinical lesion
(monosymptomatic presentation)
Dissemination in space demonstrated
by:
* MRI
* or positive CSF and 2 or more MRI
lesions consistent with MS
and
Dissemination in time demonstrated
by:
* MRI
* or second clinical attack
Insidious neurological progression
suggestive of MS
(primary progressive MS)
One year of disease progression
(retrospectively or prospectively
determined) andTwo of the following:
a. Positive brain MRI (nine T2 lesions
or four or more T2 lesions with
positive VEP)b. Positive spinal cord
MRI (two focal T2 lesions)c. Positive
CSF
27. Treatment
As of 2011, six treatments have been approved by
FDA
1. Interferon beta
1a (Avonex, CinnoVex,ReciGen and Rebif)
2. Interferon beta-1b (Betaseron )
3. Glatiramer acetate (Copaxone), a non-
steroidalimmunomodulator.
4. Mitoxantrone, is an immunosuppressant
5. Natalizumab (Tysabri)
Steroids: methylprednisolone (MP) 500–1,000 mg/d IV for 5
days
followed by tapered oral prednisone or MP 1 g/d IV for 3 days
± oral taper
28. MANAGEMENT
Spasticity Baclofen 5 mg PO 1–3 t.i.d. and increase as needed
Diazepam 2–5 mg PO at bedtime
Pain NSAIDs
Gabapentin effective vs. MS pain syndromes at 300 mg/d PO, may increase to
1,800 mg/d within 1 week, max dose 3,600 mg/d
Bladder
dysfunction
Propantheline 7.5 mg PO q3–4h to start, increase to 15 mg t.i.d. to q.i.d. plus
15–30 mg at bedtime
Oxybutynin chloride 5 mg PO t.i.d.–q.i.d.
Prophylactic antibiotics for urinary infections
Self-catheterizations for inadequate bladder emptying
Constipation: Stool softeners, bulk-producing agents, laxative suppositories
Incoordination or
tremors:
Incoordination or tremors:
Depression and
emotional lability
Antidepressant agents such as SSRIs.
Psychotherapy and support
Paranoia or
mania
Haloperidol lithium or atypical antipsychotic
Hemifacial and
dysesthesias
Carbamazepine 100–200 mg PO once or twice a day to start; increase to total
daily dosage of 600–1,600 mg t.i.d.–q.i.d.
Must monitor serum levels
29. Other regime
A main focus for MS patients is intake of foods that
lower inflammation, not aggravate it.
• Polyphenols (including flavonoids and nonflavonoids) and
carotenoids: vegetables, fruits, wine, spices, and herbs
• Polyunsaturated fats , omega-3 fatty acids and DHA: olive oil,
oily fish, fish oil.
◦ Limiting saturated
fats of animal origin
◦ limit caffeine consumption to decrease bone mineralization
loss
30. Vitamin B12 deficits is associated with
demyelination of nerve fibers so
supplementation of Vitamin B12 and
Vitamin B complex assists in prevention.
Calcium supplementation is important as
the incidence of osteoporosis , related to
decreased mobility, is higher in MS
patients.
vitamin D, selenium, and zinc have all
been found to decrease the production of
inflammatory molecules associated with
MS as well.
31. Prognostic Factors in Patients with
Multiple Sclerosis
Good prognosis
Optic Neuritis
Isolated sensory
symptoms
Long interval to
second relapse
No evidence of
disability after 5
years
Female gender
Poor Prognosis
‘Multifocal’ Clinically
Isolated Syndrome
Efferent
(motor/cerebellar)
systems
High relapse rate in 5
years
Substantial disability
after 5 years
Abnormal MRI with
32. Mortality Rates for Multiple
Sclerosis
The average life span of an individual with
MS is 25-35 years after initial diagnosis.
Most MS patients live into the 7th decade
Studies have shown that individuals with MS
die around 10 years earlier than the general
population
Studies have indicated that MS is not a cause
of death, whereas deaths occur as a result of
other chronic complications resulting from
immobility, chronic urinary tract infections,
dypsnea, dysphagia, aspiration & bacterial
pneumonia
Editor's Notes
SaltatoryConduction
Inward Na currents through the voltage-gated Na+ channels cause an action potential It regenerates the passive current to flow through the next segment of myelinated axon.
The damaged myelin forms scar tissue (sclerosis)
In MS, immune system T cells pass from the bloodstream into the central nervous system to attack the myelin coating around nerve fibers.
Autoimmune attack (of T cells and B cells) against oligodendrocytes
No 01 : Normal axon No 02 : Demylinated axon No 03 : Degenerated axon Results of demylination : slower conduction time along the affected nerve
When any part of the myelin sheath or nerve fiber is damaged or destroyed, nerve impulses traveling to and from the brain and spinal cord are distorted or interrupted, producing a wide variety of symptoms.
Affects mainly Caucasians (N. Europe)
Most common neurodegenerative disease of young adults (1 per 400)
Average age at onset 28(f)/30(m) years.
Female : male ratio = 2:1
MS appears to be more prevalent in temperate regions of the world than in the tropics leading to research on the effects of exposure to sunlight and vitamin D
In MS, an abnormal immune-mediated response attacks the myelin coating around nerve fibers in the central nervous system, as well as the nerve fibers themselves. In recent years, researchers have been able to identify which immune cells are mounting the attack, some of the factors that cause them to attack, and some of the sites (receptors) on the attacking cells that appear to be attracted to the myelin to begin the destructive process. Ongoing efforts to learn more about the immune-mediated process in MS — what sets it in motion, how it works, and how to slow or stop it — are bringing us closer to understanding the cause of MS.
MS is known to occur more frequently in areas that are farther from the equator.Growing evidence suggests that vitamin D plays an important role. People who live closer to the equator are exposed to greater amounts of sunlight year-round. As a result, they tend to have higher levels of naturally-produced vitamin D, which is thought to support the immune function and may help protect against immune-mediated diseases like MS. The possible relationship between MS and sunlight exposure is currently being looked at in a Society-funded epidemiological study in Australia. The evidence is also growing that smoking plays an important role in MS. Studies have shown that smoking increases a person’s risk of developing MS and is associated with more severe disease and more rapid disease progression. Since initial exposure to numerous viruses, bacteria and other microbes occurs during childhood, and since viruses are well-recognized as causes of demyelination and inflammation, it is possible that a virus or other infectious agent is the triggering factor in MS. More than a dozen viruses and bacteria — including measles, canine distemper, human herpes virus-6, Epstein-Barr, and Chlamydia pneumonia — have been or are being investigated to determine if they are involved in the development of MS, but none have been definitively proven to trigger MS.
While MS is not hereditary, having a first-degree relative such as a parent or sibling with MS does significantly increase an individual's risk of developing the disease. Studies have shown that there is a higher prevalence of certain genes in populations with higher rates of MS. Common genetic factors have also been found in some families where there is more than one person with MS. Some researchers theorize that MS develops because a person is born with a genetic predisposition to react to some environmental agent that, upon exposure, triggers an immune-mediated response. If you have a parent or sibling with MS there’s 1-3% of you developing MS. If you are a twin it’s 30%.
Plaques were demonstrated to occur anywhere within the white matter of the CNS, but the most frequently affected sites are the optic nerves, the brainstem, the cerebellum and the spinal cord. Lesions in these locations often correlate with clinical symptoms. In the cerebral hemispheres periventricular distribution of plaques is often seen. When plaques are adjacent to the cortex, subcortical myelinated fibers are often spared. Plaques located nearby the gray matter may rarely spread into the gray matter, including deep nuclei and the cortex. There often is axon sparing within the plaque.
Whatever route the pathological process takes from inflammation to demyelination, the effects of loss of myelin by the nerve fibers are quite dramatic. Saltatory conduction is much more energy efficient than nerve impulses transmitted along the entire length of the nerve fiber. Loss of myelin results in one or all of the following:
conduction block at the site of lesion
slower conduction time along the affected nerve
increased subjective feeling of fatigue secondary to compensation for neurologic deficits
Multiple Sclerosis most often is characterized by episodes of neurological dysfunction followed by periods of stabilization or partial to complete remission of symptoms. These symptoms (relapses or exacerbations) can appear over a few hours or days, can be gradually worsening over a period of a few weeks, or sometimes can present themselves acutely. Depending on a course and a subtype of the disease, these symptoms will either persist or slowly resolve over weeks or months and may even culminate as a complete remissions. A relapsing-remitting pattern is the most common and is characteristic for this disease.
sensory exam is the most difficult one to perform reliably and accurately in evaluation of patients with neurologic complaints. However, certain distributions of sensory problems can be suspicious for early MS.
Optic Neuritis is a frequent presenting symptom of MS. It is characterized by blurred vision, a change in color perception, visual field defect i.e.,. Central scotoma, and possible headaches and retro-orbital pain precipitated by eye movements. These symptoms may require neuro-ophthalmologic evaluation, MRI imaging and Visual Evoked Potential studies to establish a degree of optic nerve function.
Motor weakness often is accompanied by upper motor neuron signs, such as mild spasticity, hyperreflexia, and pathologic signs. The most common initial presentation is paraparesis, but weakness can be also found in just one extremity (monoparesis) or all four extremities (quadriparesis).
And all other symptoms that we discussed above in the picture.
Evoked potentials studies can be helpful in providing evidence of separation of lesions in space. An abnormal slowing of electrical impulses is used to assess this separation. The most commonly used evoked potentials in patients with MS are Visual Evoked Responses (VER), Brain stem Auditory Evoked Responses (BAER), and Somatosensory Evoked Responses (SSER). Approximately 75% of MS patients exhibit abnormal VER regardless of whether a patient does or does not have a history of clinically apparent optic neuritis. In a latter case, abnormal visual evoked response can be used to identify a para clinical second lesion and confirm the diagnosis of MS. The BAER is harder to interpret and only 30% of patients exhibit abnormal response from the central hearing areas in the brain stem. The SSEP is technically the most challenging study to perform, but is found to be abnormal in more than 80% of patients with definite MS. This study can help identify slowed conduction in the central sensory pathways, and help distinguish peripheral lesions from central ones.
The interferons (side effects include flulike symptoms, injection-site reactions, mild liver dysfunction) and glatiramer acetate are delivered by frequent injections, varying from once-per-day for glatiramer acetate to once-per-week (but intra-muscular) for Avonex. Natalizumab and mitoxantrone are given by IV infusion at monthly intervals.
Multiple sclerosis has a profound impact on patients’ social roles and the well-being of their families. Varying degrees of functional decline typically accompany MS. Because the onset is usually at about 30 years of age, the loss in productivity of people with MS can be substantial.
