Transcript In pathologic specimens, the demyelinating lesions of MS

Multiple Sclerosis
N.Beladimoghadam.MD
Shahid Beheshti University of Medical Science
MS is a leading cause of disability in
young adults
PATHOPHYSIOLOGY
• Demyelination interrupts current flow by removing the
insulator of internodal axon current flow.
• For short segments (one or two internodes) demyelination
is usually not critical because of a high safety factor for
transmission.
• However, longer segments of demyelination can result in
interruption of current flow, because current must flow by
continuous propagation.
• Persistent neurological deficits or negative symptoms of
MS are caused by regions in which conduction block persists,
such as in regions of large plaques, whereas transient
worsening of function reflects a drop below the safety
threshold for conduction because of physiological changes
involving the partially demyelinated axon (Uhthoff's
phenomenon, worsening with increased body temperature).
PATHOLOGY
• The pathological hallmark of MS is the cerebral or
spinal plaque, which consists of a discrete region of
demyelination with relative preservation of axons,
although spectroscopic and pathological studies
suggest some axonal loss may be an integral part of the
disease process.
• Gross examination of the brain in MS often reveals
variable degrees of atrophy and ventricular dilatation.
Plaques develop in a perivenular distribution and are
seen most frequently in the periventricular white
matter, brain stem, and spinal cord.
• However, large numbers of small plaques, often
detected only by microscopy, are found in cortical
regions affecting intracortical myelinated fibers.
PATHOLOGY
• Histological examination of active plaques reveals
perivascular infiltration of lymphocytes (predominantly T
cells) and macrophages with occasional plasma cells.
• In the plaque, myelin is disrupted, resulting in myelin
debris found in clumps or within lipid-laden macrophages.
Macrophages, most prominent in the plaque center, appear
to have an integral role in stripping myelin lamellae from
axons.
• Reactive astrocytes are prominent in plaques.
Immunohistochemical studies have found increased levels
of cytokines in active plaques, indicative of ongoing
immunoreactivity.
In
pathologic
specimens,
the
demyelinating lesions of MS, called
plaques), appear as indurated
areas; hence the term sclerosis.
Inflammation in multiple sclerosis
Perivascular infiltration of inflammatory cells. These
infiltrates are composed of activated T cells, B cells, and
macrophages
Mechanism of demyelination in MS
• May be activation of myelin-reactive T cells in the
periphery, which then express adhesion
molecules, allowing their entry through the
blood-brain barrier (BBB).
• T cells are activated following antigen presentation by
antigen-presenting cells such as macrophages and
microglia, or B cells. Perivascular T cells can secrete
proinflammatory cytokines, including interferon
gamma and tumor necrosis factor alpha.
• Antibodies against myelin also may be generated in the
periphery or intrathecally.
•
may be activation of myelin-reactive T
cells in the periphery, which then express
adhesion molecules, allowing their entry
through the blood-brain barrier (BBB). T
cells are activated following antigen
presentation by antigen-presenting cells
such as macrophages and microglia, or B
cells. Perivascular T cells can secrete
proinflammatory cytokines, including
interferon gamma and tumor necrosis
factor alpha. Antibodies against myelin
also may be generated in the periphery or
intrathecally. Ongoing inflammation leads
to epitope spread and recruitment of
other inflammatory cells (ie, bystander
activation). The T cell receptor recognizes
antigen in the context of human
leukocyte antigen molecule presentation
and also requires a second event (ie, costimulatory signal via the B7-CD28
pathway, not shown) for T cell activation
to occur. Activated microglia may release
free radicals, nitric oxide, and proteases
that may contribute to tissue damage.
Immune cells in MS
• Molecular studies of the white matter plaque
tissue have shown that :interleukin (IL)-12, a potent
promoter of inflammation, is expressed at high
levels in lesions that form early. A molecule
required to stimulate lymphocytes to release
proinflammatory cytokines, B7-1, is also
expressed at high levels in early MS plaques.
• Evidence exists of higher frequencies of activated
myelin-reactive T-cell clones in the circulation of
patients with RRMS and higher IL-12 production in
immune cells of patients with progressive MS,
when compared with healthy controls.
critical immune cells in the pathogenesis of
MS.
*CD4+ CD25+ T cells :regulatory role (Tregs)
Decreased function ( due to cytokine IL-23 role? )
*proinflammatory cytokine IL-17 ( TH 17 cells)
*Immune cells such as microglia (resident
macrophages of the CNS), dendritic cells, natural killer
(NK) cells, and B cells.
*nonimmune cells (ie, endothelial cells)
Etiology
• The cause of MS is unknown
• multiple factors (not a single identifiable agent or event
act in concert to trigger or perpetuate the disease.
• These factors are in part environmental and in part
hereditary
• The concordance rate for MS among monozygotic twins
is only 20-35%, suggesting that genetic factors have
only a modest effect.
• The presence of predisposing non-Mendelian factors
(ie, epigenetic modification in 1 twin), along with
environmental effects, plays an important role. For
first-degree family members (children or siblings) of
people affected with MS, the risk of developing the
disorder is only 3-5%.
It has been hypothesized that MS results when
an environmental agent or event (eg, virus,
bacteria, chemicals, lack of sun exposure) acts
in concert with a genetic predisposition to
immune dysfunction.
. HLA-DRB1 is the only chromosomal locus that
has been consistently associated with MS
susceptibility.Possibility that peripheral blood T
cells may become activated to attack a foreign
antigen and then erroneously direct their attack
toward brain proteins that share similar protein
epitopes
Etiology
• Genetic and molecular • A virus that infects cells of the
immune and nervous systems can
factors
possibly be reactivated periodically
• Viruses
and thus lead to acute exacerbations in
• Environmental factors
MS. The Epstein-Barr virus (EBV)?
• Vitamin D levels
• one early study showed 47% of MS
• Chronic
cerebrospinal brains were positive for HHV-6, and
venous insufficiency
80% showed elevation of antibodies in
• Hepatitis B vaccine
the serum
• Geography is clearly an important
factor .
• Must exert its effect in early childhood.
• Eskimos do not have a high frequency
of MS.
Etiology
• Genetic and molecular factors
• Viruses
• Environmental factors
• Vitamin D levels
• Chronic cerebrospinal
venous insufficiency
• Hepatitis B vaccine
• Vitamin
D
has a role in
regulating immune response, by
decreasing
production
of
proinflammatory cytokines and
increasing production of antiinflammatory cytokines; also,
high circulating levels of vitamin D
appear to be associated with a
reduced risk of MS.
• May be one reason for the
geographic variations in MS
incidence, and the protective
effect of traditional diets high in
vitamin D could help explain why
certain areas (eg, Norway) have a
lower incidence of MS despite
having limited sunlight.
Etiology
• Genetic and molecular
factors
• Viruses
• Environmental factors
• Vitamin D levels
• Chronic cerebrospinal
venous insufficiency
• Hepatitis B vaccine
• Paolo Zamboni described an
association between MS and
chronic cerebrospinal venous
insufficiency (CCSVI ).
Hepatitis B vaccine:
Multiple Sclerosis Society expert
panel states: “People with MS
should not be denied access to
health-preserving
and
potentially-life saving vaccines
because of their MS,
Preliminary data from Zivadinov (president of the International
Society for Neurovascular Disease) et al, from the MS research group
Buffalo:at the State University of New York
• presented findings in the first 500 participants studied with
venous Doppler looking at the prevalence of CCSVI in MS
patients and controls. Using the requirement that ≥2 CCSVI
Doppler criteria be met, CCSVI was found in 62.5% of MS
patients, 25.9% of healthy controls and 45% of other
neurological disorders.
• The study also found the prevalence of CCSVI was different
depending on a patient’s stage of the disease. About 38 per
cent of patients in the early stage of MS presented with
CCSVI, while 80 to 90 percent of patients in progressive stages
had the condition
• At least preliminarily, these results are different from the
100% sensitivity and specificity found by Zamboni and
colleagues. the University of Buffalo study neither proves nor
disproves the CCSVI theory
• Dr. Zivadinov said. "Our findings are consistent with an
increased prevalence of CCSVI in MS but with modest
sensitivity/specificity. Our findings point against CCSVI having
a primary causative role in the development of MS," he
added. "We are showing that CCSVI is connected to the
progression of disease, but whether it is a cause of the
progression or a consequence, we don't know at this time."
• Dr, Zivadinov added. "The currently ongoing placebocontrolled study in Buffalo, in collaboration with Department
of Neurosurgery at the University of Buffalo, is aiming to
answer this question and data should be available by the
second part of 2011," he said. "We are against
performing open-label endovascular treatment in patients
with MS."
Stress?
Stress does not appear to play a major role in the •
development of multiple sclerosis
from the University of Bergen, Norway June, 2011 •
Epidemiology
• Prevalence estimates for MS in the United States
vary from 58 to 95 per 100,000 population .
• MS is more common in women.
• Worldwide, approximately 2.1 million people are
affected by MS.
• low rates among Chinese, Japanese, and African
blacks; high rates among Sardinians, Parsis, and
Palestinians),
Classic MS symptoms are as follows:
• Sensory loss (ie, paresthesias) - Usually an early complaint
• Spinal cord symptoms (motor) - Muscle cramping secondary
to spasticity
• Spinal cord symptoms (autonomic) - Bladder, bowel, and
sexual dysfunction
• Cerebellar symptoms - Charcot triad of dysarthria, ataxia,
tremor
• Constitutional symptoms - especially fatigue (which occurs
in 70% of cases) and dizziness; fatigue must be differentiated
from depression (which may, however, coexist), lack of sleep,
and exertional exhaustion due to disability
• Pain - Occurs in 30-50% of patients at some point in their
illness
• Optic neuritis
• Subjective difficulties - With regard to attention span,
concentration, memory, and judgment
MS symptoms
• Depression - A common symptom
• Euphoria - Less common than depression
• Bipolar disorder or frank dementia - May appear
late in the disease course but is sometimes found at the
time of initial diagnosis.
• Trigeminal neuralgia - Bilateral facial weakness or
trigeminal neuralgia
• Facial myokymia (irregular twitching of the facial
muscles) - May also be a presenting symptom
• Partial acute transverse myelitis
• Eye symptoms - Including diplopia on lateral gaze;
these occur in 33% of patients
• Heat intolerance
MS Symptoms
• Fatigue
•
•
•
•
•
is one of the most commonly reported
symptoms of MS, being experienced in up to 90% of
patients with the disease.
Estimates of the prevalence of cognitive dysfunction
in MS range from 40-70%.
No correlation exists with the degree of physical
disability, and cognitive dysfunction.
may occur early in the course of disease.
. Areas of cognition affected include comprehension
and use of speech, attention, memory, visual
perception, planning, problem solving, and abstract
reasoning.
is a common occurrence in MS, with 30-50% of
patients experiencing it .( primary or secondary)
Attack
• An attack is defined as a neurologic disturbance of
the kind seen in MS. It can be documented by
subjective report or by objective observation,
but it must last for at least 24 hours.
Pseudoattacks and single paroxysmal episodes
must be excluded. To be considered separate
attacks, at least 30 days must elapse between
onset of one event and onset of another event.
• It is important to recognize that the progression
of physical and cognitive disability in MS may
occur in the absence of clinical exacerbations
Optic Neuritis
• Approximately 20% of patients with MS present with optic
neuritis (ON) as a first demyelinating event, and 40% of
patients may present with ON during the course of their
disease.
• Sequential episodes of optic nerve involvement and a
longitudinally extensive myelopathy (ie, neuromyelitis optica
[NMO], or Devic disease.
• Optic neuritis (ON), which involves the afferent visual
pathway, typically causes acute to subacute unilateral loss of
visual acuity, color and contrast sensitivity, visual field
changes, and pain. Onset of ON typically occurs over minutes
or hours, rarely days; however, loss of visual acuity may
progress over days to weeks.
• Only 3% of patients had no light perception (NLP). Given the
rarity of NLP in ON, other potential etiologies for vision loss
(eg, inflammatory, infiltrative, neoplastic) might need to be
considered in such patients.
Optic Neuritis
• Most cases of ON are retrobulbar.
• A relative afferent pupillary defect is present in
unilateral cases and in bilateral-but-asymmetrical cases
but may be absent in bilateral and symmetrical cases.
• The visual field defect: central scotoma-AltitudinalThree-quadrant
-One-quadrant
-Hemianopic
Peripheral rim –Arcuate-Enlarged blind spot
• fundus findings:anterior uveitis, vitreitis, vascular
sheathing, and disc and papillary hemorrhages, as well
as compromise of the central arterial and venous
circulations, are uncommon.
• In the ONTT, mild to severe pain was present in 92.2%
of patients
Visual disorders that may occur in MS:
• Diplopia due to an internuclear ophthalmoplegia (INO),
ocular motor cranial neuropathy ( 6TH>3 & 4) , The oneand-a-half syndrome , Horizontal or vertical gaze palsies
• Oscillopsia, Oscillopsia can occur secondary to
various types of nystagmus .
• Nystagmus:. A new-onset, acquired pendular
nystagmus is relatively common, but upbeat,
downbeat, convergence-retraction, and other
forms of nystagmus may develop in MS,
depending on the location of the demyelinating
lesion
Neuromyelitis optica (NMO)
• An inflammatory disease of the central nervous system (CNS)
characterized by severe attacks of optic neuritis and myelitis,
and which, unlike multiple sclerosis (MS), commonly spares the
brain in the early stages.
• NMO used to be considered as a special form of MS. During the
past 10 years, however, the two diseases have been shown to be
clearly different.
• NMO is a B-cell-mediated disease associated with antiaquaporin-4
antibodies in many cases and its pathophysiology seems to be
near the acute lesion of necrotizing vasculitis.
• Assessment of prevalence shows that NMO is far less frequent
than MS, which explains the absence of randomized clinical trials
and NMO treatment strategies validated by evidence-based
medicine.
• Recently, many data have been published that suggest that the
therapeutic option in NMO should be immunosuppressive
rather than immunomodulatory drugs
Neuromyelitis optica (NMO)
• An inflammatory disease of the central nervous
system (CNS) characterized by severe attacks of
optic neuritis and myelitis, and which, unlike
multiple sclerosis (MS), commonly spares the brain
in the early stages.
NMO
• The disease can be monophasic, i.e. a single episode
with permanent remission. However, at least 85% of
patients have a relapsing form of the disease.
• . Relapses usually occur early with about 55% of
patients having a relapse in the first year.
• In some patients (33% in one study), transverse myelitis
in the cervical spinal cord resulted in respiratory
failure and subsequent death. However, the spectrum
of Devic's disease has widened due to improved
diagnostic criteria, and the options for treatment have
improved; as a result, researchers believe that these
estimates will be lowered
• . In 2006, revised criteria for NMO were proposed
including, in addition to the two major symptoms (myelitis
and optic neuritis), any two [Bonnet et al. 1999] of the
following three criteria: extended myelitis on spinal cord MRI,
normal brain MRI at onset and positive anti-AQP4 antibodies
[Wingerchuk et al. 2006].
• Limited forms of Devic's disease, such as single or
recurrent events of longitudinally extensive myelitis, and
bilateral simultaneous or recurrent optic neuritis
• Asian optic-spinal MS. This variant can present CNS
involvement like MS[
• Longitudinally extensive myelitis or optic neuritis associated
with systemic auto-immune disease
• Optic neuritis or myelitis associated with lesions in specific
brain areas such as the hypothalamus, periventricular
nucleus, and brainstem
Clinical Rating Scales
• The most widely accepted of these is the 10-point
Kurtzke Expanded Disability Status Scale (EDSS) :1955
-has been revised over the years.
• Evaluate dysfunction in 8 neurologic systems, including
pyramidal, cerebellar, brainstem, sensory, bladder and
bowel, vision, cerebral, and "other." EDSS grades .
• 0 - Normal neurologic examination
• 5.5 - Ambulatory without aid or rest for approximately
100 m
• 6.0 - Intermittent or unilateral constant assistance
• 9.5 - Totally helpless bed patient; unable to
communicate effectively or eat/swallow
Categorizing MS
• MS is divided into the following categories on the basis
of clinical and radiologic criteria, including the
frequency of clinical relapses, time to disease
progression, and lesion development on MRI :
• Relapsing-remitting MS (RRMS) :approximately
85% of MS cases
• Secondary progressive MS (SPMS):Approximately 50%
of patients with RRMS convert to a secondary
progressive pattern within 10 years after disease onset
• Primary progressive MS (PPMS):approximately 10% of
MS cases
• Progressive-relapsing MS (PRMS):(< 5% of patients
with MS) have occasional relapses superimposed on
progressive disease
Diagnostic Considerations
• A common misconception is that any attack of demyelination
means a diagnosis of acute MS. When a patient has a first attack of
demyelination, the physician should not rush to diagnose
MS, because the differential diagnosis includes a number of other
diseases.
• commonly see patients referred for multiple, ill-defined, vague
complaints who had recent head or spinal MRI scans in which T2
hyperintense lesions have been demonstrated. Careful questioning
in these cases reveals that symptoms have been stereotyped
and vague or do not truly qualify as exacerbations
• These nonspecific lesions are relatively common in the
general adult population, and clinical correlation (ie, a high
degree of suspicion based on clinical evidence) becomes
important in the diagnosis. To confirm MS in these cases, the
physician should look for sites of involvement that are rare
for UBOs but frequent for MS (eg, the corpus callosum or
throughout the spinal cord).
• MRI shows brain abnormalities in 90-95% of MS patients and
spinal cord lesions in up to 75%, especially in elderly patients.
T2-weighted images show edema and more chronic lesions, whereas
T1-weighted images demonstrate cerebral atrophy and "black
holes." These black holes represent areas of axonal death.
One of the limitations of using MRI in patients with MS is the
discordance between lesion location and the clinical
presentation. In addition, depending on the number and location
of findings, MRI can vary greatly in terms of sensitivity and
specificity in the diagnosis of MS.
A clinician presented with an MRI report that details a few
"nonspecific white matter lesions" that are "compatible with MS" is
often frustrated with the lack of sensitivity and specificity of such a
description. For this reason,
described in detail
imaging findings need to be
Diagnostic criteria
• in 1965 Schumaker criteria
• In 1983 , Poser et al
• In 2001, the International Panel on the Diagnosis of Multiple
Sclerosis, headed by Dr. W. Ian McDonald, published a new set of
criteria .
• In 2005, the International Panel reconvened to review the
effectiveness of the criteria (Polman et al., 2005)
• In2007, Swanton et al. published a study of patients who had
Clinically Isolated Syndrome (CIS), in which a patient has a single
incident of a neurological symptom similar to early MS, and
objective evidence of a CNS abnormality (for example, from MRI,
CSF, or VEP results).
• If the diagnostic criteria can predict which patients will develop
CDMS, the criteria are established as sensitive and accurate
2010 McDonald MRI Criteria for
Demonstration of DIS
• DIS Can Be Demonstrated by 1 T2 Lesiona in at
• Least 2 of 4 Areas of the CNS:
•
•
•
•
Periventricular
Juxtacortical
Infratentorial
Spinal cordb
2010 McDonald MRI Criteria for
Demonstration of DIT
• DIT Can Be Demonstrated by:
• 1. A new T2 and/or gadolinium-enhancing lesion(s)
on follow-up MRI, with reference to a baseline scan,
irrespective of the timing of the baseline MRI
• 2. Simultaneous presence of asymptomatic
gadolinium-enhancing and nonenhancing lesions at
any time
2010 McDonald Criteria for Diagnosis of
MS in Disease with Progression from Onset
• 1. One year of disease progression (retrospectively
• or prospectively determined)
• 2. Plus 2 of the 3 following criteriaa:
• A. Evidence for DIS in the brain based on 1 T2b
• lesions in at least 1 area characteristic for MS
• (periventricular, juxtacortical, or infratentorial)
• B. Evidence for DIS in the spinal cord based
• on 2 T2b lesions in the cord
• C. Positive CSF (isoelectric focusing evidence of
• oligoclonal bands and/or elevated IgG index)
• MR spectroscopy appears to be capable of depicting
changes in white matter that are not detected with
routine pulse sequences. Because the findings are
correlated with disability scores, the use of MR
spectroscopy may prove valuable in monitoring
patients after treatment and in formulating their
prognosis.
• CT has had a limited role in the diagnosis of MS. CT
scans can help in assessing the degree of cerebral
atrophy associated with advanced MS.
• . Angiography also has a limited role in the diagnosis
and management of MS, but when CNS vasculitis is
considered in a patient with undifferentiated findings,
angiography may occasionally be considered.
Evoked Potentials
• These tests, are used to identify subclinical lesions
but are nonspecific for MS :
• Visual evoked potentials (VEPs): VEPs are not
typically necessary for patients with clear clinical
evidence of optic neuritis (ON).
• Somatosensory evoked potentials (SSEPs)
• Brainstem auditory evoked potentials
(BAEPs)
Lab Studies
to exclude
• Perform blood work
collagen
vascular disease, infections (ie, Lyme disease,
syphilis), endocrine abnormalities, vitamin B-12
deficiency, sarcoidosis, and vasculitis. Copper
studies may also be useful in MS patients.
• NMO,, can be confirmed by the presence of serum
antibodies against aquaporin 4, a water channel
expressed at major fluid-tissue barriers across the
CNS. (The NMO-IgG test)
Lumbar Puncture
• Lumbar puncture with CSF analysis is no longer
routine in the investigation of MS, but this
test may be of use when MRI is unavailable
or MRI findings are nondiagnostic. CSF is
evaluated for oligoclonal bands (OCBs) and
intrathecal immunoglobulin G (IgG) production, as
well as for signs of infection. OCBs are found in 9095% of patients with MS and intrathecal IgG
production is found in 70-90% of patients.
OCB
• Detection of oligoclonal IgG bands in CSF is the
test with the highest sensitivity to predict
conversion from CIS to MS.
• In patients suspected of having MS, but without
oligoclonal bands in CSF, alternative diagnoses
should always be thoroughly investigated.
• The correlation between presence of oligoclonal
IgG bands and disability progression is uncertain.
•The reported frequencies of oligoclonal IgG
bands differ in different parts of the word.
THE VALUE OF CEREBROSPINAL FLUID FINDINGS IN
DIAGNOSIS
•
The
McDonald
Criteria
ofthe
International Panel on Diagnosis of MS
reaffirmed
that
positive
cerebrospinal fluid (CSF) findings
(elevated immunoglobulin G [IgG] index
or 2 or more oligoclonal bands) can be
important to support the inflammatory
demyelinating nature of the underlying
condition, to evaluate alternative
diagnoses, and to predict CDMS.
MS & Pregnancy
• Investigators found that infants born to mothers
with MS did not have a significantly different mean
gestational age or birth weight compared with
infants born to mothers without the disease. MS
was also not significantly associated with assisted
vaginal delivery or caesarean section.
• Ann Neurol. Published online June 27, 2011
• 􀂾 In general,
relapse rates drop
over the nine months of pregnancy
and rise significantly in the three-six
months post partum.
• The more active a woman’s disease
was during pregnancy and the year
prior, the higher her risk of post
partum relapse.
Postpartum steroid dose reduces Multiple
Sclerosis relapses
A single dose of methylprednisolone given to
new mothers with multiple sclerosis immediately after
delivery reduced the risk of relapse for up to three
months, researchers found.
During the first postpartum trimester, relapses occurred
in 18% of new mothers who received 1 g of intravenous
methylprednisolone compared with 46% of those not
receiving treatment. .
An alternative treatment, intravenous
immunoglobulin, is significantly more expensive and
more complex to administer than IV methylprednisolone
Prognosis
• If left untreated, more than 30% of patients with MS will develop
significant physical disability within 20-25 years from onset .
• Less than 5-10% of patients have a clinically milder MS
phenotype, in which no significant physical disability accumulates
despite several decades passing since onset (sometimes in spite of
multiple new lesions seen on MRI). Detailed examination of these
patients in many instances reveals some degree of cognitive
deterioration.
• Male patients with primary progressive MS have the worst
prognosis.
• Life expectancy is shortened only slightly in persons with MS, and
the survival rate is linked to disability. Death usually results from
secondary complications (50-66%), such as pulmonary or renal
causes, but can also occur due to primary complications, suicide,
and causes unrelated to MS. Marburg variant of MS is an acute
and clinically fulminant form of the disease that can lead to
coma or death within days