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Demyelinating Diseases. DR. Abdulkader Daif, MD Consultant and Professor of Neurology KKUH, Faculty of medicine. Group 341-2014. Introduction to Multiple Sclerosis (MS). Chronic autoimmune disease Progressive disease Involves Immune System & Neurological System - PowerPoint PPT Presentation
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Demyelinating DiseasesDR. Abdulkader Daif, MDConsultant and Professor of NeurologyKKUH, Faculty of medicine
Group 341-2014
Introduction to Multiple Sclerosis (MS)•Chronic autoimmune disease•Progressive disease•Involves Immune System & Neurological
System •Multifocal areas of demyelination•Disrupts ability of the nerve to conduct
electrical impulses•Leads to symptoms
Classification of the Demyelinating diseases:
Multiple sclerosis:A- Chronic relapsing encephalomyelopathic form.B- Acute multiple sclerosis.C- Neuromyelitis optica.
Diffuse cerebral sclerosis (encephalitis periaxalis diffuse) or Schilder and concentric sclerosis of Balo.
Acute disseminated encephalomyelitis.A- Following measles, rubella & influenza.B- Following rabies or smallpox vaccination.
Acute and subacute necrotizing hemorrhagic encephalitis.A- Acute encephalopathic form (hemorrhagic leukoencephalitis of Hurst)B- Subacute necrotic myelopathyC- Acute brain purpura(acute pericapillary encephalorrhagia)
Types of MS• Relapsing-remitting MS (RRMS)
▫Affects 85% of newly diagnosed▫Attacks followed by partial or complete
recovery▫Symptoms may be inactive for months or
years
• Secondary-progressive MS (SPMS)▫Occasional relapses but symptoms remain
constant, no remission▫Progressive disability late in disease course
Types of MS
• Primary-progressive MS (PPMS)– Affects approximately 10% of MS
population– Slow onset but continuous worsening
condition
Multiple Sclerosis Subtypes(Coyle P, CNS News 2002; adapted from Lublin F, et al Neurology 1996)
Epidemiology of MS• Age onset 20 – 50 years old• Women are 2 times more likely to
develop MS• 500,000 cases in US• Over 2.5 million people around the world• More prevalent whites of northern
European ancestry
Multiple SclerosisAn Immunogenetic Disease
MS
Immune Dysregulation
Genetic Predisposition• Twins studies
• HLA-DR2 (DRß1*1501)(antigen presentation)
• IL-2R• (regulatory T-cells)
• IL-7R memory T-cells)
• ST8SIA1
Environmental FactorsDemographics/Epidemics
Microbial AgentsEBV
Vitamin D
Graphic courtesy of Dr. Suhayl Dhib-Jalbut.
1. Research into the Causes of MS
Geneticfactors
Immunologicalfactors
Environmentalfactors
MS
Other Factors Influencing MS
• Vitamin D deficiency▫ Vitamin D3 receptor important in immune function▫ Present on T regulator cells
• Infectious Mono/EBV▫ 99% of MS patients have EBV titers▫ Usually higher than in HC▫ Pseudo follicles in meninges containing B cells showing ENA antigen▫ EBER RNA found in inflammatory lesions ▫ Protein stimulates Toll 3 receptors which release proinflammatory
interferons▫ In inflammatory lesions T cells found surrounding B cells containing
ENA antigen• Genetics
▫ HLA DRB2 *1503 allele 2x risk factor▫ IL 2 receptor▫ IL 7 receptor▫ 50 new candidates genes each with low risk factors
Symptoms of MS• Vision problems• Numbness• Difficulty walking• Fatigue• Depression• Emotional changes• Vertigo &
dizziness• Sexual dysfunction
• Coordination problems
• Balance problems• Pain• Changes in
cognitive function• Bowel/bladder
dysfunction• Spasticity
Pathogenesis of MS
Multiple Sclerosis Pathophysiology
• Disease process consists of loss of myelin, disappearance of oligodendrocytes, and proliferation of astrocytes
• Changes result in plaque formation with plaques scattered throughout the CNS
Multiple Sclerosis Pathophysiology
•Initially the myelin sheaths of the neurons in the brain and spinal cord are attacked, but the nerve fiber is not affected
•Patient may complain of noticeable impairment of function
•Myelin can regenerate, and symptoms disappear, resulting in a remission
Multiple Sclerosis Etiology and Pathophysiology
•Myelin can be replaced by glial scar tissue
•Without myelin, nerve impulses slow down
•With destruction of axons, impulses are totally blocked
•Results in permanent loss of nerve function
MS Disease Timeline(Fox RJ, Sweeny PJ, Cleveland Clinic, May 2002)
Time
Preclinical
MRI Activity
Relapses/Disability
MRI T2 Burden of Disease
Axonal Loss
Dis
abili
ty
CIS
*
Trapp BD, et al. Neuroscientist. 1999;5:48-57. Reprinted with permission from Sage Publications.
Relapsing-Remitting MS
Secondary Progressive MS
Natural History of MSClinical and MRI Measures
RECENT LESIONS LATER OLD LESION
•Myelin destruction
•Relative axon sparing
•Perivenous infiltration with MNP
•Breakdown of BBB
Astrocyte proliferation
•Relatively acellular
•More clearly demarcated.
•Bare axons are surrounded by astrocytes.
The Biology of MS
How does the CNS work?
Messages travel to and from the CNS through nerve cells3
Myelin surrounds the nerve fibers, protecting them like the coating of a wire1
Nerve Cell
Nerve fibers (or axon)
MyelinNerve fibers (or axon)
Cell body
Myelin
The Biology of MS
How does MS affect the CNS?
In MS, cells of the immune system attack myelin and can cause permanent damage
Areas where myelin has been damaged interrupt communication
Exposed nerve fibers are severed, causing permanent damageNerve Cell
How could autoimmune responses cause MS?How could autoimmune responses cause MS?
Inflammation and Axonal TransectionDiseaseStage
Main Component
Main Clinical Outcome
Early Inflammation and demyelination Relapses
Late Atrophy, axonal loss, and Disability increasing tissue destruction(less Gd-defined inflammation,
demyelination ongoing)
The Biology of MS
How is MS monitored?
Magnetic Resonance Imaging (MRI) detects areas of inflammation (active lesions) and areas of permanent damage in the brain1
MRI showing no signs of damage
MRI showing an active lesion*
MRI showing permanent damage
Active lesion
Permanent damage
These images may also help detect “silent” damage (lesions detected by MRI that do not result in symptoms)1
The impact of this damage depends on the destructiveness of the lesion and where itis located
*The exact relationship between MRI findings and the clinical status of patients is unknown.
1. Polman CH, et al. Ann Neurol. 2005;58:840-846.
Diagnosis of MS• Clinically definite MS must meet criteria for1
▫ Dissemination in space▫ Dissemination in time
• A single episode of MS-like symptoms (clinically isolated syndrome [CIS]) will not meet these criteria▫ But if MS is likely based on MRI, it still should be
treated like MS Delaying treatment may be missing an important window of
opportunity to delay the onset of irreversible disability▫ Requires close monitoring over time to confirm
diagnosis
Polman CH, et al. Ann Neurol. 2005;58:840-846.
Revised McDonald Criteria for Dissemination in Time• At least 1 of the following
▫ A 2nd clinical episode▫ A Gd-enhancing lesion detected ≥3 months after onset
of initial clinical event Located at a site different from the one corresponding to the
initial event▫ A new T2 lesion detected any time after a reference
scan that was performed at least 30 days after the onset of an initial clinical event
• Thus, it is not always necessary to wait for 2 attacks to diagnose MS. A first attack plus changes on MRI may be enough
Polman CH, et al. Ann Neurol. 2005;58:840-846.
Revised McDonald Criteria for Dissemination in Space• At least 3 of the following:
▫≥1 Gd-enhancing brain or spinal cord lesion or ≥9 T2 hyperintense brain and/or spinal cord lesions of ≥3 mm in size if none of the lesions are Gd-enhancing
▫≥1 brain infratentorial lesion or spinal cord lesion ≥3 mm in size
▫≥1 juxtacortical lesion ≥3 mm in size▫≥3 periventricular lesions ≥3 mm in size
Clinical Features Suggestive of MS•Onset between 15-50 years•Blurred or double vision•Lhermitte’s sign•Fatigue•Heat sensitivity•Bladder symptoms•Cognitive or affective changes
Sensory Symptoms
• Numbness & Paraesthesia
• Impaired vibration & Joint position sensation
• Lhermitte’s Sign ( Shock-like sensation in the limb)
•Dysaesthesia + Sensory loss to pain & Temp.
Clinical Features
Clinically Isolated Syndromes
Clinically Isolated Syndromes
•Transverse Myelitis▫Risk factors for MS
Incomplete transverse myelitis Asymmetric motor or sensory findings Brain MRI lesions Abnormal CSF Abnormal VER and SSEPs
•Others (Brainstem, Cerebellum)
Optic Neuritis: Clinical Features
•Inflammatory demyelination of one or both optic nerves
• Pain around one eye
• Blurred vision
• Loss of color vision
• Swollen optic disc( Papillitis)
• Visual field defect
• Diplopia & Vertigo
Clinically Isolated Syndromes
•Optic Neuritis▫Risk factors for MS (60-75%)
History of minor neurologic sxs Unilateral optic neuritis Brain MRI lesions Abnormal CSF Abormal VERs
Diseases to rule out
• Viral infections• Lyme disease• B12 deficiency• CVA• Lupus• Rheumatoid
arthritis• Other connective
tissue disorders
• Vasculitis• Syphilis• Tuberculosis• Neurobrucellocis• HIV• Sarcoidosis
Neuro-Imaging and MS
Infratentorial Juxtacortical
C and D: Courtesy of Daniel Pelletier, MD.
Typical MRI Lesions in MS
Spinal Cord Periventricular
E: Courtesy of Daniel Pelletier, MD.F: Courtesy of Tracy M. DeAngelis, MD.
Typical MRI Lesions in MS
A and B: Courtesy of Tracy M. DeAngelis, MD.
Gd-enhancing Corpus Callosum
Typical MRI Lesions in MS
NMO
Distinguishing NMO from MS
Courtesy of Bruce A.C. Cree, MD, PhD, MCR Courtesy of Tracy M. DeAngelis, MD
MS
Other Diagnostic Tools for MSVisual Evoked Potentials (VEPs)
•Provides evidence of a lesion associated with visual pathways
•Positive if shows delayed but well-preserved wave forms▫Abnormal VEP is not specific for MS
•Can help establish dissemination in space
LABORATORY ASSISTED DIAGNOSISMS lesions in various stages can now be
seen on MRI Cerebrospinal fluid analysis can identify
immunoglobulin synthesisEvoked potentials can demonstrate
clinically and even MRI silent lesions
Other Diagnostic Tools for MSCSF Analysis
• Positive if oligoclonal IgG bands present but absent from corresponding serum sample or IgG index is elevated▫ Sensitive but not specific: other causes of CNS
inflammation can yield similar findings
• Lymphocytic pleocytosis is rarely >50/mm3• Protein levels rarely exceed 100 mg/dL• Elevated myelin basic protein is not
pathognomonic for MS
Neurophysiological Investigations
No diagnostic test. Only support the clinical suspicion.
•Visual evoked potential(VEP): in optic nerve the latency of the large positive wave is delayed . the amplitude may also be reduced.
•Somatosensory evoked response (SSEP) may detect central sensory pathway lesion.
•Brain stem auditory evoked potential (BAEP) may detect brain stem lesion.
Therapeutic Goals in MS• Prevent disability• Prevent relapses• Relieve symptoms• Maintain well-being• Optimize quality of life
An effective therapy administered early in the An effective therapy administered early in the disease course can impact all of these goals disease course can impact all of these goals
Existing Therapies and Emerging Therapies for MS
2005 2011
Injectables
IV
TeriflunomideTeriflunomide
LaquinimodLaquinimodFTY 720FTY 720
Oral CladribineOral Cladribine
DaclizumabDaclizumabGeneric Mitoxantrone (oncology) (MS)
Generic Mitoxantrone (oncology) (MS)
Orals
TysabriTysabri
IV
2006 2007
Copaxone
Betaseron
Avonex
Novantrone
RituximabII - RRMS; III - PPMS
RituximabII - RRMS; III - PPMS
Rebif
2010 2012
MLN1202MLN1202
BG 12 Oral FumarateBG 12 Oral Fumarate
Fampridineambulation indication?
Fampridineambulation indication?
MBP 8298MBP 8298
Filed
approved In phase II
In phase III
SB683699SB683699
2013
Campath
Second Second-Line MS Therapies•Mitoxantrone•Natalizumab•Generally indicated for persons with
suboptimal response to first-line agents•Require intravenous infusion•Associated with life-threatening
adverse events
Oral MS Therapies•Fingolimod•Fumarate•Teriflunomide•Laquinimod•Cladribine