Demyelinating Diseases

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