Demyelinating disorders in central nerve system

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Demyelinating disorders in central nerve system
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Myelin in CNS is formed by the oligodendrocytes

• Chemical composition
• proteolipid,
• myelin basic protein,
• 2-3 cyclic nucleotide phosphohydrolase,
• myelin-associated glyco-protein,
• myelin-oligodendrocyte glyco-protein.

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Intact myelin is required for action potential
conduction
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Myelined nerve fiber are rich in white matter of
cerebral ?cerebella?brain stem?spinal cord,optic
nerve
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Demyelinating myelin
is broken, axon remains
intact
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Inflammatory demyelinating disorders in central
nerve system
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• Inflammatory demyelinating disorders In CNS
• Multiple Sclerosis (MS)

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What is Multiple Sclerosis?

• Multiple Sclerosis (MS)
• sclerosis comes from the Greek word skleros,
  meaning hard. In multiple sclerosis, hard areas
  called plaques .
• Multiple refers to the many different areas of
  the nervous system that may have damaged myelin.

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What is Multiple Sclerosis ?

• chronic inflammatory disease of CNS
• malfunction of the immune system which leads to
  attacks against myelin sheath
• insulating myelin is damaged.
• The loss of myelin insulation degrades the nerve
  transmission ability.
• Thus a multitude of various neurological
  disabilities can be observed in patients affected
  by this disease depending on which nerves are
  damaged.

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• Epidemiology
• approximately 1.1 million people are affected in
  US
• in all parts of the world and in all races, but
  whites of northern European descent have the
  highest incidence.
• occur in any age. usually diagnosed in aged 15-45
  years average age at diagnosis is 29 years in
  women and 31 years in men.
• female to male ratio is 21.

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symptoms

• MS was first described by Cruveilhier in 1835.
• A generally valid description of MS symptoms was
  made by Charcot in the year 1868.
• In 1904 the description was supplemented by
  Müller.

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Multifocal lesions
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Multifocal lesions
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symptoms

• Other possible symptoms
• Bladder problem
• Spasticity
• Fatigue
• Facial weakness
• Trigeminal neuralgia
• slurred speech
• trouble swallowing
• Deafness
• temporary blindness
• Cognitive problems
• Epilepsy
• Depression

• Common symptoms
• Sensory disturbance
• Weakness
• Problems in walking/balance/ coordination
• Visual problems optic nerve

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signs

• Local weakness
• Local sensory disturbances
• poor coordination of upper and lower extremity
  movements, wide-based gait with inability to
  tandem walk.
• nystagmus, internuclear ophthalmoplegia,
• visual disturbances, pallor of the optic disc,
• Lhermitte sign, traverse spinal
  myelopathy,Brown-sequard syndrome in different
  levels of spinal cord

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Courses (multiple phases)
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Laboratory findings

• Magnetic Resonance Imaging (MRI) will show
  patches of tissue
• CSFWBC,protein,MBP,OB,
• specific Abs
• Evoked Potentials
• visual evoked potentials(VEP)
• auditory evoked potentials(BAEP)
• somatosensory evoked potentials (SEP)

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How is multiple sclerosis diagnosed?

• Timemutiple phases
• Space mutifocal lesions
• Exclude others

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The Diagnostic Criteria of MS (Poser,
1983 )
Evidence of More Than One Lesion
CSF OCB or IgG
Number of Attack
Clinical
Lab.
A. Clinically Definite
A1 2
2
A2 2
1 and 1
B. Lab-Supported Definite
B1 2
1 or 1

B2 1
2

B3 1
1 and 1

C. Clinically Probable
C1 2
1
C2 1
2
C3 1
1 and 1
D. Lab-Supported Probable
D1 2
0 0

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Diagnostic Criteria for Multiple Sclerosis
(McDonald Criteria,2001)(1)
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 CSF and 2 or more MRI lesions consistent with MS or further clinical attack involving different site
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 by 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
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Diagnostic Criteria for Multiple Sclerosis
(McDonald Criteria,2001)(2)
Insidious neurological progression suggestive of MS (primary progressive MS) Positive CSF and Dissemination in space demonstrated by MRI evidence of 9 or more T2 brain lesions or 2 or more spinal cord lesions or 4-8 brain and 1 spinal cord lesion or positive VEP with 4-8 MRI lesions or positive VEP with lt4 brain lesions plus 1 spinal cord lesion and Dissemination in time demonstrated by MRI or continued progression for 1 year
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Differential diagnosis

• First attack single lesion or multiple lesions
• infection, tumor, infarction,
• Relapse type
• infarction, embolism, vasculitis,
• Progressive
• inherited, degenerating,

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Pathology of MS

• Gross neuropathology
• grey plaques (acute plaque may be pink)
• may occur anywhere
• Microscopic neuropathology
• perivascular lymphocytes infiltrate
• loss of oligodendrocytes
• myelin stripping
• macrophage infiltrate
• astrogliosis
• relative sparing of axons

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What Causes MS?

• The exact cause of MS is not known
• Environmental Factors
• Geography is clearly an important factor
• the rate is approximately twice as below the
  37th parallel.
• Genetic Factors
• MS is not strictly an inherited disorder.
• Susceptibility to MS probably has a genetic
  component.

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Pathogenesis of MS incompletely understood.

• Immune-mediated disorder with an initial trigger
• Molecular mimicry
• Oligodendrocyte susceptible
• CNS infections may also lead to the
  transmigration of activated T lymphocytes into
  the CNS, which initiate the process

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How is MS Treated?

• Immunotherapy
• Corticosteroids
• corticosteroids can reduce the duration of
  symptoms, they do not cure MS.
• Used in Acute attacksintravenous
  methylprednisolone 1000 mg daily for three days.
• Prednisone Clinicians differ on whether to
  taper off treatment with oral prednisone for two
  weeks, but this probably does not improve results
  and increases side effects.

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• Interferons
• Beta interferon drugs have shown to be
  effective in treating the relapsing-remitting
  type of MS.

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• Immunosuppressants
• methotrexate,
• cyclophosphamide,
• cyclosporine,
• mitoxantrone.
• Others
• IvIg
• plasma exchange

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• Symptomatic management
• Bladder frequency and urgency will often respond
  to oxybutynin.
• Pain and spasms from spastic limbs usually
  respond to baclofen.
• Emotional lability with pathological laughing or
  crying can be managed with a tricyclic
  antidepressant.
• Amantadine reduces fatigue in half the patients.
• More difficult to manage are pain, sexual
  dysfunction, weakness, dysesthesia and other
  sensory symptoms, tremor, ataxia, and cognitive
  change, but even these may respond to various
  therapeutic approaches.
• It is important to recognise that half of
  patients with multiple sclerosis will become
  depressed and that therapy and counselling may be
  necessary.

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Prognosis

• Mortality/Morbidity
• Life expectancy is shortened only slightly with
  MS, and the survival rate is linked to
  disability.
• Usually, death is due to secondary complications
  (50-66), such as pulmonary or renal causes,
  suicide, primary complications, and causes other
  than MS seen in the general population.

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Inflammatory demyelinating disorders in CNS

• Neuromyelitis optica (NMO)

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Similarities with MS

• mutifocal lesions
• mutiple phases
• immuno-mediated inflammatory demyelination in CNS

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Differences with MS----mutifocal lesions

• Myelitislong lesion ? 3 vertebral segments.
• Optis neuritis
• Brain lesions atypical for MS.
• Multiple phases more frequently a
  relapsing-remitting course.

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Optic nerve atrophy
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Differences with MS ----Pathological features
of NMO

• demyelination and necrosis
• prominent vascular fibrosis and hyalinization
  within the lesions
• perivascular deposition of IgG and complement
• perivascular infiltrates of polymorphonuclear
  cells, leucocytes , plasma cells, eosinophils
• glial scars are less frequent and usually only
  partial in contrast to typical MS lesions

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Differences with MS ----pathogenesis of NMO

• humoral immunity
• target antigen is aquaporin-4, the dominant water
  channel in (CNS)
• IgG-antibody to aquaporin-4, named NMO-IgG

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Diagnositic criteria for NMO
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Differential diagnosis

• Ischemia of optic nerve
• Acute myelitis
• Vascular disease of the spinal cord
• Vasculitis
• Connective tissue disease

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Differences with MS----Treatment

• acute phaseintravenous steroids and plasma
  exchange therapy.
• To prevent relapseoral steroid medication and
  immunosuppressive drugs.

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Inflammatory demyelinating disorders in CNS

• Acute Disseminated Encephalomyelitis
• (ADEM)

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Acute Disseminated Encephalomyelitis

• Quite rapid in onset, often getting sick over a
  period of a few days
• Multifocal neurological dysfunction, involving
  brain?spinal cord? meninges
• MRI multifocal lesions in CNS
• CSFWBC count normal or mild elevated , immune
  proteins level elevated
• Good response to therapy corticosteroid
  treatments
• Precipitating Events recent infections and
  certain recent vaccinations,certain medications,
  trauma, idiopathic  
• Most ADEM are monophasic , some are
  MDEM(multiphasic Disseminated Encephalomyelitis),
  or develop to MS

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Inflammatory demyelinating disorders in CNS

• Concentric sclerosis
• (Balos disease)

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Concentric sclerosis(Balos )

• Balo disease (concentric sclerosis) is a rare
  variant of inflammatory demyelinating disease
• Diagnosis is made upon biopsy which shows
  alternating bands of myelinating and
  demyelinating fibers in white matter.
• Monophasic, non-remitting

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Other demyelinating disorders

• Progressive mutifocal leukoencephalopathy
• Central pontine myelinolysis
• Marchiafava-Bignami disease
• Toxic demyelination chemical agents, CO
• Irradiation encephalopathy
• Cerebral vascular disease

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Other demyelinating disordersCentral pontine
myelinolysis,CPM
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Central pontine myelinolysis,CPM

• Central pontine myelinolysis (CPM) is an uncommon
  consequence of certain metabolic derangements.
• These include rapid correction of hyponatremia,
  as well as hyperosmolar conditions, such as
  hyperglycemia.
• The microscopic appearance of CPM is loss of
  myelin with sparing of axons, without evidence of
  inflammation .

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Other demyelinating disorders Progressive
multifocal leukoencephalopathy (PML)

• It is a demyelinating disease causes by a polyoma
  virus (the JC virus).
• The JC virus preferentially infects
  oligodendrocytes, thus demyelination in CNS.
• immunosuppressed patients and AIDS patients, are
  at risk.
• Neurologic symptoms depend on the location of the
  lesions
• relentlessly progressive.

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Other demyelinating disorders Delayed
Encephalopathy of Acute Carbon Monoxide
Intoxication
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Other demyelinating disorders Marchiafava-Bignami
disease
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leukodystrophy

• inherited dysmyelinating disease
• adrenoleukodystrophy
• metachromatic leukodystrophy
• spongy degeneration (Canavan disease)
• globoid cell (Krabbe) leukodystrophy
• Alexander disease
• Pelizaeus-Merzbacher disease
• Cockayne syndrome

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adrenoleukodystrophy

• X-linked recessive
• demyelination of cerebral white matter
• adrenal insufficiency (unresponsive to ACTH)
• CT white-matter dz occipital regions --gt
  frontal
• progression --gt generalized atrophy
• MRI hypointense T1/hyperintense T2, atrophic
  splenium of corpus callosum

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metachromatic leukodystrophy

• dymyelinating disease
• autosomal recessive
• aryl sulfatase A -- absent from urine and serum
• most present by 2 yrs, die at 3-4 yrs
• may arise at any age
• MR hypointense T1 / hyperintense T2, of white
  matter, primarily in centrum semiovale

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metachromatic leukodystrophy
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metachromatic leukodystrophy