Demyelinating disorders in central nerve system

Demyelinating Demyelinating disorders in central disorders in central nerve systemnerve system

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.

Intact myelin is required for action potential conduction

Myelined nerve fiber are rich in white matter of cerebral 、 cerebella 、 brain stem 、 spinal cord ， optic nerve

Demyelinating —— myelin is broken, axon remains intact

Demelinated disorders in CNS

Congenital obtained

leukodystrophy inflammatory others

primary secondary

MS

NMO

ADEM

Balo’s

Inflammatory demyelinating disorders in central nerve system

Multiple Sclerosis(MS)1

Neuromyelitis optica (NMO)Neuromyelitis optica (NMO)2

Acute Disseminated Encephalomyelitis (ADEM)Acute Disseminated Encephalomyelitis (ADEM)3

Concentric sclerosis(BaloConcentric sclerosis(Balo’’s disease)s disease)4

Inflammatory demyelinating disorders In Inflammatory demyelinating disorders In CNSCNS

Multiple Sclerosis (MS)

What is Multiple What is Multiple Sclerosis?Sclerosis?

MMultipleultiple S Sclerosis (clerosis (MSMS)) ““sclerosis” sclerosis” comes from comes from

the Greek word the Greek word “skleros”, meaning hard. “skleros”, meaning hard. In multiple sclerosis, In multiple sclerosis, hard areas called hard areas called “plaques” .“plaques” .

““MultipleMultiple” refers to the ” refers to the many different areas of many different areas of the nervous system that the nervous system that may have damaged may have damaged myelin. myelin.

What is Multiple What is Multiple Sclerosis ?Sclerosis ?

chronic inflammatory diseasechronic inflammatory disease of CNS of CNS malfunction of the immune systemmalfunction of the immune system which leads which leads

to attacks against myelin sheathto attacks against myelin sheath insulating insulating myelin is damaged is damaged. . The loss of myelin insulation The loss of myelin insulation degrades the degrades the

nerve transmission ability. nerve transmission ability. Thus a multitude of Thus a multitude of various neurological various neurological

disabilitiesdisabilities can be observed in patients affected can be observed in patients affected by this disease depending on which nerves are by this disease depending on which nerves are damaged.damaged.

EpidemiologyEpidemiology approximately 1.1 million approximately 1.1 million

people are affected in USpeople are affected in US in all parts of the world in all parts of the world

and in all races, but whites and in all races, but whites of northern European of northern European descent have the highest descent have the highest incidence. incidence.

occur in any age. usually occur in any age. usually diagnosed in aged 15-45 diagnosed in aged 15-45 years; average age at years; average age at diagnosis is 29 years in diagnosis is 29 years in women and 31 years in women and 31 years in men. men.

female to male ratio is 2:1.female to male ratio is 2:1.

symptomssymptoms

MS was first described by MS was first described by Cruveilhier in 1835. Cruveilhier in 1835.

A generally valid description of A generally valid description of MS symptoms was made by MS symptoms was made by Charcot in the year 1868. Charcot in the year 1868.

In 1904 the description was In 1904 the description was supplemented by Müller.supplemented by Müller.

Multifocal lesions

symptomssymptoms

Common symptoms:Common symptoms: Sensory Sensory

disturbancedisturbance Weakness Weakness Problems in Problems in

walking/balance/ walking/balance/ coordination coordination

Visual problemsVisual problems ：： optic nerve optic nerve

Other possible Other possible symptoms:symptoms:

Bladder problem Bladder problem Spasticity Spasticity Fatigue Fatigue Facial weakness Facial weakness Trigeminal neuralgiaTrigeminal neuralgia slurred speechslurred speech trouble swallowingtrouble swallowing DeafnessDeafness temporary blindnesstemporary blindness Cognitive problems Cognitive problems EpilepsyEpilepsy Depression Depression

signssignsLocal weakness Local weakness Local sensory disturbancesLocal sensory disturbancespoor coordination of upper and lower poor coordination of upper and lower

extremity movements, wide-based gait with extremity movements, wide-based gait with inability to tandem walk.inability to tandem walk.

nystagmus, internuclear ophthalmoplegia, nystagmus, internuclear ophthalmoplegia, visual disturbances, pallor of the optic disc, visual disturbances, pallor of the optic disc, Lhermitte sign, traverse spinalLhermitte sign, traverse spinal myelopathymyelopathy

，， Brown-sequard syndrome in different Brown-sequard syndrome in different levels of spinal cordlevels of spinal cord

Courses (multiple Courses (multiple phases)phases)

Laboratory findingsLaboratory findings

Magnetic Resonance ImagingMagnetic Resonance Imaging (MRI) (MRI) will show patches of tissue will show patches of tissue

CSFCSF ：： WBCWBC ，， proteinprotein ，， MBPMBP ，， OBOB ，， specific Abs specific Abs Evoked PotentialsEvoked Potentials ：： visual evoked potentialsvisual evoked potentials （（ VEPVEP ）） auditory evoked potentialsauditory evoked potentials （（ BAEPBAEP

）） somatosensory evoked potentialssomatosensory evoked potentials

（（ SEPSEP ））

How is multiple sclerosis How is multiple sclerosis diagnosed?diagnosed?

Time——mutiple phasesTime——mutiple phases

Space—— mutifocal lesionsSpace—— mutifocal lesions

Exclude othersExclude others

The Diagnostic CriteriaCriteria of MS （ Poser, 1983 )

Number of Attack

Evidence of More Than One Lesion

Clinical Lab.

CSF OCB or IgG

A. Clinically Definite

B. Lab-Supported Definite

C. Clinically Probable

D. Lab-Supported Probable

A1 2 2

A2 2 1 and 1

B1 2 1 or 1 +

B2 1 2 +

B3 1 1 and 1 +

C1 2 1

C2 1 2

C3 1 1 and 1

D1 2 0 0 +

Diagnostic Criteria for Multiple SclerosisDiagnostic Criteria for Multiple Sclerosis (McDonald Criteria (McDonald Criteria ，， 20012001 ）（）（ 11 ））

Clinical Presentation Clinical Presentation Additional Data Needed Additional Data Needed

2 or more attacks (2 or more attacks (relapses) )

2 or more objective clinical lesions 2 or more objective clinical lesions

None; clinical evidence will suffice None; clinical evidence will suffice (additional evidence desirable but must be (additional evidence desirable but must be consistent with MS) consistent with MS)

2 or more attacks 2 or more attacks

1 objective clinical lesion 1 objective clinical lesion

Dissemination in space, demonstrated by: MRI Dissemination in space, demonstrated by: MRI

or a positive CSF and 2 or more MRI lesions or a positive CSF and 2 or more MRI lesions consistent with MS consistent with MS

or further clinical attack involving different site or further clinical attack involving different site

1 attack 1 attack

2 or more objective clinical lesions 2 or more objective clinical lesions

Dissemination in time, demonstrated by: MRI Dissemination in time, demonstrated by: MRI

or second clinical attack or second clinical attack

1 attack 1 attack

1 objective clinical lesion 1 objective clinical lesion

(monosymptomatic presentation) (monosymptomatic presentation)

Dissemination in space by demonstrated by: MRI Dissemination in space by demonstrated by: MRI

or positive CSF and 2 or more MRI lesions or positive CSF and 2 or more MRI lesions consistent with MS consistent with MS

andand Dissemination in time demonstrated by: MRI Dissemination in time demonstrated by: MRI

or second clinical attack or second clinical attack

Diagnostic Criteria for Multiple Diagnostic Criteria for Multiple SclerosisSclerosis

(McDonald Criteria (McDonald Criteria ，， 20012001 ）） (2)(2)

Insidious neurological Insidious neurological progression progression suggestive of MS suggestive of MS (primary progressive MS)(primary progressive MS)

Positive CSF Positive CSF andand

Dissemination in space demonstrated by: Dissemination in space demonstrated by:

MRI evidence of 9 or more T2 brain lesions MRI evidence of 9 or more T2 brain lesions

or 2 or more spinal cord lesions or 2 or more spinal cord lesions

or 4-8 brain and 1 spinal cord lesion or 4-8 brain and 1 spinal cord lesion

or positive VEP with 4-8 MRI lesions or positive VEP with 4-8 MRI lesions

or positive VEP with <4 brain lesions plus 1 or positive VEP with <4 brain lesions plus 1 spinal cord lesion spinal cord lesion andand

Dissemination in time demonstrated by: MRI Dissemination in time demonstrated by: MRI

or continued progression for 1 yearor continued progression for 1 year

Differential diagnosisDifferential diagnosis

First attack: single lesion or multiple First attack: single lesion or multiple lesions: lesions:

infection, tumor, infarction,infection, tumor, infarction, Relapse type: Relapse type:

infarction, embolism, vasculitis, infarction, embolism, vasculitis, Progressive:Progressive:

inherited, degenerating,inherited, degenerating,

Pathology of MSPathology of MS Gross neuropathologyGross neuropathology grey plaques (acute plaque may be pink) grey plaques (acute plaque may be pink) may occur anywheremay occur anywhere

Microscopic neuropathologyMicroscopic neuropathology perivascular lymphocytes infiltrate; perivascular lymphocytes infiltrate; loss of oligodendrocytes; loss of oligodendrocytes; myelin stripping; myelin stripping; macrophage infiltrate; macrophage infiltrate; astrogliosis; astrogliosis; relative sparing of axonsrelative sparing of axons

What Causes MS?What Causes MS?

The exact cause of MS is not knownThe exact cause of MS is not known Environmental FactorsEnvironmental Factors ：： Geography is clearly an important Geography is clearly an important

factor factor the rate is approximately twice as the rate is approximately twice as

below the 37th parallel. below the 37th parallel. Genetic FactorsGenetic Factors ：： MS is not strictly an inherited MS is not strictly an inherited

disorder.disorder. Susceptibility to MS probably has Susceptibility to MS probably has

a genetic component.a genetic component.

Pathogenesis of MS:Pathogenesis of MS: incompletely understood. incompletely understood.

Immune-mediated Immune-mediated disorderdisorder with anwith an initial triggerinitial trigger

Molecular mimicryMolecular mimicry OligodendrocyteOligodendrocyte

susceptiblesusceptible CNS infections may CNS infections may

also lead to the also lead to the transmigration of transmigration of activated T activated T lymphocyteslymphocytes into into the CNS, which the CNS, which initiate the processinitiate the process

How is MS Treated?How is MS Treated?

ImmunotherapyImmunotherapy CorticosteroidsCorticosteroids corticosteroids can reduce the duration of corticosteroids can reduce the duration of

symptoms, they do not cure MS. symptoms, they do not cure MS. Used in Used in Acute attacksAcute attacks

intravenous methylprednisoloneintravenous methylprednisolone 1000 mg 1000 mg daily for three days. daily for three days.

Prednisone:Prednisone: Clinicians differ on whether Clinicians differ on whether to taper off treatment with oral to taper off treatment with oral prednisone for two weeks, but this prednisone for two weeks, but this probably does not improve results and probably does not improve results and increases side effects. increases side effects.

InterferonsInterferons

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

ImmunosuppressantsImmunosuppressants methotrexate, methotrexate, cyclophosphamide, cyclophosphamide, cyclosporine, cyclosporine, mitoxantrone. mitoxantrone. OthersOthers IvIgIvIg plasma exchangeplasma exchange

Symptomatic managementSymptomatic management Bladder frequency and urgencyBladder frequency and urgency will often will often

respond to oxybutynin. respond to oxybutynin. Pain and spasmsPain and spasms from spastic limbs usually from spastic limbs usually

respond to baclofen. respond to baclofen. Emotional labilityEmotional lability with pathological laughing with pathological laughing

or crying can be managed with a tricyclic or crying can be managed with a tricyclic antidepressant. antidepressant.

Amantadine reducesAmantadine reduces fatigue fatigue in half the in half the patients. patients.

More difficult to manage are pain, sexual More difficult to manage are pain, sexual dysfunction, dysfunction, weakness,weakness, dysesthesia and other dysesthesia and other sensory symptoms, tremor, ataxia, and sensory symptoms, tremor, ataxia, and cognitive change, but even these may cognitive change, but even these may respond to various therapeutic approaches. respond to various therapeutic approaches.

It is important to recognise that half of It is important to recognise that half of patients with multiple sclerosis will become patients with multiple sclerosis will become depresseddepressed and that therapy and counselling and that therapy and counselling may be necessary. may be necessary.

Prognosis Prognosis Mortality/Morbidity:Mortality/Morbidity:

Life expectancy is Life expectancy is shortened only slightly shortened only slightly with MS, and the with MS, and the survival rate is linked to survival rate is linked to disability. disability.

Usually, death is due to Usually, death is due to secondary complications secondary complications (50-66%), such as (50-66%), such as pulmonary or renal pulmonary or renal causes, suicide, primary causes, suicide, primary complications, and complications, and causes other than MS causes other than MS seen in the general seen in the general population.population.

Inflammatory demyelinating disorders in Inflammatory demyelinating disorders in CNSCNS

Neuromyelitis optica Neuromyelitis optica (NMO)(NMO)

Similarities with MSSimilarities with MS

mutifocal lesionsmutifocal lesions mutiple phasesmutiple phases immuno-mediated inflammatory immuno-mediated inflammatory

demyelinationdemyelination in CNSin CNS

DifferencesDifferences withwith MSMS----mutifocal lesions ----mutifocal lesions

MyelitisMyelitis ：： longlong lesion ≧ 3 vertebral lesion ≧ 3 vertebral segments. segments.

Optis neuritisOptis neuritis ：： Brain lesionsBrain lesions ：： atypical for MS. atypical for MS. Multiple phasesMultiple phases ：： more frequently more frequently

a relapsing-remittinga relapsing-remitting course.course.

Optic nerve atrophy

DifferencesDifferences withwith MS MS ----Pathological features----Pathological features ofof

NMONMO demyelination and necrosis demyelination and necrosis prominent vascular fibrosis and prominent vascular fibrosis and

hyalinization within the lesionshyalinization within the lesions perivascular deposition of IgG and perivascular deposition of IgG and

complementcomplement perivascular infiltrates of perivascular infiltrates of

polymorphonuclear cells, leucocytes , polymorphonuclear cells, leucocytes , plasma cells,plasma cells, eosinophilseosinophils

glial scars are less frequent and usually glial scars are less frequent and usually only partial in contrast to typical MS only partial in contrast to typical MS lesionslesions

DifferencesDifferences withwith MS MS ----pathogenesis of NMO----pathogenesis of NMO

humoral immunity humoral immunity target antigen is target antigen is

aquaporin-4, the aquaporin-4, the dominant water dominant water channel in (CNS)channel in (CNS)

IgG-antibody to IgG-antibody to aquaporin-4, aquaporin-4, named NMO-IgGnamed NMO-IgG

DiagnositicDiagnositic criteria for criteria for NMONMO

Differential diagnosisDifferential diagnosis

Ischemia of optic nerve Ischemia of optic nerve Acute myelitisAcute myelitis Vascular disease of the spinal cordVascular disease of the spinal cord Vasculitis Vasculitis Connective tissue diseaseConnective tissue disease

DifferencesDifferences withwith MSMS----Treatment----Treatment

acute phaseacute phase ：： intravenous intravenous steroids and plasma exchange steroids and plasma exchange therapy. therapy.

To prevent relapseTo prevent relapse ：： oral steroid oral steroid medication and medication and immunosuppressive drugs.immunosuppressive drugs.


Acute Disseminated EncephalomyelitisAcute Disseminated Encephalomyelitis

(ADEM)(ADEM)

Acute Disseminated Acute Disseminated EncephalomyelitisEncephalomyelitis

Quite rapid in onsetQuite rapid in onset, often getting sick , often getting sick over a period of a few days over a period of a few days

Multifocal Multifocal neurological dysfunction, neurological dysfunction, involving involving brainbrain 、、 spinal cordspinal cord 、、 meningesmeninges

MRIMRI ：： multifocal lesions in CNSmultifocal lesions in CNS CSFCSF ：： WBC count normal or mild elevated WBC count normal or mild elevated

, immune proteins level elevated, immune proteins level elevated Good response to therapy Good response to therapy ：：

corticosteroid treatmentscorticosteroid treatments Precipitating EventsPrecipitating Events ：： recent infections recent infections

and certain recent vaccinationsand certain recent vaccinations ，， certain certain medications, trauma, idiopathic medications, trauma, idiopathic

Most ADEM are Most ADEM are monophasic monophasic ，， some are some are MDEMMDEM （（ multiphasic Disseminated multiphasic Disseminated Encephalomyelitis), or develop to MS Encephalomyelitis), or develop to MS


Concentric sclerosisConcentric sclerosis

(Balo’s disease)(Balo’s disease)

Concentric Concentric sclerosis(Balo’s )sclerosis(Balo’s )

Balo disease Balo disease (concentric sclerosis) (concentric sclerosis) is a rare is a rare variant of variant of inflammatory inflammatory demyelinating demyelinating diseasedisease

Diagnosis is made Diagnosis is made upon biopsy which upon biopsy which shows alternating shows alternating bands of myelinating bands of myelinating and demyelinatingand demyelinating fibers in white fibers in white matter.matter.

MonophasicMonophasic, non-, non-remittingremitting

Other demyelinating Other demyelinating disordersdisorders

Progressive mutifocal leukoencephalopathy

Central pontine myelinolysis Marchiafava-Bignami disease Toxic demyelination: chemical agents, CO Irradiation encephalopathy Cerebral vascular disease

Other demyelinating disordersOther demyelinating disorders

Central Central pontine pontine myelinolysismyelinolysis ，， CPMCPM

Central pontine Central pontine myelinolysismyelinolysis ，， CPMCPM

Central pontine myelinolysis (CPM) is an Central pontine myelinolysis (CPM) is an uncommon consequenceuncommon consequence of certain of certain metabolic derangements. metabolic derangements.

These include rapid correctionThese include rapid correction of of hyponatremia, as well as hyperosmolar hyponatremia, as well as hyperosmolar conditions, such asconditions, such as hyperglycemia. hyperglycemia.

The microscopic appearance of CPM is The microscopic appearance of CPM is loss ofloss of myelin with sparing of axons, myelin with sparing of axons, without evidence of inflammationwithout evidence of inflammation . .

Other demyelinating disorders Other demyelinating disorders Progressive multifocal Progressive multifocal

leukoencephalopathy (PML)leukoencephalopathy (PML)

It is a demyelinating disease causes by a It is a demyelinating disease causes by a polyoma virus (the JC virus). polyoma virus (the JC virus).

The JC virus preferentially infects The JC virus preferentially infects oligodendrocytes, thus demyelination in oligodendrocytes, thus demyelination in CNS. CNS.

immunosuppressed patients and AIDS immunosuppressed patients and AIDS patients, are at risk. patients, are at risk.

Neurologic symptoms depend on the Neurologic symptoms depend on the location of the lesions location of the lesions

relentlessly progressive. relentlessly progressive.

Other demyelinating disorders Other demyelinating disorders Delayed Encephalopathy of Acute Delayed Encephalopathy of Acute

Carbon Monoxide IntoxicationCarbon Monoxide Intoxication

Other demyelinating disorders Other demyelinating disorders

Marchiafava-Bignami diseaseMarchiafava-Bignami disease

leukodystrophyleukodystrophy

inherited dysmyelinating diseaseinherited dysmyelinating disease adrenoleukodystrophy adrenoleukodystrophy metachromatic leukodystrophy metachromatic leukodystrophy spongy degeneration (Canavan spongy degeneration (Canavan

disease) disease) globoid cell (Krabbe) leukodystrophy globoid cell (Krabbe) leukodystrophy Alexander disease Alexander disease Pelizaeus-Merzbacher disease Pelizaeus-Merzbacher disease Cockayne syndrome Cockayne syndrome

adrenoleukodystrophyadrenoleukodystrophy X-linked recessive demyelination of

cerebral white matter adrenal insufficiency

(unresponsive to ACTH)

CT: white-matter dz: occipital regions --> frontal progression -->

generalized atrophy MRI: hypointense

T1/hyperintense T2, atrophic splenium of corpus callosum

metachromatic metachromatic leukodystrophy leukodystrophy

dymyelinating diseasedymyelinating disease autosomal recessive autosomal recessive aryl sulfatase A -- absent from urine and aryl sulfatase A -- absent from urine and

serum serum most present by 2 yrs, die at 3-4 yrs most present by 2 yrs, die at 3-4 yrs may arise at any age may arise at any age MR: MR: hypointense T1 / hyperintense T2, hypointense T1 / hyperintense T2, of of

white matter, primarily in centrum white matter, primarily in centrum semiovalesemiovale

metachromatic metachromatic leukodystrophyleukodystrophy

Demyelinating disorders in central nerve system

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