DEMYELINATING DISEASES

Prof. Abdulkader DAIF, MD

King Khalid Univ.Hospital

DEMYELINATING DISEASES

• Demyelinating diseases comprise a group of neurologic disorders

• Focal or patchy destruction of myelin sheaths in the central nervous system accompanied by an inflammatory response

CALCIFICATION of Demyelinating disorders

Type Disease

Immune-mediated

Recurrent  Multiple sclerosisMonophasic  Optic neuritis  Transverse myelitis  Acute disseminated encephalomyelitis

InheritedAdrenoleukodystrophyMetachromatic leukodystrophy

MetabolicVitamin B12 deficiencyCentral pontine myelinolysis

InfectiousProgressive multifocal leukoencephalopathySubacute sclerosing panencephalitis

Incidence and prevalence

high

moderate or low

unknown

probablylow

low

low

high

probablylow

high

low

lowmoderate

moderate

Incidence and prevalenceRegional data Middle East

Country Population Total MSpatients

Total RRMSpatients

Saudi Arabia 22’024’000 1’760 1’060

Kuwait 1’974’000 185 110

Palestine 2’896’000 670 400

Tunisia 9’593’000 605 360

Libya 5’116’000 300 180

Jordan 4’999’000 550 330

Iraq 22’676’000 910 545

Lebanon 3’578’000 750 450

Incidence and prevalence

Country Population Total MS patients

Middle East 72‘853‘790 5‘730

West Europe 386‘000

South America 25‘000

Australia 12‘000

350‘367‘700

South Africa 1‘50043‘420‘000

Canada 50‘00031‘281‘100

19‘169‘100

209‘815‘550

USA 300‘000275‘562‘700

Eastern Europe 76‘75078‘475‘500

Pathology

• MS is a chronic inflammatory demyelinating disease of the central nervous system (CNS).

• MS is characterized by acute and chronic lesions of the white matter in the CNS.

• Among other aftereffects, the inflamed white matter leads to a demyelination of the axons.

• Axonal loss means that neuronal transmission of electrical signals is no longer possible and cannot be restored.

• Axonal loss might occur at an early stage of the disease, even before visible symptoms appear.

Demyelination and axonal degeneration in MS

Waxman S, NEJM 338, 5, 323, 1998

MS & AETIOLOGY

• Remains unresolved• Suggestive

1. Environmental agent2. genetically susceptible

individual• Incidence of the disease• Results of migration

MS & AETIOLOGY

3- Viral4- Genetic

• Japaness low incidence• Twin studies

– Higher in monozygotic than dizygotic 30% vs 4%

– Association of MS with HLA

PATHOLOGY AND PATHOGENESIS

• MS lesions characterized by – Demyelination of white matter with relative preservation of axons, gliosis and varying degrees of inflammation

– Sites predilections• Optic nerve , perivantricular, spinal cord, brain stem, and cerebellum

PATHOLOGY AND PATHOGENESIS

• Acute lesion lymphocutes and plasmscells

• Chronic lesions astrocytic gliosis and remyelination

IMMUNOLOGICAL MECHANISM

• Presence of immunocompetent cells: T and B lymphocytes and macrophage in areas of recent demyelination

• Macrophages, endothelial and astrocytes cells

• The detection of interleukin-2 receptors on lymphocytes

IMMUNOLOGICAL MECHANISM

• Elevated level of IgG in the CSF of MS patients

• The oligoclonal bands pattern on immunoelectrophoresis in CSF and not in the serum

• Myelin basic protein-reactive T lymphocytes have been

identified in the CSF and serum of patients with MS

CLINICAL MANIFESTATIONS and COURSE

Unpredictable courserapidly progressive

Benign» mild exacerbation» complete remissions » minimal disability

Exacerbation-remitting Chronic - relapsing Chronic progressive

CLINICAL MANIFESTATIONS

• Common mode of presentation– Optic neuritis– Sensory disturbances– Leg weakness– Sphincters disturbances– Brain stem and cerebellum dysfunction

• Relapsing -Remitting 90%• Many patients with R-R course pass into progressive course

• Progressive course 10%

CLINICAL MANIFESTATIONS

• OPTIC NEURITIS– Eye pain often on eye mouvements– Progressive visual loss

• Visual deficit usually improves after 2-3 weeks

• Persistent severe visual loss is uncommon

CLINICAL MANIFESTATIONS

• Fondus examination– Often is normal– Swollen disc– white disc, haziness of the cup

• Pupillary reflexes often showed afferent pupillary defect

BRAIN STEMSYMPTOMS AND SIGNS

• Diplopia, facial pain, vertigo, diziness,and hearing disorders

• Signs suggestive cranial neuritis– Diplopia– Internuclear ophthalmoplagia (INO)– Reduced adduction of the eye on the side of the

lesion with nystagmus in the abducting eye– Uni/bilateral

SYMPTOMS AND SIGNS SUGGESTIVE LONG TRACTS SYSTEMS

• Weakness, Pyramidal signs• Sensory symptoms

Patchy sensory distribution, LHERMITT’S sign

Pain Usually chronic, dysaestheasia, painful leg spasm.

• Sphincters disorders:Frequency, urgency, incontinent, and hesitancy and

difficulty initiating micturation

Constipation, faecal incontinence

SYMPTOMS AND SIGNS

• Cognitive and psychiatric abnormalities:

Failure of memory, lack of concentration and executive functions

Depression, anxiety, and euphoria

DIAGNOSIS of MS

No specific test for MS Multiple signs and symptoms Remissions and exacerbation's Criteria for clinical diagnosis of MS

Criteria for clinical diagnosis of MS

NO of Attacks Evidence of more

than one lesion CSF,OCB

Clinically Definite Clinical Laboratory or IgG– A1 2 2– A2 2 1 and 1

Laboratory-Supported Definite– B1 2 1 or 1 + – B2 1 2 + – B3 1 1 and 1 +

Clinical Probable– C1 2 1 – C2 1 2– C3 1 1 and 1

Laboratory-Supported probable– D1 2 0 0 +

McDonald committee for Diagnosis of MS

DIS=disseminated in space, DIT=disseminated in time • 1. Definite MS on clinical grounds: 

– DIS: 2 or more lesions – DIT: 2 or more attacks

• 2. Localized disease – DIS: 1 lesion, need

• MRI to prove DIS, or • MRI finding and positive CSF finding; or  • urther clinical attack at a different location

• 3. Multifocal single attack, need – 2nd attack to confirm diagnosis

• 4. Single attack, single lesion – DIS: Need MRI prove of – DIS, plus DIT: Need MRI or clinical proof of second attack

• 5. Primary progressive disease – DIS: Need MRI, Evoked potential and CSF– DIT: 

• MRI proof of DIT,• or progression for over one year

Differential Diagnosis

Encephalomyelopathy SLE, CNS vasculitis Vascular malformation Gliomas of the brainstem Syringomyelia Progressive multifocal leuckoencephalopathy Infection : Brucella, TB, AIDS

TREATMENT & MS

No curative treatment yet

For the acute attack: » ACTH IM injection for 10-14 days» Methylprednisolone 1 gm daily for 5 days

Prophylactic therapy» Reduce the frequency of exacerbations/slow the

rate of progression of disability» Immunosupressive therapy

– Beta-Interferon-1B, 1A

Symptomatic treatment

ACUTE DISSEMINATED ENCEPHALOPATHY

• Monophasic encephalitis or myelitis• White matter of the brain or spinal cord• Process may be severe, fatal, or mild• Multiple foci of perivenular lymphocyte and

mononuclear cell infiltration with demyelination

• Follow vaccinations, acute infectious illnesses and may occur without any obvious antecedent

Laboratory Data

There is no pathognomonic test for MS. Neuroradiolog CSF investigations Evoked Responses

MRI & MS

Multiple white matter lesions Gadolinium contrast differentiates between

new and old lesion Similar lesions can be seen encephalitis,

vasculitis Asymptomatic patients

MRI: FLAIR & T1 with Gadolinium(Noseworthy J, et al NEJM, 2000)

MRI: T1 “Black Holes”

CSF & MS

Oligoclonal bandsOften positive 80-90 %Can be seen in other CNS disorders :

infection, SSPE Myelin basic protein

CSF & MS

WBC is often increasedLymphocytic plucytosisActivity of the disease>100 cells/mm3

Total protein is increased 40%< 100mg/dlIncreased IgG 60-70 %

Increased IgG Index 80-90

Evoked Responses &

MS– Demonstrate the existence of clinically unsuspected

lesions– Simple, noninvasive and harmless tests

Visual Evoked Responses Auditory Evoked Responses Somatosensory Evoked Responses

Visual Evoked Potentials(Baker’s Clin Neurol 2003)

CLINICAL MANIFESTATIONS

• Headache, delirium and coma , Seizures• Meningeal irritation and fever• Focal signs• Spinal cord involvement• Cerebellum and cranial nerve palsies are rare• CSF:

Increase protein, Increase cells lymphocytes

Rarely it is normal• MRI is often abnormal