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

TypeDisease Immune-mediated Recurrent Multiple sclerosis Monophasic Optic neuritis Transverse myelitis Acute disseminated encephalomyelitis Inherited Adrenoleukodystrophy Metachromatic leukodystrophy Metabolic Vitamin B 12 deficiency Central pontine myelinolysis Infectious Progressive multifocal leukoencephalopathy Subacute sclerosing panencephalitis

Incidence and prevalence high moderate or low unknown probably low high probably low high low moderate

Incidence and prevalence Regional data Middle East CountryPopulation Total MS patients Total RRMS patients Saudi Arabia 22’024’0001’7601’060 Kuwait 1’974’ Palestine 2’896’ Tunisia 9’593’ Libya 5’116’ Jordan 4’999’ Iraq22’676’ Lebanon 3’578’

Incidence and prevalence Country Population Total MS patients Middle East72‘853‘790 5‘730 West Europe 386‘000 South America 25‘000 Australia12‘ ‘367‘700 South Africa 1‘500 43‘420‘000 Canada 50‘000 31‘281‘100 19‘169‘ ‘815‘550 USA 300‘ ‘562‘700 Eastern Europe 76‘750 78‘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 agent 2.genetically susceptible individual Incidence of the disease Results of migration

MS & AETIOLOGY 3- Viral 4- 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 n Unpredictable course n rapidly progressive n Benign »mild exacerbation »complete remissions »minimal disability n Exacerbation-remitting n Chronic - relapsing n 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 STEM SYMPTOMS 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 n No specific test for MS n Multiple signs and symptoms n Remissions and exacerbation's n Criteria for clinical diagnosis of MS

Criteria for clinical diagnosis of MS NO of Attacks Evidence of more than one lesion CSF,OCB than one lesion CSF,OCB n Clinically Definite C linical Laboratory or IgG –A1 2 2 –A2 2 1 and 1 n Laboratory-Supported Definite –B1 2 1 or 1 + –B –B3 1 1 and 1 + n Clinical Probable –C1 2 1 –C2 1 2 –C3 1 1 and 1 n Laboratory-Supported probable –D

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

TREATMENT & MS n No curative treatment yet n For the acute attack: »ACTH IM injection for days »Methylprednisolone 1 gm daily for 5 days n Prophylactic therapy »Reduce the frequency of exacerbations/slow the rate of progression of disability »Immunosupressive therapy –Beta-Interferon-1B, 1A n 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 n There is no pathognomonic test for MS. n Neuroradiolog n CSF investigations n Evoked Responses

MRI & MS n Multiple white matter lesions n Gadolinium contrast differentiates between new and old lesion n Similar lesions can be seen encephalitis, vasculitis n Asymptomatic patients

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

MRI: T1 “Black Holes”

CSF & MS n Oligoclonal bands n Often positive % n Can be seen in other CNS disorders : infection, SSPE n Myelin basic protein

CSF & MS n WBC is often increased n Lymphocytic plucytosis n Activity of the disease n >100 cells/mm3 n Total protein is increased 40% n < 100mg/dl n Increased IgG % n Increased IgG Index 80-90

Evoked Responses & MS –Demonstrate the existence of clinically unsuspected lesions –Simple, noninvasive and harmless tests n Visual Evoked Responses n Auditory Evoked Responses n 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