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 sclerosis Monophasic   Optic neuritis   Transverse myelitis   Acute disseminated encephalomyelitis Inherited Adrenoleukodystrophy Metachromatic leukodystrophy Metabolic Vitamin B12 deficiency Central pontine myelinolysis Infectious Progressive multifocal leukoencephalopathy Subacute sclerosing panencephalitis

Incidence and prevalence high high low moderate moderate or low low probably low low probably low unknown low moderate high 5

Incidence and prevalence Regional data Middle East Country Population Total MS patients Total RRMS patients 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 6

Incidence and prevalence Country Population Total MS patients Middle East 72‘853‘790 5‘730 West Europe 350‘367‘700 386‘000 Eastern Europe 78‘475‘500 76‘750 Canada 31‘281‘100 50‘000 USA 275‘562‘700 300‘000 South Africa 43‘420‘000 1‘500 South America 209‘815‘550 25‘000 Australia 19‘169‘100 12‘000 7

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. 8

Demyelination and axonal degeneration in MS Figure 1: Demyelination and axonal degeneration in MS Panel A: shows a normal healthy axon, surrounded by myelin sheaths, which is arranged in segments. These segments are separated by nodes of Ranvier, where sodium channels are clustered at high density in the axon membrane. In a normal myelinated axon, the action potential (dashed arrow) travels, at a high velocity and reliability, to the postsynaptic neurone. Panel B: In acutely demyelinated axons, conduction is blocked (black bar). Myelin sheaths have been destroyed by cells of the immune system, i.e. T-cells, macrophages, microglial cells, B-cells. The myelin acts as an insulator around axons. Damage to the myelin is accompanied by a decrease in conduction velocity and by a conduction block, i.e. reduced or no information flow. This produces major MS symptoms ---> relapse. Panel C: In some chronically demyelinated axons that acquire a higher-than- normal density of sodium channels, conduction is restored. Recovery from a relapse may be partly due to remodeling of the demyelinated axonal membrane, so that it acquires a higher-than-normal sodium channel density, which permits conduction despite myelin loss. But this is only a ‘temporary’ solution. Panel D: Axonal degeneration, by contrast, interrupts action potential propagation in a permanent manner. The damaged axon will degenerate sooner or later. Degenerated axons are characterized by a ‘swollen’ end, also named ‘ovoid’ in the Trapp et al. paper 1998 Waxman SG. Demyelinating Diseases-New Pathological Insights, New Therapeutic Targets. The New England Journal of Medicine, 338, 5:323-325, 1998 Waxman S, NEJM 338, 5, 323, 1998 9

genetically susceptible individual MS & AETIOLOGY Remains unresolved Suggestive Environmental agent 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 Unpredictable course rapidly 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 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

Cognitive and psychiatric abnormalities: 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

No curative treatment yet For the acute attack: 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 bands Often positive 80-90 % Can be seen in other CNS disorders : infection, SSPE Myelin basic protein

CSF & MS WBC is often increased Total protein is increased 40% Lymphocytic plucytosis Activity of the disease >100 cells/mm3 Total protein is increased 40% < 100mg/dl Increased IgG 60-70 % Increased IgG Index 80-90

Evoked Responses & MS Visual Evoked Responses 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