Neuroscience Demyelination Diseases PDF

**OUTLINE** I. **Primary Demyelination** II. **Acquired Demyelination Syndrome** a. Acute disseminated encephalomyelitis b. Optic Neuritis c. Acute Transverse Myelitis III. **Neuromyelitis Optica Spectrum Disorder** IV. **Multiple Sclerosis** V. **Demyelinating Diseases of the Periphera...

**OUTLINE** I. **Primary Demyelination** II. **Acquired Demyelination Syndrome** a. Acute disseminated encephalomyelitis b. Optic Neuritis c. Acute Transverse Myelitis III. **Neuromyelitis Optica Spectrum Disorder** IV. **Multiple Sclerosis** V. **Demyelinating Diseases of the Peripheral System** a. Guillain-Barre Syndrome VI. **Plenary Session** +-----------------------+-----------------------+-----------------------+ | **LEGEND** | | | +=======================+=======================+=======================+ | ⭐ | 🖊️ | 📖 | | | | | | Must | Lecture | Book | | | | | | Know | *\[lec\]* | *\[bk\]* | +-----------------------+-----------------------+-----------------------+ PRIMARY DEMYELINATION {#primary-demyelination.TransOutline} ===================== Destruction of myelin sheets, oligodendrocytes, and Schwann cells Axonal injury may be seen in patients with demyelinating lesions PATHOGENESIS {#pathogenesis.TransSubtopic1} ------------ **Immune-mediated inflammatory process** resulting in destruction of the normally developed myelin **Metabolic and genetic disorders** of myelin metabolism resulting in abnormally formed myelin (dysmyelinating diseases) **Toxic disorders** DEMYELINATING DISEASES {#demyelinating-diseases.TransSub-subtopic2} ---------------------- Can affect: **Central Nervous System (CNS)** Acute disseminated encephalomyelitis Clinically Isolated syndrome Optic neuritis (ON) Transverse myelitis Neuromyelitis optica Multiple sclerosis (MS) **Peripheral Nervous System (PNS)** GBS +-----------------------------------+-----------------------------------+ | Table 1. Classification of CNS | | | Myelin Disorders | | +===================================+===================================+ | I. Noninfectious Inflammatory, | Acute Demyelinating | | Probably Autoimmune | Encephalomyelitis (ADE) | | | | | | Acute Hemorrhagic | | | Encephalomyelitis (AHE) | | | | | | Multiple Sclerosis (MS) | | | | | | Marburg Disease | | | | | | Optic Neuromyelitis or Devic | | | Disease | | | | | | Concentric Sclerosis or Balo | | | Disease | | | | | | Diffuse Cerebral Sclerosis or | | | Schilder Disease | | | | | | Optic Neuritis (ON) | | | | | | Transverse Myelitis | | | | | | Postinfectious Cerebellitis | | | | | | Postinfectious Brainstem | | | Encephalitis | +-----------------------------------+-----------------------------------+ | II. Inflammatory or Infectious | Progressive Multifocal | | Demyelinating Disorder | Leukoencephalitis | | | | | | Subacute Sclerosing | | | Panencephalitis (SSPE) | | | | | | Progressive Rubella | | | Panencephalitis | | | | | | Human Immunodeficiency Virus | | | Subacute Encephalitis | | | | | | Cytomegalovirus Subacute | | | Encephalitis | +-----------------------------------+-----------------------------------+ | III. Toxic and Metabolic | CO Poisoning | | Disorders | | | | Vitamin B12 Deficiency | | | | | | Folate Deficiency | | | | | | Mercury poisoning | | | | | | Post-Hypoxic-Ischemic Newborn | | | Leukoencephalopathy | | | | | | Central Pontine and Extrapontine | | | Myelinolysis | | | | | | Marchiafava-Bignami | +-----------------------------------+-----------------------------------+ | IV. Hereditary Disorders of | Adrenoleukodystrophy | | Myelin Metabolism | | | (Dysmyelinating diseases) | Metachromatic Leukodystrophy | | | | | | Multiple SulfataseDeficiency | | | | | | Krabbe Disease | | | | | | Alexander Disease | | | | | | Canavan Disease | | | | | | Pelizaeus-Merzbacher Disease | | | | | | Phenylketonuria | | | | | | Tay-Sachs Disease | | | | | | Niemann-Pick Disease | | | | | | Gangliosidosis GM1 and GM2 | | | | | | Fabry Disease | +-----------------------------------+-----------------------------------+ | V. Peroxisomal Disorders | Mitochondrial | | | leukoencephalopathies | +-----------------------------------+-----------------------------------+ | VI. Vascular | Vasculitis | +-----------------------------------+-----------------------------------+ ACQUIRED DEMYELINATING SYNDROME (ADS) {#acquired-demyelinating-syndrome-ads.TransOutline} ===================================== First demyelinating attack in childhood - Monophasic or sentinel attack of chronic disorder - Incidence: 0.5-1.66 per 100,000 children - Examples include: - **Transverse myelitis**: 3-22% - **Optic neuritis**: 22-36% - **ADEM**: 19-32% - 15-45% ultimately diagnosed as Multiple Sclerosis A. ACUTE DISSEMINATED ENCEPHALOMYELITIS (ADEM) {#acute-disseminated-encephalomyelitis-adem.TransSubtopic1} ------------------------------------------- 80% occur in age 10 years or below Peak incidence: 5-8 years old (+/-) preceding infection or vaccination 72-77% with antecedent infection - CMV, EBV, HSV, Hep A, HIV, Influenza, Measles, Rubella, Varicella, West Nile virus - Mycoplasma, Beta-hemolytic Streptococcus \< 5% follow immunization mostly MMR vaccine ***PGH Data 2011-2016*** - 6 cases total or 1 case/year - \ - Hemiparesis - Cerebellar ataxia - Cranial neuropathies - Optic neuritis - Transverse myelitis DIAGNOSTIC CRITERIA {#diagnostic-criteria.TransSub-subtopic2} ------------------- #### **CLINICAL** **FEATURES** **(All are required)** {#clinical-features-all-are-required.TransSub-subtopic3} - A first polyfocal, clinical central nervous system event with presumed inflammatory demyelinating cause - Encephalopathy that cannot be explained by fever, systemic illness, or postictal symptoms - No new clinical and MRI findings emerge 3 months or more after the onset - Brain MRI is abnormal during the acute (3-month) phase #### **LESION CHARACTERISTICS ON BRAIN MRI** {#lesion-characteristics-on-brain-mri.TransSub-subtopic3} - Diffuse, poorly demarcated, large (\1 to 2 cm) lesions involving predominantly the cerebral white matter - Deep gray matter lesions (e.g., involving basal ganglia or thalamus) can be present - T1 hypo intense lesions in the white matter are rare https://lh5.googleusercontent.com/Kt1bhfNzInMe0EGsviEicwUu0vVAreSQGiXDbnc11VKMTI4U3U5NqCcPFOgTXKCfd-7DASpVyCqWhScfAx\_EizjGeeGcJ2Rj8rD9dOjKbTK13y9yr\_QavzDhovInEe0tiiCCjWz0ruBFixdhTbI1D8g **Figure 1.** Lesions of ADEM in brain and spine using MRI ⭐ MRI PREDICTORS {#mri-predictors.TransSub-subtopic2} ---------------- - Predictors of evolution to **multiple sclerosis** - - - CSF STUDIES {#csf-studies.TransSub-subtopic2} ----------- - TREATMENT {#treatment.TransSub-subtopic2} --------- - - - - - - OUTCOME {#outcome.TransSub-subtopic2} ------- - - - - - B. OPTIC NEURITIS (ON) {#optic-neuritis-on.TransSubtopic1} ------------------- - Acute inflammatory condition affecting optic nerve - Incidence: 1 to 5/100,000 per year - More frequent in whites, high altitude countries - Mean age of onset: **9-10 years** - No gender predilection (pre-pubertal) - **Female** predominance (2:1) after puberty - Infection within 2 weeks prior to onset of ON - ️Some would have a history of immunization prior*.* - **Infectious agents:** - Adenovirus, measles, mumps, chickenpox, EBV, HHV7, human parvovirus B19 - Mycoplasma, pertussis, Lyme - **Immunization:** - Measles, mumps, rubella, hepatitis B, tetanus, rabies, diphtheria, smallpox CLINICAL MANIFESTATIONS {#clinical-manifestations.TransSub-subtopic2} ----------------------- - **Prodrome:** fever, frontal or retro-orbital headache with scotoma and painful eye movements - Blurring of vision progressing to visual loss (mono-ocular in adolescents) - Color vision abnormalities common - **Fundoscopic Findings:** - Optic nerve swelling (neuritis or papillitis) - Optic atrophy - Hemorrhages at optic nerve margin - Vascular tortuosity or sheathing of veins - Normal (retrobulbar neuritis) DIAGNOSTICS {#diagnostics.TransSub-subtopic2} ----------- - **Visual evoked potentials (VEPs) abnormal** - Absent or delayed P100 - **MRI of brain and orbits with contrast** - Signal abnormalities in optic nerves - Cerebral white matter lesions may be seen TREATMENT {#treatment-1.TransSub-subtopic2} --------- - **IV Methylprednisolone** - For severe attacks - 30 mg/kg/day x 3-5 days - **Oral Prednisone** - ⭐ Should be avoided - May increase the risk of recurrent ON PROGNOSIS {#prognosis.TransSub-subtopic2} --------- - Majority recover vision completely within weeks or months - 4 to 26% risk of developing MS #### **Good Outcome** {#good-outcome.TransSub-subtopic3} - Younger age - Bilateral disease - Normal MRI #### **Sequalae** {#sequalae.TransSub-subtopic3} - Optic nerve atrophy - Impairment of color vision #### **Predictors of MS** {#predictors-of-ms.TransSub-subtopic3} - Bilateral sequential or recurrent ON - Uhthoff symptom - Oligoclonal bands in CSF - Abnormal MRI C. ACUTE TRANSVERSE MYELITIS (ATM) {#acute-transverse-myelitis-atm.TransSubtopic1} ------------------------------- - Sudden onset of rapidly progressive weakness of the lower extremities, accompanied by loss of sensation and sphincter control - Often preceded by a respiratory infection EPIDEMIOLOGY {#epidemiology.TransSub-subtopic2} ------------ - Incidence: 1-4 new cases/million/year - Bimodal peak: 10-19 years and 30-39 years - Male:Female = 0.5-0.9:1 - No familial predisposition PATHOGENESIS {#pathogenesis-1.TransSub-subtopic2} ------------ - Antecedent respiratory, gastrointestinal, or systemic illness - **Mechanisms of autoimmunity** - A. Molecular mimicry - Infectious agents possess antigens resembling self-antigens in the spinal cord - B. Fulminant activation of lymphocytes by microbial super antigens INFECTIOUS AGENTS {#infectious-agents.TransSub-subtopic2} ----------------- - Viruses - Herpes simplex, herpes zoster, CMV, EBV, echo, coxsackie, hep B and A, influenza, measles, mumps, rubella, varicella, HTLV-1, HIV - Bacteria - Borrelia, Mycoplasma, Yersinia, Chlamydia, Mycobacteria, Listeria - Parasites - Schistosoma, Cysticercus, Toxocara, Toxoplasma ASSOCIATED VACCINES {#associated-vaccines.TransSub-subtopic2} ------------------- - These are the vaccines that have been reported to cause ATM - Rabies - Tetanus toxoid - Flu - Measles - Smallpox - Hepatitis B CLINICAL MANIFESTATIONS {#clinical-manifestations-1.TransSub-subtopic2} ----------------------- Infection to neuro symptoms in 5-10 days **Prodrome:** nausea, muscle aches, fever **Neuro symptoms:** back pain, pain and weakness in legs, and paresthesia, neck stiffness Peak symptoms in 3-10 days Full blown disease in 4 weeks NEUROLOGIC FINDINGS {#neurologic-findings.TransSub-subtopic2} ------------------- Motor weakness -- legs +/- arms Flaccid initially then spastic tone Sensory level with deficits in pain and temperature and sparing of vibration and proprioception DIAGNOSTIC CRITERIA {#diagnostic-criteria-1.TransSub-subtopic2} ------------------- #### INCLUSION CRITERIA FOR DIAGNOSIS OF TRANSVERSE MYELITIS (IDIOPATHIC OR DISEASE ASSOCIATED) {#inclusion-criteria-for-diagnosis-of-transverse-myelitis-idiopathic-or-disease-associated.TransSub-subtopic3} Development of sensory, motor, or autonomic dysfunction attributable to the spinal cord Bilateral symptoms Clearly defined sensory level Exclusion of compressive etiology by MRI or CT myelography Spinal cord inflammation demonstrated by CSF pleocytosis or elevated IgG or gadolinium enhancement in MRI Progression to clinical nadir between 4 hours and 21 days from onset of symptoms #### EXCLUSION CRITERIA FOR DIAGNOSIS OF TRANSVERSE MYELITIS (IDIOPATHIC OR DISEASE ASSOCIATED) {#exclusion-criteria-for-diagnosis-of-transverse-myelitis-idiopathic-or-disease-associated.TransSub-subtopic3} History of radiation to the spine within 10 years Clear arterial distribution clinical defect consistent with anterior spinal artery occlusion Abnormal flow voids on the surface of the cord consistent with AVM #### EXCLUSION CRITERIA FOR IDIOPATHIC TRANSVERSE MYELITIS {#exclusion-criteria-for-idiopathic-transverse-myelitis.TransSub-subtopic3} Serologic or clinical evidence of connective tissue disease (sarcoidosis, Behcet's disease, Sjogren's syndrome, SLE, mixed connective tissue disorder) CNS manifestations of syphilis, Lyme disease, HIV, HTLV-1, Mycoplasma, other viral infections Brain abnormalities suggestive of MS History of clinically apparent optic neuritis  **Figure 2. Typical MRI patterns of Transverse Myelitis. Sagittal MRI sequences** **demonstrating typical patterns of Transverse Myelitis.** **A:** Segmental transverse myelitis in pediatric multiple sclerosis. **B:** Idiopathic transverse myelitis in an infant with longitudinal extension from the cervical to thoracic cord (left image) and faint contrast enhancement (right image). **C:** Longitudinally extensive transverse myelitis in an infant with neuromyelitis optica. The entire spinal cord demonstrates abnormal signal (left image) with associated enhancement (right image). TREATMENT {#treatment-2.TransSub-subtopic2} --------- **IV methylprednisolone** 30 mg/kg to 1 gram/day x 5-7 days followed by oral 1 mg/kg/day followed by tapering over a 3--4-week period PROGNOSIS {#prognosis-1.TransSub-subtopic2} --------- Usually monophasic but some recurrent Neurologic improvement in 1-6 months Low risk in evolving to MS Variable outcome +-----------------------------------+-----------------------------------+ | **Table 2. Predictors of | | | Outcome** | | +===================================+===================================+ | **FAVORABLE OUTCOME** | **UNFAVORABLE OUTCOME** | +-----------------------------------+-----------------------------------+ | Plateau \