Lecture 1: Demyelinating Diseases PDF

Lecture 1: pathology of demyelinating diseases ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Overview: the myelin present in white matter surrounds the nerve these myelin fibers are like the insulation on electrical cables if damaged → nerve conduction is affected Myelin sheath covers many CNS & PNS fibers Some...

Lecture 1: pathology of demyelinating diseases ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Overview: the myelin present in white matter surrounds the nerve these myelin fibers are like the insulation on electrical cables if damaged → nerve conduction is affected Myelin sheath covers many CNS & PNS fibers Some fibers (axons) are unmyelinated CNS: myelin is produced by oligodendrocytes PNS: myelin is produced by schwann cells Luxol fast blue is a special stain for myelin, which stains it blue ○ We use it to identify areas of demyelination Demyelination: Loss of myelin surrounding axons of nerves CNS or PNS with relative preservation of axon Can be caused from damage to: ○ Myelin sheath ○ Cells producing myelin Myelin is crucial for proper nerve conduction Loss of myelin sheath results in interruption of nerve transmission → neurologic deficits (giving rise to neurologic signs & symptoms) CNS has limited capacity to regenerate myelin MS is the most common autoimmune demyelinating disorder Clinical Presentation of Demyelinating Disorders: they should be considered in any patient with unexplained neurologic deficits A primary demyelinating disorder can be suggested by the following: ○ Diffuse or multifocal neurologic deficits ○ Sudden or subacute onset ○ Onset in young adults ○ Onset after infection or vaccination ○ Deficits that wax & wane ○ Specific symptoms of demyelinating: ■ Unexplained optic neuritis ■ Ophthalmoplegia (MS) Pathogenesis of demyelination of central or peripheral NS: ● Autoimmune: ○ Multiple sclerosis ○ Acute disseminated encephalomyelitis ○ Guillain barre syndrome ○ Chronic inflammatory demyelinating polyneuropathy ● Infectious: ○ Progressive multifocal leukoencephalopathy (PML) ● metabolic/toxic: ○ CO poisoning ○ ↓ Vitamin B12 ○ Mercury poisoning ○ Central pontine myelinolysis ○ Hypoxia ○ Radiation ○ Alcohol ● Inherited disorders of myelin metabolism: ○ Metachromatic leukodystrophy (MLD) ○ Adrenoleukodystrophy (ALD) ■ ABCD1 mutation → impaired degeneration of VLCFAs in peroxisomes → accumulation → demyelinating neuropathy (patho 5 note) ○ Phenylketonuria ● Vascular: ○ Binswanger (very rare) Multiple Sclerosis: - an autoimmune demyelinating disorder characterized by distinct episodes of neurologic deficits that are separated in time & are attributable to patchy white matter lesions that are separated in space Pathogenesis: ● Autoimmune response against components of the Myelin Sheath (antigen is myelin) ● Genetic factors: ○ Higher incidence in 1st degree relative ○ Higher incidence in affected monozygotic twin ○ Strong association with a DR haplotype of MHC ○ Associations with IL-2 & IL-7 receptor genes ○ Associations with genes encoding proteins involved in the immune response ● Environmental factors: ○ Geographic variation → ↓ vitamin D level ● Book extra: infections (EBV & HHV-6) ● Genetic studies have not explained why clinical course for individuals with MS is so variable Immune mechanism of myelin damage in MS: Th1 & Th17 T cells react against myelin antigens Th1 cells secrete IFN- γ, which activates macrophages Th17 cells promote recruitment of leukocytes demyelination is caused by activated leukocytes & their chemical products ● Inflammatory lesion in MS (plaques) consists of: ○ T-lymphocytes (CD4+, few CD8+) ○ Macrophages ● Mechanism of Initiation of autoimmune reaction not clear (??Viral) ● ● ● ● Pathology of MS lesions (Plaques): Gross Appearance: ● Multiple ● Firmer than the surrounding white matter (Sclerosis) ● Well circumscribed ● Sharp borders ● Variable size ● Lesions can be seen on MRI CSF in MS: ● ● ● ● ● ● ● Microscopically: ● Location of lesions: ● Adjacent to lateral ventricles ● Corpus callosum ● Optic nerves & chiasm ● Brainstem fibers ● Spinal cord ● Active plaque: ○ Myelin absent ○ Mc & lymphocytes ○ Centered on small veins ○ axon relatively preserved ● ● ● ● ● ● ↑ IgG ● Oligoclonal IgG bands on immunoelectrophoresis → indirect indication that there is ↑ stimulation of immune system but is not sufficient to be malignant ↑ protein Serum Glucose: Normal Lymphocytes Macrophages Plasma cells Differential diagnosis of MS: (demyelinating disorders**) Spinal cord neoplasms Acute disseminated encephalomyelitis (ADEM) Sarcoidosis Transverse myelitis Infarction of spinal cord Vasculitis Radiation myelitis Neuromyelitis optic (NMO): ● A syndrome with synchronous bilateral optic neuritis & spinal cord demyelination ● Distinct from MS ● More prevalent in women ● Poor recovery ● Presence of a pathogenic antibody ● Areas of demyelination show loss of aquaporin-4 ● WBC & neutrophils in CSF ● ● Inactive plaques: ○ no inflammatory infiltrate ○ Loss of myelin ○ Reactive gliosis ○ Damage to axons ● Arteriovenous fistula ● Progressive multifocal leukoencephalitis (PML) ● Subacute combined degeneration of the sc (vitamin B12 deficiency) ● Small-vessel ischemic disease (diabetes, HTN, hyperlipidemia, old age) ● CNS lesion: ○ Necrosis ○ Inflammatory infiltrate ○ Vascular deposition of immunoglobulin & complement Acute Disseminated Encephalomyelitis (ADEM): ● Diffuse Demyelinating Disease (Unlike MS) ● Follows: ○ Viral infection ○ Viral immunization ● Symptoms develop 1 or 2 weeks after the antecedent event ● Brain lesions appear similar (in stage) ● Rapid clinical course (20% death rate) ● Most patients recover completely ● Lesions similar to those induced by immunization of animals with: ○ Myelin components ○ Rabies vaccines prepared from brains of infected animals ● ADEM is possibly an acute autoimmune reaction to myelin Central Pontine Myelinolysis: (a ● Symmetric loss of myelin in the base of the pons & portions of the pontine tegmentum ● Arise 2 to 6 days after rapid correction of hyponatremia **high yield ● Associated with: ○ Severe electrolyte disturbance ○ Osmolar imbalance ● Rapid ↑ in osmolality damage oligodendrocytes ● Inflammation is absent (so no inflammatory cells) ● Neurons & axons preserved ● Rapid clinical presentation: ○ Quadriplegia ○ Severe long-term deficits ○ “locked-in” syndrome ● Hyponatremia must be corrected slowly & carefully to prevent this tragic complication Acute Necrotizing Hemorrhagic Encephalomyelitis (aka: Hemorrhagic leukoencephalitis; Weston Hurst Disease ● ● ● ● ● ● ● Fulminant syndrome of CNS demyelination Young adults & children Follows URT infection Histology similar to ADEM Severe damage Disease usually fatal Significant neurologic deficits in survivors Progressive multifocal leukoencephalopathy (PML) ● ● ● ● ● ● ● Demyelinating disease of CNS Immunocompromised host, usually HIV Widespread lesions Infection of oligodendrocytes by JC virus (reactivation of virus) Associated with HIV-1 & HIV-2 or other immune deficiencies In situ hybridization demonstrates JC viral DNA in tissue Immunostains can detect JC like particle in tissue Subacute combined degeneration of the SC (↓ vitamin B12): ● Acquired demyelinating disease caused by ↓ Vitamin B12 (cobalamin) ● Accumulation of methylmalonyl CoA causes a ↓ in myelin synthesis ● ​Clinical: ○ Progressive sensory abnormalities ○ Ascending paresthesias ○ Weakness ○ Ataxia ○ Loss of sphincter control ○ Gait impairment ○ Megaloblastic anemia Tabes Dorsalis: ● ● ● ● ● Manifestation of tertiary syphilis Demyelination limited to dorsal columns of sc No inflammatory reaction Trypanosoma pallidum absent from lesion !! Hypoxic ischemic demyelination: ● Brain hypoxia usually induces necrosis not demyelination ● Demyelination can develop if hypoxia affects primarily oligodendrocytes ● Etiology: ○ Severe small vessel disease: ■ HTN ■ Diabetes ■ Old age ○ Global brain hypoxia: ■ Cardiac arrest ■ Asphyxia ■ Drug overdose ● Carbon Monoxide Injury: ○ Affects globus pallidus & white matter ■ Cherry red spots ○ Exposure: Accidental or suicide attempt ● Presentation: ○ Acute: ■ Headache, Myalgia ■ Dizziness ■ Coma ■ Psychological impairment ○ Chronic: ■ Delayed personality changes ■ Cognitive deficit ■ Dementia ■ Parkinsonism ● Pathology: ○ Acute: ■ Cherry red discoloration of white matter ○ Chronic: ■ Necrosis of globus pallidus ■ Demyelination of white matter Peripheral Nervous System Demyelination Disorders: ● Acute Inflammatory Demyelinating Polyradiculoneuropathy (AIDP): ○ Guillain-Barré Syndrome (GBS) (aka: Acute Idiopathic Polyneuritis) ■ mc acquired inflammatory neuropathy ■ Demyelination of peripheral nerves ■ Etiology unknown: autoimmune ■ Starts 5 days to 3 weeks after infection, surgery, vaccination (Covid-19) ■ If weakness progresses > 2 months, diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy is established ■ Ascending symmetric weakness & paresthesias in legs progresses to arms ■ Weakness maximal at 3 to 4 weeks then resolves ■ Loss of deep tendon reflexes ■ Sphincters spared ● Chronic Inflammatory demyelinating polyradiculoneuropathy: ○ Acquired demyelinating disorder ○ T-cell mediated or humoral immunity ● Anti-Myelin Associated Glycoprotein (MAG) Neuropathy: ○ Associated with IgM monoclonal gammopathy against MAG (transmembrane glycoprotein) ● POEMS Syndrome: ○ Paraneoplastic syndrome with demyelinating neuropathy (plasma cell neoplasms) ● Charcot Marie Tooth Disease: ○ Most common hereditary neuropathy (Type 1 & type X) ○ Affects motor & sensory ○ PMP22 gene