Super MS lecture. Basic Facts about MS. Demyelinating Conditions. Multiple Sclerosis Progressive Multifocal Leukoencephalopathy Acute Disseminated Encephalomyelopathy (ADEM) Post infectious, post-vaccinial leukoencephalitis Infection induced demyelination
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Super MS lecture Basic Facts about MS
Demyelinating Conditions • Multiple Sclerosis • Progressive Multifocal Leukoencephalopathy • Acute Disseminated Encephalomyelopathy (ADEM) • Post infectious, post-vaccinial leukoencephalitis • Infection induced demyelination • Demyelination of autoimmune disease eg “lupoid sclerosis”, Hashimoto’s related demyelination • Dysmyelinating Conditions • Transverse Myelitis • Tropical Spastic Paraparesis • Progressive mulitfocal leukoencephalopathy • SSPE
ADEM • Problem diagnosis is it MS or ADEM?? • ADEM fulminent single attack • Post viral or post vaccination esp Rabies • Can be acute hemorrhagic leukoencphalitis • May require aggressive therapy e.g. iv Cyclophosphamide or plasmapheresis
Dysmyelination • Disturbance in the formation and preservation of myelin so that its proper functioning is never established. These disorders are also termed leukodystrophies, and almost all of them manifest themselves early in life and are genetically determined.
Metachromatic Leukodystrophy • Most common of these disorders • Autosomal recessive disorder • Both central and peripheral white matter involved • Predominantly a disease of infancy, but juvenile and adult forms do exist • Course is progressive, usually fatal in a few years • Pathology is diffuse, confluent loss of myelin that is most advanced in the cerebrum. • Due to inborn error of metabolism in which arylsulfatase A, although present, is enzymatically inactive. Leads to breakdown of myelin and the accumulation of sulfatide-rich lipids that appear as small globules of metachromatic material in the white matter.
Krabbe’s Disease • Usually appears in early months of life and progresses to death in one to two yearsAutosomal recessive caused by a deficiency of galactocerebroside, B-galactosidaseExpressed histologically by the presence of perivascular aggregates of globoid cells
Schilder’s Sudanophilic Leukodystrophy • Clinical symptoms (motor, sensory and cognitive) develop in the first decade and progress insidiously.The central nervous system is depleted of myelin, and the peripheral nervous system to a lesser degree.Ordinarily X-Linked
Alexander’s Disease • characterized pathologically by lack of formation of myelin and innumerable Rosenthal fibers.
Adrenoleukodystrophy • Progressive nervous system deterioration • paralysis • hearing loss • visual impairment or blindness • deteriorating fine motor control • vegetative state • Seizures • Symptoms of adrenal gland failure • muscular weakness (asthenia) • wasting (loss of weight, muscle mass) • decreased appetite • increased skin pigmentation
Adrenoleukodystrophy 2 • X-linked or neonatal recessive types • Increased Long Chain Fatty Acids • Special (‘Lorenzo Oil’) Diet • EMG, Skin test, blood for long chain fatty acids,MRI, make diagnosis • Chromosome defect in 7q21-q22 : Neonatal form • Treat Adrenal failure
Tropical Spastic Paraparesis • Now Ass’d with HTLVI • i.v. drug use, positive sexual partner, breast milk, blood transfusion • No known established treatment • Trials with Steroids Interferon Beta 1a • HTLV ass’d myelopathy (HAM)/TSP
TSP/HAM • Progressive muscle weakness • Sensory disturbance • Sphincter dysfunction • Urinary incontinence • Uveitis • Arthritis • Pulmonary lymphocytic alveolitis • Polymyositis • Keratoconjunctivitis sicca • Infectious dermatitis
Progressive multifocal leukoencephalopathy • Immunosuppressed • Multifocal confluent white matter abnormalities • Relentlessly progressive with no cure • Human papilloma virus, JC virus • Vision loss, speech disturbance, ataxia, paralysis, depressed sensorium, seizures
PML Bizarre bodies in oligos, Transformed astrocytes demyelination
MS • A disease leading to the destruction of Central Nervous system Myelin. Myelin speeds electrical conduction through axons. • Recent work has revived concept of destruction of axon cylinders as well as myelin. • Characterized by relapses and remissions in 85% of cases at presentation
MS: What it is • The disease is believed to be caused by the destruction of myelin by the immune system. Myelin is the fatty tissue that surrounds and protects CNS nerve fibers and facilitates the flow of nerve impulses to and from the brain. The loss of myelin disrupts the conduction of nerve impulses, producing the symptoms of MS
What is MS? MS is a chronic, inflammatory disease of the CNS in which most patients incur disability over time. MS affects approximately 400,000 people in the United States, two thirds of whom are women. Disease onset typically occurs in young adults between the ages of 20 and 40. • .
Clinical features • In 80-85% of persons MS is characterized by relapses and remissions. These are new symptoms that persist at least days and often weeks. Most patients early on have good recovery from attacks but they do not fully recover.
Highly Characteristic Symptoms • There are some highly characteristic i.e. common symptoms that are so frequently part of the disease they are easily recognized and help confirm the diagnosis
Characteristic Symptoms/signs • Optic Neuritis • LHermitte’s phenomenon • Double Vision • Evidence for spinal cord attack • Band like sensation • Loss of abilitities with both legs • Tic Doloreux esp on both sides or in young • INO • LE spastic weakness • Heat exacerbation of neurological symtoms/signs • Fatigue Related Neurologic Dysfunction (FRND)
Optic neuritis • Eye pain on movement • Usually one eye • Central (macular visual loss) • Color vision, acuity affected • Afferent pupillary defect • Anterior: Papillitis, Posterior: retrobulbar • Attack in optic nerve lasts weeks • More common in young women • Positive vs. negative MRI scans
Afferent (Marcus-Gunn) Pupil • Swinging flashlight • Consensual light response>> direct response • Affected pupil dilates when you shine light in eye • Optic atrophy, optic neuritis
LHermitte Phenomenon • Ephaptic transmission • Neck flexion yeilds electrical shock sensation • Increased proximity of denuded axons
Charcot Triad • Scanning speech • Nystagmus • Intention tremor
Vague Symptoms • Fatigue • Tingling • Muscle, joint aches and pains • Depression • Dizziness
Vague Symptoms • Many persons with vague symptoms may lack MRI or spinal fluid abnormalities and do not have MS • Often persons with vague symptoms will eventually be diagnosed to have MS.
Symptoms • Disease symptoms vary. Common symptoms are weakness, numbness, fatigue, vision problems, slurred speech, poor coordination, short-term memory loss, and bladder dysfunction. Severe cases of MS can be characterized by partial or complete paralysis.
Diagnosis Depends on: • History • Relapses and remissions • Multiple Attacks • Characteristic symptoms • Physical Exam • MRI • Blood Tests • Mostly to exclude other entities
Diagnosing MS • Dissemination in time and space. • MRI scans • Laboratory supported esp. spinal fluid tests • Evoked responses • No other disease entity or other explanation for two separate abnormalities in the nervous system So-called possible, probable and definite MS
CSF • Cell count: 1/3 have 5-50 mononuclears Myelin basic protein: Can be found in first 2 weeks after a substantial exacerbation in 50-90% of patientscan be seen in other neuro disease.
CSF continued • Immunoglobulin: IgG synthesis rateIndicates activity of Plasma cells>3 in 80-90% of MSelevated in 12% of normal individual, and 30-50% of CNS infections • Immunoglobulin: IgG index>0.7 in 86-94% of MSfirst CSF abnormality in early MS • Oligoclonal bandspresent in over 90% of definite MSseen in other inflammatory diseasesseen in 7% of normal control
What Causes MS?? • We don’t know • Best Theory: MS is a chronic infection but we don’t yet know the agent which reacts like all infections do to affect the nervous system in a vulnerable host. • The Immune system plays a role. • Immune system helps to destroy myelin • Myelin destruction may also be part of chronic infection. • People with MS have certain inherited characteristics of their immune system e.g. HLA types
Candidates • Measles, dystemper • Herpes 6 • Chlamidia pneumoniae • Other viruses and bacteria
Distinct patterns of multiple sclerosis pathology indicates heterogeneity in pathogenesisLucchinetti, et al.BRAIN PATHOLOGY6: (3) 259-274 JUL 1996 • demyelination with relative preservation of oligodendrocytes • myelin destruction with concomitant and complete destruction of oligodendrocytes or primary destruction or disturbance of myelinating cells with secondary demyelination. • Primary Selective demyelination followed by secondary oligodendrocyte loss in the established lesions. • Destructive lesions with loss of myelin, oligodendrocytes, axons and astrocytes.
NEJM 349(2):139-145July 10, 2003Antimyelin Antibodies as a Predictor of Clinically Definite Multiple Sclerosis after a First Demyelinating EventThomas Berger,MD et al • myelin oligodendrocyte glycoprotein (MOG) and myelin basic protein (MBP) in patients with a clinically isolated syndrome predicts the interval to conversion to clinically definite multiple sclerosis. • RR in dual Ab Pos pts was 76.5!! • All Pts had clinically isolated syndrome pos MRI and Pos CSF
SYMPTOMS • Disease symptoms vary. Common symptoms are weakness, numbness, fatigue, vision problems, slurred speech, poor coordination, short-term memory loss, and bladder dysfunction. Severe cases of MS can be characterized by partial or complete paralysis.
Diagnosing MS • Clinical Presentation: A person has to have evidence of two separate attacks • MRI scans • Laboratory especially spinal fluid tests • Evoked responses • No other disease entity or other explanation for two separate abnormalities in the nervous system • So-called possible, probable and definite MS
Classes of Proof • History of two attacks with positive oligoclonal bands or increased IgG in CSF; no clinical or para clinical evidence of a disease. =Probable MS with laboratory support • History of two attacks without laboratory abnormalities.---Clinically probable MS • History of two attacks with clinical and para clinical evidence of one lesion; Oligoclonal bands or increased IgG present in CSF=Laboratory-supported definite MS • History of at least two attacks; Clinical evidence of at least one lesion and clinical or para clinical evidence of another lesion=Clinically-definite MS
McDonald Criteria • Idea: Dissemination in time and space • 2 attacks (time), 2 lesions (space) • 2 attacks, one lesion: need MRI to find other lesions • 1 attack, 2 lesions: need to wait for 2nd attack • 1 attack, 1 lesion “clinically isolated syndrome” need 2nd attack, 2nd lesion
McDonald Criteria • Insidious progression sugg’v for MS • 1) 9 or more T2 lesions in brain, or 2) 2 or more lesions in spinal cord, or 3) 4-8 brain lesions plus 1 spinal cord lesion; or • Abnormal visual evoked potentials, and MRI demonstrating 4-8 brain lesions, or fewer than 4 brain lesions plus 1 spinal cord lesion; or • Dissemination in time demonstrated by MRIb; or • Continued progression for 1 year PLUS • Positive CSF
CSF • Cell count: 1/3 have 5-50 mononuclears • Myelin basic protein: Can be found in first 2 weeks after a substantial exacerbation in 50-90% of patientscan be seen in other neuro disease.
CSF cont’d • Immunoglobulin: IgG synthesis rateIndicates activity of Plasma cells>3 in 80-90% of MSelevated in 12% of normal individual, and 30-50% of CNS infections • Immunoglobulin: IgG index>0.7 in 86-94% of MSfirst CSF abnormality in early MS • Oligoclonal bandspresent in over 90% of definite MSseen in other inflammatory diseasesseen in 7% of normal control
Types of MS There are distinctive disease patterns in MS. In each case a person experiences sudden deterioration in normal physical abilities that may range from mild to severe. This attack, sometimes referred to as an exacerbation of MS, may last a brief time or continue for months.About 80% of patients begin with Relapsing-Remitting (RR) MS, the most common pattern. In this form, patients experience a series of attacks followed by complete or partial disappearance of the symptoms (remitting) until another attack occurs (relapse). It may be weeks to years between relapses.
Types of MS (2) In Primary- Progressive (PP) MS, there is a gradual decline in physical abilities.About 20% of patients begin with PP-MS. At least half of patients starting with relapsing remitting MS eventually develop a secondary progressive pattern within 10 or so years. A rarer pattern is called Progressive-Relapsing (PR) MS is characterized by a steady decline in abilities accompanied by frequent attacks. Some patients, 10-30% have so called “benign” MS, a patient experiences an initial attack followed by little or no progression. Finally, there is a rare, rapidly progressive form of MS called malignant MS.
Secondary Progressive MS • Over half of RR MS patients enter secondary progressive phase: • Exacerbations no longer prominent or identifiable • Gradually increasing mostly LE dysfunction