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CNS Pathology - Demyelinating Diseases - Neurodegenerative diseases Associate Professor Dr. Alexey Podcheko Spring 2015 Demyelinating diseases Conditions characterized by a preferential damage to myelin, with relative preservation of axons Diseases of oligodendrocyte / myelin sheath Clinical deficits are due to the effect of myelin loss on the transmission of electrical impulses along axons Examples include: – Leukodystrophies – Multiple Sclerosis (MS) – Acute Disseminated Encephalomyelitis (ADEM) Leukodystrophies Inherited mutations in enzymes necessary for production or maintenance of myelin The characteristics of leukodystrophies are: Age: infancy through adolescence Lysosomal or peroxisomal enzyme defects Involve both the CNS and the PNS Disease is progressive, resulting in death at an early age Metachromatic Leukodystrophy • Most Common type of Leukodystrophy • Genetic Deficiency of arylsulfatase enzyme • Myelin can not be degraded – accumulates in lysosomes • Loss of myelin and gliosis • Macrophages containing sulfatides (when the sulfatides bind some types of dyes, they change the absorbance spectrum, called metachromasia Here the macrophages are clustered around a vessel, as well as scattered in the parenchyma. Krabbe's Disease (Globoid Cell Leukodystrophy) • Defect in galactocerebroside bgalactosidase • A breakdown product of galactocerebroside is toxic causing oligodendrocyte injury • Autosomal Recessive • Pathology characterized by – loss of myelin and oligodendrocytes (and Schwann cells in the PNS) – reactive astrogliosis – multinucleated macrophages called globoid cells accumulate around blood vessels (blue arrows) •Severe sensory, motor and cognitive defects •Death within 1-2 years Adrenoleukodystrophy • X-linked (Note: this is the disease that was the topic of the film Lorenzo's Oil) • Impaired addition coenzyme A to long-chain fatty acids • lack of catabolism of very long chain fatty acids (VLCFA's) in peroxisomes, and increased levels of VLCFA's can be found in serum • Atrophy of the ADRENAL gland • CNS Pathology consists of – myelin loss - LEUKODYSTROPHY – gliosis – lymphocytic inflammation Adrenoleukodystrophy • Clinical Features: • Children 3-10 years old • Severe sensory, motor and cognitive defects • Adrenal failure (Addison Disease) • Rx: Manipulation with dietary lipid composition Multiple Sclerosis Autoimmune destruction of CNS myelin and oligodendrocytes Most common demyelinating disorder More commonly seen in regions away from equator Prevalence ~ 1 per 1000 persons in US Onset at any age – Relatively rare in childhood or after age 50 Women > men 2:1 Multiple Sclerosis Etiology: – Not clearly established – Implicated factors: Environmental Genetic Immune Factors: associated with HLA DR2 Multiple Sclerosis - Clinical features Demyelinating lesions can occur anywhere in the central nervous system and, as a consequence, may induce a wide range of symptoms Common clinical presentation: Blurred vision in one eye (optic nerve) Vertigo Scanning speech (brainstem) Internuclear ophtalomoplegia (damage of medial longitudinal fasciculus) Multiple Sclerosis - Clinical features Hemiparesis or unilateral loss of sensation (cerebral white matter injury) Lower extremity loss of sensation or weakness (spinal cord) Bowel, bladder and sexual dysfunction (ANS injury) Natural course of multiple sclerosis is variable Episodes of neurologic deficits develop over short periods of time (days to weeks) and show gradual partial remission Frequency of relapses tends to decrease over the course of time A 29-year-old Caucasian female complains of decreased vision and pain around her eye, which is aggravated by eye movement. Several months later she is found to have an intention tremor of her left arm. This patient’s condition is most likely caused by: A. Bacterial infection B. Vascular disease C. Trauma D. Autoimmune disease E. Inherited metabolic disease F. Intoxication Corr D Explanation: The patient’s complaints of pain with ocular movements and decreased vision are consistent with optic neuritis. Intention tremor is a sign of cerebellar dysfunction. Both of these symptoms are commonly seen in multiple sclerosis. Waxing and waning neurological deficits in a 20-30 year old patient are suggestive of this disorder. The etiology of multiple sclerosis remains unknown. Currently, it is considered an autoimmune disease, with viral and environmental factors also playing a role in its pathogenesis. The autoimmune character of this disorder is supported by the following features: 1. There is an elevated immunoglobulin G (lgG) level in the cerebrospinal fluid (CSE). It is seen as an oligoclonal band on electrophoresis and suggests an activation of B cells in multiple sclerosis. 2. The incidence of multiple sclerosis is increased in people with certain HLA types. 3. Immunomodulatory agents, such as interferon beta, have a positive impact on multiple sclerosis. Its mechanism is counteraction of the inflammatory action of immune cells. Environmental factors are also important in the pathogenesis of MS. This disease is much more common in temperate latitudes. Its prevalence is 30-50 times as high in the USA, Canada and Northern Europe as it is in equatorial Africa. The factors listed in the other choices do not participate in the development of multiple sclerosis. Educational Objective: Multiple sclerosis is viewed as an autoimmune condition. Viral and environmental factors are also considered to play a role in its development. Increased levels of lgG in the CSF, detected as an oligoclonal band on electrophoresis, supports the immunologic theory. Diagnosis of MS 1. Lumbar puncture: a. elevated immunoglobulin G (lgG) level in the cerebrospinal fluid seen as oligoclonal band on electrophoresis (due to activation of B cells) b. Increased level of lymphocytes c. Myelin basic protein 2. MRI : reveals plaques Multiple Sclerosis-Morphology MS is a white matter disease Gross examination: Foci of demyelination appear as glassy, gray lesions Microscopic examination: Characteristic multiple lesions scattered in white matter - Plaques Plaque!!! Subacute Sclerosing Panecephalitis Progressive debilitating encephalitis leading to death Result of slowly progressing infection of the brain by measles virus Clinical signs develop several years after measles, with extensive brain damage leading to death usually within one to two years after onset Morphology – intranuclear, eosinophilic inclusion bodies with associated demyelination and gliosis Subacute Sclerosing Panencephalitis (SSPE) Associated with measles (rubeola) virus either as a primary infection or , rarely, as a complication of immunization against measles since it is a live attenuated vaccine!!!! Progressive Multifocal Leukoencephalopathy • JC virus infection of oligodendrocytes • Immunosuppression leads to reactivation of latent virus • Prominent in the pathology of AIDS and patients who are immunocompromised (leukemia) • Present with rapidly progressive neurological signs leading to death • Dementia, myoclonic fasciculations; normal funduscopic exam; no other focal neurologic signs Central Pontine Myelinolysis Focal demyelination of pons Caused by rapid Intravenous correction of hypo Na emia Occurs in severely malnourished patients Present as acute paralysis (“Locked in” syndrome) Locked-in syndrome is a condition in which a patient is aware and awake but cannot move or communicate verbally due to complete paralysis of nearly all voluntary muscles in the body except for the eyes Degenerative Diseases Are diseases of gray matter Characterized principally by: – Progressive loss of neurons with associated secondary changes in white matter tracts. – Pattern of neuronal loss is selective, affecting one or more groups of neurons, while leaving others intact. – Disease arises without any clear inciting event in a patient without previous neurologic deficits Degenerative Diseases Degenerative Diseases Affecting the Cerebral Cortex – lead to dementia!!! – Alzheimer’s disease (AD) – Vascular dementia – Pick’s disease Degenerative Diseases of Basal Ganglia and Brain Stem – lead to movement disorders!!! Spinocerebellar Degenerations Degenerative Diseases Affecting Motor Neurons Degenerative Diseases Affecting the Cerebral Cortex Major cortical degenerative diseases are – Alzheimer’s disease (AD) – MC cause of dementia! – Vascular Dementia – Pick’s disease – Levy body dementia – Vascular disease (multi-infarct dementia) – Creutzfeldt-Jakob disease – Neurosyphilis Dementia is not part of normal aging and always represents a pathologic process. Alzheimer’s Disease Insidious impairment of higher intellectual function, with alterations in mood and behavior, F:M=2:1 Later, progressive disorientation, memory loss, and aphasia indicate severe cortical dysfunction, and eventually, over 5 to 10 years, the patient becomes profoundly disabled, mute, and immobile Down Syndrome patients become symptomatic before 50 years of age Although pathologic examination of brain tissue remains necessary for the definitive diagnosis of AD, the combination of clinical assessment and modern radiologic methods allows for a diagnostic accuracy of 80 to 90%. Alzheimer’s Disease (AD)-Morphology Major microscopic abnormalities of AD are – Neurofibrillary tangles – Senile (neuritic) plaques – Amyloid angiopathy Diagnosis of AD is based on a clinicopathologic correlation between the patient’s neurologic status and the frequency of plaques and tangles Morphology 1. Hydrocephalus ex vacuo 2. Neuritic plaques (extracellular AB amyloid + Neuritic processes) 3. Neurofibrillary tangles are intracytoplasmic intraneuronal accumulations of polymerized hyperphosphorylate d tau microtubular protein (arrows). Alzheimer’s Disease • DIFFUSE!!!! Cortical atrophy (right side meninges removed) Pathogenesis of AD 1. hypothetical mechanism for the formation of senile plaques (SP) from soluble APP peptides produced inside cells and secreted into the extracellular space. Conversion of normal tau protein overlying two microtubules into paired helical filaments. Overactive kinase(s) or hypoactive phosphatase(s) may contribute to this effect. Abnormally phosphorylated tau loses the ability to bind microtubules, thus causing their depolymerization, disruption of axonal transport and degeneration of neurons. Clinical Features • • • • • • Slow-onset of memory loss Progressive disorientation Loss of learned motor skills and language Behavior and personality changes Patients become mute and bedrdden Focal neurologic deficits not seen early Risk Factors Sporadic form of AD a. Age b. Presence of E4 allele of ApoE (E2 allele decreases risk) Early form of AD: a. Presenillin 1 (MC) and 2 b. Down Syndrome due to APP is on the chromosome 21 Vascular Dementia • Due to multifocal infarction and injury • Due to Hypertension, Atherosclerosis or Vasculitis • Second most common cause of dementia!!!!! • Better prognosis, partially reversible Pick’s Disease Pick’s disease occurs far less frequently than Alzheimer’s disease but is also clinically manifested as profound dementia over a comparable time course. The brain in Pick’s disease invariably exhibits a pronounced atrophy of the frontal and temporal lobes with conspicuous sparing of the posterior two-thirds of the superior temporal gyrus The atrophy can be severe, reducing the gyri to a thin wafer (“knife-edge” appearance). Behavioral and language symptoms arise early; progress to dementia Pick’s Disease Microscopically: Neuronal loss is most severe in the outer three layers of the cortex and may be severe enough to resemble superficially (pseudo)laminar necrosis Round aggregates of Tau protein (not tangles as in AD!!!!) in neurons (Pick cells or Pick bodies) Degenerative Diseases of Basal Ganglia and Brain Stem Diseases affecting these regions of the brain frequently are associated with movement disorders, including rigidity, abnormal posturing, and chorea. In general, they can be categorized as manifesting either: – A reduction of voluntary movement – An abundance of involuntary movement. The nigro-striatal pathway plays an important role in the system of positive and negative regulatory synaptic pathways that serve to modulate feedback from the thalamus to the motor cortex. – – – – – Parkinsonism Idiopathic Parkinson’s Disease (IPD) Progressive Supranuclear Palsy Multiple System Atrophies Huntington’s Disease Normal interactions between nigra-striatal complex and cortex of the brain SN Pc Substantia Nigra parts compacta Dopamine BG (STRIATUM) D2 D1 Dopamine receptors increase stimulation Dopamine receptors Decrease inhibition Cortex Parkinsonism Parkinsonism is a clinical syndrome characterized by – – – – – – – – Tremor “Pill-rolling” tremor Rigidity Akinesia/Bradikynesia Postural instability and shuffling gait Diminished facial expression Stooped posture Slowness of voluntary movement Festinating gait (progressively shortened, accelerated steps) This type of motor disturbance is seen in a number of conditions that have in common damage to the nigrostriatal dopaminergic system Parkinsonism may also be induced by drugs that affect this system – Dopamine antagonists – Toxins (notably, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine [MPTP ]) The principal diseases that involve the nigrostriatal system are – Idiopathic Parkinson’s disease – Striatonigral degeneration – Lewy body dementia Idiopathic Parkinson’s Disease (IPD) Patients with progressive parkinsonism in the absence of a toxic or other known etiology. As in Alzheimer’s disease, it is seen with increasing frequency in older age cohorts. In addition to the movement disorder, there are other less well-characterized changes in mental function, and a few patients with the pathologic findings of idiopathic Parkinson’s disease present with a dementia clinically similar to that of Alzheimer’s disease. Idiopathic Parkinson’s Disease The dopaminergic neurons of the substantia nigra project to the striatum, and their degeneration in Parkinson’s disease is associated with a reduction in the striatal dopamine content. The severity of the motor syndrome is proportional to the dopamine deficiency Can be partly corrected by replacement therapy with L-dopa (the immediate precursor of dopamine) Treatment does not, however, reverse the morphologic changes or arrest the progress of the disease, and with progression, drug therapy tends to become less effective, and symptoms become more difficult to manage. Idiopathic Parkinson’s Disease The most dramatic recent development in the treatment of IPD has been in the field of neural transplantation. Stereotactic implants of fetal mesencephalic tissue into the striatum Morphology Pathologically, the typical gross findings are pallor of the substantia nigra and locus ceruleus Microscopically Loss of the pigmented, catecholaminergic neurons in these regions associated with gliosis Lewy bodies may be found in some of the remaining neurons – These are intracytoplasmic, eosinophilic, round to elongated inclusions that often have a dense core surrounded by a paler rim – contain alphasynuclein protein!!!! • Normal Substantia Nigra Depigmented Substantia Nigra Lewy Body in Substantia Nigra Dementia and Parkinson disease Early-onset dementia suggests Lewy body dementia disease: A. Early dementia B. Hallucinations!!!!! C. Parkinsonism D. Lewy bodies (filled with a-synuclein) in the cortex of brain!!! Progressive Supranuclear Palsy Usually present with loss of vertical gaze Progressing to difficulty with all eye movements Associated with – Truncal rigidity – Dysequilibrium – Loss of facial expression – Progressive dementia Onset: fifth and seventh decades Male: females = 2:1 Death occurs often within 5 to 7 years Huntington’s Disease Appears between 20 and 50 years of age Degeneration of GABAergic neurons in caudate nucleus of basal ganglia AD, Caucasians Uncontrolled movements and progressive dementia Chorea – Jerky, hyperkinetic, sometimes dystonic movements affecting all parts of the body – ATHETOSIS!!!! May later develop parkinsonism with bradykinesia and rigidity. Early signs of higher cortical dysfunction – Forgetfulness and thought and affective disorders DEPRESSION, SUICIDE high rate – An average course of about 15 years to death. Morphology Gross examination: Brain is small Striking atrophy of the caudate nucleus and putamen Lateral and third ventricles are dilated Microscopically: Severe loss of striatal neurons Huntington’s Disease Hydrocephalus Ex vacuo Internal capsule Corpus Striatum GABA!!! Caudate Nucleus Putamen Nucleus • Normal Cerebral Hemisphere (left) • Atrophy of Striatum and ventricular dilatation (Right) Huntington’s Disease Expanded trinucleotide repeats (CAG) Huntingtin gene (Ch.4) Future expansion occurs during spermatogenesis (meiosis) Anticipation effect (grandfather, father and son – 60, 50 and 40 years manifestation of disease, respectively) Normal Pressure Hydrocephalus • Increased CSF results in dilated ventricles • Causes dementia in adults • Arachnoid granulations defect to absorb excess of CSF • Stretching of corona radiata Clinical: triad of Urinary Incontinence, Gait Instability, Dementia Lumbar Puncture improves symptoms Treatment: Ventriculo-peritoneal shunting` A 5-year-old boy is brought to the physician after he was hit in the head with a baseball The incident occurred about two hours ago He had no loss of consciousness, but was a little dazed after being hit However he seemed to improve after a short time About 30 minutes ago. the patient began to complain of a headache vomited twice, and is currently not acting nght according to his parents On examination, the child is sleepy and his left pupil is larger than his nght A CT scan of his head is shown below. Which of the following is the most appropriate next step in management? A Cerebral angiogram B MRI of the brain C Repeat CT in 24 hours D Dexamethasone E Emergent craniotomy PRIONS •PrP found in neurons (PrPc – normal protein) •Role of PrP in the cell –it is platform for the assembly of signaling modules •Conformational changes in the protein structure (misfolding) makes it resistant to action of proteases •Misfolded PrP turns normal protein into misfolded PrP Cause transmissable diseases -Transmissable spongioform encephalopathies: •Kuru disease (cannibalism) •Creutzfeldt-Jakob disease (from cattle to human) •Fatal familial insomnia •Way of infection: via blood products, organ transplant, surgery, meat products Pathogenesis of Prion Diseases Prion protein (PrP) is normally found in neurons and has an a-helical structure. If the conversion of a-helix into beta- pleated sheet occurs the protein becomes resistant to proteases. Accumulation of this abnormal protein in gray matter is most likely causing prion diseases Prion Diseases, Common Features: 1. They are associated with an abnormal prion protein (PrP). This protein is normally present in host neurons. A change in its secondary structure renders it resistant to enzymatic digestion by proteases and leads to its accumulation 2. These diseases have long incubation periods. However they are rapidly progressive after the onset of clinical symptoms 3. Characteristic morphologic changes in brain are described as spongiform encephalopathy 4. Vacuoles form in the cytoplasm of the neutrophils and neurons. As the disease progresses, the vacuolated areas transform into cysts. 5. No inflammatory changes are present 6. There is no treatment for prion diseases. These conditions are invariably fatal Vacoulization (sponginess) of CNS tissue is the consistent diagnostic finding Bovine Spongiform Encephalitis, Creutsfeldt-Jakob Disease Q: PrP is a normal cellular protein found in neurons that has an a-helical secondary structure. In some patients, this protein undergoes a conformational change to a β-pleated sheet isoform, making it highly resistant to proteases, thus causing intracellular accumulation. Which of the following best describes histological changes that may be seen in the brain of these patients? A. Cytoplasmic inclusions in oligodendrocytes B. Neurofibrillary tangles and neocortical plaques C. Microglial nodules and multi nucleated giant cells D. Patches of white matter destruction E. Spongiform transformation of gray matter Creutzfeldt-Jakob disease, Clinical Presentation • • • • • Rapidly progressive dementia Startle Myoclonus, Ataxia Spike-wave complexes seen on EEG Death in <1 year May be history of transplant or usage extracts of Hypophysis A 42-year-old Caucasian male treated for impaired vision develops rapidly progressive dementia and myoclonic jerks. He lapses into a coma and dies six months later. A sample of brain tissue shows gray matter changes with many uniform vacuoles between neuron cell bodies and in the perikaryon of neurons. No inflammatory changes are present. This patient most likely suffered from: A. Myastenia gravis B. Bacterial Meningitis C. Creutzfeldt-Jakob disease D. Multiple sclerosis Other Prion Diseases Variant CJD – due to exposure to bovine spongioform encephalopathy (beef meat) in young people Familial fatal insomnia – inherited form of prion disease – insomnia + exaggerated startle response (The startle response or startle reaction is a response to sudden, startling stimuli, such as sudden noise or sharp involves flexion of most skeletal muscles and a variety of visceral reactions ) Spinocerebellar Degenerations Group of diseases affecting the cerebellar cortex, spinal cord, peripheral nerves Pathologically: – Degeneration of the neurons in the affected areas Clinically: – Combination of cerebellar and sensory ataxia – Spasticity – Peripheral motor and sensory defects Types: Paraneoplastic cerebellar degeneration Alcoholic cerebellar degeneration also predominantly affects Purkinje cells, especially in the superior vermis Friedreich’s Ataxia (FA) Ataxia-Telangiectasia Friedreich’s Ataxia Autosomal recessive condition Frataxin gene (iron and mitochondrial metabolism) accumulation of GAA repeats Male preponderance Average age at onset of about 11 years Symptoms – – – – – – – Gait ataxia Hand clumsiness Dysarthria Deep tendon reflexes are absent Extensor plantar reflex is typically present Joint position and vibratory sense are impaired Most patients become paralyzed over the course of about 20 years There is a high incidence of concomitant diabetes and cardiac disease – Manifests as cardiac arrhythmias and Cardiomyopathy (congestive heart failure) Ataxia-Telangiectasia Autosomal recessive disease Presents in childhood Loss of cerebellar function in the setting of recurrent infections. Neurologic signs appear before the appearance of the numerous telangiectatic lesions in conjunctiva and in other areas. Pathologic findings: Predominantly in the cerebellum – Loss of Purkinje and granule cells Systemic findings: – Absence of a thymus as well as hypoplastic gonads. Strong tendency for lymphoid malignancy Degenerative Diseases Affecting Motor Neurons Amyotrophic Lateral Sclerosis (ALS) ALS is a degenerative disease of upper and lower motor neurons of the brain and spinal cord, with progressive weakness and wasting of the extremities and tongue, a sometimes confusing combination of hyperreflexia and hyporeflexia and eventual impairment of respiratory muscles. Patients have loss of both – Lower motor neurons Muscular atrophy Fasciculations Weakness – Upper motor neurons Hyperreflexia Spasticity Babinski reflex Men > women Amyotrophic Lateral Sclerosis (ALS) Autosomal Dominant inheritance pattern in 5% cases Mutation in SOD1 – free radical detoxifying enzyme Intellectual capacities preserved