Pathology of CNS degenerations


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Pathology of CNS degenerations

  1. 1. “ Each individual creature on this beautiful planet is here to fulfill a particular role. We are all born with a divine fire in us. Our efforts should be to give wings to this fire and fill the world with the glow of its goodness. - Wings of Fire : An Autobiography of Dr. APJ Abdul Kalam (1999)
  2. 2. CPC 4.3.5 – Helena, 65y Fem. <ul><li>Helena is a 65 year old married local GP. She is known as a ‘ pillar of the community ’ and works full time as the senior partner at a GP surgery in Townsville. She is actively involved in many GP related educational activities. Her husband, Brad, is a local orthopedic surgeon. Although you have been their GP for sometime, they seldom consult you. Today they have booked a double appointment with you. </li></ul><ul><ul><li>Brad : ‘ I’ve come with Helena to discuss some memory problems she seems to be having ’ </li></ul></ul><ul><ul><li>Helena : “ I hope it’s nothing ; Brad has always been a worrier’ </li></ul></ul>
  3. 3. CPC 4.3.5 – Helena, 65y Fem. <ul><li>I haven’t been sleeping so well so I think my memory is a bit worse- it’s a combination of stress and fatigue’ </li></ul><ul><li>she can’t remember where she parked the car </li></ul><ul><li>She has forgotten social arrangements several times </li></ul><ul><li>Couldn’t remember their names … </li></ul><ul><li>she is struggling with organizing … </li></ul>
  4. 4. CPC 4.3.5 – Helena, 65y Fem. <ul><li>Duration of symptoms: ? about 6/12 </li></ul><ul><li>Mood: low, quite tearful at times ; not enjoying life much </li></ul><ul><li>Concentration: poor , struggling to read books/journal.. </li></ul><ul><li>Sleep: disrupted , often up during early hours of morning. </li></ul><ul><li>Appetite and weight: no change </li></ul><ul><li>I am very tired . It’s probably time for me to retire .’ </li></ul>
  5. 5. CPC 4.3.5 – Helena, 65y Fem. <ul><li>Physical Examination: NAD . </li></ul><ul><li>Cranial nerves, muscle power & tone, sensation & reflexes normal . </li></ul><ul><li>Co-ordination + proprioception normal bilaterally </li></ul><ul><li>MMSE : 30/30 ? , K10 : 36/50 ? </li></ul><ul><li>Word list task : recall of 2 words after 20 minutes …? </li></ul>
  6. 6. CPC 4.3.5 – Helena, 65y Fem. <ul><li>Differential diagnoses: Dementia </li></ul><ul><ul><li>Depression – reactive? </li></ul></ul><ul><ul><li>Age related Mild cognitive impairement? </li></ul></ul><ul><ul><li>Hormonal e.g. hypothyroidism , drugs etc. </li></ul></ul><ul><ul><li>Alzheimer’s Disease ? </li></ul></ul><ul><li>Physical Examination… </li></ul><ul><li>Investigations: </li></ul><ul><ul><li>FBC, Liver FT & Thyroid FT normal, </li></ul></ul><ul><ul><li>HIV negative. (?) </li></ul></ul><ul><ul><li>CT scan : no space occupying lesion; ?some loss of grey matter with increased ventricular space. </li></ul></ul>
  7. 7. Brain: Functional areas. Memory
  8. 8. Brocas area (1878) consists primarily of cingulate and parahippocampal gyri.
  9. 9. Hippocampus: where short-term memories are converted to long-term memories Thalamus : receives sensory and limbic information and sends to cerebral cortex Hypothalamus : monitors and controls internal clock & other activities. Limbic system : controls emotions and instinctive behavior (includes the hippocampus and parts of the cortex) Functional Neuro Anatomy Slide 8
  10. 10. Dendritic tree - vs - Intelligence Rat CA1 pyramidal cell labeled with EGFP (Two photon laser scanning microscopy) Synaptic bouton in rat CA1 stratum radiatum (Electron microscopy)
  11. 11. What is Success? &quot;To laugh often and much; to win the respect of intelligent people and the affection of children. To leave the world a better place. To know even one life has breathed easier because you have lived… that is success..! -- Ralph Waldo Emerson
  12. 12. Pathology of C.N.S. Degenerative Disorders Dr. Venaktesh M. Shashidhar A/Prof. & Head of Pathology James Cook University
  13. 13. Age related / Senile degeneration: <ul><li>Dementia: All spheres of intellect affected. </li></ul><ul><li>Decreasing mass - Slow 4th decade – rapid 7th decade. </li></ul><ul><li>progressive neuronal loss Neuronophagia . (hippocampus and cerebral cortex) </li></ul><ul><li>reduction in size & numbers of dendritic branches in surviving neurones </li></ul><ul><li>Cortical atrophy, hydrocephalus. </li></ul><ul><li>Thickening of leptomeninges. </li></ul><ul><li>NF tangles, A β Amyloid plaques. </li></ul><ul><li>increase in number of astrocytes </li></ul><ul><li>Athero & artero sclerosis. </li></ul>
  14. 14. CNS Degenerations: Classification <ul><li>Neuronal Degenerations. </li></ul><ul><ul><li>Primary Degenerations: </li></ul></ul><ul><ul><ul><li>Global – Alzheimer & Lewibody </li></ul></ul></ul><ul><ul><ul><li>Selective/System – Parkinsons , Huntingtons , MND </li></ul></ul></ul><ul><ul><li>Secondary Degenerations: </li></ul></ul><ul><ul><ul><li>Toxic, metabolic(storage), infections, nutritional. </li></ul></ul></ul><ul><ul><ul><li>Alcohol & B12 def. </li></ul></ul></ul><ul><li>Disorders of Myelin: </li></ul><ul><ul><li>Demyelinating Disorders - Multiple sclerosis </li></ul></ul><ul><ul><li>Dysmylinating disorders – Leukodystrophies. </li></ul></ul>
  15. 15. Dementia: <ul><li>Acquired global impairment of intellect-intact consciousness </li></ul><ul><li>> 15% of adults over 80 are demented…! (>30y, >70y…!) </li></ul><ul><li>Primary & secondary dementias </li></ul><ul><li>Primary: </li></ul><ul><ul><li>Alzheimer's disease </li></ul></ul><ul><ul><li>Diffuse Lewy body disease, Huntington's Dis, Pick's, </li></ul></ul><ul><li>Secondary: </li></ul><ul><ul><li>Cerebrovascular disease – stroke. </li></ul></ul><ul><ul><li>Infections (e.g. Creutzfeldt-Jakob, syphilis, HIV) </li></ul></ul><ul><ul><li>Neoplasms, haematoma, hydrocephalus. </li></ul></ul><ul><ul><li>drugs and toxins (barbiturates, digoxin , alcohol, heavy metals) </li></ul></ul><ul><ul><li>metabolic disorders (e.g. hypothyroidism, hypoparathyroidism, uraemia, hepatic failure) </li></ul></ul><ul><ul><li>vitamin deficiencies (e.g. B1-Wernicke-Korsakoff sy., B2, B12) </li></ul></ul>
  16. 16. Alzheimer’s disease: <ul><li>Commonest cause of dementia in elderly </li></ul><ul><li>insidious with mood and behavior change. </li></ul><ul><li>Prevalence 1% in 6 th to >40% 8 th decade. </li></ul><ul><li>Pathology: </li></ul><ul><ul><li>Significant cortical atrophy </li></ul></ul><ul><ul><li>secondary ventricular enlargement </li></ul></ul><ul><ul><li>Neurofibrillary tangles – Intracellular ( Tau ) </li></ul></ul><ul><ul><li>Neuritic plaques ( A β amyloid ) – Extracellular. </li></ul></ul><ul><ul><li>Amyloid angiopathy. </li></ul></ul>
  17. 17. Aloysius Alzheimer: <ul><li>German Psychiatrist. </li></ul><ul><li>1901 - Auguste Deter </li></ul><ul><ul><li>51 year male Patient. </li></ul></ul><ul><ul><li>Behavioural abnormality </li></ul></ul><ul><ul><li>Short term memory loss </li></ul></ul><ul><li>Colleague Franz Nissl </li></ul><ul><ul><li>silver stain. </li></ul></ul><ul><ul><li>Observed amyloid plaques & NF tangles. </li></ul></ul><ul><li>Case Presented at Berlin 1906. </li></ul><ul><li>International Brain Research Organization. </li></ul>Aloysius Alzheimer’s first Patient
  18. 18. Alzheimer’s – Pathogenesis: <ul><li>Deposition of neurotoxic amyloid protein (peptide Aβ derived from APP) around blood vessels & neurons – extracellular plaques </li></ul><ul><li>Abnormal forms of axonal microtubule protein (protein tau) in neurons ‘neurofibrillary intracellular tangles ’ </li></ul><ul><li>Leading to Atrophy of neurons, gliosis. </li></ul>
  19. 19. Alzheimers Disease: Cortical Atrophy Neurofibrillary tangles & Extraneuronal Neuritic plaques
  20. 20. Alzheimer’s disease: Genetics <ul><li>Autosomal dominant genetic pattern – rare. </li></ul><ul><li>4 genes on chromosomes 1, 14, 19, and 21, influence initiation and progression. </li></ul><ul><li>Chromosome 21 generates the precursor protein for the amyloid protein (APP). Trisomy 21 produces early Alzheimer's disease in persons with Down syndrome. </li></ul><ul><li>Chromosome 19 generates apolipoprotein (apo) 3 allelic forms ε 2, ε 3, and ε 4, resulting in six combinations, of these risk for Alzheimer's disease is high with ε 4/ ε 4 & low with ε 2/ ε 2. </li></ul>
  21. 21. Generation of Amyloid ( Aβ) Plaque Normal
  22. 22. Alzheimer’s - Amyloid Angiopathy Cerebrum stained with polyclonal antibody against βA4 peptide showing amyloid deposits in plaques in brain substance (arrow A) and in blood vessel walls (arrow Amyloid core Dystrophic neurites
  23. 23. <ul><ul><li>Neurofibrillary Tangles </li></ul></ul>Neurons have an internal support structure partly made up of microtubules. A protein called tau helps stabilize microtubules. In AD, tau changes, causing microtubules to collapse, and tau proteins clump together to form neurofibrillary tangles. Slide 18
  24. 24. Neurofibrillary Tangles in AD: C: Neurofibrillary tangles (arrowheads) are present within the neurons (H & E). D: Silver stain showing a neurofibrillary tangle within the neuronal cytoplasm
  25. 25. Alzheimer’s - Amyloid Angiopathy Congo Red stain & Polarised Microscopy showing apple green” birefringence
  26. 26. Neuron degeneration- granulovcuolar. Several neurons display granulovacuolar degeneration of the cytoplasm. B. A neuron (center) contains an eosinophilic Hirano body (arrow).
  27. 27. Cerebral atrophy in Alzheimer's: A-Neuritic Plaque, B-Amyloid
  28. 28. Cerebral atrophy in Alzheimer's:
  29. 29. Knife blade Fronto-temporal atrophy in Picks.
  30. 30. Cerebral atrophy in Alzheimer's:
  31. 31. Cerebral atrophy in Alzheimer's:
  32. 32. Cerebral atrophy in Alzheimer's: Severe cortical atrophy, narrow gyri, wider sulci. White matter loss leading to dilated ventricles (compensatory hydrocephalus). Hippocampus Atrophy
  33. 33. <ul><li>Degenration starts in the entorhinal cortex, then proceed to hippocampus. </li></ul><ul><li>Neuronal loss leads to shrinkage. </li></ul><ul><li>Changes can begin 10-20 years before symptoms appear. </li></ul><ul><li>Memory loss is the first sign of AD. </li></ul>AD Morphology – Early / Preclinical Slide 20
  34. 34. <ul><li>Involves cerebral cortex </li></ul><ul><li>Mild signs: M emory loss, confusion, trouble handling money, poor judgment, mood changes, and anxiety. </li></ul><ul><li>Moderate signs: increased memory loss and confusion, problems recognizing people, difficulty with language and thoughts, restlessness, agitation, wandering, and repetitive statements. </li></ul>AD Morphology - Mild to Moderate Slide 21
  35. 35. <ul><li>Extreme shrinkage of brain. </li></ul><ul><li>Patients are completely dependent on others for care. </li></ul><ul><li>Symptoms: weight loss, seizures, skin infections, groaning, moaning, or grunting, loss of bladder and bowel control. </li></ul><ul><li>Death usually occurs from aspiration pneumonia or other infections. </li></ul>AD Morphology: Severe AD Slide 22
  36. 36. Neurofibrillary Tangles in AD: Plaque around Blood Vessels. Neurofibrillary Tangles -Intracellular A β Protein Amyloid tau protein – Microtubule.
  37. 37. AD & Intelligence.… <ul><li>In early life, higher skills in grammar and density of ideas are associated with protection against AD in late life. </li></ul><ul><li>Mentally stimulating activity protects against AD. </li></ul><ul><li>Use it or loose it…..! </li></ul>
  38. 38. Pick’s Disease: <ul><li>Severe, 40-65y. Rare. </li></ul><ul><li>Frontal & temporal lobes. </li></ul><ul><li>Progressive aphasia, personality change. </li></ul><ul><li>Relatively preserved memory. </li></ul>
  39. 39. Picks Disease: Knife blade Fronto-temporal atrophy
  40. 40. Pick’s Disease: <ul><li>Gross: Gyral atrophy of frontal and parietal lobes. </li></ul><ul><li>Micro: Hippocampus stained with anti-tau antibody. Many neuronal cell bodies contain sharply circumscribed, spherical cytoplasmic inclusion bodies (Pick bodies) </li></ul>
  41. 41. CNS Degenerations: Classification <ul><li>Neuronal Degenerations. </li></ul><ul><ul><li>Primary Degenerations: </li></ul></ul><ul><ul><ul><li>Global – Alzheimer & Lewibody </li></ul></ul></ul><ul><ul><ul><li>Selective/System – Parkinsons , Huntingtons , MND </li></ul></ul></ul><ul><ul><li>Secondary Degenerations: </li></ul></ul><ul><ul><ul><li>Toxic, metabolic(storage), infections, nutritional. </li></ul></ul></ul><ul><li>Disorders of Myelin: </li></ul><ul><ul><li>Demyelinating Disorders - Multiple sclerosis </li></ul></ul><ul><ul><li>Dysmylinating disorders – Leukodystrophies. </li></ul></ul>
  42. 42. Systemic Degenerations: <ul><li>Degeneration in functionally related areas of the CNS </li></ul><ul><li>Neuronal death  neuronophagia  fibrillary gliosis </li></ul><ul><li>Dementia: Intellectual disability. </li></ul><ul><li>Several types with overlapping features: </li></ul><ul><li>Many show neurotransmitter abnormalities (Parkinsons, Alzheimers ) </li></ul><ul><li>Mostly unknown Aetiology , some genetic (Friedreich‘s) </li></ul>
  43. 43. Huntington’s <ul><li>Dementia, depression, choreiform movement ( Jerking dementia ) </li></ul><ul><li>5 th decade. Autosomal dom. </li></ul><ul><li>Huntington gene on 4p </li></ul><ul><li>Excess CAG tandem repeats = severity. </li></ul><ul><li>Atrophy of caudate & putamen with compensatory hydrocephalus of lateral ventricles. </li></ul>
  44. 44. Huntington’s
  45. 45. Normal - Huntington’s Striatum Atrophy
  46. 46. Huntington’s
  47. 47. Huntington’s
  48. 48. Parkinson’s disease <ul><li>&quot;shaking palsy&quot; </li></ul><ul><li>Disease of substantia nigra - dopaminergic system in the and corpus striatum </li></ul><ul><li>Clinical features: </li></ul><ul><ul><li>tremor, bradykinesia and rigidity (45-60 years) </li></ul></ul><ul><ul><li>inhibition of movement & dementia in some cases. </li></ul></ul><ul><ul><li>Diminished facial expressions, stooped posture, decreased voluntary movements, festinating gait, rigidity & fine rolling tremors. </li></ul></ul>
  49. 49. Parkinson’s disease <ul><li>Common Causes: </li></ul><ul><ul><li>Idiopathic (? free radical-induced oxidative damage) </li></ul></ul><ul><ul><li>Post-encephalitic </li></ul></ul><ul><ul><li>Post-traumatic </li></ul></ul><ul><ul><li>Ischaemia </li></ul></ul><ul><ul><li>Drug-induced (heroin) </li></ul></ul><ul><ul><li>Toxic damage (CO, manganese poisoning) </li></ul></ul>
  50. 50. Pathology <ul><li>Pallor of the substantia nigra </li></ul><ul><li>Decrease in number of pigmented neurones </li></ul><ul><li>Other neurones in the same region show shrinkage and vacuolation </li></ul><ul><li>Loss of neurons replaced by macrophage </li></ul><ul><li>Marked degree of astrocyte gliosis. </li></ul><ul><li>Lewy bodies (hyaline bodies) </li></ul>
  51. 51. Parkinson’s: The pigmented neurones in the substantia nigra within the midbrain degenerate and die off in Parkinson's disease, giving a pale appearance in comparison to an age-matched normal control. Normal Parkinson’s
  52. 52. Parkinson’s: Surviving neurone in the substantia nigra contains an intracytoplasmic Lewy body (L). Normal
  53. 53. Parkinsons disease: Lewy body
  54. 54. Vascular Dementia: (Multi-infarct) <ul><li>Second most common after AD. Different from senile dementia. </li></ul><ul><li>Different pathophysiological types. </li></ul><ul><ul><li>Mild vascular cognitive impairment – artereosclerosis. </li></ul></ul><ul><ul><li>Multi-infarct / single large infarct </li></ul></ul><ul><ul><li>Hypertensive lacunar lesions. </li></ul></ul><ul><ul><li>Binswanger disese – subcortical leukoencephalopathy - boxers, trauma. </li></ul></ul><ul><ul><li>Mixed – AD+vascular. </li></ul></ul>
  55. 55. System Degenrations: Unknown Ataxia Sensory loss Tremor Orthostatic hypotension Substantia nigra Purkinje cells Pontine nuclei Spinal autonomic nuclei Multiple system atrophy ( Shy-Drager syndrome ) CAG triplet expansion in gene on 12p Chorea Myoclonic epilepsy Dementia Autosomal dominant inheritance Dentate nucleus Globus pallidus Subthalamus Red nucleus Dentatorubro-pallidoluysial atrophy ( DRPLA ) CAG triplet expansion in ataxin-1 gene on 6p Ataxia Nystagmus Autosomal dominant inheritance Purkinje cells Granular neurones Inferior olivary nuclei Autosomal dominant cerebellar ataxia type 1 CAA triplet expansion in frataxin gene on 9q Ataxia Sensory loss Deafness Autosomal recessive inheritance Spinal cord Sensory nuclei Cerebellum Friedreich's ataxia Genetic basis Clinical features Sites affected Disease
  56. 56. The only real mistake is the one from which we learn nothing. JOHN POWELL:
  57. 57. CNS Degenerations: Classification <ul><li>Neuronal Degenerations. </li></ul><ul><ul><li>Primary Degenerations: </li></ul></ul><ul><ul><ul><li>Global – Alzheimer & Lewibody </li></ul></ul></ul><ul><ul><ul><li>Selective/System – Parkinsons , Huntingtons , MND </li></ul></ul></ul><ul><ul><li>Secondary Degenerations: </li></ul></ul><ul><ul><ul><li>Toxic, metabolic(storage), infections, nutritional. </li></ul></ul></ul><ul><li>Disorders of Myelin: </li></ul><ul><ul><li>Demyelinating Disorders - Multiple sclerosis </li></ul></ul><ul><ul><li>Dysmylinating disorders – Leukodystrophies. </li></ul></ul>
  58. 58. Demyelinating Disorders: <ul><li>Selective myelin damage - axon sparing. </li></ul><ul><li>Defective transmission of impulse. </li></ul><ul><li>Prognosis  repair & axon damage. </li></ul><ul><li>Types & Classification </li></ul><ul><ul><li>Immune – Multiple sclerosis </li></ul></ul><ul><ul><li>Genetic – Metabolic, Leukodystrophy. </li></ul></ul><ul><ul><li>Vitamin deficiency – Vit B12 </li></ul></ul><ul><ul><li>Infections – JC virus </li></ul></ul>
  59. 59. Multiple Sclerosis <ul><li>Commonest. CNS only. </li></ul><ul><li>Autoimmune ( Gen+Env+AI ) </li></ul><ul><li>Limb Weakness, paraesthesia </li></ul><ul><li>Relapsing & remitting. </li></ul><ul><li>Progressive  death in years. </li></ul><ul><li>Multiple soft pink plaques of demyelination- periventricular. </li></ul><ul><li>Inflammation, perivascular T lymphocytes & plasma cells. </li></ul><ul><li>CSF - oligoclonal IgG. </li></ul><ul><li>Reactive gliosis. </li></ul>
  60. 60. Multiple Sclerosis Plaque: Section of fresh brain showing brown plaque around occipital horn of the lateral ventricle.
  61. 61. Multiple Sclerosis: Demyelinated plaques Microscopy showed loss of myelination with many lipid macrophages.
  62. 62. Multiple Sclerosis - plaques
  63. 63. Multiple Sclerosis - plaques
  64. 64. MS – Periventricular plaque MS Like patches of grey matter within white matter…! Normal
  65. 65. MS- Plaques – Myelin stain.
  66. 66. Multiple Sclerosis – Chronic plaque <ul><li>Sharp area of myelin loss (white area in this blue myelin stain) </li></ul><ul><li>Plaque contain fibrillary astrocytes. A few lymphocytes and macrophages are present around blood vessels (V) </li></ul><ul><li>Normal myelinated white matter appears blue. </li></ul>
  67. 67. Metabolic CNS Disorders: <ul><li>Alcoholism induced CNS disorders: </li></ul><ul><ul><li>Wernicke syndrome (vit B1 def.) </li></ul></ul><ul><ul><li>Central pontine myelinolysis </li></ul></ul><ul><ul><li>Cortical atrophy </li></ul></ul><ul><ul><li>Atrophy of vermis of the cerebellum </li></ul></ul>
  68. 68. Wernicke's encephalopathy: Recurrent petechial hemorrhages in the hypothalamus, mamillary bodies with atrophy. Wernicke’s Sy: Altered Thermal regulation & consciousness, ophthalmoplegia, nystagmus. Korsokoff Psychosis: Loss of recent memory compensated by confabulation.
  69. 69. Korsakoff's disease: Note: Shrunken, bodies brown mammillary bodies indicating chronic stage or Korsakoff's disease. Central pontine myelinolysis. Demyelination of the center of the basis pontis. Cause is unknown but is usually in chronic alcoholics and is often associated with rapid over-correction of hyponatremia. Alcoholic cerebellar atrophy. Shrunken folia and widened fissures of the anterior, superior vermis of the cerebellum. Another change which may be found in chronic alcoholics.
  70. 70. Kernictirus – Neonatal hyperbilirubinemia <ul><li>Kern+Ictirus – yellow nuclei. </li></ul><ul><li>Complication of Neonatal jaundice. </li></ul><ul><ul><li>Polycythemia, </li></ul></ul><ul><ul><li>Hemolytic disease of new born. </li></ul></ul><ul><ul><li>Hemolytic anemia. </li></ul></ul>
  71. 71. Pathology of CNS degenerations: Intracytoplasmic α-Synuclein Lewy bodies Parkinson disease Intracytoplasmic tau Glial inclusions Multiple system atrophy Intracytoplasmic tau Neurofibrillary tangles Frontotemporal dementias (Pics disease) Intracytoplasmic α-Synuclein Lewy bodies Dementia with Lewy bodies Intracytoplasmic Neurofilament subunits/super-oxide dismutase (SOD-1) Spheroids Amyotrophic lateral sclerosis Extracellular Intracytoplasmic β-Amyloid tau Senile plaques & Neurofibrillary tangles Alzheimer disease Location Components Lesion Disease
  72. 72. Anybody who thinks money will make you happy, hasn't got it….!
  73. 73. CPC-3.6– CNS –Degenerations <ul><li>Pathology - Core Learning Issues: </li></ul><ul><ul><li>Pathology & Pathogenesis of common Dementias/CNS degenerations. </li></ul></ul><ul><ul><li>Overview of rare forms of degenerative CNS disorders. </li></ul></ul><ul><ul><li>Dementia diagnosis & Laboratory investigations. </li></ul></ul><ul><li>Basic science - Core Learning Issues: </li></ul><ul><ul><li>Structure and function of brain </li></ul></ul><ul><ul><li>Areas of brain dealing with higher cognitive function </li></ul></ul><ul><ul><li>Age related changes in structure & function of brain. Senile dementia. </li></ul></ul>
  74. 74. 38y recurrent limb weakness ? Diagnosis <ul><li>Multiple sclerosis </li></ul><ul><li>Parkinsons </li></ul><ul><li>Alzheimer’s </li></ul><ul><li>Huntington’s </li></ul><ul><li>Pick’s disease </li></ul>
  75. 75. 38y depression, chorea ? Diagnosis <ul><li>Multiple sclerosis </li></ul><ul><li>Parkinsons </li></ul><ul><li>Alzheimer’s </li></ul><ul><li>Huntington’s </li></ul><ul><li>Pick’s disease </li></ul>
  76. 76. A 45-year-old woman is brought to the emergency room after experiencing a generalized seizure. An x-ray film of the skull reveals a lytic bone mass. A portion of the skull and the adherent mass are removed. Microscopic image of tumor is shown. Most likely diagnosis? <ul><li>Glioblastoma multiforme </li></ul><ul><li>Hemangioblastoma </li></ul><ul><li>Medulloblastoma </li></ul><ul><li>Meningioma </li></ul><ul><li>Oligodendroglioma </li></ul>
  77. 77. A 56-year-old man is rushed to the emergency room after collapsing while shoveling snow. The patient has no pulse on admission but is resuscitated. Laboratory studies show elevated serum levels of cardiac-specific proteins, and ECG confirms a transmural infarct of the left ventricle. The patient expires 2 weeks later of cardiac tamponade. Examination of the patient's brain at autopsy would most likely reveal necrosis of Purkinje cells and selective loss of neurons in which of the following regions? <ul><li>Frontal lobes </li></ul><ul><li>Hippocampus </li></ul><ul><li>Hypothalamus </li></ul><ul><li>Occipital lobes </li></ul><ul><li>Thalamus </li></ul>
  78. 78. 38y female recurrent limb weakness. Image shows white mater stained for myelin. ? Diagnosis <ul><li>Multiple sclerosis </li></ul><ul><li>Parkinsons </li></ul><ul><li>Alzheimer’s </li></ul><ul><li>Huntington’s </li></ul><ul><li>Pick’s disease </li></ul>
  79. 79. 78y Male dementia, amyloid stain ? Diagnosis <ul><li>Multiple sclerosis </li></ul><ul><li>Parkinsons </li></ul><ul><li>Alzheimer’s </li></ul><ul><li>Multi-infarct dementia </li></ul><ul><li>Pick’s disease </li></ul>
  80. 80. 38y recurrent limb weakness ? Diag <ul><li>Multiple sclerosis </li></ul><ul><li>Parkinsons </li></ul><ul><li>Alzheimer’s </li></ul><ul><li>Huntington’s </li></ul><ul><li>Pick’s disease </li></ul>
  81. 81. A 60-year-old man with a 15-year history of diabetes mellitus type II complains of deep burning pain and sensitivity to touch over his hands and fingers. Nerve conduction studies show slow transmission of impulses and diminished muscle stretch reflexes in both ankles and knees. Sensations to vibrations and light touch are also markedly diminished. Laboratory analysis of CSF shows no biochemical abnormalities. Which of the following is the most likely type of peripheral nerve disease in this patient? <ul><li>Autonomic neuropathy </li></ul><ul><li>Distal polyneuropathy </li></ul><ul><li>Inflammatory neuropathy </li></ul><ul><li>Mononeuropathy </li></ul><ul><li>Paraproteinemic polyneuropathy </li></ul>
  82. 82. 58y M, Progressive bradykinesia, mild dementia ? Diagnosis <ul><li>Alzheimer’s </li></ul><ul><li>Parkinson’s </li></ul><ul><li>Motor neurone disease </li></ul><ul><li>Syringomyelia </li></ul><ul><li>Pick’s disease </li></ul>
  83. 83. 68y M, Dementia ? Diagnosis <ul><li>Alzheimer’s </li></ul><ul><li>Parkinson’s </li></ul><ul><li>Motor neurone disease </li></ul><ul><li>Syringomyelia </li></ul><ul><li>Pick’s disease </li></ul>
  84. 84. A 35-year-old man with Down syndrome dies of acute lympho-blastic leukemia. Gross examination of the patient's brain at autopsy shows mild microcephaly and underdevelopment of the superior temporal gyri. Histologic examination would most likely show which of the following neuropathologic changes? <ul><li>AA amyloidosis </li></ul><ul><li>Lewy bodies </li></ul><ul><li>Negri bodies </li></ul><ul><li>Neurofibrillary tangles </li></ul><ul><li>Spongiform encephalopathy </li></ul>
  85. 85. 38y fem, recurrent attacks of limb weakness, paraesthesia worsened over 7 years resulting in death due to respiratory failure. Image shows her brain specimen. What is the most likely Diagnosis? <ul><li>Multiinfarct dementia. </li></ul><ul><li>Parkinsons disease. </li></ul><ul><li>Multiple sclerosis </li></ul><ul><li>Motor neurone disease. </li></ul><ul><li>Lacunar infarcts. </li></ul>
  86. 86. 52y male, dementia, depression with choreiform movements. Image of his brain(B) compared with normal (A) ?Diagnosis <ul><li>Binswanger disease </li></ul><ul><li>Parkinsons disease </li></ul><ul><li>Alzheimers disease </li></ul><ul><li>Pick’s disease </li></ul><ul><li>Huntington’s disease </li></ul>A B
  87. 87. 78y, Dementia, Aphasia, Image shows Hippocampus tissue with anti tau stain. ? Diagnosis <ul><li>Multiple sclerosis </li></ul><ul><li>Parkinsons </li></ul><ul><li>Alzheimer’s </li></ul><ul><li>Multi-infarct dementia </li></ul><ul><li>Pick’s disease </li></ul>
  88. 88. 38y progressive weakness. Image shows section of spinal cord stained for myelin. Diagnosis? <ul><li>Multiple sclerosis </li></ul><ul><li>Parkinsons </li></ul><ul><li>Motor neurone disease </li></ul><ul><li>Syringomyelia </li></ul><ul><li>Spinal cord infarction. </li></ul>
  89. 89. 30y woman, 8-day history of mild tremor in her arms and impaired balance when walking. Vital signs are normal. Her symptoms disappear the following week. About 18 months later, the patient experiences another episode of weakness and requires assistance when walking. Neurologic examination reveals ataxia, dysarthria, decreased vibratory sensation in her legs, absent abdominal reflexes, increased deep tendon reflexes, and a Babinski sign on the left. Fifteen years after the onset of symptoms, the patient becomes bedridden and dies. A coronal section of the patient's brain at autopsy is stained for myelin (shown). Which of the following histopathologic findings would be expected in the lesions seen in the patient's brain? <ul><li>Astrogliosis </li></ul><ul><li>Lewy bodies </li></ul><ul><li>Negri bodies </li></ul><ul><li>Neuritic plaques </li></ul><ul><li>Neuronophagia . </li></ul>
  90. 90. CPC-3.6– KFP Questions: <ul><li>Dementia – definition, classification. </li></ul><ul><li>Primary: </li></ul><ul><ul><li>Alzheimer's, Pick's, Huntington's & Diffuse Lewy body disease. </li></ul></ul><ul><li>Secondary: </li></ul><ul><ul><li>CVD, Infections, Neoplasms, haematoma, hydrocephalus.drugs and toxins metabolic, vitamin def. (e.g. B1, B2, B12). </li></ul></ul><ul><li>Demyelinating disorders: </li></ul><ul><ul><li>Multiple sclerosis, MND, </li></ul></ul>
  91. 91. &quot;Education is for ‘life’.. not for mere ‘living’ &quot;The end of education is character&quot;                                                                - BABA
  92. 92. MND: Case study: <ul><li>A 25 year old woman developed progressive weakness of the left arm during the second trimester of her first pregnancy.Over the next few months she developed progressive weakness of the arms and later the legs and respiratory muscles. On examination she had reduced limb reflexes, with grade 1 power in the arms and grade 1 - 2 in the legs. Wasting and fasciculation were not seen. Sensation was normal. Nerve conduction studies showed evidence of axonal degeneration in motor nerves only. Normal investigations included MRI of the brain, cervical spine and brachial plexus, sural nerve biopsy, antiganglioside antibodies, CSF examination, lyme, syphilis and HIV serology, heavy metal levels, hexosaminidase levels, SOD-1 gene and mitochondrial DNA analyses. 10 months after the onset of her symptoms she required ventilation. Despite treatment with intravenous gammaglobulin, methyl prednisolone and plasma exchange her condition deteriorated and she became globally weak and areflexic, with involvement of bulbar muscles. Ocular movements were preserved until shortly before death. At times she appeared inappropriately cheerful, but cognition was normal. Sensation and autonomic function remained normal throughout the disease duration. She was ventilated for 27 months prior to death. </li></ul>
  93. 93. MND: Atrophy of anterior nerve roots.
  94. 94. Case study 1 <ul><li>62-year-old minister is having trouble composing his sermons. </li></ul><ul><li>wife tells that members of the church have complained that the pastor is making many mistakes. (Patient denies) </li></ul><ul><li>&quot;I can't grasp the profounder thoughts.“ </li></ul>
  95. 95. Case study 2 <ul><li>A 73y widow, brought by daughter. She lives alone, and continues to drive. </li></ul><ul><li>The daughter reports that her mother has become more disoriented during telephone conversations. Discussions with the mother's friends reveal memory lapses and inappropriate decisions. </li></ul>
  96. 96. Case study 3 <ul><li>A 62-year-old tool-and-die maker, accompanied by his wife, appears for an office visit. He has no physical complaints, but his wife reports a progressive decline in his short-term memory. </li></ul>
  97. 97. Case study 4 <ul><li>64y male, 2-year history severe depression. insomnia and early morning wakening. The patient typically woke feeling &quot;unrefreshed&quot;, and the collateral history from the spouse suggested that the patient was &quot;less active&quot; during sleep, with reduced turning, and a tendency to sleep on his back throughout the night. </li></ul><ul><li>attention and concentration were impaired, experiencing &quot;slowing&quot; and &quot;difficulty getting going&quot; with tasks. The patient reported feeling suspicious of others, and had concerns that people intended him harm. However, the patient did not describe any hallucinations. </li></ul><ul><li>When questioned further, the patient reported that he was slower in his day-to-day activities, gait change, uncontrolled walking gait.. with a reduction in spontaneity and physical activity. He also reported a relatively recent onset of anxiety and irritability with associated tremor, which he thought was perhaps more marked on the left side. His appetite and weight were unchanged. </li></ul>
  98. 98. Neuropathies And Myopathies <ul><li>Neuronal / Muscular damage: </li></ul><ul><li>Causes: </li></ul><ul><ul><li>Hereditary Motor & Sensory neuropathies </li></ul></ul><ul><ul><li>Inflammatory - Diphtheria, </li></ul></ul><ul><ul><li>Infectious: HZV, HIV, Leprosy </li></ul></ul><ul><ul><li>Acquired/ Metabolic: Diabetes, Uraemia </li></ul></ul><ul><ul><li>Vitamin B12 def </li></ul></ul><ul><ul><li>Toxins: Alcohol, Lead toxicity, Drugs </li></ul></ul>
  99. 99. Diabetic Neuropathy <ul><li>Types: </li></ul><ul><ul><li>Distal symmetric sensory neuropathy: tingling numbness, loss of pain in toes, hands, legs. </li></ul></ul><ul><ul><li>Autonomic neuropathy </li></ul></ul><ul><ul><li>Focal asymmetric neuropathy: cranial/ peripheral nerve involvement </li></ul></ul><ul><li>Pathogenesis: </li></ul><ul><ul><li>Microangiopathy, ischemia, Hyperosmolar cell damage by polyols, myelin loss in sensory nerves. </li></ul></ul>
  100. 100. Herpetic Neuralgia (HZ infection) <ul><li>Sensory ganglia of spinal cord & brain stem. </li></ul><ul><li>Reactivation of latent infection following decrease in cell mediated immunity. </li></ul><ul><li>Painful vesicular lesions in the distribution of sensory dermatome, trigeminal nerve. </li></ul><ul><li>Intranuclear inclusions are generally not found in the peripheral nerve lesions. </li></ul>
  101. 101. Inflammatory/ Immune Neuropathy (Guillain-Barre Syndrome): <ul><li>Life threatening spinal neuropathy following an acute viral illness: </li></ul><ul><li>Clinical Features: </li></ul><ul><ul><li>Distal limb weakness & paraesthesia which progresses to affect proximal muscles (Ascending Paralysis) </li></ul></ul><ul><ul><li>Death usually due to respiratory paralysis </li></ul></ul><ul><li>Pathogenesis: </li></ul><ul><ul><li>T-cell mediated response, inflammation of peripheral nerves & segmental demyelination </li></ul></ul><ul><li>Pathology: </li></ul><ul><ul><li>CSF: Albumino-Cytological dissociation </li></ul></ul>
  102. 102. Myopathies: <ul><li>Muscular degeneration, weakness & wasting. </li></ul><ul><li>3 main groups </li></ul><ul><ul><li>Muscular dystrophies – Abnormal structure. </li></ul></ul><ul><ul><li>Myositis – Inflammation / immune. </li></ul></ul><ul><ul><li>Myopathy- Degeneration. Usually sec to systemic disease: eg.Thyrotoxicosis or Neurogenic muscular atrophy. </li></ul></ul>
  103. 103. Brain Activity: PET Scan (language skills) Hearing Words Speaking Words Seeing Words Thinking about Words Different mental activities take place in different parts of the brain. Positron emission tomography (PET) scans can measure this activity. Chemicals tagged with a tracer “light up” activated regions shown in red and yellow. Slide 13
  104. 104. Neuro Anatomy - Function
  105. 105. Vitamin Def & Neuropathy: <ul><li>A - Benign intracranial hypertension (rare) </li></ul><ul><li>B 1Wernicke-Korsakoff syndrome </li></ul><ul><li>B 2Peripheral neuropathy, ataxia,dementia </li></ul><ul><li>B 6Convulsions in infants </li></ul><ul><li>B 12Weakness and paraesthesiae in the lower limbs (1 & 3) </li></ul><ul><li>C Scurvy </li></ul><ul><li>E Weakness, sensory loss, ataxia, nystagmus </li></ul>
  106. 106. 78y Male memory loss? Diagnosis <ul><li>Multiple sclerosis </li></ul><ul><li>Parkinsons </li></ul><ul><li>Alzheimer’s </li></ul><ul><li>Multi-infarct dementia </li></ul><ul><li>Pick’s disease </li></ul>