RCSI CNS 2 Neurodegeneration/Demyelination PDF

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn CPC CNS 2 Neurodegeneration / Demyelination Class Year 2 Course Pathology CPC Lecturer Dr. Michael Farrell, Beaumont Hospital Date November 22nd 2023 Clinical Scenario  A 31-year-old lady pres...

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn CPC CNS 2 Neurodegeneration / Demyelination Class Year 2 Course Pathology CPC Lecturer Dr. Michael Farrell, Beaumont Hospital Date November 22nd 2023 Clinical Scenario  A 31-year-old lady presents with a 4-day history of weakness and numbness in her left leg  Episode of painful blurred vision in right eye 1 year ago that resolved over a week.  No other past medical history and not on regular medications  On examination →  ↑tone in left leg;  Power 3/5.  Reflexes brisk in left leg  Sensory exam shows ↓ pin prick & proprioception  Pale Right Optic Nerve Questions  What is the most likely diagnosis in this case?  How else can this condition present? Answers: Common presenting symptoms of MS  Visual loss → Optic neuritis  Gait ↓ & Lower limb weakness → Transverse myelitis  Facial Pain → Trigeminal neuralgia [Pons]  Double Vision → Brain Stem - MLF  Gait / balance disturbance → Cerebellum / Spinal Cord  Vertigo → Brain Stem  Bladder dysfunction → Spinal Cord Unusual Signs of Demyelination  Lhermitte’s sign  Neck flexion results in rapid tingling or electric shock-like feeling that passes down the spine and into the limbs  Uhtoff’s phenomenon  Raised body temperature can result in an exacerbation of symptoms Questions  How would you categorise the patient’s clinical syndrome of MS? Answers  Clinically isolated syndrome  Relapsing-remitting MS  Majority of cases are relapsing-remitting at onset  Secondary progressive MS  Primary progressive MS Question  Name 3 investigations that will support your clinical diagnosis Answer  MS is primarily a clinical diagnosis supplemented by tests that will show inflammatory disease in brain +/- spinal cord dissociated in time and place :-  MRI Brain & Spine with contrast  CSF analysis and SPEP  Oligoclonal bands (OCBs)  Should be unmatched  Visual evoked potentials  Delayed P100 potentials supportive of MS diagnosis MRI Brain + contrast -MS Question  What name is given to the diagnostic criteria for MS? Question  What name is given to the diagnostic criteria for MS? Sir W. Ian McDonald 1933 - 2006 Diagnosis  McDonald Criteria:  Objective demonstration of dissemination of CNS lesions in both space and time based on either clinical findings alone or a combination of clinical and MRI findings Question  What pathologic process is going on in the brain during a MS relapse (i.e. active MS plaque)? Demyelination Active MS plaque Perivascular and parenchymal inflammation c/o lymphocytes and macrophages.. Ellison, Love. Ref text CNS Pathology. Elsevier. Question  How does demyelination affect axonal transport? Demyelination Impaired Saltatory Conduction Question  What cell is responsible for myelination in the CNS?  Myelin & The Oligodendrocyte CNS - 1 oligodendrocyte myelinates several internodes PNS – 1 Schwann cell myelinates only one internode Question  What types of treatment might be used for this patient  What are the management goals  Answer  What type of treatment might be used for the patient outlined at the beginning?  Acute  Steroids (sometimes plasma exchange)  Long term  Disease modifying agents  Injectable, Oral, Infusion medications  What are the management goals ?  Shorten relapse & prolong remissions  Prevent Entry to Progressive Phase  Improve Quality of Life – Multidisciplinary Team in Dedicated Clinics  Fatigue; Spasticity; Urogenital Problems; Learning objectives 1  Range of symptoms of multiple sclerosis  Clinical classification of MS  Investigation of MS  Multiple sclerosis whilst an inflammatory disease will ultimately enter a progressive degenerative phase which is characterised by :-  axonal loss leading to spinal cord thinning and  brain atrophy due to loss of white matter Learning Objectives 2  Distinguish between delirium and dementia  How to investigate above  List clinical features of neurodegenerative disease affecting different anatomic sites  Discuss how to make a diagnosis of a neurodegenerative disease.  List pathologic features of a neurodegenerative disease Next case  A 70-year-old man presents to the Emergency Department with a fever, disorientation, altered personality and volatile behaviour for 2 days.  Urinalysis indicates nitrites, leucocytes and ketones. Urinary culture demonstrates pure growth of E. coli.  Treated with appropriate antibiotics for a urinary tract infection and improves.  After returning home he does not remember the event well and cannot say what hospital he was in. Question  What do you understand by the term delirium?  List the symptoms of this man’s delirium. Answer  What do you understand by the term delirium? Delirium is an acute disorder of attention and global cognition, which is reversible, by treating underlying cause.  List the symptoms of this man’s delirium. Disorientation, altered personality and volatile behaviour Question  What is there in the man’s story that might indicate he has more than just delirium ? Answer  Q. What is there in the man’s story that might indicate he may have dementia? A. He does not remember the event well and cannot say what hospital he was in. Dementia is characteristically progressive decline function of at least 2 cognitive areas, and is irreversible.  How will you investigate this further? Investigation of Progressive Cognitive Decline 1) Exclude acute reversible cause of cognitive decline eg. infection 2) Take a detailed history [family] & carry out cognitive assessment to identify affected cognitive domains a. eg. MMSE, Montreal Cognitive assessment +/- psychological evaluation 3) Exclude any treatable conditions. a. Metabolic cause of cognitive decline – thyroid function tests, vitamin B12 levels, U&E, LFTs b. Autoantibody work up (vasculitis) 4) Brain imaging (CT, MRI +/- PET) – exclude other causes such as stroke and assess distribution of any atrophy 5) Rarely brain biopsy to identify treatable cause eg. vasculitis, lymphoma History from Family members  On detailed questioning his family outline a change in personality over the preceding 18 months along with a ‘forgetfulness’ they had attributed to getting older. Question  Q. What anatomical part[s] of his brain are affected by memory impairment ? Answer  More detailed examination reveals moderate impairment of short term memory. Question  What is the most likely clinical diagnosis and how may the diagnosis be confirmed?  Question  What is the most likely clinical diagnosis?  Alzheimer disease CSF measurement of : Tau 135-345 Amyloid beta 42 591-997 Phospho –Tau 35-64 18F-FDG and Pittsburg Compound B (PiB) Question  Over the next year he shows progressive decline, fails to recognise close family member, becomes withdrawn.  Totally dependent on others until death.  How might a diagnosis be confirmed? Answer  Over the next year he progressively declines, fails to recognise close family member, becomes withdrawn. He is totally dependent on others until he dies.  How might a diagnosis be confirmed?  Autopsy (postmortem) brain examination  This is the only way to confirm AD or other diagnosis. Question  A pathologic diagnosis of ALZHEIMER TYPE PATHOLOGY is made.  What are the macroscopic and microscopic features?  Alzheimer Disease Gravestones Alois Alzheimer Auguste Deter 1849 - 1906 Plaques & Tangles “AD - a clinical entity and AD - a pathologic process with a prodrome” A Generation & Propagation Plaques Aß42 Dimeric Polymeric Sink & Source Recruitment of Aß42 Monomeric Aß42 Shankar et al Nature Medicine 2008 Barry J Neuroscience 2011 βA4 Amyloid Plaques in Cerebral Cortex AD – Plaque Distibution Vascular Amyloid Alzheimer Disease - Tau Heiko BRAAK Seeding  AXONS Tau & Microtubules Major microtubule - associated protein – Located in the axon – Binds & Stabilises MTs – Functions as Spring & damper Microtubules  Tau Function Transgenics Tau -/- nerve cells – demonstrate neuritic sprouting but show failure of elongation to form axons Tau +/+ non-neural cells – elaborate long thin processes with compacted MTs Neurodegeneration Amyloid Tau Question  Why is this type of postmortem examination so important? Answer  Why is this type of post mortem examination so important? 1. Considerable overlap between different clinical phenotypes & different pathologic diagnoses 2. Clinical diagnosis of Alzheimer’s disease NOT always matched by pathologic diagnosis of Alzheimer’s disease 3. Accurate diagnosis for family 4. Likelihood of an Hereditary Component 5. Contributes to understanding of disease and response to new treatments Learning outcomes  Correctly interpret a classical clinical history of a patient with multiple sclerosis  Provide appropriate key investigations for a patient suspected of having multiple sclerosis  Describe the pathology and physiologic effects of demyelination and why they cause neurological symptoms  Distinguish and demonstrate clinical differences between delirium and dementia  Describe the key investigations for cortical neurodegenerative disease  Describe the macroscopic and microscopic features seen in the brain of a patient with Alzheimer’s disease