Boards and Beyond: Neurology A Companion Book to the Boards and Beyond Website Jason Ryan, MD, MPH Version Date: 11-18-2016
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Table of Contents Cells of the Nervous System Nerve Damage Blood Brain Barrier Neurotransmitters Neurotrans mitters Dermatomes and Reflexes Cerebral Cortex Spinal Cord Spinal Cord Syndromes Brainstem Cranial Nerves Auditory System Vestibular System Thalamus, Hypothalamus, Limbic Cerebellum Basal Ganglia Ventricles and Sinuses Cerebral/Lacunar Cerebral/La cunar Strokes Vertebrobasilar Vertebrob asilar Strokes Cerebral Aneurysms Intracranial Intracran ial Bleeding TIA/Stroke Autonomic Nervous System
1 4 8 10 13 15 19 21 26 32 38 40 44 49 54 57 61 66 69 71 76 78
ANS: Norepinephrine Norepinephrine ANS: Acetylcholine Acetylch oline The Pupil The Lens The Retina Eye Movements Structural Structu ral Eye Disorders Visual Fields Gaze Palsies Glaucoma General Anesthesia Anesthesi a Local Anesthesia Neuromuscular Blockers Meningitis Meningit is Seizures Neuroembryology Delirium and Dementia Demyelinating Demyelinat ing Diseases Headaches Brain Tumors Parkinson’s, Huntington’s HIV CNS Infections
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83 89 95 100 105 110 112 116 118 121 125 131 133 136 142 148 152 158 162 165 169 174
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Nervous System Cells •
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Cells of the Nervous System
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Neurons Astrocytes Microglia Oligodendroglia Schwanncells
Jason Ryan, MD, MPH
Neuron Action Potentials
Glial Cells •
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Support neurons Macroglia •
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Key Facts •
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Astrocytes, oligodendrocytes, ependyma
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Microglia Gliosis: •
Proliferation/hypertrophy of glial cells
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Reaction to CNS injury
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Astrocytes undergo major changes
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Glioma •
Na channels open along axon propagation At axon terminal, Ca channels open Triggers release of neurotransmitter neurotransmitter Vesicles fuse with membrane exocytosis
Astrocytes
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Agents that block Na channels will inhibit signals
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Localanesthetics
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To depolarize, Na channels open This allows Na into cell and raises voltage
Astrocytoma, Oligodendroglioma, Ependymomas
Clinical Relevance
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At rest, neurons have voltage of -70mV This is maintained by “leak” of K+ out of cell
Lidocaine, Benzocaine, T etracaine, Cocaine, Cocaine, etc.
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Some neurotoxins block Na channels •
Pufferfish tetrodotoxin
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Japanese food
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Important for support of neurons Found in CNS: Gray and white matter Removesexcess neurotransmitter neurotransmitter Repair, scar formation Major part of reactive gliosis •
Hypertrophy
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Hyperplasia
GFAP is key astrocyte marker
Astrocytes
Microglia
Clinical Relevance •
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Astrocytomas •
Cerebellum of children
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GFAP positive
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JC Virus infects astrocytes and oligodendrocytes oligodendrocytes •
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Causes PML in HIV patients •
Oligodendroglia •
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CNS macrophages Proliferate in response to injury Differentiate into larger phagocytes after injury HIV can persist in the brain via microglia Chronic HIV encephalitis: nodules of activated microglia
Schwann Cells
Myelinate CNS axons Each cell myelinates multiple axons
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Most common glial cell in white matter Destroyed in multiple sclerosis
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Myelin •
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Very important for neuron regeneration Destroyed in Guillain-Barre syndrome syndrome Form Schwannomas •
Also called acoustic acoustic neuromas
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Classically affect CN VIII
Types of Nerve Fibers
Lipids and proteins Increases SPEED of impulse propagation propagation in axon Saltatory Conduction •
Myelinate PNS axons Each cell myelinates one axons
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Classification by diameter, myelin
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A-alpha:
Only need to depolarize Nodes of Ranvier
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Large, myelinated fibers, 6 to 15 microns diameter
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Most efferent motor fibers
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Touch, Touch, vibration, and position position
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Do not need to depolarize entire entire axon
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This makes process process faster
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↑ conduction velocity
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Small, myelinated fibers, 3 to 5 microns in diameter
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↑ length constant
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Cold, pain
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CNS: Oligodendrocytes
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PNS: Schwann cells
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Large
A-delta
C fibers •
Unmyelinated fibers, 0.5 to 2 microns in diameter
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Warm, pain Small
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How Nerves Sense •
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Free Nerve Endings
Four structures on nerve ending allow us to sense the world Free nerve endings
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Meissner’s Corpuscles PacinianCorpuscles Merkel’s disks
Meissner’s Corpuscles •
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“Glabrous” (hairless) skin
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Deformed by pressure nerve stimulation A-alpha (large, myelinated) fibers
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Pressure,positionreceptors Many locations, but especially hair follicles A-alpha (large, myelinated) fibers Sustained response to pressure “Slowly adapting”
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Provide continues information
Contrast with Meissner’s, Pacinian •
“Rapidly adapting”
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Respond mostly to changes
C and A-delta fibers fibers
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Concentrated sensitive areas like fingers
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Separate pain, cold and warm receptors
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Merkel’s Discs •
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Pacinian Corpuscles
Touch receptor s Located near surface of skin •
Mostly found in skin skin Sense pain and temperature
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Vibration,pressurereceptors Located deep skin, joints, ligaments Egg-shapedstructure Layers of tissue around free nerve ending Deformed by pressure nerve stimulation stimulation A-alpha (large, myelinated) fibers
Peripheral Nerve Damage •
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Mild: Neurapraxia Moderate: Axonotmesis Severe: Neurotmesis Can result in weakness or sensory loss
Nerve Damage
Epineurium Perineurium Endoneurium
Nerve
Jason Ryan, MD, MPH
Myelin
Neurapraxia
Neurotmesis
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Mild injury
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Focal demyelination
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Axon distal to injury intact Continuity across injury Excellent recovery
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Epineurium Perineurium Endoneurium
Nerve
Axonotmesis
Demyelination plus damage to axon Endoneurium, perineurium remain intact
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Distal to the lesion: “Wallerian degeneration” •
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Nerve
Epineurium Perineurium Endoneurium
Myelin
Axonotmesis •
External continuity of the injured nerve disrupted No significant regeneration occurs Bad prognosis
Nerve
Myelin
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Severe lesions Axon, myelin sheath irreversibly damaged
Epineurium Perineurium Endoneurium
Myelin
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Also occurs just just proximal to injury
Axon degenerates, myelin sheath involutes Axon regrowth sometimes occurs Possible if Schwann cells maintainintegrity
Axonotmesis •
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Proximal to the lesion: “ Axonal reaction” Also called central chromatolysis
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Up-regulation Up-regulation of protein synthesis for repair Cell body changes •
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Axonotmesis
Swelling
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Chromatolysis (disappearance of Nissl bodies)
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Nucleus moves to periphery
Variable prognosis •
Extent of damage
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Distance to target
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Complexity of nerve nerve
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Usually partial recovery
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Longer recovery time than neurapraxia
Resolves with time
Central Nerve Damage
Central Nerve Damage
Ischemia
Changes after Infarction
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~ 4-5 minutes of ischemia irreversible damage Neurons more sensitive than glial cells •
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Higher energy demands; demands; lack glycogen
Most sensitive neurons: •
Hippocampus
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Purkinje cells cells (Cerebellum)
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Neocortex
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Striatum (Basal ganglia)
12-24 hours No changes for about 12 hours
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First changes occur in neurons
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Microvacuoles (small holes) develop develop in neuron cytoplasm
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Neurons become deep pink- red color “ Red neurons ”
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Nucleus changes changes shape, color
Central Nerve Damage
Central Nerve Damage
Changes after Infarction
Changes after Infarction
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24-48 hours
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Days to weeks
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Neutrophils, macrophages, microglia
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Macrophages eliminate debris
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Liquefactive necrosis from lysosomal lysosomal enzymes enzymes release
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Cyst forms
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Astrocytes undergo gliosis - multiply, enlarge Astrocyte processes form wall around cyst
UMN and LMN •
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Somatics: two neuron chain Upper motor neuron •
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UMN and LMN
CNS to muscle/target
UMN and LMN
Upper motor damage (pyramidal signs)
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Spastic paralysis paralysis (stiff, rigid muscles)
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Hyperreflexia
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Fasciculation (spontaneous contractions/twitches)
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Muscle overactive
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Loss of reflexes
Clasp knife spasticity: passive movement sudden release
Bulbar
UMN cross just below medulla •
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Decussation
Lesions above decussation •
Contralateral dysfunction
Lesions below decussation decussation •
Flaccid paralysis
initial resistance,
Decussation
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Lower motor damage
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LMN: Brainstem, spinal cord (anterior horn)
Brain to second nerve
UMN and LMN
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UMN: Cortex, internal capsule, corticospinal tract
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Lower motor neuron •
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Ipsilateral dysfunction
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Bulbar muscles are supplied by CN in brainstem •
V (jaw)
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VII (face)
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IX (swallowing)
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X (palate)
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XI (head)
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XII (tongue)
Bulbar vs. Pseudobulbar Pseudobulbar •
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Key Differences Differences
Bulbar palsy
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Bulbar
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Cranial nerve damage
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Absent jaw/gag reflex
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LMN signs
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Tongue flaccid/wasted
Pseudobulbar
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Pseudobulbar
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Corticobulbar tract damage
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UMN signs
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Tongue spastic (no wasting)
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Spastic dysarthria
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Exaggerated gag reflex
Blood Brain Barrier •
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Surrounds CNS blood vessels Controls content CNS interstitial fluid Tight junctions btw endothelial cells of capillaries Astrocytes foot processes •
Blood Brain Barrier
Terminate in overlapping fashion on capillary capillary walls
Jason Ryan, MD, MPH
Blood Brain Barrier •
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Circumventricular Circumventricular Organs (CVO)
Water, some gases, and lipid soluble small molecules easily diffuse across Keeps out bacteria, many drugs
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Glucose/amino Glucose/amino acids can’t cross cross directly •
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Use carrier-mediated transport
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Vascular brain structures around ventricles No blood brain barrier Allow communication CNS blood stream Some sensory, some secretory Key CVOs •
Area Postrema •
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Area postrema
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OVLT
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Subfornical Organ (SFO)
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Median Eminence of Hypothalamus
OVLT
Caudal end of 4th ventricle in medulla
“Chemoreceptor trigger zone” Outside blood brain barrier Chemo agents affect this area Sends signals to vomiting center in the medulla
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Organum vasculosum of the lamina terminalis
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Anterior wall of the third ventricle
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Osmosensoryneurons
Median Eminence of Hypothalamus
Subfornical Organ (SFO) •
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Anterior wall 3rd ventricle Responds to many circulating substances substances
Allows hypothalamus to regulate pituitary
Projects to other brain areas
Vasogenic (Cerebral) Edema
Posterior Pituitary Gland •
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Releases hormones into vascular system to pituitary
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Exact roles not clear clear Responds to angiotensin II
Other Brain Areas Without BBB •
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Oxytocin, ADH
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Pineal Gland •
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Melatonin
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Breakdown of blood brain barrier Trauma, stroke Swelling of brain tissue
Peripheral Neurotransmitters •
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Norepinephrine Acetylcholine Dopamine
Neurotransmitters Jason Ryan, MD, MPH
Key CNS Neurotransmitters •
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Norepinephrine
Norepinephrine Acetylcholine(ACh)
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Dopamine Serotonin(5-HT) γ-aminobutyric -aminobutyric acid (GABA)
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Decreased levels in depression •
Glutamate
Locus Ceruleus •
Stress/panichormone Increased levels in anxiety Some antidepressants antidepressants ↑NE levels
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Serotonin–norepinephrine reuptake inhibitors (SNRIs)
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Desipramine (TCA)
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Monoamine Oxidase inhibitors (MAOi)
Dopamine
Posterior pons near 4th ventricle
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Main source of NE in brain Critical for response to stress •
Extensive projections that activate under stress Activated in opiate withdrawal withdrawal
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Synthesized in: •
Ventral Ventral tegmentum (midbrain)
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Substantia nigra (midbrain)
Increased levels in schizophrenia Decreased levels in Parkinson’s Decreased levels in depression
GABA
GABA Receptor Anesthetics
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γ-aminobutyric acid
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GABA is largely inhibitory
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Synthesized in nucleus accumbens (subcortex) Decreased levels in anxiety
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Decreased levels in Huntington’s disease
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GABA Receptor •
Etomidate Propofol Benzodiazepines Barbiturates These drugs activate receptor sedation
GABA Synthesis
GABA binds to receptor allows Cl- into cell
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Synthesized via glutamate decarboxylase in neurons Broken down by GABA transaminase Both enzymes need B6 cofactor
ClGABA
Glutamate decarboxylase Glutamate
GABA Receptor •
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GABA
Nucleus Accumbens
Three GABA receptor subtypes GABAA GABAB in brain GABAc in retina Benzodiazepines Benzodiazepines act on GABAA •
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GABA Transaminase
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Stimulate Cl influx
Alcohol, zolpidem, and barbiturates also GABAA
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Importantfor pleasure/reward
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Research shows NA activated in •
Drug addiction
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Fear
Breakdown Products
Serotonin •
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Serotonin Syndrome
Variousfunctions Synthesized in raphe nucleus (pons)
Some antidepressants antidepressants ↑5-HT levels
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Selective-serotonin reuptake inhibitors (SSRIs)
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Serotonin–norepinephrine reuptake inhibitors (SNRIs)
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Monoamine Oxidase inhibitors (MAOi)
Can occur any drug that that ↑serotonin
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Classicallytriad
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#1: Mental status changes
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#2: Autonomic Autonomic hyperactivity
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#3: Neuromuscularabnormalities abnormalities
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Decreased levels in anxiety Decreased levels in depression •
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SSRIs, MAO inhibitors, SNRis, TCAs
Anxiety, delirium, restlessness, and disorientation Diaphoresis, tachycardia, hyperthermia
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Serotonin Syndrome •
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Acetylcholine
Watch for patient on anti-depressants with fever, confusion, and rigid muscles muscles Don’t confusewith N MS •
Both: muscle rigidity, fever, fever, Δ MS, and autonomic instability
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NMS: “Lead pipe” rigidity, ↑CK
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SS: Clonus
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Synthesized in basal nucleus of Meynert (subcortex) Increased levels in REM sleep Decreased levels in Alzheimer’s Decreased levels in Huntington’s disease
Treatment: cyproheptadine (5 –HT antagonist)
Phencyclidine (PCP)
Glutamate •
Tremor, Tremor, clonus, hyperreflexia, bi lateral Babinski sign
Angel Dust
Majorexcitatory neurotransmitter neurotransmitter
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N-methyl-D-aspartate N-methyl-D-aspartate (NMDA) receptor is target glutamate toxicity Huntington’s: neuronal death from glutamate •
Glutamate binds NMDA receptor
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Excessive influx calcium
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Cell death
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Antagonist to NMDA receptor Violentbehavior Hallucinations Ataxia, nystagmus Hypertension, tachycardia, diaphoresis Can cause seizures, coma, or death
Dermatomes C1 Nerve Root C1 Vertebrae
Dermatomes and Reflexes
C7
Jason Ryan, MD, MPH
T1
C7 Vertebrae C8 T1 Vertebrae
Herpes Zoster
Key Spinal Nerves •
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Shingles
Phrenic nerve C3-C5
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Innervates diaphragm
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Primary VZV = chicken chicken pox
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Diaphragm irritation “referred” shoulder pain
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Fever, Fever, pharyngitis, vesicular rash
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Classic example is gallbladder disease
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Shingles = reactivated VZV
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Also lower lung masses
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Irritation can cause cause dyspnea and and hiccups
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Cut nerve diaphragm elevation, elevation, dyspnea
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T10 = umbilicus
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Referred pain for appendicitis
Clinically Tested Reflexes •
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Reactivation Reactivation of latent varicella-zoster virus
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T2 Vertebrae
Lies dormant in dorsal root ganglia Rash along dermatome Does not cross midline midline Common in elderly or immunocompromised immunocompromised
Reflexes
Biceps – C5
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Triceps – C7 Patella – L4 L4
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Achilles (ankle jerk) – S1
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0 = No reflex 1+ = diminished(LMN lesion) 2+ = Normal 3+ = Brisk (UMN lesion) lesion) 4+ = Very brisk 5+ = Sustainedclonus
Babinski Sign
Nerve Root Syndromes •
L5 (L4/L5 disc)
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Plantar Reflex
S1 ( L5/S1 disc)
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Most common
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2nd most common
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Back pain down lat leg
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Pain down back back of leg
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Foot strength reduced
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Weakness plantar flexion
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Reflexes normal
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Ankle reflex lost
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Babies lacking these may have CNS pathology Reflexes that persist can indicate pathology
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Inhibited by mature frontal lobe Can reappear with frontal lobe pathology Six key reflexes: Moro, Rooting, Sucking, Palmar, Palmar, Plantar, Galant
Other Primitive Reflexes •
Rooting •
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Stroke baby’s palm, fingers will grasp
Plantar •
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Baby will suck anything anything touching roof of mouth
Palmar •
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Stroke cheek, baby turns toward side of stroke
Sucking •
Babinski reflex normal up to to 1 year
Galant •
UMN damage
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UMN suppress reflex
Upward = normal infants •
<12mo
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Incomplete myelination
Startle Reflex
All present at birth in normal babies Disappear in first year of life or less
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Dorsiflexion
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Moro Reflex
Primitive Reflexes •
Plantarflexion
Abnormal: upward •
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Rub bottom foot Normal: downward
Stroke skin along babies back, baby swings swings legs to that side
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Lie baby on back Lift slightly off back Let go Three phase reflex •
Spreading of arms
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Unspreading of arms
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Crying
Frontal Lobe •
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Cerebral Cortex Jason Ryan, MD, MPH
Homunculus
Largest lobe Motor function, planning movements Thinking, feeling, imagining, making decisions Key Areas •
Motor cortex
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Frontal Eye Fields
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Broca’s speech area
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Prefrontal Cortex
Frontal Eye Fields •
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Found in frontal lobe Brodmann’s Area 8 Performs conjugate movement eyes to opposite side Saccadicmovements:back-forth(reading) Complex function helps track objects Destructivelesion: •
Both eyes deviate deviate to side of lesion R
MCA: Upper limb, face ACA: Lower limb
Right FEF Lesion
Broca’s Speech Area •
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Wernicke’s Aphasia
Located in frontal lobe – LEFT hemisphere
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Speech production (not comprehension) comprehension) Moves muscles for speech
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Makes speech clear, fluent Destruction “expressive” aphasia •
Know what you want to say say but cannot express speech
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Short sentences, sentences, stutters, stops
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Located in temporal lobe – LEFT hemisphere Speech comprehension (not production) Destruction “fluent” aphasia •
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Watch for “broken” speech: stuttering, stop/start
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Fluent, but meaningless speech
Watch for LACK of stutters, starts/stops
Global Aphasia •
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Prefrontal Cortex
Both Broca's and Wernicke's (left side) Patient’s often mute Cannot follow commands Can occur immediately following stroke Usually occurs with extensive CNS damage •
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Right Hemiparesis
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Deficits in concentration
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Disorientation
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Poor judgment
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Reemergence of primitive reflexes
Parietal Lobes
Railroadworker1848 Railroad iron thru skull
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Survived Personalitychange
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Contain sensory cortex Damage to right parietal lobe: spatial neglect •
Contralateral (left) agnosia
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Can’t perceive objects in part of space
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Despite normal vision, somatic sensation
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Failure to report or respond to stimuli affected side
Right-sided spatial neglect rare •
Parietal Lobes •
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Disinhibition
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Right visual loss
Phineas Gage •
Anterior 2/3 of frontal lobe Lesions:
Redundant processing processing of right by left/right brain
Temporal Lobe
Baum’s Loop Part of visual pathway Damage: Quadrantic Anopia
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Primary auditory auditory cortex •
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Wernicke’s speech area •
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Baum’s Loop Lesion Parietal Lobe “Pie in the floor” Parietal lobe damage
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Lesions “cortical” deafness Lesions Wernicke’s aphasia
Olfactorybulb Meyer’s Loop
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Hippocampus
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Amygdala
Meyer’s Loop
Olfactory Bulb •
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Destruction ipsilateral anosmia Psychomotor epilepsy •
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Quadrantic Anopia
Sights, sounds, smells smells that are not there
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Can result from irritation olfactory bulb
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Part of temporal lobe epilepsy
Rare, olfactory groove meningiomas •
About 10% of all meningiomas
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Cause anosmia
3 Meyer’s Loop Temporal Lobe “Pie in the sky” MCA stroke, Temp lobe damage
Amygdala •
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Kluver-Bucy Syndrome
Temporal lobe nuclei Important for decision making, higher functions
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Part of limbic system
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Damage to bilateral amygdala (temporal lobes) Hyperphagia - Weight gain Hyperorality - tendency to examine all with mouth InappropriateSexualBehavior •
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Occipital Lobe •
Vision
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Lesions cause cortical blindness blindness
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Blood supply PCA
Atypical sexual behavior, behavior, mounting inanimate objects
Visual Agnosia Inability to recognize recognize visually presented objects
Rare complication of HSV1 e ncephalitis
Homonymous Hemianopsia
Left PCA Stroke Right visual loss
Right PCA Stroke Left visual loss
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Macular Sparing •
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Macula: central, high-resolution vision ( reading) Dual blood supply: MCA and PCA PCA strokes often spare the macula
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Cervical (8) Thoracic (12) Lumbar (5) Sacral (5)
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Cord ends L1/L2
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Cauda Equina
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Spinal Cord
Conus medullaris
Jason Ryan, MD, MPH
Spinothalamic Tract
Terminology
Pain/temperature/crude Pain/temperature/crude touch Thalamus
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Dorsal •
Posterior
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Towards Back Anterior
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Towards Front
Rostral
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Caudal
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Ventral •
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Towards top of head
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Towards tail
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Away from head
1st Neuron: Spinal root to cord 2nd Neuron: Dorsal Horn to Thalamus 3rd Neuron: VPL Thalamus Thalamus to Cortex
Midbrain
Pons
Medulla
Spinal Cord
Posterior Posterior Column
Sensory Info to Brain
Thalamus
Dorsal Column-Medial Lemniscus 1st Neuron: Spinal root up cord 2nd Neuron: Gracilis (lower) Cuneatus (upper) 3rd Neuron: VPL Thalamus Thalamus to Cortex Vibration/proprioception/fine touch
Midbrain
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Pons Nucleus Gracilis
Medulla
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Nucleus Cuneatus Lower Medulla Pacinian Corpuscle
Meissner's Corpuscle
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Spinal Cord
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Spinothalamic •
Pain/temperature/crude touch
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Synapse cord level
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Cross cord level
Posteriorcolumn •
Vibration/proprioception/fine touch
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Ascend in cord
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Synapse nucleus gracilis/cuneatus
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Cross medulla
Key point: Both cross but in different places
Corticospinal Tract Motor 1st Neuron: Cortex to Anterior Horn nd 2 Neuron: Anterior Horn to muscle Decussation Lower Medulla
Key Points
Posterior Limb Internal Capsule
1. Anterior Horn – Motor nerves 2. Posterior Horn – Sensory Nerves (pain/temp)
Midbrain
3. Lateral Horn – Autonomic Nerves 4. Spinothalamic Tract – Pain/Temp
Pons
5. Mediallemniscus – Vibration/Proprioception Vibration/Proprioception 6. Corticospinal Corticospinal Tract - Motor
Medulla Lower Medulla Spinal Cord
Testing Sensation •
Testing Sensation
Romberg •
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Vibration
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Proprioception
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Pain
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Temp
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Tuning fork
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Close eyes; “Is toe up or down?”
Peripheral Neuropathy •
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Positive suggests posterior column problem
Diabetes complication complication •
Pin prick weak at at feet, better further up leg
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Changes with going up the leg
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Not spinal cord problem
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Pin prick Hot/cold water (rarely done)
Spinal Cord Syndromes 1. Poliomyelitis and Werdnig-Hoffman disease 2. Multiplesclerosis 3. Amyotrophic lateral sclerosis (ALS) 4. Anterior spinal artery occlusion
Spinal Cord Syndromes
5. Tabes dorsalis 6. Syringomyelia 7. Subacute combined degeneration (SCD)
Jason Ryan, MD, MPH
Polio •
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Polio
Single stranded RNA virus Preventedby vaccination vaccination
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Destruction of anterior horn LMN lesions Flaccid paralysis
Werdnig-Hoffman Disease •
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Classicpresentation •
Unvaccinated child
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Febrile illness
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Neuro symptoms 4-5 days later
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Weakness (legs>arms)
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Flaccid muscle tone
Multiple Sclerosis
Spinal muscle atrophy disease Hypotonia/weakness in newborn Classic finding: tongue fasciculations
“Floppybaby” “Floppy baby” Similar lesions to polio Death in few months months
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Mostly cervical white matter
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Random, asymmetriclesions
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Relapsing,remittingpattern
Amyotrophic lateral sclerosis •
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Combined UMN/LMN disease No sensory symptoms!! Spasticity, exaggerated reflexes
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Most common 40-60 years old
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Dysphagia
Usually fatal 3-5 years Common cause of death: aspiration pneumonia Riluzole for treatment (↓glutamate release neurons)
Amyotrophic lateral sclerosis
Familialcases:
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ClassicPresentation
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Zinc copper superoxide superoxide dismutase deficiency
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Increased free radical damage
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Slowly progressive course
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Arm weakness
ASA Occlusion •
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Wasting, fasciculations
Amyotrophic lateral sclerosis •
Cranial nerves can be involved
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Lower symptoms •
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Upper symptoms •
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Amyotrophic lateral sclerosis
50-year old patient
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Dysphagia to solids/liquids
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Some flaccid muscles
•
Some spastic muscles
•
No sensory symptoms
Tabes dorsalis
Loss of all but posterior columns
•
Only vibration, proprioception intact Acute onset (stroke) Flaccid bilateral paralysis (loss of LMN) below lesion
22
Tertiary syphilis
•
Demyelination of posterior columns
•
Loss of dorsal roots roots
Tabes dorsalis •
Syringomyelia
Classic Signs/Symptoms •
Patient with other STDs
•
Difficulty walking
•
5/5 strength legs legs and arms
•
•
•
Positive Romberg (no proprio)
•
Wide-based gate
•
Fleeting, recurrent shooting pains
•
Loss of ankle/knee ankle/knee reflexes
•
Argyll Robertson pupils
Syringomyelia •
•
•
•
Horner’s syndrome
•
•
Symptoms only at level of the syrinx
•
UsuallyC8-T1
•
•
•
•
From trauma or congenital Can occur years after spinal cord injury Seen in Chiarimalformations malformations
Can cause kyphoscoliosis (spine curve)
Syringomyelia
•
Usually C8-T1 (arms/hands) (arms/hands)
•
Can expand to affect lateral horn Loss of sympathetic sympathetic to face
Bilateral loss pain/temp
•
•
Muscle weakness
•
•
Syringomyelia
Can expand to affect anterior horn •
Fluid-filled space in spinal canal Damages ST nerve fibers crossing center
•
Watch for pin prick/temp loss on only hands/back
•
Legs will be normal
Syringomyelia •
•
Position, vibration normal all levels Temp loss may present as burns not felt Pain loss may present as cuts not felt If large, motor symptoms may develop If large, Horner’s syndrome may develop
23
Classicpresentation •
Cuts/burns on hands hands that were not felt
•
Loss of pinprick and temp in back, shoulders, shoulders, arms
May also include: •
Motor weakness weakness arms
•
Horner’s syndrome
SCD •
•
•
•
•
•
•
SCD
B12Deficiency Demyelinationposteriorcolumns (vibr/proprio) (vibr/proprio)
•
Loss of lateral motor tracts Slowly progressive Weakness Ataxia
•
•
•
•
Problems walking
•
Positive Romberg
•
Spastic paresis in legs
•
Lower extremity hyperreflexia
•
Positive Babinski
May not have macrocytosis
Brown-Sequard Syndrome •
Classicpresentation
Below Level of Injury
Loss of half of spinal cord Trauma or tumor Lose pain/temp contralateral side Lose motor, position, vibration ipsilateral side
No Motor, Proprio, Vibration Injured Side No Pain or Temp Contralateral Side
Level of Injury
Brown-Sequard Syndrome •
•
•
No Motor, Proprio, Vibration, Pain, or T emp
24
Weak side = side with lesion UMN signs below 1: Level of lesion lesion •
LMN signs
•
Loss of all sensation
•
If above T1 Horner’s
•
Constricted pupil, eyelid eyelid droop
•
2: Loss of motor, posterior columns
•
3: Loss of pain/temp
Brown-Sequard Syndrome •
Cauda Equina Syndrome
ClassicPresentation •
•
Level of injury: No sensation
•
Side with injury •
•
•
•
Prior trauma (knife, gunshot)
•
•
Loss of vibration/proprioception vibration/proprioception •
Loss of pain/temp
Cauda Equina Syndrome •
•
Motor to lower extremity
•
Sensory to lower extremity
•
Pelvic floor/sphincter innervation
Severe low back pain
•
“Saddle anesthesia”
•
Loss of anocutaneous anocutaneous reflex
•
Bowel and bladder bladder dysfunction
•
Normal Babinski
Cauda equina syndrome: •
Compression cauda equina
•
Massive disk rupture
•
Trauma, tumor
Conus Medullaris Syndrome
ClassicPresentation •
Cauda equina nerve roots:
Spastic paresis; Babinski sign
Other side •
Spinal cord ends about L2 (conus medullaris) Spinal nerves continue inferiorly (cauda equina)
25
•
Perianalanesthesia,bilateral
•
Impotence
Terminology •
•
Brainstem
Dorsal •
Posterior
•
Towards Back
Ventral •
Anterior
•
Towards Front
•
Rostral •
•
Towards top of head
Caudal •
Towards tail
•
Away from head
Jason Ryan, MD, MPH
Brainstem Sections
The Brainstem •
•
•
Sensory and motorfibers Nuclei of cranialnerves Important to know what lies in each section •
•
Midbrain
•
Pons
•
Medulla
Focus on •
Which cranial nerves nerves each level?
•
Where are the tracts tracts traveling btw brain/cord?
•
Medial versus lateral? lateral?
Midbrain
Benedikt Syndrome
Mesencephalon Cerebral Aqueduct
MLF •
SpinalthalamicTract
•
•
•
Medial Lemniscus
Cerebral Peduncle
Red Nucleus
Corticospinal Tract Corticobulbar Tract Oculomotor Nerve
26
CN 3, medial lemniscus, red nucleus Oculomotor palsy Contralateralloss proprioception/vibration proprioception/vibration Involuntary movements •
Tremor
•
Ataxia
Weber’s Syndrome •
•
•
•
Parinaud’s Syndrome
CN3, corticospinal tract, corticobulbar corticobulbar tract Oculomotor nerve palsy
•
•
Contralateral hemiparesis Pseudobulbarpalsy •
UMN cranial nerve motor weakness
•
Exaggerated gag reflex
•
Tongue spastic (no wasting)
•
Spastic dysarthria
•
•
•
•
Pons
Posterior midbrain Superior colliculus and pretectal area Can’t look up (vertical gaze palsy)
Pseudo Argyll Robertson pupil Often from pinealoma/germinoma pinealoma/germinoma of pineal region Watch for cerebral aqueduct obstruction •
Non-communicating hydrocephalus
•
Compression from a pineal tumor
Medial Pontine Syndromes
Vestibular Spinal Tract Nuclei (VIII) & Nucleus Trigeminal (V)
•
4th Ventricle •
PPRF MLF
•
•
Vestibular N (CN VIII)
CN VII
Corticospinal tract, tract, CN 6, CN 7 Contralateral hemiparesis CN 6 palsy Facial weakness/droop affected side
•
Lateral gaze structures: MLF, CN VI nucleus
•
Gaze palsies •
Can’t look to affected side
•
Damage to either either PPRF or nucleus nucleus CN VI
Spinothalamic Tract
Medial Lemniscus Corticospinal Tract
CN VI
Medulla
Lateral Pontine Syndromes •
•
•
•
•
•
Vestibular nuclei: nystagmus, vertigo, N/V
Ipsilateral facial droop
•
Loss corneal reflex
Spinal Tract Trigeminal N (V)
Dorsal Motor Nucleus X
Sympathetictract: Horner’s syndrome Facialnucleus: •
Hypothalamospinal Tract
Spinal Nucleus Trigeminal N (V)
4th Ventricle
Nucleus Solitarius
Spinothalamic Spinothalamic tract:Contralateral pain/temp pain/temp Spinal V nucleus: ipsilateral face pain/temp
CN X
Spinothalamic Tract
Nucleus Ambiguus
Cochlear nuclei •
•
Vestibular Nuclei (VIII)
Inferior Olivary Nucleus
Deafness
AICA stroke CN XII Medial Lemniscus
27
Pyramids (corticospinal)
Lateral Medullary Syndrome
Medial Medullary Syndrome •
•
•
•
Corticospinal, medial medial lemniscus, CN 12 Contralateral Hemiparesis
•
•
Contralateralloss ofproprioception/vibration proprioception/vibration Flaccid paralysis tongue •
•
Wallenberg's Syndrome
•
•
Deviation to side of lesion
•
Anterior spinal artery stroke
How to Find Lesions Option 1: Know the syndromes
•
Option 2: Use the Rule of 4s
Spinothalamic Spinothalamic tract:Contralateralpain/temp Spinal V nucleus: ipsilateral face pain/temp Nucleus ambiguus (IX, X) •
•
•
Vestibular nuclei: Nystagmus, vertigo, N/V Sympathetictract: Horner’s syndrome
Hoarseness, dysphagia
PICA Stroke
Rule of 4s •
•
•
4 CNs in:
•
4 midline columns
•
Medulla
•
Motor nucleus
•
Pons
•
Motor pathway
•
Above Pons
•
MLF
•
Medial Lemniscus
4 CNs divide into 12 •
III, IV, VI, XII
•
Motor nuclei are midline
•
4 CNs do not divide/12
4 lateral (side) columns •
Sympathetic
•
Spinothalamic
•
V, VII, IX, XI
•
Sensory
•
All are lateral
•
Spinocerebellar
Dr. Peter Gates. The rule of 4 of the brainstem: a simplified method for understanding brainstem anatomy and brainstem vascular syndromes for the non-neurologist. Internal Medicine Journal Volume 35, Issue 4, pages 263–266, April 2005
4 Above Pons CNs
Localizing Lesions •
Medial vs. Lateral
•
Medulla vs. Pons vs. Midbrain
•
•
Which tracts affected? Which cranial nerves affected?
28
4 Pons CNs
4 Medulla CNs
Midline Structures (M)
Side/Lateral Structures (S)
Rule of 4s Caveats
Case 1
•
•
Trigeminal Nerve (V) •
Lesion: loss of ipsilateral pain/temp face
•
Rule of 4 Pons Nuclei and and side (lateral tract)
•
Don’t use to localize to Pons
•
Use for lateral lateral tract localization
•
Vestibulocochlear (VIII) •
Don’t use vestibular sings to localize to pons
•
Vestibular signs can be medulla/pons
•
Lesion: hearing loss
29
A 75-year-old man presents for evaluation of weakness. He reports that two hours ago he suddenly was unable to move his left arm or leg. He denies any difficulty with speech. On examination, he is able to move all facial muscles normally. There is no ophthalmoplegia. ophthalmoplegia. On tongue protrusion, the tongue is deviated to the right. He in unable to detect lower or upper extremity vibration on the left.
Brainstem Blood Supply
Case 1
Lateral •
Complete motor weakness
•
Tongueinvolved:brainstemlesion
•
Motor pathway involved – left side weak
•
Medial lemniscus involved left (vibration/prop) (vibration/prop)
•
•
•
•
•
•
Not MCA or ACA stroke
4
Right medial lesion
AICA Basilar
Right medial lesion
Case 2 Right sided weakness Left eye down/out, dilated
•
Right sided weakness •
Motor pathway
•
Medial lesion
•
Complete motor loss: not MCA, ACA
Left eye down/out, dilated
•
Left medial midbrain lesion
•
Case 3
•
•
•
9,10,11
Medulla
•
•
•
12
Pons
Case 2
•
•
5,7,8
ASA
Answer: Right medial medullary syndrome Anterior spinal artery
•
6
PICA
Medulla
•
Midbrain
3
PCA
CN XII involved – tongue deviation •
Medial
CNIII
Weber’s syndrome Stroke of branches of PCA
Case 3
Unable to do left hand finger to nose test
•
Loss of pain and temperature to left face Left eyelid droop, small pupil
•
•
Loss of pain/temp right arm and leg Hoarse voice
•
•
•
Loss of gag reflex left throat
•
•
Palate raised on right side
•
30
Unable to do left hand finger to nose test Loss of pain and temperature to left face
Left ataxia Left CN V
Left eyelid droop, small pupil Loss of pain/temp right arm and leg
Left Horner’s
Hoarse voice
CN X
Loss of gag reflex left throat Palate raised on right side
CN X
Left ST Tract
CN IX
Case 3 •
•
•
•
•
•
•
•
Case 4
Left ataxia = spinocerebellar Left face pain/temp = sensory (CN V) face
•
•
Left Horner’s = sympathetic Right pain/temp = left spinothalamic spinothalamic Speaking, gag, palate = CN IX, X Left lateral medulla Wallenberg's syndrome
•
•
•
•
•
•
•
Right facial numbness No corneal reflex Right facial spasms
Left PICA stroke
Rule of 4s
Case 4 •
Right deafness/tinnitus deafness/tinnitus Loss right finger to nose
Right deafness/tinnitus deafness/tinnitus Loss right finger to nose Right facial numbness No corneal reflex Right facial spasms
Right VIII Midline
Side Sympathetic Spinothalamic Sensory V Spinocerebellar
Right spinocerebellar Right sensory Right CN V Right CN VII
3
Motor Motor Nucleus Motor Pathway MLF Medial Lemniscus
Right Lateral Pons Cerebellopontine angle syndrome Often caused by tumors (schwannomas)
S
Brainstem Blood Supply Lateral
Medial
Midbrain
3
PCA
4
AICA Basilar
6
5,7,8
12
9,10,11
Pons
Medulla
PICA ASA
31
Midbrain
4
M
6
5,7,8
12
9,10,11
Pons
Medulla
Cranial Nerves •
•
•
Cranial Nerves
12 nerves with roots in brainstem and CNS Sensory , Motor, Motor, Visceral Things to know: •
Sensory vs. Motor vs. Both
•
Special features
•
Lesions
Jason Ryan, MD, MPH
Olfactory (I)
Optic (II) Right Optic Nerve Compression
•
•
•
•
•
•
Smell (sensory) Pathway: cribriform plate of ethmoid bone
•
Synapse in olfactory bulb piriform cortex Lesions: anosmia
•
•
Only sensory nerve no thalamus input Damage by trauma •
•
•
Skull fracture •
Rarely infections or tumors
Oculomotor (III) •
•
•
•
Up (superior rectus)
•
Medial (medial rectus)
•
Inferior (inferior rectus)
•
Superior rotation (inferior oblique)
Not really a peripheral nerve Arises from diencephalon diencephalon •
Embryonic structure
•
In adults: upper upper end of brain stem
•
Thalamus, hypothalamus
Only CN I & II found outside brainstem
Trochlear(IV)
Moves eye •
Sight (sensory) Pathway: optic canal of the sphenoid bone
•
•
•
Elevates eyelid ( levator palpebrae) Pupillary constriction (sphincter pupillae) Palsy: eye down, out, pupil dilated, ptosis
•
32
Eye movement (motor) Smallest cranial nerve Superioroblique •
Turns eye down/in
•
Reading/stairs
Palsysymptoms •
Diplopia
•
Eye tilted outward
•
Unable to look down/in (stairs, (stairs, reading)
•
Head tilting away from affected side (to compensate)
Trigeminal (V) •
•
•
•
Sensory and Motor Key function: Sensor (touch-pain-temp) to face
•
Largest cranial nerve 3 divisions: ophthalmic, maxillary, mandibular •
•
Trigeminal (V)
•
•
•
•
•
•
•
•
Numb face
•
Weak jaw deviates to affected side
•
Trigeminal neuralgia
V1, V2, V3
•
3 important functions: functions:
Unopposed action of normal side Recurrent, sudden sharp pains in half of face
•
Tic douloureux (painful tic)
•
Part of corneal reflex (sensory, (sensory, V1)
•
So intense you wince (“tic”)
•
Muscles of mastication (chewing)
•
Treatment:Carbamazepine
Abducens (VI)
Touch eye with Q-tip Sensed by V1 of CN V
•
•
Transmit to VII (bilaterally) CNVII blink
•
Key points: •
Need CN V for sense
•
Need CN VII for blinking
Facial (VII) •
•
•
Corneal Reflex •
Palsy
Palsy •
Diplopia
•
Can’t laterally move (look out) affected eye
Lower Facial Droop
Motor, sensory
•
Muscles of facial expression Taste, salivation, lacrimation •
Some ear muscles Specialfeature •
Eye movement (motor) Lateral rectus
UMN damage (MCA Stroke) Stroke) •
Upper face intact (dual supply)
•
Lower face affected
LMN damage •
Dual UMN innervation
33
Whole half of face affected
Bell’s Palsy
Facial (VII) •
•
Idiopathic mononeuropathy mononeuropathy of CN VII
•
Loss of corneal corneal reflex (motor part)
•
Facial paralysis
•
Loss of taste anterior 2/3 tongue
•
Usually resolves in weeks to months
•
Hyperacusis (stapedius paralysis)
•
Thought to be due to to HSV-1 induced nerve nerve damage
•
Other causes of CN VII neuropathy neuropathy (technically not BP)
Palsy
•
Pt cannot tolerate sounds
Vestibulocochlear Vestibulocochlear (VIII) •
•
•
•
•
Vestibular portion •
Lyme
•
Tumor
•
Stroke
Testing CN VIII
Sensory Equilibrium, balance, hearing •
•
Compensatory eye movements
Awake patient •
Ask them to focus eyes eyes on object while you rotate rotate head
•
If eyes stay fixed both CN VIII are working
•
VIII lesion “Doll’s eyes” CN VIII
•
Lesions: vertigo, nystagmus, disequilibrium
Cochlear portion •
Hearing
•
Lesions: tinnitus, tinnitus, hearing loss
Testing CN VIII
When head rotate toward lesion side, eye moves with head then quickly adjusts adjusts when the head stops moving (saccade)
Testing CN VIII
•
Unconscious Unconscious patient
•
Unconsciouspatient
•
Inject cold water into ear
•
Inject warm water into ear
•
Cold water disrupts CN VIII function
•
•
Eyes slowly move toward cold water
•
Creates “relative” opposite side CN VIII dysfunction
•
Rapid correct opposite side
•
Eyes slowly move away away warm water
•
Normal response is slow toward cold cold then fast away
•
Rapid correct back back towards warm water
•
If CN VIII not working, no slow toward
•
Normal response is slow away then fast toward
•
If cortex not working, working, slow toward, no fast away
•
If CN VIII not working, no slow away
•
If cortex not working, slow away, away, no fast toward
34
Warm water stimulates CN VIII function
Testing CN VIII •
COWS: Cold Opposite, Warm Same •
•
Glossopharyngeal (IX) •
Named for side of fast correction
•
Easy way: •
•
If warm or cold water in ear yields no eye response, lesion is on that side
•
Motor, Sensory Taste/sensation posterior 1/3 tongue Swallowing Salivation(parotidgland)
•
Carotid body and sinus
•
Stylopharyngeus(elevatespharynx)
•
Glossopharyngeal Glossopharyngeal (IX) •
•
Vagus (X)
Palsy •
Loss of gag reflex
•
Loss of taste posterior 1/3 tongue
•
Loss sensation sensation upper pharynx/tonsils
•
•
•
•
Hemodynamic Hemodynamic effects •
•
•
Tricks body into thinking low BP
•
↑HR, Vasoconstriction, ↑BP
Motor, sensory Taste epiglottis Swallowing (dysphagia = vagus) Palateelevation Midline uvula Talking
•
Coughing
•
Autonomicsystem •
Vagus (X) •
•
Chemo- and baroreceptors
Aortic arch chemo/baroreceptors
Cranial Nerve Speech Test
Palsy
•
“Kuh kuhkuh” kuh kuh”
•
Hoarseness, dysphagia, dysarthria
•
CN X
•
Loss of gag reflex
•
Raise palate
•
Loss of sensation pharynx and larynx
•
Weak side of palate collapses collapses (lower)
•
Uvula deviates AWA AWAY Y from affected side
•
Hemodynamic Hemodynamic effects •
Unopposed sympathetic stim of heart
•
Result is ↑HR
•
35
“Mi mi mi” •
CN VII
•
Move lips
“La La La” •
CN XII
•
Move tongue
Recurrent Laryngeal Nerve •
•
Branch of vagus Ascends towards larynx between trachea/esophagus •
•
•
Vasovagal Syncope •
•
"tracheoesophageal groove”
•
Right RL: loops around R subclav Left RL: loops around aortic arch Compression hoarseness
•
Dilated left atrium (mitral stenosis)
•
Aorticdissection
•
•
Accessory (XI) •
•
•
•
Shouldershrugging Sternocleidomastoid
•
Trapezius
Hypoglossal (XII) •
•
•
Motor
•
•
Hot weather
•
Prolonged standing
•
Pain
•
Sight of blood
Palsy •
Difficulty turning head head toward normal side (SCM)
•
Shoulder droop (affected side)
Cranial Nerve Reflexes •
Tongue movement Palsy: •
Increased parasympathetic outflow via vagus
↓HR ↓BP fainting Many triggers
Accessory (XI)
Motor Turninghead •
Most common cause of syncope (fainting) Trigger to vagus nerve
Corneal •
•
V1 sense, sense, VII blinki ng
Lacrimation
Protrusion of tongue TOWARD TOWARD affected side
•
V1 sense, VII VII for tearing
Opposite side pushes tongue away unopposed
•
Cut V1 No reflex tears, Yes emotional tears
•
Gag •
36
IX sense, X gag
Cranial Nerve Reflexes •
Jaw Jerk •
•
Tongue •
•
Jaw will jerk upwards
•
V3 sense, V3 jerk (Trigeminal nerve nerve test)
•
•
•
Pupillary •
II senses light
•
III constricts pupil
Motor: •
Place finger patient’s chin and tap finger
General Sensory (pain, pressure, temp, touch) •
•
•
•
•
•
Cranial Nerve Skull Skul l Pathways •
•
•
Cribriformplate – CN I Middle cranial fossa – CN II-VI •
CNII: Optic canal
•
III, IV, V1, VI: Superior orbital fossa
•
V2: Foramen rotundum
•
V3: Foramen Ovale
Posterior cranial fossa – CN VII-XII •
VII, VIII: Internal Internal auditory meatus
•
IX, X, XI: Jugular for amen
•
Foramen magnum: XI (also brainstem)
•
XII: Hypoglossal canal
37
Anterior 2/3: Mandibular branch (CN V3) Posterior 1/3: Glossopharyngeal (IX) Tongue root: CN X
Taste •
•
Hypoglossal (XII) Lesion deviates tongue to affected affected side One exception: palatoglossus (CN X)
Anterior 2/3: CN VII Posterior 1/3: Glossopharyngeal (IX) Tongue root, larynx, upper esophagus: esophagus: CN X
Terminal sulcus separates ant 2/3 from post 1/3
How We Hear •
•
•
Auditory System
•
Jason Ryan, MD, MPH •
Auditory Pathway •
•
•
•
•
•
•
Tiny bones
•
Amplify tympanic membrane motion
Stapes pushes fluid-filled cochlea Tiny hair hair cells stimulated •
Organ of Corti
•
Different frequencies of sound move move different fibers
Nerve (electrical) signal generated
Types of Hearing Loss
Cochlear nerve (CN VIII) Cerebellopontineangle
•
Conductive •
Sound waves can’t covert to nerve signals
•
Lateral Pons
•
Obstruction (wax)
•
Watch for brainstem brainstem lesions with hearing hearing loss
•
Infection (otiti s media)
•
Otosclerosis (bony overgrowth of stapes)
Connects with many structures •
Sensorineural
•
Superior olivary nucleus nucleus
•
Trapezoid body
•
Cochlea disease
•
Lateral lemniscus
•
Cochlear nerve failure (acoustic neuroma)
•
Inferior colliculus
•
CN damage
•
Medial geniculate body
•
Transverse temporal gyri of Heschl
Presbycusis •
Sound waves cause tympanic membrane vibration Malleus, incus, stapes
Weber Test
Age-related hearing loss
•
Degeneration of Organ of Corti Results in sensorineural hearing loss Slow development over time
38
Vibrating tuning fork
•
Bridge of the forehead, nose, or teeth
•
Should be equal in both ears
Weber Test
Rinne Test •
Tuning fork placed mastoid bone (behind the ear)
•
Wait until patient no longer hears
•
Move tuning fork to just outside ear
•
Ask if patient can still hear
•
•
Normal Signal equal both ears
Conductive Louder bad ear No background noise
Tests bone conduction => vibration waves through bone
Tests air conduction only
Sensorineural Louder good ear No nerve to sense vibration
If sound goes to one side, tells you there is a hearing defect Does not tell you which type
Diagnosing Hearing Loss
Rinne Test •
Normal patient can still hear next to ear
•
ConductiveLoss
•
•
AC > BC
•
Patient CANNOT hear hear next to ear
•
AC
Sensorineuralloss •
Patient can still hear next next to ear
•
Both AC and BC reduced
•
AC still > BC
Normal AC>BC Weber Equal
Noise-induced Noise-induced Hearing Loss •
Sudden after loud noise noise •
•
Tympanic membrane rupture
Long term noise exposure •
Damage to ciliated ciliated (hair) cells Organ of Corti
•
High-frequency hearing lost first
39
Vestibular System •
•
Vestibule: Central portion inner ear Found within temporal bone
•
Contains system for balance, posture, equilibrium
•
Also coordinates head and eye movements
Vestibular System Jason Ryan, MD, MPH
Vestibular System •
Vestibular System
Three semicircular canals (x, y, z planes of motion)
•
Respond to ROTATION ROTATION of h ead
•
Respond to LINEAR LINEAR motion
•
Filled with endolymph
•
Gravity, moving forward/backward
•
Bulges at base base (ampulla)
•
Contain otoliths (Greek (Greek word: ear stones)
•
Ampulla have hair cells that bend with rotation
•
Calcium carbonate crystals
•
Hair cells release neurotransmitters
•
Sit on top of hair cells
•
More/less signals signals based on motion
•
Drag hair cells in response to motion
•
This generates vestibular neural activity
action potential
Vestibular Nerve Signals •
•
Vestibular Dysfunction
Vestibulocochlear nerve •
•
Utricle and saccule (otolith organs)
•
•
Two nerves in 1 sheath: Vestibular & Cochlear
•
Vestibular nerve •
Send signals to brainstem (vestibular nuclei)
•
Also sends signals to Cerebellum
Vestibular nuclei •
Beneath floor of 4 th ventricle in pons/medulla
•
Receive input from vestibular nerve
•
Many outputs: Cerebellum, CNs III, IV, VI, Thalamus
Vertigo: Room spinning when head still
40
Contrast with dizzy, lightheaded
•
Nystagmus : Rhythmic oscillation of eyes
•
Nausea/vomiting
Nystagmus
Nystagmus •
•
Right Ear CN VIII
CN VIII
Left Ear
•
•
•
•
•
•
Seen with “peripheral” “peripheral” vestibular dysfunction
Upbeat, downbeat •
Seen with “central” “central” vestibular dysfunction •
Clinical Features •
“Jerk” nystagmus named for fast direction •
Left
•
Right
•
Torsional/rotational
•
Upbeat
•
Downbeat
Pendular nystagmus – Rare, congenital
Nystagmus/Vertigo
Left, right,torsional/rotational torsional/rotational •
Vestibulardysfunction disrupts reflex Eyes move slowly one direction fast correction
Central vs. Peripheral
Nystagmus •
Vestibulo-ocular reflex Focuses eyes when body moves
Peripheral = Benign (usually) •
Inner ear problem
•
Benign positional positional vertigo (BPV)
•
Vestibular neuritis
•
Meniere's disease
Central = BAD •
Brainstem or cerebellar cerebellar lesion
•
Vertebrobasilar stroke/TIA
•
Cerebellar infarction/hemorrhage
•
Tumor (posterior fossa)
Clinical Features
Central Vertigo
•
Peripheral Features
•
Purely vertical nystagmus
•
•
Nystagmus changes direction with gaze
•
Positional testing: DELAYED DELAYED nystagmus
•
Positional testing: IMMEDIATE nystagmus
•
Nystagmus may fatigues with time
•
Skew deviation: Vertical Vertical misalignment of eyes
•
No other symptoms
•
Diplopia, Dysmetria (ataxia)
•
Normal proprioception, stable Romberg
•
Other CNS symptoms (weakness, sensory)
41
Mixed horizontal/torsional horizontal/torsional nystagmus
Dix-Hallpike Maneuver •
Done to reproduce vertigo and cause nystagmus
•
Seatedpatient
•
Extend neck, turn head to side
•
Rapidly lie patient down on table
•
Dix-Hallpike Maneuver •
Let head hang over end of table
•
•
•
No symptoms for 5-10 seconds
•
Vertigo develops
•
Torsional nystagmus develops
•
Symptoms resolve with sitting up
•
Fewer symptoms wi th repeated maneuvers
Labyrinthitis •
Vertigo with head turning/position Due to calcium debris semicircular canals •
•
•
Vestibular Neuronitis
Benign Positional Vertigo •
Typical result in BPV
•
Canalithiasis
Diagnosis: Dix Hallpike Maneuver Deviations from typical result = consider imaging
Cause of vertigo Neuropathy of vestibular portion CN VIII
•
Benign,self-limited
•
Usually viral or post-inflammatory
Epley Maneuver can reposition otoconia
Meniere’s Disease
Meniere’s Disease
•
Endolymph fluid accumulation (hydrops)
•
•
Swelling of the labyrinthine system
•
•
42
Tinnitus Sensorineural hearing hearing loss •
Weber louder normal ear
•
Rinne: AC>BC
Vertigo
Meniere’s Disease •
Treatment •
Avoid high salt – decrease decrease swelling
•
Avoid caffeine, nicotine –vasoconstrictors, ↓flow from inner ear
•
Diuretics
43
Subcortical Structures
Thalamus, Hypothalamus, Limbic System
•
•
•
•
Jason Ryan, MD, MPH
Coronal Section
Thalamus Hypothalamus LimbicSystem Basal Ganglia •
Substantia Nigra
•
Subthalamic nucleus
•
Putamen
•
Caudate nucleus
•
Globus pallidus
Axial Section
Thalamus
Thalamus
Thalamus •
•
•
•
•
Thalamic Nuclei
“Gateway to the cortex” Greek word: “Inner chamber” Sits on top of brainstem
Consciousness
•
Sleep
•
Alertness
Most named by location location
•
Six nuclei worth knowing knowing •
Except olfaction
•
Many, many thalamic nuclei
•
•
Symmetrical– two halves Sensory relay cortex •
•
44
Anterior, posterior, ventral, medial Ventral Ventral posterolateral (VPL)
•
Ventral posteromedial (VPM)
•
Lateral geniculate nucleus (LGN)
•
Medial geniculate nucleus (MGN)
•
Ventral lateral (VL)
Thalamic Syndrome
Thalamic Nuclei
•
•
•
Usually a lacunarstroke Contralateral sensory loss •
Face, arms, legs
•
All sensory modalities
Resolution can lead to long term chronic pain •
Hypothalamus •
•
Contralateral side
•
Sensory exam normal
•
Severe pain in paroxysms or exacerbated exacerbated by touch
Hypothalamic Functions
Found below thalamus Like thalamus, many nuclei with different functions
•
Autonomiccontrol
•
Temperature regulation
•
•
•
Excites sympathetic/parasympathetic system
Water balance Pituitarycontrol
Fever
Hypothalamic Areas
•
•
•
•
•
•
45
Triggered by py rogens, inflammatory proteins IL-1, IL-6, and TNF enter brain Stimulate prostaglandin E2 synthesis •
Via arachidonic acid pathway
•
Mediated by PLA2, PLA2, COX-2, and prostaglandin E2 synthase
Increases anterior hypothalamus set point Temp >42C = hyperpyrexia May cause permanent brain damage •
Facilitate heat loss: cooling blankets, blankets, fans
•
Lower set point: NSAIDs, tylenol (block PGE2 PGE2 synthesis)
Hormones •
•
•
•
•
Hormones
Hypothalamus Hypothalamus releases multiple hormones to stimulate release of other hormones from anterior pituitary
•
TRH TSH CRH ACTH GHRH Growth Hormone (GH)
•
•
•
•
•
•
Dopamine (prolactin inhibiting hormone) ↓Prolactin
•
Somatostatin (GHRH inhibiting hormone) hormone) ↓ GH
Prolactinfeedback ↓ GnRH
GNRH FSH, LH
Hormones •
Some HT substances shut down hormone release
Leptin
ADH and Oxytocin synthesized by HT Supraoptic nucleus ADH
•
•
Paraventricular Paraventricular nucleus Oxytocin Both stored/released by posterior pituitary •
** Post. Pituitary also also called neurohypophysis
•
** Ant. Pituitary also called adenohypophysis
•
•
•
Hormone secreted by adipocytes Involved in food intake Regulation of homeostasis Lateral HT (hunger) inhibited by Leptin Ventromedial (satiety) stimulated by Leptin
Loss of ADH Diabetes Insipidus •
Polyuria, polydipsia, dilute dilute urine
Craniopharyngioma
Hypothalamic Syndrome
•
Rare tumor from Rathke’s pouch
•
•
Pressure on optic chiasm chiasm
•
•
Pressure on hypothalamus hypothalamus
•
Hypothalamic syndrome
•
Bitemporal hemianopia
•
•
46
Diabetes insipidus (loss of ADH) Fatigue (loss of CRH low cortisol) Obesity Loss of temperature regulation
Limbic System
Limbic System •
•
•
•
•
Key Components
Emotion Long-termmemory
•
•
Smell Behavior modulation
•
•
Autonomic nervous system function
•
Kluver-Bucy Syndrome •
•
•
•
•
•
•
•
Hyperorality - tendency to examine with mouth InappropriateSexualBehavior
•
•
Atypical sexual behavior, mounting inanimate inanimate objects
Visual Agnosia •
Wernicke:Acute encephalopathy encephalopathy
•
Korsakoff:Chronicneurologiccondition •
Very sensitive to hypoxic damage Infarction: •
Hippocampal branches PCA
•
Anterior choroidal choroidal arteries
Wernicke-Korsakoff Syndrome •
Usually a consequence consequence of Wernicke
Both associated with: •
Thiamine (B1) deficiency deficiency
•
Alcoholism
•
Atrophy of mammillary mammillary bodies common finding •
•
Anterogradeamnesia Cannot make new memories
Inability to recognize recognize visually presented objects
•
•
Mammillary bodies
Rare complication of HSV1 encephalitis
Wernicke-Korsakoff Syndrome
•
Fornix Amygdala
Hippocampus Lesion
Damage to bilateral amygdala (temporal lobes) Hyperphagia - Weight gain
•
Cingulate gyrus Hippocampus
80% for both conditions
Associated with damage to thalamic nuclei
47
Triad Wernicke: •
Visual disturbances/nystagmus
•
Gait ataxia
•
Confusion
•
Often reversible with thiamine
Korsakoff:Amnesia •
Recent memory affected more than than remote
•
Can’t form new memories
•
Confabulation: Can’t remember so make things up
•
Lack of interest or concern
•
Personality changes
•
Usually permanent
Wernicke-Korsakoff Syndrome •
•
Wernicke precipitated by glucose without thiamine •
Thiamine co-factor glucose metabolism
•
Glucose will worsen thiamine deficiency
Banana bag •
IV infusion to alcoholics
•
Thiamine, folic acid, and magnesium sulfate
48
Cerebellum •
•
“Littlebrain” “Little brain” Posture/balance
•
Muscle tone
•
Coordinates movement
Cerebellum Jason Ryan, MD, MPH
Cerebellar Peduncles
Inferior Cerebellar Peduncle
In and Out Pathways •
•
•
Inferior cerebellar peduncle Middle cerebellar peduncle
•
•
Superior cerebellar peduncle
•
Middle
•
Cerebellum
Major pathway INTO cerebellum from spine Numerousinputs:
Superior
Spinocerebellar tract
•
Cuneocerebellar tract
•
Olivocerebellar tract
•
Vestibulocerebellar tract
Ipsilateral spinal cordinformation: cord information:proprioception Middle
Inferior
Inferior
Middle Cerebellar Peduncle Pontocerebellar tract fibers
•
•
Fibers from contralateralpons contralateralpons
•
•
•
Middle
Inferior
Superior
Climbing and Mossy Fibers
•
Cerebellum
Cerebellum
Superior
49
Two types of axons that e nter cerebellum Climbing fibers: arise from inferior olivary nucleus Mossy fibers: all other cerebellar inputs Synapse on Purkinje cells and deep nuclei
Superior Cerebellar Peduncle •
•
•
•
Purkinje Cells
Major pathway OUT of cerebellum Axons from deep cerebellar nuclei
•
•
All outputs originate from deep nuclei Fibers to red nucleus and thalamus
•
•
•
Cerebellarneurons Receive numerous inputs Project to deep nuclei Inhibitory Release GABA
Middle
Inferior
Cerebellum
Superior
Cerebellar Circuitry
Deep Nuclei •
•
Projections OUT of cerebellum Dentate nucleus: •
•
•
•
Contralateral VA/VL nuclei nuclei of thalamus
iddle Peduncle nferior Peduncle ClimbingFibers Mossy Fibers
Contralateral red nucleus
Fastigial: •
Outputs
Inputs
Interposed nuclei:globose/emboliform
Vestibular nuclei and reticular formation
Cerebellum Purkinje Cells Deep Nuclei
Cerebellum Control •
•
•
•
•
•
Clinical Disease
In general, cerebellum controls IPSILATERAL side
•
Cerebellar fibers contralateral contralateral cortex Contralateral Contralateral cortex contralateralarm/leg Crosses twice Also right proprioception rightcerebellum
•
Result: •
Left cerebellar lesion left symptoms
•
Right cerebellar lesion
right symptoms
50
Lateral lesions •
Cerebellar hemispheres
•
Dentate nucleus
•
Affect extremities
Midline lesions •
Vermis
•
Emboliform, globus and fastigial nuclei
•
Floculonodular lobe
•
Affect trunk
Deep Nuclei
Lateral Lesions •
•
•
•
Central Lesions
Extremities Direction, force, speed, and amplitude of movements
•
•
Lesions: •
Dysmetria
•
Intention tremor
Fall toward injured side
•
Cerebellar Ataxia Loss of balance
•
•
Classically a “wide-based” gait
•
•
•
•
•
•
Truncal ataxia
•
Can’t stand independently
•
Falls over when sitting
Flocculonodularlobe •
Connects to vestibular vestibular nuclei
•
Lesions: nystagmus, vertigo
Test for sensory (not cerebellar) ataxia Loss of proprioception: proprioception: compensate though vision Feet together, eyes closed Positive test: patients will lose balance or fall If test positive: ataxia is SENSORY Cerebellar ataxia occurs even with eyes open
Dyssynergia
Other Cerebellar Cerebellar Symptoms
•
•
Romberg Test
•
•
Affect trunk/midline trunk/midline Central (vermis)
Loss of coordinated activity
Hypotonia
•
Dysmetria
•
Loss of muscle resistance to passive manipulation
•
Loss of movement coordination
•
Loose-jointed, floppy joints
•
Under or over-shoot intended position of hand
Scanningspeech
•
Intention tremor
•
Irregular speech
•
Can’t get hand to target
•
“How are you doing?”
•
Contrast with resting tremor (Parkinson’s)
•
“How…are…you…do…ing”
•
Dyssynergia
51
Dysdiadochokinesia •
Can’t make movements exhibiting a rapid change of motion
•
Can’t flip hand in palm
Other Cerebellar Cerebellar Symptoms •
Cerebellar Strokes
Nystagmus •
Up/down beat (vertical) (vertical)
•
Gaze-evoked
•
Nausea/vomiting
•
Vertigo
Hereditary Ataxias •
•
•
•
•
SCA, AICA, PICA
•
Often has other brainstem stroke signs/symptoms
Ataxia Telangiectasia Telangiectasia
Numeroushereditarydisorders Motor incoordination related to ce rebellum
•
•
Ataxia Telangiectasia Friedreich's Ataxia
Autosomal recessive Cerebellaratrophy •
•
Telangiectasias •
Dilation of capillary capillary vessels on skin
•
Ears, nose, face, face, and neck
•
Repeatedsinus/respiratoryinfections
•
High risk of cancer
•
Ataxia Telangiectasia Telangiectasia •
•
Most children healthy for first year Begin walking at normal age but slow development Progressivemotorcoordinationproblems
•
By 10 years old, most in wheelchairs
•
Other symptoms
•
•
Recurrent sinus/respiratory sinus/respiratory infections
•
Telangiectasias
Severe immunodeficiency
Ataxia Telangiectasia Telangiectasia
Clinical Features •
Ataxia in 1 st year of life
•
Cause: DNA hypersensitivity to ionizing radiation
•
Defective ATM gene on chromosome 11
•
High risk of cancer
52
•
Ataxia Telangiectasia Mutated gene
•
Repairs double stranded DNA breaks
•
Nonhomologous end-joining (NHEJ)
Mutation: Failure to repair DNA mutations
Ataxia Telangiectasia Telangiectasia
Friedreich’s Ataxia
Lab Abnormalities Abnormalities •
↑AFP •
•
•
Often elevated in pregnant women
•
Also elevated in ataxia telangiectasia
•
Most consistent consistent lab fi nding
•
•
Dysgammaglobulinemia •
Low or absent absent IgA •
•
•
•
•
Degeneration of spinocerebellar spinocerebellar tract Ataxia, dysarthria
•
Loss of spinal cord: dorsal columns
•
Loss of corticospinal corticospinal tract
•
•
Increased number of trinucleotide (GAA) repeats present
•
More repeats = worse prognosis
•
Leads to decreased decreased frataxin levels
Frataxin:mitochondrial Frataxin:mitochondrial protein •
High levels in brain, heart, and pancreas
•
Abnormal frataxin mitochondrial dysfunction
Other Features
Begins in adolescence with progressive symptoms Cerebellar and spinal cord degeneration •
Needed for normal mitochondrial mitochondrial function
•
Friedreich’s Ataxia
Friedreich’s Ataxia •
Autosomal recessive Mutation of frataxin gene chromosome 9
Hypertrophic cardiomyopathy Diabetes •
Insulin resistance and impaired insulin release release
•
Beta cell dysfunction
Position/vibration UMN weakness in lower extremity
Friedreich’s Ataxia
Other Cerebellar Disorders
Other Features •
Kyphoscoliosis
•
Foot abnormalities (pes cavus)
•
Tumors •
Pilocytic astrocytoma Medulloblastoma Ependymoma
•
High arch of foot; does not flatten with weight weight bearing
•
•
Seen in other other neuromuscular diseases (Charcot-Marie-Tooth)
•
•
53
Congenitaldisease •
Dandy Walker malformation
•
Chiari malformations
Basal Ganglia •
•
•
•
•
Basal Ganglia
Substantia Nigra Subthalamic Subthalamic nucleus Putamen Caudate nucleus Globuspallidus
Jason Ryan, MD, MPH
Basal Ganglia
Basal Ganglia Terms Thalamus
Caudate Nucleus Putamen
•
Globus Pallidus •
Striatum = Putamen + Caudate •
Also called striate nucleus
•
Putamen/Caudate divided by internal capsule
•
Major INPUT from cortex
Lentiform Nucleus = Putamen + Globus Palidus
Subthalamic Nucleus Substantia Nigra
Function •
•
•
•
Movement Execution Pre-Motor Cortex Decides To Execute a Movement
Modifiesvoluntarymovements Receives cortex input Provides feedback to cortex to either •
#1: Stimulate motor activity
•
#2: Inhibit motor activity
Basal Ganglia Activated
Combination stim/inhibition complexmovements Direct Pathway ACTIVATES 1°Motor Cortex
Indirect Pathway INHIBITS 1°Motor Cortex
Complex Movement/Action
54
To Stimulate Movement
Basal Ganglia Connections
Direct Pathway
Brainstem Spinal Cord
Cortex
+
Brainstem Spinal Cord
Cortex
Substantia Nigra Thalamus
-
Substantia Nigra
Pars Compacta
Striatum
Glutamate
Thalamus
Striatum
Pars Reticulata
GABA
GABA
GP Externus GP Internus
GABA
Key Points
Indirect Pathway Brainstem Spinal Cord
Cortex
•
Substantia Nigra D2
Striatum
Globuspallidus internus
Subthalamic Nucleus
To Inhibit Movement
Thalamus
Pars Compacta Pars Reticulata
GABA
-
Subthalamic Nucleus
D1
Pars Compacta Pars Reticulata
•
Direct pathway •
Goal is to create movement
•
Striatum inhibits (GABA) (GABA) GPi and Pars Reticulata
•
GPi and Pars Pars STOP inhibiting Thalamus
•
Thalamus free to activate cortex
Modifier: SN pars compacta modifies striatum via D1
+GABA +GABA
Subthalamic Nucleus
GP externus GP internus
Key Points •
•
Pars Compacta
Indirect pathway •
Goal is to further further inhibit movement
•
Striatum inhibits GPe (GABA)
•
GPe stops inhibiting Subthalamic nucleus
•
Subthalamic nucleus stimulates GPi
•
GPi further inhibits inhibits thalamus
Direct Pathway D1
Striatum
Substantia Nigra Pars Compacta
Modifier: SN pars compacta modifies striatum via D2
Indirect Pathway D2
55
Basal Ganglia Connections
Movement Disorders •
•
•
•
•
Parkinson’s disease Huntington'sDisease
-
Hemiballism Wilson’s Disease
Cortex
Huntington’s -
All result from damage to part of basal ganglia
Thalamus
Striatum
Brainstem Spinal Cord Substantia Nigra Pars Compacta Pars Reticulata Parkinson’s
Subthalamic Nucleus Hemiballism
56
GABA
GP Externus GP Internus GABA
Wilson’s
CNS Ventricles •
Ventricles and Sinuses
•
Four structures that contain CSF in brain •
Two lateral ventricles
•
3rd ventricle
•
4th ventricle
Continuous with central canal of spinal cord
Jason Ryan, MD, MPH
Ventricles
Cerebrospinal Cerebrospinal Fluid •
•
•
CSF Production •
•
•
•
Ependymal cells of choroid plexus plexus (ventricles)
•
Absorption •
Arachnoid villi
CSF drained to superior sagittal sinus •
•
Mechanical protection
•
Shock absorber
Also circulates nutrients removes waste
Choroid Plexus Cysts
Production •
Clear, colorless fluid Acts as cushion for brain
Then to venous system
57
Can be detected by ultrasound in utero A normal finding but associated with chromosome chromosome abnormalities
Communicating Hydrocephalus
Hydrocephalus •
•
•
•
Dilation of ventricles Excessive accumulation of CSF
•
•
Communicating •
Ventricles CAN communicate
•
CSF not being absorbed
•
•
Non-communicating •
There is a blockage to flow
•
Ventricles CAN’T communicate
↓ CSF absorption by arachnoid, ↑ ICP Headache Key sign: papilledema papilledema CT Hallmark: Dilation ALL ventricles
•
Often occurs from scarring after meningitis
•
Can cause herniation herniation
•
Key clinical scenario •
Non-Communicating Hydrocephalus •
•
•
•
•
•
Manyetiologies Three worth knowing: knowing: Aqueductal stenosis
•
Chiari Malformations
•
Dandy Walker malformation
•
•
•
•
•
Enlarged ventricles on on CT scan
Stenosis of cerebral aqueduct Blocked drainage from 3rd to 4th ventricle
•
Congenitalnarrowing
•
Inflammation due to intrauterine infection
•
Presentation: Enlarging head circumference
•
X-linked (boys)
Rubella, CMV, toxo, syphilis
Dandy Walker Malformation
(Spina Bifida)
•
Papilledema on eye exam
•
Myelomeningocele •
Headache
•
Aqueductal Stenosis
Structural blockage blockage of CSF flow within ventricles Oftencongenital
•
Prior meningitis
•
Type of neural tube defect
•
Failure of spine and meninges to close around cord Myelomeningocele: Myelomeningocele:cord/meninges outsidespine
•
•
Almost always has Chiari II malformation Hydrocephalus major cause morbidity
•
•
Obstruction 4th ventricular outflow
•
58
Developmental anomaly of the fourth ventricle Hypoplasia or agenesis of cerebellar vermis Cysts of 4th ventricle hydrocephalus Massive 4th ventricle, small cerebellum Many, many associated symptoms/conditions Affectedchildren •
Hydrocephalus (macrocephaly)
•
Delayed development
•
Motor dysfunction (crawling, walking)
Normal Pressure Hydrocephalus (NPH)
Pseudotumor Cerebri •
•
•
•
•
•
•
•
Idiopathicintracranialhypertension ↑ICP in absence of tumor or other cause Intractable,disablingheadaches Papilledema, visual loss Pulsatiletinnitus
•
•
•
•
•
•
•
•
Classic triad:
Rushing water or wind sound
•
Urinary incontinence, incontinence, gait disturbance, dementia
•
Transmission of vascular pulsations
•
Wet, wobbly, and wacky
Classic patient: overweight woman, childbearing age Diagnosis: spinal tap (measure pressure)
•
Treatment: Ventriculoperitoneal(VP) Shunt •
Drains CSF to abdomen
Medicaltreatment: acetazolamide acetazolamide
Dural Sinuses
Ventricularenlargementthat: •
Occurs with age
•
As cortex atrophies (Alzheimer’s, Pick, HIV)
•
•
•
Brainshrinkage
•
Usually after age 60 Increase size of ventricles •
•
Compression of corona radiata Normal opening pressure on LP Suspected mechanism: Impaired absorption CSF
•
Hydrocephalus ex Vacuo •
Enlarged ventricles on imaging
•
Large venous channels Travel through dura Drain blood from cerebral veins Receive CSF from arachnoid granulations Empty into internal jugular vein
IN PROPORTION to increase increase size of sulci
If out of proportion: hydrocephalus hydrocephalus
Some Key Sinuses
Cavernous Sinus
•
Sagittal – Superior sagittal receives CSF
•
•
Cavernous
•
•
•
•
•
•
59
Large collection veins Bilateral Betweentemporal/sphenoidbones Collects blood eye/cortex Drains into internal jugular vein Many nerves: •
CN III, IV, V1, V2 , VI, VI, sympathetic fibers
•
All traveling to orbit
Also portion of internal carotid artery
Cavernous Sinus Syndrome •
•
•
Compression by tumor, thrombus, fistula Infections of face, nose, orbits, tonsils, and soft palate can spread to cavernous sinus (septic thrombosis) Internal carotid travels THROUGH venous structure •
•
AV Malformations
Rupture carotid
•
•
•
•
fistula
•
Symptoms •
•
•
•
•
Headache Swollen eyes Impairment of ocular motor nerves Horner's syndrome Sensory loss 1 st /2nd divisions trigeminal trigeminal nerve
•
60
Artery to vein connection no capillary bed Enlarge over time Commonly result in Vein of Galen enlargement Usually occur in utero May be asymptomatic until adolescence/adulthood Cause headaches and seizures
Etiology •
Ischemic (80%) •
Cerebral and Lacunar Strokes
•
•
Jason Ryan, MD, MPH
CNS Blood Supply
Insufficient bl ood flow
•
Thrombosis, embolism, hypoperfusion
•
Symptom onset over over hours
Hemorrhagic(20%) •
Brain bleeding
•
Sudden onset
Best first test: Non-contrast CT CT of head
Homunculus
Main Cerebral Arteries: MCA, ACA, PCA
MCA: Upper limb, face ACA: Lower limb PCA: Vision
MCA Stroke Caudate Putamen
•
Globus Pallidus Internal Capsule
Thalamus
61
A 75-year-old man presents with recent onset loss of movement of his right arm. The right side of his face also droops and there is drooling from the corner of his mouth on the right side. He has difficulty speaking.
MCA Stroke •
•
•
•
•
Most common site of stroke Contralateral Contralateral motor/sensorysx
•
•
Arm>leg,face Spastic(UMN) paralysis •
If left sided •
•
•
Lower Facial Droop
Aphasia Speech center center is left sided most patients
Contralateral Motor Cortex
•
Fibers run in corticobulbar tract
MCA stroke damage UMN damage •
Upper face intact (dual supply)
•
Lower face affected
Hemineglect
ACA Stroke
Anterior Cerebral Artery (ACA)
A 75-year-old man presents with acute loss of ability to move his right hip and leg. On exam, he has decreased sensation to pinprick and vibration of his right leg.
•
•
•
•
•
PCA Stroke •
•
If right (nondominant) side •
•
Upper face: Dual UMN supply; right & left Lower face: Single UMN supply
Left ACA stroke Leg>Arm Second most common stroke site Medial cortex (midline portion) Leg-foot area (motor and sensory)
PCA Stroke
An 80-year-old man presents with acute visual loss. He reports difficulty seeing objects on his right side. His wife said he also reports seeing people who are not in the room. On exam, there are no motor or sensory deficits. Visual fields are shown below (black = no vision).
•
•
•
•
•
62
Posterior portion of brain Visualcortex Visual hallucinations hallucinations Visual agnosia (seeing things but can’t recognize) Contralateral hemianopia with macular sparing
Homonymous Hemianopsia
Macular Sparing •
•
L Eye
R Eye
Left PCA Stroke Left Optic Tract Lesion Right visual loss
•
Macula: central, high-resolution vision (re ading) Dual blood supply: MCA and PCA PCA strokes often spare the macula
Right PCA Stroke Right Optic Tract Lesion Left visual loss
Left Posterior Lobe
Right Posterior Lobe
Thalamic Syndrome •
•
•
•
•
Hypoxic Encephalopathy
PCA lateral thalamus Contralateral sensory loss: face, arms, legs Proprioception deficit: loss of balance, falls No motor defects
•
•
•
•
•
Thalamus
Hypoxic Encephalopathy Hippocampus Hippocampus (pyramidal cells) first area damaged
•
Cerebellum (Purkinje cells) also highly susceptible
Permanent damage <4min •
Chronic pain contralateral side
•
Loss of CNS blood flow Loss of consciousness <10sec Neurons: No glycogen glycogen storage!
Coma, vegetative states common Causes: •
Shock
•
Anemia
•
Repeated hypoglycemia
Watershed Area Infarct •
Most distal branches of major arteries vulnerable •
63
“Watershed infract”
•
Bordersbetween MCA/ACA/PCA MCA/ACA/PCA
•
Classic scenario: CNS damage after massive MI
Watershed Area •
•
Lacunar Strokes
Weakness of the shoulders and thighs Sparing of the face, hands, and feet
•
Bilateralsymptoms
•
A "man-in-a-barrel“
•
•
•
•
•
•
•
Noncorticalinfarcts Different from ACA, MCA, PCA
•
•
Lack “cortical signs” •
•
Aphasia, agnosia, or hemianopsia
•
Vessels •
•
•
•
•
Lacunae = Latin for “empty space”
May not show initial CT Also associated with DM, smoking
Common Locations
Lacunar Strokes •
Anatomically small strokes associated with HTN Stroke resolves and leaves lacunae in brain
Internalcapsule Thalamus Basal ganglia Pons
Lacunar Strokes
Lenticulostriate Lenticulostriate branches(MCA) Anterior choroidal artery (ICA) Recurrent artery of Heubner (ACA) Thalamoperforate Thalamoperforate branch(PCA) Paramedian Paramedian branches (basilar artery)
64
•
Substrate: arteriolar sclerosis (HTN)
•
Proposedcauses: •
Lipohyalinosis: small vessel destruction, necrosis
•
Microatheroma: macrophages in vessel
Hemiballism
Lacunar Strokes
•
•
•
Classic Lacunar Stroke •
•
•
Patient with uncontrolled hypertension Symptoms consistent with 1 of 5 lacunar subtypes •
Pure motor (legs=arms; internal capsule)
•
Pure sensory sensory (thalamus)
Negative initial head CT
65
Wild, flinging movements of extremities (ballistic) Damage to subthalamic nucleus Seen in rare subtypes of lacunar strokes
Brainstem Blood Supply Lateral
Vertebral Basilar Stroke Syndromes
AICA
Jason Ryan, MD, MPH
PICA
Medial
Midbrain
3
PCA
4
Basilar
6
5,7,8
12
9,10,11
Pons
Medulla ASA
Basilar Artery Stroke
SCA Stroke •
•
•
•
Rarest of all cerebellar (AICA, PICA) strokes Mostly cerebellar symptoms
•
•
Ipsilateralcerebellarataxias Nausea and vomiting
•
•
Central Pontine Myelinolysis •
•
•
•
•
•
Patient can blink (upper brainstem intact)
•
Contrast with vegetative state •
Motor function intact
•
Cortical dysfunction
Top of the Basilar Syndrome
“Osmotic demyelination syndrome” •
Locked-in Syndrome Ventral pontine syndrome Loss of corticospinal and corticobulbar tracts Bilateralparalysis (quadriplegia) (quadriplegia)
Demyelination of central pontine axons
•
Lesion at base of pons Loss of corticospinal corticospinal and corticobulbar corticobulbar tracts
•
•
Associated with overly rapid correction↓Na Quadriplegia
•
•
Can be similar to locked-in syndrome
•
66
Very rare Occlusion of upper basilar artery (usually embolic) Changes in the level of consciousness (coma) Visual symptoms: hallucinations, blindness Eye problems: •
3rd nerve palsy
•
Loss of vertical gaze
•
Problems with convergence
Usually no significant motor loss
Key VB Stroke Syndromes •
•
•
AICA Stroke
AICA PICA
•
•
ASA
•
•
•
•
Lateral pontine syndrome Vestibular nuclei: nystagmus, vertigo, N/V Spinothalamic Spinothalamic tract:Contralateralpain/temp Spinal V nucleus: ipsilateral face pain/temp Sympathetictract: Horner’s syndrome Facialnucleus: •
Ipsilateral facial droop
•
Loss corneal reflex
•
Cochlear nuclei
•
Taste on anterior tongue (VII)
•
PICA Stroke
Horner’s Syndrome •
•
•
•
•
Compression/disruption Compression/disruptionsympatheticganglia Hypothalamus T1 Face/eyes
•
•
Lesion anywhere along pathway = Horner’s Miosis, ptosis, and anhidrosis
•
•
Small/constricted Small/constricted pupil(miosis) •
Unequal pupils
•
Affected side smaller
•
Drooping eyelid (ptosis)
•
No sweat (anhidrosis) (anhidrosis)
Deafness
Lateral medullary (Wallenberg's) syndrome Vestibular nuclei: Nystagmus, vertigo, N/V Sympathetictract: Horner’s syndrome Spinothalamic Spinothalamic tract:Contralateralpain/temp
•
Spinal V nucleus: ipsilateral face pain/temp
•
Nucleus ambiguus (IX, X) •
Hoarseness, dysphagia, ↓gag reflex
ASA Stroke
ASA Stroke
Level of Spinal Cord
•
Midline structures damaged damaged
•
•
Can affect medulla or spinal cord
•
•
67
Anterior spinal artery syndrome ASA supplies anterior 2/3 of spinal cord Loss of all but posterior columns
•
Only vibration, proprioception intact
•
Paralysis below lesion
ASA Stroke
Key VB Stroke Syndromes
Level of Medulla •
•
•
•
•
Medial medullary syndrome syndrome Corticospinal, Corticospinal, medial lemniscus, CN 12 Contralateral Hemiparesis Contralateral Contralateral loss of proprioception/vibration proprioception/vibration Flaccidparalysistongue •
Deviation to side of lesion
68
Aneurysms •
Weak vessel wall
•
Abnormaldilation
Cerebral Aneurysms Jason Ryan, MD, MPH
Aneurysms •
Saccular or Berry •
•
Berry Aneurysms Associations •
More common type
•
Charcot-Bouchard aneurysms •
Microaneurysm
•
Cause of hemorrhagic hemorrhagic stroke in HTN
•
Severe HTN
•
•
•
•
•
Similar: lacunar strokes strokes
•
Aneurysm Rupture •
•
Bleeding into CSF space
•
Neuro symptoms rare mostly headache
•
Hemorrhagic Hemorrhagicstroke (micro) •
Marfansyndrome Older age Hypertension Smoking Black race
Subarachnoid Hemorrhage
Subarachnoid Subarachnoidhemorrhage (berry) •
ADPKD Ehlers-Danlos
Symptoms based on site of bleeding
69
Bleeding into space b/w arachnoid & pia mater
Subarachnoid Hemorrhage •
•
•
•
•
•
Subarachnoid Hemorrhage
headache of my life” “Worst headache Sudden onset symptoms Fever, nuchal rigidity common CT scan usually diagnostic Xanthochromia on spinal tap No focal deficits!
•
•
•
•
AComm Aneurysm •
•
Treat with clipping or e ndovascular coiling Re-bleedingcommon Vasospasm •
Triggered by blood
•
Worsening neuro symptoms
•
Days after initial bleed
Nimodipine(calcium-channelblocker) •
Improves outcome
•
Unclear mechanism
•
May prevent vasospasm
PComm Aneurysm
Headache Visual field defects
•
•
Unilateral headache, eye pain CN III palsy •
Bitemporal Hemianopsia Optic Chiasm Compression Pituitary Tumor/Aneurysm
Pupil Sparing •
•
•
•
•
Is pupil n ormal (not dilated)?
Palsy often associated associated with DM
•
Ischemic neuropathy neuropathy of CN III (small vessel disease)
•
Sometimes painful
•
Spontaneously resolves
Ptosis
•
Pupil dilation – nonreactive nonreactive to light
Charcot-Bouchard Aneurysms •
If yes, pupil is spared lesion not aneurysm Pupillary constrictors easily compressed in subarachnoid space If pupil is “spared” •
Eye: “down and out"
•
•
•
•
“Rule of thepupil” the pupil”
70
Micro-aneurysms Small branches lenticulo-striate lenticulo-striate arteries Basal ganglia, thalamus Possible origin of hypertensive ICH
Raised Intracranial Pressure ICP •
•
Intracranial Bleeding
•
•
•
Mass lesions (tumors) Cerebral edema (large stroke, severe trauma) Hydrocephalus Obstruction of venous outflow (thrombosis) Idiopathicintracranialhypertension •
Pseudotumorcerebri
Jason Ryan, MD, MPH
Increased Intracranial Pressure
Papilledema
General symptoms •
•
Headache (pain fibers CN V in dura) Depressed consciousness consciousness •
•
•
•
Pressure on midbrain reticular formation
Optic disc swelling Due to ↑ICP •
Vomiting
•
•
•
Cushing’s Triad
i.e. Mass effect
Also seen in severe HTN Usuallybilateral Blurred margins optic disc on fundoscopy
Glasgow Coma Scale
•
Hypertension
•
•
Bradycardia
•
•
Irregularrespiration
•
Three tests: eye, verbal and motor GCS score: 3 to 15 Eye (1-4 points) points) •
•
Verbal (1-5 points) •
•
No sound, incomprehensible sounds, inappropriate words, confused, oriented
Motor (1-6 points) •
71
Does not open, opens to painful stimuli, opens to voice, opens spontaneously
No movements, decerebrate posturing, decorticate posturing, withdrawal to pain, localizes to pain, pain, obeys commands
Herniation •
Expanding volume: blood, tumor
•
Forces brain through weakest points
Where can displaced brain go? Subfalcine
•
•
•
Side to bottom
•
Transtentorial
Central
•
•
•
•
•
•
•
•
Cingulate gyrus Extends under falx Drags ipsilateral ACA with it ACAcompression Contralateral leg paresis
•
•
•
•
•
•
•
•
•
Loss of parasympathetic innervation Dilated (“blown”) pupil Lack of pupillary pupillary constriction to light
•
•
Collapses ipsilateral posterior cerebral artery •
Visual loss – cortical blindness Homonymous hemianopsia
Cerebralpedunclecompression •
•
Can be on side of lesion (contralateral paresis) Can also be on opposite side side (ipsilateral paresis) Kernohan's notch •
•
Duret hemorrhage of pons and midbrain •
Cerebellum thru the “hole”
Uncus = medial temporal lobe Acrosstentorium Midbraincompression
Uncal herniation
IpsilateralCNIIIcompression •
midbrain
Uncal herniation
Uncal herniation •
Diencephalon
Tonsillar
•
Subfalcine Herniation
Side to side
Uncal
•
Perforating branches basilar artery draining draining veins
72
Dilated pupil (side of lesion) Visual loss Hemiparesisor quadriparesis quadriparesis
Transtentorial Herniation •
•
•
•
•
Tonsillar Herniation
Thalamus, hypothalamus, and medial parts of both temporal lobes forced through tentorium cerebelli Somnolence, LOC
•
•
Initially: small, reactive pupils Later: nonreactive nonreactive
•
Posturing •
Types of Intracranial Bleeds •
•
•
•
Cerebellar tonsils herniate downward through the foramen magnum Most commonly caused caused by a posterior fossa mass lesion Compression of medulla results results in depression centers for respiration and cardiac rhythm control Cardiorespiratory failure
Epidural Hematoma
Epidural Hematoma Subdural Hematoma
•
Subarachnoid Hemorrhage Hemorrhagic Stroke
Rupture of middle meningeal artery •
•
•
Convex Shape on CT
•
Dura attached sutures sutures
Generalsymptoms: •
•
Lesion cant cross suture lines
Subdural Hematoma
Symptoms •
Often fracture of temporal bone
•
•
Epidural Hematoma
Branch of maxillary maxillary artery
Traumatic:
•
Headache, drowsiness, loss of consciousness consciousness
•
Lucidinterval
•
•
73
Usually traumatic Rupture bridging veins Blood b/w dura and arachnoid space SLOW bleeding due to low pressure veins
Subdural Hematoma •
•
•
Subdural Hematoma
Crescent shaped bleed Crosses suture lines
•
Limited by dural reflections •
falx cerebri
•
tentorium
•
falx cerebelli
Classic history is confusion weeks after head injury
•
Classic injury in shaken baby syndrome
•
•
•
Branch points of AComm artery
•
Other associations: associations: •
•
•
•
•
•
Marfan syndrome
•
ADPKD
•
Ehlers-Danlos
headache of my life” “Worst headache Sudden onset symptoms Fever, nuchal rigidity common CT scan usually diagnostic diagnostic Xanthochromia Xanthochromia on spinal tap No focal deficits!
Intraparenchymal Intraparenchymal Bleed
Usually from ruptured berry aneurysms •
More vulnerable to rupture
Hemorrhagic Stroke
Subarachnoid Hemorrhage
AVMs
Blood thinners
•
•
•
•
Brain atrophy increases space veins must cross
•
Most common site: site: anterior circle of of Willis
Alcoholics
Subarachnoid Hemorrhage
Bleeding into space b/w b/w arachnoid & pia mater
•
Old age
•
•
•
•
•
•
Subarachnoid Hemorrhage •
Risk factors
74
Often small arteries or arterioles HTN Anti-coagulation CNS malignancy Ischemic stroke followed by reperfusion
Sites of Bleed
Hemorrhage Stroke
Intraparenchymal Intraparenchymal Bleed
Intraparenchymal Intraparenchymal Bleed
•
•
•
•
•
Putamen (35%) Subcortex(30%)
•
•
Cerebellum(16%) Thalamus (15%)
•
•
Pons (5-12%) •
Charcot-Bouchard Aneurysms •
•
•
•
Micro-aneurysms Smallbranches lenticulo-striate lenticulo-striatearteries
•
•
Basal ganglia, thalamus Possible origin of hypertensive ICH
•
•
•
•
Watch for: •
Left paralysis, sensory loss
•
Eyes deviated to right
Recurrenthemorrhagicstrokes Beta-amyloid deposits in artery walls •
•
Intraventricular Hemorrhage •
Hemisensory loss (thalamus) Gaze deviation toward side of bleed (FEF)
Cerebral Amyloid Angiopathy
•
•
Putamen stroke Contralateralhemiparesis(IC)
Weak, prone to rupture
Typicallylobar hemorrhages •
Frontal, parietal, occipital
•
Usually smaller smaller stokes
•
Contrast with HTN: HTN: Basal ganglia
Watch for: •
Elderly person
•
Recurrent hemorrhagic strokes
Intraventricular Hemorrhage
Complication Complication of premature birth
•
Hemorrhage into lateral ventricle Usually first 5 days of life
Clot can obstruct the Foramen of Monro •
Sometimes asymptomatic LOC, hypotonia, loss of spontaneous movements
•
Normal 3rd/4th ventricle
•
Treatment: Ventriculoperitoneal Ventriculoperitoneal (VP)
Germinal matrix problem •
Massive bleeds can cause seizures, coma
75
Enlargement of lateral lateral ventricles
•
Highly vascular area area near ventricles
•
Premature infants: poor autoregulation autoregulation of blood blood flow here
•
In full term infants, this area has decreased vascularity
Stroke •
•
Treatment of TIA/Stroke
•
•
•
Brain attack Patient appears “struck” down Sudden loss of neurological function function Symptoms resolve <24 hrs = TIA Resolve >24hrs or persist = Stroke
Jason Ryan, MD, MPH
Etiology •
Ischemic (80%) •
•
•
•
Insufficient blood flow
•
Thrombosis, embolism, hypoperfusion
•
Symptom onset over hours
•
•
Hemorrhagic Hemorrhagic (20%) •
Brain bleeding
•
Sudden onset
•
Best first test: Non-contrast CT of head •
•
Head CT Tells you ischemic versus hemorrhagic If ischemic must consider thrombolysis thrombolysis If he morrhagic •
Thrombolysis contraindicated
•
Reduce BP, BP, reverse anti-coagulants, surgery
NO benefit to heparin, warfarin, anti-platelets anti-platelets during acute stroke •
Some role in prevention prevention of recurrent stroke
Provided patient is stable
Diffusion weighted MRI is most accurate
Thrombolysis for Stroke •
3-hour window of benefit for TPA (alteplase)
•
Contraindications •
Stroke or head trauma past 3 months
•
Arterial puncture in non-compressible site past week
•
Internal bleeding or trauma
•
BP>185/110
•
INR>1.7
•
Platelets <100k
•
Elevated PTT
•
Glucose <50mg/dL
•
ANY history of intracranial intracranial bleed
Post-Stroke Management •
Aspirin for prophylaxis •
•
EKG: Look for afib •
•
•
Afib plus stroke = Warfarin or other AC
Echocardiogram (source of embolism/PFO) Carotidultrasound •
76
If allergic: clopidogrel
Surgery considered if >70% stenosis
Stroke in Afib •
Stroke
CHADs Score
•
CHF (1point)
•
•
HTN (1point)
•
HTN (1pont)
•
Age >75yrs (1point)
•
Diabetes (1point)
•
Diabetes (1point)
•
Stroke (2points)
•
Stroke (2point)
•
Female (1point)
•
Age 65-75 (1point)
•
Age >75yrs (2points)
•
Vascular disease (1point)
•
Score >2 = Warfarin or other AC
•
Score 0 -1 = Aspirin
Anticoagulation •
•
Warfarin •
Requires regular INR monitoring
•
Goal INR usually 2-3
Rivaroxaban, Apixaban •
•
Factor X inhibitors
Dabigatran •
•
CHADs VASCScore
•
Direct thrombin inhibitor
Whether Afib persists or sinus rhythm restored anticoagulation anticoagulation MUST be addressed
77
CHF (1point)
•
Score >2 = Warfarin or other AC
•
Score 0 -1 = Aspirin
Vocabulary •
Somatic •
Autonomic Nervous System
•
Jason Ryan, MD, MPH
•
Two Switch System
Brain flips Switch #1
Switch #1 flips Switch #2
Greek: “Of the body”
•
Voluntary actions (muscles)
•
Movement, speech, etc.
Autonomic •
Auto = “self”, nomos = “arrangement”
•
Involuntary actions
•
Salivation, vessel constriction, etc.
Enteric – GI nervous system
Synapses NT
Switch #2 Creates Physiologic Effect
Ganglion (cluster nerve cells) Effect Site Pre-ganglionic Neuron
Sympathetic System
The Two Systems •
•
Major Actions
Sympathetic System •
Activating Actions
Fight or flight
•
Parasympathetic System •
Effect Site
NT
Post-ganglionic Neuron
•
Rest and digest
•
•
•
•
78
Eyes: dilates pupils pupils Lungs: dilates bronchioles rate, Heart: ↑ heart rate, contractility Liver: Glycogen to glucose Kidneys:↑ renin ↑sweat glands
Deactivating Actions •
•
•
•
•
GI: ↓peristalsis Skin: vasoconstriction ↓saliva ↓tears Inhibiturination •
Relaxes bladder
•
Constricts urethra
Parasympathetic Parasympathetic System
Vascular Smooth Muscle
Major Actions •
•
•
•
•
•
•
Eyes: constricts pupils Lungs: constricts bronchioles
•
rate Heart: ↓ heart rate GI: ↑peristalsis Promotesurination •
Constricts bladder
•
Relaxes urethra
•
Exception is muscle, muscle, liver (vasodilates)
•
Overall effect in ↑BP
Parasympathetic dilates •
Indirect endothelium releases NO
•
Lowers BP
Salivation, lacrimation, urination, digestion, and defecation
Anatomy
•
•
Promotes defecation SLUDD •
•
Sympatheticconstricts(mostly)
Signal Transmission Transmission
Sympathetic ganglia •
Paravertebral
•
T1-L5
•
•
•
Parasympathetic •
Brainstem, sacrum
•
Ganglia near target organs
•
Two synapses for both systems First synapse (neuron 1 - neuron 2) Second synapse (neuron 2 - target) Need to know: •
Neurotransmitters
•
Receptor types
Acetylcholine Synapses
Key Points
Choline •
NE: Main NT for sympathetic system •
Responsible for most effects
•
Exceptions: •
Sweat glands (ACh M)
•
Adrenal gland (ACh N)
•
Dopamine
•
ACh M: Main system for parasympathetic
•
ACh N: Main system for somatic muscle
-
Choline + AcCoa
Hemicholinium
ChAT ACh
ACh stored in vesicles Depolarization Ca influx Ca influx exocytosis of vesicles Release of AcH into synapse
79
Choline + Acetate
AChE
ACh
M or N Receptor
Vesamicol
-
Botulism
Botulism •
•
•
•
Paralyticneurotoxin clostridium botulinum Three types: food, wound, infant
•
•
Food (toxin ingestion) •
Undercooked food
•
Canned food: anaerobic environment environment promotes growth
•
Watch for multiple sick adults adults after a meal
•
Wound(bacterialgrowth) •
•
Botulism
Infection with c. botulinum
Symptoms: 12-48 hours after ingestion Symptoms: 3 D’s •
Diplopia, dysphagia, dysphonia
•
Nicotinic blockade signs dominate
Treatment: •
Antitoxin blocks circulating toxin
•
Cannot block toxin already in nerves
•
Supportive care toxin washout
Infant (spores) •
Ingestion of spores growth in infant intestine
•
Watch for contaminated honey!
BoTox
Adrenergic Synapses Tyrosine
•
•
Cosmetic
Tyrosine
•
Prevents/limits wrinkles
•
Paralysis of facial muscles
Dopa
Spasms,dystonias
Dopamine Norepinephrine
m2
+ -
NE stored in vesicles Depolarization Ca influx Ca influx exocytosis of vesicles Release of NE into synapse
Adrenergic Synapses
•
Tyrosine
-
Metyrosine •
Dopa
•
Dopamine
-
•
Resirpine
•
m2
+ -
Cocaine,TCAs Amphetamines
NE
α2
α or β Receptor
Cocaine Intoxication
Tyrosine
Norepinephrine
NE
•
AII
+
Guanethidine Bretylium Amphetamine
α or β Receptor
80
Inhibition of reuptake NE, dopa, serotonin Agitation Hypertension Dilated pupils Chest pain (coronary vasoconstriction) vasoconstriction) Look for abnormal nasal mucosa/septum
α2
AII
Adrenergic Receptors Subtypes •
•
Adrenergic Receptors Subtypes
α1 receptors in periphery
•
Peripheral vessels: Vasoconstrict (↑BP)
•
Heart: ↑ heart rate and contractility
•
Eye: Mydriasis (dilation (dilation of pupil)
•
Kidneys: Stimulate renin release - JG apparatus
α2 receptors in CNS
•
•
•
•
•
β2 receptors in periphery
•
Presynaptic receptor
•
•
Feedback to nerve nerve when NE released
•
Liver, muscle: vasodilation (↓BP)
•
Activation leads to ↓NE release
•
GI: ↓motility
•
Also pancreas: pancreas: inhibit insulin release
•
Bladder: Relaxation
Adrenergic Hemodynamics •
β1 receptors in heart, kidneys
•
Lungs: Bronchodilate
G Proteins Subtypes
Vasoconstriction α1: Vasoconstriction α2: Vasodilation Rate β1: Heart Rate β2: Vasodilation Stimulation Stimulation of all receptors ↑HR, ↑BP
•
•
•
Gs and Gi Systems
Gi inhibitory to adenylate cyclase Gs stimulatory to adenylate cyclase Gq
Gs and Gi Systems Cardiac Muscle
Cardiac Muscle SR +
PK-A
SR
Ca++
Ca++
+
CONTRACTION
PK-A
+ ATP
AC +
Gs
Gi
Stimulation (Gs) ↑Contraction Inhibition (Gi) ↓Contraction
ATP
AC +
Gi -
Ca++
Gs
CM
cAMP
ATP
Stimulation (Gs) ↑Contraction Inhibition (Gi) ↓Contraction
81
MLCK CONTRACTION
cAMP
-
SR Ca++
CONTRACTION
+
cAMP
Gs
Ca++
Ca++
Vascular Smooth Muscle
AC +
Gi -
Stimulation (Gs) Relaxation Inhibition (Gi) Contraction
Gq Systems
G-Protein Receptors and Types
Cardiovascular Cardiovascular Effects Vascular Smooth Muscle SR
Ca++
+ CONTRACTION
IP3
PIP2 PLC
Gq
Gq only in v ascular smooth muscle Contraction
G-Protei G-Pro tein n Subclasse Subcl assess
Take Take Home Points Points Sympathetic
Parasympathetic
Somatic
ACh M
ACh N
NE αβ
Gi
82
Gs
Gq
Ligand-Gated Ion Channels
Adrenergic Drugs •
Autonomic Drugs: Norepinephrine
•
Amplify sympathetic system •
Sympathomimetic drugs
•
Direct: NE receptor receptor agonists
•
Indirect: Block NE reuptake
Block sympathetic system •
Adrenergic antagonists/blockers
•
Alpha blockers
•
Beta blockers
Jason Ryan, MD, MPH
Adrenergic Activation
Direct Agonists
Hemodynamic Effects •
•
•
•
Vasoconstriction α1: Vasoconstriction α2: Vasodilation β1: ↑ Heart Rate/Contractility β2: Vasodilation
*Only Dopamine activates D1 receptors
Dopamine •
•
•
•
Peripheral effects highly dependent on dose Low dose: dopamine agonist
•
Also dose dependent effects
•
Low dose: beta-1 and beta-2 agonist
•
•
Increased heart rate/contractility rate/contractility
•
Vasodilation
High dose: alpha agonist agonist •
Increased heart rate and contractility
High dose: alpha agonist agonist •
•
Vasodilation in kidneys
Medium dose: beta-1 agonist •
↑renal blood flow
Epinephrine
Does not cross blood brain barrier (no CNS effects)
•
Vasoconstriction
83
Vasoconstriction
Alpha Agonists
Other Direct Agonists
Clonidine and Methyldopa
Alpha Agonists •
•
Used in hypertension hypertension
•
Agonists to CNS α2 receptors
Indirect Agonists
Apraclonidine •
•
Used in glaucoma Agonists to α2 receptors (weak α1 activity) Lowersintraocularpressure
Indirect Agonists
Cocaine •
Enhancesmonoamine Enhances monoamine neurotransmitter activity •
•
•
•
Dopamine, Norepinephrine, Serotonin
Blockade of presynaptic reuptake pumps Generalized sympathetic activation Also blocks Na channels in nerves (local anesthetic)
Norepinephrine
-
Cocaine Amphetamines
NE
+
Ephedrine Amphetamines
α or β Receptor
Dopamine
84
Norepinephrine
Serotonin
Cocaine Intoxication •
•
•
•
Cocaine Intoxication
Massivealpha Massive alpha and beta stimulation Hypertension
•
•
Tachycardia Classic case: •
College student
•
Agitated, tremulous
•
Tachycardic/hypertensive
•
Chest pain (coronary spasm; increased increased O2 demand)
Treatment: Benzodiazepines
•
•
•
Sedatives/anxiolytics
•
Activate GABA receptors
•
Inhibitory to central central nervous system
Avoid beta blockers for chest pain/hypertension pain/hypertension
β2 activation blunting alpha activation Beta blocker unopposed α severe HTN
Alpha Blockers
Clinical Scenarios
Nonselective (α1α2 ) •
Phenoxybenzamine (irreversible)
•
Phentolamine (reversible)
•
•
Used in pheochromocytoma
•
Used to reverse “cheese “cheese effect”
•
MAOi drugs block block breakdown neurotransmitters (depression)
•
Also block breakdown tyramine
•
Eat cheese (tyramine) dangerous HTN
Side Effects:hypotension, Effects: hypotension, reflex tachycardia
Tyramine Dopamine
Alpha Blockers
Alpha Blockers
α1 Blockers
α2 Blockers
•
Prazosin, terazosin, doxazosin, tamsulosin
•
•
Used in hypertension, urinary retention BPH
•
•
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Mirtazapine Depression drug Affects serotonin and NE levels in CNS
Beta Blockers •
β1-selective antagonists •
•
Drug Experiments •
Esmolol, Atenolol, Metoprolol Metoprolol
•
β1β2 (nonselective)antagonists •
β1β2α1
•
Partial-agonists •
Question: Which receptors effected by drug?
Propranolol, Timolol, Nadolol
•
•
•
Unknown drug given Heart rate and blood pressure response shown
Carvedilol, Labetalol
Pindolol, Acebutolol
Drug Experiments
Drug Experiments
Heart Rate Effects
Blood Pressure Effects
•
•
•
•
β1 tachycardia β2 vasodilation tachycardia tachycardia (reflex)
•
Systolic blood pressure
•
Diastolic blood pressure
•
bradycardia (reflex) α1 vasoconstriction bradycardia α2 ↓ norepinephrine bradycardia
•
Primary determinant: cardiac output
Primary determinant: peripheral resistance
Drug Experiments
Drug Experiments
Blood Pressure Effects
Blood Pressure Effects
•
•
Beta-1 effects
•
Beta-2 effects
•
Increased heart rate/contractility rate/contractility
•
Vasodilation
•
Increased cardiac output
•
Main effect: Diastolic blood pressure f alls
Main effect: systolicpressure systolic pressure goes up •
Mean blood pressure rises
•
Overall result: Mean blood pressure will fall
•
Reflex tachycardia HR
HR
β2
β1 MAP
MAP
SBP
DBP
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Drug Experiments
Drug Experiments
Blood Pressure Effects
Blood Pressure Effects
•
Alpha-1effects •
Vasoconstriction
•
Main effect: Diastolic blood pressure rises
•
Alpha-2 effects
•
Heart rate and MAP will fall
•
Clonidine/Methyldopa Clonidine/Methyldopaused inhypertension
•
•
Overall result: Mean blood pressure will increase
•
Reflex bradycardia
Blunts sympathetic sympathetic nervous system
HR
HR
α2
α1
MAP
MAP DBP
Drug Experiments
Dobutamine •
β1
HR
α1 MAP
HR
•
AP
•
•
HR
β2
α2 MAP
HR MAP •
•
Mostly β1 ↑ cardiac output rate ↑ heart rate MAP pressure usually falls •
↓ TPR (β2)
•
Limited α1 effects
•
↑ cardiac output
CO ↑ HR ↑ MAP ↓
Myocyte effect > SA node More inotropy than chronotropy
Peripheral vasoconstriction Reflex bradycardia Peripheral vasodilation Reflex tachycardia
Dopamine/Epinephrine •
•
•
•
•
•
β1β2α1 Effects vary withdose ↑ cardiac output ↑ SBP rate ↑ heart rate ↑ DBP (α1 – dose dependent) ↑ MAP
Norepinephrine •
CO ↑ HR ↑ MAP ↑
•
•
α1β1 α1 >> β1 Major effect: Increased TPR •
•
•
•
Some ↑ HR from β1
•
Some ↓ HR from reflex bradycardia
•
Can see no change in heart rate
Cardiac output usually goes up from β1 •
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Increased D BP and MAP
Heart rate effects variable
Rise in SBP
CO ↑ HR ↑↓ MAP ↑↑
Isoproterenol •
•
•
•
β1β2 ↑ HR/CO fromβ1 from β1 Mean blood pressure will fall
Phenylephrine
CO ↑↑ HR ↑↑ MAP ↓
•
•
•
•
Lower diastolic pressure pressure (β2)
•
•
Reflex tachycardia
•
CO ↓ HR ↓ MAP ↑↑
α1α2 Vasoconstrictor (↑TPR) ↑ DBP and MAP Reflex bradycardia More afterload less CO
Systolic may rise (β1) •
Pulse pressure may significantly increase Systolic
Mean Diastolic
Epinephrine Reversal
Phenylephrine Block
Classic Pharmacology Experiment
Drug A
HR MAP
Drug A HR + Drug B MAP
Drug A
HR MAP
Drug A + Drug B
HR MAP
Drug A = Epinephrine β1 β2 α1
Drug A = Phenylephrine α1
Drug B = Phenoxybenzamine Blocks α1
Drug B = Phenoxybenzamine Blocks α1
β2 effects dominate dominate (↓BP)
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Vocabulary •
Adrenergic
•
Cholinergic
•
Anti-adrenergicor anti-cholinergic anti-cholinergic
•
Autonomic Drugs: Acetylcholine
•
Related to norepinephrine norepinephrine or epinephrine
Related to acetylcholine
Jason Ryan, MD, MPH
Receptors Clinical Effects •
•
Muscarinic Agonist Effects
Muscarinic
•
Visceral smooth muscle
•
Parasympathetic PLUS sweat
•
Increase GI motility
•
No sweat = ↑temp
•
Nausea, vomiting, cramps, diarrhea
•
↑temp = skin flushing
•
Nicotinic •
Secretoryglands •
Blockers: paralytics
•
Bladder •
Muscarinic Agonist Effects •
•
Sweating, salivation, lacrimation lacrimation
Detrusor (smooth muscle) contraction: contraction: Urination
Muscarinic Agonist Effects
Heart
•
Endothelial cells
•
Decreased contractility contractility (less Ca into cells)
•
No direct effect on vascular smooth smooth muscle
•
Decreased HR (less (less Ca in SA/AV nodes)
•
Indirectly stimulate NO release release
Lungs •
Bronchoconstriction
•
Wheezing, dyspnea, dyspnea, flare of asthma/COPD
89
•
Activates guanylate cyclase
•
↓BP
less Ca vasodilation
Acetylcholine Agonists
Acetylcholine Esterase Inhibitors
Myasthenia Gravis •
•
•
Myasthenia Gravis
Autoimmunedisease Antibodies block ACh receptors
•
Nicotinic receptors in muscles clinically affected •
Classic signs/symptoms: signs/symptoms: •
Eye problems
•
Chewing, talking, swallowing problems
Classic finding is fatigability •
•
Myasthenia Gravis •
•
•
•
•
•
•
#1: Insufficient dose AChE inhibitor #2: Cholinergic crisis crisis Too much medication
•
Muscle refractory to ACh
Treatment •
Neostigmine, Pyridostigmine, Edrophonium
•
Immunosuppressants
Lambert-Eaton Syndrome
Exacerbations Exacerbations can occur for two reasons
•
Repetitive movements ↓ACh levels, problem worsens
•
•
Similar to MG Paraneoplastic Paraneoplastic syndrome (small cell lung cancer) Antibodies against pre-synaptic Ca channels •
•
Tensilon test: Give edrophonium If muscle function improves:↑dose Muscle function fails to improve:↓dose
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Prevent ACh release
Edrophonium test: No improvement
COPD and Peptic Ulcers •
•
Organophosphate Poisoning
Any cholinergic medication can worsen ACh agonists and AChE inhibitors
•
Bronchoconstriction COPD flare
•
↑gastric acid ulcers
•
Organophosphate Poisoning •
•
•
A 44-year-old farmer presents to the ER with difficulty breathing. There is audible wheezing. He also reports diarrhea and unintentional loss of urine. He appears agitated. On exam, he has pinpoint pupils. He is sweaty, drooling, and his eyes are watery. His pulse is 30.
Organophosphate Poisoning
Exposure to insecticides often through skin Irreversible block of AChE
•
ctivity ↑Muscarinica •
All acetylcholine synapses in overdrive •
↑Nicotinic activity
•
↑CNS activity
•
•
Organophosphate Poisoning •
•
Atropine – Muscarinic antagonist
•
Pralidoxime – regenerates regenerates AChE
Fasciculation Confusion, lethargy, seizures
ACh Antagonist Effects
Treatment: •
Diarrhea, urination, bronchospasm, bradycardia, salivation (drool), (drool), lacrimation (tears)
•
Dry skin •
•
Farmer with confusion, sweating, pinpoint pupils
Hyperthermia •
•
Loss of sweating
Flushing •
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Blockade of sympathetic sweat glands
Reflex vasodilation in response to hyperthermia
Acetylcholine Antagonists
ACh Antagonist Effects •
Dry mouth and eyes eyes
•
Dilated eyes
•
Delirium
•
•
•
•
Muscarinic Blockers
No lacrimation, salivation
Can trigger acute angle closure glaucoma Blockade of central central ACh
Red as a beet, dry as a bone, blind as a bat, mad as a hatter, and hot as a hare
Motion Sickness •
•
•
•
Atropine
Overstimulation Overstimulation of M1 and H1 nausea/vomiting Scopolamine Scopolamine patch blocks M1
•
Also antihistamines antihistamines •
Meclizine
•
Dimenhydrinate
Side effects: dry mouth, urinary retention, constipation
Atropine •
•
A 50-year-old man feels dizzy after a central line is placed in his left jugular vein. His EKG is shown below.
Atropine
His is given Atropine and his dizziness resolves. His EKG converts the tracing below.
Later that night he has pelvic discomfort and is unable to urinate.
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•
Muscarinicantagonist
•
Used for bradycardia and pupil dilation
•
ACLS algorithm for cardiac arrest
Atropine •
•
Atropine
Toxicity:
•
↑temperature (no sweating)
•
Decreases outflow of fluid
•
Dry skin
•
Sudden eye pain, halos
•
Dry mouth
•
Constipation
•
Urinary retention
•
Confusion (elderly)
Treatment: Physostigmine
Gardner’s Mydriasis •
•
•
•
•
•
•
Contraindicated Contraindicated inglaucoma
•
ACh Synapse Poisoning
Jimson weed toxin Anticholinergic Anticholinergicproperties (likeatropine)
•
Dilatedpupils Tachycardia •
Hypertension Dry mouth Treatment: Physostigmine
•
Botulism •
Nicotinic and muscarinic blockade
•
Paralysis dominates picture (cranial nerves/descending)
•
GI symptoms if food borne contamination
Atropine overdose •
Muscarinic blockade
•
No muscle effects
Organophosphates •
Anticholinergic Side Effects •
•
•
•
Tricyclic antidepressants
•
First gen antihistamines - chlorpheniramine, diphenhydramine
•
Antipsychotics
•
Anti-parkinsons
•
•
•
•
Urinaryretention
•
Sedation
Muscarinic stim: miosis, bradycardia, tears, sweat
Common side effect anti-cholinergic anti-cholinergic drugs More common older men with BPH Watch for this after atropine, others Other drugs with anti-cholinergic properties •
Pupil dilation Dry mouth Constipation
•
Weakness from depolarizing blockade: blockade: fasciculations
•
Urinary Retention
Caused by many drugs •
Nicotinic and muscarinic activation
•
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TCAs, Haldol
Nicotinic Blockers •
Used for paralysis in anesthesia
94
Pupil •
•
•
•
Controls amount of light entering eye Contraction = miosis Dilation = mydriasis Under autonomic control control
The Pupil Jason Ryan, MD, MPH
Iris
Iris •
•
•
•
•
•
Contractilestructure Mainly smooth muscle Controls size of pupil pupil Two muscle groups Circulargroup: sphincter pupillae Radial group: dilator pupillae
Sphincter Pupillae
Miosis
Miosis
Pupillary contraction
Pupillary contraction
•
•
•
Parasympathetic control
•
•
•
Ciliary Ganglion
Midbrain: Near oculomotor oculomotor (CNIII) nucleus
Nerve fibers enter orbit with cranial nerve III Synapse at ciliary ganglion (behind the eye) Ciliary ganglion signals sphincter pupillae •
•
EW Nucleus CNIII
Two neuronpathway Begins at the Edinger-Westphal nucleus •
Dilator Pupillae
Via the short short ciliary nerves
Sphincter Pupillae
Muscarinic receptors (ACh)
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Adie’s Tonic Pupil
Rule of the Pupil •
•
•
Cranial nerve III lesion: eye down and out Pupil dilation: dilation: Parasympathetic nerves impacted •
Parasympathetic fi bers run on outside outside of nerve
•
Easily compressed by mass (Pcomm aneurysm)
•
•
•
•
Absence of pupillary pupillary dilationsuggests dilation suggests ischemia •
CNIII ischemic nerve damage common in diabetes
•
Spares superficial superficial fibers to pupil
•
Dilatedpupil Blocked parasympathetic parasympatheticinnervation Most cases idiopathic Can be caused by orbit disorders of ciliary ganglion Tumor, inflammation, trauma, surgery, infection
Mydriasis
Mydriasis
Pupillary dilation
Pupillary dilation
•
•
Sympathetic control Activation of dilator pupillae •
•
•
•
•
#1: Post hypothalamus to spinal cord
•
#2: Spinal cord to superior cervical ganglion
•
Also inhibition of sphincter pupillae
Norepinephrine receptors (α1) Long, three neuron chain Brain to spinal cord back up to eye •
Mydriasis
•
Exit at T1
•
Crosses apical pleura pleura of the lung
•
Travels with cervical sympathetic sympathetic chain (near subclavian)
#3: Superior cervical ganglion to dilator pupillae •
Courses with internal carotid artery
•
Passes through cavernous cavernous sinus
Horner Syndrome
Pupillary dilation Midbrain
Ends at ciliospinal ciliospinal centre of Budge Budge (C8-T2)
Superior Cervical Ganglion
•
Disruption of sympathetic chain to face
•
Small pupil (miosis)
•
Eyelid droop (ptosis)
•
Medulla
•
Dilator Pupillae
Spinal Cord
Center of Budge T1
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Loss of sympathetic sympathetic innervation
pupillary contraction
•
Sympathetic system supplies superior tarsal muscle
•
Assists levator palpebrae palpebrae in raising eyelid
No sweat (anhidrosis) (anhidrosis)
Horner Syndrome
Cocaine
Causes
Diagnostic Test for Horner Syndrome
•
•
Apical lung tumor Aorticdissection
•
•
•
Carotiddissection
•
•
PICA stroke (lateral medullary syndrome)
•
•
Anisocoria •
•
•
•
•
•
•
Testing: Cocaine applied to eye Normal e ye: Dilation Horner syndrome eye: No dilation
Pupillary Reflexes 1. Light
Difference in pupil sizes Seen in Horner syndrome syndrome
2. Accommodation Accommodation
CNIII palsy with pupillary involvement Adie’s pupil
Pupillary Light Reflex •
Blocks reuptake of norepinephrine No effect with impaired sympathetic innervation
Pupillary Light Reflex Sphincter Pupillae
Shine light in one eye both eyes constrict •
Illuminated eye: direct response
•
Opposite eye: consensual response
Sphincter Pupillae
Ciliary Ganglion
Light signals to pretectal nucleus (midbrain) Pretectal nucleus to bilateralEW bilateral EW nucleus Does not involve cortex - purely a reflex of nerves CNIII
CNIII
Angusng/Wikipedia
97
Marcus Gunn Pupil •
•
•
Swinging Flashlight Test
Relative afferent pupillary defect (RAPD) Light shone in 1 eye produces less constriction
•
•
Diagnosed by the “Swinging Flashlight Test”
•
•
•
Marcus Gunn Pupil •
•
Problem sensing light appropriately
•
Many potential causes: retina, optic nerve
•
Classic cause: Optic neuritis •
Inflammatory, demyelinating disorder
•
Commonly occurs in multiple sclerosis
•
•
Accommodation Reflex •
•
•
•
•
Eyes move medially to track object
•
#2 Accommodation •
Shape of lens changes
•
Focal point maintained maintained on retina
•
•
•
#3 Miosis •
Pupil constricts
•
Block entry of divergent divergent light rays from near object
If constriction less (dilation (dilation)) APD
Changes optical power to focus on near objects Ciliary muscle changes shape of lens Associated with miosis (pupillary constriction)
Argyll Robertson Pupil
#1Convergence: •
Swing light to other eye Constriction should remain same
Accommodation
Caused by lesion in “afferent” light reflex limb •
Shine light in one eye eye Should see bilateral constriction
•
•
“Prostitute’spupil” “Prostitute’spupil” Strongly associated with neurosyphilis (tertiary) Bilateral, small pupils No constriction to light Constriction to accommodation -near dissociation” “Light -near Believed to involve pretectal nucleus •
Complex reflex circuit: involves visual cortex
98
Part of light reflex; not part of accommodation accommodation reflex
PERRLA •
•
Documentation Documentation of normal pupil exam Pupils equal, round, reactive to light and accommodation
99
How Lenses Work Refraction
Light Focal Point
The Lens
Object
Lens
Jason Ryan, MD, MPH Most refraction performed by cornea (fixed) Some performed by lens (adjustable)
The Lens •
•
Surrounded by a capsule with type IV collagen Avascular •
•
•
Accommodation
•
•
•
Lens modifies shape to focus on near objects
•
Lens changes optical power of eye
Nutrients via diffusion
Contains elongated fiber cells Anaerobicmetabolism •
Principle source of energy production
•
Glucose lactic acid
Accommodation
Accommodation •
•
Ciliary muscle: Smooth muscle within ciliary body Changes shape of lens Circular muscle – surrounds lens Connected to lens by ligaments (zonules)
Rest State Ciliary muscles relaxed Zonules pulled tight Lens flattens Focus on far objects
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Accommodation Ciliary muscles contract Zonules relax Lens rounds Focus on near objects
Lens of the Eye •
Far objects •
•
•
Presbyopia
Ciliary relax Lens flatter
•
•
Ciliary contract
•
Lens rounder
•
•
•
Impaired vision due to abnormal focal point of eye
•
Improved with glasses or contact lenses
Eyes move medially to track object
#2 Miosis •
Pupil constricts
•
Block entry of divergent divergent light rays from near object
#3 Accommodation •
Shape of lens changes
•
Focal point maintained maintained on retina
Myopia
Refractive Errors •
focus on near objects (reading) Can’t focus
Refractive Errors
3 reflex responses as object moves closer to eye #1Convergence: •
•
Lens stiffens withage
•
Near objects
Accommodation Reflex •
•
Nearsightedness Eye
Corneal curvature must match eye size Failure to match = refractive error
Cornea Object
Light
Eye Cornea Object
Light
Lens
Focal point is in front of retina Eye too long or cornea has too much curvature Can’t focus on far objects objects (nearsighted)
Lens
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Myopia
Hyperopia
Nearsightedness
Farsightedness Eye
Object
Eye
Cornea
Light
Cornea Object
Light
Lens
Lens
Focal point is behind retina Eye too short or cornea has too little curvature Can’t focus on near objects (farsighted)
Corrected with a negative lens Example: -1.75
Hyperopia
Astigmatism
Farsightedness Eye
Object
Eye Cornea
Cornea
Light
Object
Light
Lens
Lens
Uneven curvature of cornea Multiple focal points Objects blurry
Corrected with a positive lens Example: +1.50
Astigmatism
Ectopia Lentis •
•
•
•
Normal Cornea
stigmatism
Corrected with lenses lenses or surgery
102
Dislocation of lens Commonly due to trauma Rarely associated with systemic disease Can occur as ocular manifestation manifestation of systemic disease
Ectopia Lentis •
•
Cataracts
Marfan Syndrome
•
•
Most commonly associated systemic condition condition
•
Autosomal dominant dominant disorder; fibrillin defect
•
Tall, long wing span
•
•
•
•
50-80% of cases cases have lens dislocation
•
Classically upward/outward lens dislocation
Opacification of lens Painless
Lead to ↓ vision Treated with surgery
Homocystinuria •
Cystathionine β synthase deficiency
•
Markedly elevated homocysteine levels
•
Marfanoid body habitus
•
Mental retardation
•
Classically downward/inward downward/inward lens dislocation
Cataracts
Aldose Reductase
Risk Factors
Polyol Pathway
•
•
•
•
Older age Smoking
NADPH
Corticosteroids
•
Trauma, infection
Sorbitol
Glucose
Alcohol Excessivesunlight
•
NADP+
Galactose
Diabetes Glucose can be metabolized tosorbitol to sorbitol in lens
NADPH
•
NADP+
•
Sorbitol
Glucose Aldose Reductase
Accumulation ↑ lens osmolarity Galactitol
Galactose Disorders
Cataract Risk Factor •
Cataracts
Aldose Reductase
Fructose Sorbitol Dehydrogenase
Classic Galactosemia •
Presents in infancy
•
Live failure
•
Cataracts
Galactokinase Galactokinase deficiency •
Milder form of galactosemia
•
Main problem: cataracts as child/young adult
Galactose
103
Aldose Reductase
Galactitol
TORCH Infections •
•
Can lead to cataracts Classically part of congenital rubella syndrome •
Deafness
•
Cardiac malformations
•
“Blueberry muffin” skin (extramedullary hematopoiesis)
104
Retina and Macula •
•
The Retina Jason Ryan, MD, MPH
•
Fundoscopy •
•
•
Retina •
Inner layer of eye
•
Contain photosensitive photosensitive cells: rods and cones
•
Major blood supply supply via choroid
Macula •
Oval-shaped area near center of retina
•
Contains fovea (largest amount of cone cone cells)
•
High-resolution, color vision
Both structures essential for n ormal vision
Retinitis Pigmentosa
Fundus = back of eye opposite lens Includes retina, optic disc, macula
•
•
“Fundoscopy” = visual examination of fundus
•
•
•
•
Retinitis Pigmentosa Pigmentosa
Inherited retinal disorder Visual loss usually begins in childhood Loss of photoreceptors (rods and cones) Night and peripheral vision lost progressively Constricted visual field No cure – most patients legal blind by age 40
Retinitis
Fundoscopy •
Intraretinal pigmentation pigmentation in a bone-spicule pattern
•
•
Form in retina where photoreceptors are missing
•
•
•
•
105
Retinal edema/necrosis edema/necrosis Floaters, ↓ vision Classiccause: Cytomegalovirus (CMV) Usually in HIV/AIDS (low CD4 <50) Also in transplant patients on immunosuppression immunosuppression
Retinitis
Diabetic Retinopathy
Fundoscopy •
Retinalhemorrhages
•
•
Whitish appearance to retina
•
•
Can cause blindness among diabetics Pericyte degeneration •
Cells that wrap capillaries
•
Microaneurysms
•
Rupture hemorrhage
Annual screening for prevention
Diabetic Retinopathy
Diabetic Retinopathy
Nonproliferative Nonproliferative retinopathy
Nonproliferative retinopathy
•
•
Most common form of diabetic retinopathy (95%) “Background retinopathy”
•
•
Microaneurysms Microaneurysms( earliestsign) “Dot -and-blot -and-blothemorrhages” •
•
Damaged capillary leakage of fluid
Cotton-wool Cotton-wool spots •
Nerve infarctions
•
Occlusion of precapillary arterioles
•
Also seen in hypertension
Diabetic Retinopathy
Diabetic Retinopathy
Nonproliferative Nonproliferative retinopathy
Proliferative retinopathy
•
Hardexudates/macularedema
•
Vessel proliferation (“proliferative retinopathy”)
•
Macular swelling
•
Retinal ischemia new vessel growth
•
Yellow Yellow exudates of fatty fatty lipids
•
“Neovascularization”
•
Can lead to blindness i n diabetics
•
Abnormal vessels: friable, friable, grow on surface of retina
•
Can lead to retinal detachment
•
Can cause macular edema
106
blindness
Diabetic Retinopathy
Retinal Detachment
Proliferative retinopathy •
Treatments:
•
•
Photocoagulation (laser
•
Vitrectomy (bleeding/debris)
•
Anti-VEGF inhibitors (intravitreal injections; ranibizumab)
stops vessel vessel growth)
•
•
•
•
Often precedes retinal detachment
•
Vitreous shrinks with age
•
May cause retinal holes/tears
•
Floaters (black spots)
•
Flashes of light
Retinal Vein Occlusion Central or branch of retinal vein
•
Can lead to visual loss loss
•
Myopia (near-sightedness) (near-sightedness)
•
Prior eye surgery or trauma
•
Proliferativediabetic retinopathy
•
can pull pull on retina
•
Surgicalemergency
Risk Factors
Posterior vitreous membrane detachment •
Photoreceptors(rods/cones)degenerate Vision loss (curtain drawn down)
Retinal Detachment
Retinal Detachment •
Retina peels away from underlying layer Loss of connection to choroid ischemia
Larger eyes; thinner thinner retinas
Retinal Vein Occlusion •
Branch retinal vein occlusion (BRVO) •
•
Occurs at arteriovenous crossing crossing points
•
Associated with arteriosclerosis
•
Sclerotic arterioles compress compress veins in an arteriovenous sheath
Central retinal vein occlusion (CRVO) •
107
Compression of the branch vein by retinal arterioles
•
Usually a primary thrombus disorder
Retinal Vein Occlusion
Retinal Artery Occlusion
Fundoscopy •
Engorged retinal veins and hemorrhages hemorrhages
•
•
Leads to formation of a “cherry red spot” •
Red circular area area of macula surrounded by halo
•
Also seen in Tay Tay Sachs Disease (lysosomal (lysosomal storage disease)
Commonly caused by carotidartery atherosclerosis atherosclerosis •
Papilledema •
•
•
•
•
•
Giant cell arteritis
•
Macula = central vision
•
Degeneration visual disruption
i.e. mass effect
Usuallybilateral Blurred margins optic disc on fundoscopy
Macular Degeneration Degeneration •
Cardiac source (thrombus)
Macular Degeneration Degeneration
Optic disc swelling Due to ↑ intracranial intracranial pressure •
Internal carotid ophthalmic retinal
•
•
Distortion(metamorphopsia) (metamorphopsia)
•
Loss of central vision (central scotomas)
Dry Macular Degeneration Degeneration
Dry
•
Bruch's membrane
•
More common (80%)
•
Innermost layer of the the choroid
•
Slowly progressive symptoms
•
Between choroid and retina
Wet
•
Retinal pigment epithelium
•
Less common (10-15%)
•
Retina layer beneath photoreceptors
•
Symptoms may develop develop rapidly (days/weeks)
•
Next to choroid (Bruch’s membrane)
108
Dry Macular Degeneration Degeneration •
•
•
•
Wet Macular Degeneration
Accumulation Accumulation ofdrusen of drusen •
Yellow extracellular material
•
Form between Bruch’s membrane and RPE
•
•
•
Gradual ↓ in vision No specific treatment Vitamins and antioxidant supplements may prevent
•
•
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Break in Bruch’s membrane Blood vessels form beneath retina Leakage/hemorrhage Can progress rapidly to vision loss Treatments: •
Laser therapy
•
Anti-VEGF (ranibizumab)
Eye Movement Superior Rectus Superior Oblique Medial Rectus
Lateral Rectus
Eye Movements
Inferior Oblique
Jason Ryan, MD, MPH Blue = CN III Red = CN IV (Trochlear) Green = CN VI (Abducens)
Inferior Rectus
LR6SO 4
Eye Nerve Palsies •
•
•
•
Terminology
Oculomotor(III) Trochlear(IV)
•
Abducens (VI) Many causes: strokes, tumors, aneurysms
•
Diplopia •
Two different images of same object
•
Diplopia due to nerve palsies is binocular •
Resolves when one eye is covered
•
Monocular diplopia: diplopia: usually lens problem (astigmatism)
CN III Raise Eyebrow Constrict Pupil
Move eye away from nose •
Lateral
•
Abduction
Move eye toward nose •
Medial
•
Adduction
Oculomotor (III) •
Moves eye up and medially •
Up (superior rectus)
•
Medial (medial rectus)
•
Elevates eyelid (levator palpebrae)
•
Pupillary constriction (sphincter pupillae) •
110
Parasympathetic fibers from Edinger-Westphal nucleus
Oculomotor Nerve Palsy •
Rule of the Pupil
Effected side •
Eye down, out
•
Ptosis (eyelid droop)
•
Pupil dilated
•
•
•
Trochlear (IV) •
•
Turns eye down/in
•
Reading/stairs
•
•
•
Palsysymptoms •
Diplopia
•
Eye tilted outward
•
Unable to look down/in (stairs, reading)
•
Head tilting away from affected affected side (to compensate)
•
Parasympathetic fibers run on outside of nerve
•
Easily compressed compressed by mass (Pcomm aneurysm)
suggestsischemia Absence of pupillary pupillary dilation dilationsuggests •
CNIII ischemic nerve damage common in diabetes
•
Spares superficial superficial fibers to pupil
Abducens (VI)
Superior oblique •
Cranial nerve III lesion: eye down and out Pupil dilation: dilation: Parasympathetic nerves impacted
•
Lateral rectus Affected eye may be pulled medially at rest Problems worse on horizontal gaze Affected eye can’t move move laterally Right VI Lesion
R
L
Rest
R
L
Right Gaze
Estropia
Pseudotumor Cerebri
•
Type of strabismus (misalignment of the eyes)
•
•
Inward turning of one or both eyes
•
•
Can be seen in CN VI palsy
•
•
•
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High intracranial pressure (ICP) can cause CN VI palsy Nerve course highly susceptible to pressure forces Sometimes bilateral palsy May see papilledema on fundoscopy Classicpatient: •
Overweight woman
•
Childbearing age
•
Headaches
Eye Structures •
•
Structural Eye Disorders
•
•
•
•
•
Pupil/Iris Lens Sclera Conjunctiva Cornea Uvea Retina/Macula
Jason Ryan, MD, MPH
Sclera •
•
•
•
•
Scleritis
Composed of collagen Rigid structure – stabilizes eyeball
•
•
Extraocular muscles insertion site Avascular
•
•
Inflammation of sclera Dark red eyes Severe “boring” pain with eye movement Potentiallyblinding
Nutrients from episclera and choroid
Scleritis
Episcleritis
•
50% cases associated with systemic disease
•
•
Rheumatoid arthritis is most common
•
•
•
•
•
•
•
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Acute inflammation Episclera layer only Usually idiopathic Tearing Localizedredness Mild or no pain Usuallyself-limited Also associated with rheumatoid arthritis
Keratitis •
•
•
•
•
•
•
Corneal Abrasion
Corneal inflammation Bacterial/viral/fungal
•
•
Contact lens wearers Pain/Photophobia
•
•
Red eye Foreign body sensation
•
•
•
•
Infection of cornea/conjunctiva cornea/conjunctiva
•
Pain, redness, discharge
•
•
•
•
Most ocular disease is recurrent HSV
•
Adenovirus
•
Measles
•
HSV-1
•
•
•
Bacterialcauses •
Discharge Commonest “red eye”
Adenovirus
Viral causes (80%) •
Viral, bacterial, allergic allergic Conjunctivalinjection
Reactivation after establishment of viral latency
Conjunctivitis
•
Often treated with ciprofloxacineye ciprofloxacineye drops
Conjunctivitis
Causes herpes labialis Can also cause keratoconjunctivitis
•
•
Visualized with fluorescein dye and blue light Can become infected with pseudomonas
Sightthreateningdisorder
HSV-1 •
Common among contact lens wearers Painful (due to superficial cornea nerve endings)
S. Aureus
•
H. influenza
•
Neisseria
•
Chlamydia
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65% to 90% viral conjunctivitis Watery discharge Non-enveloped, DNA virus Also causes pharyngitis, pneumonia
Measles Virus
Adenovirus •
•
Rubeola
Very stable - survive on surfaces Transmission: •
Aerosol droplets
•
Fecal-oral
•
Contact with contaminated surfaces
•
•
•
•
•
Bacterial Conjunctivitis •
•
•
•
Staph aureus, S pneumonia, H influenzae
•
Children •
•
H influenzae, S pneumoniae, and Moraxella catarrhalis
•
Reactive Arthritis Autoimmune arthritis triggered by infection
•
•
Intestinalinfections
•
•
•
Salmonella, Shigella, Campylobacter, Yersinia, C. Difficile
•
Chlamydia trachomatis Classic triad (Reiter's syndrome) •
Arthritis
•
eye, discharge) Conjunctivitis (red eye,
•
Urethritis (dysuria, frequency)
Koplik spots in mouth
Ophthalmianeonatorum Neisseria gonorrhea or Chlamydia Infection from passage through birth canal Untreated can lead to visual impairment Prophylaxis:Erythromycinophthalmicointment
Allergic Conjunctivitis
•
•
Cough, Coryza, Conjunctivitis Maculopapular rash
Neonatal Conjunctivitis
Copious purulent discharge Adults: •
•
Paramyxovirus Enveloped, RNA virus
•
114
Bilateral, Bilateral, itchy,watery eye s Type I hypersensitivity reaction Histaminerelease Treatment: antihistamines
Uveitis
Uveitis •
Terminology
Uveal coat inflammation •
Iris, ciliary body, choroid
•
White cells in uvea
•
Anterioruveitis
•
Intermediate uveitis
•
Posterioruveitis
•
•
•
Iritis; Iridocyclitis
Vitreous humor inflammation
Chorioretinal inflammation
Uveitis
Uveitis
Symptoms
Causes
•
•
Anterior uveitis: pain, redness Posterior uveitis: painless, floaters, ↓ vision
•
•
Uveitis •
•
•
•
•
•
•
Often agents that that infect CNS
•
HSV, HSV, CMV, Toxoplasmosis, Syphilis
Often associated with systemic inflammatory disease
Hypopyon
Associations •
Can be infectious
Ankylosing spondylitis
•
Inflammatory infiltrate in anterior chamber
•
Seen in endophthalmitis endophthalmitis
Rheumatoid arthritis
•
Can be seen in keratitis, uveitis
Sarcoid Psoriaticarthritis
•
Bacterial or sterile
Reactive arthritis Juvenileidiopathicarthritis
•
Inflammatory Inflammatory boweldisease
115
Inflammation of aqueous and/or vitreous humor
Visual Fields •
Divided into four quadrants for each eye
•
Quadrantstested individually
Visual Fields Jason Ryan, MD, MPH
Visual System
Visual System
Key Points •
•
1. 2. 3. 4. 5.
Optic Nerve Optic Chiasm Optic Track Baum’s Loop Meyer’s Loop
•
•
L Eye 1 LGN
R Eye
2
Left side of world right cortex Right side of world left cortex Optic nerve carries signals from right/left retina Optic chiasm •
Crossing of fibers from middle middle of both retina
•
Carrying signals from lateral (temporal) (temporal) images
3
5 4 L Eye
Left Posterior Lobe
1
Right Posterior Lobe
Visual System
•
R Eye
Anopia
Key Points •
2
Lateral geniculate nucleus •
Found in thalamus
•
Major termination site of retinal projections
Two projections LGN visual cortex •
Meyer’s loop (temporal (temporal lobe)
•
Baum’s loop (parietal lobe)
L Eye L Eye
2
1 LGN
R Eye 1
R Eye
3
5
Left Posterior Lobe
4
Left Posterior Lobe
1 Left Optic Nerve Compression Left Retinal Lesion
Right Posterior Lobe
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Right Posterior Lobe
Optic Neuritis •
•
•
Amaurosis Fugax
Inflammatory, demyelinating disease Acute monocular visual loss
•
•
Highly associated with MS
•
•
Presenting feature 15 to 20%
•
Occurs 50% during course of illness
•
•
•
Bitemporal Hemianopsia
Painless, transient vision loss in one eye Classic description: Curtain shade over vision Damage to optic tract or retina Symptom of TIA Often embolism to retinal artery Common source is carotid artery
Homonymous Hemianopsia
2 L Eye
R Eye
L Eye
Optic Chiasm Compression Pituitary Tumor/Aneurysm
R Eye
Left PCA Stroke Left Optic Tract Lesion Right visual loss
3 Right PCA Stroke Right Optic Tract Lesion Left visual loss
Left Posterior Lobe
Left Posterior Lobe
Right Posterior Lobe
Quadrantic Anopia
Macular Sparing •
Macula:central, high-resolution high-resolutionvision
•
Often a dual blood supply: supply: MCA and PCA
•
PCA strokes often spare the macula
Right Posterior Lobe
LEye
R Eye
5
5 Meyer’s Loop Temporal Lobe “Pie in the sky” Temporal lobe damage
4
Left Posterior Lobe
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Right Posterior Lobe
4 Baum’s Loop Parietal Lobe “Pie in the floor” Parietal lobe damage
Conjugate Gaze •
•
•
•
Gaze Palsies
Movement of both eyes at same time Looking right or left with both eyes Trackingobjects Conjugate gaze palsy •
Eyes cannot move in same same direction
•
Results in diplopia
Jason Ryan, MD, MPH
Pons
Conjugate Gaze Right Eye
Left Eye
PPRF MLF
Me i a Lateral Rectus
Lateral Rectus
Rectus
CN III
CN VI Abducens
CN VIII
CN III
Medial Longitudinal Fasciculus PPRF
CN VII
CN VI Abducens PPRF
CN VI
Conjugate Gaze
Internuclear Ophthalmoplegia Ophthalmoplegia
Summary •
•
Paramedian Paramedian pontinereticular formation formation •
Initiates lateral gaze gaze from brainstem
•
Located in pons
•
•
Medial longitudinal longitudinalfasciculus •
•
•
•
Signal transmission to opposite side
•
Requires functioning CN CN III and CN VI
•
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Horizontal gaze disorder Weak adduction (medial movement) of one eye Affected eye cannot move toward nose Unaffected eye develops nystagmus Caused by lesions of the MLF Convergence is usually spared •
Different neural pathway
•
CN III working normally
Internuclear Ophthalmoplegia
Internuclear Ophthalmoplegia
Example: Left INO Left
Right
R
Rest
Right Gaze L
Left Gaze
Normal
Left INO
Right INO
Need MLF to move eye medially medially when other eye goes goes lateral Side that cannot go medial is side w ith MLF lesion Problem looking right = left MLF lesion
MLF Syndrome
MLF Syndrome •
•
•
Lost MLF input to oculomotor oculomotor nucleus on lateral gaze Adducting eye unable to move medially past midline
•
Commonly occurs in multiple sclerosis
•
MLF is highly myelinated
Abducting eye: Monocular horizontal nystagmus •
Abducting eye moves smoothly laterally
•
Followed by rapid movement back to midline (saccade) Lateral Gaze
Abducting Eye Nystagmus Saccades
Adducting Eye No movement past midline
Abducens (VI) Nerve Palsy Rest R
Right Gaze
PPRF Lesions
Left Gaze
L
Normal
Left ANP
Right ANP
Look at the eye that that is stuck Trying to move medial medial or lateral? If medial INO If lateral CNVI Palsy
119
•
IpsilateralGaze IpsilateralGaze Palsy
•
Paralysis of conjugate gaze to side of lesion •
Can’t look to side of lesion
•
Left PPRF coordinates coordinates leftward gaze
•
Preservation of convergence
•
Medial pons lesions
Abducens (VI) Nucleus Lesion
One and a Half Syndrome
•
Same as PPRF lesion
•
•
Loss of lateral gaze gaze
•
•
•
Damage to PPRF and MLF INO plus loss of lateral gaze to affected side Convergencespared Side with frozen eye has lesion R
L
Look Right INO Damage Left MLF
Left One-and-a-Half Syndrome
Look Left Conj Gaze Palsy Damage Left PPRF
Frontal Eye Fields
Frontal Eye Fields
•
Region of frontal cortex (Brodmann area 8)
•
Normal gaze central due to equal FEF activation
•
Projections to contralateral contralateral PPRF
•
Lesion: Both eyes deviate to side of lesion
•
Stimulation: Both eyes deviate to opposite side •
Can be seen in frontal lobe seizures R
L
Normal R
L
Right FEF Lesion
Gaze Palsy Summary
120
Aqueous Humor •
•
Ciliarymuscle (accommodation) (accommodation)epithelium •
Produces aqueous humor
•
Sympathetic stim (β receptors)
Trabecular meshwork •
Glaucoma
•
Drains aqueous humor from anterior anterior chamber
Canal of Schlemm •
Drains aqueous humor from trabecular trabecular meshwork
Jason Ryan, MD, MPH
Intraocular Pressure •
Measured by tonometry
•
Determined by amount of aqueous humor
Intraocular Pressure •
•
Glaucoma •
•
•
•
High intraocular pressure pressure
•
•
•
Two types: Open angle
•
Close angle
•
Constricts ciliary muscle
•
Allows fluid to drain
•
↓pressure
Sympathetic (β2 ) •
Produces fluid
•
Allows the eye to focus during during fight/flight
•
More fluid = ↑pressure
Closed Angle Glaucoma
Results in optic neuropathy Visual loss: peripheral first, then central •
Parasympathetic Parasympatheticsystem (M)
•
•
121
Angle for drainage suddenly closes Abrupt onset Painful, red eye Blurred vision withhalos Eye is firm (“rock hard”) (“rock hard”)
Closed Angle Glaucoma •
•
Closed Angle Glaucoma
Symptoms can be triggered when pupil dilates
•
Entering dark room
•
•
Drug with dilating side side effect (scopolamine, (scopolamine, atropine)
•
Mannitol (osmotic diuretic)
•
Timolol (BB)
•
Pilocarpine (M agonist)
Ophthalmologic Ophthalmologic emergency •
Closed Angle Glaucoma •
Chronic angle closure •
Portion of angle blocked
•
Develops scarring
•
Over time angle progressively more closed
•
Intraocular pressure not as high
•
Fewer symptoms (pain, (pain, etc.)
•
Delayed presentation
•
More damage to the optic optic nerve
•
Diagnosis made when peripheral vi sion loss occurs
•
•
Age
•
Family history
•
African-American race
Eye surgery
Chronic most patients have this form No symptoms until loss of eyesight occurs •
•
•
•
•
Peripheral then central
Overproduction fluid or decreased drainage Angle for drainage of fluid is “open” Too much fluid or too little drainage Chronic drug therapy
Open Angle Glaucoma
Associations •
Acetazolamide (carbonic anhydrase inhibitor)
Open Angle Glaucoma
Open Angle Glaucoma •
Medicaltreatment:
•
•
Primary •
•
Secondary •
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Cause unclear Uveitis
•
Trauma
•
Steroids
•
Retinopathy
Chronic Glaucoma Drugs •
M3 agonists •
•
•
Contract ciliary muscle
•
α2 agonists •
•
Parasympathomimetics
•
Block ciliary epithelium from releasing aqueous
•
β blockers •
•
Prostaglandin Prostaglandin analogues
•
Carbonicanhydrase inhibitors
•
•
•
Block ciliary epithelium from releasing aqueous
•
•
Contract ciliary muscle Opens trabecular meshwork meshwork Moredrainage
Vasodilate the Canals of Schlemm: Schlemm: increase outflow Decrease synthesis of aqueous
Alpha Agonists •
Carbachol,pilocarpine Muscarinicagonists
Beta Blockers
Apraclonidine, Apraclonidine, Brimonidine Decrease aqueous production
•
•
Timolol,betaxolol,carteolol ↓ aqueous humor production by ciliary epithelium
Can have (<15%) ocular side effects •
Blurry vision
•
Ocular hyperemia
•
Foreign body sensation
•
Itchy eyes
Prostaglandin analogues
Carbonic anhydrase inhibitors
•
Bimatoprost,latanoprost,tafluprost, travoprost
•
Acetazolamide Acetazolamide (oral)
•
More drainage/outflow
•
Diuretic
•
Will darken iris
•
Less fluid production by ciliary epithelium
123
Epinephrine •
•
•
Mixed alpha-beta agonist Early effect: ↑aqueous humor (beta effect) Later effect: Vasoconstriction Vasoconstriction ciliary body •
•
↓production aqueous humor
Never give in closed angle glaucoma •
Dilates pupil
•
Worsens angle closure
124
Anesthetic •
Drugs that produce: produce: •
General Anesthetics
Analgesia
•
Loss of consciousness
•
Amnesia
•
Muscle relaxation
Jason Ryan, MD, MPH
Types of Anesthesia Drugs
Inhaled Anesthetic Principles
•
Inhaledanesthetics
•
•
Intravenous anesthetics
•
•
•
Localanesthetics Neuromuscular blocking agents
•
Special properties determine effectiveness Solubility of gas for blood determines onset/offset Solubility of gas for lipids de termines potency
Blood Solubility
Blood Solubility
Inhaled Anesthetics
Inhaled Anesthetics •
Partial Pressure
•
•
•
125
Molecules dissolved in blood: No anesthetic effect Molecules NOT dissolved: Anesthetic effect Need to saturate blood to generate partial pressure So MORE solubility in blood = LONGER to take effect
Blood Solubility
Blood Solubility
Inhaled Anesthetics
Inhaled Anesthetics •
Highersolubility •
Alveolar Gas
Saturated Blood
Brain Effect
Sedation •
Higher tendency to stay in blood
•
Less likely to leave blood for brain
•
Longer time to saturate blood
•
SLOWER induction time (also washout washout time)
Low solubility •
Quickly saturate blood
•
Quickly exert effects on brain
•
SHORTER induction time (also washout washout time)
Blood Solubility
Blood Solubility
Inhaled Anesthetics
Inhaled Anesthetics •
d o o l B
Max Anesthesia Effect
e r u s s e r P l a i t r a P
Blood/gaspartitioncoefficient •
Isoflurane: 1.4
•
[blood]1.4 > [alveoli]
A B
Time
Drug A: Less soluble in blood, faster rise in pressure, fast anesthetic effect Drug B: More soluble soluble in blood, slower rise in pressure, pressure, slower effect
Blood Solubility
Lipid Solubility
Inhaled Anesthetics
Inhaled Anesthetics •
•
•
Halothane SLOW induction (like to stay in blood) Nitric Oxide FAST induction (quickly (quickly leaves leaves blood)
126
Affinity of gas for a lipids Oil/gas partition coefficient
↑lipid affinity = more potent (Meyer-Overton rule)
Inhaled Anesthetic Principles •
Minimumalveolar concentration •
Low MAC = High potency
•
MAC changes with age •
•
Concentration of anesthetic that prevents movement in 50 percent of subjects subjects in response response to pain
•
•
Inhaled Anesthetics Summary
•
Lower in elderly
Onset of action •
Blood:gas partition coefficient coefficient (↑higher = slower)
•
Solubility in blood (↑higher = slower)
Potency •
Oil/gas partition coefficient (↑higher = more potent)
•
MAC (↓lower = more potent)
MAC related to lipid solubility (not blood!!) d o o l B e r u s s e r P l a i t r a P
1 Lipid Solubility = MAC
Fast Onset
Slow Onset
Time
Inhaled Anesthetics •
•
•
•
•
•
•
Common Effects
Desflurane Sevoflurane
•
Myocardial depression
Halothane Enflurane
•
Respiratory depression
Isoflurane Methoxyflurane
•
•
•
Nitrousoxide •
Halothane – Hepatotoxicity & NMS •
Liver tox: Rare, life-threatening
•
Massive necrosis, increased AST/ALT
•
Methoxyflurane– Nephrotoxicity Nephrotoxicity
•
Enflurane – Seizures
•
•
Nausea and vomiting ↑ cerebral blood flow •
Cerebral vasodilation
•
Blood flow goes up
•
ICP goes up
Decreased GFR
Malignant Hyperthermia
Special Side Effects •
↓CO
•
Rare,dangerous reaction:halothane,succinylcholine
•
Fever, muscle rigidity after surgery
•
•
Renal-toxic metabolite
•
Tachycardia, hypertension Muscle damage: ↑K, CK Cause: ryanodine receptor sarcoplasmic sarcoplasmic reticulum •
Lowers seizure threshold
•
127
Ca channel in SR of muscle muscle cells
•
Abnormal in patients who get MH (autosomal dominant)
•
Dumps calcium
•
Ca consumption of ATP for SR reuptake
•
ATP consumption
heat tissue damage
Treat with dantrolene (muscle relaxant)
Nitrous Oxide •
•
•
•
Intravenous Anesthetics
Diffuses rapidly into air spaces Will increase volume
•
•
Cannot use: •
Pneumothorax
•
Abdominal distention
•
•
•
50% NO doubling of cavity size
•
•
•
•
•
Different mechanism from benzodiazepines
•
High potency from high lipid solubility Rapid onset •
Ultra short acting
•
Myocardial/respiratory depression
•
↓ cerebral blood flow
•
•
•
Rapid entry into brain
•
Ketamine Propofol
Midazolam, Lorazepam, Diazepam, Alprazolam
Thiopental(Pentothal) Binding to GABA-receptor •
•
Opioids Etomidate
Benzodiazepines
Barbiturates •
Barbiturates Benzodiazepines
Bind to GABA receptors ↑ frequency of GABA ion channel opening Low dose: anti-anxiety (anxiolytic) High dose: sedation, amnesia, anticonvulsant Causecardio-respiratorydepression •
•
Rapid distribution to muscle and fat
•
↓BP
Overdose:Flumazenil Midazolam (Versed): Short procedures (en doscopy)
Opioids
Opioids Mechanism
Morphine, Fentanyl, Hydromorphone Hydromorphone
Morphine, Fentanyl, Hydromorphone Hydromorphone
•
•
•
•
•
Sedatives, analgesics
•
No amnesia Act on opioid (mu) receptors in brain
•
•
Side effects: •
↓respiratory drive
•
↓BP
•
Nausea/vomiting
•
Ileus
•
Urinary retention
Tolerance: Decreased effectiveness chronic use
128
Mu receptors G-proteinlinked 2nd messengers not clearly understood understood
•
Increase K efflux from cells
•
This HYPERpolarizes HYPERpolarizes less pain transmission
Naloxone •
•
•
•
•
•
Opioid Tolerance
Opioidantidote Used for overdose
•
•
Mu antagonist Competes with opioids, displaces from binding site
•
Reverses effects within minutes Must be given IV inactivated inactivated by liver if PO
•
Effect wanes with chronic use Major problem with cancer pain Decreased effect on •
Pain
•
Sedation
•
Nausea, vomiting
•
Respiratory depression
•
Cough suppression
•
Urinary retention
No tolerance to constipation or miosis •
Ketamine •
•
•
•
Ketamine
PCP derivative Antagonist of NMDA receptor (glutamate) (glutamate)
•
Patient enters trancelike state
•
Analgesia and amnesia
•
Few respiratory or CV effects
Disorientation
•
Dreams, hallucinations
•
Can be frightening to patients
•
Co-administer midazolam to help
Can cause ↑BP ↑HR
Etomidate •
“EmergenceReactions” “EmergenceReactions” •
“Dissociative” drug •
These effects persist
Propofol
Modulates GABA receptors •
Blocks neuroexcitation
•
Anesthesia but not analgesia analgesia
•
Relativelyhemodynamicallyneutral
•
Blocks cortisol synthesis
•
Rapid sequence intubation intubation
•
Good for hypotensive patients
129
•
GABA modulator
•
Sedation,amnesia
•
Myocardialdepression, hypotension
GABA Receptor Anesthetics •
•
•
•
•
•
Induction & Maintenance Maintenance
Etomidate Propofol
Typical Open Heart Case
•
Paralysis
•
Maintenance
•
•
•
•
Maintenance – Keep patient asleep •
GABA is largely inhibitory These drugs activate receptor sedation
Induction
Induction – Put patient to sleep •
Benzodiazepines Barbiturates
•
•
Propofol, Midazolam Rocuronium Sevoflurane, fentanyl
130
Propofol, Etomidate, Ketamine
Propofol, sevoflurane, desflurane desflurane
Local Anesthetics •
Local Anesthetics
•
Jason Ryan, MD, MPH
Local Anesthetic B + H+
BH+
Amides •
Lidocaine
•
Mepivacaine
•
Bupivacaine
Esters •
Procaine
•
Cocaine
•
Benzocaine
•
Tetracaine
Adding Epinephrine •
Na+
Cell Membrane
LA can be given with epinephrine •
Causes vasoconstriction
•
Less bleeding
•
Less washout more local local effect
X
B + H+ 1. 2. 3. 4.
BH+
Key Points Uncharged form crosses membrane Charged form blocks Na channel Drugs work on inside of cell membrane Acidic environments = more drug needed for effect
Differential Blockade
Differential Blockade
•
Small fibers > largefibers
•
Different effects different senses
•
Myelinated > unmyelinated
•
Pain blocked first, pressure last
131
Local Anesthetics Uses •
Minor surgical procedures
•
Epidural/spinal Epidural/spinal anesthesia
Local Anesthetics Side Effects •
CNS Stimulation Stimulation •
•
•
•
Methemoglobinemia •
•
•
•
•
•
•
•
•
When Fe3+ is present methemoglobin Fe3+ cannot bind oxygen
•
•
Remaining Fe 2+ cannot release to tissues Acquired methemoglobinemia from drugs Local anesthetics anesthetics (benzocaine)
•
Nitric oxide
•
Dapsone
Later: Drowsiness, coma
Cardiovascular •
Hypotension, arrhythmia, bradycardia, heart block
•
Cocaine is exception: hypertension, vasoconstriction
Bupivacaine most cardiotoxic
Clinical Scenario
Iron in hemoglobin normally normally reduced (Fe2+) Certain drug oxidize iron to Fe3+
•
Initial (excitation):Talkativeness, anxiety, confusion, stuttering speech
•
•
•
Treatment: methylene blue
132
Endoscopypatient Benzocaine spray used for throat analgesia Post procedure shortness of breath “Chocolate brownblood” brown blood” O2 sat (pulse oximetry) = variable (80s-90s) PaO2 (blood gas) = normal Also premature babies given NO for pulmonary vasodilation
Types of Anesthesia Drugs •
•
Neuromuscular Blockers
Inhaledanesthetics Intravenous anesthetics
•
Local anesthetics
•
Neuromuscularblockingagents
Jason Ryan, MD, MPH
Paralytics •
•
•
•
•
•
•
Succinylcholine
Succinylcholine Tubocurarine
•
•
Atracurium Mivacurium
•
•
Pancuronium Vecuronium
•
•
Basically two ACh molecules joined together Strong ACh (nicotinic)receptor (nicotinic)receptor agonist Sustaineddepolarization depolarization Prevent muscle contraction
Rocuronium
Succinylcholine – Phase 1
Succinylcholine •
Two phases to depolarizing block
•
•
Phase 1
•
•
Different from all other paralytics DEPOLARIZINGneuromuscularblocker
•
Depolarizing phase
•
Muscle fasciculations fasciculations occur
•
•
Phase 2 •
Desensitizing phase
•
Depolarization has occurred
•
Muscle no longer reacts reacts to ACh
•
133
Na channels open and then close - become inactivated Membrane potential must reset Normally rapid as Ach hydrolysed by AChE Succinylcholine Succinylcholine NOT metabolized metabolized by AChE Prolonged activation of ACh receptors occurs
Succinylcholine – Phase 2 •
•
•
Succinylcholine
Desensitizingphase Normally ACh washed out quickly – no desensitization
•
•
Longer depolarization (succ) desensitization
•
•
Fast acting Rapidwashout No reversal Main side effect is ↑K •
•
Non-depolarizing Non-depolarizing NMBA
Malignant Hyperthermia •
•
•
•
•
•
Tubocurarine, Atracurium, Mivacurium, Pancuronium, Vecuronium, Rocuronium
Rare,dangerousreaction: halothane,succinylcholine succinylcholine High fever, muscle rigidity after surgery
•
•
Tachycardia, hypertension Muscle damage: ↑K, CK
•
•
Cause: ryanodine receptor sarcoplasmic sarcoplasmic reticulum •
Ca channel in SR of muscle cells
•
Abnormal in patients patients who get MH (autosomal dominant)
•
Dumps calcium
•
Ca consumption of ATP for SR reuptake
•
ATP consumption
•
•
Produce paralysis Many cause marked histamine release Hypotension compensatory tachycardia
•
Can be reversed by flooding synapse with ACh
•
This is done by inhibitingAChE
heat tissue damage
Treat with dantrolene (muscle relaxant)
ICU Weakness
Reversal of non-depolarizing non-depolarizing neuromuscular blockers
•
Competitiveantagonists antagonists Compete with ACh for nicotinic receptors
•
AChE Inhibitors •
Caution in burn patients, dialysis patients
MalignantHyperthermia
Physostigmine Neostigmine Pyridostigmine Edrophonium
134
•
Common after prolonged ICU treatment
•
May be associated with NMBA
Assessing Neuromuscular Blockade •
Peripheralnerve stimulator
•
Train of 4 impulses
Train of 4 •
•
•
Rapid Sequence Intubation •
•
Standard practice for emergent intubation intubation Renders patient sedated and flaccid
•
Induction: Etomidate
•
Paralysis: Succinylcholine
•
Sometimes ketamine, benzos
135
Used to assess neuromuscular blockade in patients under anesthesia 4 electrical stimulations to nerve (i.e.ulnar) Goal usually ¼ or 2/4
Meningitis •
•
•
Inflammation of the leptomeninges Usually infectious: viral, bacterial, fungal Rarely: cancer, sarcoid, inflammatory diseases
Meningitis Jason Ryan, MD, MPH
Symptoms •
•
Symptoms
Fever, headache, photophobia Nuchalrigidity •
•
Nape = back of neck
•
Nuchal = related to nape
•
Nuchal rigidity = hurts hurts to move back of neck
•
•
Diagnosis of Meningitis •
Suggestive signs & symptoms
•
Spinal tap
Kernig sign •
Thigh bent at hip with knee at at 90 degrees
•
Subsequent extension of knee is painful (resistance)
Brudzinskisign •
Lye patient flat
•
Lift head off table
•
Involuntary lifting of legs
Both signs of meningismus meningismus •
Usually meningitis
•
Also subarachnoid hemorrhage
Spinal Tap
Line between iliac crests = fourth lumbar vertebral body L4/5 interspace used well below termination of cord. Needle crosses skin, ligaments, dura, arachnoid. Enter subarachnoid space. Does not pierce pia
136
Opening Pressure •
•
•
Patient must lie on their side Normal pressure up to 250mm H20
•
•
•
Elevated pressure (>250): •
•
Complications of Meningitis
•
Bacterial
•
Fungal/TB
•
Rarely viral
•
•
•
•
•
Hearing loss Seizures Most from bacterial meningitis
Elevated pressure in hydrocephalus Therapeutic for ↑ICP
Selecting Treatment •
Death Hydrocephalus
Spinal Fluid Testing
Antibiotics Culture takes days
•
•
Cannot wait for culture to drive choice of drug Choose drugs based on: •
Patient age, co-morbidities
•
Spinal fluid cell types, protein, glucose
•
•
Cells Protein Glucose Culture
Normal CSF
CSF Meningitis Findings
•
•
•
•
Clear 0-5lymphocytes <45mg/dlprotein >45mg/dlglucose •
137
About 2/3 of blood glucose (80-120)
Causes of Meningitis
Meningitis Antibiotics •
•
•
•
•
Ceftriaxone Vancomycin Ampicillin Gentamycin All have good CSF penetration
Ceftriaxone plus Vancomycin
Ampicillin plus Gentamycin Gentamycin
Streptococcus Pneumoniae •
•
•
•
•
Neisseria Meningitidis
Most common cause meningitis all ages Lancet-shaped, gram positive cocci in pairs
•
•
Can follow strep respiratory infection Increased risk •
Asplenic patients
•
Sickle cell
•
Alcoholics
•
•
•
•
Also causes otitis media (kids), pneumonia, sinusitis
Neisseria Meningitidis •
•
•
•
•
•
•
Gram negative cocci in pairs ( diplococci) diplococci) Transmitted by respiratory droplets Enters pharynx then bloodstream then CSF Manyasymptomaticcarriers Polysaccharide Polysaccharide capsuleprevents phagocytosis phagocytosis Lipooligosaccharide Lipooligosaccharide(LOS) outer membrane •
Like LPS on gram negative rods
•
Endotoxin many toxic effects on body
•
Activates severe inflammatory response
Neisseria Meningitidis
Bacteremia can complicate meningitis
•
Meningococcemia Sepsis: fevers, chills, tachycardia
Can cause outbreaks •
•
•
•
Waterhouse-Friderichsen syndrome Adrenal destruction from meningococcemia
Life-threatening
•
138
Dorms, barracks
Can infect young, healthy people •
Purpuric rash DIC •
Ceftriaxone plus Vancomycin plus Ampicillin
College students in dorms
Infected patients need droplet precautions precautions Close contracts receive prophylaxis •
Rifampin
•
Also Ceftriaxone or Ciprofloxacin
Vaccine available •
Contains capsular polysaccharides
•
Only used in high high risk groups
anti-capsule antibodies
Haemophilus Influenzae
H. Influenza Vaccine
•
Small, gram negative r od (coccobacillus)
•
•
Enters pharynx then lymphatics then CSF
•
•
HIB once most common cause bacterial meningitis Hib conjugate vaccines given in infancy H. Flu meningitis almost always occurs in unimmunizedchildren •
Listeria •
•
•
•
•
•
“Tumblingmotility” “Tumblingmotility” Multiplies in cells with poor cell-mediated immunity
•
•
Neonates, HIV, HIV, organ transplant •
Undercooked meat, unwashed vegetables Unpasteurized cheese/milk •
Likes cold temperatures
•
•
•
•
Motile, gram-negative bacillus (rod) Some strains have K-1 capsular antigen Inhibits complements, complements, other immune responses
•
Allows bacteria to evade host immunity Blood agar
•
MacConkey agar
•
Eosin methylene blue agar
CAMP test positive
Most common cause meningitis in newborns •
Transmitted when baby passes passes through birth canal
•
Ampicillin during labor can prevent
May not have classic symptoms Hypotonia, w eak sucking reflex reflex
•
Bulging fontanels, sunken eyes
•
Poor feeding
Old name: “aseptic” •
•
•
•
139
Evidence of meningitis without bacteria
Usually enteroviruses •
Grows on: •
Beta hemolytic bacteria
•
Viral Meningitis
2nd most common meningitis cause neonates
•
Catalase negative
•
•
In neonates, transplacental or vaginal transmission
E. Coli •
Strep Agalactiae Gram positive cocci in chains •
In adults, often from contaminated food •
•
Group B Strep
Gram positive positive rod Facultativeintracellular organism
•
•
May immigrate from other countries countries without vaccination
Coxsackievirus, echovirus, poliovirus
Self-limited Supportive care – no specific treatment
•
All single stranded RNA viruses
•
Fecal-oral transmission
Viral Meningitis •
Herpes Virus
Rare causes
•
HSV-1
•
HSV
•
•
HIV
•
Eye infections (keratoconjunctivitis)
•
West Nile virus
•
Encephalitis - Loves to infect infect the TEMPORAL lobe
•
Varicella Zoster virus
•
HSV-2 •
•
•
•
Viral Meningitis •
•
•
Genital herpes 13 to 36% primary genital herpes pts have clinical findings of meningitis (headache, (headache, photophobia and and meningismus) Genital lesions in 85% patients with HSV-2 meningitis
Treatmen t: acyclovir, valacyclovir,famciclovir
TB Meningitis
Usually no specific virus testing If HIV suspected •
•
Oral herpes
•
•
Blood testing for HIV HIV RNA and HIV antibody
•
If HSV suspected anti-virals can be given Other viruses tested only special circumstances
•
•
•
M. tuberculosis infection of the meninges CSFlymphocytes High protein, low glucose Need multiple CSF samples for culture Acid-fast bacilli (AFB) sometimes seen in CSF Nucleic acid amplification tests (NAATs) used •
Use polymerase chain reaction (PCR) (PCR) techniques
Encephalitis
Encephalitis
Other (rare) causes
•
Encephalitis = brain inflammation
•
Varicella-zoster (chickenpox, shingles)
•
Must make sure meningitis patients don’t have: have:
•
Mosquitoviruses
•
•
Altered mental status
•
•
Motor or sensory deficits
•
Eastern/western equine
•
Altered behavior and personality changes
•
West Nile
•
Speech/movement disorders
•
California encephalitis
If these are present, HSV-1 is common cause
140
St. Louis encephalitis encephalitis virus
Encephalitis Other (rare) causes •
•
•
•
Lassa fever encephalitis •
Spread by mice
•
Hemorrhagic virus like Ebola (many other symptoms)
Measles Naegleriafowleri (protozoa) HIVEncephalitis
141
What is a seizure •
Sudden alteration in behavior
•
Due to transient brain pathology
Seizures Jason Ryan, MD, MPH
Seizure symptoms •
•
•
•
Seizure Causes
Loss of consciousness Abnormal motor activity
•
Many people have 1 seizure
•
Often “provoked”
Abnormal sensation Range •
Mild: Loss of awareness awareness (absence)
•
Severe: Tonic-clonic
•
Seizure Causes by Age Group
Fever (children)
•
Lack of sleep
•
Drugs, alcohol
•
Hypoglycemia
•
Other causes more serious: tumors, strokes
•
Multiple, unprovoked seizures is epilepsy
Seizure Workup •
•
•
•
•
Genetic: Juvenile myoclonic epilepsy epilepsy Metabolic: Hyponatremia, hypernatremia, hypoMg, hypoCa Infection: Meningoencephalitis
142
Blood work EKG (cardiac syncope) EEG Brain imaging (CT or MRI) Sometimes lumbar puncture (LP)
EEG
Seizure Types
Electroencephalogram •
•
Records voltage changes in brain Different leads •
•
•
Frontal, parietal, occipital •
Characteristic patterns
Partial – One discrete part of brain •
Simple partial – No alteration alteration consciousness
•
Complex partial – Alteration Alteration consciousness
Generalized – Entire brain effected •
•
Psychic Symptoms •
•
•
•
•
•
•
•
•
•
•
Tonic-clonic “Grand mal”
•
Atonic “Drop seizure”
•
Myotonic
Secondarygeneralized
Autonomic Symptoms
Can occur with partial seizures Higher cortical areas affected
•
Epigastric "rising"sensation
Dysphasia Feelings of familiarity familiarity ("deja-vu")
•
Sweating
Distortions of time Fear
•
•
•
Common aura with medial temporal lobe lobe epilepsy
Piloerection Pupillarychanges
Hallucinations
Auras •
Absence “Petit mal”
•
Post-ictal State
Warning before major seizure
•
Auras = simple, partial seizures Seizure affects enough brain to cause symptoms
•
•
Not enough to interfere with consciousness Symptoms depend on area of brain •
Occipital lobe: flashing lights
•
Motor cortex: muscle muscle jerking (Jacksonian (Jacksonian Seizure)
•
•
143
Transition period seizure normal state Period of brain recovery Confusion,lack of alertness Focal neurologic deficits may present Variable time, minutes to hours
Partial Seizures •
•
•
•
Juvenile Myoclonic Epilepsy
Most common site: temporal lobe Mesial temporal sclerosis sclerosis •
Also called hippocampal sclerosis
•
Neuronal loss in hippocampus
•
•
•
•
Often bilateral but one side>other Can diagnose by MRI
•
•
Childhood Absence Epilepsy •
•
•
•
•
•
•
•
•
Last few seconds Usually remits by puberty
•
•
Classic EEG finding: 2.5 - 5 Hertz spike wave activity superimposed on normal background background EEG
•
•
•
•
Grand mal seizures soon after Hallmark: •
Myoclonic jerks on awakening from sleep
•
Shock-like, irregular movements of both arms
Common: 2-4% children <5 years old Child loses consciousness,shakes Children at risk for more febrile seizures Overall prognosis generally good This is NOT considered epilepsy
No post-ictal confusion confusion Ethosuximide Ethosuximide is first line treatment Blocks thalamic T-type Ca++ channels
Eclampsia •
Absence seizures first (~5 years of age) Myoclonic seizures later (~15 years)
Febrile Seizures
Sudden impairment of consciousness No change in body/motor tone
•
•
Absence, myoclonic, and grand mal Common in children
Seizure Treatment Principles
Pregnancyrelated condition
•
20weeks to 6weeks post-partum Hypertension, proteinuria, edema = Preeclampsia
Breakingseizures •
Eclampsia = preeclampsia + seizures Treatment:MgSO4 •
144
Status epilepticus
•
Continuous seizure >30min
•
Or seizure that recurs recurs <30min
•
Medical emergency
•
Arrhythmias, lactic acidosis, hypertension
Preventing seizures
Preventing Seizures
Breaking Seizures
Na Inactivators
•
First line treatment is benzodiazepines benzodiazepines
•
Lorazepam drug of choice
•
•
Also often administer:
•
•
Rapid acting
•
Phenytoin (PO) or fosphenytoin (IV)
•
Prevent recurrent seizures
•
If still seizing after benzo/phenytoin phenobarbital
•
Often will then give general anesthesia and intubuate
•
•
•
•
•
•
Niche Drugs
•
•
Benzodiazepines
•
Absenceseizures •
Ethosuximide
Carbamazepine •
•
•
•
•
•
•
Useful for partial and generalized seizures Also: bipolar disorder, trigeminal neuralgia •
Many, many side effects Diplopia, ataxia Agranulocytosis Aplastic anemia
•
Phenobarbital Tiagabine Vigabatrin ValproicAcid
Gabapentin Topiramate Ethosuximide Levetiracetam Primidone
All AEDs carry risk if taken during pregnancy Valproic Acid carries the greatest risk •
Most teratogenic
•
1-3% chance of neural neural tube defects
Bone marrow suppression suppression •
Anemia, low WBC, low platelets
•
Monitor CBC
Livertoxicity •
•
Low blood counts •
•
Carbamazepine
Inactivates Na channels
•
•
Teratogenicity
StatusEpilepticus •
•
Other Mechanisms •
•
Phenytoin Carbamazepine Lamotrigine Valproic Acid
GABA Activators
•
•
145
Monitor LFTs
SIADH (low Na level) Stevens-Johnson syndrome Drug blood levels monitored
Stevens Johnson Syndrome •
•
•
•
•
Ethosuximide
Rare, life-threatening skin condition Malaise and fever (URI Sx)
•
•
Extensive skin lesions lesions Skin necrosis and sloughing sloughing
•
•
•
•
•
•
•
•
Nausea/vomiting
Carbamazepine
•
Sleep disruption
•
Ethosuximide
•
Fatigue, Hyperactivity
•
Phenytoin
•
Lamotrigine
Cytochrome P450
Barbiturate Binding to GABA-receptor •
Different mechanism from benzodiazepines
•
Increase duration channel is open
•
More Cl- flux
•
Less firing
•
•
•
•
•
Myocardial/respiratory depression CNS depression, worse with EtoH Contraindicated Contraindicatedin porphyria
•
AEDs that induce CYP450 •
Carbamazepine
•
Phenobarbital
•
Phenytoin
Some Examples Inducers
Can cause drug levels levels to rise
•
Cyclosporine, some macrolides, azole antifungals antifungals
•
Luckily, many P450 metabolized drugs rarely used •
•
If inhibited drug levels rise If induced drug levels fall
P450 Drugs
Inhibitors are more dangerous •
•
Intracellularenzymes Metabolize many drugs
Induces P450 enzyme system
Cytochrome P450 •
Can cause SJS Other side effects
•
Can be triggered by meds, often AEDs
Phenobarbital •
Blocks thalamic T-type Ca++ channels Drug of choice: childhood absence seizures
•
Theophylline, Cisapride, Terfenadine
•
Some clinically relevant possibilities possibilities •
Some statins + Inhibitor Rhabdo
•
•
Warfarin
•
146
Chronic EtOH Rifampin Phenobarbital Carbamazepine Griseofulvin Phenytoin
Inhibitors •
Isoniazid
•
Erythromycin
•
•
•
•
Cimetidine Azoles Grapefruitjuice Ritonavir(HIV)
Phenytoin •
•
•
•
•
•
Phenytoin
Inactivates Na channels Very useful tonic-clonic seizures
•
•
Gingival hyperplasia, hair growth Rash
•
•
Folic acid depletion ( supplement) Decreased bone density
•
Long term use: nystagmus, diplopia, ataxia
•
Teratogenic
•
Monitor blood levels
•
Na and GABA effects effects •
•
↑synthesis, ↓breakdown GABA
•
•
Also a mood stabilizer (bipolar disorder, acute mania)
•
•
BAD for pregnancy
•
•
•
•
•
Associated with spina bifida
•
Nausea / vomiting
•
Co-admin with P450 drugs alters levels
Exact mechanism unknown Useful for many types of seizures Blood levels can be monitored Drug titrated to clinical effect Well tolerated: few important/serious side effects
Hepatotoxic – Che ck LFTs Tremor, weight gain
Other AEDs •
High dose enzymes saturated rapid ↑ levels Induces and is metabolized by P450
Levetiracetam
Valproic Acid •
Dose-dependenthepatic metabolism Low dose small ↑ blood levels
Other AEDs
Lamotrigine
•
Topiramate
•
Na channel drug
•
•
SJS – Discontinue if rash develops, develops, especially especially kids
•
Mental dulling, sedation
•
Weight loss
•
Kidney stones
Gabapentin •
Affects Ca channels
•
Sedation, ataxia
•
Primidone •
147
Na and GABA effects
Exact mechanism not clear
•
Metabolized to phenobarbital
•
Also can be used for essential essential tremor
Germ Layers •
Mesoderm
•
Endoderm
•
Ectoderm (Most CNS)
•
•
Neuroembryology
CV system, muscles, bone
Liver, lungs, GI tract
•
Surface ectoderm: ant pituitary, lens, cornea
•
Neural tube: brain, spinal cord, post pituitary, retina
•
Neural crest: Autonomic, sensory nerves, nerves, skull
Jason Ryan, MD, MPH
Neural Tube Development
Neural Tube Development
Neural Plate •
•
•
•
Developmental process starts with notochord Secretes signal molecules (Sonic Hedgehog protein)
Neural Crest
Ectoderm
Notochord
Induces overlying ectoderm neuroectoderm Neuroectoderm becomes neural plate
•
Neural plate becomes neural tube
•
All occurs days 17-21 in embryo
•
Notochord in adult: nucleus pulposus (IV discs)
•
Also neural crest crest cells
Neural Fold
Ectoderm
Neural Tube Neural Crest
Notochord
Regional Brain Development Development •
Neural tube has bulges/swellings bulges/swellings
•
3 primary vesicles (bulges)
•
Neuro Congenital Defects •
Neural Tube Defects •
•
Forebrain (prosencephalon)
•
•
Midbrain (mesencephalon)
•
•
Hindbrain (rhombencephalon)
Cephalicdisorders
•
Posterior Fossa Defects
•
Telencephalon
Anencephaly (rostral end) Encephalocele
•
5 secondary vesicles vesicles •
Spina Bifida (caudal (caudal end of tube)
Holoprosencephaly
•
Diencephalon
•
Chiari malformations
•
Mesencephalon
•
Dandy Walker
•
Metencephalon
•
Myelencephalon
148
Neural Tube Defects •
•
•
Neural Tube Defect Risks
Neuropores fail to fuse in 4th week •
Neuropore = opening of neural tube
•
Rostral neuropore at head, caudal at at tail
•
•
•
Spina Bifida •
Caudal neuropore neuropore fails to close posteriorly
•
Bones do not close around spinal cord/meninges
•
Anencephaly (“without head”) (“without head”) •
Rostral neuropore fails to close close anteriorly
•
Absence of of major portions portions brain/skull
Spina Bifida •
•
Anencephaly
Defects can be detected in utero Surgery can repair the defect •
•
↓folic acid intake Type I diabetes diabetes Obesity Valproic acid and/or carbamazepine
•
•
Sometimes in utero, often after birth
•
Permanent neuro deficits often result •
Leg weakness or paralysis (wheelchair)
•
Bowel/bladder problems
•
•
•
Forebrain/brainstem Forebrain/brainstemexposedin utero Fail to develop Not compatible with life Stillbirth or death shortly after birth Ultrasound: •
Open calvaria
•
Frog-like appearance of fetus
Mother will have polyhydramnios polyhydramnios •
Encephalocele
Baby can’t swallow amniotic fluid normally
Alpha Fetal Protein
•
Brain or meninges herniate through skull defect
•
•
Least common NTD
•
•
Most common site: occipital bone
•
•
•
Fetal specific globulin globulin Made by fetal yolk sac, fetal organs Functionunknown Excreted by fetal kidneys 16 to 18 weeks measure maternal serum level
•
If high, MAY indicated NTD
•
Follow-uptests
•
•
149
Interpretation complex Amniotic fluid AFP (requires amniocentesis)
•
Amniotic fluid acetylcholinesterase (AChE)
•
If both elevated, elevated, strongly suggests suggests NTD
Prenatal Screening •
•
•
Holoprosencephaly
Neural tube defect screening •
Ultrasound
•
Maternal blood level Alpha Fetal Fetal Protein (AFP)
•
•
•
Screening also done for Down Syndrome •
Nuchal translucency translucency by ultrasound
•
Serum markers
•
AFP
•
Estradiol
•
•
Failure of signaling molecules
•
Key findings are facial abnormalities: abnormalities:
HCG •
Chiari Malformations •
•
•
Downward displacement displacement of the cerebellum
•
•
•
Abnormal shape of cerebellar tonsils
•
Tonsils displaced below foramen magnum
•
Associatedwith Syringomyelia
•
Worse with cough: “cough headache”
Downward displacement displacement cerebellar vermis & tonsils
•
Brainstem malformation malformation
•
Spinal myelomeningocele myelomeningocele
•
•
Other symptoms •
Cerebellar dysfunction (ataxia)
•
Cranial nerve dysfunction (brainstem compression)
Tonsils = small rounded rounded structure bottom of cerebellum
•
Headaches Due to meningeal irritation
Cyclopia
Associations: Associations: trisomy 13 (Patau syndrome), trisomy 18 (Edward’s syndrome), Fetal alcohol syndrome
Arnold-Chiari Malformation
Mean age 18 years
•
Cleft lip/palate
•
Chiari II Malformation Malformation
Usually no symptoms until adolescence/adulthood •
•
•
Chiari I through IV
Chiari I Malformation •
Sonic hedgehog hedgehog implicated
Chiari I Malformation Malformation
Anatomic anomalies of cerebellum Group of congenital disorders •
Left/right hemispheres fail to separate Usually happens during weeks 5-6 •
“Triplescreen” “Triplescreen” •
Cephalic malformation malformation Failure of cleavage of prosencephalon
150
Beaked midbrain on neuroimaging
Usually detected prenatal/birth
Chiari II Malformation
Dandy Walker Malformation
Arnold-Chiari Malformation •
•
•
•
Blockage of aqueduct Hydrocephalus
•
•
Myelomeningocele paralysis below defect Hydrocephalusin infants •
Large head circumference on growth curves
•
Anterior fontanelle distended
•
Sutures widely split
•
Abnormal percussion: “cracked pot” sound or Macewen’s sign
•
•
Developmental anomaly of the fourth ventricle Often detected by ultrasound in utero Hypoplasia or agenesis of cerebellar vermis Cerebellar hemispheres often flattened •
•
•
•
151
Separated by “Dandy-Walker cyst”
Cysts of 4th ventricle hydrocephalus Many, many associated symptoms/conditions Affectedchildren •
Hydrocephalus
•
Delayed development
•
Motor dysfunction (crawling, walking)
Dementia vs. Delirium •
Delirium & Dementia
•
Dementia •
Chronic, progressive cognitive decline
•
Usually irreversible
Delirium •
Acute
•
Waxing/waning
•
Usually reversible
Jason Ryan, MD, MPH
Delirium •
•
•
•
Delirium Causes
Loss of focus/attention focus/attention Disorganized Disorganized thinking
•
•
Hallucinations Hallucinations (oftenvisual) Sleep-wakedisturbance •
Up at night
•
Sleeping during day
•
•
Records voltage changes in brain Different leads •
•
•
•
•
Dementia patient in unknown setting
•
Most common reason AMS in hospital
Classic scenario: scenario: demented patient with PNA
Delirium Treatment
Electroencephalogram
•
Alcohol Withdrawal •
EEG •
Usually secondary to another cause Infection
•
Frontal, parietal, occipital
Characteristic patterns NORMAL in dementia •
ABNORMAL in delirium
•
Fix underlying cause •
Treat infection, withdrawal, etc.
•
Maintain O2 levels
•
Treat pain
•
Hydrate
Calm, quiet environment Drugs •
152
Haloperidol (vitamin H)
Haloperidol
Haloperidol
Trifluoperazine, Trifluoperazine, fluphenazine, thioridazine, chlorpromazine
Trifluoperazine, fluphenazine, thioridazine, thioridazine, chlorpromazine chlorpromazine
•
•
Neuroleptics
•
Main effect is to block CNS dopamine dopamine (D2) receptors
•
Haloperidol, trifluoperazine, fluphenazine
•
Also block Ach (M), α1, histamine
•
More neurologic side side effects
•
Extrapyramidal side effects effects
Uses
•
Schizophrenia
•
Psychosis
•
Thioridazine, chlorpromazine
•
Mania
•
More non-neurologic side effects
•
EPS Side Effects Haloperidol
Pyramidal system •
Corticospinal tract
•
Run in pyramids of medulla
•
Damage
•
•
•
weakness
Extrapyramidal system •
Basal ganglia nuclei nuclei and associated associated tracts
•
Rubrospinal, tectospinal, others
•
Modulation of movement
•
Damage movement disorders
EPS Side Effects Haloperidol •
•
Low potency agents
•
Pyramidal vs. Extrapyramidal •
High potency agents
•
Exact mechanism unknown Response to dopamine receptor blockade Four movement side effects •
Dystonia
•
Akathisia
•
Bradykinesia
•
Tardive dyskinesia
EPS Side Effects Haloperidol
Dystonia – acute, within hours/days
•
Bradykinesia - weeks
•
Involuntary contraction of muscles
•
“Drug-induced Parkinsonism”
•
Spasms, stiffness
•
Slow movements, like Parkinson’s
•
Treatment: benztropine
•
Treatment: benztropine
Akathisia - days
•
Tardive dyskinesia – months/years
•
Restlessness, urge to move
•
Chorea
•
Sometimes misdiagnosed as worsening agitation
•
Smacking lips
•
Treatment: Lower dose, benzos, benzos, propranolol
•
Grimacing
•
Often irreversible! (stopping drug doesn’t help!)
153
Other Haloperidol Side Effects
EPS Side Effects Haloperidol •
•
Common with high potency drugs •
Haloperidol
•
Trifluoperazine
•
Fluphenazine
•
•
Less common with low potency drugs
Blocksdopamine •
Hyperprolactinemia
•
Galactorrhea
•
Blocks ACh muscarinic muscarinic receptors
•
Thioridazine
•
Dry mouth
•
Chlorpromazine
•
Constipation
•
Blocks α1 receptors
•
Blocks H receptors
•
Qt prolongation
•
•
More common with low potency agents •
Thioridazine
•
Chlorpromazine
Hypotension
Sedation
NMS
NMS
Neuroleptic Malignant Syndrome
Neuroleptic Malignant Syndrome
•
•
•
Rare, dangerous reaction to neuroleptics Very similar to malignant hyperthermia •
Reaction to halothane, halothane, succinylcholine
•
Same treatment: dantrolene (muscle relaxant)
•
•
•
•
•
•
Dementia •
•
•
•
•
Hypertension, tachycardia •
Usually 7-10 days after treatment with haldol
•
•
Fever, rigid muscles Mental status changes (encephalopathy) (encephalopathy) Autonomic instability
Elevated CK Myoglobinuria Myoglobinuria - acute renal failure from rhabdo Watch for fever, rigidity, confusion after Haldol Treatment: •
Dantrolene (muscle relaxant) relaxant)
•
Bromocriptine (dopamine agonist)
Dementia
Gradual decline in cognition
•
No change LOC Usually irreversible (unlike delirium) Memorydeficits Impairedjudgment
•
Personalitychanges •
154
Aphasia •
Inability to communicate effectively
•
Forget words
•
Can’t understand (may nod to pretend)
Apraxia •
Inability to do pre-programmed motor tasks
•
Can’t do their job
•
Later: chewing, swallowing, walking
Agnosia •
Inability to correctly interpret senses
•
Can’t recognize people
•
Can’t interpret full bladder, pain
Mini Mental Status Exam •
•
•
•
•
•
Dementia Causes
Pointsystem >=27 (out of 30) is normal
•
•
Oriented to time, place place Repeat three objects, remember them
•
•
Serial 7s or spel l WORLD backwards Name an object pointed out (agnosia)
•
Repeat a phrase
•
Draw an object shown
•
•
Lewy body dementia dementia Rare stuff •
Pick’s disease
•
NPH
•
Creutzfeldt-Jakob
•
HIV
•
Vitamin deficiencies
•
Wilson’s disease
Alzheimer’s BioChem
Alzheimer’s Disease •
Alzheimer’s disease - 60% of cases Multi-infarct dementi dementia a (stroke) ~20% of cases
Most common cause dementia Degeneration of cortex •
Contrast with basal basal ganglia in movement movement disorders
•
Generalized no focal focal deficits
Amyloid Precursor Protein (APP) (on neurons) Apolipoprotein E (ApoE) Epsilon 2 Allele
Characterized Characterized by loss of ACh cortical activity •
Deficiency of choline acetyltransferase acetyltransferase
•
Prominent in basal nucleus nucleus of Meynert and and hippocampus
-
+
Apolipoprotein E (ApoE) Epsilon 4 Allele
Beta Breakdown Product (cleavage)
Alpha-Beta (AB) Amyloid CNS Buildup
Alzheimer’s
Alzheimer’s Disease
Amyloid •
•
•
•
•
•
Proteins in many diseases
•
Extracellulardeposits All stain with Congo red •
All have apple-green birefringence (polarized light) Disease process depends on where they are found
Alzheimer’s: Brain
155
Major risk factor is age •
Disease of elderly
•
Sporadic
Early disease •
Down syndrome – APP on Chromosome 21
•
Familial Form: Presenilin 1 & 2 gene gene mutations
Alzheimer’s Disease •
Alzheimer’s Brain
Other risk factors: •
African American race race
•
Family history
•
Obesity
•
Type II diabetes (insulin resistance)
•
HTN, Hyperlipidemia
•
Traumatic brain injury
•
•
•
•
•
•
•
Sulci widen Hydrocephalus ex vacuo •
Alzheimer’s Symptoms •
Corticalatrophy Gyri narrow
Alzheimer’s Drugs
Patient may not notice cognitive decline Often brought in by family member
•
Memantine •
Diagnosis: clinical Confirmed at autopsy
•
•
Multi-infarct Dementia •
•
•
•
NMDA receptor blocker
•
N-methyl-D-aspartate receptor (glutamate receptor)
•
Side Fx: Dizziness, confusion, hallucinations
Donepezil,galantamine, rivastigmine rivastigmine •
Inhibit acetylcholinesterase
•
Side Fx: Nausea, Nausea, dizziness, insomnia
Vitamin E •
•
Ventricles appear larger due to atrophy
Believes to protect against oxidation
Lewy Body Dementia
Second most commoncause
•
Dementia after multiple strokes Vascular risk factors: HTN, ↑chol, smoking
•
•
Stepwise progression of symptoms Treat risk factors
•
156
Lewy body: protein alpha-synuclein Found in basal ganglia in Parkinson’s If found in cortex: LB dementia Triad •
Dementia
•
Parkinson’s symptoms
•
Hallucinations
Pick’s Disease •
•
•
Creutzfeldt-Jakob
Rare cause of dementia Affects frontal and temporal lobes •
Frontal: Change in personality, behavior
•
Temporal: Aphasia
•
•
•
“Spongiform encephalopathy” Intracellularvacuoles Caused by PrPSC prion prion •
Path: Pick bodies •
SPHERICAL tau proteins
•
Not tangles like AD
•
Creutzfeldt-Jakob
Sporadic mutation
•
Familial
•
Transmitted
Mad Cow Disease
Creutzfeldt-Jakob •
PrPc (normal)
•
•
PrPsc (abnormal) •
(abnormal) Beta-pleated Sheet
157
Rapidlyprogressivedementia Death within a year Classicfeatures •
Ataxia
•
“Startle myoclonus”
•
Spike-wave complexes on EEG
Diagnosis •
Brain biopsy (gold (gold standard)
•
Clinical criteria
Demyelinating Diseases •
•
Demyelinating Diseases
•
•
•
•
•
Multiple Sclerosis Guillain-Barresyndrome Progressivemultifocalleukoencephalopathy(PML) Postinfectious encephalomyelitis Charcot-Marie-Tooth disease Metachromatic leukodystrophy Krabbe'sdisease
Jason Ryan, MD, MPH
Multiple Sclerosis •
•
•
•
•
•
Multiple Sclerosis
AutoimmunedemyelinationCNS Brain and spinal cord
•
•
White women in 20s & 30s is classic demographic demographic Relapsing, remitting course (most commonly)
•
•
•
•
MS Diagnosis
Any neuro symptom possible Few classic ones important to know Optic neuritis •
Demyelination of optic nerve
•
Pain and loss loss of vision One eye cannot move medially on lateral gaze
Bladderdysfunction •
Spastic bladder
•
Overflow incontinence
•
MRI is gold standard
•
Path:Periventricularplaques
•
MLF syndrome (INO) •
•
Type IV hypersensitivity reaction
Diverse neuro symptoms that come/go over time Fatigue is extremely common
Symptoms •
Lymphocytes react to myelin antigens Secrete cytokines(interferon-gamma)
158
•
Oligodendrocyte loss
•
Reactive gliosis
CSF •
High protein
•
Oligoclonal bands
MS Treatment •
Guillain-Barre syndrome
Rare patients do not require treatment •
•
1 or 2 lesions, lesions, no flairs
•
Interferon (avonex, rebif, betaseron)
•
Newer agents:
•
•
•
Starts in legs
Natalizumab (Tysabri)
•
Spreads to other other areas
•
Dimethyl fumarate (Tecfidera)
•
Respiratory failure 10-30%
•
Facial muscle weakness >50%
•
Guillain-Barre syndrome •
Tachycardia
•
Urinary retention
•
Hypertension/hypotension
•
Arrhythmias
•
Ileus
Sensory deficits occur (paresthesias) but mild Symptoms usually resolve over weeks to months
Guillain-Barre syndrome
Autonomicdysfunction>70%
•
•
Ascending muscle weakness over daysweeks
•
•
•
Acute inflammatory inflammatory demyelinatingradiculopathy Schwann cells destroyed by immune system
•
•
Often triggered by infection Classic agent: Campylobacter jejuni •
•
Loss of sweating
Severe autonomic dysfunction can cause SCD
Guillain-Barre syndrome
Bloody diarrhea
Classic agent: CMV •
Usually asymptomatic asymptomatic infection
•
Detected by rise in CMV antibodies
•
Immunosuppressed patient (1-6months after xplant)
•
Febrile illness
Guillain-Barre syndrome
•
CSF shows elevated protein level
•
Treatment:Respiratorysupport
•
Normal CSF cell count
•
Plasmapheresis
•
IV immune globulins
159
Progressive Progressive multifocal leukoencephalopathy (PML) •
•
•
•
•
•
•
Postinfectious encephalomyelitis
Severe demyelinating disease of CNS
•
Reactivation Reactivation of a latent JC virus Demyelination: multiple white matter lesions imaging Destroys oligodendrocytes
•
•
CD4 < 200 cells/mm3 cells/mm3 Causes slow onset encephalopathy encephalopathy •
Altered mental status
•
Focal neuro defects defects (motor, (motor, gait, etc)
•
Dx: JC Virus DNA in CSF or brain biopsy
Charcot-Marie-Tooth •
•
•
•
•
•
•
•
Progressive hereditary peripheral nerve disorders Onset usually late childhood/adolescence childhood/adolescence Defective production nerve proteins or myelin Leg muscles (bilateral) become wasted Legs have characteristic characteristic stork-like contour Foot drop Foot deformities usually develop Upper extremities also affected (
•
•
Late infantile (6 months to 2 ys)
•
Juvenile (3 to 16 yrs)
•
Adult (age >16)
Mean 26 days days after
•
Infections: Varicella or measles measles
•
Vaccines: Rabies, small pox
Most common histopathology: histopathology: perivenous infiltration •
Lymphocytes, neutrophils, other cells
•
Inflammation/demyelination
Lysosomalstoragedisease
•
Rare, autosomal-recessive •
•
•
Both parents must have mutation to pass on
Progressive demyelination CNS, PNS Arylsulfatase A deficiency Buildup of sulfatides impaired production myelin
Krabbe's disease
Three forms •
•
•
•
Metachromatic leukodystrophy •
Often rapid deterioration hospitalization Rare sequelae of infection or vaccinations
Metachromatic leukodystrophy
Hereditary motor and sensory neuropathy (HMSN) •
Acute onset multifocal neurologic symptoms symptoms
•
•
•
•
Infants/children Infants/children can present with failure to reach milestones Children/adults Children/adults canhave ataxia/dementia ataxia/dementia
•
160
Lysosomalstoragedisease Autosomal recessive Deficiencyof galactocerebrosidase galactocerebrosidase Buildupof galactocerebroside galactocerebroside Destroys myelin sheath
Krabbe's disease •
•
•
•
•
•
Most patients present <6mo of age Progressivemotor/sensoryproblems Irritability Developmental delay Limb spasticity Hypotonia
•
Absentreflexes
•
Microcephaly
161
Headache Causes •
•
•
•
•
Headaches
•
•
CNS Tumors CNS Bleeds (SAH) Hydrocephalus Inflammation(temporalarteritis) In clinical practice, must rule all these things out History, exam are key Lack of papilledema very important
Jason Ryan, MD, MPH
Primary Headache Disorders •
•
•
Tension Headache
Tension Migraine
•
•
Cluster
•
•
•
•
Migraine Headache •
•
•
•
•
•
Very common Etiology not clear, probably multifactorial Bilateral, constant constant pain Pain is pressing, tightening around head 30min to several hours Lack of photophobia, phonophobia, or aura
•
Diagnosis: clinical
•
Treatment:NSAIDs
Aura
Unilateralpain
•
Pulsating Photophobia, phonophobia
Gradual development of non-headache non-headache symptom •
•
Often nausea, vomiting vomiting Often has aura
•
•
Clinicaldiagnosis
162
Patients will recognize recognize their aura
About 25% of migraine patients Classically precedes HA (but may be same time) Often visual •
Bright, dark spots
•
“Scintillating scotoma”
•
Sensory: tingling in limb or face
•
Rare auras: speech, motor
Triggers •
•
•
Migraine Etiology
Menstruation Stress
•
•
Not eating
Still incompletely understood Irritation of CNS structures is important •
•
•
•
Leads to release of vasoactive vasoactive neuropeptides
•
Substance P, calcitonin calcitonin gene-related peptide, neurokinin A
Sensitization is important •
Migraine Treatment •
Abortive therapy
•
Prophylactic Therapy
•
•
Vasoconstrictor
•
Before triptans, major migraine drug
•
Limited by overuse headache, gangrene
Triptans (sumatriptan) •
5-HT agonists
•
Inhibit trigeminal nerve
•
↓vasoactive peptide release
•
Also causes vasoconstriction: vasoconstriction: May raise BP
•
Contraindicated: •
CAD
•
Coronary vasospasm (Prinzmetal’s angina)
Preventive Therapy
Ergotamine •
Neurons increasingly responsive responsive to stimuli
Abortive Therapy
Abortive Therapy •
Trigeminal nerve (CNV), meninges, bl ood vessels
Activation of trigeminal nerve is important
•
Topiramate, Valproate •
•
Propranolol •
NSAIDs
163
Anticonvulsants
Beta blocker
Topiramate •
•
•
•
•
Valproic Acid (Valproate)
Very effective for migraine Mental dulling/sedation dulling/sedation
•
•
Paresthesias Weight LOSS
•
•
Kidney stones •
•
•
•
•
•
Leads to more Ca in urine
•
May ↑risk kidney stones
•
Patients need to hydrate
•
•
•
•
Non-selective beta blocker Caution: •
COPD
•
Diabetes
•
•
•
Usually less headaches while pregnant Triptans are okay for abortive Avoid:Anti-convulsants,ErgotamineNSAIDs
Fatigue Erectile dysfunction
Cluster Headache
Very rare Poorlyunderstood mechanism Mostly men (classic presentation)
Lacrimation, rhinorrhea
•
Autonomic dysfunction •
•
Come in clusters: attacks daily for few weeks
•
Circadianrhythm:
•
Attacks last 15min to several hours
•
Treatment:Oxygen,triptans
•
More common in smokers Excruciating, unilateral headache behind eye
•
•
Weightgain
Pregnancy and Migraines
Cluster Headache •
Hepatotoxicity Hepatotoxicity (measureLFT's), Neural tube defects (spina bifida)
Weak carbonic anhydrase i nhibitor
Propranolol •
Anti-convulsant GI distress, tremor tremor
•
Horner’s syndrome: syndrome: ptosis, miosis
Unlike migraine: no aura, no nausea/vomiting
164
Daily attacks (same time of day) Contrast with trigeminal trigeminal neuralgia: <1min
•
Mechanism for oxygen unclear
•
May be related to O2 induced vasoconstriction
•
O2 also inhibits neuronal neuronal activation in the trigeminal nucleus
Brain Tumors Adult •
•
•
Brain Tumors
•
•
Glioblastoma Meningioma Schwannoma Oligodendroma PituitaryAdenoma
Children •
•
•
•
•
Astrocytoma Medulloblastoma Ependymoma Hemangioblastoma Craniopharyngioma
Jason Ryan, MD, MPH
Most adult tumors above tentorium: Supratentorial
Brain Tumors •
•
Symptoms
Primary 50% Secondary 50% •
Multiple lesions
•
Most common: Lung, breast, renal
•
•
•
Treatment •
•
•
•
Most child tumors below tentorium: Infratentorial
Headache Seizures Motor/sensorysymptoms
Glioblastoma
Surgery
•
Radiation Chemotherapy
•
•
Different depending on type of tumor
•
•
Most common primary brain tumor adults Occurs in cerebral cortex Rapidlyprogressive, malignant Usually fatal <1year <1year Half of patients >65 >65
•
Older age = worse prognosis
•
Often crosses corpus callosum
•
Express GFAP
•
165
Butterfly glioma
Meningioma •
•
•
•
•
Parasagittal Meningioma
2nd most common brain tumor Convexities of hemispheres near surfaces of brain
•
Arise from arachnoid cells “Extra-axial” - external to brain
•
•
•
•
•
Neurofibromatosis
3rd most common adult primary brain tumor Schwann cells are glial (non neurons) of PNS
•
•
Classically located located to CN VIII Hearing loss, tinnitus, ataxia
•
•
Cerebellopontineanglesymptoms •
•
Treatablewithsurgery,radiation
•
Stain positive for protein S-100
Neurofibromatosis
•
Neurofibromas Lisch nodules Café-au-lait Café-au-lait spots
Oligodendroglioma
Type 1: •
Most common
•
Café-au-lait spots, Neurofibromas
•
•
•
Type 2: •
Bilateral schwannomas (almost all patients)
•
Meningiomas
•
Multiple tumors
•
Autosomaldominantdisease Mutation NF1 /NF2 genes genes
Facial nerve and vestibulocochlear nerve emerge here
•
•
Classicpresentation
Can have dural attachment ("tail")
Schwannoma •
Will compress the leg area similar to ACA stroke
•
•
MISME: Multiple inherited schwannomas, meningiomas, and ependymomas
166
Rare tumors Slow growing Usually in frontal lobe Often presents with seizures Tumor of white matter
Pituitary adenoma •
•
Benign (usually) growths of pituitary gland Often cause endocrine symptoms •
•
•
•
•
•
•
Hypo/hyper secretion secretion of hormones
•
Most commonly secrete prolactin •
•
Childhood CNS Tumors
•
•
•
•
•
•
Bitemporalhemianopsia <10mm = microadenoma >10mm = macroadenoma
Medulloblastoma
Most common brain tumor children Low grade astrocytoma
•
•
Usually in posterior fossa (cerebellum) Usually benign without mets
•
GFAP positive
Medulloblastoma
•
Usually occurs in cerebellum
•
Type of primitive neuroectodermal neuroectodermal tumor (PNET)
Treatment:Surgery,radiation,chemo
•
•
75% children survive to adulthood
•
Many with complications complications of treatment
•
Can compress 4th ventricle hydrocephalus Can spread to CSF •
•
Nodules in dura dura of spinal cord: cord: “Drop metastasis”
•
Tend to occur in lower spinal cord, cord, cauda equina
•
Back pain, focal neuro neuro lesions can occur
Often in midline (truncal ataxia)
Ependymoma
•
•
Highly malignant primary brain tumor Usually occurs in children •
Well-circumscribed, Well-circumscribed, cystic or solid Often successfully treated with surgery Contain Rosenthal fibers fibers
•
Craniopharyngioma
Headache
•
•
Cerebellar
Amenorrhea, galactorrhea, impotence
Pilocytic astrocytoma •
Pilocytic astrocytoma Medulloblastoma Ependymoma
167
Ependyma: epithelium-like lining of ventricles Found in brain and the spinal cord Often found in 4th ventricle Can cause hydrocephalus
Hemangioblastoma •
•
•
Hemangioblastoma
Very rare, slow growing CNS tumors Often cerebellar, also brainstem & spinal cord
•
•
Well-circumscribed, Well-circumscribed,highly vascular
•
Craniopharyngioma •
•
•
•
Rarely younger adults Anywhere pituitary gland
base 3
rd
ventricle
Benign Symptomsfrom compression •
Visual field defects
•
•
•
Hormonal imbalance
•
Behavioral change (frontal lobe dysfunction)
•
•
LOTS of tumors
•
Hemangioblastomas of the brain (cerebellum) (cerebellum) and spine
•
Retinal angiomas
•
Renal cell carcinomas carcinomas (RCCs)
•
Pheochromocytomas
Derived from remnants of Rathke's pouch
Paralysis of upward gaze
•
Pseudo-Argyll-Robertson pupils
•
React to accommodation accommodation but not light
Can compress cerebral aqueduct Hydrocephalus, papilledema
168
Invagination of the ectoderm
•
Protrudes from roof of mouth
•
Also forms anterior anterior pituitary
Often calcified and cystic
•
Contain epithelial cells Appearances similar to pulp of developing teeth
Can compress optic chiasm •
Compression pretectal area of midbrain Parinaudsyndrome
•
Tumor suppressor suppressor gene mutation
•
•
Rare germ cell tumors or parenchymal tumors
•
Autosomal dominant disease
•
•
Pineal Tumors •
•
•
Suprasellar •
•
#2: Occur in von Hippel-Lindau syndrome
Craniopharyngioma
Mostly children 10-14 years old •
Two key facts to know #1: Can produce EPO polycythemia (↑Hct)
Bitemporal hemianopsia
Movement Disorders
Parkinson’s, Huntington’s, and Movement Disorders
•
•
•
•
•
Parkinson’s disease Huntington'sDisease Hemiballism Wilson’s Disease All result from damage to part of basal ganglia
Jason Ryan, MD, MPH
Parkinson’s Disease
Basal Ganglia Connections -
Cortex
-
•
•
Substantia Nigra
Huntington’s
Thalamus
Brainstem Spinal Cord
Striatum
Degenerative disease of substantia nigra Depletion of dopamine in SN Pars Compacta
•
Loss of melanin-containing melanin-containing dopaminergic neurons SN
•
Pathologic hallmark: Lewy bodies in SN
•
Pars Compacta Pars Reticulata
•
Depigmentation Inclusion in neurons of α-synuclein
Parkinson’s
Subthalamic Nucleus Hemiballism
ABA
GP Externus GP Internus GABA
Wilson’s
Parkinson’s Disease
MPTP •
•
•
•
Methyl-phenyl-tetrahydropyridine
•
Destroys dopamine neurons Causes Parkinson’s
Classic case: older, male patient •
•
•
May be contaminant of opioid drugs
•
•
169
Average age onset in 60s
Rest tremor (pill-rolling tremor) Bradykinesia – can’t initiate movements Movement gets better with exercise Shufflinggate
•
Stoopedposture
•
Cogwheelrigidity
L-dopa/carbidopa
Parkinson’s Treatments
Sinemet •
•
L-dopa crosses blood-brain barrier Converted to dopamine in CNS •
•
Dopa decarboxylase
Peripheral decarboxylase can breakdown L-dopa •
This limits its benefit
•
Also creates peripheral dopa
•
Can cause heart side effects
•
Can cause nausea/vomiting (vomiting center outside outside BBB)
L-dopa/carbidopa
L-dopa/carbidopa
Sinemet
Sinemet
•
•
•
Carbidopainhibitsperipheral decarboxylase decarboxylase Given together:L-dopa/Carbidopa
•
•
Still get CNS side effects of L-dopa •
L-dopa becomes becomes dopa in CNS
•
Anxiety, agitation, insomnia
•
Use lowest dose possible possible
•
Avoid vi tamin B6
•
•
•
•
Entacapone and Tolcapone •
Inhibitcatechol-O-methyltransferase catechol-O-methyltransferase(COMT)
•
Enzyme that breaks down L-dopa •
•
•
•
•
Long-term use Motor side effects Drug reduces natural L-dopa production
“On-off “ phenomenon Akinesia occurs between doses Involuntary movements Use lowest dose possible to avoid
Selegiline •
Even with carbidopa, COM T limits L-dopa L-dopa benefit •
Only work in combination with L-dopa Entacapone: peripheral COMT inhibition inhibition Tolcapone: peripheral and central COMT inhibition
•
•
Tolcapone associated with hepatotoxicity
170
Inhibits MAO-b •
Central dopamine breakdown enzyme
•
Breaks down dopamine more than 5HT
Increases central dopamine levels Can be added to L-dopa/carbidopa Side effects: •
Nausea, vomiting
•
Hypotension
•
Excessive daytime sleepiness sleepiness
Selegiline
Parkinson’s Drugs
Side Effects •
•
Serotoninsyndrome •
When given with SSRI
•
Confusion, fever, myoclonus
COMT
Inactive L-dopa MAOb Form -
Hypertensive crisis
•
Tyramine foods: Red Red wine, aged cheese, or aged aged meat
•
MAO inhibitors (a or b) block breakdown breakdown of tyramine
•
Tyramine HTN
-
-
“Cheeseeffect” “Cheese effect” •
Entacapone Tolcapone
Tolcapone
L-dopa
COMT
-
Inactive Form
Carbidopa
Selegiline Dopamine
Dopamine
Blood Brain Barrier
Surgical Therapy Parkinson’s
Parkinson Drugs in Practice •
•
Tremorpredominantsymptoms •
Trihexyphenidyl (anti-muscarinic)
•
Side effects: sedation, dry mouth
•
•
Bradykinesia, rigidity •
Ropinirole, pr amipexole (dopamine agonists)
•
Levodopa/carbidopa
•
Young patients patients often develop toxicity from long term use of L-dopa/carbidopa L-dopa/carbidopa Prior surgeries used: •
Pallidotomy (partial ablation of globus pallidus)
•
Thalamotomy (partial ablation of thalamus)
Modern option: Deep brain stimulation •
Huntington’s Disease •
•
•
Striatum = caudate caudate + putamen
•
Loss of GABA neurons neurons (also ACh)
•
•
•
•
•
Brainimaging •
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Huntington’s Disease
Inherited autosomal dominant disorder Degeneration in striatum •
High frequency DBS suppresses n eural activation
Mutation in the HTT gene gene CAG repeat in gene Normal 10-35 repeats
Huntington’s 36 to 120 repeats Worse/earlier symptoms each generation •
Lateral ventricles may may appear la rge Marked caudate degeneration
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Also has atrophy of frontal/temporal lobes
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“Anticipation”
Neuronal death from glutamate glutamate toxicity Glutamate binds NMDA receptor
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Excessive influx calcium
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Cell death
Huntington’s Disease •
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Huntington’s Treatment
Onset of symptoms30s-40s Death after 10-20 years
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Chorea Aggression
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Depression Dementia
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Tetrabenazineandreserpine •
Inhibit VMAT
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Limit dopamine vesicle packaging packaging /release
Haloperidol •
Can be mistaken for substance abuse
Dopamine receptor antagonist
Wilson’s Disease
Hemiballism •
Dopamine associated with chorea Blocking dopamine can reduce chorea
Wild, flinging movements of extremities (ballistic) Damage to subthalamic nucleus
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Seen in rare subtypes of lacunar strokes
Disorder of Copper metabolism Leads to accumulation of copper in tissues
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Lesions occur in basal ganglia
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Movementsymptoms
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Lentiform nucleus (putamen/globus pallidus)
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Can be parkinsonian
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Wing-beating tremor
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Dysarthria
Chorea
Other movement disorders
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Two important causes: •
Huntington’s disease
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Acute rheumatic fever
History is key
Essential Tremor
Tremors
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Old name: “Benign familial tremor”
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Genetic predisposition
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Distinguish from Parkinson’s
EtOH helps – patients self-medicate self-medicate Drug treatment •
Propranolol (beta blocker) blocker)
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Primidone
CNS Infections in HIV Patients •
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Cryptococcus Cytomegalovirus (CMV) Toxoplasmosis JC virus •
HIV CNS Infections
Progressive multifocal leukoencephalopathy (PML)
Jason Ryan, MD, MPH
Cryptococcus Neoformans •
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Cryptococcus Neoformans
Invasive fungus Thickpolysaccharidecapsule
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Present in soil and pigeon droppings
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Cryptococcus Neoformans •
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Chemo, post-transplant
Cryptococcus Neoformans
Indolent symptoms over weeks •
Inhaled lungs blood stream meninges Can also occur immunocompromised
Fever, headache
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Sabouraud'sagar
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Latex agglutination test
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Soap bubble lesions on MRI
Can cause ↑ICP
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Risk of herniation with LP Must do CT or MRI Treatment: Amphotericin Amphotericin B or Fluconazole
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Detects polysaccharide capsular antigen
CMV Retinitis •
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Toxoplasma gondii
Retinal edema/necrosis edema/necrosis Floaters, ↓vision
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CMV in HIV/AIDS: •
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Low CD4 (50-100)
Progressive Progressive multifocal leukoencephalopathy (PML) •
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Severe demyelinating disease of CNS Reactivation Reactivation of a latent JC virus demyelination CD4 < 200 cells/mm3 cells/mm3 Causes slow onset encephalopathy encephalopathy •
Altered mental status
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Focal neuro defects defects (motor, (motor, gait, etc)
Dx: JC Virus DNA in CSF or brain biopsy
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Multiple “ring-enhancing” lesions on imaging CD4 <100cells/mm3 <100cells/mm3 Treatment:
Sulfadiazine/pyrimethamine