Exam 1 Flashcards
Division of PNS
- 2 divisions
- 2 systems
- •Efferent Division
- •Autonomic system
- •Parasympathetic
- •Sympathetic
- •Enteric
- •Somatic system (no ganglion)
- •Autonomic system
- •Afferent division:
- • Afferent nerves provide sensory input to the CNS that in turn modulates the efferent division (reflex arcs)
General anatomy (explain)
- •Parasympathetic and sympathetic ANS
- •CNS → Preganglionic nerve → Ganglia → Postganglionic nerve → Effectors
- •Sympathetic ANS
- •CNS → preganglionic nerve → adrenal → Epinephrine (80%) & norepinephrine (20%)
- •CNS → Efferent somatic nerve → Neuromuscular Junction at skeletal muscle → skeletal muscle contraction
Describe autonomic outflow from CNS (both parasympathetic and sympathetic)
•Parasympathetic
- oPreganglionic nerves emerge from the brain stem and from the sacral region of the spinal cord (Craniosacral)
- oCranial outflow via cranial nerves III (oculomotor), VII (facial), IX (glossopharyngeal) and X (vagus)
•Sympathetic
- oPreganglionic neurons of the sympathetic nerves system emerge from the thoracic and lumbar regions (T1 to L2) of the spinal cord
Identify functions of the PNS (7)
**Is it essential for life?
- •Preganglionic nerves are long and postganglionic nerves are short
- •Ganglia are near or within effector organ
- •One-to-one connection between pre and postganglionic nerves, allowing for discrete, fine control of effector targets.
- •Essential for life
- •Visceral emptying
- •Conservation, and replenishment of body resources
- •Effects are usually (but not always) antagonistic towards sympathetic effects
Identify features of SNS (6)
**Is it essential for life?
- •Preganglionic nerves are short and postganglionic nerves are long
- •Extensive preganglionic branching (affecting several ganglia), postganglionic nerves are branched at effector targets. Thus, a single stimulus can initiate a large response.
- •Diffuse and extensive innervation throughout body
- •Not essential for life
- •Adaptation to stress
- •Induces fight or flight response
- Be able to diagram the steps in the synthesis, storage, release, receptor interaction and termination of the action of acetylcholine (ACh) released from cholinergic neurons.
***WHat is the neurotransmitter of cholinergic nerves vs adrenergic nerves?
- ·Acetylcholine (ACh) is the neurotransmitter of cholinergic nerves
- ·Norepinephrine (NE) is the neurotransmitter of adrenergic nerves
- First ANS nerve “out” of the CNS is a cholinergic nerve.
- ACh is the neurotransmitter at all autonomic ganglia
- •ACh induces the Adrenal to release Epinephrine (Epi)
- •ACh is the neurotransmitter at the neuromuscular junction
- •Most postganglionic parasympathetic nerves are cholinergic (those that are not release nitric oxide)
- -Postganglionic sympathetic nerves that innervate sweat glands are cholinergic
- -The remaining postganglionic sympathetic nerves are adrenergic
Steps in cholinergic neurotransmission
- oActive uptake of choline into the nerve ending
- oAddition of acetyl group to choline by choline acetyl transferase (CAT) to form ACh
- oUptake and storage of ACh in vesicles
- oCa2+-dependent exocytosis release of ACh in response to action potential
- oReversible interaction of ACh with presynaptic and postsynaptic nicotinic and muscarinic receptors.
- oPresynaptic muscarinic receptors suppress the release of ACh (negative feedback control) from the cholinergic nerve
- oPostsynaptic muscarinic receptors are located at effector target tissue
- oPostsynaptic nicotinic receptors are located in ganglia and at the neuromuscular junction
- oRapid hydrolysis of ACh by acetylcholinesterase (AChE) to form choline and acetate
- oCholine actively taken up by cholinergic nerve (back to the first bullet point)
•To know which drugs affect cholinergic transmission
- Blocks Na channels which in turn prevents action potentials
- Blocks the uptake of choline which in turn prevents ACh synthesis
- Induces transient release of ACh, and a subsequent permanent block. It, therefore, has transient cholinomimetic effects followed by anticholinergic effects.
- Prevents the release of ACh. It, therefore, has anticholinergic effects.
- Agonist of the muscarinic receptor. It, therefore, has cholinomimetic effects.
- oAgonist of nicotinic receptors. Induces transient activation of nicotinic receptors, and a subsequent block. It, therefore, initially has cholinomimetic effects followed by anticholinergic effects.
- Tetrodotoxin and saxitoxin
- ·Hemichlolinum
- ·Black Widow Spider; more specific to cholinergic nerves. Initiate transient release of Ach from cholinergic nerves.
- Botulinus toxin; act as muscle relaxant, prevent migraine attacks. Specific to Ach
- Bethanechol
- Nicotine
Drugs that affect cholinergic neurotransmission
- Antagonist of muscarinic receptors. It, therefore, has anticholinergic effects.
- oAntagonist of ganglionic nicotinic receptors. It, therefore, has anticholinergic effects.
- oAntagonist of the neuromuscular junction nicotinic receptors. It, therefore, induces skeletal muscle paralysis.
- Anticholinesterase that by inhibiting acetylcholinesterase (AChE) increases ACh at all cholinergic synapses. It, therefore, has initial cholinomimetic effects followed by anticholinergic effects.
- Atropine
- Mecamylamine; only block with nicotinic receptors at the ganglia
- Curare (used in surgery)
- Physotigmine
•To introduce the physiological effects of Muscarinic Receptors
- Cholinergic effects at skeletal muscle
- Cholinergic effects at muscarinic receptors
•Skeletal Muscle
- •ACh stimulates nicotinic receptors at the neuromuscular junction (NMJ)
- •Nicotinic receptor is a ligand-gated cation channel. Its activation induces the influx of Na+ ions and depolarization
- •Depolarization causes a muscle action potential and leads to contraction
•Muscarinic receptors
- oACh stimulates muscarinic receptors at various effector target tissue.
- oMuscarinic Receptors are G protein coupled receptors
- Cholinergic effects at autonomic ganglia
- Cholinergic effects at
•Autonomic Ganglia
- •ACh stimulates nicotinic receptors at Ganglia.
- •Nicotinic receptors at Ganglia resemble nicotinic receptors at the neuromuscular junction (NMJ) because they are ligand-gated cation channels that upon activation induce depolarization.
- •However, nicotinic receptors at Ganglia are not identical to those at NMJ
•Presynaptic Receptors
- •ACh binding to Muscarinic receptors (M) located on the presynaptic cholinergic neuron inhibits ACh release.
- •M2 and M4 are presynaptic receptors that suppress ACh release.
- •Norepinephrine (NE) binding to presynaptic α2 receptors inhibits the release of NE
Physiolgic effects of muscarinic receptors
- 5 subtypes and functions
- do drugs target all 5 subtypes?
- which types are stimulatory (induce calcium based signaling to modulate effector targets)
- which types are inhibitory
- what slows the heart down? (major muscarinic receptor in the heart)
- major rle in CNS?
- majo role in visceral ?
- •Five distinct subtypes of muscarinic receptors (M) (M1-M5)
- •The muscarinic drugs are non-specific, meaning that each muscarinic receptor-targeting drug will bind to all five muscarinic receptor subtypes.
- •In general, M1, M3, and M5 (thus the odd numbers) are stimulatory and they induce Calcium –based signaling to modulate effector targets.
- •In general, M2, and M4 (thus the even numbers) are inhibitory. Meaning they induce inhibitory signaling at effector targets by inducing hyperpolarization and decreasing cAMP signaling
- •M2 is the major muscarinic receptor in the heart. It slows down heart rate (SA node), conduction (AV node) and contraction (atria > ventricle)
- •M1 plays a major role in the CNS (brain).
- •M3 plays a major role at visceral targets and is stimulatory inducing smooth muscle contraction (GI, bladder, pulmonary), secretion from glands and the eye.
•Be able to outline the processes involved in the synthesis, storage, release, receptor interaction and termination of action of NE (norepinephrine) and Epi (epinephrine) released from adrenergic nerve endings and the adrenal medulla.
Storage of NE
- •Vesicular amine transporter (VAT) mediates the uptake of dopamine and NE into intracellular storage vesicles
- •Being in a vesicle protects NE from being degraded
- •Dopamine is converted to NE in vesicles (by DβH)
- •Reserpine blocks NE and dopamine uptake by vesicles
Release of NE
- Depolarization → Ca2+ enters the neuron → triggers the fusion of the vesicle with the plasma membrane → exocytosis release of NE
Identify NE and Epi interaction with adrenergic receptors
- NE interacts with α1, α2, β1
- Epi interactions with α1, α2, β1, β2
- Note at β2 receptors Epi >>> NE
Describe ways of terminating the action of NE
- Active reuptake
- Metabolism
- MAO
- COMT
Active Reuptake of NE into nerve terminal
- •most important in terminating action of neuron-released NE
- •NE transporter (NET) mediates the active uptake of NE
Metabolism
- •Less important than reuptake in terminating action of neuron-released NE
Monoamine Oxidase (MAO)
- •non-specific - metabolizes many monoamines
- •in nerve terminals → metabolism of amines in cytoplasmic pool
- •in liver, kidney & gut (also in other tissues)
- •protects against circulating and exogenous biologically active amines
Catechol-O-methyl-transferase (COMT)
- •specifically metabolizes catechols (NE, Epi, Dopamine)
- •widely distributed (e.g. liver, kidney, brain)
- •important for metabolism of circulating catecholamines
Metabolites of NE and Epi
**DO you find NE and Epi in urine? what do you find? (3)
- •both MAO & COMT usually act on Epi & NE before excretion
- •most abundant urinary metabolite is 3-Methoxy-4-hydroxy-mandelic acid (VMA)
- •other metabolites include: metanephrine and normetanephrine
Effects of drugs on adrenergic neurotransmission. **Identify the drugs
- Inhibit tyrosine hydroxylase
- Used to reduce NE & Epi in pheochromocytoma
-
Displacement of Transmitter from Nerve Terminal
- enter the nerve terminal via amine uptake pump (NET) causing a rapid release of NE → sympathomimetic effect
- •induces release of NE → sympathomimetic effect
- no direct effect at receptors
- Dietary constituent
effects enhanced by MAOIs → hypertensive crisis
- Metyrosine
- Many Amines e.g Tyramine (releasing agents)
- Tyramine
- Can induce hypertensive crisis
Identify drug and adverse effects
- •Effects
- •Promotes the release of NE → sympathomimetic effect
- •peripheral effects similar to NE (vasoconstriction → ↑ TPR (total peripheral resistance), ↑ HR)
- •+ pronounced CNS stimulation
- •Clinical uses
- •attention deficit/hyperactivity disorder (ADHD)
- •narcolepsy
- •Obesity (short term)
Amphetamine (Adderall)
Adverse effects
- •similar to NE
- •+ marked CNS effects
Identify drug
- •α1, α2, β1, β2 agonist and it also stimulates the release of NE and Epi
- •Clinical uses
- •Hypotension in the setting of anesthesia
- •Effects similar to Amphetamine
Ephedrine
- Not everyday use. can cause hypertension. so only use when you are hypotensive from anesthesia
Identify drug that Block reuptake into nerve terminal
- •inhibition of NE reuptake → ↑NE in synapse → ↑NE effects sympathomimetic
•Cocaine and Imipramine (Antidepressant)
identify drug that inhibit MAO (MAOIs) - 3
•Effects:
- •Potentiates monoamine neurotransmitter activity in the CNS
•Clinical use:
- •Major depressive order
•Tranylcypromine, Phenelzine and Selegiline
- •predispose patients toward hypertensive crises
- •MAO in liver & gut protects against exogenous active amines (e.g. tyramine)
- •MAO inhibition → ↑ circulating levels of dietary amines → hypertension
Effects mediated by adrenergic receptor
- •α1-Receptor mediated effects (4)
- •β1-Receptor mediated effects (3)
1. α1-Receptor mediated effects
- mydriasis (contraction of the iris dilator muscle in eye)
- constriction of arteries & veins
- constriction of GI & GU sphincters
- ejaculation, orgasm (β receptors also involved)
2. β1-Receptor mediated effects
- •Heart
- o↑ automaticity (SA) → ↑ HR
- o↑ contractility (atria and ventricles)
- o↑ conduction velocity (AV node)
- •↑ renin secretion → ↑ plasma renin activity
- •↑ lipolysis ↑ → plasma free fatty acids
- •β2-Receptor mediated effects (5)
- α2-Receptor mediated effects (3)
- β2-Receptor mediated effects
- oBronchodilation
- odilation of arteries in skeletal muscle
- o↑ glycogenolysis and gluconeogenesis
- o↑ insulin secretion
- orelaxation of uterus
- α2-Receptor mediated effects (generally sympatholytic)
- o↓ sympathetic outflow from Central Nervous System (CNS)
- o↓ NE release (peripheral & CNS)
- o↓ insulin secretion
Agonists and antagonists at adrenergic receptors (and drugs)
Autonomic receptors in the Eye clinical importance (adrenergic and cholinergic)
- Iris dilator
- Iris Sphincter
- Ciliary processes
- Ciliary muscles
- Conjunctivae blood vessels
Therapeutic indications of adrenergic agonists for eye therapy (idnetify receptor and ocular use)
- Phenylephrine
- Apraclonidine
- Brimonidine
- Cocaine
- Hydroxy amphetamine
Therapeutic indications for β antagonists for Eye therapy (identify receptor and ocular use)
- Betaxolol
- Carteolol
- Levobunolol
- Metipranolol
- Timolol
Describe the cause and 3 effects in the following
- Horner’s Cocaine and Hydroxyamphetamine
·Loss of Sympathetic Innervation to the Eye Results in:
- Miosis: Loss of Iris Dilator Function
- Ptosis (Mild Lid Droop): Loss of Mueller’s Muscle Function
- Anhydrosis (Above Orbit, Forehead): Loss of Sweat Gland function
How to know someone has Horner’s syndrome (2 drugs)
- what drug do you give to diagnose and what is the effect (cause dilation in normal eye but nothing in the horner’s eye)
- second drug that Differentiates Pre or Post Ganglionic Horner’s Syndrome
Cocaine MOA: (Typically replaced with Apraclonidine now)
- Prevents reuptake of NE that has been released at the synaptic junction between the Sympathetic Post-Ganglionic Neuron and the Iris Dilator:
- Normal Eye: Causes DILATION (Increased Iris Dilator Function)
- Horner’s Eye: Causes NOTHING (No Nerve Activity: No NE in Synapse)
Hydroxyamphetamine (Stimulate Release of NE)
- Differentiates Pre or Post Ganglionic Horner’s Syndrome
- MOA: Causes release of NE from the presynaptic axon terminals of the Post-ganglionic Neuron on to the Iris Dilator
- Preganglionic: Pupil DILATES from Topical Hydroxyamphetamine
Preganglionic vs postganglionic lesions in horner’s
**Hydroxyamphetamine (Stimulate Release of NE)
- Pre-ganglionic Lesions can be serious:
- Pancoast’s Tumor: Tumor of Apex of Lung
- Thoracic Aortic Aneurysm ◦ S/p Carotid Endarterectomy
- Postganglionic: NO Pupil Dilation from Topical Hydroxyamphetamine
- Post-ganglionic Lesions typically less serious, but NOT always:
- Goiter
- Cavernous Sinus Syndrome
- Post-ganglionic Lesions typically less serious, but NOT always:
Unique xters of CNS
- Protective bony enclosure
- Autoregulation of cerebral blood flow
- Metabolic substrate requirements
- No conventional lymphatic system
- Special cerebrospinal fluid circulation
CNS cells (7)
- neurons
- astrocytes
- oligodendrocytes
- ependymal cells
- microglia
- choroid plexus epithelial cells
- Schwann cells
Identify CNS cells
- •Postmitotic (Permanent)
- •Vary in: Structure, size, function, neurotransmitter used, metabolic requirements etc.
- •Selective vulnerability
**How do these CNS cells react to injury
Neurons
Neuronal reactions to Injury
- •Acute Neuronal Injury (“Red Neuron”)
- •Necrosis
- •liquefactive
- •Subacute and chronic injury (Degeneration)
- •Axonal Injury
- •Neuronal Inclusions
- •Intracytoplasmic Deposits
identify acute neuronal injury
- •12-24 h after irreversible injury due to:
- •Hypoxic/Ischemic Insult -OR-
- •Infectious Insult -OR-
- •Toxic Insult
- •Morphology
- •Cell body shrinks
- •Pyknosis of nucleus
- •Cytoplasm intensely eosinophilic
RED NEURON
Subacute and Chronic Neuronal Injury (Degeneration)
- examples of condition
- morphology
- •Neuronal death over long duration
- •e.g., ALS
- •Morphology
- •Cell loss, often selective – hard to detect at first
- •Reactive gliosis – first sign
- Dispersion of Nissl Substance to the periphery (Central Chromatolysis) (II)
- Rounding-up (III)
- Peripheral displacement of nucleus (III)
- Cell death (IVa) OR Cell recovery (IVb)
Axonal Sprouting after axonal injury / transection
- Axonal Sprouting of proximal axon
- Distal axon undergoes degenerative changes
Identify CNS cells
- •Aging – Intracytoplasmic lipofuscin,
- •Genetic Disorders
- •Viruses
- •Intranuclear
- •Herpes (Cowdry A Inclusion)
- •Intracytoplasmic
- •Rabies (Negri Body)
- •Intranuclear and intracytoplasmic - CMV
- •Intranuclear
*****Identify neuronal intracytoplasmic deposites in 3 degenerative diseases
Neuronal Inclusions
Intracytoplasmic deposits
- •Alzheimer Disease
- •Neurofibrillary Tangles
- •Parkinson Disease
- •Lewy Bodies
- •Creutzfeldt-Jacob Disease
- •Abnormal vacuolization
CNS cells
types of glial cells (2)
- •Macroglia
- •Astrocytes (Barrier Function; GLIOSIS)
- •Oligodendrocytes (Myelin)
- •Ependymal Cells (Line Ventricles)
- •Microglia (Fixed Macrophage)
Identify CNS cells
- •Found in BOTH Gray & White Matter
- •BARRIER function, supply nutrients, act as a buffer, detoxifier, insulator
- •Reaction to injury - Repair and scar
- •Gliosis – non-neoplastic proliferation
- •Most important histopathologic indicator of CNS Injury
- •BOTH hypertrophy and hyperplasia
- •Stains for GFAP (glial fibrillary acidic protein)
- •Rosenthal Fibers – thick, eosinophilic
- •Long Standing Gliosis
- •Cerebellar Pilocytic Astrocytoma
- •Gliosis – non-neoplastic proliferation
Astrocytes
- •Cellular Swelling
- •Failure of cell’s pump system in hypoxia, hypoglycemia, toxins, Creutzfeldt-Jakob Disease
- •Corpora Amylacea (polyglucosan body)
- •Concentrically lamellated
- •Indicates degenerative change
- •↑ with age
- •Alzheimer type II astrocyte – long-standing hyperammonemia
Identify CNS cell
- Form myelin
- Injury
- •Seen in demyelinating disorders
- •Viral nuclear inclusions may occur in Progressive Multifocal Leukoencephalopathy
Oligodendrocytes
CNS cels
- Line ventricles
- CMV may cause
- •Extensive ependymal injury
- •Viral inclusions
Ependymal cells
CNS cells
- •Mesoderm-Derived
- •Fixed MACROPHAGE System
- •Responds to Injury by
- •Proliferation
- •Elongating nuclei - Rod Cell
- •Aggregate around necrotic tissue -
- Microglial Nodules
- •Engulf dying neurons - Neuronophagia
Microglia
•Vasogenic Edema ( ↑ intercellular fluid, most common)
- •Infections, trauma, tumors, metabolic
- •Due to
- •Capillary damage –OR–
- •Disrupted blood-brain barrier –OR–
- •Permeability of new vessels (Tumors)
- •Resorption impaired because of paucity of lymphatics
Cerebral Edema; Increased “brain volume” (in a closed space)
- •Cytotoxic – ↑ intracellular fluid
- •Seen in cell membrane injury, e.g. ischemia
CSF review
- found where
- secreted by?
- how they flow?
- absorbed?
CSF
- Subarachnoid space
- •SECRETED: Choroid Plexus
- •FLOW: Lateral Ventricles to Foramen of Munro into 3rd Ventricle then through Cerebral Aqueduct (Aqueduct of Sylvius) in Midbrain then into 4th Ventricle then through Foramina of Luschka and Magendie into the Subarachnoid Space and then to Superior Sagittal Sinus.
- •ABSORBED: Arachnoid Villi of Superior Sagittal Sinus
Identify condition
- •Excessive CSF in ventricular system
- •Dilated Ventricles
- •Causes:
- •Obstruction of Flow
- •Failure of resorption
- •Increased Secretion: Neoplasm of Choroid Plexus
Hydrocephalus
Identify type of hydrocephalus
- CSF does NOT pass into subarachnoid space
**congenital vs acquired causes
- Non-Communcating Hydrocephals
- •CSF does NOT Pass into Subarachnoid Space
- •Congenital Causes:
- •Aqueductal Stenosis or Atresia
- •Dandy-Walker Syndrome
- Acquired Causes:
- •Neoplasms and cysts
- •Gliosis of aqueduct
- •Obstruction of 4th ventricle opening
- •Organized subarachnoid hemorrhage at base of brain
Identify type of hydrocephalus
•CSF Flows Out of Ventricular system BUT
- •Excess CSF -OR-
- •Flow obstructed in subarachnoid space -OR-
- •Reabsorption is reduced
**Causes
Communicating Hydrocephalus
- Choroid Plexus Papilloma ( ↑ Secretion)
- •Deficient Absorption of CSF
- •Dural sinus thrombosis
- •Organized subarachnoid hemorrhage
- •Organized meningitis
- •? Deficiency of arachnoid villi
Identfi type of hydrocephalus
- UNCOMMON
- Slow dilation of ventricles due to cerebral atrophy
- •Free flow of CSF
***What is the triad??
Normal Pressure Hydrocephalus (Hydrocephalus ex vacuo)
- Dementia, gait disturbance, incontinence
ICP
- definition (CSF pressure greater than?) what position?
- common cause of?
- complication?
- Etiology of increased ICP
ICP (Increased intracranial pressure)
- •Definition: CSF pressure >200mmH2O (>20mm Hg) in the Lateral Decubitus Position
- •Common cause of neurological sx
- •May cause death from herniation
- Etiology of Increased ICP
- •Usually mass effect
- •Diffuse – cerebral edema
- •Local – tumor, abscess, hemorrhage
- •Obstructive (non-communicating) hydrocephalus
- •Usually mass effect
Type of brain herniation
- •Due to unilateral expansion of cerebral hemisphere
- •Displace cingulate gyrus under falx cerebri
- •Compresses anterior cerebral artery
SUPRATENTORIAL Herniation:
- Subfalcine
Type of brain herniation
- •Uncinate Gyrus of Temporal Lobe through the Tentorial Opening
- •3rd Cranial nerve (Unequal Pupils)
- •Compress contralateral cerebral peduncle – ipsilateral hemiparesis
- •Duret Hemorrhage may occur (in midbrain & pons)
•TRANSTENTORIAL Herniation
Type of brain herniations
- Cerebellar Tonsils through Foramen Magnum
- Medulla Compressed (Cardiorespiratory center) → DEATH
- Can occur when there is ↑ ICP AND lumbar puncture done
•TONSILLAR Herniation
- Identify clinical signs/symptoms of increased ICP (3)
- What procedure is contraindicated when pt has increased ICP
Increase ICP signs
- •Headache
- •Vomiting
- •Papilledema
•Do NOT do Lumbar Puncture
Treatment of increased ICP
- what can yoe remove if possible
- what will decompress 3rd ventricle
- how to treat cerebral edema (2 drugs and 1 equipment)
- •Remove Mass, if present/possible
- •Shunt to decompress 3rd ventricle
- •Treat Cerebral Edema
- •Mannitol
- •Corticosteroids
- •Stabilize Blood-Brain Barrier
- •Decrease Cerebral Edema
- •Mechanical ventilation
Hypoxia and hypercapnia increase blood circulation to brain, O2 and increased respiratory rate improve hypoxia and hypercapnia (useful in trauma) May not actually be effective
compare and contrast neuropathologic entities (5)
- bacterial meningitis
- tuberculous/mycobacterial meningoencephalitis
- viral meningoencephalitis
- fungal meningitis
- neurosyphilis
CNS infection
Acute meningitis (Leptomeningitis)
- Identify 4 routes of infection. ** What is major NUMBER 1 ROUTE
-
Bloodstream (hematogenous) is #1
a. Primary entry site:
- 1) Respiratory tract (N. meningitides, H. influenza, S. pneumoniae,C. neoformans, many viruses)
- 2) Skin (neonatal meningitis)
- 3) Intestine (enterovirus)
- Direct implantation
- a. Skull fractures
- b. Iatrogenic – surgery, lumbar puncture, etc.
- c. Congenital malformations – e.g. meningomyelocele
- d. Through the intact CRIBIFORM plate (free living amebas)
- Local extension – otitis media, mastoiditis or frontal sinusitis, infected tooth, cranial or spinal osteomyelitis
- Peripheral nervous system into CNS – rabies, herpes zoster, etc.
Acute vs bacterial meningitis (classification by etiology)
- which can be rapidly fatal
- how do neonates get acute bacterial
- cause of acute bacterial in neonates vs children (up to 5 yars) vs adolescents vs older vs all ages
- what cause viral meningtis
- Acute BACTERIAL meningitis can be rapidly fatal
- a. In U.S.A. 2000 deaths/yr
- b. Neonatal (passage through the birth canal)
- 1) Escherichia coli
- 2) Streptococcus agalactiae (a group B streptococcus)
- c. Children up to 5 years of age
- 1) Streptococcus pneumonia
- 2) Neisseria meningitidis
- 3) Haemophilus influenza type b was most common but H. influenza cases in this age group declined 99% from 1989 to 2000 since vaccine was introduced in 1990
- d. Adolescents: Neisseria meningitidis
- e. Older, debilitated, immunosuppressed: Listeria monocytogenes and gram-negative bacilli
- f. All ages: Streptococcus pneumoniae
- Acute VIRAL meningitis
- a. 90% occur in patients under 30 years of age
- b. Rarely causes death
- c. Mild, benign course
- d. Enteroviruses: Echovirus, coxsackievirus, nonparalytic poliomyelitis – 80% of cases
- e. 10% develop meningitis when they seroconvert in HIV
Cause of acute bacterial meningitis based on agegroup
- newborns (3)
- infants and children (3)
- Adolescents and young adults (3)
- Older adults (3)
Pathology of meningitis
- Gross
- microscopy
- Gross: Leptomeninges are congested and covered by exudates (yellow-white)
- Microscopic:
- a. Hyperemia
- b. Fibrin
- c. Inflammatory cells
- 1) Bacterial: neutrophils
- 2) Viral: lymphocytes
clinical presentation of meningitis (5)
- Present with fever, headache, neck pain and vomiting
- PE: Neck stiffness; Kernig sign (pain with straight leg raising) both due to nerves passing across the inflamed meninges
- Bacterial meningitis is serious due to risk of death
- Viral meningitis is usually mild and self-limited
- Waterhouse-Friderichsen syndrome; meningitis-associated septicemia
Identify clinical presentation of meningitis
a. Meningitis-associated septicemia
b. Hemorrhagic infarction of adrenal glands
- 1) Hypotension and shock
- 2) Petechiae (pin point hemorrhage) or purpura (bruise like) from DIC
c. Most common with meningococcal or pneumococcal meningitis
Waterhouse-Friderichsen syndrome
How to diagnose meningitis
- acute vs viral findings in the CSF
Diagnosis
1. Examine CSF by lumbar puncture
- a. Cell count
- b. Chemistry (protein, glucose, chloride)
- c. Culture and Gram stain
- Findings
* *a. Bacterial**
- 1) Cell count – neutrophils
- 2) Chemistry: protein is HIGH, glucose is VERY LOW
- 3) Culture is positive in 90%
b. Viral
- 1) Cell Count – lymphocytes
- 2) Chemistry: protein is slightly elevated, glucose is NORMAL
- 3) Viral cultures are positive in 70%
Treatment of meningitis
bacteria vs viral
- Antibiotics for bacterial
- a. Until cultures are back from the lumbar puncture choose antibiotics based on
- 1) Chemical examination (protein, glucose)
- 2) Type of cells present
- 3) Gram stain
- b. Start antibiotics FIRST, LP within 30 minutes
- Viral meningitis is usually supportive therapy
Infection of brain parenchyma
**Identify focal suppurative infections (2)
- Brain Abscess
- Subdural empyema
Infection of brain parenchyma - cerebral/brain abcess
- Cavity
- Etiology
Cavity; pus: Liquefied brain and PMN’s
Etiology
- a. Streptococci and staphylococci most common, anaerobes common
- b. Complications of other diseases
- 1) Chronic suppurative infections of the middle ear and mastoid air spaces and paranasal sinuses (local extension)
2) Infective endocarditis – often develop small and multiple abscesses
3) Right-to-left shunts (e.g. congenital cyanotic heart disease)
4) Tooth extraction
5) Suppurative lung disease (RARE cause); leads to parietal lobe abscesses
Pathology of brain abcess
a. Appears as mass lesion
b. Liquefied center with pus surrounded by
c. Fibrogliotic wall - thickness depends on duration
d. Adjacent brain: frequent vasogenic edema
e. Most common sites: Frontal lobe, parietal lobe, and cerebellum
Clinical features and diagnosis and treatment of the following
BRAIN ABCESS
- Clinical features & diagnosis
- a. Space-occupying lesion (increased intracranial pressure: headache, vomiting and papilledema)
- b. Focal neurologic signs – depends on location
- c. Evidence of infection (fever, elevated erythrocyte sedimentation rate, weight loss in chronic cases)
- d. If untreated may cause death by increased intracranial pressure or rupture into ventricles
- e. Dx’d clinically, confirmed by CT or MRI scan
- 1) Lumbar puncture dangerous, risk of herniation
- a) CSF normal -or-
- b) Mild increases in protein, neutrophils and lymphocytes
- c) Cultures: may or may not grow
- Rx – surgical evacuation (drain abcess), followed by antibiotics. Former high mortality rate has been reduced to 5-10%
identify CNS infection
- Collection of pus in the subdural space
- Source is bacterial or fungal (less common) infection of skull bones or air sinuses
- Mass effect
- Can cause a thrombophlebitis of bridging veins → venous occlusion → infarction of brain
- Sx
- a. Early – fever, headache, neck stiffness
- b. Later (untreated) – focal neurologic signs, lethargy, coma
- Rx – surgery & antibiotics
Subdural empyema
**Thrombophlebitis (inflammation of veins which gets prothrombotic)
Identify chronic bacterial meningoencephlitis (3)
- TB (tuberculosis)
- Neurosyphilis
- Neuroborreliosis (Lyme Disease)
Viral meningoencephalitis
- clinical features
- Treatment
- Clinical Features
- a. Acute onset with fever, headache, and signs of brain dysfunction
- b. Convulsions may occur
- c. May have papilledema
- d. May have meningeal inflammation causing neck stiffness and CSF like viral meningitis
- e. Dx by clinical picture
- f. Lumbar puncture may give etiology
- Rx
- a. Supportive
- 1) High dose corticosteroids to treat cerebral edema
- 2) Anti-virals
- b. In severe encephalitis
- 1) Mortality HIGH
- 2) Frequently left with permanent neurologic deficits due to irreversible neuronal necrosis
CSF finding in TB vs bacteria meningitis vs viral meningitis
- Cell count
- Protein
- Glucose
Identify clinical presentation and complication of the following chronic bacterial meningoencephalitis
- Morphology
- a. Macroscopic; Gelatinous or fibrinous exudates at base of brain
- b. ENTIRE brain and meninges involved. Microscopic;
- 1) Lymphocytes, plasma cells, macrophages
- 2) In fully developed cases: caseating granulomas, caseous necrosis, giant cells
- 3) Obliterative arteritis of arteries crossing the subarachnoid space
TB (Tuberculosis); seeded from a pulmonary infection
- Clinical
- a. Sx – headache, malaise, mental confusion, vomiting
- b. Dx – Lumbar puncture
- 1) Cell count – BOTH neutrophils and lymphocytes
- 2) Chemistry: protein is VERY high, Glucose is low or normal
- 3) Acidfast stain positive (may see mycobacterium)
- 4) Mycobacterial culture is positive; takes 2 weeks to grow
- c. Rx – long term antibiotics
- Complications
- a. Arachnoid fibrosis in long-standing cases, resulting in hydrocephalus
- b. Obliterative endarteritis → arterial occlusion → infarction
Chronic bacterial meningoencephalitis - Neurosyphilis
- What percent progress when left untreated
- 3 major forms
- Treatment (that stop progression)
- 10% of untreated cases progress to teriary or neurosyphilis
- Three major forms
* *a. Meningovascular neurosyphilis**
- 1) Involves base of brain, cerebral cortex, spinal leptomeninges
- 2) Obliterative endarteritis and perivascular inflammation with plasma cells and lymphocytes
- 3) Cerebral gummas (masses of plasma cells)
b. Paretic neurosyphilis
- 1) Invasion of brain by Treponema pallidum
- 2) Progressive loss of mental and physical functions
- 3) Loss of neurons, increased microglia, gliosis and iron deposits in cerebral ctx
c. Tabes dorsalis
- 1) Damage to sensory nerves in dorsal roots by spirochetes
- 2) Ataxia, loss of pain sensation and absence of deep tendon reflexes
- 3) Loss of axons and myelin in dorsal columns
3. Penicillin will prevent the progression of developed neurosyphilis but will NOT reverse the damage
Identify type of neurosyphilis
1) Involves base of brain, cerebral cortex, spinal leptomeninges
2) Obliterative endarteritis and perivascular inflammation with
plasma cells and lymphocytes
3) Cerebral gummas (masses of plasma cells)
Meningovascular neurosyphilis
Identify type of neursyphilis
1) Invasion of brain by Treponema pallidum
2) Progressive loss of mental and physical functions
3) Loss of neurons, increased microglia, gliosis and iron deposits in cerebral ctx
Paretic neurosyphilis
Identify type of neurosyphilis
1) Damage to sensory nerves in dorsal roots by spirochetes
2) Ataxia, loss of pain sensation and absence of deep tendon reflexes
3) Loss of axons and myelin in dorsal columns
Tabes Dorsalis
Identify chronic bacterial meningoencephalitis
- Highly variable symptoms: aseptic meningitis, facial nerve palsies, mild encephalopathy
- Microscopic: microglial cells and scattered organisms
Neuroborreliosis (Lyme Disease)
Identify viral meningoencephalitis (9)
- Arthropod-borne viral encephalitis
- Herpes simplex encephalitis
- Varicella Zoster
- CMV (cytomegalvirus)
- Poliomyelitis (poliovirus)
- Rabies
- HIV encephalopathy
- PML (progressive multifocal leukoencephalopathy)
- SSPE (Subacute sclerosing panencephalitis)
Viral meningoencephalitis
General points
- parenchymal infecion of brain associated with?
- define tropism
- pathology
- Parenchymal infection of brain with associated meningeal inflammation +/- spinal cord involvement
- “Tropism” – some viruses infect certain cells and/or certain areas of brain
- Pathology
- a. Usually blood-borne
- b. Affects brain
- 1) Perivascular and parenchymal mononuclear infiltrates (lymphocytes, plasma cells, macrophages)
- 2) Microglial nodules
- 3) Neuronophagia
- 4) May be specific inclusion bodies
- 5) Severe cases, hemorrhage occurs
- 6) Cerebral edema
- c. Result: cerebral dysfunction and increased intracranial pressure (HA, vomiting, papilledema)
Identify viral encephalitis
a. Cause epidemic encephalitis
b. In Western hemisphere – Eastern and Western equine, St. Louis, LaCrosse, West Nile, Venezuelan
c. CSF: neutrophils first then lymphocytes, protein elevated, glucose normal
d. Histology: Perivascular lymphocytic cuffing, necrosis with
neuronophagia, microglial nodules
e. Serious morbidity and high mortality
Arthropod-borne viral encephalitis
Identify viral encephalitis (incidence) based on pathology, dx and treatment
b. Pathology
- 1) Infects the temporal and inferior frontal lobes and orbital gyri
- 2) Necrotizing, hemorrhagic acute encephalitis
- Intranuclear cowdry A inclusion bodies
- 3) May be rapidly fatal (CAUSE DEATH) or
- 4) May be subacute, developing over 4-6 wks (usually HSV-1)
c. Dx:
- 1) PCR of CSF***
- 2) Brain bx, necessary for dx prior to PCR
- a) Intranuclear Cowdry A inclusions in neurons and glia
- b) EM, immunohistochemical, in situ hybridization –demonstrates the virus in most cases
d. Rx: if given early, antiviral agent (acyclovir)
Herpes Simplex encephalitis
a. Incidence (occurs in 2 groups)
1) Children and young adults, may be any age
- a) Only 10% have h/o prior herpes
- b) Usually HSV-1
- c) HSV-1 is most common cause of sporadic encephalitis in US
2) Neonates
- a) Delivery in a woman with active herpes genitalis
- b) Usually HSV-2
- c) Do caesarian section
identify viral CNS infection
a. Rare cause of encephalitis in immunosuppressed pts
b. Due to reactivation of latent virus
c. Lesions show demyelination then necrosis
Varicela-Zoster
- Causes Shingles
Identify viral CNS infection
a. The fetus is infected in the last trimester due to transplacental infection (TORCH)
* 1) Causes periventricular necrosis and calcification resulting in microcephaly
b. Also occurs in immunocompromised, esp. AIDS
- 1) Prior to ART (antiretroviral therapy) was the most common opportunistic viral pathogen in HIV/AIDS pts
- 2) Now rare in HIV/AIDS
- 3) Most often occurs as subacute encephalitis
- 4) Predilection for paraventricular subependymal regions
CMV (Cytomegalovirus)
Identify viral CNS infection
a. Infects via fecal-oral route
b. Causes a mild gastroenteritis, invades CNS in few patients (via bloodstream)
c. Selectively infects
- 1) Meninges (Acute lymphocytic meningitis)
- 2) Anterior horn motor neurons of the spinal cord – Perivascular lymphocytic cuffing and neuronophagia
d. Clinically
- a) Flaccid paralysis, muscle wasting, hyporeflexia (asymmetrical)
-
Identify the condition???????
- 1) 25-35 yrs after initial illness
- 2) Weakness, loss of muscle mass, pain
Poliomyelitis (poliovirus)
- Acute paralysis
- Asymmetircal
- Flaccid muscle paralysis
- Muscle wasting
- Hyporeflexia (can sometimes affect the diaphragm)
**Post polio syndrome
- 1) 25-35 yrs after initial illness
- 2) Weakness, loss of muscle mass, pain
Identiy viral CNS infection
f. Clinical
- 1) Fever, malaise, paresthesias around bite site (even after the bite/wound is healed)
- 2) CNS hyperexcitability even generalized convulsions stimulated by the slightest sensations
- 3) Contracture of pharyngeal muscles – drooling and foaming at the mouth
- 3) Death is essentially inevitable. (some people tho have survived)
g. Rx: Prevention and pre- or post-exposure vaccine prophylaxis
Rabies (aka Hydrophobia - fear of water. Seen first in dogs with rabies that couldn’t drink water)
- a. Rare in humans
- b. From bite of infected mammal, rabies virus ascends along peripheral nerves to CNS
- c. Incubation: 1-3 months (longer for virus to travel up nerve that bloodstream)
- d. CNS infection causes severe neuronal degeneration and inflammation
- 1) Midbrain
- 2) Medulla
- 3) Basal ganglia
- e. Dx: Diagnostic eosinophilic intracytoplasmic inclusion bodies (Negri bodies )
- 1) In pyramidal neurons of hippocampus or Purkinje cells (no inflammation)
Identify viral CNS infection
- Less common now than prior to the availability of HAART (2 types)
HIV Encephalopathy
- HIV aseptic meningitis (no bacteria)
- 1) 1-2 weeks after seroconversion
2) 10% of patients
3) Virus in CSF and antibodies in serum
- 1) 1-2 weeks after seroconversion
- HIV meningoencephalitis
- 1) Morphology
- a) Virus gains access to CNS via infected macrophages
b) Chronic inflammation
c) Microglial nodules with multinucleated giant cells
d) May see foci of necrosis and gliosis
e) Virus found in CD4+ macrophages and microglia, not in neurons or oligodendrocytes -
2) Clinical
a) Mild to severe cognitive changes (HIV associated dementia) - b) Related to number of activated microglia in the brain
Identify viral CNS infection
a. Etiology: Reactivation of the JC virus (a polyoma virus) in setting of immunosuppression. (everyone gets infected with JC virus by age 14)
b. Seen in
- 1) Chronic lymphoproliferative and myeloproliferative diseases
- 1) HIV/AIDS
- 2) Cancer chemotherapy
c. Pathology
- 1) Infects oligodendrocytes
- 2) Widespread focal demyelination of white matter involving entire brain
- 3) Giant atypical astrocytes
- 4) Enlarged oligodendrocytes with intranuclear inclusions
d. Dx: CT and MRI show multifocal demylinated lesions in white matter. Grey matter has no myelin
e. Clinical
- 1) Acute, rapidly progressive illness with multifocal cerebral dysfunction
- 2) Mortality rate is high
Progressive Multifocal Leukoencephalopathy (PML)
Identify viral CNS infection
a. RARE especially since initiation of measles vaccine (MMR vaccine)
b. Children and adults months to years after measles
c. A persistent measles viral infection
d. Pathology
- 1) Widespread gliosis
- 2) Myelin degeneration
- 3) Intranuclear inclusions
- 4) Variable inflammation
- 5) Neurofibrillary tangles
e. Clinical
- 1) Cognitive decline
- 2) Spasticity of limbs
- 3) Seizures
- 4) Relentless, causes death in 1 to 2 years from onset
Subacute Sclerosing Panencephalitis (SSPE)
Identify the following body part
gross collection of convoluted bulges referred to as gyri which are separated from each other by involutions called sulci
**various parts?
Cerebral Cortex
Lobes are separated by the major sulci
- A sulcus termed the lateral fissure (of Sylvius) separates the frontal and temporal lobe
- The central sulcus separated the frontal and parietal lobe
* a. On the medial aspect of the brain the cingulate sulcus separates the frontal and parietal lobes
- The central sulcus separated the frontal and parietal lobe
Understand term dominant hemisphere and its implication on language localization
- Most people (80-85%) are right-handed which implies that the left hemisphere is dominant and houses language production and comprehension.
- Many left handed people also have left hemisphere dominance (70-85%)
Define and localize Wernicke and Broca Type Asphasia
There are two main areas involved in the production and comprehension of language:
a. Broca’s Area is located in the frontal lobe and sits adjacent to the primary motor cortex.
- i. Damage to the Broca’s area by stroke or other structural defect causes impaired language production with intact language comprehension.
b. Wernicke’s area is located in the superior temporal gyrus of the temporal lobe
- i. Damage to the Wernicke’s area causes impaired language comprehension with intact language production in some sense. Because one does not comprehend the content of language, there language in-turn also makes no sense but has normal fluency and prosody (rhythm and emotional tone inflections of speech)
Lobes of the brain
largest lobe of the brain and controls movement of the contralateral side of the body. It is comprised of many eloquent areas which will described below ?
**WHich area is just anterior to the main motor strip? damage results in?
FRONTAL LOBE
Premotor cortex
- This area is just anterior to the main motor strip.
- Damage results in apraxia (disruption of planning of patterning and execution of learned motor movements).
* a. An example of ideomotor apraxia: A 76 y/o wood worker suffers a stroke. In follow-up he states he can no longer use his tools. In testing you hand him a hammer and he can readily tell you the function of the tool and its name but cannot perform the proper movements to use it.
- Damage results in apraxia (disruption of planning of patterning and execution of learned motor movements).
- Damage in the region of the premotor cortex often affects the frontal eye field as well
* a. Lesion to the frontal eye field results in impairment of horizontal gaze to the contralateral side. Patients have forced eye deviation toward the side of the lesion.
- Damage in the region of the premotor cortex often affects the frontal eye field as well
Parts of frontal lobe
- part that results in apraxia? what is apraxia?
- located in the anterior frontal lobe and used in panning intellectual and emotional aspects of behavior
- This aspect of the frontal lobe is located anterior to the central sulcus
-
Premotor cortex
- Damage results in apraxia (disruption of planning of patterning and execution of learned motor movements).
- Damage also affect frontal field; patients have forced eye deviation TOWARD side of lesion
- Prefrontal Cortex
- Located in the anterior frontal lobe
- Used in planning the intellectual and emotional aspects of behavior
a. Some patients who suffer lesions to the prefrontal cortex have symptoms of apathy and abulia (dramatic lack of motivation). - Motor Cortex
- This aspect of the frontal lobe is located anterior to the central sulcus
- It controls motor functions and is designed in the form of the motor homunculus detailed below:
a. Patients having lateral frontal lobe stroke tend to have greater facial weakness where as those with high frontal lobe infarcts have more arm and leg weakness.
the second largest lobe of the brain and interprets sensory of the contralateral side of the body. It is also comprised of many eloquent areas which will be described below
**2 parts of parietal lobe
- area posterior to sulcus
- area posterior to somatosensory. defect result in?
PARIETAL LOBE
Primary somatosensory cortex
- This aspect of the parietal lobe is located posterior to the central sulcus
- It controls the interpretation of somatosensory stimuli (light touch, pressure, two point discriminative touch, vibration, position sense, and temperature) and is oriented in the sensory homunculus below:
* a. Lesion to this aspect of the parietal lobe results in contralateral impairment of all somatosensory input types
- It controls the interpretation of somatosensory stimuli (light touch, pressure, two point discriminative touch, vibration, position sense, and temperature) and is oriented in the sensory homunculus below:
iii. Posterior parietal association cortex
- This region is posterior to the somatosensory cortex.
- When lesioned it also presents with symptoms of apraxia (described above under “premotor cortex”)
- A lesion in this location may also result in the inability to recognize objects based on touch alone- “astereognosia”.
Part of parietal lobe
The sensory homunculus is represented in this Claymation character to further emphasize the cortical space occupied for each sensory area
***Excessive areas?
**note that hands and mouth have an excessive area of dedicate cortical tissue to process the immense amount of neural information from the numerous nerve endings in these areas
the very medial aspect of the occipital lobe adjacent to the interhemispheric fissure
b. It is designed in a way the each part of the retina is schematically arranged onto the cortical surface
Primary visual cortex
- a. This area is on the very medial aspect of the occipital lobe adjacent to the interhemispheric fissure
- b. It is designed in a way the each part of the retina is schematically arranged onto the cortical surface
- i. When one small area is damaged by stroke, the corresponding retinal information is lost resulting in a scotoma (blind spot)
Be able to recall the visual pathway and localize visual field cuts
A. Right Optic nerve damgae; ipsilateral blindness in right eye
B. Optic chaism; Bitemporal hemianopsia
- Caused by pituitary tumor, MS, berry aneurysm
C. Optic tract; homonymous hemianopsia
D. Right meyer’s loop; left upper quadrantonosia
E. Occipital cortex? ; caused by PCA infarction (right)
- Left homonymous hemianopsia with macula sparing.
- If MCA (middle cerebral arteyr is lost, there will be no macula sparing)
Visual case
62 y/o man presents with his neighbor to the ED because of presumed vision problems over the last two days. The neighbor noted he required holding onto objects as he walked through his home and has had multiple trips and falls on his walkway and steps. The man states there is nothing wrong and that he could see normally. There was no clear blink to threat. On exam he was unable to count fingers or even identify large objects. Pupillary light exam and fundoscopic examination was unremarkable. Imaging showed the following:
•
•Patient is exhibiting classic symptoms for Anton’s Syndrome
•Anton’s Syndrome- cortical blindness due to lesion of both occipital lobes (including primary visual cortex).
•The patient exhibits profound anosognosia (lack of regard for deficit) which is common in this syndrome
Understand basic functioning of thalamic and hypothalamic nuclei with eventual goal of memorization for testing
Thalamic nuclei; motor nuclei? sensory nuclei? visual?
Hypothalamic nuclei;
- water balance
- body temperature
- blood presure
- water balance/stress
- shivering
- GI tract
- biologic clock
- satiety
- feeding
Thalamic Nuclei
-
Motor Nuclei
- Ventral Anterior (VA)- gets input from the basal ganglia
- Ventral Lateral (VL)-gets input from the basal ganglia AND cerebellum
-
Sensory Nuclei
- Ventral posteromedial (VPM)- input from the trigeminal nucleus (think M as Mouth)
- Ventral posterolateral (VPL) input from the medial lemniscus and spinothalamic tract (think L as Limbs)
- Medial Geniculate- input from the inferior colliculus, processes sounds (think Medial Geniculate= Music)
* a. Auditory Pathway pneumonic “NCS LIMA”
* i. Acoustic Nerve → Cochlea Nucleus → Superior Olive (Pons) → Lateral Lemniscus (Pons) → Inferior Colliculus (mid brain) → Medial Geniculate (thalamus) → Auditory Association Cortex
- Medial Geniculate- input from the inferior colliculus, processes sounds (think Medial Geniculate= Music)
- Lateral Geniculate Nucleus- Input from the optic tract (think Lateral Geniculate= Light)
-
Medial Nuclear Group
- i. Dorsal Medial Nucleus (main medial nuclei but not pictured above)- input from the limbic system- involved in memory and emotion
- Lesion here results in amnesia
- i. Dorsal Medial Nucleus (main medial nuclei but not pictured above)- input from the limbic system- involved in memory and emotion
-
Pulvinar
- i. No true input from outside the thalamus- responsible for visual attention
Hypothalamus
- a. The hypothalamus is also a very complicated network of hard-to-remember nuclei that have multiple afferent and efferent connections throughout the nervous system.
- b. It is involved in hunger, thermoregulation, water balance, reproduction, and even the sleep wake cycle.
- c. It is also highly involved in the limbic and autonomic systems and has numerous projections to the pituitary gland
- Paraventricular AND Supraoptic- These nuclei synthesize antidiuretic hormone and oxytocin. They function in the management of water balance.
a. Lesion in this nuclear group results in central (central meaning from the brain, not the kidneys) diabetes insipidus
i. Clinically appears as polyuria and excess water consumption. -
Satiety/Hunger
a. Ventromedial Nucleus- satiety center. Lesion in this area makes affected individuals obese
b. Lateral Hypothalamic Area- hunger center. Lesion in this area makes affected individuals have no desire to eat (aphagia-refusal to eat or swallow) - Temperature Regulation
a. Anterior Hypothalamic Area - senses increase in temperature and induces sweating to dissipate heat. Lesion here results in hyperthermia
b. Posterior Hypothalamic Area-senses decrease in body temperature and induces shivering. Lesion here results in poikilothermy (body temperature will vary with environment) - Circadian Rhythm
a. Suprachiasmatic nucleus obtains visual input from the retina via the optic tract. This area sets the circadian rhythm to the day/night surroundings. - Memory
a. Mammillary bodies are part of the limbic system and critical to the formation of memory. Lesion here results in anterograde and retrograde memory impairment.
i. Review of memory formation: Papez Circuit- memory formation (limbic system) - Think H. MACE for memory formation
a. Hippocampus → Mammillary Bodies → Anterior Nucleus of the Thalamus → Cingulate Gyrus → Entorhinal Cortex
Case
A 56 y/o male presents to the ED with his wife for confusion. Historically she states he is a long-term drinker and regularly consumes a pint of liquor daily. On exam you find him to be somewhat combative and agitate. He has decreased horizontal and vertical eye movements appearing as ophthalmoparesis. His gait is ataxic and his reach for objects is cumbersome and inaccurate. Neuroimaging shows the following:
- Patient is exhibiting classic symptoms for Wernicke’s encephalopathy (confusion, ataxia, and ophthalmoparesis).
- Wernicke’s encephalopathy is typically seen in alcoholism and severe malnourished states and is caused by a deficiency vitamin B1 (thiamine)
- The deficiency results in damage to the mamillary bodies and ultimately results in necrosis (as seen on the MRI). If patients survive they often suffer from Korsakoff’s syndrome (anterograde and retrograde amnesia with confabulation.
Case
A 57 y/o male presents to the neurology clinic for evaluation of chronic irregular limb movements which are progressively worsening. He recalls a family history of similar movement disorder in his father and paternal uncle. On exam he demonstrates bilateral choreiform movements involving the upper and lower extremity which worsen with distraction. Imaging is obtained and shown below.
This case is the classic presentation for Huntington’s disease (HD). HD is a neurodegenerative condition resulting in a hyperkinetic (fast irregular movements) movement disorder. Genetically there is a problem with trinucleotide expansion of CAG in the Huntington gene on chromosome 4. This disease has genetic anticipation meaning that each subsequent generation will have more trinucleotide repeats and will therefore express the disease earlier and often with more severe symptoms.
Ferguson questions
- C
- D
- B
Muscarinic agonists - effect on if; metabolized by cholinestease? muscarinic activity? blocked by atropine? nicotinic activity? quaternary amines?
- Ach
- Methacholine
- Carbachol
- Bethanechol
- Muscarine
- Pilocarpine
**what do all 6 do (2)
Whats 3 have nicotinic activity? what 3 don’t
what 2 are metabolized by cholinesterases? (major one? )
what has no quaternary amines?
***If you have muscarinic activity means can activate ganglia?
All Muscarinic agonist have muscarinic activity and are blocked by atropine
MoA of muscarinic agonists
Physiologic effects (organ system effects)
- Cardiovascular (low dose vs high dose)
- GI
- Urinary
- Resp tract
- Eye
- Glands
Muscarinic Agonists
- Mechanism of action: Bind to and activate muscarinic receptors
Describe MoA of succinylcholine
- Phase I vs Phase II
•Phase I depolarization: prolonged depolarization (overstimulation), end plate can no longer respond to further stimulation and this leads to muscle paralysis.
•There is no antidote (just stop administering drug). Acetylcholinesterase inhibitor potentiates Block.
•Phase II depolarization: Repolarized, BUT blocked by succinylcholine (functioning like a non-depolarizing nicotinic receptor antagonist).
Identify Usual Predominant tone of ANS at various effector sites, and consequences of Autonomic Ganglionic Block
- Arterioles
- Veins
- Heart
- Iris
- Ciliary muscle
- GI tract
- Urinary bladder
- Salivary glands
- sweat glands
- Genital tract
Identify major transmitters (examples) based on the following classes
- Biogenic amines (5)
- Amino acids (4)
- Nucleotides/Nucleosides (2m)
- Peptides (1 major)
- Biogenic amines; Acetylcholine, Dopamine, Norepinephrine, Epinephrine, Histamine, Serotonin
- Amino acids; GABA, Glutamate, Glycine, Aspartate
- Nucleotides/Nucleosides; Adenosine, ATP
- Peptides; Enkephalins
Dopamine
- 3 dopaminergic traits
- role of DA in disease
- metabolites of DA
Three dopaminergic tracts:
- Mesocortical/Mesolimbic Pathway
- o Behavior/Emotion
- Nigrostriatal Pathway
- o Motor Function (75% of brain DA)
- Tuberoinfundibular Pathway
- o Neuroendocrine function
Identify neurotransmitter (receptors - 3, metabolites)
Produced in nuclei of the pons and medulla
- o Locus ceruleus produces ~50% brain NE neurons
- Innervates forebrain, brainstem and spinal cord
- o Other nuclei are in the brainstem
- Predominately innervate brainstem and spinal cord
Involved in:
- o anxiety, cerebellar function, learning, memory, mood, sensory processing, sleep (dreaming), arousal
Norepinephrine (NE)
- Receptors
- alpha 1, alpha 2, beta receptors
- Metabolites of NE
- VMA; vanillymandelic acid
Identify neurotransmitter
- produced by several brain stem nuclei in rostral and caudal clusters.
- o Rostral nuclei innervate most of the brain
- o Caudal Nuclei Innervate cerebellum, brainstem and spinal cord
Involved in:
- appetite, pain processing, hallucinations, sleep, mood (through interactions in limbic areas), temperature regulation, sensory perception
*****Desrcibe effect of the NT on; schizophrenia, depression, suicide, impulsive behavior, aggression
**Syntheis, termination and metabolism
**Receptors (4)
Indoleamines; serotonin (5-HT)
Identify neurotransmitter
Nuceli in the basal forebrain and brainstem supply the cholinergic innervation of the brain
Involved in:
Memory, Sensory Processing, Motor Coordination, Wakefulness
- Effect on; myasthernia gravis, parkinsons, alzheimers
- Synthesis, termination and metabolism
- Receptors
Cholinergic (Ach)
Amino Acid Neurotransmitters
- Excitatory amino acid neurotransmitters
- involved in?
- Synthesis, deactivation and metabolism
- Receptors
Excitatory amino acid neurotransmitters:
Glutamate, Aspartate
Glutamate is the major excitatory neurotransmitter found throughout the brain
Involved in:
Regulation of neuronal function, LTP
Synthesis, deactivation and metabolism:
Glutamine converted to glutamate in mitochondria and packaged
into vesicles
Deactivated predominantly by astrocytic uptake, where it is converted to glutamine
Glutamine can be shuttled back to neurons
Receptors:
Ligand gated ion channels
AMPA, Na+, K+
Kainate, Na+, K+
NMDA, Na+, K+, Ca2+
Metabotropic
mGluR I
o Gi activation
mGluR II & III
o Gq activation
Inhibitory Amino Acids:
Gamma aminobutyric acid (GABA) – major inhibitory amino acid
- Present in inhibitory interneurons and projection neurons throughout the brain.
Involved in ?
Disease with a role for GABA?
Synthesis, deactivation, metabolism
Receptors
GABA
Identify types of Opiod peptides (3)
- o Leucine enkephalin, methionine enkephalin;
o CNS interneurons
o Location: Nerve plexuses of GI tract
o Location (pain perception):
Lamina I, II of spinal cord
o Location (modulation of affective behavior):
amygdala, hippocampus, locus ceruleus, cerebral cortex
o Location (regulation of autonomic nervous system):
medulla oblongata - o Localized in arcuate nucleus of hypothalamus, nucleus tractus solitarius and in the anterior lobe of pituitary where it is coreleased with ACTH in response to stress
o Localized in spinal cord
o Localized in pancreatic islet cells - o Dynorphin colocalizes with vasopressin in the hypothalamus and posterior lobe of the pituitary gland
o Dynorphin present in laminae I and II of the spinal cord
- Enkephalins: (derived from proenkephalin)
- Endorphins: (derived from proopiomelanocortin)
- Dynorphins: (derived from prodynorphin)
Opioid receptors are very important targets for pain treatment and are also important in drugs of abuse
Define the following concepts in neuropharmacology
- Receptor number modulation
- Tolerance
- Dependence
- Drug abuse
- Drug addiction
- Withdrawal
Understand the medications available to treat Parkinson’s Disease
Medications vs surgical tx
***Advantages and disadvantages of the main drug***
Carbidopa/Levodopa (Sinemet™)
- o Gold standard treatment
- o Acts by crossing the blood brain barrier and converting to dopamine by ALAA-decarboxylase
- o Eventually all PD patients require it
MAO-B Inhibitors
- o Selegiline, Rasagiline
- o Act by selective inhibition of MAO-B enzyme involved in dopamine metabolism
- o Is possible neuroprotective
- o Drawbacks:
- ▪ Tons of drug interactions
- ▪ Very mild anti-Parkinson’s dug
• Dopamine Agonists
- o Pramipexole and ropinirole
- o Directly stimulate D2/D1 receptors
- o Less efficacious than levodopa but more than MAO-BI and amantadine
- o Also has indication in restless leg syndrome
- o Drawback:
- ▪ Pathologic gambling and impulsivity in general
- ▪ Can cause sudden sleep attacks
• Amantadine
- o Mechanism of action not known: NMDA blockade?
- o Effective at reducing dyskinesia
• COMT Inhibitors
- o Entacapone, Tolcapone
- Inhibit COMT => slows dopamine breakdown => prolongs the half life of levodopa
- o Used in advanced PD when patients are experiencing motor fluctuations
- o Tolcapone has longer half-life but use limited by bimonthly LFT monitoring to monitor for hepatoxicity
- o Always have to be given with levodopa
Surgical treatment
Deep Brain Stimulator (DBS)
o Which patients to consider for DBS
- ▪ Advanced PD patients, who are not demented, having any of the following symptoms which cannot be adequately controlled with medications.
- • Motor fluctuations;
- Disabling dyskinesia or dystonia
- • Medically refractory tremor
- • Medication induced intolerable side effects
- o Positive effects of DBS on Parkinson’s Disease Patients
- ▪ Marked improvement in motor symptoms
- ▪ Improvement in tremor by ~80%
- ▪ Increases the ‘On’ time and ‘smoothes’ out motor fluctuations when using carbidopa/levodopa
- ▪ Dyskinesias improve 60-80 %
- ▪ Quality of life improvement ~ 50%
- o Symptoms which fail to improve with DBS
- ▪ Speech (may even worsen)
- ▪ Cognition
- ▪ Postural instability and gait (if unresponsive to levodopa)
- ▪ Autonomic symptoms (constipation, orthostasis)
role of various picornaviruses in causing infections of the CNS.
Possible infections by poliovirus
a. Inapparent infections- vast majority of cases in young individual (90%)
b. Abortive poliomyelitis - fever, malaise, headache, vomiting, sore throat- About 5%
c. Nonparalytic CNS disease (“aseptic meningitis”) - stiffness and pain in neck and back;crossesfenestrated endothelial cells at the choroid plexus,1-2%
d. Paralytic –spinal, bulbar (back of neck, pons & medulla) - flaccid paralysis - changes in voluntary muscle most likely to occur in teenagers and young adults, 0.1-2%
Paralysis induced by poliovirus infection
Spectrum of levels of flaccid paralysis
- Asymmetric paralysis with no sensory loss
- Localized flaccid paralysis
- Multiple Sites (arms and legs affected)
3 outcomes of recovery from flaccid paralysis
- Full recovery
- Residual paralysis
- Death (bulbar poliomyelitis)
Know the status of the two types of poliovirus vaccines and the advantages and disadvantages of each. Know the proper specimens for virus isolation at each stage of infection and laboratory procedures used for diagnosis.
Vaccine induced immunity, two primary types of vaccines –killed
(Salk= IPV)) vs. live (Sabin= oral) vaccines
Salk (Killed) induces serum AB vs. Sabin (live attenuated)induces both secretary Ab and serum AB
“vaccine - associated” paralysis may be linked to the Sabin live vaccine, absolute need to maintain immunization, once begun
Tests to identify meningitis (4)
Meningeal irritation
- •Nuchal rigidity
- •Back pain
- •Kernig
- •Brudzinski
Treatment of bacterial meningitis based on age
**what is gold standard to tell you organism
- neonate
- strep pneumo
- Neisseria
- H flu b
- Immunocompromised
Other non abx treatments
CULTURE is gold standard to tell you what organism. but you don’t really wait till results come out before starting treat. treat based on age.
NEVER DELAY THERAPY WAITING ON THE LP
Other non-abx
- •Corticosteroids
- –Limits production of inflammatory mediators
- –Data supports use only in H. flu b meningitis
- •Supportive
- –IVF
- –ICP
- –Seizures
CNS findings - pressure, WBC, protein, glucose, comments
- normal
- bacterial
- partially tx (e.g tx w/ amoxillin)
- viral
- TB
- fungal
- brain abcess
