Patho2test 3: Day 1: CNS Overview: Structure and Function

CNS Overview: Structure and Function

• Central Nervous System (CNS) = brain and spinal cord
• Peripheral Nervous System (PNS) = cranial nerves and spinal nerves
• PNS pathways divided into:
  • Ascending (afferent) pathways: carry sensory information towards CNS
  • Descending (efferent) pathways: carry motor information away from CNS to innervate effector organs
• Descending (efferent) division further divided into:
  • Somatic nervous system: regulates voluntary motor control of skeletal muscle
  • Autonomic nervous system: regulates involuntary control of organ systems/internal viscera, divided into sympathetic and parasympathetic systems

Cells of the Nervous System

• Neurons:
  • Electrically excitable cells that transmit electrical or chemical information between other neurons to an effector organ
  • Three main components: cell body, dendrites, and axons
• Neuroglia (support cells):
  • Provide structural support, nutrition, protection for neurons, and facilitate neurotransmission
  • Types: astrocytes, microglia, oligodendrocytes (CNS), Schwann cells, satellite cells (PNS)

Neuron Structure

• Cell Body:
  • Located mainly in CNS
  • Components: microtubules, neurofibrils, Nissl substances (granules made of rough ER, responsible for protein synthesis)
• Dendrites:
  • Receptive portion of neuron, receives signals from other neurons and sends impulses to cell body
• Axons:
  • Long projection from cell body that carries nerve impulses away from cell body
  • Myelinated neurons have a myelin sheath wrapped around the axon, insulating layer that speeds up transmission
  • Nodes of Ranvier: interruptions of myelin sheath that allow saltatory conduction (faster transmission)

Neuron Communication Principles

• Axon Convergence:
  • Axon branches allow one neuron to receive many messages from several different cells at the same time
• Axon Divergence:
  • Axon branching allows one neuron to influence/send messages to many different neurons simultaneously

Neuron Classification

• Structural Classification:
  • Unipolar, pseudounipolar, bipolar, multipolar (most common)
• Functional Classification:
  • Sensory neurons: transmit impulses from sensory receptors in periphery to CNS
  • Motor neurons: transmit impulses from CNS to an effector organ
  • Interneurons (associational neurons): transmit impulses between neurons

Neuroglia (Glial Cells)

• Central Nervous System:
  • Oligodendrocytes: deposit myelin within CNS
  • Astrocytes: fill spaces between neurons and surround blood vessels in CNS
  • Microglia: remove debris within CNS (brain macrophages)
  • Ependymal cells: line CSF-filled cavities in CNS and create CSF
• Peripheral Nervous System:
  • Schwann cells: wrap around and cover axons in PNS, forming and maintaining myelin sheath

Anatomy Review

• White matter: myelinated axons, organized into tracts
• Gray matter: unmyelinated cell bodies, on the cortical surface and subcortical regions
• Basal ganglia: group of gray matter nuclei deep in the forebrain, connected with cortex, thalami, and brain stem, controlling muscle tone, posture, and large muscle movements
• Thalamus: relay center for sensory information, associating sensory input with emotions, memory, and motor planning

Neurotransmitters & Synapses

• Review: Action Potentials
  • When a stimulus depolarizes the cellular membrane, it triggers an action potential
  • Action potential must meet the threshold to be propagated down the axon
• Chemical Synapses
  • Presynaptic and postsynaptic cells separated by a thin synaptic cleft
  • Signaling from one cell to the next occurs through release of neurotransmitters from the terminal of the presynaptic neuron
• Neurotransmitters:
  • Acetylcholine, norepinephrine, dopamine, serotonin, GABA
  • Two possible effects on the postsynaptic neuron: excitation (depolarization) or inhibition (hyperpolarization)
  • Summation of EPSPs and IPSPs determines whether an action potential will occur

Neurotransmitters

• Excitatory:
  • Acetylcholine
  • Dopamine
  • Norepinephrine
  • Epinephrine
  • Serotonin
• Inhibitory:
  • GABA
  • Serotonin

Acetylcholine

• Made when acetyl CoA attaches to choline molecule
• Always the first signal on efferent (motor) pathways in PNS
• Released, binds to receptors on postsynaptic membrane, triggers opening of ion channels, and depolarizes the neuron
• Acetylcholinesterase breaks down acetylcholine within the synapse
• Clinical correlation: Myasthenia gravis, acetylcholinesterase inhibitors are used as treatment

Catecholamines (Dopamine, Epi, Norepi)

• Made from amino acid tyrosine
• Norepinephrine and epinephrine are crucial in the sympathetic nervous system
• Dopamine is involved in pleasure, reward centers, movement, and learning
• Clinical correlation: MAO inhibitors (antidepressants) work by inhibiting the action of MAO

Serotonin

• Made from amino acid tryptophan
• Slower than other neurotransmitters, more of a "neuromodulator"
• Can be both excitatory and inhibitory
• Clinical correlation: GABA, benzodiazepines, anticonvulsants, and muscle relaxants affect GABA signaling

Cerebrovascular Disease

• Refers to a group of conditions that affect blood flow and blood vessels in the brain
• Most common type is stroke/CVA, which can be ischemic or hemorrhagic

Stroke/CVA

• Abrupt onset of focal or global neurologic impairment lasting > 24 hours
• Ischemic stroke (87%) and hemorrhagic stroke (13%) are two main types
• Ischemic stroke can be further divided into:
  • Focal (territorial) ischemia: due to occlusion of a particular blood vessel, causes infarct within territory of occluded vessel
  • Global (generalized) ischemia: due to cardiac arrest, shock, or increased ICP, causes widespread ischemia and necrosis

Types of Ischemic Strokes

• Transient ischemic attack (TIA): episode of neurologic dysfunction lasting < 1 hour, due to transient focal cerebral ischemia
• Thrombotic stroke: arterial occlusion caused by thrombus formation in large or small arteries
• Embolic stroke: fragments break off from thrombus formed outside the brain, commonly in the heart, aorta, or carotid arteries
• Lacunar stroke: also called "small vessel disease", caused by perivascular edema/inflammation of arteries that supply small subcortical vessels
• Hypoperfusion stroke: systemic hypoperfusion due to cardiac arrest, leading to inadequate blood supply to the brain

Transient Ischemic Attack (TIA)

• Clinical manifestations depend on the location of the blockage
• Symptoms include:
  • Weakness/numbness
  • Confusion
  • Loss of balance
  • Loss of vision
  • Sudden severe headache
• Causes of TIA include:
  • Embolic TIA
  • Lacunar TIA
  • Large artery, low flow TIA

Thrombotic Stroke

• Smooth stenotic area degenerates, leading to ulcerated area of vessel wall, platelets/fibrin adhere to damaged wall, forming clots
• Thrombus formation in large or small arteries, most often due to atherosclerosis and inflammatory diseases

Embolic Strokes

• Fragments break off from thrombus formed outside the brain, commonly in the heart, aorta, or carotid arteries
• Risk factors include:
  • Atrial fibrillation
  • LV aneurysm/thrombus
  • Valvular disease/endocarditis
• Clinical correlation: Afib and stroke, due to loss of atrial systole, blood pools in the atria, and especially in the left atrial appendage, forming a blood clot

Lacunar Infarcts

• Perivascular edema/inflammation of arterial walls, leading to small vessels, predominantly occur in basal ganglia, internal capsules, and pons
• Risk factors include:
  • Hyperlipidemia
  • Tobacco use
  • HTN
  • Diabetes
• Make up ~ 25% of all ischemic strokes

Pathophysiology of Infarction

• Infarction occurs when occlusion leads to loss of blood supply and ischemia, causing cell death
• Infarction leads to necrosis and swelling (cerebral edema) in 48-72 hours
• Ultimately causes disintegration of tissue (infiltration of macrophages/phagocytosis)
• After ~ 2 weeks, left with a cavity surrounded by glial scarring

Ischemic Core vs Penumbra

• Central core of irreversible ischemia/necrosis
• Surrounded by zone of borderline ischemic tissue called the penumbra
• Penumbra is area of salvageable damage
• Restoration of perfusion to the penumbra can prevent necrosis and loss of function
• Window of opportunity is ~ 3 hours

Clinical Correlation: Thrombolytics

• Goal in stroke treatment is to intervene early enough to restore perfusion to the penumbra
• Tenecteplase (TNK) is now the standard of care, rather than Alteplase (tPA)
• Patients who present < 4.5 hours from onset of symptoms

Clinical Correlation: Thrombectomy

• Patients who are "out of the window" for thrombolytics, not a candidate due to bleeding risk, or who have significant symptoms and a "large vessel occlusion (LVO)" on imaging, can undergo mechanical thrombectomy
• Specially trained radiologist will access the cerebral vessel and physically remove the thrombus

Hemorrhagic Strokes

• Presenting with headache and vomiting
• Intracerebral: most commonly due to HTN, vascular changes in HTN can evolve over several years, leading to necrosis and vessel rupture
• Subarachnoid: associated with ruptured aneurysms, AV malformations, or head trauma
• Subdural: most often due to trauma

Infarction due to Hemorrhage

• Mass of blood is formed as bleeding occurs, surrounding brain tissue is compressed and displaced, leading to ischemia, edema, and necrosis
• Rupture and seepage of blood can occur into the ventricular system, often associated with higher mortality rates
• In massive ICH (> 150 mL), cerebral perfusion falls to zero, leading to death

Aftermath of Hemorrhage

• In the absence of massive cerebral edema, most patients survive a hemispheric stroke
• Cerebral hemorrhage is reabsorbed, macrophages and astrocytes clear away blood
• Cavity forms surrounded by dense scarring

Subarachnoid Hemorrhage (SAH)

• Most common cause of spontaneous SAH is trauma
• Aneurysmal: weak bulging areas of arterial wall, due to atherosclerosis, HTN, congenital abnormalities, drug use, or inflammation
• May be single, but more than one is present in 20-25% of patients
• Peak incidence for aneurysmal rupture occurs in people 50-59

Saccular (Berry) Aneurysms

• Arises at forks of arteries in the base of the brain
• 85% in anterior circulation and 15% posterior
• Occur in ~ 2% of the population, but rupture is rare
• Due to a combination of factors, including congenital abnormalities of tunica media, loss of smooth muscle cells/inflammation, thrombus formation, and degenerative changes

Arteriovenous Malformation (AVM)

• Tangle of abnormal arteries and veins with no intervening capillary bed
• Developmental abnormality due to a persistence of embryonic patterns of blood vessels
• Direct shunting of arterial blood into venous vasculatures without time to "slow down" and decrease pressure in the capillary leads to a risk for ruptures
• Can lead to hemorrhagic stroke, seizures, chronic headaches, or focal neurologic deficits due to shunting of blood flow from nearby structures

Stroke Syndromes

• MCA (middle cerebral artery) stroke: largest artery and most commonly affected, contralateral weakness and sensory loss, visual field abnormalities, language disturbance or spatial perception problems
• Posterior circulation (Vertebrobasilar) stroke: double vision, clouding/blurring or loss of vision, vertigo, unilateral or bilateral weakness or numbness, dysarthria or difficulty swallowing, lack of coordination, gait instability

Cerebral Edema

• Three types:
  • Vasogenic edema: most common, increased permeability of capillaries that make up blood-brain barrier, causes include tumors, infection, and inflammatory/autoimmune diseases
  • Cytotoxic (metabolic) edema: most common cause is cerebral ischemia, ischemia leads to damage of Na+/K+ membrane pumps, Na+ accumulates in cell, pulling in water
  • Interstitial edema: most often seen with noncommunicating hydrocephalus, increased pressure in ventricles leads to CSF migration out of ventricles into interstitial space

Nerve Cell Injury and Repair

• Can nerve cells repair themselves? It depends...
• Nerve repair in CNS: mature neurons that become injured lead to permanent loss, common clinical example is with acute ischemic stroke
• Nerve repair in PNS: peripheral nerves can repair, Wallerian degeneration (anterograde) occurs distal to the injury, and retrograde changes occur at the proximal end of the injured neuron