9 - Neurology - 2021 Edition

USMLE ENDPOINT,
NEUROLOGY
DR. AHMED SHEBL
Dr Ahmed Shebl
[DATE]
[COMPANY NAME]
[Company address]
https://t.me/USMLEEndopoint https://t.me/USMLEEndopoint
USMLE ENDPOINT, NEUROLOGY Dr. Ahmed Shebl
EMBRYOLOGY
NEURAL DEVELOPMENT
 Notochord (mesoderm) induces overlying ectoderm to
differentiate into neuroectoderm and form neural plate.
 Notochord induces differentiation by sonic
hedgehog gene.
 Neural plate gives rise to neural tube and neural crest
cells.
 Notochord becomes nucleus pulposus of intervertebral
disc in adults.
 Alar plate (dorsal): sensory.
Basal plate (ventral): motor.
Both have the same orientation as spinal cord.
REGIONAL SPECIFICATION OF DEVELOPING BRAIN

 Telencephalon is the 1st part.
 Diencephalon is the 2nd part.
 The rest are arranged alphabetically:
mesencephalon, metencephalon, myelencephalon.
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CENTRAL AND PERIPHERAL NERVOUS SYSTEMS ORIGINS

 Neuroepithelia in neural tube form:
 CNS neurons.
 Ependymal cells (inner lining of ventricles, make CSF).
 Oligodendrocytes.
 Astrocytes.
 Neural crest:
 PNS neurons.
 Schwann cells.
 Ganglion (collection of neuronal cell bodies outside the CNS.)
 Mesoderm
 Microglia (like Macrophages).
UW notes:
 Anterior pituitary  from oral ectoderm (Rathke’s pouch) = surface ectoderm.

 Posterior pituitary (neurohypothesis)  from neuroectoderm.
 Neurofibromatosis type I arise from Schwann cells  neural crest cell origin.
NEURAL TUBE DEFECTS

 Neural plate deepens in the center to create the neural groove that is bound on both
sides by neural folds.
 The folds fuse to create a neural tube which is connected to the amniotic cavity by
openings at the ends called anterior and posterior neuropores.
 These openings close during the 4th week of fetal life.
 Failure of the neuropores to close leads to the formation of neural tube defects (NTDs) 
persistent connection between amniotic cavity and spinal canal.
 Failure of the caudal neuropore to close  spina bifida.
 Failure of the rostral (cranial) neuropore  anencephaly (complete absence of
the brain).
 ↑ α-fetoprotein (AFP) in amniotic fluid and maternal serum (except spina bifda occulta
= normal AFP). (AFP also increases in any body wall defect)
 ↑ Acetylcholinesterase (AChE) in amniotic fluid is a helpful confirmatory test.
 Associated with maternal diabetes as well as low folic acid intake before conception
and during pregnancy.
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 Folic acid antagonists (anti-epileptic drugs, trimethoprim) during pregnancy are

risk factors for neural tube defects.
SPINA BIFDA OCCULTA
 Failure of caudal neuropore to close, but no herniation.

 Spinal tube fails to induce bone to form vertebral arch  missing spinous processes
(bony defect).
 Usually seen at lower vertebral levels. Dura is intact.
 Associated with tuft of hair or skin dimple at level of bony defect.
 Normal AchE & AFP.
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SPINA BIFIDA CYSTICA
 ↑ AFP (there is a body wall defect) + normal AChE (neural tissue is not exposed
outside).
MENINGOCELE
 Meninges (but no neural tissue) herniate through bony defect.
MENINGOMYELOCELE
 Meninges and neural tissue (eg, cauda equina) herniate through bony defect.
 Almost always has Chiari II malformation.
 Hydrocephalus major cause morbidity (Obstruction 4th ventricular outflow due to
compression by cerebellar herniation in Chiari II).
MYELOSCHISIS
 Also known as rachischisis.

 Exposed unfused neural tissue without skin/meningeal covering.
 ↑ AFP + ↑ AChE.
ANENCEPHALY
 Failure of rostral (anterior or cranial) neuropore to

close  no forebrain, open calvarium.
 'frog-like' appearance of the fetus.
 ↑ AFP + ↑ AChE.
 Associated with maternal polyhydramnios (fetal
swallowing of amniotic fluid is impaired).
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HOLOPROSENCEPHALY
 Embryology:
 Failure of left and right hemispheres to separate.
 Usually occurs during weeks 5–6.
 Etiology:
 Genetic:
o May be related to mutations in sonic hedgehog signaling pathway.
o Seen in trisomy 13.
 Environmental:
o Fetal alcohol syndrome.
 Clinical features: range of phenotypic findings:
 Mild: closely set eyes (hypotolerism), cleft lip/palate.
 Severe: single midline eye (cyclopia), primitive nasal
structure (proboscis), midfacial clefts.
 Imaging:
 MRI A reveals monoventricle and fusion of basal ganglia
(star in A).
UW: It is an example of a congenital malformation.
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POSTERIOR FOSSA MALFORMATIONS
CHIARI I MALFORMATION
 Ectopia of cerebellar tonsils (1 structure) A.
 Congenital, usually asymptomatic in childhood, manifests in adulthood with headaches
and cerebellar symptoms.
 Associated with spinal cavitations (eg, syringomyelia).
CHIARI II MALFORMATION
 Herniation of low-lying cerebellar vermis and tonsils (2 structures) through foramen
magnum with aqueductal stenosis  hydrocephalus.
 Usually associated with lumbosacral meningomyelocele (may present as
paralysis/sensory loss at and below the level of the lesion).
DANDY-WALKER SYNDROME
 Failure of foramen Luscka and Magendie to open  dilated 4th ventricle.

 Agenesis of cerebellar vermis leads to cystic enlargement of 4th ventricle (arrow in B)
that fills the enlarged posterior fossa.
 Associated with:
 Noncommunicating hydrocephalus:
 Due to atresia of the foramina of Luschka and Magendie.
 Resulting in symptoms of elevated intracranial pressure (eg, irritability,
vomiting).
 Spina bifida.
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Red arrow  agenesis of

cerebellar vermis.
Blue arrow  cystic dilation

of the fourth ventricle with
posterior fossa enlargement
SYRINGOMYELIA
 Cystic cavity (syrinx) within central canal of spinal cord (yellow arrows in A).
Syrinx = tube, as in syringe.
 Most common at C8–T1  affecting the upper limbs.
 Fibers crossing in anterior white commissure (spinothalamic tract) are typically
damaged first.
1. Results in a “cape-like,” bilateral symmetrical loss of pain and temperature
sensation in upper extremities.
2. Fine touch sensation is preserved as it runs in the posterior column).
 Associated with Chiari malformations (red arrow shows low-lying cerebellar tonsils in
A) and other congenital malformations; acquired causes include trauma and tumors.
 Syrinx expansion results in involvement of other spinal tracts leading to:
1. Muscle atrophy and weakness with decreased muscle tone and impaired reflexes-
due to damage to lower motor neurons of the anterior horn cells.
2. Horner syndrome with ptosis (droopy eyelid), miosis (constricted pupil), and
anhidrosis (decreased sweating) due to disruption of the lateral horn cells of the
hypothalamospinal tract.
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TONGUE DEVELOPMENT
 Anterior 2/3
 From 1st and 2nd branchial arches.
 Thus sensation via CN V3, taste via CN VII.
 Posterior 1/3
 From 3rd and 4th branchial arches form
 Thus sensation and taste mainly via CN IX, extreme
posterior via CN X.
 Motor innervation is via:
 CN XII to hyoglossus (retracts and depresses tongue), genioglossus (protrudes
tongue), and styloglossus (draws sides of tongue upward to create a trough for
swallowing).
 CN X to palatoglossus (elevates posterior tongue during swallowing).
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ANATOMY AND PHYSIOLOGY

CNS
cells
Non-neurons =
Neurons
glial cells
macroglial microglial
ependymal
Astrocytes oligodendrocytes
GLIAL CELLS
 Support neurons.
 Gliosis:
 Proliferation/hypertrophy of glial cells.
 Reaction to CNS injury.
 Astrocytes undergo major changes.
 Glioma:
 Neoplasms of glial origin (astrocytomas, ependymomas, and
oligodendrogliomas).
 Stain positive for GFAP.
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NEURONS
 Signal-transmitting cells of the nervous
system.
 Permanent cells—do not divide in
adulthood.
 Signal-relaying cells with
 dendrites (receive input)
 Cell bodies and axons (send
output).
 Cell bodies and dendrites can be seen on Nissl staining (stains RER).
 RER is not present in the axon.
 Injury to axon  Wallerian degeneration:
 Occurs in the segment of axon that has lost connection with the cell body.
 Degeneration of axon and myelin distal to a point of injury.
 Within a week the axon is destroyed and its fragments are digested by
Schwann cells and macrophages.
 Similar degenerative changes occur in the segment of axon that lies
proximal to the injury. Degeneration of the proximal segment extends to the
closest node of Ranvier.
 Allows for potential regeneration of axon (if in PNS).
 UW: Axonal regeneration does not occur in the central nervous system due to
the persistence of myelin debris, secretion of neuronal inhibitory factors,
and development of dense glial scarring.
 Macrophages remove debris and myelin.
 UW: CNS tumors of neuronal origin frequently stain positively for synaptophysin
on immunohistology.
 Synaptophysin is a protein found in the presynaptic vesicles of neurons,
neuroendocrine and neuroectodermal cells.
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 UW: In the peripheral nervous system:

 Schwann cells sense the axonal degeneration and begin to degrade
their myelin and secrete cytokines and chemokines that recruit
macrophages.
 This allows effective clearance of myelin debris which, along with
trophic factor secretion by Schwann cells, stimulates formation of a
growth cone from the stump of the proximal axon and facilitates
nerve regeneration.
 In the central nervous system:
 Phagocytic macrophages/microglia are recruited more slowly
because of the blood-brain barrier.
 Myelin-producing oligodendrocytes also become inactive or
undergo apoptosis and do not assist with phagocytosis.
 This slows removal of the myelin debris, which can persist for
years in the degenerating tracts and suppress axonal growth via
myelin-associated inhibitory factors.
 Astrocytes also release inhibitory molecules and proliferate in the
weeks to months following injury, forming a glial scar that acts as a
barrier to axon regeneration.
NEURON ACTION POTENT IALS

 Resting Membrane Potential:
 Difference in charges across the cell membrane at rest.
 Prevents free diffusion of ions.
 Typically an excess of positive ions outside cell, excess of negative ions
inside, giving rise to electrical potential difference that ranges from -60 to -
80 mV (typically -70 mV).
 Caused by:
 Efflux of K+ (high conductance, EK = -80 mV) = leak of K+.
 With some influx of Na+ (low conductance, ENa = +60 mV).
 Potential maintained by Na+/K+-ATPase.
 Cl- contributes little to resting membrane potential
 To depolarize:
 Na channels open  allows Na into cell and raises voltage.
 Na channels open along axon propagation.
 At axon terminal, Ca channels open  Triggers release of neurotransmitter
 Vesicles fuse with membrane exocytosis.
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CLINICAL RELEVANCE
 Agents that block Na channels will inhibit signals  inhibits depolarization.
 Example: Local anesthetics:
 Lidocaine, Benzocaine, Tetracaine, Cocaine, etc.
 Some neurotoxins block Na channels:
AXONAL TRANSPORT
 Kinesin and dynein are microtubular motor proteins responsible for rapid axonal
transport.
 Kinesin participates in anterograde transport,
 i.e. moving intracellular vesicles and organelles toward the plus (rapidly growing)
ends of microtubules.
 Anterograde transport is usually directed away from the nucleus, down the axon,
toward the nerve terminal.
 Dynein participates in retrograde transport.
 i.e. moving organelles toward the nucleus.
 Dynein also functions in ciliary and flagellar movement.
 These two motor proteins derive energy for movement from ATP hydrolysis.
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ASTROCYTES
 Most common glial cell type in CNS.
 Functions:
1. Physical support, repair.
2. Extracellular K+ buffer.
3. Removal of excess neurotransmitter.
4. Component of blood-brain barrier.
5. Glycogen fuel reserve buffer.
 Reactive gliosis (hypertrophy and hyperplasia) in response to neural injury.
 Derived from neuroectoderm.
 Astrocyte marker: GFAP ―glial fibrillary acid protein‖.
CLINICAL RELEVANCE
 Astrocytoma:
1. Cerebellum of children.
2. GFAP positive.
 JC Virus infects astrocytes and oligodendrocytes  Causes PML in HIV patients.
MICROGLIA
 CNS macrophages:
 Phagocytic scavenger cells  clean up injured areas.
 Mesodermal, mononuclear origin.
 Activated in response to tissue damage.
 Not readily discernible by Nissl stain.
 HIV can persist in the brain via microglia.
 HIV-infected microglia fuse to form multinucleated giant cells
in CNS.
EPENDYMAL CELLS
 Glial cells with a ciliated simple columnar form that line the ventricles and central canal
of spinal cord.
 Apical surfaces are covered in cilia (which circulate CSF) and microvilli (which help in
CSF absorption).
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MYELIN
 Increases SPEED of impulse propagation in axon.
 Saltatory conduction:
1. At the nodes of Ranvier, where there are high concentrations of Na+ channels.
 allow the depolarization to jump from node to node.
2. Only need to depolarize Nodes of Ranvier.
3. Do not need to depolarize entire axon.
4. This makes process faster.
5. ↑ Conduction velocity.
6. ↑ Length constant = space constant:
 A measure of how long the depolarization signal can
propagate.
 Demyelination  ↓ length constant due to increased
charge dissipation along a nerve axon.
7. ↓ Time constant:
 The time it takes for a change in membrane potential to achieve 63% of
the new value.
 Lower time constants allow quicker changes in membrane potential, thus
increasing axonal conduction speed.
 Demyelination would increase the time constant and lead to slower
impulse conduction.
 Synthesis of myelin by:
1. Oligodendrocytes in CNS (including CN I and II)
2. Schwann cells in PNS (including CN III-XII).
COPS: CNS = Oligodendrocytes, PNS = Schwann cells.
 Wraps and insulates axons (arrow in A): ↑ space constant and ↑ conduction velocity.
What are the Nodes of Ranvier?

They are areas of discontinuation of the myelin.
What voltage gated channels are concentrated in the nodes of Ranvier?

Voltage-gated Na channels.
What is the function of these channels?

Provide salutatory conduction  speeding up postconduction.
What happen to these channels in individuals with demyelinating disease?

They will not be concentrated in the nodes of ranvier, but they will spread all over the axon 
slow down the impulse conduction.
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SCHWANN CELLS
o Each Schwann cell myelinates only 1 PNS axon.
o Also promote axonal regeneration.
o Derived from neural crest.
o Injured in Guillain-Barré syndrome.
OLIGODENDROCYTES
 Myelinates axons of neurons in CNS. The optic nerve is the only
cranial nerve that is myelinated by oligodendrocytes; so it is
affected in MS.
 Each oligodendrocyte can myelinate many axons (∼ 30).
 Predominant type of glial cell in white matter.
o Derived from neuroectoderm.
 “Fried egg” appearance histologically.
 Injured in multiple sclerosis, progressive multifocal leukoencephalopathy (PML),
leukodystrophies.
TYPES OF NERVE FIBER S

 Classification by diameter, myelin:
1. A-alpha:
 Large, myelinated fibers, 6 to 15 microns diameter Large.
 Most efferent motor fibers.
 Touch, vibration, and position.
2. A-delta (δ):
 Small, myelinated fibers, 3 to 5 microns in diameter.
 Cold, pain.
3. C fibers:
 Unmyelinated fibers, 0.5 to 2 microns in diameter.
 Warm, pain.
 These small fibers are more easily blocked by local anesthetics.
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SENSORY RECEPTORS
Receptor Sensory neuron fiber type Location Senses

type
Free nerve  C—slow, unmyelinated  All skin, Pain, temperature.
endings fibers epidermis
 Aδ—fAst, myelinated  Some viscera
fibers
Meissner  Large, myelinated fibers.  Glabrous Dynamic, fine/light
corpuscles  Adapt quickly. (hairless) skin touch, position sense
Pacinian  Large, myelinated fibers.  Deep skin Vibration, pressure
corpuscles  Adapt quickly. layers,
ligaments, joints
Merkel  Large, myelinated fibers.  Finger tips Pressure, deep static
discs  Adapt slowly  Superficial skin touch (eg, shapes,
edges), position
sense
Ruffini  Dendritic endings with  Finger tips, Pressure, slippage of
corpuscles capsule. joints objects along
 Adapt slowly. surface of skin, joint
angle change
PERIPHERAL NERVE
 Endoneurium:
 Invests single nerve fiber layers.
 Inflammatory infiltrate in Guillain-Barré syndrome.
 Perineurium (blood-nerve Permeability barrier)
 Surrounds a fascicle of nerve fibers.
 Must be rejoined in microsurgery for limb reattachment.
 Epineurium
 Dense connective tissue that surrounds entire nerve (fascicles and blood vessels).
 Endo = inner. Peri = around. Epi = outer.
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PERIPHERAL NERVE DAMAGE
 Mild: Neurapraxia:
 Focal demyelination.
 Axon distal to injury intact.
 Continuity across injury.
 Excellent recovery.
 Moderate: Axonotmesis:
 Demyelination plus damage to axon.
 Endoneurium, perineurium remain intact.
 Severe: Neurotmesis:
 Axon, myelin sheath irreversibly damaged.
 External continuity of the injured nerve disrupted.
 No significant regeneration occurs.
 Bad prognosis.
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AXONOTMESIS
 Distal to the lesion: ―Wallerian degeneration”.
 Axon degenerates, myelin sheath involutes.
 Axon regrowth sometimes occurs.
 Possible if Schwann cells maintain integrity.
 Proximal to the lesion: “Axonal reaction”
 The changes in the body of a neuron after the axon has been severed.
 Also called central chromatolysis.
 Up-regulation of protein synthesis for repair.
 Cell body changes:
 Swelling.
 Chromatolysis (disappearance of Nissl bodies).
 Nucleus moves to periphery.
 Resolves with time.
 Variable prognosis:
 Extent of damage, distance to target, complexity of nerve.
 Usually partial recovery.
 Longer recovery time than neurapraxia.
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CENTRAL NERVE DAMAGE
ISCHEMIA
 ~ 4-5 minutes of ischemia  irreversible damage.

 Neurons more sensitive than glial cells.
 Higher energy demands; lack glycogen.
 Most sensitive neurons: • Hippocampus • Purkinje cells (Cerebellum) •
Neocortex
• Striatum (Basal ganglia).
CHANGES AFTER INFARCTION
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NEUROTRANSMITTERS
NOREPINEPHRINE
 Stress/panic hormone.
 Increased levels in anxiety.
 Decreased levels in depression.
 Some antidepressants ↑NE levels (eg, SNRIs).
 Its main source is locus ceruleus (in the posterior pons near 4th ventricle).
DOPAMINE
 Synthesized in:
 Ventral tegmentum (midbrain)
 Substantia nigra (midbrain)
 Increased levels in schizophrenia.
 Decreased levels in Parkinson’s and depression.
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GABA
 GABA is largely inhibitory.

 Synthesized in nucleus accumbens (subcortex).
 Important for pleasure/reward.
 Research shows that it is activated in:
o Drug addiction.
o Fear.
 Decreased levels in anxiety and Huntington’s disease.
 GABA Receptor Anesthetics:
 Etomidate, Propofol, Benzodiazepines, Barbiturates.
 These drugs activate receptor  sedation.
 GABA Receptor:
 GABA binds to receptor allows Cl- into cell  more negative membrane
potential (hyperpolarization)  make it harder to get depolarized 
decreases the neuronal excitation  inhibitory.
 GABA Synthesis:
 Synthesized via glutamate decarboxylase in neurons.
 Broken down by GABA transaminase.
 Both enzymes need B6 cofactor.
o B6 deficiency  seizures.
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SEROTONIN
 Synthesized in raphe nucleus (pons).

 Decreased levels in anxiety & depression.
SEROTONIN SYNDROME
 Can occur any drug that that ↑serotonin (SSRIs, MAO inhibitors, SNRis, TCAs).
 Classically triad:
1. Mental status changes:
 Anxiety, delirium, restlessness, and disorientation.
2. Autonomic hyperactivity:
 Diaphoresis, tachycardia, hyperthermia.
3. Neuromuscular abnormalities:
 Tremor, clonus, hyperreflexia, bilateral Babinski sign.
 Watch for patient on anti-depressants with fever, confusion, and rigid muscles.
 Don’t confuse with NMS “neuroleptic malignant syndrome”
 Both: muscle rigidity, fever, changes in mental status, and autonomic
instability.
 NMS: ―Lead pipe‖ rigidity, ↑CK.
 SS: Clonus.
 Treatment: cyproheptadine (5 –HT antagonist).
ACETYLCHOLINE
 Synthesized in basal nucleus of Meynert (subcortex).

 Increased levels in REM sleep.
 Decreased levels in Alzheimer’s & Huntington’s disease.
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GLUTAMATE
 Major excitatory neurotransmitter.

 N-methyl-D-aspartate (NMDA) receptor is target.
 Huntington’s: neuronal death from glutamate toxicity:
 Glutamate binds NMDA receptor.
 Excessive influx calcium  Cell death.
PHENCYCLIDINE (PCP) (ANGEL DUST)

 Antagonist to NMDA receptor.
 Violent behavior.
 Hallucinations.
 Ataxia, nystagmus.
 Hypertension, tachycardia, diaphoresis.
 Can cause seizures, coma, or death.
NEUROTRANSMITTER CHANGES WITH DISEASE
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MENINGES
 Three membranes that surround and protect the brain and spinal cord:
1. Dura mater
 Thick outer layer closest to skull.
 Derived from mesoderm.
2. Arachnoid mater
 Middle layer, contains web-like connections.
 Derived from neural crest.
3. Pia mater
 Thin, fibrous inner layer that firmly adheres to brain and spinal cord.
 Derived from neural crest.
 CSF flows in the subarachnoid space, located between arachnoid and pia mater.
 Epidural space—a potential space between the dura mater and skull containing fat and
blood vessels.
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BLOOD-BRAIN BARRIER
 Prevents circulating blood substances (eg, bacteria, drugs) from reaching the CSF/ CNS.
 Formed by 3 structures:
1. Tight junctions between nonfenestrated capillary endothelial cells.
2. Basement membrane.
3. Astrocyte foot processes.
 Which substances to pass? :
1. Glucose and amino acids cross slowly by carrier-mediated transport
mechanisms.
2. Nonpolar/lipid-soluble substances cross rapidly via diffusion.
 A few specialized brain regions with fenestrated capillaries and no blood-brain barrier
allow molecules in blood to affect brain function
1. Area postrema ―Chemoreceptor trigger zone‖
 Caudal end of 4th ventricle in medulla.
 Chemo agents affect this area.
 Sends signals to vomiting center in the medulla vomiting after chemo.
2. OVLT [organum vasculosum lamina terminalis]
 Osmotic sensing.
 Anterior wall of the third ventricle.
3. Median Eminence of Hypothalamus:
 Releases hormones into vascular system to pituitary.
 Allows hypothalamus to regulate pituitary.
4. Posterior Pituitary Gland:
 Oxytocin, ADH secretion.
5. Pineal Gland:
 Melatonin.
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 Infarction and/or neoplasm destroys endothelial cell tight junctions  vasogenic edema.
 Other notable barriers include:
1. Blood-testis barrier.
2. Maternal-fetal blood barrier of placenta.
UW: Tight junctions between nonfenestrated capillary endothelial cells:

 Prevent the paracellular passage of fluid and solutes.
 This barrier only permits the passage of substances from the blood to the brain
via transcellular movement across the endothelial plasma membrane, which
is limited by
diffusion or carrier-mediated transport.
 Transcellular movement of dopamine is limited by the molecule's low lipid
solubility
and the lack of dopamine-specific transport carriers.
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VOMITING CENTER
 Coordinated by nucleus tractus solitarius (NTS) in the medulla, which receives
information from the chemoreceptor trigger zone (CTZ, located within area postrema in
4th ventricle), GI tract (via vagus nerve), vestibular system, and CNS.
 CTZ and adjacent vomiting center nuclei receive input from 5 major receptors:
muscarinic (M1), dopamine (D2), histamine (H1), serotonin (5-HT3), and neurokinin
(NK-1) receptors.
1. 5-HT3, D2, and NK-1 antagonists used to treat chemotherapy-induced
vomiting.
2. M1 and H1 antagonists used to treat motion sickness and hyperemesis
gravidarum.
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SLEEP PHYSIOLOGY
 Sleep cycle is regulated by the circadian rhythm, which is driven by suprachiasmatic
nucleus (SCN) of hypothalamus.
 Circadian rhythm controls nocturnal release of ACTH, prolactin, melatonin,
norepinephrine.
 SCN  norepinephrine release  pineal gland  melatonin.
 SCN is regulated by environment (eg, light).
 UW: Melatonin supplementation is recommended for the treatment of insomnia
associated with jet lag (Ramelteon).
 Two stages: rapid-eye movement (REM) and non-REM.
 Alcohol, benzodiazepines, and barbiturates are associated with ↓ REM sleep and
delta wave sleep.
 Norepinephrine also ↓ REM sleep.
 Benzodiazepines are useful for night terrors and sleepwalking by ↓ N3 and REM
sleep.
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CEREBRAL CORTEX REGIONS
FRONTAL LOBE
 Motor function (initiation of movements), planning movements, thinking, feeling,

imagining, making decisions.
 Key Areas: Motor cortex, Frontal Eye Fields, Broca’s speech area, Prefrontal Cortex.
PRIMARY MOTOR AREA:

 Site:
 Floor of central sulcus & posterior part of precentral gyrus.
 Function :
 Initiation of voluntary motor activity of the opposite side of the body
through the pyramidal (A) tract.
 In this area the body is represented upside down.
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 Lesion:
 Irritative:
o Contralateral motor Jacksonian fits: there are convulsions
involving the muscles of one side of the body.
o The fit has a focal onset either in the thumb, angle of the mouth or
big toe (depending on whether the irritative lesion starts in the
lower or upper part of the motor area).
o The fit spreads in a march course e.g. thumb  arm  shoulder 
trunk  L.L.
 Destructive: Contralateral paralysis usually affecting one limb
(monoplegia).
PREMOTOR AREA (AREA 6):

 Site: anterior part of the precentral gyrus.
 Function:
1. Partly supplies pyramidal tract.
2. Gives extra pyramidal fibers.
3. This area inhibits the muscle tone & the deep reflexes on the opposite
side of the body.
 Lesion:
1. Contralateral hypertonia & exaggerated deep reflexes.
2. Contralateral fanning of the lateral 4 toes on eliciting the plantar reflex
 positive babiniski.
FRONTAL EYE FIELDS

 Site: posterior part of middle frontal gyrus.
 Function:
 Voluntary conjugate eye movement to the opposite side.
 e.g. while reading the action of passing from the end of one line
to the beginning of the next line; this movement is usually rapid
& is termed "saccadic."
 Lesion:
 Irritative: attacks of conjugate eye deviation to the opposite side of the
lesion.
 Destructive: both eyes deviate to side of lesion.
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BROCA’S SPEECH AREA

 Site: posterior part of inferior frontal gyrus of DOMINANT hemisphere
 Function:
 Speech production (not comprehension).
 Moves muscles for speech (motor center for speech).
 Makes speech clear, fluent.
 Responsible for all communicative motor planning (lesion  difficulty
writing and signing).
 Lesion:
 Destruction “expressive” aphasia:
o Know what you want to say but cannot express speech.
o Short sentences, stutters, stops.
o Watch for “broken” speech: stuttering, stop/start.
 DD: Wernicke’s aphasia:
 Located in temporal lobe – LEFT hemisphere.
 Speech comprehension (not production).
 Destruction ―fluent‖ aphasia. Fluent, but meaningless speech.
 Watch for LACK of stutters, starts/stops (unlike Broca’s aphasia).
 DD: Global Aphasia
 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 (right Hemiparesis, right
visual loss).
EXNER'S AREA (AREA 45) :

 Site: adjacent to the Broca’s area in the DOMINANT hemisphere.
 Function: center for writing.
 Lesion: agraphia; the patient cannot express his ideas in written words.
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PREFRONTAL CORTEX
 Site: Anterior 2/3 of frontal lobe.
 Functions:
1. Higher center for mentality, personality & behavior.
2. Inhibition of primitive reflexes which are present normally in the
newborn.
 Lesion:
1. Mentality, personality & behavioral changes: lack of attention &
judgment, disinterest in people & surroundings, lack of personal hygiene,
ending in dementia.
2. Reappearance of primitive reflexes.
PARACENTRAL LOBULE:
 Site: medial surface of the superior frontal gyrus, adjacent to the foot & leg area.
 Function: cortical inhibition (control) of bladder & bowel voiding.
 Lesion: incontinence of urine & faeces.
PARIETAL LOBES
PRIMARY SOMATOSENSORY AREA:

 Site: post-central gyrus.
 Function:
 Perception of cortical sensations from the opposite side of the body; like in
the motor area, the body is represented upside down.
 Lesion:
 Irritative:
o Contralateral sensory Jacksonian fits in the form of numbness or
tingling with focal onset & a march course.
o It may be followed by a motor fit if the irritation extends to the
adjacent motor area.
 Destructive: contralateral cortical sensory loss.
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ANGULAR GYRUS:
 Site: in the postero-inferior part of the parietal lobe.
 Function:
 In the DOMINANT hemisphere, it is concerned with reading i.e. the
recognition & recall of letters & numbers.
 Lesion:
 Alexia; the patient who could read before the lesion, becomes unable to do
so, because he cannot understand the letters &
numbers which he sees.
BAUM’S LOOP:
 Part of visual pathway.
 Damage: Quadrantic Anopia.
 Damage to right (non-dominant) parietal lobe: spatial neglect:

 Contralateral (left) agnosia.
 Can’t perceive objects in part of space.
 Despite normal vision, somatic sensation is impaired.
 Failure to report or respond to stimuli affected side.
TEMPORAL LOBE
PRIMARY AUDITORY CORTEX:

 Site: superior temporal gyrus.
 Function: auditory sensory area.
 Lesion:
 Irritative: auditory hallucinations.
 Destructive: Slight hearing impairment, never deafness as hearing is
bilaterally represented.
AUDITORY ASSOCIATIVE AREA:

 Site: adjacent to areas primary auditory cortex.
 Function: recognition & recall of sounds.
 Lesion: Auditory agnosia: the patient hears but does not understand (recognize)
what he hears.
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WERNICKE’S SPEECH AR EA:

 Lesions  Wernicke’s aphasia.
 UW: The middle cerebral artery supplies Broca's area (superior division) and
Wernicke's area (inferior division).
OLFACTORY BULB:
 Destruction ipsilateral anosmia.
 Psychomotor epilepsy:
 Sights, sounds, smells that are not there.
 Can result from irritation olfactory bulb.
 Part of temporal lobe epilepsy ―commonly with HSV encephalitis‖.
 Rare, olfactory groove meningiomas:
 About 10% of all meningiomas.
 Cause anosmia.
MEYER’S LOOP:
 Part of the visual pathway.
HIPPOCAMPUS:
 Very sensitive to hypoxic damage.
 Lesion:
 Anterograde amnesia: Cannot make new memories.
 Can be damaged by infarction in:
 Hippocampal branches PCA.
 Anterior choroidal arteries.
AMYGDALA:
 Temporal lobe nuclei. Part of limbic system.
 Important for decision making, higher functions.
 Kluver-Bucy Syndrome
 Damage to bilateral amygdala (temporal lobes).
 Hyperphagia - Weight gain.
 Hyperorality - tendency to examine all with mouth.
 Inappropriate Sexual Behavior (hypersexuality)
o Atypical sexual behavior, mounting inanimate objects.
 Visual Agnosia:
o Inability to recognize visually presented objects.
 Rare complication of HSV1 encephalitis.
Page 34 of 235
OCCIPITAL LOBE
 Visual Sensory Area: for the reception of visual images.

 Visual Associative Area:
 Function:
1. Recognition & recall of images.
2. Center for reflex conjugate eye movement to the opposite side e.g. while
reading, following the words of a line, one after the other; this movement
is usually slow & is termed "pursuit."
 Lesion to the visual areas results in:
 Irritative: Unformed visual hallucinations e.g. sparks, lines, flashes ...; this
occurs e.g. in the aura of classic migraine or in epilepsy when the occipital lobe is
involved.
 Destructive:
 Cortical blindness  Homonymous Hemianopsia with macular
sparing.
o Dual blood supply to the macula: MCA and PCA.
o PCA strokes often spare the
macula..
 Visual Agnosia: the patient sees
(e.g. a familiar face) but does not
recognize what he sees.
 Paralysis of reflex conjugate eye movements.
 Blood supply PCA.
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HOMUNCULUS
 Topographic representation of motor (shown) and sensory areas in the cerebral cortex.
 Distorted appearance is due to certain body regions being more richly innervated and thus
having ↑ cortical representation.
MCA: Upper limb, face.

ACA: Lower limb.
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MOTOR SYSTEM
 The motor system consists of 4 main components:
THE PYRAMIDAL SYSTEM (U.M.N.):

 It originates in the primary motor area & premotor area.
 Terminates at the anterior horn cells (A.H.C.) of the different levels of the spinal cord.
 It supplies the opposite side of the body.
THE EXTRAPYRAMIDAL (EXTRA A) SYSTEM:

 It originates from centers situated at various levels of C.N.S. mainly the Basal Ganglia.
 It controls the opposite side of the body.
THE CEREBELLAR SYSTEM:

 It is composed of the Neo, Archi & Paleo-cerebellum.
 It coordinates the movements of the same side of the body.
THE LOWER MOTOR NEURON (L.M.N.)

 It is formed of A.H.C. s & peripheral motor nerves (which transmit the motor impulses to
the voluntary muscles).
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UPPER MOTOR NEURONS VS LOWER MOTOR NEURONS
DECUSSATION
 UMN cross just below medulla.

 Lesions above decussation  contralateral
dysfunction.
 Lesions below decussation  ipsilateral
dysfunction.
BULBAR
 Bulbar muscles are supplied by CN in brainstem •

V (jaw), VII (face), IX (swallowing), X (palate),
XI (head), XII (tongue).
BULBAR VS. PSEUDOBULBAR

 Bulbar palsy
 Cranial nerve damage  LMN signs.
 Absent jaw/gag reflex.
 Tongue flaccid/wasted.
 Pseudobulbar palsy
 Corticobulbar tract damage  UMN
signs.
 Exaggerated gag reflex.
Page 38 of 235
CEREBRAL PERFUSION
 Brain perfusion relies on tight autoregulation.
 Cerebral perfusion is primarily driven by Pco 2 (Po2 also modulates perfusion in severe
hypoxia).
 Cerebral perfusion relies on a pressure gradient between mean arterial pressure (MAP)
and ICP.
 ↓ Blood pressure or ↑ ICP  ↑ cerebral perfusion pressure (CPP).
 Therapeutic hyperventilation  ↓ Pco2  vasoconstriction  ↓ cerebral blood flow
 ↓ intracranial pressure (ICP). May be used to treat acute cerebral edema (eg, 2° to
stroke) unresponsive to other interventions.
 CPP = MAP – ICP. If CPP = 0, there is no cerebral perfusion  brain death.
 Hypoxemia increases CPP only if Po 2 < 50 mm Hg.
 CPP is directly proportional to Pco 2 until Pco2 > 90 mm Hg.
CEREBRAL ARTERIES—CORTICAL DISTRIBUTION
Page 39 of 235
WATERSHED ZONES
 Sites:
 Cortical border zones:
 Between anterior cerebral/middle cerebral,
posterior cerebral/middle cerebral arteries
(blue areas in A).
 typically appear as bilateral wedge-shaped
strips of necrosis over the cerebral
convexity, parallel and adjacent to the
longitudinal cerebral fissure
 Internal border zones:
 Between the superficial and deep vascular
territories of the middle cerebral artery (red areas in A).
 Damage by severe hypotension.
 Symptoms of watershed area damage:
 If internal border zone stroke:
 Weakness of the shoulders and thighs.
 Sparing of the face, hands, and feet.
 Bilateral symptoms.
 A "man-in-a-barrel―
 If posterior cerebral/middle cerebral cortical border zone stroke:
 Higher order visual dysfunction.
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CIRCLE OF WILLIS
 System of anastomoses between anterior and posterior blood supplies to brain.
Page 41 of 235
A  basilar artery.
B & C  PCA.
D  superior cerebellar artery (SCA).
E  parapontine perforating artery.
F  anterior inferior cerebellar artery
(AICA).
VENTRICULAR SYSTEM
 Lateral ventricles  3rd ventricle via right and
left interventricular foramina of Monro.
 3rd ventricle  4th ventricle via cerebral aqueduct
of Sylvius.
 4th ventricle  subarachnoid space via:
 Foramina of Luschka = Lateral.
 Foramen of Magendie = Medial.
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CEREBROSPINAL FLUID (CSF)

 Made by ependymal cells of choroid plexus.
 Travels to subarachnoid space via foramina of Luschka and Magendie.
 Reabsorbed by arachnoid granulations.
 Then drains into dural venous sinuses.
HYDROCEPHALUS
 ↑ CSF volume  ventricular dilation +/- ↑ ICP.
COMMUNICATING
 Ventricles can communicate with each other.
COMMUNICATING HYDROCEPHALUS
 ↓ CSF absorption by arachnoid granulations  ↑ ICP.
 Usually due to arachnoid scarring post-meningitis or
subarachnoid/intraventricular hemorrhage.
 Presentation:
 Headache.
 Key sign: papilledema.
 CT Hallmark: Dilation ALL ventricles.
 Can cause herniation.
NORMAL PRESSURE HYDROCEPHALUS (NPH)

 Pathophysiology:
 Gradual decline in the reabsorptive capacity of the arachnoid villi, with
slow accumulation of CSF, is the root of the problem.
 Pressure remains normal in NPH because gradual ventricular distention
accommodates the CSF increase.
 Enlarged ventricles on imaging  Compression
of corona radiate  triad:
 Urinary incontinence (urge
incontinence).
 Gait apraxia (magnetic gait).
 Cognitive dysfunction (sometimes
reversible). ―Wet, wobbly, and wacky‖.
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 Normal opening pressure on LP:

 CSF pressure elevated only episodically.
 Does not result in increased subarachnoid space volume.
 Gradual ventricular distention.
 Affects the elderly; idiopathic.
 Suspected mechanism: impaired absorption CSF.
 Treatment: Ventriculoperitoneal (VP) Shunt
 Drains CSF to abdomen.
 UW: Micturition reflex (urination) is regulated by the following centers:

1. Sacral micturition center - located in S2-S4 level and responsible for
bladder contraction. Parasympathetic fibers travel from S2-S4 ventral
white matter within pelvic nerves and stimulate cholinergic receptors in
the bladder wall.
2. Pontine micturition center - located in the pontine reticular formation.
It coordinates relaxation of external urethral sphincter with bladder
contraction during voiding.
3. Cerebral cortex - inhibits sacral micturition center.
NONCOMMUNICATING (OBSTRUCTIVE)
 Ventricles cannot communicate with each other’s.
NONCOMMUNICATING HYDROCEPHALUS
 Structural blockage of CSF flow within ventricles.
 Often congenital.
 Many etiologies:
 Aqueductal stenosis.
 Chiari Malformations.
 Dandy Walker malformation.
 Colloid cyst blocking foramen of Monro.
 Tumor B.
AQUEDUCTAL STENOSIS
 Blocked drainage from 3rd to 4th ventricle.
 Congenital narrowing (X-linked in boys)
 Inflammation due to intrauterine infection (eg, Rubella, CMV, toxo, syphilis)
 Presentation: Enlarging head circumference
Page 44 of 235
HYDROCEPHALUS MIMICS
 Ex vacuo ventriculomegaly
 Appearance of ↑ CSF on imaging C, but is
actually due to ↓ brain tissue and neuronal
atrophy (eg, Alzheimer disease, advanced HIV,
Pick disease, Huntington disease).
 ICP is normal; NPH triad is not seen.
 Dx: Increase size of ventricles:
o IN PROPORTION to increase size of sulci.
IDIOPATHIC INTRACRANIAL HYPERTENSION (IIH)

 Also known as pseudotumor cerebri.
 ↑ ICP with no apparent cause on imaging (eg, hydrocephalus, obstruction of CSF
outflow).
 Risk factors include female gender, Tetracyclines, Obesity, vitamin A excess,
Danazol (female TOAD).
 Symptoms:
o Intractable, disabling headache.
 Worse with lying flat and improves with standing.
o Pulsatile tinnitus:
 Rushing water or wind sound.
 Transmission of vascular pulsations.
o Diplopia (usually from CN VI palsy).
 Physical examination:
o Impaired optic nerve axoplasmic flow  papilledema.
o Visual field testing shows enlarged blind spot and peripheral constriction.
o No change in mental status.
 Lumbar puncture:
o ↑ Opening pressure (CSF pressure > 250 mmHg with normal analysis).
o Provides temporary headache relief.
 Treatment:
o Weight loss, acetazolamide, invasive procedures for refractory cases (eg,
CSF shunt
placement, optic nerve sheath fenestration surgery for visual loss).
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DURAL VENOUS SINUSES
 Large venous channels.

 Travel through dura.
 Drain blood from cerebral veins.
 Receive CSF from arachnoid granulations (superior sagittal sinus).
 Empty into internal jugular vein.
 Venous sinus thrombosis:
 Presents with signs/symptoms of ↑ ICP (eg, headache, seizures, focal neurologic
deficits).
 May lead to venous hemorrhage.
 Associated with hypercoagulable states (eg, pregnancy, OCP use, factor V
Leiden).
Page 46 of 235
CAVERNOUS SINUS
 Collection of venous sinuses on either side of pituitary.

 Bilateral, between temporal/sphenoid bones.
 Collects blood eye/cortex.
 Drains into internal jugular vein.
 Structures:
 Many nerves: CN III, IV, V1, V2, VI, sympathetic fibers (all traveling to orbit).
 Also portion of internal carotid artery
CAVERNOUS SINUS SYNDROME

 Causes:
 Compression by tumor (pituitary tumor), thrombus, fistula.
 Infections of face, nose, orbits, tonsils, and soft palate can spread to cavernous
sinus (septic thrombosis) through the
valveless veins.
 Carotid-cavernous fistula.
 Symptoms: ―CN VI is most susceptible to
injury.‖
 Headache.
 Swollen eyes.
 Impairment of ocular motor nerves
(ophthalmoplegia).
 Horner's syndrome.
 Sensory loss 1st/2nd divisions
trigeminal nerve.
Page 47 of 235
SUBCORTICAL STRUCTURES
Structures that lie between the cortex and the brain stem and include: (Thalamus,
Hypothalamus, Limbic System, Basal Ganglia).
You should be able to identify these structures anatomically and by imaging.
THALAMUS
 ―Gateway to the cortex‖  major relay for all ascending sensory information to the
cortex except olfaction.
 Epithalamus = pineal gland.
Page 48 of 235
 UW: Thalamic stroke  complete contralateral pure sensory loss (eg, touch,
pain/temperature, vibration/proprioception). Severe proprioceptive defects may cause
unsteady gait.
THALAMIC SYNDROME
 Neuropathic pain due to thalamic lesions. Occurs in 10% of stroke patients.
 Usually a lacunar stroke in the thalamus.
 Contralateral sensory loss:
 Face, arms, legs.
 All sensory modalities.
 Resolution can lead to long term chronic pain:
 Initial paresthesias followed in weeks to months by allodynia (ordinarily painless
stimuli cause pain) and dysesthesia “unpleasant, abnormal sense of touch‖.
 Contralateral side.
 Sensory exam normal.
 Severe pain in paroxysms or exacerbated by touch.
Page 49 of 235
HYPOTHALAMUS
 Maintains homeostasis by regulating:
1. Thirst and water balance.
2. Controlling Adenohypophysis (anterior pituitary) and Neurohypophysis (posterior
pituitary) release of hormones produced in the hypothalamus.
3. Regulating Hunger, Autonomic nervous system, Temperature, and Sexual urges
(TAN HATS).
 Inputs (areas not protected by blood-brain barrier):
1. OVLT (senses change in osmolarity).
2. Area postrema (found in medulla, responds to emetics).
Lateral nucleus  Hunger. Lateral injury makes you

 Destruction  anorexia, failure to Lean.
thrive (infants).
 Stimulated by ghrelin, inhibited
by leptin.
Ventromedial  Satiety. VentroMedial injury makes
nucleus  Destruction (eg, you Very Massive.
craniopharyngioma) 
hyperphagia.
 Stimulated by leptin.
Anterior  Cooling. Anterior nucleus = cool off
nucleus  Parasympathetic (VD to cool). (cooling, pArasympathetic).
A/C = anterior cooling.
Posterior  Heating. Heating controlled by
nucleus  Sympathetic (VC to heat). Posterior hypothalamus (―Hot
Pot‖). If you zap your
posterior hypothalamus, you
become a poikilotherm (cold-
blooded, like a snake).
Suprachiasmatic  Circadian rhythm. You need sleep to be
nucleus charismatic (chiasmatic).
Supraoptic and  Synthesize ADH and oxytocin. ADH and oxytocin are carried
paraventricular by neurophysins down axons
nuclei to posterior pituitary, where
these hormones are stored and
released.
Preoptic nucleus  Thermoregulation, sexual
behavior.
 Releases GnRH.
 Failure of GnRH-producing
neurons to migrate from olfactory
pit  Kallmann syndrome.
Page 50 of 235
HYPOTHALAMIC SYNDROME
 Diabetes insipidus (loss of ADH).
 Fatigue (loss of CRH low cortisol).
 Obesity.
 Loss of temperature regulation.
LIMBIC SYSTEM
 Collection of neural structures involved in emotion, long-term memory, olfaction,
behavior modulation, ANS function.
 Consists of hippocampus (red arrows in A), amygdalae, mammillary bodies, anterior
thalamic nuclei, cingulate gyrus (yellow arrows in A), entorhinal cortex.
 Responsible for Feeding, Fleeing, Fighting, Feeling, and Sex.
Page 51 of 235
A  fornix
B  mammillary body
C  pons
D  thalamus
E  inferior colliculus
Page 52 of 235
WERNICKE-KORSAKOFF SYNDROME
 Wernicke: Acute encephalopathy.
 Korsakoff: Chronic neurologic condition.
 Usually a consequence of Wernicke.
 Both associated with:
 Thiamine (B1) deficiency from alcoholism.
 Macroscopic:
 Atrophy of mammillary bodies (emotion and memory) common finding.
 Associated with damage to thalamic nuclei (anterior and dorsomedial).
 Triad Wernicke:
 Confusion.
 Gait ataxia. Wernicke precipitated by
 Visual disturbances/nystagmus. glucose without thiamine:
 Often reversible with thiamine.
 Korsakoff: Amnesia: • Thiamine co-factor glucose
 Recent memory affected more than metabolism (pyruvate
remote. dehydrogenase enzyme).
 Can’t form new memories.
• Alcoholic or malnourished
 Confabulation: Can’t remember so make
patients should receive
things up.
 Lack of interest or concern. intravenous thiamine
 Personality changes. supplementation before
 Usually permanent. intravenous dextrose
administration because giving
dextrose without prior thiamine
can precipitate a Wernicke
encephalopathy.
Page 53 of 235
DOPAMINERGIC PATHWAYS
 Commonly altered by drugs (eg, antipsychotics) and movement disorders (eg, Parkinson
disease).
Pathway Symptoms of Altered activity Notes

Mesocortical ↓ Activity  ―negative‖ symptoms Antipsychotic drugs have
(eg, anergia, apathy, lack of limited effect.
spontaneity).
Mesolimbic ↑ Activity  ―positive‖ symptoms (eg, 1° therapeutic target of
delusions, hallucinations). antipsychotic drugs  ↓
positive symptoms (eg, in
schizophrenia).
Nigrostriatal ↓ Activity  extrapyramidal Major dopaminergic pathway
symptoms (eg, dystonia, akathisia, in brain.
parkinsonism, tardive dyskinesia). Significantly affected by
movement disorders
and antipsychotic drugs.
Tuberoinfundibular ↓ Activity  ↑ prolactin  ↓ libido,
sexual dysfunction, galactorrhea,
gynecomastia (in men).
Page 54 of 235
CEREBELLUM
 Function:
 Posture/ balance.
 Muscle tone.
 Coordinates movement.
CEREBELLAR PEDUNCLES
 In and Out Pathways.
Page 55 of 235
INFERIOR CEREBELLAR PEDUNCLE

 Major pathway INTO cerebellum from spine.
 Numerous inputs: Spinocerebellar tract, Cuneocerebellar tract, Olivocerebellar
tract, Vestibulocerebellar tract.
 Ipsilateral spinal cord information: proprioception from spinal cord.
MIDDLE CEREBELLAR PEDUNCLE

 Pontocerebellar tract fibers.
 Fibers from contralateral pons.
SUPERIOR CEREBELLAR PEDUNCLE

 Major pathway OUT of cerebellum.
 Axons from deep cerebellar nuclei.
 All outputs originate from deep nuclei.
 Fibers to red nucleus and thalamus to modulate the cortical movement.
PURKINJE CELLS
 Cerebellar neurons.
 Receive numerous inputs.
 Project to deep nuclei.
 Inhibitory  Release GABA.
DEEP NUCLEI
Deep nuclei (lateral  medial)—

Dentate, Emboliform, Globose,
Fastigial.
Don’t Eat Greasy Foods.
 Projections OUT of cerebellum.
Page 56 of 235
 Dentate nucleus:
 The most important & the most lateral.
 Projects to contralateral VA/VL nuclei of thalamus to modify the movements.
 The same projection as the basal ganglia.
 Interposed nuclei: globose/emboliform
 To contralateral red nucleus.
 Fastigial:
 To vestibular nuclei and reticular formation
CEREBELLUM INPUT:
 Contralateral cortex via middle cerebellar peduncle.

 Ipsilateral proprioceptive information via inferior cerebellar peduncle from spinal cord.
CEREBELLUM OUTPUT:
 The only output of cerebellar cortex = Purkinje cells (always inhibitory)  deep nuclei
of cerebellum  contralateral cortex via superior cerebellar peduncle.
CEREBELLUM CONTROL
 In general, cerebellum controls IPSILATERAL side.

 Cerebellar fibers contralateral cortex.
 Contralateral cortex contralateral arm/leg.
 Crosses twice.
 Also right proprioception right cerebellum.
 Result:
 Left cerebellar lesion  left symptoms.
 Right cerebellar lesion  right symptoms.
Page 57 of 235
CEREBELLUM LESIONS
Lateral lesions Midline lesions

 Cerebellar hemispheres  Vermis.
 Dentate nucleus  Emboliform, globus and fastigial
nuclei.
 Floculonodular lobe.
 Affect extremities  Affect trunk
 Fall toward injured (ipsilateral)  Truncal ataxia
side.  Widebased gait.
 Dysmetria.  Can’t stand independently.
 Intention tremor.  Falls over when sitting.
 Lesion in the vermis.
 Nystagmus, vertigo.
 Lesion in Floculonodular
lobe.
ROMBERG TEST
 Test for sensory (not cerebellar) ataxia.
 Loss of proprioception: compensate though vision.
 How? 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.
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OTHER CEREBELLAR SYMPTOMS

 Hypotonia:
 Loss of muscle resistance to passive manipulation.
 Loose-jointed, floppy joints.
 Scanning speech:
 Spoken words are broken up into separate syllables, often separated by a
noticeable pause, and spoken with varying force.
 ―How are you doing?‖  ―How…are…you…do…ing‖
 It is also a typical symptom of multiple sclerosis.
 Dyssynergia: Loss of coordinated activity:
 Dysmetria:
 Loss of movement coordination.
 Under or over-shoot intended position of hand.
 Intention tremor:
 Can’t get hand to target.
 Contrast with resting tremor (Parkinson’s).
 Dysdiadochokinesia:
 Can’t make movements exhibiting a rapid change of motion.
 Can’t flip hand in palm.
 Nystagmus:
 Up/down beat (vertical), Gaze-evoked.
 Nausea/vomiting.
 Vertigo (central).
CEREBELLAR STROKES
 Affect any of the blood supply of the cerebellum (SCA, AICA, PICA).
 Often has other brainstem stroke signs/symptoms.
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HEREDITARY ATAXIAS
 Motor incoordination related to cerebellum.

 Ataxia Telangiectasia & Friedreich's Ataxia.
ATAXIA TELANGIECTASIA:
 Autosomal recessive cerebellar atrophy.
 Ataxia in 1st year of life.
 Telangiectasias:
 Dilation of capillary vessels on skin.
 Ears, nose, face, and neck.
 Severe immunodeficiency (IgA deficiency)  Repeated sinus/respiratory
infections.
 High risk of cancer.
 Cause: DNA hypersensitivity to ionizing radiation:
 Defective ATM gene (Ataxia Telangiectasia Mutated) on chromosome 11:
 Function of ATM gene:
 Repairs double stranded DNA breaks.
 Nonhomologous end-joining (NHEJ).
 Mutation of ATM gene: Failure to repair DNA mutations.
 Lab Abnormalities:
 ↑ AFP
 Often elevated in pregnant women.
 Also elevated in ataxia telangiectasia. Most consistent lab finding.
 Dysgammaglobulinemia
 Low or absent IgA.
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FRIEDREICH ATAXIA
 Autosomal recessive.
 Mutation of frataxin gene chromosome 9:
 Needed for normal mitochondrial function.
 Increased number of trinucleotide (GAA) repeats present.
 More repeats = worse prognosis.
 Leads to decreased frataxin levels.
 Frataxin: mitochondrial protein (iron binding protein):
 High levels in brain, heart, and pancreas.
 Abnormal frataxin  mitochondrial dysfunction.
 Cerebellar and spinal cord degeneration:
 Degeneration of spinocerebellar tract  Ataxia (staggering gait),
dysarthria.
 Loss dorsal columns  Position/vibration.
 Loss of corticospinal tract  spastic paralysis in lower extremity.
 Loss of dorsal root ganglia  loss of DTRs.
 Other Features:
 Hypertrophic cardiomyopathy (cause of death).
 Diabetes:
 Insulin resistance and impaired insulin release.
 Beta cell dysfunction.
 Kyphoscoliosis.
 Foot abnormalities (pes cavus):
 High arch of foot; does not flatten with weight bearing.
 Seen in other neuromuscular diseases (Charcot-Marie-Tooth)
 Staggering gait, frequent falling, nystagmus, dysarthria, pes cavus, hammer toes,
diabetes mellitus, hypertrophic cardiomyopathy (cause of death).
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 Friedreich is Fratastic (frataxin): he’s your favorite frat brother, always staggering and
falling but has a sweet, big heart. Ataxic GAAit.
PARANEOPLASTIC CEREBELLAR DEGENERATION
 Autoimmune phenomenon results from immune reactions against tumor cells that cross-
react with normal cells (eg, purkinje cells of the cerebellum).
 Acute-onset rapid degeneration of the cerebellum.
 Most commonly associated with small cell lung cancer as well as breast, ovarian, and
uterine malignancies.
 Anti-Yo, anti-P/Q, and anti-Hu are the most common antibodies detected in the serum.
BASAL GANGLIA
Structures of basal
ganglia:
• Substantia Nigra
• Subthalamic nucleus
• Putamen
• Caudate nucleus
• Globus pallidus
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Basal Ganglia Terms
 Striatum = Putamen
(motor) + Caudate
(cognition)
o Also called striate
nucleus.
o Putamen/Caudate
divided by internal
capsule.
o Major INPUT from
cortex.
 Lentiform Nucleus =
Putamen + Globus Palidus.
UW: Wilson's disease can cause cystic degeneration of the putamen as well as damage to other basal ganglia
structures.
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 Function of basal ganglia:

 Modifies voluntary movements and makes postural adjustments.
 Receives cortex input.
 Provides feedback to cortex to either
• #1: Stimulate motor activity
• #2: Inhibit motor activity
 Combination stim/inhibition complex movements.
At rest, GPi and Pars Reticulata inhibit

the thalamus by GABA  inhibits
movements.
D1-Receptor = D1Rect pathway.

Indirect (D2) = Inhibitory.
 Direct (excitatory) pathway

 SNc input stimulates the striatum, stimulating the release of GABA, which
inhibits GABA release from the GPi, disinhibiting the thalamus via the GPi (↑
motion).
 Indirect (inhibitory) pathway
 SNc input stimulates the striatum, releasing GABA that disinhibits STN via GPe
inhibition, and STN stimulates GPi to inhibit the thalamus (↓ motion).
 Dopamine binds to
 D1  stimulating the excitatory pathway.
 D2  inhibiting the inhibitory pathway  ↑ motion.
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MOVEMENT DISORDERS
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UW: Nigrostriatal degeneration in Parkinson disease reduces activity of the thalamus

and its projections to the cortex, resulting in bradykinesia and rigidity.
Nigrostriatal degeneration  excessive excitation of the globus pallidus internus by the

subthalamic nucleus, which in turn causes excessive inhibition of the thalamus.
Patients with medically intractable symptoms of Parkinson disease may benefit from
high-frequency deep brain stimulation of the globus pallidus internus or subthalamic
nucleus as it promotes thalamo-cortical disinhibition with improved mobility.
INTERNAL CAPSULE
 The posterior limb:

 Separates the globus pallidus and putamen from the thalamus.
 Anterior two-thirds  corticospinal tract.
 Posterior one-third  contains sensory fibers (eg, thalamocortical tract).
 As well as visual and auditory fibers.
 The genu, or "knee"
 Carries corticobulbar fibers and part of the corticospinal fibers.
 The anterior limb:
 Separates the caudate nucleus from the globus pallidus and putamen
 Carries a portion of the thalamocortical fibers.
WILSON DISEASE
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BRAIN STEM
 It is formed of: 1. Midbrain 2. Pons 3. Medulla.

 It is connected to the cerebral hemispheres by 2 cerebral peduncles and to the cerebellum,
on each side, by the superior, middle & inferior cerebellar peduncles.
 It contains groups of nerve cells (gray matter) intermingled with several ascending and
descending fibers (white matter).
 The Motor nuclei of the Cranial Nerves are arranged in the Brain Stem as follows:
 Cr 3 & 4 in Midbrain.
 Cr 5, 6 & 7 in Pons.
 Cr 9, 10, 11 & 12 in Medulla.
 N.B. Cr 1 , 2 & 8 are sensory nerves concerned with special sensations, perceived
in special areas of the cerebral cortex.
 Cr 1 ,2 & 8 have no motor nuclei.
MIDBRAIN:
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BENEDIKT SYNDROME
 Due to occlusion of the perforating branch of PCA.
 Lesion in:
 CN 3  ipsilateral oculomotor palsy (down out gaze & dilated pupils).
 Medial Lemniscus  contralateral loss proprioception/vibration.
 Red nucleus  involuntary movements:
 Tremor
 Ataxia
WEBER’S SYNDROME
 Lesion in:
 CN3  ?!
 Corticospinal tract  contralateral hemiparesis.
 Corticobulbar tract  pseudobulbar palsy.
 UMN cranial nerve motor weakness
 Exaggerated gag reflex
 Tongue spastic (no wasting)
 Spastic dysarthria
PARINAUD’S SYNDROME
 Posterior midbrain.
 Often from pinealoma/germinoma of pineal region which can compress:
 Posterior midbrain (tectum)  Parinaud’s syndrome.
 Cerebral aqueduct  non-communicating hydrocephalus.
 Lesion in:
 Superior colliculus and pretectal area:
 Can’t look up (vertical gaze palsy).
 Pseudo Argyll Robertson pupil.
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UW: Pineal germinoma symptoms:
1. Precocious puberty may occur in males and is caused by β-hCG production

(histologically, germinomas are similar to testicular seminomas.)
2. Aqueductal compression by the tumor may lead to obstructive hydrocephalus.
3. Parinaud syndrome includes paralysis of upward gaze and of convergence - these
symptoms occur due to compression of the tectal area of the midbrain.
PONS
MEDIAL PONTINE SYNDROMES

 Lesion in:
 Corticospinal tract  contralateral hemiparesis.
 CN 6  lateral gaze palsy.
 CN 7  Facial weakness/droop affected side & loss of corneal reflex.
 MLF  lateral gaze palsy.
 PPRF  lateral gaze palsy.
LATERAL PONTINE SYNDROMES

 AICA stroke or cerebellopontine angle tumors (schwanoma).
 Lesion in:
 Vestibular nuclei  nystagmus, vertigo, N/V.
 Spinothalamic tract  contralateral pain/temp.
 Spinal V nucleus  ipsilateral face pain/temp.
 Sympathetic tract  Horner’s syndrome.
 Facial nucleus  ipsilateral facial droop & Loss corneal reflex.
 Cochlear nuclei  deafness.
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UW: The trigeminal nerve (CN V) exits the brainstem at the lateral aspect of the mid-pons at the level of the
middle cerebellar peduncles (a key neuro-anatomic landmark for locating the nerve).
Infarcts involving the anterior portion of the medial pons can affect:
o Corticospinal tract  contralateral hemiparesis, Babinski sign.
o Corticobulbar tract  contralateral lower facial palsy, dysarthria.
o Disruption of the corticopontine fibers (convey motor information from the cortex to the
ipsilateral pontine grey  middle cerebellar peduncle)  contralateral dysmetria
and dysdiadochokinesia (ataxic hemiparesis).
MEDULLA
MEDIAL MEDULLARY SYNDROME

 Anterior spinal artery stroke.
 Lesion in:
 Corticospinal  contralateral Hemiparesis.
 Medial lemniscus  contralateral loss of proprioception/vibration.
 CN 12  Flaccid paralysis tongue & Deviation to side of lesion.
LATERAL MEDULLARY SYNDROME

 Wallenberg's Syndrome.
 PICA Stroke.
 Lesion in:
 Vestibular nuclei: Nystagmus, vertigo, N/V.
 Sympathetic tract: Horner’s syndrome.
 Spinothalamic tract: Contralateral pain/temp.
 Spinal V nucleus: ipsilateral face pain/temp.
 Nucleus ambiguous (IX, X): Hoarseness, dysphagia.
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A  supracellar region.
B  Thalamus.
C  posterior midbrain (tectum).
D  Midbrain.
E  Pons.
HOW TO FIND LESIONS

 Option 1: Know the syndromes
 Option 2: Use the Rule of 4s
RULE OF 4
 4 CNs in:
 Medulla
 Pons
 Above Pons
 4 CNs divide into 12:
 III, IV, VI, XII
 Motor nuclei are midline
 4 CNs do not divide/12:
 V, VII, IX, XI
 All are lateral
 4 Midline columns:
 Motor nucleus
 Motor pathway
 MLF
 Medial Lemniscus
 4 lateral (side)columns:
 Sympathetic
 Spinothalamic
 Sensory nucleus of CN5
 Spinocerebellar
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LOCALIZING LESIONS
 Medial vs. Lateral
 Which tracts affected?
 Medulla vs. Pons vs. Midbrain
 Which cranial nerves affected?
CRANIAL NERVE LESION (HINTS)
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RULE OF 4 CAVEATS
 Trigeminal Nerve (V)
 Lesion: loss of ipsilateral pain/temp face
 Rule of 4 Pons Nuclei and side (lateral tract)
 Don’t use to localize to Pons (extends in pons and medulla)
 Use for lateral tract localization
 Vestibulocochlear (VIII)
 Don’t use vestibular sings to localize to pons
 Vestibular signs can be medulla/pons
 Lesion: hearing loss used to be in the pons.
Case: 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. On tongue protrusion, the tongue is
deviated to the right. He in unable to detect lower or upper extremity vibration on the left.
 Complete motor weakness.

o Not MCA or ACA stroke
 Tongue involved: brainstem lesion
 Motor pathway involved – left side weak
o Right medial lesion
 Medial lemniscus involved left (vibration/prop)
o Right medial lesion
 CN XII involved – tongue deviation
o Medulla
 Answer: Right medial medullary syndrome
 Anterior spinal artery
BRAINSTEM BLOOD SUPPLY
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VENTRAL VIEW
4 CN are above pons (I, II, III, IV).
4 CN exit the pons (V, VI, VII, VIII).
4 CN are in medulla (IX, X, XI, XII).
4 CN nuclei are medial (III, IV, VI, XII).
―Factors of 12, except 1 and 2.‖
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DORSAL VIEW
 Pineal gland—melatonin secretion, circadian rhythms.

 Superior colliculi—direct eye movements to stimuli (noise/movements) or objects of
interest.
 Inferior colliculi—auditory.
 Your eyes are above your ears, and the superior colliculus (visual) is above the inferior
colliculus (auditory).
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UW: Acoustic neuromas (schwanoma):
 Commonly located at the cerebellopontine angle.

 Arise from cranial nerve (CN) VIII.
 Presentation:
 Ipsilateral sensorineural hearing loss/tinnitus and vertigo (CN VIII).
 Loss of facial sensation (CN V).
 Facial paresis (CN VII).
 Bilateral acoustic neuromas are associated with neurofibromatosis type 2.
CRANIAL NERVE NUCLEI

 Located in tegmentum portion of brain stem (between dorsal and ventral portions):
 Midbrain—nuclei of CN III, IV
 Pons—nuclei of CN V, VI, VII, VIII
 Medulla—nuclei of CN IX, X, XII
 Spinal cord—nucleus of CN XI
 Lateral nuclei = sensory (aLar plate). —Sulcus limitans—
Medial nuclei = Motor (basal plate).
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CRANIAL NERVE AND VESSEL PATHWAYS
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UW: Jugular foramen (Vernet) syndrome:
 Lesions due to tumors, trauma, or infection.

 Characterized by CN IX, X, and XI dysfunction.
 Symptoms are related to the nerve affected:
 Loss of taste from the posterior 1/3 of the tongue (CN IX).
 Loss of gag reflex (CN IX, X).
 Dysphagia (CN IX, X).
 Dysphonia/hoarseness (CN X).
 Soft palate drop with deviation of the uvula toward the normal side (CN X).
 Sternocleidomastoid and trapezius muscle paresis (CN XI).
CRANIAL NERVES
Nerve Function Type Mnemonic

1- Olfactory  Smell (only CN without thalamic relay Sensory Some
to cortex)
2- Optic  Sight. Sensory Say
 Not really a peripheral nerve (arises from
diencephalon)
3- Oculomotor  Eye movement (SR, IR, MR, IO). Motor Marry
 Pupillary constriction (sphincter
pupillae: Edinger-Westphal nucleus,
muscarinic receptors)
 Accommodation.
 Eyelid opening (levator palpebrae).
 Palsy: eye down, out, pupil dilated,
ptosis.
4- Trochlear  Eye movement (Superior Oblique) Motor Money
 Turns eye down/in (internally rotate).
 Reading/ down stairs.
 Palsy symptoms
 Vertical diplopia when to look
down/in (stairs, reading)
 Eye tilted outward
 Head tilting away from affected side
(to compensate)
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5- Trigeminal  Mastication (medial and lateral pterygoid, Both But

masseter, temporalis).
 Facial sensation (ophthalmic, maxillary,
mandibular divisions).
 Somatosensation from anterior 2/3 of
tongue.
 Part of corneal reflex (sensory, V1)
6- Abducens  Eye movement (LR) Motor My
7- Facial  Facial movement (motor to the face). Both Brother
 Eyelid closing (orbicularis oculi).
 Taste from anterior 2/3 of tongue (chorda
tympani)
 Lacrimation, salivation (submandibular
and sublingual glands are innervated by
CN seven)
 Auditory volume modulation (stapedius)
 hyperacusis.
8-  Hearing, balance. Sensory Says
Vestibulocochlear  Vestibular portion:
 Compensatory eye movements.
 Lesions: vertigo, nystagmus,
disequilibrium.
 Cochlear portion:
 Hearing
 Lesions: tinnitus, hearing loss.
9-  Exits the skull through jugular foramen. Both Big
Glossopharyngeal  Somatic motor:
 Stylopharyngeus muscle only
(elevates larynx during
swallowing).
 Parasympathetic:
 Inferior salivatory nucleus  CN
IX  otic ganglion  travels
along auriculotemporal nerve (CN
V)  parotid gland secretion.
 General sensory:
 Tympanic membrane (inner
surface), eustachian tube.
 Posterior third of tongue.
 Tonsillar region, upper pharynx
(afferent portion of gag reflex).
 Carotid body, and carotid sinus.
 Special sensory (taste):
 Posterior third of tongue.
Page 79 of 235
 Glossopharyngeal palsy:
 Loss of gag reflex.
 Loss of taste posterior 1/3 tongue.
 Loss sensation upper pharynx/tonsils.
 Hemodynamic effects:
 Tricks body into thinking
low BP.
 ↑ HR, Vasoconstriction, ↑
BP.
10- Vagus  Taste from supraglottic region. Both Brains
 Swallowing.
 Soft palate elevation.
 Midline uvula.
 Talking, cough reflex.
 Parasympathetic to thoracoabdominal
viscera.
 Monitoring aortic arch chemo- and
baroreceptors.
11- Accessory  Head turning. Motor Matter
 Shoulder shrugging (SCM, trapezius).
 Palsy:
 Difficulty turning head toward normal
side (SCM).
 Shoulder droop (affected side).
12- Hypoglossal  Tongue movement. Motor Most
 Palsy:
 Protrusion of tongue TOWARD
affected side.
 Opposite side pushes tongue away
unopposed.
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VAGAL NUCLEI
Nucleus Function Cranial nerves

Nucleus  Visceral Sensory information (eg, taste, VII, IX, X
Solitarius baroreceptors, gut distention)
Nucleus  Motor innervation of pharynx, larynx, upper IX, X, XI (cranial
aMbiguus esophagus (eg, swallowing, palate portion)
elevation)
Dorsal motor  Sends autonomic (parasympathetic) fibers X
nucleus to heart, lungs, upper GI
CRANIAL NERVE REFLEXES
CRANIAL NERVE SPEECH TEST
 “Kuh kuhkuh”  CN X  Raise palate.

 “Mi mi mi”  CN VII  Move lips.
 “La La La”  CN XII  Move tongue.
MASTICATION MUSCLES
 3 muscles close jaw: Masseter, teMporalis, Medial pterygoid.

 1 opens: Lateral pterygoid.
 M’s Munch. Lateral Lowers (when speaking of pterygoids with respect to jaw motion).
―It takes more muscle to keep your mouth shut.‖
 All are innervated by trigeminal nerve (V3 = mandibular).
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TEMPOROMANDIBULAR DISORDER (TMD)

 Constellation of symptoms:
 Unilateral facial pain that worsens with jaw movement.
 Headache, and ear discomfort.
 Pathophysiology:
 Temporomandibular joint (TMJ) derangement.
 Pathologic contraction of the muscles of mastication.
 Hypersensitivity of the nerves that supply the jaw.
 The involved nerve in TMD  mandibular nerve (V3)
 Motor: to TMJ muscles (mastication), tensor tympani in the middle ear.
 Sensory: TMJ and mandibular teeth as well as the floor of the mouth, inside of
the cheeks, anterior tongue, and much of the skin of the lower part of the face.
 As a result, patients with TMD involving the mandibular nerve can have both
jaw pain and otologic symptoms.
COMMON CRANIAL NERVE LESIONS
 CN V motor lesion:
 Jaw deviates toward side of lesion due to unopposed force from the opposite
pterygoid muscle.
 CN X lesion:
 Uvula deviates away from side of lesion. Weak side collapses and uvula points
away.
 CN XI lesion:
 Vulnerable to injury in the posterior triangle of the neck.
 Weakness turning head to contralateral side of lesion (SCM).
 Shoulder droop on side of lesion (trapezius).
 The left SCM contracts to help turn the head to the right.
 CN XII lesion:
 LMN lesion. Tongue deviates toward side of lesion (―lick your wounds‖) due to
weakened tongue muscles on affected side.
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DIABETIC CN III MONONEUROPATHY
 All ocular motor nerves (III, IV, VI)

can be affected in diabetes but
unilateral cranial nerve III involvement
is most common.
 It is caused by predominantly central
ischemia, which affects the somatic
nerve fibers but spares peripheral
parasympathetic fibers.
 Symptoms include ptosis, a ―down and
out gaze‖, and normal light and
accommodation reflexes.
 NB: pupillary dysfunction is often an
early manifestation of external nerve
compression due to injury of the
peripherally located parasympathetic
fibers (e,g, compression by PCom
aneurism).
Page 83 of 235
FACIAL NERVE LESIONS
 UMN damage (MCA Stroke)

 Upper face intact (dual supply).
 Lower face affected.
 LMN damage
 Whole half of face affected.
BELL’S PALSY:
 Idiopathic mononeuropathy of CN VII.
 The most common cause of peripheral facial palsy
A.
 Usually develops after HSV reactivation.
 Other causes of peripheral facial palsy include
Lyme disease, herpes zoster (Ramsay Hunt
syndrome), sarcoidosis, tumors (eg, parotid
gland), diabetes mellitus.
Page 84 of 235
 Treatment: corticosteroids ± acyclovir.

 Most patients gradually recover function, but aberrant regeneration can occur.
SPINAL NERVES
 There are 31 pairs of spinal nerves in total: 8 cervical, 12 thoracic, 5 lumbar, 5 sacral, 1
coccygeal.
 Nerves C1–C7 exit above the corresponding vertebra.
 C8 spinal nerve exits below C7 and above T1.
 All other nerves exit below (eg, C3 exits above the 3rd cervical vertebra; L2 exits below
the 2nd lumbar vertebra).
 Vertebral disc herniation:
 Nucleus pulposus (soft central disc) herniates through annulus fibrosus (outer
ring).
 Usually occurs posterolaterally at L4–L5 or L5–S1.
 Nerve usually affected is below the level of herniation (eg, L3–L4 disc spares L3
nerve and involves L4 nerve).
 Compression of S1 nerve root  absent ankle reflex.
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SPINAL CORD
LOWER EXTENT
 In adults, spinal cord ends at lower border of L1–L2 vertebrae.

 Subarachnoid space (which contains the CSF) extends to lower border of S2 vertebra.
 Lumbar puncture is usually performed between L3–L4 or L4–L5 (level of cauda
equina).
 Goal of lumbar puncture is to obtain sample of CSF without damaging spinal cord.
 To keep the cord alive, keep the spinal needle between L3 and L5.
SPINAL CORD LEVELS
The thoracic part is

characterized by the presence
of the lateral horn which
represents the cell bodies of
the sympathetic nerves.
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SPINAL CORD AND ASSOCIATED TRACTS
 Legs (Lumbosacral) are Lateral in Lateral corticospinal, spinothalamic tracts A.

 Dorsal columns are organized as you are, with hands at sides. ―Arms outside, legs
inside.‖
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SPINAL TRACT ANATOMY AND FUNCTIONS

 Ascending tracts synapse and then cross.
Tract Function 1st order neuron Synapse 1 2nd order Synapse 2 +

neuron projections
Ascending tracts
Dorsal Pressure, Sensory nerve Nucleus Decussates
column vibration, ending  bypass gracilis, in medulla
fine touch, pseudounipolar cell nucleus  ascends
proprioception body in dorsal root cuneatus contralaterally
ganglion  enter (ipsilateral as the medial
spinal cord  medulla) Lemniscus.
ascend ipsilaterally VPL
in dorsal columns. (thalamus)
Spinothalami Lateral: Sensory nerve Ipsilateral Decussates  sensory
c tract pain, ending (Aδ and C gray matter in spinal cortex
temperature fibers)  bypass (spinal cord) cord as the
Anterior: pseudounipolar cell anterior white
crude touch, body in dorsal root commissure
pressure. ganglion  enter  ascends
spinal cord. contralaterally.
Descending tracts
Lateral Voluntary UMN: cell body in Cell body of LMN: leaves NMJ 
corticospinal movement of 1° motor cortex  anterior spinal cord muscle
tract contralateral descends horn (spinal fibers
limbs. ipsilaterally cord)
(through posterior
limb of internal
capsule), most
fibers decussate at
caudal medulla
(pyramidal
decussation)
 descends
contralaterally.
Page 88 of 235
SPINOTHALAMIC TRACT
 Lateral: pain, temperature.

 Anterior: crude touch, pressure.
 1st Neuron: Spinal root to cord.
o Bypass pseudounipolar cell
body in dorsal root ganglion.
 2nd Neuron: Dorsal Horn to
Thalamus.
o Decussates in spinal cord as the
anterior white commissure
 ascends contralaterally.
o Crosses at the level that
sensory information enters the
spinal cord.
 3rd Neuron: VPL Thalamus to
Cortex.
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POSTERIOR COLUMN
 Dorsal Column-Medial Lemniscus

pathway.
 Vibration/proprioception/fine touch.
 1st Neuron: Spinal root up cord.
o Sensory nerve ending
(meissner’s and pacinian
corpuscles)  bypass
pseudounipolar cell body in
dorsal root ganglion  enter
spinal cord  ascend
ipsilaterally in dorsal columns.
nd
 2 Neuron: Gracilis (lower) Cuneatus
(upper).
o In ipsilateral medulla.
o Decussates in medulla 
ascends contralaterally as the
medial Lemniscus.
rd
 3 Neuron: VPL Thalamus to Cortex.
Page 90 of 235
CORTICOSPINAL TRACT
 Voluntary movement of contralateral

limbs.
 1st Neuron (UMN): Cortex to Anterior
Horn.
 Cell body in 1° motor cortex 
descends ipsilaterally (through
posterior limb of internal
capsule).
 Most fibers decussate at caudal
medulla (pyramidal
decussation)  descends
contralaterally.
 2nd Neuron (LMN): Anterior Horn to
muscle.
 Decussation in Lower Medulla.
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CLINICAL REFLEXES
 Reflexes count up in order (main nerve root bolded):
 Achilles reflex = S1, S2 (―buckle my shoe‖)
 Patellar reflex = L3, L4 (―kick the door‖)
 Biceps and brachioradialis reflexes = C5, C6 (―pick up
sticks‖)
 Triceps reflex = C7, C8 (―lay them straight‖)
 Additional reflexes:
Cremasteric reflex = L1, L2 (―testicles move‖)
Anal wink reflex = S3, S4 (―winks galore‖)
REFLEXES
 0 = No reflex
 1+ = diminished (LMN lesion).
 2+ = Normal.
 3+ = Brisk (UMN lesion).
 4+ = Very brisk.
 5+ = Sustained clonus.
NERVE ROOT SYNDROMES
BABINSKI SIGN
 Plantar Reflex.
 Rub bottom foot:
 Normal: downward  Plantar flexion.
 Abnormal: upward  Dorsiflexion ―positive Babinski sign‖.
 UMN damage.
 UMN suppress reflex.
 Upward = normal infants.
 <12mo.
 Incomplete myelination.
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 Lumbosacral radiculopathy:
Page 93 of 235
PRIMITIVE REFLEXES
 CNS reflexes that are present in a healthy infant, but are absent in a neurologically intact
adult.
 Normally disappear within 1st year of life.
 These ―primitive‖ reflexes are inhibited by a mature/ developing frontal lobe.
 They may reemerge in adults following frontal lobe lesions  loss of inhibition of these
reflexes.
Moro reflex ―Hang on for life‖ reflex—abduct/extend arms when startled, and then draw
together
Rooting reflex Movement of head toward one side if cheek or mouth is stroked (nipple
seeking)
Sucking reflex Sucking response when roof of mouth is touched
Palmar reflex Curling of fingers if palm is stroked
Plantar reflex Dorsiflexion of large toe and fanning of other toes with plantar stimulation
Babinski sign—presence of this reflex in an adult, which may signify a UMN
lesion
Galant reflex Stroking along one side of the spine while newborn is in ventral suspension
(face down) causes lateral flexion of lower body toward stimulated side.
LANDMARK DERMATOMES
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KEY SPINAL NERVES
PHRENIC NERVE
 C3-C5. < C three to C Five keeps your diaphragm aliFe  >

 Innervates diaphragm.
 Diaphragm irritation  ―referred‖ shoulder pain.
 Classic example is gallbladder disease  referred right shoulder pain.
 Also lower lung masses.
 Irritation can cause dyspnea and hiccups.
 Cut nerve  diaphragm elevation, dyspnea.
T10
 Umbilicus.
 Referred pain for appendicitis.
 UW: Atlantoaxial subluxation:

o Predisposing factor: chronic rheumatoid arthritis.
o Symptoms: Neck pain, stiffness, or neurological findings (eg. radicular pain).
o Endotracheal intubation with extension of the neck can worsen the
subluxation with possible acute compression of the spinal cord and/or vertebral
arteries.
 Patients can develop paralysis with decreased or absent reflexes below
the level of the compression (spinal shock), hypotension due to loss of
sympathetic tone, and/or sudden death.
―Please, take care when intubating RA patient!! You may kill him‖
Page 95 of 235
NEUROPATHOLOGY
COMMON BRAIN LESIONS
Area of lesion Consequence Examples/comments

Frontal lobe  Disinhibition and deficits in concentration,
orientation, judgment.
 May have reemergence of primitive reflexes.
Frontal eye  Eyes look toward (destructive) side of lesion.
fields  In seizures (irritative), eyes look away from side
of the lesion.
Paramedian  Eyes look away from side of lesion. Ipsilateral gaze palsy
pontine (inability to look toward
reticular side of lesion).
formation
Medial  Internuclear ophthalmoplegia (impaired Multiple sclerosis.
longitudinal adduction of ipsilateral eye; nystagmus of
fasciculus contralateral eye with abduction).
Dominant  Agraphia, acalculia, finger agnosia, left-right Gerstmann syndrome.
parietal disorientation.
cortex
Nondominant  Agnosia of the contralateral side of the world. Hemispatial neglect
parietal syndrome.
cortex
Hippocampus  Anterograde amnesia—inability to make new
(bilateral) memories.
Basal ganglia  May result in tremor at rest, chorea, and Parkinson disease,
athetosis. Huntington disease.
Subthalamic  Contralateral hemiballismus.
nucleus
Mammillary  Wernicke-Korsakoff syndrome—Confusion, Wernicke problems
bodies Ataxia, Nystagmus, Ophthalmoplegia, memory come in a CAN O’ beer.
(bilateral) loss (anterograde and retrograde amnesia),
confabulation, personality changes.
Amygdala  Klüver-Bucy syndrome—disinhibited behavior HSV-1 encephalitis.
(bilateral) (eg, hyperphagia, hypersexuality, hyperorality).
Dorsal  Parinaud syndrome—vertical gaze palsy, Stroke, hydrocephalus,
midbrain pupillary light-near dissociation, lid retraction, pinealoma.
convergence-retraction nystagmus.
Page 96 of 235
Reticular  Reduced levels of arousal and wakefulness (eg,

activating coma).
system
(midbrain)
Cerebellar  Intention tremor, limb ataxia, loss of balance; Cerebellar hemispheres
hemisphere damage to cerebellum  ipsilateral deficits; fall are laterally located—
toward side of lesion. affect lateral limbs.
Red nucleus  Decorticate (flexor) posturing: Worse prognosis with
 Lesion above red nucleus. decerebrate posturing.
 Presents with flexion of upper extremities
and extension of lower extremities.
 ―You point upwards toward your cortex,
the lesion is higher‖.
 Decerebrate (extensor) posturing:
 Lesion at or below red nucleus.
 Presents with extension of upper and
lower extremities.
Cerebellar  Truncal ataxia (wide-based, ―drunken sailor‖ Vermis is centrally
vermis gait), dysarthria. located—affects central
body.
Degeneration associated
with chronic alcohol
use.
Page 97 of 235
DECEREBRATE VS DECORTICATE POSTURING:
 Damage to the brainstem at/below the level of the red nucleus (eg, midbrain
tegmentum, pons) typically results in decerebrate (extensor) posturing. This is due to the
loss of descending excitation to the upper limb flexors (via the rubrospinal tract) and
predominance of the extensors (controlled by the vestibulospinal tract).
 Damage to neural structures above the red nucleus (eg, cerebral hemispheres) typically
results in decorticate (flexor) posturing due to loss of descending inhibition of the red
nucleus and subsequent
hyperactivity of upper- extremity flexor muscles.
Page 98 of 235
ISCHEMIC BRAIN DISEASE/STROKE

 Irreversible damage begins after 5 minutes of hypoxia.
 Most vulnerable: hippocampus, neocortex, cerebellum (Purkinje cells), watershed areas.
 Hippocampus is most vulnerable to ischemic hypoxia (―vulnerable hippos‖).
 Ischemia to the cortex involves the pyramidal neurons (layers 3,5,6) leading to
laminar necrosis.
 Irreversible neuronal injury.
 Stroke imaging: noncontrast CT to exclude hemorrhage (before tPA can be given).
 CT detects ischemic changes in 6–24 hr.
 Diffusion-weighted MRI can detect ischemia within 3–30 min.
ISCHEMIC STROKE
 Acute blockage of vessels  disruption of blood flow
and subsequent ischemia  liquefactive necrosis.
 3 types:
1. Thrombotic:
 Due to a clot forming directly at site of
infarction (commonly the MCA A).
 Usually over an atherosclerotic
plaque.
 Results in a pale infarct at the
periphery of the cortex.
2. Embolic:
 Embolus from another part of the body obstructs vessel.
 Can affect multiple vascular territories.
 Examples: atrial fibrillation, carotid artery stenosis, DVT with patent
foramen ovale.
 Results in a hemorrhagic infarct at the periphery of the cortex.
 This embolous can be easily lysed by the fibrinolytic system  blood
rush to cortex.
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3. Hypoxic:
 Due to hypoperfusion or hypoxemia.
 Common during cardiovascular surgeries, tends to affect watershed
areas.
 Treatment:
1. tPA (if within 3–4.5 hr of onset and no hemorrhage/risk of hemorrhage).
2. Reduce risk with medical therapy (eg, aspirin, clopidogrel)
3. Optimum control of blood pressure, blood sugars, lipids; and treat conditions that
increases risk (eg, atrial fibrillation, carotid artery stenosis).
TRANSIENT ISCHEMIC ATTACK

 Brief, reversible episode of focal neurologic dysfunction without acute
infarction (⊝ MRI), with the majority resolving in < 15 minutes; deficits due
to focal ischemia.
LACUNAR STROKES
 Anatomically small strokes associated
with HTN. Lacunae = Latin for ―empty
space‖.
 They are most often due to hypertensive
arteriolosclerosis of small, penetrating
arterioles.
 Also associated with DM, smoking.
 Stroke resolves and leaves lacunae in
brain.
 Pathophysiology:
 Substrate: arteriolar sclerosis (HTN).
 Proposed causes:
 Lipohyalinosis: small vessel
destruction, necrosis.
 Microatheroma: macrophages in
vessel.
 Noncortical infarcts  different from ACA,
MCA, PCA infarction:
 Lack ―cortical signs‖ ―Aphasia, agnosia,
or hemianopsia‖
 Common Locations:
 Internal capsule, thalamus, basal ganglia, pons.
Page 100 of 235
 Vessels:
 Lenticulostriate branches (MCA)
 Anterior choroidal artery (ICA)
 Recurrent artery of Heubner (ACA)
 Thalamoperforate branch (PCA)
 Paramedian branches (basilar artery)
 Types:
 In the acute setting, CT imaging may not show the expected hypodensity of ischemic
stroke due to the small infarct size (usually <15 mm). After several weeks, these necrotic
lesions turn into cavitary spaces filled with cerebrospinal fluid and surrounded by scar
tissue called lacunas.
Page 101 of 235
EFFECTS OF STROKES
Artery Area of lesion Symptoms Notes

Anterior circulation
Middle  Motor and sensory  Contralateral paralysis and Wernicke aphasia is
cerebral cortices A —upper sensory loss—face and upper associated with right
artery limb and face. limb. superior quadrant visual
 Temporal lobe  If left side (dominant) field defect due to
(Wernicke area);  Aphasia. temporal lobe
frontal lobe (Broca  If right side (non-dominant) involvement.
area).  Hemineglect.
Anterior  Motor and sensory  Contralateral paralysis and
cerebral cortices—lower sensory loss—lower limb.
artery limb.  If bilateral:
 Urinary incontinence.
Lenticulostriate  Striatum, internal  Pure motor weakness affecting Common location of
artery capsule. the contralateral arm, leg, and lacunar infarcts B, due
lower face. to hyaline
 Absence of cortical signs (eg, arteriosclerosis 2° to
neglect, aphasia, visual field unmanaged
loss). hypertension.
Posterior
circulation
Anterior  Lateral corticospinal  Contralateral paralysis—upper Medial medullary
spinal tract. and lower limbs. syndrome—
artery  Medial lemniscus.  ↓ Contralateral proprioception. caused by infarct of
 Caudal medulla—  Ipsilateral hypoglossal paramedian branches of
hypoglossal nerve. dysfunction (tongue deviates ASA and/or vertebral
ipsilaterally). arteries.
Posterior  Lateral medulla:  Dysphagia, hoarseness, ↓ gag Lateral medullary
inferior  Nucleus ambiguous reflex, hiccups. (Wallenberg)
cerebellar (CN IX, X, XI).  Vomiting, vertigo, nystagmus. syndrome.
artery  Vestibular nuclei.  ↓ Pain and temperature sensation Nucleus ambiguous
 Lateral spinothalamic from contralateral body, effects are specific to
tract. ipsilateral face. PICA lesions C. ―Don’t
 Spinal trigeminal  Ipsilateral Horner syndrome. pick a (PICA) horse
nucleus.  Ipsilateral ataxia, Dysmetria. (hoarseness) that can’t
 Sympathetic fibers eat (dysphagia).‖
 Inferior cerebellar Also supplies inferior
peduncle. cerebellar peduncle
(part of cerebellum).
Page 102 of 235
Anterior  Lateral pons:  Paralysis of face (LMN lesion vs Lateral pontine

inferior  Facial nucleus UMN lesion in cortical stroke). syndrome.
cerebellar  Vestibular nuclei  ↓ Lacrimation, ↓ salivation, ↓ Facial nucleus effects
artery (AICA)  Spinothalamic tract taste from anterior 2⁄3 of tongue. are specific to AICA
 Spinal trigeminal  Vomiting, vertigo, nystagmus. lesions.
nucleus.  ↓ Pain and temperature sensation ―Facial droop means
 Sympathetic fibers. from contralateral body, AICA’s pooped.‖
Also supplies middle
 Middle and inferior ipsilateral face.
cerebellar peduncles.  Ipsilateral Horner syndrome. and inferior cerebellar
 peduncles (part of
 Labyrinthine artery. Ataxia, Dysmetria.
cerebellum).
 Ipsilateral sensorineural deafness,
vertigo.
Basilar artery  Ventral pontine  RAS spared, therefore preserved Locked-in syndrome
syndrome. consciousness. (locked in the
 Pons, medulla, lower  Quadriplegia; loss of voluntary basement).
midbrain. facial, mouth, and tongue The patient can feel and
 Bilateral movements. see the world around
Corticospinal and  Loss of horizontal, but not him but cannot respond
corticobulbar tracts. vertical, eye movements (upper to it.
 Ocular cranial nerve brain stem intact)
nuclei, paramedian
pontine reticular
formation.
Posterior  Occipital lobe D  Contralateral hemianopia with
cerebral macular sparing; alexia without
artery agraphia (dominant hemisphere).
 Key points in vertebrobasilar stroke syndromes:
Page 103 of 235
INTRACRANIAL HEMORRHAGE
EPIDURAL HEMATOMA
 Rupture of middle meningeal artery (branch of maxillary artery).

 Often 2° to skull fracture (circle in A) involving the pterion (thinnest area of the lateral
skull).
 Lucid interval.
 Scalp hematoma (arrows in A) and rapid intracranial expansion (arrows in B) under
systemic arterial pressure  transtentorial herniation, CN III palsy.
 CT shows biconvex (lentiform), hyperdense blood collection B not crossing suture
lines.
SUBDURAL HEMATOMA
 Rupture of bridging veins.

 Venous bleeding is relatively slow, which explains the gradual onset of symptoms.
 Types:
 Acute (traumatic, high-energy impact  hyperdense on CT)
 Chronic (associated with mild trauma, cerebral atrophy, elderly, alcoholism 
hypodense on CT).
 Also seen in shaken babies.
 Predisposing factors: brain atrophy, trauma ―often in elderly individuals after a minor
trauma”.
 Crescent-shaped hemorrhage (red arrows in C and D) that crosses suture lines.
 Can cause midline shift (yellow arrow in C), findings of ―acute on chronic‖ hemorrhage
(blue arrows in D).
Page 104 of 235
SUBARACHNOID HEMORRHAGE
 Bleeding into space between arachnoid & pia mater E F.

 Causes:
 Rupture of saccular (berry) aneurysm E ―the most common cause‖.
 Usually occur at the circle of Willis, with the anterior communicating artery
being the most common site.
 Ehlers-Danlos syndrome and autosomal dominant polycystic kidney disease.
 Trauma.
 Arteriovenous malformation.
 Presentation:
 “Worst headache of my life”.
 Sudden onset symptoms.
 Fever, nuchal rigidity common.
 No focal deficits ―the bleeding is between the lobes of the brain‖!
 Diagnosis:
 CT without contrast (best initial test)  hyperdensity within the cistems/sulci.
 Bloody or yellow (xanthochromic due to bilirubin breakdown products) spinal
tap (most sensitive).
 If the CT scan does not show SAH, but the clinical suspicion remains high, a
lumbar puncture needs to be performed to evaluate the cerebrospinal fluid for the
presence of xanthochromia (blood in the CSF).
 Thus, presence of the xanthochromia in a clinical scenario suggestive of SAH is
the most sensitive test for diagnosing SAH.
Page 105 of 235
 Complications of SAH:
 Rebleeding (first 24 hours).
 Sudden development of a severe headache, severe nausea and vomiting, a
change in level of consciousness, and the appearance of new neurological
deficits.
 Identifiable by CT.
 Vasospasm (after 3 days):
 Due to blood breakdown  ischemic infarct.
 Presents as new-onset confusion and/or focal neurological deficit 4 -12
days after the initial insult.
 CT scan may fail to show vasospasm, so transcranial color Doppler is
needed.
 Nimodipine used to prevent/reduce vasospasm.
 Increased risk of developing communicating and/or obstructive hydrocephalus.
Page 106 of 235
INTRAPARENCHYMAL HEMORRHAGE
 Causes:
 Systemic hypertension (most common).
 Hypertensive hemorrhages (Charcot Bouchard microaneurysm) most often
occur in putamen of basal ganglia (lenticulostriate vessels G), followed by
thalamus, pons, and cerebellum H.
 Amyloid angiopathy (recurrent lobar hemorrhagic stroke in elderly).
 Vasculitis, neoplasm.
 May be 2º to reperfusion injury in ischemic stroke.
 Rupture cavernous hemangioma (UW).
Page 107 of 235
FETAL INTRAVENTRICUL AR HEMORRHAGE (GERMINAL MATRIX HEMORRHAGE)
 Germinal matrix is a dense cellular and vascular layer of subependymal zone from
which neurons and glial cells develop in utero.
 Begins to involute at 28 weeks gestation and is
absent by term.
 Unlike other parts of brain, its vascular network is
weak and lacks structural support, making it
vulnerable to spontaneous hemorrhage.
 Due to reduced glial fiber support and impaired
autoregulation of BP in premature infants.
 Hemorrhage begins between caudate nucleus and
thalamus, then extends into lateral, 3rd, and 4th ventricles.
 Presents with:
 Hydrocephalus (bulging fontanelle).
 Patient may be asymptomatic or develop seizures, altered mental status, and
apnea.
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ABUSIVE HEAD TRAUMA (AHT)
 Formerly known as "shaken baby syndrome.”

 Intracranial injury due to:
1. Blunt force trauma.
2. Vigorous shaking in a to-and-fro fashion.
 The resultant injuries are due to infants' unique anatomic features:
1. Infants have larger heads.
2. Enlarged subarachnoid spaces.
3. Higher brain water content.
4. Decreased cervical muscle tone compared to older children.
 Presentation:
1. Subdural hemorrhages:
 Due to tearing of the bridging veins.
 Due to movement of the immature brain in relation to the skull.
 Because AHT may occur repeatedly over weeks to months, acute on
chronic subdural hemorrhages are often seen.
2. Retinal hemorrhages:
 Due to rupture of congested retinal veins.
 Highly suggestive of AHT.
3. Posterior rib fractures:
 Infants' ribs are flexible and pliable.
 Trauma by a perpetrator's grasp on the torso.
Page 109 of 235
CEPHALOHEMATOMA
 Rupture of subperiosteal blood

vessels.
 May occur after a traumatic birth
(e.g. forceps or vacuum delivery).
 Presents as scalp swelling that
does not cross suture lines.
CEREBRAL AMYLOID ANGIOPATHY

1. β-amyloid deposition in the walls of small- to medium-sized cerebral arteries, resulting in
vessel wall weakening and predisposition to rupture.
2. The disease is not associated with systemic amyloidoses; rather, the amyloidogenic
proteins are usually the same as those seen in Alzheimer disease.
 Old age + recurrent lobar hemorrhage.
1. The most common cause of spontaneous lobar hemorrhage, particularly in adults age
>60.
2. Hemorrhage tends to be recurrent and most often involves the occipital and parietal
lobes.
Page 110 of 235
DIFFUSE AXONAL INJURY

 Caused by traumatic shearing forces during rapid acceleration and/or deceleration of
the brain (eg, motor vehicle accident).
 Usually results in devastating neurologic injury, often causing coma or persistent
vegetative state. A
 Shows multiple lesions (punctate hemorrhages) involving the white matter tracts.
Page 111 of 235
APHASIA
 Aphasia—higher-order language deficit (inability to understand/produce/use language
appropriately).
 Caused by pathology in dominant cerebral hemisphere (usually left).
 Dysarthria—motor inability to speak (movement deficit).
Type Speech Comprehension Comments

fluency
Repetition
impaired
Broca Nonfluent Intact  Broca = Broken Boca (boca = mouth
(expressive) in Spanish).
 Broca area in inferior frontal gyrus
of frontal lobe.
 Patient appears frustrated, insight
intact.
Wernicke Fluent Impaired  Wernicke is Wordy but makes no
(receptive) sense.
 Patients do not have insight.
 Wernicke area in superior temporal
gyrus of temporal lobe.
Conduction Fluent Intact  Can be caused by damage to arCuate
fasciculus.
Global Nonfluent Impaired  Arcuate fasciculus; Broca and
Wernicke areas affected (all areas).
Repetition
intact
Transcortical Nonfluent Intact  Affects frontal lobe around Broca
motor area, but Broca area is spared
ranscortical Fluent Impaired  Affects temporal lobe around
sensory Wernicke area, but Wernicke area is
spared.
Transcortical, Nonfluent Impaired  Broca and Wernicke areas and arcuate
mixed fasciculus remain intact; surrounding
watershed areas affected.
Page 112 of 235
Page 113 of 235
ANEURYSMS
 Abnormal dilation of an artery due to weakening of vessel wall.
SACCULAR (BERRY) ANEURYSM

 Occurs at bifurcations in the circle of
Willis.
 The blood vessels at the
bifurcations lack the medial layer.
 Most common site is junction of ACom
and ACA.
 Associated with ADPKD, Ehlers-
Danlos syndrome.
 Other risk factors: advanced age,
hypertension, smoking, race (↑ risk in
African-Americans).
 Usually clinically silent until rupture
(most common complication) leading to 
 Subarachnoid hemorrhage:
 ―Worst headache of my life‖ or ―thunderclap headache‖.
 Neuro symptoms are rare mostly headache.
 Focal neurologic deficits (hemorrhagic stroke based on the site of the
bleeding).
 Can also cause symptoms via direct compression of surrounding structures by
growing aneurysm.
 ACom:
 Compression  bitemporal hemianopia (compression of optic
chiasm); visual acuity deficits.
 Rupture  ischemia in ACA distribution  contralateral lower
extremity hemiparesis, sensory deficits.
 MCA:
 Rupture  ischemia in MCA distribution  contralateral upper
extremity and lower facial hemiparesis, sensory deficits.
 PCom:
 Compression  ipsilateral CN III palsy  mydriasis (―blown
pupil‖); may also see ptosis, ―down and out‖ eye.
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CHARCOT-BOUCHARD MICROANEURYSM:
 Common, associated with chronic hypertension.
 Affects small vessels (eg, lenticulostriate arteries in basal ganglia, thalamus)
and can cause lacunar strokes.
 Not visible on angiography.
Page 115 of 235
SEIZURES
 Characterized by synchronized, high-frequency neuronal firing. Variety of forms.
 Epilepsy—a disorder of recurrent seizures (febrile seizures are not epilepsy).
 Status epilepticus—continuous (≥ 5 min) or recurring seizures that may result in brain
injury.
CAUSES OF SEIZURES BY AGE:
 Genetic: Juvenile myoclonic epilepsy.

 Metabolic: Hyponatremia, hypernatremia, hypoMg, hypoCa.
 Infection: Meningoencephalitis.
TYPES OF SEIZURES:
Page 116 of 235
o Partial (focal) seizures usually affects medial temporal lobe.

o Atonic seizures
 ―Drop‖ seizures (falls to floor). Commonly mistaken for fainting.
 Loss of muscle tone Vs absence seizures  no loss of muscle tone.
JUVENILE MYOCLONIC EPILEPSY

 Common in children.
 Can be absence, myoclonic, or grand mal.
 Absence seizures first (~5 years of age).
 Myoclonic seizures later (~15 years).
 Grand mal seizures soon after.
 Hallmark:
 Myoclonic jerks on awakening from sleep.
 Shock-like, irregular movements of both arms.
AURAS
o Warning before major seizure.
o Auras = simple, partial seizures.
o Seizure affects enough brain to cause symptoms, not enough to interfere with
consciousness.
o Symptoms depend on area of brain:
 Occipital lobe: flashing lights.
 Motor cortex: muscle jerking (Jacksonian
Seizure).
Above 42.2 C (108 F), oxidative

phosphorylation ceases and
ATP becomes rapidly
depleted, leading to end-organ
damage.
Page 117 of 235
UW: Febrile seizures:
 The most common neurologic disorder affecting children and are benign sequelae of fever.
 Children who experience a febrile seizure are at risk for recurrence but have a low risk of
developing epilepsy.
 Antipyretics can improve patient comfort during fever but do not prevent future seizures.
HEADACHES
 Pain due to irritation of structures such as the dura, cranial nerves, or extracranial
structures.
 More common in females, except cluster headaches.
 Most common types of headache are tension, migraine, and cluster headaches.
TENSION HEADACHE:
 Bilateral.
 > 30 min (typically 4–6 hr); constant.
 Steady, “band-like” pain.
 No photophobia or phonophobia. No aura.
 Treatment: Analgesics, NSAIDs, acetaminophen; amitriptyline for chronic pain.
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MIGRAINE HEADACHE
 Characters:
 POUND–Pulsatile, Photophobia, Phonophobia, One-day duration,
Unilateral, Nausea, Disabling.
 4–72 hr.
 May have “aura”
 Gradual development of non-headache symptom.
 Patients will 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:
 Menstruation, stress, not eating.
 Mechanisms of pain:
 Still incompletely understood.
 Irritation of CNS structures is important:
 Trigeminal nerve (CNV), meninges, blood vessels.
 Activation of trigeminal nerve is important:
 Leads to release of vasoactive neuropeptides.
 Substance P, calcitonin gene-related peptide, neurokinin A.
 This results in neurogenic inflammation due to vasodilation and plasma
protein extravasation.
 Neuronal sensitization is important:
 Neurons increasingly responsive to stimuli.
 Triptans (eg, sumatriptan) are serotonin 5-HT1B/5-HT1D agonists that
directly counter the pathophysiologic mechanism of migraine headaches
by inhibiting the release of vasoactive peptides, promoting
vasoconstriction, inhibiting trigeminal nerve, and blocking pain pathways
in the brainstem.
 Treatment:
 Abortive Therapy:
 Triptans (sumatriptan): Contraindicated in CAD, Coronary
vasospasm (Prinzmetal’s angina).
 NSAIDs.
 Ergotamine:
o Vasoconstrictor.
o Before triptans, major migraine drug.
o Limited by overuse headache, gangrene.
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 Preventive Therapy:
 Lifestyle changes (eg, sleep, exercise, and diet).
 Topiramate:
o Very effective for migraine.
o Mental dulling/sedation.
o Paresthesias, weight LOSS.
o Kidney stones:
 Weak carbonic anhydrase inhibitor.
 Leads to more Ca in urine.
 Patients need to hydrate.
 Valproic Acid (Valproate)
o Anti-convulsant that blocks Na channels & increase GABA.
o GI distress, tremor.
o Hepatotoxicity (measure LFT's).
o Neural tube defects (spina bifida).
o Weight gain.
 Propranolol
o Non-selective beta blocker.
o Caution: COPD, Diabetes.
o Fatigue.
o Erectile dysfunction.
 Amitriptyline.
CLUSTER HEADACHE
 Unilateral.
 Lasts 30 minutes to 2 hours.
 Tends to occur around the same time each day on consecutive days for a period
of weeks.
 Often patients will have a pain-free interval of about a year between each series of
attacks.
 Excruciating periorbital pain (―suicide headache‖) with lacrimation and
rhinorrhea.
 May present with Horner syndrome.
 More common in males.
 Treatment:
 Acute: sumatriptan, 100% O2.
 Prophylaxis: verapamil.
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COMPARE WITH TRIGEMINAL NEURALGIA:

 Produces recurrent, unilateral, shooting pain in the distribution of CN
V.
 Triggered by chewing, talking, touching certain parts of the face.
 Lasts (typically) for seconds to minutes, but episodes often increase in
intensity and frequency over time.
 First-line therapy: carbamazepine.
 Other causes of headache include subarachnoid hemorrhage (―worst headache of my

life‖), meningitis, hydrocephalus, neoplasia, giant cell (temporal) arteritis. Lack of
papilledema very important.
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NEURODEGENERATIVE DISORDERS (DEMENTIA)
Dementia Delirium
 Chronic  Acute
 progressive cognitive decline  Waxing/waning
 Usually irreversible  Usually reversible
 Gradual decline in cognition.  Loss of focus/attention.
 No change in level of consciousness.  Disorganized thinking.
 Memory deficits.  Hallucinations (often visual).
 Impaired judgment.  Sleep-wake disturbance:
 Personality changes.  Up at night.
 Dementia Triad:  Sleeping during day.
1. Aphasia:
a. Inability to communicate effectively.
b. Forget words.
c. Can’t understand (may nod to pretend).
2. Apraxia:
a. Inability to do pre-programmed motor
tasks.
b. Can’t do their job.
c. Later: can’t do chewing, swallowing,
walking.
3. Agnosia:
a. Inability to correctly interpret senses.
b. Can’t recognize people.
c. Can’t interpret full bladder, pain.
 Causes:  Causes: (Usually secondary to
1. Alzheimer’s disease - 60% of cases. another cause)
2. Multi-infarct dementia (stroke) ~20% of cases. 1. Infection.
3. Lewy body dementia. 2. Alcohol.
4. Rare stuff: 3. Withdrawal.
a. Pick’s disease 4. Dementia patient in unknown
b. NPH setting:
c. Creutzfeldt-Jakob a. Classic scenario: demented
d. HIV patient with pneumonia.
e. Vitamin deficiencies
f. Wilson’s disease.
 Must rule out depression as cause of dementia
(known as pseudodementia).
 Normal EEG.  Abnormal EEG.
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COGNITIVE TESTING & RELATED DOMAINS (UW)
 By the use of Mini-Mental State Examination (MMSE).

 Point system. >=27 (out of 30) is normal.
Element Sample assessment metric

Orientation Providing name, location & current date.
Comprehension Following multistep commands.
Concentration = Reciting months of the year backwards.
attention Counting down from 100 by intervals of 3 or 7.
Spelling "world" backwards.
Short-term Recalling 3 unrelated words after 5 minutes.
memory
Long-term Providing details of significant life events.
memory
Language Writing a complete sentence containing at least one noun and verb.
Visual-spatial Drawing intersecting pentagons.
Executive Drawing a clock oriented to the time requested.
function
 In order to make a diagnosis of dementia, the patient must demonstrate:
1. Impairment across several cognitive domains during testing.
2. As well as functional impairment in activities of daily living.
ALZHEIMER DISEASE
 Epidemiology:
 Most common cause of dementia in elderly.
 Down syndrome patients have ↑ risk of developing Alzheimer disease,
as APP is located on chromosome 21.
 Degeneration of cortex:
 Generalized  no focal deficits.
 Loss of ACh cortical activity:
 This occurs due to the deficiency of choline acetyltransferase.
 The decline in acetylcholine levels is most notable in the basal nucleus
of Meynert and hipoocampus, which participates in memory and
cognition.
 This nucleus is located at the base of the forebrain and widely projects to
the neocortex.
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 Associated with the following altered proteins:

 ApoE-2: ↓ risk of sporadic form.
 ApoE-4: ↑ risk of sporadic form.
 APP, presenilin-1, presenilin-2: familial forms (10%) with earlier
onset.
 Alzheimer’s Brain:
 Widespread cortical atrophy (normal cortex B; cortex in Alzheimer
disease C), especially hippocampus (arrows in B and C).
 Narrowing of gyri and widening of sulci.
 Hydrocephalus ex vacuo  ventricles appear larger due to atrophy.
 Findings:
 Senile (neuritic) plaques D in gray matter:
Extracellular deposition of β-amyloid core.
Often found in the medial temporal lobe (eg, hippocampus, amygdala).
Composed of a central amyloid beta (Aβ) core surrounded by dystrophic
neurites.
 Abnormal accumulation of (Aβ) is toxic to neurons and is thought to
occur secondary to impaired clearance or overproduction of amyloid
precursor protein (APP).
 May cause amyloid angiopathy  intracranial hemorrhage.
 Amyloid is stained with apple-green birefringence when stained with
Congo red and viewed under polarized light.
 Neurofibrillary tangles E:
 Found in the neuronal cytoplasm (intracellular)
 Consist of aggregates of hyperphosphorylated tau protein, which
normally mediates microtubule stabilization.
 Hyperphosphorylated tau protein = insoluble cytoskeletal elements.
 Number of tangles correlates with degree of dementia.
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 Treatment:
 Enhanced cholinergic neurotransmission:
 Donepezil, a cholinesterase inhibitor.
 Improve cognition, behavior, and functioning in activities of daily
living.
 Although they do not appear to prevent the ultimate progression of
cerebral neurodegeneration.
 May delay institutionalization and mortality.
 Neuroprotection via antioxidants:
 Vitamin E (α-tocopherol).
 NMDA receptor antagonism:
 Memantine.
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VASCULAR DEMENTIA “MULTI-INFARCT DEMENTIA”

 2nd most common cause of dementia in elderly.
 Result of multiple arterial infarcts and/or chronic ischemia.
 Step-wise decline in cognitive ability with late onset memory impairment.
 MRI or CT shows multiple cortical and/or subcortical infarcts.
LEWY BODY DEMENTIA
 Lewy body:
o Protein alpha-synuclein.
o Its increase in basal ganglia  Parkinson’s.
o Its increase in cortex  LB dementia.
 Triad:
o Dementia.
 With fluctuating cognition/ alertness.
 REM sleep behavior disorder.
o Parkinsonism.
o Hallucinations.
 Visual hallucinations (―haLewycinations‖).
 Called Lewy body dementia if cognitive and motor symptom onset < 1 year apart,
otherwise considered dementia 2° to Parkinson disease.
 Intracellular Lewy bodies A primarily in cortex.
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FRONTOTEMPORAL DEMENTIA (PICK’S DISEASE)

 Degeneration of the frontal lobes that eventually progresses to include the temporal
lobes F.
 Characteristic symptoms include:
1. Early personality and behavioral changes:
 Disinhibition, apathy, social inappropriateness, compulsive behaviors.
2. Altered speech patterns:
 Paucity of speech, repeated phrases.
3. May have associated movement disorders (eg, Parkinsonism).
 Biopsy:
1. Inclusions of hyperphosphorylated tau (round Pick bodies G)
2. or ubiquitinated TDP-43.
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CREUTZFELDT-JAKOB DISEASE
 Rapidly progressive (weeks to months) dementia with
myoclonus (―startle myoclonus‖) and ataxia.
 Commonly see periodic sharp waves on EEG and ↑ 14-3-
3 protein in CSF.
 Prion protein (PrP) is normally found in neurons
and has an α-helical structure.
 If the conversion of α-helix into (β-pleated sheet
occurs, the protein becomes resistant to proteases.)
 Accumulation of this abnormal protein in gray matter is thought to cause prion
diseases.
 Affected gray matter undergoes spongiform change.
 Vacuoles form within the cytoplasm of neurons and neutrophils.
 Later they grow bigger and form cysts, involving larger areas of the brain
tissue.
 Microscopic:
 Multiple vacuoles are seen in the gray matter of the brain (spongiform
encephalopathy).
 Prions (PrPc  PrPsc sheet [β-pleated sheet resistant to proteases]) H.
 Transmission:
 CJD is a rare disorder that can be sporadic or infectious.
 Most of the transmitted cases are iatrogenic, seen in patients that received
contaminated corneal transplants, implantable electrodes or preparation of
growth hormone.
UW: All prion diseases have a number of common features:
1. They are associated with an abnormal prion protein (PrP). This protein is normally
present in host neurons. A change in its secondary structure renders it resistant to enzymatic
digestion by proteases and leads to its accumulation.
2. These diseases have long incubation periods. However, they are rapidly progressive after
the onset of clinical symptoms.
3. Characteristic morphologic changes in brain are described as spongiform encephalopathy.
Vacuoles form in the cytoplasm of the neutrophils and neurons. As the disease progresses,
the vacuolated areas transform into cysts. No inflammatory changes are present.
4. There is no treatment for prion diseases. These conditions are invariably fatal.
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HIV - ASSOCIATED DEMENTIA
1. Progressive cognitive decline.

2. Usually presents in patients with CD4 counts <200 cells/mm and drug noncompliance.
3. Patients typically have features of subcortical dementia (eg, attention/working memory
problems, executive dysfunction, slow information processing) as HIV affects primarily
the subcortical/deep gray matter structures.
4. The characteristic histopathology finding is microglial nodules, groups of activated
macrophages/microglial cells formed around small areas of necrosis that may fuse to
form multinucleated giant cells.
5. Neuronal damage is believed to occur from inflammatory cytokine release by
macrophages/microglial cells and the direct toxic effects of HIV-derived proteins.
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DEMYELINATING DISEASES
MULTIPLE SCLEROSIS
 Autoimmune destruction of CNS myelin ―brain & spinal cord‖ and oligodendrocytes:
1. Most common chronic CNS disease of young adults (20-30 years of age)
2. More commonly seen in women.
3. Associated with HLA-DR2.
4. More commonly seen in regions away from the equator.
 Lymphocytes react to myelin antigens.
 Secrete cytokines (interferon-gamma).
 Type IV hypersensitivity reaction.
 Clinical picture:
 Relapsing, remitting course (most commonly).
 Diverse neuro symptoms that come/go over time.
 Exacerbated with increased body temperature (eg, hot bath, exercise).
 Any neuro symptom possible.
 Few classic symptoms important to know:
 Fatigue is extremely common.
 Acute optic neuritis
o Painful unilateral visual loss.
o Associated with Marcus Gunn pupil.
 Bladder dysfunction
o Spastic bladder.
o Overflow incontinence.
 Brain stem/cerebellar syndromes:
o Diplopia, ataxia, scanning speech, intention tremor.
o Nystagmus/ internucleus ophthalmoplegia (bilateral > unilateral).
 Pyramidal tract weakness.
 Spinal cord syndromes:
o Electric shock-like sensation along spine on neck flexion [Lhermitte
phenomenon].
o Neurogenic bladder.
o Paraparesis, sensory manifestations affecting the trunk or one or more
extremity.
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 Findings
 Lumbar puncture:
 ↑ IgG level and myelin basic protein in
CSF.
 Oligoclonal bands of IgG are diagnostic.
 MRI:
 Periventricular plaques A (areas of
oligodendrocyte loss and reactive gliosis).
 Gold standard.
 Multiple white matter lesions disseminated in space and time.
 Visual evoked potentials:
 Used to assess conduction velocity, which slows in MS due to
demyelination of nerve fibers.
 Treatment:
 Stop relapses and halt/slow progression with disease-modifying therapies (eg, β-
interferon, glatiramer, natalizumab).
 Treat acute flares with IV steroids.
 Symptomatic treatment for:
 Neurogenic bladder  catheterization, muscarinic antagonists.
 Spasticity:
o Baclofen (skeletal ms relaxant ―GABAB receptor agonists‖)
o Tizanidine.
 Pain  TCAs, anticonvulsants.
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UW: Fatigue is the most common non-specific symptom of MS. Patients may feel
particularly fatigued after taking a hot shower or after strenuous activity in heated
environments. This is due to decreased axonal transmission associated with increased
heat. Heat exposure also may lead to episodes of worsening neurological deficits
(heat sensitivity).
UW: Polycythemia can cause pruritus when exposed to hot shower because of the
release of histamine from basophils.
ACUTE INFLAMMATORY D EMYELINATING POLYRADICULOPATHY
 Most common subtype of Guillain-Barre syndrome.

 Autoimmune condition associated with infections (eg, Campylobacter jejuni,
viruses [eg, Zika and CMV]) that destroys Schwann cells by inflammation and
demyelination of peripheral nerves (including cranial nerves III-XII) and motor
fibers likely.
 Due to molecular mimicry, inoculations, and stress, but no definitive link to
pathogens.
 Presentations:
 Ascending paralysis that starts a few weeks after a febrile illness:
 Symmetric, ascending, flaccid paralysis and areflexia beginning in lower
extremities.
 Facial paralysis (usually bilateral) and respiratory failure are common.
 Respiratory support is critical until recovery.
 Autonomic dysfunction (>70%)
 Tachycardia, arrhythmias.
 Urinary retention.
 Hypertension / hypotension.
 Ileus.
 Loss of sweating.
 Severe autonomic dysfunction can cause sudden cardiac death.
 Sensory deficits occur (paresthesias) but mild.
 Almost all patients survive; majority recover completely after weeks to months.
 Diagnosis:
 ↑ CSF protein with normal cell count (albuminocytologic dissociation).
 Microscopic:
 Demyelination is accompanied by an "endoneural inflammatory infiltrate"
consisting of lymphocytes and macrophages.
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 Treatment:
 Respiratory support.
 Disease-modifying treatment: plasmapheresis, IV immunoglobulins.
 No role for steroids.
OSMOTIC DEMYELINATION SYNDROME “CENTRAL PONTINE MYELINOLYSIS‖
 Massive axonal demyelination in pontine white matter A 2° to

rapid osmotic changes, most commonly iatrogenic correction
of hyponatremia but also rapid shifts of other osmolytes (eg,
glucose).
 Symptoms:
 Quadriplegia due to demyelination of the
corticospinal tracts.
 Pseudobulbar palsy due to demyelination of the
corticobulbar tracts of CN IX, X and XI.
 Characterized by head and neck muscle weakness, dysphagia, and dysarthria.
 This palsy is called ―pseudobulbar‖ because the nuclei of corresponding cranial
nerves remain intact. Bulbar palsy, to the contrary, is caused by a pathologic
process in the nuclei of these nerves.
 Loss of consciousness.
 Can cause “locked-in syndrome” preserved consciousness.
 Correcting serum Na+ too fast:
 ―From low to high, your pons will die‖ (osmotic demyelination syndrome).
 ―From high to low, your brains will blow‖ (cerebral edema/herniation).
ACUTE DISSEMINATED (POSTINFECTIOUS) ENCEPHALOMYELITIS
 Acute onset of multifocal inflammation and demyelination.

 Rare sequelae of infection or vaccinations:
 Mean 26 days after.
 Infections: Varicella or measles.
 Vaccines: Rabies, small pox.
 Most common histopathology: perivenous infiltration
 Lymphocytes, neutrophils, other cells.
 Inflammation/demyelination.
 Presents with rapidly progressive multifocal neurologic symptoms, altered mental status.
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CHARCOT-MARIE-TOOTH DISEASE
 Also known as hereditary motor and sensory neuropathy (HMSN).
 Onset usually late childhood/adolescence.
 Defective production nerve proteins or myelin.
 Autosomal dominant inheritance.
 Presentations:
 Leg muscles (bilateral) become wasted.
 Legs have characteristic stork-like contour.
 Foot drop, Foot deformities (eg, pes cavus, hammer toe).
 Upper extremities also affected (<lower).
 Falls, clumsiness.
 Sensory deficits.
 Most common type, CMT1A, is caused by PMP22 gene duplication.
PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

 Demyelination of CNS B due to destruction of
oligodendrocytes
 2° to reactivation of latent JC virus infection.
 Seen in 2–4% of patients with AIDS.
 Presents with rapidly progressive neurologic signs (visual
loss, weakness, dementia) leading to death.
 Predominantly involves parietal and occipital areas; visual
symptoms are common.
 ↑ Risk associated with natalizumab, rituximab.
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SUBACUTE SCLEROSING PANENCEPHALITIS

 Progressive, debilitating encephalitis leading to death.
 Due to slowly progressing, persistent infection of the brain by measles virus.
 Pathogenesis:
o It is thought to be caused by a form of measles virus with a mutated or absent
matrix
protein that prevents mature (enveloped) virion particles from forming.
o However, the virus continues to replicate intracellulariy, leading to a persistent,
nonproductive infection that evades eradication by the immune system.
o Accumulation of viral nucleocapsids within neurons and oligodendrocytes
results in the formation of intranuclear inclusions and eventually leads to
inflammation, demyelination, and gliosis in many cerebral areas.
 Diagnosis:
o ↑ Measles antibodies in the serum and CSF (detectable as oligoclonal bands).
o Viral inclusions within neurons (gray matter) and oligodendrocytes (white
matter).
 Panencephalitis = gray and white matter.
OTHER DEMYELINATING DISORDERS
 Metachromatic leukodystrophy:
 Due to a deficiency of arylsulfatase (autosomal recessive).
 Buildup of sulfatides  impaired production myelin.
 Progressive demyelination CNS, PNS.
 Most common leukodystrophy.
 Krabbe disease:
 Deficiency of galactocerebroside β-galactosidase (autosomal recessive).
 Galactocerebroside accumulates in macrophages and destroys myelin.
 Adrenoleukodystrophy:
 Due to impaired addition of coenzyme A to long-chain fatty acids (X-linked
defect).
 Accumulation of fatty acids damages adrenal glands and white matter of the
brain.
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MOVEMENT DISORDERS
Disorder Presentation Characteristi Notes

c lesion
Akathisia Restlessness and intense Can be seen with neuroleptic
urge to move. use or as a side-effect of
Parkinson treatment.
Asterixis Extension of wrists causes Associated with hepatic
―flapping‖ motion. encephalopathy, Wilson
disease, and other metabolic
derangements.
Athetosis Slow, snake-like, writhing Basal ganglia
movements; especially
seen in the fingers.
Chorea Sudden, jerky, purposeless Basal ganglia Chorea = dancing.
movements. Seen in Huntington disease
and in acute rheumatic fever
(Sydenham chorea)
Essential High-frequency tremor Often familial. Patients often self-
tremor with sustained posture (eg, medicate with alcohol, which
outstretched arms), decrease tremor amplitude.
worsened with movement Treatment: nonselective
or when anxious. β-blockers (eg, propranolol),
primidone.
Hemiballism Sudden, wild flailing of 1 Contralateral Pronounce ―Half-of-body
us arm +/- ipsilateral leg subthalamic ballistic.‖
nucleus (eg, Contralateral lesion.
lacunar
stroke)
Intention Slow, zigzag motion when Cerebellar
tremor pointing/extending toward dysfunction
a target
Myoclonus Sudden, brief, Jerks; hiccups; common in
uncontrolled muscle metabolic abnormalities such as
contraction. renal and liver failure.
Resting Uncontrolled movement Substantia Occurs at rest; ―pill-rolling
tremor of distal appendages (most nigra tremor‖ of Parkinson disease.
noticeable in hands); (Parkinson When you park your car, it is at
tremor alleviated by disease) rest
intentional movement
Restless legs Worse at rest/nighttime. Associated with iron deficiency,
syndrome Relieved by movement CKD. Treat with dopamine
agonists (pramipexole, ropinirole)
Page 136 of 235
PARKINSON DISEASE
 Parkinson TRAPS your body:

 Tremor (pill-rolling tremor at rest)
 Rigidity (cogwheel)
 Akinesia (or bradykinesia)
 Postural instability
 Shuffling gait
 MPTP ―Methyl-phenyl-tetrahydropyridine‖:
 Contaminant in illegal drugs.
 Metabolized to MPP+, which is toxic to substantia nigra.
 Histologic/gross Findings:
 Loss of dopaminergic neurons (ie, depigmentation) of SN pars compacta.
 Lewy bodies: composed of α-synuclein (intracellular eosinophilic
inclusions).
SURGICAL THERAPY PAR KINSON’S:

 Young patients often develop toxicity from long term use of L-dopa/carbidopa.
 Prior surgeries used:
o Pallidotomy (partial ablation of globus pallidus).
o Thalamotomy (partial ablation of thalamus).
 Modern option: Deep brain stimulation:
o High frequency DBS suppresses neural activation.
o Globus pallidus internus or subthalamic nucleus.
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HUNTINGTON DISEASE
Clinical  Chorea: varies from fidgetiness to uncontrollable, swinging movements of the

extremities.
 Dementia: memory and cognitive decline (sometimes initially mistaken for
substance abuse).
 Behavioral abnormalities: aggressiveness, apathy, or depression.
 Symptoms manifest between ages 20 and 50.
Macroscopic  Pronounced atrophy of caudate nucleus with ex vacuo ventriculomegaly.

 Moderate atrophy of the putamen and frontal lobes
Microscopic  Loss of neurons in the caudate nucleus and putamen.
Biochemical  ↓ GABA, ↓ ACh in striatum. (Caudate loses ACh and GABA.)
 ↑ Dopamine.
Genetic  Autosomal dominant.
 Trinucleotide (CAG)n repeat expansion in the huntingtin (HTT) gene on
chromosome 4 (4 letters).
 Anticipation results from expansion of CAG repeats.
Molecular  NMDA (N-methyl-D-aspartate) receptors bind glutamate and cause neuronal

death (NMDA-associated toxicity). (Glutamate excitotoxicity).
Page 138 of 235
NEUROCUTANEOUS DISORDERS
STURGE-WEBER SYNDROME
 Also known as encephalotrigeminal angiomatosis.

 Congenital, noninherited (sporadic), developmental anomaly of neural crest
derivatives due to somatic mosaicism for an activating mutation in one copy of
the GNAQ gene.
 Presentations:
 Affects small (capillary-sized) blood vessels  port-wine stain of the
face A (nevus flammeus, a non-neoplastic ―birthmark‖ in CN V1/V2
distribution).
 Ipsilateral leptomeningeal angioma B  seizures/epilepsy; intellectual
disability.
 Episcleral hemangioma  ↑ IOP  early-onset glaucoma.
 STURGE-Weber: Sporadic, port-wine Stain; Tram track calcifications (opposing
gyri); Unilateral; Retardation (intellectual disability); Glaucoma, GNAQ gene;
Epilepsy.
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TUBEROUS SCLEROSIS
 TSC1 mutation on chromosome 9 or TSC2 mutation on chromosome 16.

 Tumor suppressor genes.
 Autosomal dominant, variable expression.
 HAMARTOMAS: Hamartomas in CNS and skin; Angiofibromas C; Mitral
regurgitation; Ash-leaf spots D ; cardiac Rhabdomyoma; (Tuberous sclerosis);
autosomal dOminant; Mental retardation (intellectual disability); renal
Angiomyolipoma E ; Seizures, Shagreen patches.
 ↑ Incidence of subependymal giant cell astrocytomas and ungual fibromas.
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NEUROFIBROMATOSIS TYPE I
 Also known as von Recklinghausen disease.

 Genetics:
 Mutation in NF1 tumor suppressor gene on chromosome 17 (17 letters in
―von Recklinghausen‖), which normally codes for neurofibromin, a
negative regulator of RAS.
 Autosomal dominant, 100% penetrance.
 Findings:
 Café-au-lait spots F, cutaneous neurofibromas G, optic gliomas,
pheochromocytomas, Lisch nodules (pigmented iris hamartomas H).
NEUROFIBROMATOSIS TYPE II
 Genetics:
 Mutation in NF2 tumor suppressor gene on chromosome 22.
 Autosomal dominant.
 Findings:
 Bilateral acoustic schwannomas.
 Meningiomas.
 Ependymomas.
 Juvenile cataracts.
 NF2 affects 2 ears, 2 eyes, and 2 parts of the brain.
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VON HIPPEL-LINDAU DISEASE
 Genetics:
 Deletion of VHL gene on chromosome 3p (VHL = 3 letters).
 pVHL ubiquitinates hypoxia-inducible factor 1a.
 Autosomal dominant.
 Characterized by:
 Development of numerous tumors, both benign and malignant.
 HARP:
 Hemangioblastomas (high vascularity with hyperchromatic nuclei
I) in retina, brain stem, cerebellum, spine J.
 Angiomatosis (eg, cavernous hemangiomas in skin, mucosa,
organs);
 Bilateral Renal cell carcinomas.
 Pheochromocytomas.
 UW: can be associated with congenital cysts and/or neoplasms in the
kidney, liver, and pancreas.
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BRAIN TUMORS
ADULT PRIMARY BRAIN TUMORS
GLIOBLASTOMA MULTIFORME
 Grade IV astrocytoma.
 Common, highly malignant 1° brain tumor with ~ 1-year median survival.
 Macroscopic:
 Found in cerebral hemispheres A.
 Significantly large, causing mass effect with midline shift (red arrow).
 Can cross corpus callosum (―butterfly glioma‖).
 Central areas of necrosis and hemorrhage.
 Microscopic:
 Astrocyte origin, GFAP ⊕.
 “Pseudopalisading” pleomorphic tumor cells B border.
 And/or microvascular proliferation.
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OLIGODENDROGLIOMA
 Relatively rare, slow growing.
 Most often in frontal lobes C.
 “Chicken-wire” capillary pattern.
 Oligodendrocyte origin. “Fried egg” cells— round nuclei with clear cytoplasm D.
 Often calcified.
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MENINGIOMA
 Common, typically benign. Females > males.
 Often asymptomatic; may present with seizures or focal neurologic signs.
 Resection and/or radiosurgery.
 Arachnoid cell origin (neural crest cell origin).
 Gross picture:
 Well-circumscribed, round masses attached to the dura (―tail‖ E).
 Most often occurs near surfaces of brain and in parasagittal region.
 Extra-axial (external to brain parenchyma).
 Microscopic:
 Spindle cells concentrically arranged in a whorled pattern.
 Psammoma bodies F (laminated calcifications).
 UW: Other examples of tumors that form psammoma bodies include papillary
thyroid carcinoma, mesothelioma, and papillary serous carcinoma of the ovary and
endometrium.
HEMANGIOBLASTOMA
 Most often cerebellar G.
 Associated with von Hippel-Lindau syndrome when found with retinal angiomas.
 Can produce erythropoietin  2° polycythemia.
 Blood vessel origin. Closely arranged, thin walled capillaries with minimal
intervening parenchyma H.
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PITUITARY ADENOMA
 Adenoma may be nonfunctioning (silent) or hyperfunctioning (hormone producing).
 Most commonly from lactotrophs (prolactinoma) I  hyperprolactinemia; less
commonly adenoma of somatotrophs (GH)  acromegaly/ gigantism; corticotrophs
(ACTH)  Cushing disease. Rarely, adenoma of thyrotrophs (TSH) and gonadotroph
(FSH, LH).
 Nonfunctional tumors present with mass effect (bitemporal hemianopia,
hypopituitarism, headache).
 Bitemporal hemianopia due to pressure on optic chiasm ( J shows normal visual field
above, patient’s perspective below).
 Sequelae include hyper- or hypopituitarism, which may be caused by pituitary
apoplexy.
 Hyperplasia of only one type of endocrine cells found in pituitary (ie, lactotroph,
gonadotroph, somatotroph, corticotroph).
 Prolactinoma:
 In women classically presents as galactorrhea, amenorrhea, and decrease bone
density due to suppression of estrogen.
 In men classically presents as low libido and infertility.
 Treatment: dopamine agonists (eg, bromocriptine, cabergoline),
transsphenoidal resection.
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SCHWANNOMA
 Presentations:
 The most common site of intracranial schwannomas is the cerebellopontine
angle K at CN VIII.
 Schwannomas in this particular location are also called acoustic neuromas,
and can present with tinnitus, vertigo and sensorineural hearing loss.
 Bilateral vestibular schwannomas found in NF-2.
 Can arise from the peripheral nerves, nerve roots, and cranial nerves (except
CNII).
 Schwann cell origin, S-100 ⊕.
 Due to their neural crest cell origin.
 Another important S-100 positive tumor is melanoma (also derived from the neural
crest).
 Biphasic:
 Dense, hypercellular areas containing spindle cells alternating with
hypocellular, myxoid areas.
 Treatment:
 Resection or stereotactic radiosurgery.
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CHILDHOOD PRIMARY BRAIN TUMORS
PILOCYTIC ASTROCYTOMA
 Most common 1° brain tumor in childhood.
 Low-grade astrocytoma. Benign; good prognosis.
 Usually well circumscribed.
 In children, most often found in posterior fossa A (eg, cerebellum).
 May be supratentorial.
 Glial cell origin, GFAP ⊕.
 Microscopic:
o Rosenthal fibers—eosinophilic, corkscrew fibers B.
o Spindle cells with hair-like glial processes that are associated with microcysts.
o Cystic + solid (gross).
MEDULLOBLASTOMA
 Most common malignant brain tumor in childhood.
 Second most common posterior fossa tumor in children.
 Form of primitive neuroectodermal tumor (PNET).
 Presentations:
o Commonly involves cerebellum C.
o Can compress 4th ventricle, causing noncommunicating hydrocephalus 
headaches, papilledema.
o Can send ―drop metastases‖ to spinal cord.
 Microscopic:
o Poorly differentiated, with scant cytoplasm and little stroma.
o A high mitotic index is common.
o Homer-Wright rosettes, small blue cells D.
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EPENDYMOMA
 Ependymal cell origin. Most commonly found in 4th ventricle E.
 Can cause hydrocephalus.
 Poor prognosis.
 Characteristic perivascular pseudorosettes F.
 Rod-shaped blepharoplasts (basal ciliary bodies) found near the nucleus.
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CRANIOPHARYNGIOMA
 Most common childhood supratentorial tumor.
 May be confused with pituitary adenoma (both cause bitemporal hemianopia).
 Derived from remnants of Rathke’s pouch (ectoderm).
 Microscopic:
o Cystic or partially cystic with solid areas.
 The cysts are usually filled with a brownish-yellow, viscous fluid that
resembles machine oil due to the presence of protein and cholesterol crystals.
 Cysts are lined by cords/nests of stratified squamous epithelium with
peripheral palisading and internal areas of lamellar "wet" keratin.
o Calcification is common G H.
o Cholesterol crystals found in ―motor oil‖-like fluid within tumor.
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PINEALOMA
 Tumor of pineal gland.
 Can cause Parinaud syndrome (compression of tectum → vertical gaze palsy);
obstructive hydrocephalus (compression of cerebral aqueduct); precocious puberty in
males (β-hCG production).
 Similar to germ cell tumors (eg, testicular seminoma).
UW: NEUROBLASTOMA:
 The most common extracranial childhood cancer.

 It develops from neuroblasts located in the adrenal medulla.
 Opsoclonus-myoclonus is a paraneoplastic syndrome associated with neuroblastoma:
 Non-rhythmic conjugate eye movements associated with myoclonus.
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HERNIATION SYNDROMES
Increased intracranial pressure  brain herniate outside the skull or outside/ into a structure
within the skull.
1. Cingulate (subfalcine) herniation under falx cerebri.

 Can compress anterior cerebral artery.
2. Transtentorial (central/downward) herniation.
 Caudal displacement of brain stem  rupture of paramedian basilar artery
branches  Duret hemorrhages.
 Usually fatal.
3. Uncal herniation.
 Uncus = medial temporal lobe.
 Expanding space occupying lesions within the temporal lobe
(tumor “red arrow” or hemorrhage) can cause elevated
intracranial pressure with transtentorial herniation of the
uncus.
 Herniation compresses:
 Ipsilateral CN III  ipsilateral dilated fixed pupil
 Contralateral crus cerebri against tentorial edge 
ipsilateral hemiparesis, ie, a false localizing sign.
 As the herniation progresses, damage to the midbrain
results in mid-positioned and fixed pupils bilaterally.
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4. Cerebellar tonsillar herniation into the foramen magnum.

 Coma and death result when these herniations compress the brain stem.
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SPINAL CORD LESIONS
Affected area Disease Characteristics

Spinal  Congenital degeneration of anterior horns of spinal
muscular cord.
atrophy  LMN lesions only, symmetric weakness.
 “Floppy baby” with marked hypotonia (Flaccid
paralysis) and tongue Fasciculations.
 Autosomal recessive inheritance of mutation in
SMN1.
 SMA type 1 is called Werdnig-Hoffmann disease.
Amyotrophic  Combined UMN (corticobulbar/corticospinal) and
lateral LMN (medullary and spinal cord) degeneration.
sclerosis  Upper symptoms:
(ALS)  Spasticity, exaggerated reflexes.
 Lower symptoms:
 Denervation atrophy of the muscles
(amyotrophy).
 Fasciculations.
 No sensory or bowel/bladder deficits.
 Can be caused by defect in zinc copper superoxide
dismutase 1 which is a free radical scavenger 
increase free radical damage in the neurons.
 LMN deficits due to anterior horn cell
involvement (eg, dysarthria, dysphagia,
asymmetric limb weakness, fasciculations, atrophy)
and UMN deficits (pseudobulbar palsy, eg,
dysarthria, dysphagia, emotional lability, spastic
gait, clonus).
 Aspiration pneumonia from progressive dysphagia
is the most common cause of death.
 Commonly known as Lou Gehrig disease.
 Treatment: riluzole (↓glutamate release neurons.)
Complete  Spares dorsal columns and Lissauer tract.
occlusion of  Midthoracic ASA territory is watershed area, as
anterior artery of Adamkiewicz supplies ASA below T8.
spinal artery  Can be caused by aortic aneurysm repair.
 Presents with:
 UMN deficit below the lesion (corticospinal
tract)
 LMN deficit at the level of the lesion
(anterior horn)
 Loss of pain and temperature sensation
below the lesion (spinothalamic tract).
Page 154 of 235
Tabes  Caused by 3° syphilis.

dorsalis  Degeneration (demyelination) of:
 Dorsal columns:
 Progressive sensory ataxia
(impaired proprioception  poor
coordination).
 ⊕ Romberg sign.
 Charcot joints.
 Spinal roots:
 Absent DTRs.
 Fleeting, recurrent shooting pain.
 Associated with:
 Argyll Robertson pupils.
Syringomyelia  Syrinx expands and damages anterior white
commissure of spinothalamic tract (2nd-order
neurons)  bilateral symmetrical loss of pain and
temperature sensation in cape-like distribution.
 Seen with Chiari I malformation.
 Can affect other tracts:
 Can expand to affect anterior horn 
Muscle weakness.
 Can expand to affect lateral horn  Loss of
sympathetic to face  Horner’s syndrome.
Vitamin B12  Subacute combined degeneration (SCD)
deficiency  Demyelination of:
 Spinocerebellar tracts  paresthesia.
 Lateral Corticospinal tracts  UMN
weakness.
 Dorsal columns  impaired
position/vibration sense  ataxic gait.
 These symptoms may develop in absence of
macrocytosis.
 SCD = tabes dorsalis + UMN damage.
 "Combined" refers to the degeneration of both
ascending (dorsal columns) and descending
(corticospinal tract) pathways.
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Cauda  Compression of spinal roots L2 and below.

equina  Often due to intervertebral disc herniation or tumor.
syndrome  Cauda equina syndrome typically results from a
massive rupture of an intervertebral disk that
is capable of causing compression of two or
more of the 18 spinal nerve roots of the cauda
equina.
 Classic presentation:
 Unilateral radicular pain.
 Low back pain radiating to leg.
 Absent knee and ankle reflex.
 Loss of bladder and anal sphincter control.
 Saddle anesthesia.
 Loss of anocutaneous reflex.
 Normal Babiniski (the cauda equine nerves
are peripheral nerves although they still in
the vertebral canal)
 Treatment: emergent surgery and steroids.
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CONUS MEDULLARIS:
 Lesions at L2.
 Similar to cauda equine syndrome except:
 Saddle anesthesia (S3,4,5).
 Impotence.
 There is usually mild weakness of the leg muscle if the lesion spares both the
lumbar cord and the adjacent spinal and lumbar nerve roots.
POLIOMYELITIS
 Caused by poliovirus (fecal-oral transmission).
 Replicates in oropharynx and small intestine before spreading via bloodstream to CNS.
 Infection causes destruction of anterior horn cells of spinal cord (LMN death).
 Classic presentation:
 Unvaccinated child with signs of infection (malaise, headache, fever, nausea,
etc.).
 Neuro symptoms 4-5 days later  Signs of LMN lesion:
 Asymmetric weakness (legs>arms), hypotonia, flaccid paralysis,
fasciculations, hyporeflexia, muscle atrophy.
 Respiratory muscle involvement leads to respiratory failure.
 Labs:
 CSF shows
 ↑ WBCs (lymphocytic pleocytosis).
 Slight ↑ of protein (with no change in CSF glucose).
 Virus recovered from stool or throat.
 Differential diagnosis:
 Werdnig-Hoffmann disease.
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BROWN-SÉQUARD SYNDROME
 Hemisection of spinal cord.
 Findings:
1. Ipsilateral loss of all sensation at level of lesion.
2. Ipsilateral LMN signs (eg, flaccid paralysis) at level of lesion.
3. Ipsilateral UMN signs below level of lesion (due to corticospinal tract damage).
4. Ipsilateral loss of proprioception, vibration, light (2-point discrimination) touch,
and tactile sense below level of lesion (due to dorsal column damage).
5. Contralateral loss of pain, temperature, and crude (nonadiscriminative) touch
below level of lesion (due to spinothalamic tract damage).
 If lesion occurs above T1, patient may present with ipsilateral Horner syndrome due to
damage of oculosympathetic pathway.
 Lose pain/temp contralateral side.

 Lose motor, position, vibration
ipsilateral side.
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MENINGITIS
 Inflammation of the leptomeninges.
 Symptoms:
1. Fever, headache, photophobia.
2. Nuchal rigidity  hurts to move back of neck.
3. Kernig sign:
 Thigh bent at hip with knee at 90 degrees.
 Subsequent extension of knee is painful (resistance).
4. Brudzinski sign:
 Lye patient flat.
 Lift head off table.
 Involuntary lifting of legs.
 Both signs of meningismus.
 Also subarachnoid hemorrhage.
 Complications:
1. Death.
2. Hydrocephalus.
3. Hearing loss.
4. Seizures.
5. Most from bacterial meningitis.
SPINAL FLUID TESTING:

 Normal CSF:
1. Clear.
2. 0-5 lymphocytes.
3. < 45 mg/dl protein.
4. >45 mg/dl glucose.
 About 2/3 of blood glucose (80-120).
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CAUSES OF MENINGITIS & TREATMENT:
ENCEPHALITIS
 Encephalitis = brain inflammation.
 Must make sure meningitis patients don’t have:
1. Altered mental status.
2. Motor or sensory deficits.
3. Altered behavior and personality changes.
4. Speech/movement disorders.
5. If these are present, HSV-1 is common cause.
 Other (rare) causes of encephalitis:
1. Varicella-zoster (chickenpox, shingles).
2. Mosquito viruses: • St. Louis encephalitis virus, • Eastern/western equine, • West Nile, •
California encephalitis.
3. Lassa fever encephalitis:
 Spread by mice.
 Hemorrhagic virus like Ebola (many other symptoms).
4. Measles.
5. Naegleria fowleri (protozoa).
6. HIV Encephalitis.
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OTOLOGY
AUDITORY PHYSIOLOGY
OUTER EAR:
 Visible portion of ear (pinna), includes
auditory canal and tympanic membrane.
UW: The vagus nerve provides
 Transfers sound waves via vibration of
cutaneous sensation to the posterior
tympanic membrane.
external auditory canal via its small
auricular branch. Sensation to the
rest of the canal is from the
mandibular division of the trigeminal
nerve.
Stimulation of posterior external

auditory canal by an otoscope 
vasovagal syncope, parasympathetic
outflow via the vagus nerve leads to
decreased heart rate and blood
pressure.
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MIDDLE EAR
 Air-filled space with three bones called the ossicles (malleus, incus, and stapes).
 Ossicles conduct and amplify sound from tympanic membrane to inner ear.
UW: The stapedius muscle is

innervated by the facial nerve.
Paralysis of the stapedius muscle
results in hyperacusis (eg,
increased
sensitivity to sound).
Tensor tympani  trigeminal

(mandibular branch V3)
INNER EAR
 Snail-shaped, fluid-filled cochlea.
 Contains basilar membrane that vibrates 2° to sound waves.
 Vibration transduced via specialized hair cells  auditory nerve signaling 
brain stem.
 Each frequency leads to vibration at specific location on basilar membrane
(tonotopy):
 Low frequency heard at apex near helicotrema (wide and flexible).
 High frequency heard best at base of cochlea (thin and rigid).
Page 162 of 235
TYPES OF HEARING LOSS
CONDUCTIVE:
 Sound waves can’t covert to nerve signals.
 Obstruction (wax).
 Infection (otitis media).
 Otosclerosis (bony overgrowth of stapes).
SENSORINEURAL:
 Cochlea disease.
 Cochlear nerve failure (acoustic neuroma).
 CN damage.
NOISE-INDUCED HEARING LOSS

 Sudden after loud noise (explosion)
 Tympanic membrane rupture.
 Long term noise exposure (drummers)
 Damage to ciliated (hair) cells Organ of Corti
 High-frequency hearing lost first
PRESBYCUSIS
 Aging-related progressive bilateral/symmetric sensorineural hearing loss (often of

higher frequencies).
 Due to destruction of hair cells at the cochlear base (preserved low-frequency hearing
at apex).
Page 163 of 235
DIAGNOSING HEARING LOSS
Weber test Rinne test

Conductive hearing loss Louder bad ear Abnormal (bone > air)
Sensorineural hearing loss Louder good ear Normal (air > bone)
CHOLESTEATOMA
 Overgrowth of desquamated keratin debris within the middle ear space ( A, arrows).
 May erode ossicles, mastoid air cells  conductive hearing loss.
 Often presents with painless otorrhea.
Page 164 of 235
VESTIBULAR SYSTEM
 Vestibule: Central portion inner ear.
 Found within temporal bone.
 Contains system for balance, posture, equilibrium.
 Also coordinates head and eye movements.
ANATOMY OF THE VESTIBULAR SYSTEM:

 Three semicircular canals (x, y, z planes of motion)
 Respond to ROTATION of head.
 Filled with endolymph.
 Bulges at base (ampulla)
 Ampulla have hair cells that bend with rotation.
 Hair cells release neurotransmitters  action potential.
 More/less signals based on motion.
 Utricle and saccule (otolith organs)
 Respond to LINEAR motion.
 Gravity, moving forward/backward.
 Contain otoliths (Greek word: ear stones).
 Calcium carbonate crystals.
 Sit on top of hair cells.
 Drag hair cells in response to motion.
 This generates vestibular neural activity.
VESTIBULAR DYSFUNCTION
 Vertigo: Room spinning when head still.
 Contrast with dizzy, lightheaded.
 Nystagmus: Rhythmic oscillation of eyes.
 Nausea/vomiting.
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NYSTAGMUS
 Vestibulo-ocular reflex:
 Focuses eyes when body moves.
 Vestibular dysfunction disrupts reflex.
 Eyes move slowly one direction fast correction.
 ―Jerk‖ nystagmus named for fast direction:
 Left, right
 Torsional/rotational
 Upbeat, downbeat
 “Peripheral” vestibular dysfunction  Left, right, torsional/rotational nystagmus.
 “Central” vestibular dysfunction  Upbeat, downbeat nystagmus (vertical).
CENTRAL VS PERIPHERAL VESTIBULAR DYSFUNCTION (VERTIGO/NYSTAGMUS)
Central = Bad Peripheral = Benign (usually)

 Brainstem or cerebellar lesion  Inner ear problem
affecting vestibular nuclei.
 Vertebrobasilar stroke/TIA  Benign positional vertigo (BPV)
 Cerebellar infarction/hemorrhage  Vestibular neuritis
 Tumor (posterior fossa)  Meniere's disease
 Semicircular canal debris
 Purely vertical nystagmus  Mixed horizontal/torsional nystagmus.
 Positional testing: IMMEDIATE  Positional testing: DELAYED
nystagmus nystagmus
 Nystagmus changes direction with  Nystagmus may fatigues with time.
gaze. (Rt gaze may produce upward
nystagmus and Lt  downward n.)
 Skew deviation: Vertical
misalignment of eyes.
 Other symptoms:  No other symptoms.
 Diplopia, Dysmetria (ataxia)  Normal proprioception, stable Romberg.
 Other CNS symptoms (weakness,
sensory)
Page 166 of 235
DIX-HALLPIKE MANEUVER
 Done to reproduce vertigo and cause nystagmus to test the presence of BPV.
 Maneuver:
 Seated patient, Extend neck, and turn head to side.
 Rapidly lie patient down on table.
 Let head hang over end of table.
 Typical result in BPV:
 No symptoms for 5-10 seconds (delayed as it is peripheral).
 Vertigo develops.
 Torsional nystagmus develops.
 Symptoms resolve with sitting up.
 Fewer symptoms with repeated maneuvers.
BENIGN POSITIONAL VERTIGO

 The most common cause of peripheral vertigo.
 Vertigo with head turning/position.
 Due to calcium debris semicircular canals (Canalithiasis)
 Diagnosis: Dix Hallpike Maneuver.
 Deviations from typical result = consider imaging (may be a central cause).
 Treatment:
 Epley Maneuver can reposition otoconia.
VESTIBULAR NEURONITIS = LABYRINTHITIS

 Neuropathy of vestibular portion CN VIII.
 Benign, self-limited.
 Usually viral or post-inflammatory.
 Cause vertigo (peripheral).
Page 167 of 235
MENIERE’S DISEASE
 Endolymph fluid accumulation (hydrops).
 Swelling of the labyrinthine system.
 Triad of:
 Tinnitus.
 Sensorineural hearing loss.
o Weber louder normal ear
o Rinne: AC>BC
 Vertigo.
 Treatment:
 Avoid high salt – decrease swelling.
 Avoid caffeine, nicotine–vasoconstrictors, ↓flow from inner ear.
 Diuretics.
Page 168 of 235
TESTING CN VIII (VESTIBULOCOCHLEAR)

 Awake patient:
 Ask them to focus eyes on object while you rotate head.
 If eyes stay fixed  both CN VIII are working.
 “Doll’s eyes”  CN VIII lesion.
 When head rotate toward lesion side, eye moves with head then quickly
adjusts when the head stops moving (saccade).
 Unconscious patient:
 Inject cold water into ear:
 Cold water disrupts CN VIII function.
 Eyes slowly move toward cold water.
 Rapid correct opposite side.
 Normal response is slow toward cold then fast away.
 If CN VIII not working, no slow toward.
 If cortex not working, slow toward, no fast away.
 Inject warm water into ear:
 Warm water stimulates CN VIII function.
 Creates ―relative‖ opposite side CN VIII dysfunction.
 Eyes slowly move away warm water.
 Rapid correct back towards warm water.
 Normal response is slow away then fast toward.
 If CN VIII not working, no slow away.
 If cortex not working, slow away, no fast toward.
Page 169 of 235
OPHTHALMOLOGY
NORMAL EYE
SCLERA
 Composed of collagen, rigid structure – stabilizes eyeball.
 Extraocular muscles insertion site.
 Avascular.
 Nutrients from episclera and choroid.
SCLERITIS
 Inflammation of sclera.
 Dark red eyes.
 Severe ―boring‖ pain with eye movement (insertion of the extraocular muscles).
 Potentially blinding.
 50% cases associated with systemic disease.
 Rheumatoid arthritis is most common.
CORNEAL ABRASION
 Common among contact lens wearers.
 Painful (due to superficial cornea nerve endings).
 Visualized with fluorescein dye and blue light.
 Can become infected with pseudomonas.
 Often treated with ciprofloxacin eye drops.
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CONJUNCTIVA
 The transparent layer separating the sclera from the overlying environment. The cornea
has no conjunctival layer covering it.
CONJUNCTIVITIS
 Viral, bacterial, allergic.
 Conjunctival injection.
 Discharge.
 Commonest ―red eye‖ A.
VIRAL CAUSES (80%)

 Adenovirus, measles (Cough, Coryza, Conjunctivitis), HSV-1.
 Swollen preauricular node. Self-resolving.
 Adenovirus:
 Most common. 65% to 90% of viral conjunctivitis.
 Watery discharge.
 Non-enveloped, DNA virus.
 Also causes pharyngitis, pneumonia.
 Very stable - survive on surfaces
 Transmission: • Aerosol droplets • Fecal-oral • Contact with contaminated
surfaces.
BACTERIAL CAUSES
 Copious purulent discharge.
 Adults:
 Staph aureus, S pneumonia, H influenza.
 Children:
 H influenzae, S pneumoniae, and Moraxella catarrhalis.
 Neonatal Conjunctivitis:
 Ophthalmia neonatorum.
 Neisseria gonorrhea or Chlamydia.
 Infection from passage through birth canal.
 Untreated can lead to visual impairment.
 Prophylaxis: Erythromycin ophthalmic ointment.
ALLERGIC
 Itchy eyes, bilateral.
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UVEITIS
 Inflammation of uvea (iris, ciliary body, choroid).
 Specific name based on location within affected eye:
 Anterior uveitis:
 Iritis, iridocyclitis.
 Pain, redness.
 Posterior uveitis:
 Choroiditis and/or retinitis.
 Painless, floaters, ↓ vision.
 May have hypopyon (accumulation of pus in anterior chamber A) or conjunctival
redness.
 Associated with systemic inflammatory disorders (eg, sarcoidosis, rheumatoid arthritis,
juvenile idiopathic arthritis, HLA-B27–associated conditions).
THE LENS
 Surrounded by a capsule with type IV collagen.
 Avascular; Nutrients via diffusion.
 Contains elongated fiber cells.
 Anaerobic metabolism:
 Principle source of energy production.
 Glucose  lactic acid.
ACCOMMODATION
 Lens modifies shape to focus on near objects.
 Lens changes optical power of eye.
 Ciliary muscle:
 Smooth muscle within ciliary body.
 Changes shape of lens.
 Circular muscle – surrounds lens.
 Connected to lens by ligaments (zonules).
 Far objects:
 Ciliary relax
 Lens flatter
 Near objects:
 Ciliary contract
 Lens rounder
 Presbyopia:
 Lens stiffens with age.
 Can’t focus on near objects (reading).
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ACCOMMODATION REFLEX
 3 reflex responses as object moves closer to eye:
1. Convergence:
a. Eyes move medially to track object.
2. Miosis:
a. Pupil constricts.
b. Block entry of divergent light rays from near object.
3. Accommodation:
a. Shape of lens changes.
b. Focal point maintained on retina.
REFRACTIVE ERRORS
 Common cause of impaired vision, correctable with glasses.
HYPEROPIA
 Also known as ―farsightedness.‖ Eye too short for refractive power of cornea and lens
 light focused behind retina.
 Correct with convex (converging) lenses.
MYOPIA
 Also known as ―nearsightedness.‖  Eye too long for refractive power of cornea and
lens  light focused in front of retina.
 Correct with concave (diverging) lens.
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ASTIGMATISM
 Abnormal curvature of cornea  different refractive power at different axes.
 Correct with cylindrical lens.
PRESBYOPIA
 Aging-related impaired accommodation (focusing on near objects)
 Primarily due to ↓ lens elasticity, changes in lens curvature, ↓ strength of the ciliary
muscle.
 Patients often need ―reading glasses‖ (magnifiers).
ECTOPIA LENTIS
 Dislocation of lens.
 Commonly due to trauma.
 Rarely associated with systemic disease:
 Marfan syndrome  upward/outward lens dislocation.
 Homocystinuria  downward/inward lens dislocation.
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CATARACT
 Painless, often bilateral, opacifcation of lens A.

 Often resulting in glare and ↓ vision, especially at night.
 Risk factors:
 Acquired: ↑ age, smoking, excessive alcohol use, excessive sunlight, prolonged
corticosteroid use, diabetes mellitus, trauma, infection.
 Congenital: classic galactosemia, galactokinase deficiency, trisomies (13, 18,
21), ToRCHeS infections (eg, rubella), Marfan syndrome, Alport syndrome,
myotonic dystrophy, neurofibromatosis 2.
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AQUEOUS HUMOR PATHWAY

 Aqueous humor is produced by the epithelial cells of the ciliary body.
 It is secreted into the posterior chamber and transferred through the pupil into the
anterior chamber.
 The anterior chamber angle (iridocorneal angle) contains a trabecular meshwork
through which the aqueous humor diffuses into Schlemm's canal (scleral venous sinus)
and subsequently into episcleral and conjunctival veins.
 Ciliary muscle (accommodation) epithelium:

 Produces aqueous humor to the posterior chamber.
 Sympathetic stim (β receptors).
 Trabecular meshwork:
 Drains aqueous humor from anterior chamber.
 Canal of Schlemm:
 Drains aqueous humor from trabecular meshwork.
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INTRAOCULAR PRESSURE
 Measured by tonometry.
 Determined by amount of aqueous humor.
 Parasympathetic system (M):
 Constricts ciliary muscle.
 Allows fluid to drain.
 ↓ Pressure.
 Sympathetic (β2):
 Produces fluid.
 Allows the eye to focus during fight/flight.
 More fluid = ↑ pressure.
GLAUCOMA
 High intraocular pressure that results in optic neuropathy.
 Diagnostic features of glaucoma include:
 Elevated IOP.
 Abnormal visual field testing with decreased peripheral vision.
 Funduscopic examination:
 Increased cup-to-disc ratio due to loss of ganglion cell axons.
 Optic disc atrophy with characteristic cupping (thinning of outer rim of
optic nerve head B versus normal A).
 Treatment is through pharmacologic or surgical lowering of IOP.
OPEN-ANGLE GLAUCOMA
 Risk factors:
 ↑ Age, African-American race, family history.
 More common than closed angle.
 Painless.
 No symptoms until loss of eyesight occurs (chronic progressive loss of
peripheral vision).
 Causes: Overproduction fluid or decreased drainage. Angle for drainage of fluid is
―open‖.
 Primary—cause unclear.
 Secondary—blocked trabecular meshwork from WBCs (eg, uveitis), RBCs (eg,
vitreous hemorrhage), retinal elements (eg, retinal detachment).
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CLOSED- OR NARROW ANGLE GLAUCOMA

 Angle for drainage suddenly closes.
 Abrupt onset.
 Painful, red eye.
 Blurred vision with halos.
 Eye is firm (―rock hard‖).
 Causes:
 Primary—enlargement or anterior movement of lens against central iris (pupil
margin)  obstruction of normal aqueous flow through pupil  fluid builds up
behind iris, pushing peripheral iris against cornea C and impeding flow through
trabecular meshwork.
 Secondary—hypoxia from retinal disease (eg, diabetes mellitus, vein occlusion)
induces vasoproliferation in iris that contracts angle.
 Chronic closure:
 Often asymptomatic with damage to optic nerve and peripheral vision.
 Acute closure
 True ophthalmic emergency.
 ↑ IOP pushes iris forward  angle closes abruptly.
 Very painful, red eye D.
 Sudden vision loss, halos around lights.
 Frontal headache, fixed and mid-dilated pupil.
 Mydriatic agents contraindicated.
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THE RETINA AND MACUL A

 Retina:
 Inner layer of eye.
 Contain photosensitive cells: rods and cones.
 Major blood supply via choroid.
 Macula:
 Oval-shaped area near center of retina.
 Contains fovea (largest amount of cone cells).
 High-resolution, color vision.
 Both structures essential for normal vision.
RETINITIS 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.
 Fundoscopy:
 Intraretinal pigmentation (dark spots in the retina) in a bone-spicule pattern.
 Form in retina where photoreceptors are missing.
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RETINITIS
 Retinal edema/necrosis.
 Floaters (dark spots seen in the visual field), ↓ vision.
 Classic cause: Cytomegalovirus (CMV).
 Usually in HIV/AIDS (low CD4 <50).
 Also in transplant patients on immunosuppression.
 Fundoscopy:
 Retinal hemorrhages.
 Whitish appearance to retina.
MACULA
 Yellowish spot approximately 1.5 mm in diameter located near the center of the retina.
 It is characterized histologically by the presence of
 Densely packed cones.
 Few overlying cells and no blood vessels.
 Each macular cone synapses to a single bipolar cell, which, in turn, synapses to a single
ganglion cell.
 Due to this arrangement the visual acuity in the macula, and particularly the fovea, is
greater than in any other area of the retina.
 The neural fibers that serve the macula transmit to an area of the occipital visual cortex
that is separate from the area of representation of the peripheral fields (this area is also
relatively large in size).
 Due to this peculiar cortical representation, macular sparing is common in lesions of the
occipital cortex.
 Macular lesions impair central vision and result in central scotomata.
 The term scotoma refers to any visual defect surrounded by a relatively
unimpaired field of vision.
 Scotomas occur due to pathologic processes that involve parts of the retina or
optic nerve.
 Examples of such processes include demyelinating diseases such as multiple
sclerosis, diabetic retinopathy and retinitis pigmentosa.
 Pathologic processes that involve the entire optic nerve lead to monocular
blindness.
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AGE-RELATED MACULAR DEGENERATION (MD)

 Degeneration of macula (central area of retina = loss of central vision).
 The most common cause of blindness in people over 50 years old in the US.
 Characterized by:
1. Progressive loss of central vision (scotomas) due to:
 Deposition of fatty tissue (drusen) behind the retina (dry MD)
 And neovascularization of the retina (wet MD).
2. Distortion (metamorphopsia).
 Types:
1. Dry (nonexudative, > 80%):
 More common (80%).
 Slowly progressive symptoms.
 Deposition of yellowish extracellular material
in between Bruch membrane and retinal
pigment epithelium (―Drusen‖) A.
 Bruch's membrane:
o Innermost layer of the choroid.
o Between choroid and retina.
 Retinal pigment epithelium:
o Retina layer beneath photoreceptors.
o Next to choroid (Bruch’s membrane)
 Prevent progression with multivitamin and antioxidant supplements.
2. Wet (exudative, 10–15%):
 Less common (10-15%).
 Symptoms may develop rapidly (days/weeks).
 Due to bleeding 2° to choroidal neovascularization.
 Break in Bruch’s membrane  formation of blood vessels form beneath
retina.
 Leakage/hemorrhage.
 Treat with anti-VEGF (vascular endothelial growth factor) injections (eg,
bevacizumab, ranibizumab).
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DIABETIC RETINOPATHY
 Retinal damage due to chronic hyperglycemia.

 Mechanism:
 Pericyte degeneration:
o Cells that wrap capillaries.
o Microaneurysms due to degeneration.
o Rupture  hemorrhage.
 Two types:
 Nonproliferative:
 Most common type (95%).
 Damaged capillaries leak blood  lipids and fluid seep into retina 
Hemorrhages (arrows in A) and macular edema.
 Findings:
 Microaneurysms (earliest sign).
 ―Dot-and-blot hemorrhages‖.
o Damaged capillary  leakage of fluid.
 Cotton-wools pots:
o Nerve infarctions.
o Occlusion of precapillary arterioles.
o Also seen in hypertension.
 Hard exudates/macular edema:
o Macular swelling due to accumulation of yellow exudates of
fatty lipids.
o Can lead to blindness in diabetics.
 Treatment: blood sugar control.
 Proliferative:
 Chronic hypoxia results in new blood vessel formation with resultant
traction on retina  can lead to retinal detachment and macular edema.
 Treatment:
 Peripheral retinal photocoagulation (laser  stops vessel growth).
 Surgery (vitrectomy).
 Anti-VEGF (intravitreal injections; ranibizumab).
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HYPERTENSIVE RETINOPATHY
 Retinal damage due to chronic uncontrolled HTN.

 Flame-shaped retinal hemorrhages, arteriovenous nicking,
microaneurysms, macular star (exudate, red arrow in A),
cotton-wool spots (blue arrow in A).
 Presence of papilledema requires immediate lowering of BP.
 Associated with ↑ risk of stroke, CAD, kidney disease.
CENTRAL RETINAL ARTERY OCCLUSION
 Acute, painless monocular vision loss.

 Causes:
 Commonly caused by carotid artery atherosclerosis.
 Internal carotid  ophthalmic  retinal.
 Cardiac source (embolus).
 Giant cell arteritis.
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 Fundoscopy:
 “cherry red spot”
 Red circular area of at fovea (center of macula) surrounded by halo due to
ischemia.
 Also seen in Tay Sachs Disease (lysosomal storage disease) due to accumulation
of sphingolipids.
RETINAL VEIN OCCLUSION
 Blockage of central or branch retinal vein due to compression from nearby arterial
atherosclerosis.
 Fundoscopy:
 Retinal hemorrhage
 venous engorgement (―blood and thunder appearance‖; arrows in A)
 Edema in affected area.
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RETINAL DETACHMENT
 Retina peels away from underlying layer:

 Separation of neurosensory layer of retina
(photoreceptor layer with rods and cones) from
outermost pigmented epithelium (normally
shields excess light, supports retina).
 Loss of connection to choroid ischemia.
 Photoreceptors (rods/cones) degenerate.
 Vision loss (curtain drawn down).
 Surgical emergency.
 Preceded by posterior vitreous membrane detachment:
 Often precedes retinal detachment.
 Vitreous shrinks with age  can pull on retina.
 May cause retinal holes/tears.
 Floaters (black spots).
 Flashes of light.
 Risk Factors:
 Myopia (near-sightedness).
 Larger eyes; thinner retinas.
 Prior eye surgery or trauma.
 Proliferative diabetic retinopathy.
 Fundoscopy:
 Crinkling of retinal tissue A and changes in vessel direction.
PAPILLEDEMA
 Optic disc swelling.
 Usually bilateral.
 Due to ↑ ICP (eg, 2° to mass effect).
 Enlarged blind spot.
 Elevated optic disc with blurred margins A.
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PUPILLARY CONTROL
MIOSIS
 Constriction, parasympathetic:
 1st neuron: Edinger-Westphal nucleus to ciliary ganglion
via CN III.
 2nd neuron: short ciliary nerves to sphincter pupillae
muscles.
Short ciliary nerves shorten the pupil diameter.
 Muscarinic receptors (ACh).
PUPILLARY LIGHT REFLEX
Light in either retina sends a

signal via CN II to pretectal
nuclei bilaterally (dashed lines in
image) in midbrain that activates
bilateral Edinger Westphal
nuclei  parasympathetic fibers
through CNIII bilaterally 
pupils constrict bilaterally (direct
and consensual reflex).
Result: illumination of 1 eye
results in bilateral pupillary
constriction.
Pretectal nucleus is located in the
superior colliculus.
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MYDRIASIS
 Dilation, sympathetic (α1):

1. 1st neuron: hypothalamus to
ciliospinal center of Budge (C8–T2).
2. 2nd neuron: exit at T1 to superior
cervical ganglion (travels along
cervical sympathetic chain near lung
apex, subclavian vessels).
3. 3rd neuron: plexus along internal
carotid, through cavernous sinus;
enters orbit as long ciliary nerve to
pupillary dilator muscles.
Sympathetic fibers also innervate
smooth muscle of eyelids (minor
retractors) and sweat glands of
forehead and face.
Long ciliary nerves make the pupil
diameter longer.
MARCUS GUNN PUPIL

 When the light shines into a normal eye, constriction of the ipsilateral (direct reflex) and
contralateral eye (consensual reflex) is observed.
 When the light is then swung to the affected eye, both pupils dilate instead of constrict
due to impaired conduction of light signal along the injured optic nerve.
 Caused by lesion in “afferent” light reflex limb
 Problem sensing light appropriately.
 Many potential causes: retina, optic nerve.
 Classic cause: Optic neuritis:
 Inflammatory, demyelinating disorder
 Commonly occurs in multiple sclerosis
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HORNER SYNDROME
 Sympathetic denervation of face :
 Ptosis (slight drooping of eyelid: superior tarsal muscle).
 Anhidrosis (absence of sweating) and flushing of affected side of face.
 Miosis (pupil constriction).
 Associated with lesions along the sympathetic chain:
 1st neuron: pontine hemorrhage, lateral medullary syndrome, spinal cord lesion
above T1 (eg, Brown-Séquard syndrome, late-stage syringomyelia).
 2nd neuron (stellate ganglion): Pancoast tumor.
 3rd neuron: carotid dissection
(painful).
UW: Horner + upper limb weakness
and paresthesia  Pancost tumor.
Pancost tumor can compress superior

cervical sympathetic ganglion.
 Diagnostic Test for Horner

Syndrome:
 Cocaine test:
• Blocks reuptake of
norepinephrine.
• No effect with impaired
sympathetic innervation
• Testing: Cocaine applied to
eye
• Normal eye: Dilation.
• Horner syndrome eye: No
dilation.
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ACCOMMODATION REFLEX
 Changes optical power to focus on near objects.
 Ciliary muscle changes shape of lens.
 Associated with miosis (pupillary constriction).
 The reflex:
 Convergence:
 Eyes move medially to track object
 Accommodation
 Shape of lens changes
 Focal point maintained on retina
 Miosis
 Pupil constricts
 Block entry of divergent light rays from near object
ARGYLL ROBERTSON PUPIL

 ―Prostitute’s pupil‖.
 Strongly associated with neurosyphilis (tertiary).
 Bilateral, small pupils.
 No constriction to light.
 Constriction to accommodation.
 ―Light-near dissociation‖
 Believed to involve pretectal nucleus which is part of light reflex; not part of
accommodation reflex.
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OCULAR MOTILITY
 CN VI innervates the Lateral Rectus.

 CN IV innervates the Superior Oblique.
 CN III innervates the Rest.
 The ―chemical formula‖ LR6SO4R3.
 Oblique muscles:
o SO  turns the eyeball inward and downward.
o IO  turns the eyeball inward and upward.
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CN III, IV, VI PALSIES
TERMINOLOGY
 Move eye away from nose:
 Lateral
 Abduction
 Move eye toward nose:
 Medial
 Adduction
 Diplopia:
 Two different images of same object.
 Diplopia due to nerve palsies is binocular
 Appears when the patient uses both eyes.
 Resolves when one eye is covered.
 Monocular diplopia: usually lens problem (astigmatism).
CN III DAMAGE
 CN III has both motor (central) and parasympathetic (peripheral) components.
 Common causes include:
 Ischemia  pupil sparing ―parasympathetic sparing‖.
 Uncal herniation  coma.
 PCA aneurysm  sudden-onset headache.
 Cavernous sinus thrombosis  proptosis, involvement of CNs IV, V1/V2, VI.
 Midbrain stroke  contralateral hemiplegia.
 Central lesion:
 Motor output to extraocular muscles.
 Affected primarily by vascular disease (eg, diabetes mellitus: glucose 
sorbitol)
 Due to ↓ diffusion of oxygen and nutrients to the interior fibers from
compromised vasculature that resides on outside of nerve.
 Signs: ptosis, ―down and out‖ gaze.
 Peripheral lesion
 Parasympathetic output.
 Fibers on the periphery are first affected by compression (eg, PCom aneurysm,
uncal herniation).
 Signs: diminished or absent pupillary light reflex, ―blown pupil‖ often with
―down-and-out‖ gaze A.
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CN IV DAMAGE
 Supplies superior oblique:
 Turns eye down/in.
 Reading/stairs.
 Palsy symptoms:
 Diplopia.
 Eye tilted upward, outward B.
 Unable to look down/in (stairs, reading).
 Head tilting away from affected side (to compensate)
 Can’t see the floor with CN four damage.
CN VI DAMAGE
 Affected eye may be pulled medially at rest.
 Problems worse on horizontal gaze.
 Affected eye can’t move laterally.
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VISUAL FIELD DEFECTS
VISUAL SYSTEM
 Key Points
 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 of both retina.
 Carrying signals from lateral (temporal) images.
 Lateral geniculate nucleus:
 Found in thalamus.
 Major termination site of retinal projections.
 Two projections LGN visual cortex:
 Meyer’s loop (temporal lobe).
 Baum’s loop (parietal lobe).
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 UW: Optic tract fibers project mainly to the lateral geniculate nucleus (LGN), but
also project to superior colliculus (reflex gaze), pretectal area (light reflex), and the
suprachiasmatic nucleus (circadian rhythms).
 UW: Optic tract lesions:
 Contralateral homonymous hemianopia.
 Contralateral Marcus Gunn pupil.
CONJUGATE GAZE
 Movement of both eyes at same time.
 Looking right or left with both eyes.
 Tracking objects.
 Conjugate gaze palsy:
 Eyes cannot move in same direction.
 Results in diplopia.
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COMPONENTS OF CONJUGATE GAZE:
 Paramedian pontine reticular

formation:
 Initiates lateral gaze from
brainstem.
 Located in pons.
 Medial longitudinal fasciculus:
 Signal transmission to opposite
side.
 Pair of tracts that allows for
crosstalk between CN VI and
CN III nuclei.
 Coordinates both eyes to move
in same horizontal direction.
 Highly myelinated (must
communicate quickly so eyes
move at same time).
 Requires functioning CN III and
CN VI.
 Mechanism:
 When looking left, the left nucleus
of CN VI fires, which contracts
the left lateral rectus and
stimulates the contralateral (right)
nucleus of CN III via the right
MLF to contract the right medial
rectus.
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INTERNUCLEAR OPHTHALMOPLEGIA (INO)

 Conjugate horizontal gaze disorder.
 Caused by lesions of the MLF.
 Lesions may be unilateral or bilateral (latter classically seen in multiple sclerosis) MLF
in MS.
 Lack of communication such that when CN VI nucleus activates ipsilateral lateral rectus,
contralateral CN III nucleus does not stimulate medial rectus to contract.
 Weak adduction (medial movement) of one eye.
 Affected eye cannot move toward nose.
 Unaffected (abducting) eye develops nystagmus.
 CN VI overfires to stimulate CN III.
 Convergence is usually spared.
 Different neural pathway.
 CN III working normally.
 Directional term (eg, right INO, left INO) refers to which eye is paralyzed.
INO = Ipsilateral adduction failure, Nystagmus Opposite.
Side that cannot go medial is side

with MLF lesion.
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PPRF LESIONS
 Ipsilateral Gaze Palsy.
 Paralysis of conjugate gaze to side of lesion.
 Can’t look to side of lesion.
 Left PPRF coordinates leftward gaze.
 Preservation of convergence.
 Medial pons lesions.
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RETINOBLASTOMA
 Malignancy of the retina.
 Caused by mutation (Chr 13) of Rb tumor suppressor gene.
 Loss of heterozygosity (2-hit hypothesis) leads to suppression and increased
cancer risk.
 Inherited loss of Rb leads to bilateral disease.
 Young child (<3).
 Associated with osteosarcoma (familial retinoblastoma a predisposing factor for
development).
 Presents with visual loss, leukocoria (absence of red-light reflex), unilateral
exophthalmos, and strabismus.
 Treat with surgical enucleation of affected eye.
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PHARMACOLOGY
EPILEPSY DRUGS
BREAKING SEIZURES:
 First line ttt is benzodiazepines:
o Rapid acting; lorazepam is the drug of choice.
 Also often administer:
o Phenytoin (PO) or fosphenytoin (IV).
o Prevent recurrent seizures.
 If still seizing after benzo/phenytoin phenobarbital.
 Often will then give general anesthesia and intubuate.
ANTICONVULSANTS WORKING ON GABA

 BDZ.
 Barbiturates “phenobarbital”.
 Gabapentin  GABA analogue.
 Tiagabine  inhibiting reuptake.
 Topiramate  ↑ GABA action.
 Valporate  inhibiting GABA transaminase.
 Vigabatrin  Irreversible GABA transaminase inhibitor.
 Levetiracetam  modulate GABA.
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Page 202 of 235
UW: Broad-spectrum anticonvulsants (eg, lamotrigine, levetiracetam, topiramate, valproic

acid) successfully treat most seizure types (eg, focal or generalized at onset).
In contrast, narrow-spectrum anticonvulsants (eg, carbamazepine, gabapentin, phenobarbital,

phenytoin) are favored for focal onset seizures and should usually be avoided in generalized
epilepsy syndromes as they may aggravate seizure.
UW: Status epilepticus:
 Recurrent or continuous generalized tonic-clonic seizures that last for more than 30
minutes without a return to consciousness.
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UW: Sodium valproate is the drug of choice for patients with absence and associated
tonic-clonic seizures.
Ethosuximide is also effective against absence seizures but does not suppress tonic-
clonic seizures.
UW: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome:
 Rare, potentially fatal drug reaction.

 2-8 weeks after drug exposure.
 Commonly associated drugs include anticonvulsants (eg, phenytoin,
carbamazepine), allopurinol sulfonamides (eg, sulfasalazine), and antibiotics (eg,
minocycline, vancomycin).
 Although the exact mechanism is unknown, it likely involves drug-induced
herpes virus reactivation followed by clonal expansion of T cells that cross-
react with the drug.
 Presentation:
o Fever, generalized lymphadenopathy.
o Facial edema.
o Diffuse morbilliform skin rash that can progress to a confluent erythema
with follicular accentuation.
o Other affected organs can include the liver (hepatomegaly, jaundice),
kidney (acute interstitial nephritis), and lung (cough, dyspnea).
 Laboratory:
o Eosinophilia, atypical lymphocytosis, and elevated serum alanine
transaminase.
 Clinical findings improve over several weeks following withdrawal of the drug.
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BARBITURATES
 Phenobarbital, pentobarbital, thiopental, secobarbital.
 Mechanism:
 Facilitate GABAA action by ↑ duration of Cl- channel opening, thus ↓ neuron
firing (barbidurates ↑ duration).
 Clinical use:
 Sedative for anxiety, seizures, insomnia, induction of anesthesia (thiopental).
 Adverse effects
 Respiratory and cardiovascular depression (can be fatal).
 CNS depression (can be exacerbated by alcohol use).
 Dependence.
 Drug interactions (induces cytochrome P-450).
 Overdose treatment is supportive (assist respiration and maintain BP).
 Contraindicated in porphyria.
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BENZODIAZEPINES
 Mechanism:
 Facilitate GABAA action by ↑ frequency of Cl- channel opening.
 ―Frenzodiazepines‖ ↑ frequency.
 Allosteric binding to the GABA receptor  stimulating the influx of
chloride ions into the neurons (causing neuronal hyperpolarization) 
suppression of action potential firing.
 Benzos, barbs, and alcohol all bind the GABA A receptor, which is a
ligand-gated Cl- channel.
 ↓ REM sleep.
 Most have long half-lives and active metabolites (exceptions [ATOM]:
Alprazolam, Triazolam, Oxazepam, and Midazolam are short acting  higher
addictive potential).
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 Clinical use:
 Anxiety, spasticity, status epilepticus (IV lorazepam, diazepam, midazolam),
eclampsia, detoxification (especially alcohol withdrawal– DTs), night terrors,
sleepwalking, general
anesthetic (amnesia, muscle relaxation), hypnotic (insomnia).
 Oxazepam, Temazepam, and Lorazepam are OK for Terrible Livers: they can be
used to treat alcohol withdrawal in patients with liver disease due to minimal first-
pass metabolism.
 Adverse effects:
 Dependence.
 Additive CNS depression effects with alcohol.
 Less risk of respiratory depression and coma than with barbiturates.
 Treat overdose with flumazenil (competitive antagonist at GABA benzodiazepine
receptor).
 Can precipitate seizures by causing
acute benzodiazepine withdrawal.
UW: First generation H1-histamine receptor

antagonists, including diphenhydramine and
chlorpheniramine, can cause significant sedation,
especially when used with other medications that
cause CNS depression (such as benzodiazepines).
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NONBENZODIAZEPINE HYPNOTICS
 Zolpidem, Zaleplon, esZopiclone. ―These ZZZs put you to sleep.‖

 Mechanism:
 Act via the BZ 1 subtype of the GABA receptor.
 Effects reversed by flumazenil.
 Sleep cycle less affected as compared with benzodiazepine hypnotics.
 Clinical use:
 Insomnia.
 Ataxia, headaches, confusion.
 Advantages:
 Short duration because of rapid metabolism by liver enzymes.
 Unlike older sedative-hypnotics, cause only modest day-after psychomotor
depression and few amnestic effects.
 ↓ Dependence risk than benzodiazepines.
SUVOREXANT
 Mechanism: Orexin (hypocretin) receptor antagonist.
 Clinical use: Insomnia.
 CNS depression, headache, dizziness, abnormal dreams, upper respiratory tract
infection.
 Contraindicated in patients with narcolepsy.
 Not recommended in patients with liver disease.
 Contraindicated with strong CYP3A4 inhibitors.
 No or low physical dependence.
Page 208 of 235
RAMELTEON
 Mechanism
 Melatonin receptor agonist.
 Binds MT1 and MT2 in suprachiasmatic nucleus.
 Clinical use: Insomnia.
 Few side effects: dizziness, nausea, fatigue, headache.
 Advantages:
 No dependence (not a controlled substance).
 No dosage adjustment is necessary in geriatric patients  safe in elderly.
NON-PHARMACOLOGIC TREATMENT OF INSOMNIA
Page 209 of 235
TRIPTANS
 Sumatriptan
 Mechanism:
 5-HT 1B/1D agonists.
 Inhibit trigeminal nerve activation.
 Prevent vasoactive peptide release.
 Induce vasoconstriction.
A sumo wrestler trips and falls on your head.
 Clinical use:
 Acute migraine.
 Cluster headache attacks.
 Coronary vasospasm (contraindicated in patients with CAD or Prinzmetal
angina).
 Mild paresthesia.
 Serotonin syndrome (in combination with other 5-HT agonists).
Page 210 of 235
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PARKINSON DISEASE DRUGS

 Parkinsonism is due to loss of dopaminergic neurons and excess cholinergic activity.
 Bromocriptine, Amantadine, Levodopa (with carbidopa), Selegiline (and COMT
inhibitors), Antimuscarinics (BALSA).
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Strategy Agents
Dopamine  Ergot—Bromocriptine.
agonists  Non-ergot (preferred)—pramipexole, ropinirole:
 Toxicity includes impulse control disorder (eg, gambling), postural
hypotension, hallucinations/confusion.
↑ dopamine  Amantadine:
availability  ↑ Dopamine release and ↓ dopamine reuptake.
 Toxicity = ataxia, livedo reticularis.
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↑ L-DOPA  Agents prevent peripheral (pre-BBB) L-DOPA degradation  ↑ L-

availability DOPA entering CNS  ↑ central L-DOPA available for conversion to
dopamine.
 Levodopa (L-DOPA)/carbidopa:
 Carbidopa blocks peripheral conversion of L-DOPA to dopamine
by inhibiting DOPA decarboxylase.
 Also reduces side effects of peripheral L-DOPA conversion into
dopamine (eg, nausea, vomiting).
 Entacapone:
 Prevents peripheral L-DOPA degradation to 3-O-methyldopa (3-
OMD) by inhibiting COMT.
 Used in conjunction with levodopa.
 Entacapone: peripheral COMT inhibition.
 Tolcapone: peripheral and central COMT inhibition.
 Tolcapone associated with hepatotoxicity.
Prevent  Agents act centrally (post-BBB) to inhibit breakdown of dopamine:

dopamine  Selegiline, rasagiline:
breakdown  Inhibits MAO-B:
o Central dopamine breakdown enzyme.
o Breaks down dopamine more than 5HT.
 Increases central dopamine levels.
 Side effects:
o Nausea, vomiting.
o Hypotension, Excessive daytime sleepiness.
o Serotonin syndrome:
 When given with SSRI.
 Confusion, fever, myoclonus.
o “Cheese effect”
 Hypertensive crisis.
 Tyramine foods: Red wine, aged cheese, or aged
meat.
 MAO inhibitors (a or b) block breakdown of
tyramine.
 Tyramine  HTN.
 Entacapone:
 Blocks conversion of dopamine to 3-methoxytyramine (3-
MT) by inhibiting central COMT.
Curb excess  Benztropine, trihexyphenidyl (Antimuscarinic; improves tremor and

cholinergic rigidity but has little effect on bradykinesia in Parkinson disease). Park
activity your Mercedes-Benz.
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LEVODOPA/CARBIDOPA (SINEMET)
 Mechanism:
 ↑ Level of dopamine in brain.
 Unlike dopamine, L-DOPA can cross blood-brain barrier and is converted by dopa
decarboxylase in the CNS to dopamine.
 Carbidopa, a peripheral DOPA decarboxylase inhibitor, is given with L-DOPA to
↑ the bioavailability of L-DOPA in the brain and to limit peripheral side effects.
 Clinical use:
 Parkinson disease.
 Nausea, postural hypotension from ↓ peripheral formation of catecholamines.
 ↑ Dopa available in the CNS  behavioral changes (anxiety, agitation, insomnia,
confusion, delusions, and hallucinations):
 Use lowest dose possible.
 Long-term use can lead to periodic fluctuations in motor function ("on-off"
phenomenon):
 Patients have good mobility during "on" periods and increased
bradykinesia/rigidity during ―off‖ periods.
 Causes of “on-off phenomenon”:
o Drug reduces natural L-dopa production  Akinesia occurs between
doses (eg, reduced mobility 4 hours after the last dose).
o As PD progresses, the therapeutic window for levodopa narrows,
possibly due to natural or levodopa-induced nigrostriatal
degeneration. As a result, small changes in serum drug levels can
result in motor fluctuations (eg. mild elevations may result in
dyskinesia, whereas slight reductions may result in
bradykinesia/rigidity).
 Drug response is unpredictable.
 Use lowest dose possible to avoid.
SELEGILINE, RASAGILINE
 Mechanism:
 Selectively inhibit MAO-B (metabolize dopamine)  ↑ dopamine availability.
 Clinical use:
 Adjunctive agent to L-DOPA in treatment of Parkinson disease.
 May enhance adverse effects of L-DOPA.
Page 215 of 235
PARKINSON DRUGS IN PRACTICE
 Tremor predominant symptoms:

 Trihexyphenidyl (anti-muscarinic).
 Side effects: sedation, dry mouth.
 Bradykinesia, rigidity:
 Ropinirole, pramipexole (dopamine agonists).
 Levodopa/carbidopa.
TETRABENAZINE, RESERPINE
 Mechanism:
 Inhibit vesicular monoamine transporter (VMAT) dopamine  ↓ vesicle
packaging and release.
 Clinical use:
 Huntington chorea, tardive dyskinesia.
RILUZOLE
 Mechanism: ↓ Neuron glutamate excitotoxicity. For Lou Gehrig disease, give rilouzole.
 Clinical use: ALS, ↑ survival.
ALZHEIMER DISEASE DRUGS
MEMANTINE
 Mechanism
 NMDA receptor antagonist.
 Helps prevent excitotoxicity (mediated by Ca2+).
 Dizziness, confusion, hallucinations.
DONEPEZIL, RIVASTIGMINE, GALANTAMINE
 Mechanism
 AChE inhibitors. Dona Riva dances at the gala.
 Adverse effects
 Nausea, dizziness, insomnia.
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ANESTHETICS—GENERAL PRINCIPLES
 Drugs that produce:
 Analgesia
 Loss of consciousness
 Amnesia
 Muscle relaxation.
 Types of Anesthesia Drugs:
 Inhaled anesthetics
 Intravenous anesthetics
 Local anesthetics
 Neuromuscular blocking agents.
INHALED ANESTHETIC PRINCIPLES

 Desflurane, halothane, enflurane, isoflurane, sevoflurane, methoxyflurane, N2O.
 Mechanism: Mechanism unknown.
 Special properties determine effectiveness:
 Solubility of gas for blood determines onset/offset.
 Solubility of gas for lipids determines potency.
BLOOD SOLUBILITY
 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.
 Higher solubility:
 Higher tendency to stay in blood.
 Less likely to leave blood for brain.
 Longer time to saturate blood.
 SLOWER induction time (also washout time).
 Low solubility:
 Quickly saturate blood.
 Quickly exert effects on brain.
 SHORTER induction time (also washout time).
Page 217 of 235
 Measured by blood/gas partition coefficient: Isoflurane: 1.4  [blood]1.4 >

[alveoli]
 Anesthetics with higher blood solubility have larger blood/gas partition
coefficients.
 Halothane  high PC  SLOW induction (like to stay in blood).
 Nitric Oxide  low PC  FAST induction (quickly leaves blood).
Page 218 of 235
LIPID SOLUBILITY
 Affinity of gas for a lipids.
 CNS drugs must be lipid soluble (cross the blood-brain barrier) or be actively
transported.
 Measured by oil/gas partition coefficient.
 ↑ Lipid affinity = more potent.
 MAC = Minimal Alveolar Concentration (of inhaled anesthetic):
 Concentration of gas in the lungs that produces the desired effect in 50% of
patients.
 Concentration required to prevent 50% of subjects from moving in response to
noxious stimulus (eg, skin incision).
 Determine the potency of the inhaled drug (inversely related).
o Potency = 1/MAC.
o Low MAC = High potency.
o Potent anesthetics require lower partial pressures to be effective.
o MAC changes with age: Lower in elderly.
o MAC related to lipid solubility (not blood!!).
 Examples:
 Nitrous oxide (N2O):
 Has ↓ blood and lipid solubility  fast induction and low potency.
 Halothane, propofol, and thiopental:
 ↑ Lipid and blood solubility  high potency and slow induction.
Page 219 of 235
COMMON EFFECTS OF INHALED ANESTHETICS

 Myocardial depression  hypotension.
 Respiratory depression.
 Except nitrous oxide.
 Halothane and sevoflurane have bronchodilation properties and are preferred in
patients with asthma.
 Nausea/emesis.
 ↑ Cerebral blood flow (↓ cerebral metabolic demand)  increased intracranial
pressure.
 Special adverse effects:
 Hepatotoxicity (halothane).
 Nephrotoxicity (methoxyflurane),
 Proconvulsant (enflurane, epileptogenic),
 Expansion of trapped gas in a body cavity (N2O).
o Diffuses rapidly into air spaces  used by the dentist d2 cavity
diffusion.
o Will increase space volume  cannot use in pneumothorax,
abdominal distention. 50% NO doubling of cavity size.
 Malignant hyperthermia.
Page 220 of 235

Types of troponin:
1. Troponin C: binds to Ca+2.
USMLE2.ENDPOINT,
Troponin T: NEUROLOGY
binds tropomyosin. Dr. Ahmed Shebl
3. Troponin I: inhibits myosin binding to actin.
 Malignant hyperthermia:
1. Dangerous reaction to anesthetics (halothane, succinylcholine).
2. Caused by: abnormal ryanodine receptors (autosomal dominant):
 Excessive calcium release.
 Consumption of ATP for SR to reuptake the calcium by SERCA.
 ATP consumption  heat  tissue damage.
3. Muscle damage  ↑ CK, ↑ K.
4. Fever and muscle rigidity after surgery.
5. Treat with Dantrolene
 Ryanodine receptor antagonist  blocks the release of calcium from SR.
 Reduces calcium in cytoplasm for contraction  skeletal muscle relaxant.
FACTORS INFLUENCING ANESTHETIC CONCENTRATION
Compartment Determinants of Effect

anesthetic concentration
Inhaled air The partial pressure (i.e, Anesthetic tension throughout the body
tension) of the anesthetic in will eventually equilibrate with its tension in
the inspired gas. the inspired air. When this occurs, the tissues
are said to become saturated.
Lungs Pulmonary ventilation rate. The rate of rise of gas tension in alveoli is
directly proportional to both the rate & depth
of respiration.
Blood Solubility of the anesthetic in Higher blood solubility means that more
the blood (blood/gas partition anesthetic must be absorbed by the blood
coefficient) before it can be effectively transferred to
other tissues.
Target organ Solubility of the anesthetic in Higher peripheral tissue solubility means
(brain) the peripheral tissues more anesthetic is extracted from the arterial
negatively affects brain blood. This increases the arteriovenous
saturation. concentration gradient meaning that more
anesthetic must be absorbed to saturate the
blood & then the brain.
 UW: The arteriovenous concentration gradient reflects the overall tissue solubility of an
anesthetic. Anesthetics with high tissue solubility are characterized by large arteriovenous
concentration gradients and slower onsets of action.
Page 221 of 235
INTRAVENOUS ANESTHETICS
 Induction – Put patient to sleep:
 Propofol, Etomidate, Ketamine.
 Maintenance – Keep patient asleep:
 Propofol, sevoflurane, desflurane.
Agent Mechanism Anaesthesia use Notes

Thiopental Facilitate  Induction of  ↓ Cerebral blood flow.
GABAA anesthesia.  High lipid solubility.
(barbiturate).  Short surgical  Ultra short acting:
procedures.  Rapid distribution to muscle
and fat.
 Effect terminated by rapid
redistribution into tissue
and fat.
Midazolam Facilitate  Procedural sedation  May cause severe postoperative
GABAA (eg, endoscopy). respiratory depression, ↓ BP.
(benzodiazepine)  Anesthesia  Anterograde amnesia.
induction.
Propofol Potentiates  Rapid anesthesia  Myocardial depression,
GABAA. induction. hypotension
 Short procedures.
 ICU sedation.
Ketamine NMDA receptor  Dissociative  ↑ Cerebral blood flow.
antagonist. anesthesia.  “Emergence Reactions”
PCP derivative.  Patient enters  Disorientation.
trancelike state.  Vivid dreams, hallucinations.
 Analgesia and  Can be frightening to patients.
amnesia.  Co-administer midazolam to
 Few respiratory or help.
CV effects.
 Sympathomimetic.
Etomidate Modulates  Anesthesia but not  Relatively hemodynamically
GABA analgesia. neutral  Good for hypotensive
receptors.  Rapid sequence patients.
Blocks neuro intubation ―rapid  Blocks cortisol synthesis 
excitation. inset/offset. potential for adrenal
insufficiency.
Page 222 of 235
GABA Receptor Typical Open Heart

Anesthetics Case
• Etomidate
• Propofol  Induction  Propofol, Midazolam.
• Benzodiazepines  Paralysis  Rocuronium.
• Barbiturates  Maintenance  Sevoflurane, fentanyl.
o Sevoflurane has no analgesic
• GABA is largely inhibitory. effect, so the patient may be in
• These drugs activate pain  tachycardia; so give
receptorsedation. analgesic like fentanyl with it.
LOCAL ANESTHETICS
 Esters—procaine, tetracaine, benzocaine, chloroprocaine.
 Amides—lIdocaIne, mepIvacaIne, bupIvacaIne, ropIvacaIne (amIdes have 2 I’s in name).
MECHANISM:
 Key Points:
1. Uncharged form crosses membrane.
2. Charged form blocks Na channel.
3. Drugs work on inside of cell
membrane.
4. Acidic environments ―infected
tissues‖ = more drug needed for effect.
 Most effective in rapidly firing neurons.
 Can be given with vasoconstrictors (usually epinephrine) to enhance local action—
↓ bleeding, ↑ anesthesia by ↓ systemic concentration.
 Order of nerve blockade:
 Small-diameter fibers > large diameter.
 Myelinated fibers > unmyelinated fibers.
 Overall, size factor predominates over myelination such that small myelinated
fibers > small unmyelinated fibers > large myelinated fibers > large
unmyelinated fibers.
 Order of loss:
 (1) Pain, (2) temperature, (3) touch, (4) pressure.
CLINICAL USE:
 Minor surgical procedures, spinal anesthesia.
 If allergic to esters, give amides.
Page 223 of 235
ADVERSE EFFECTS:
 CNS Stimulation:
 Initial (excitation): Talkativeness, anxiety, confusion, stuttering speech.
 Later: Drowsiness, coma.
 Cardiovascular:
 Hypotension, arrhythmia, bradycardia, heart block.
 Cocaine is exception: hypertension, vasoconstriction.
 Bupivacaine most cardiotoxic.
 Methemoglobinemia (benzocaine).
 Iron in hemoglobin normally reduced (Fe2+).
 Certain drugs like benzocaine oxidize iron to (Fe3+).
 When Fe3+ is present Methemoglobin.
 Fe3+ cannot bind oxygen.
 Remaining Fe2+ cannot release oxygen to tissues.
 Treatment: methylene blue (Fe3+  Fe2+).
Acquired methemoglobinemia
from drugs:
• Local anesthetics (benzocaine).
• Nitric oxide “premature babies
given NO for VD in pulmonary
HTN.
• Dapsone.
Page 224 of 235
NEUROMUSCULAR BLOCKING DRUGS

 Muscle paralysis in surgery or mechanical ventilation.
 Selective for Nm nicotinic receptors at neuromuscular junction but not autonomic Nn
receptors.
DEPOLARIZING NEUROMUSCULAR BLOCKING DRUGS

 Succinylcholine:
 Strong ACh receptor agonist ―basically two ACh molecules joined together‖.
 Produces sustained depolarization and prevents muscle contraction.
 Fast acting, rapid washout  rapid sequence intubation.
 Two phases to depolarizing block.
 Phase 1 “Depolarizing phase”:
o Muscle fasciculations occur.
o Na channels open and then close - become inactivated.
o Membrane potential must reset.
o Normally rapid as Ach hydrolysed by AChE.
o Succinylcholine NOT metabolized by AChE.
o Prolonged activation of ACh receptors occurs.
 Phase 2 “Desensitizing phase”:
o Depolarization has occurred.
o Muscle no longer reacts to Ach.
o Normally ACh washed out quickly – no desensitization.
o Longer depolarization (succ) desensitization.
 Reversal of blockade:
 Phase I (prolonged depolarization):
o No antidote.
o Block potentiated by cholinesterase inhibitors.
 Phase II (repolarized but blocked; ACh receptors are available, but
desensitized):
o May be reversed with cholinesterase inhibitors.
 Complications:
 Hypercalcemia, hyperkalemia, malignant hyperthermia.
Page 225 of 235
NONDEPOLARIZING NEUROMUSCULAR BLOCKING DRUGS

 Atracurium, cisatracurium, pancuronium, rocuronium, tubocurarine, vecuronium.
 Competitive with ACh for receptors.
 Reversal of blockade:
 Neostigmine (must be given with atropine or glycopyrrolate to prevent
muscarinic effects such as bradycardia).
 Edrophonium, and other cholinesterase inhibitors.
ASSESSING NEUROMUSCULAR BLOCKADE

 Peripheral nerve stimulator ―Train of 4 impulses‖.
 Used to assess neuromuscular blockade in patients under anesthesia.
 4 electrical stimulations to nerve (i.e. ulnar).
 The ratio between T4/T1 should be ¼ or 2/4 to ensure adequate relaxation.
Page 226 of 235
DANTROLENE
 Mechanism:
 Prevents release of Ca2+ from the sarcoplasmic reticulum of skeletal muscle by
binding to the ryanodine receptor.
 Clinical use:
 Malignant hyperthermia (a toxicity of inhaled anesthetics and succinylcholine)
 Neuroleptic malignant syndrome (a toxicity of antipsychotic drugs).
BACLOFEN
 Mechanism
 Skeletal muscle relaxant.
 GABAB receptor agonist in spinal cord.
 Clinical use
 Muscle spasticity, dystonia, multiple sclerosis.
CYCLOBENZAPRINE
 Mechanism
 Skeletal muscle relaxant. Acts within CNS.
 Clinical use
 Muscle spasms.
 Adverse effects
 Anticholinergic side effects.
 Sedation.
Page 227 of 235
OPIOID ANALGESICS
 Mechanism
 Act as agonists at opioid receptors (μ = β-endorphin, δ = enkephalin, κ = dynorphin).
 Modulate synaptic transmission:
 Close presynaptic Ca2+ channel.
 Open postsynaptic K+ channels  ↓ synaptic transmission.
 Inhibit release of ACh, norepinephrine, 5-HT, glutamate, substance P.
 Efficacy:
 Full agonist: morphine, heroin, meperidine, methadone, codeine.
 Partial agonist: buprenorphine.
 Has low intrinsic activity (efficacy) for opioid mu-receptors.
 However, it binds with high affinity (potency) and can prevent binding of
other opioid medications.
 Therefore, buprenorphine acts as an opioid receptor antagonist in the presence
of full opioid agonists and can precipitate withdrawal in opioid-tolerant
patients with chronic pain.
 Mixed agonist/antagonist: nalbuphine, pentazocine.
 Antagonist: naloxone, naltrexone, methylnaltrexone.
 Although naloxone binds to mu, kappa, and delta opioid receptors, it has the
greatest affinity for mu receptors, making it an ideal agent for treating opioid
intoxication.
Page 228 of 235
 Clinical use:
 Moderate to severe or refractory pain, cough suppression (dextromethorphan),
diarrhea (loperamide, diphenoxylate), acute pulmonary edema, maintenance programs
for heroin addicts (methadone, buprenorphine + naloxone).
 Nausea, vomiting, pruritus, addiction, respiratory depression, constipation, sphincter
of Oddi spasm, miosis (except meperidine  mydriasis), additive CNS depression
with other drugs.
 Tolerance does not develop to miosis and constipation.
 Toxicity treated with naloxone (opioid receptor antagonist) and relapse prevention
with naltrexone once detoxified.
 UW: long-term activation of mu-opioid receptors on nociception-transmitting neurons is

associated with increased pain sensitivity (central sensitization) due to:
 Increased turnover of inhibitory opioid receptors (receptor downregulation) and
decoupling of receptors from their second messenger system (receptor
decoupling).
 Upregulation of excitatory N-methyl-D-aspartate (NMDA) receptors.
 This manifests as an increasing dose requirement to provide the same level of pain relief
(tolerance) and pain sensations triggered by benign stimuli (opioid-induced
hyperalgesia).
PENTAZOCINE
 Mechanism
 κ-opioid receptor agonist and μ-opioid receptor weak antagonist or partial agonist.
 Clinical use
 Analgesia for moderate to severe pain.
 Adverse effects
 Can cause opioid withdrawal symptoms if patient is also taking full opioid agonist
(due to competition for opioid receptors).
BUTORPHANOL
 Mechanism: κ-opioid receptor agonist and μ-opioid receptor partial agonist.

 Clinical use:
 Severe pain (eg, migraine, labor). Causes less respiratory depression than full opioid agonists.
 Use with full opioid agonist can precipitate withdrawal. Not easily reversed with naloxone.
Page 229 of 235
TRAMADOL
 Mechanism: Very weak opioid agonist; also inhibits 5-HT receptors.
 Clinical use: Chronic pain.
 Similar to opioids.
 Decreases seizure threshold.
 Serotonin syndrome.
NEONATAL ABSTINENCE SYNDROME (NAS)
Page 230 of 235
GLAUCOMA DRUGS
 ↓ IOP via ↓ amount of aqueous humor (inhibit synthesis/secretion or ↑ drainage).
 BAD humor may not be Politically Correct.
Page 231 of 235
UW MISCELLANEOUS
TOPICS:
UW: Beta-endorphin is one endogenous opioid peptide that is derived from
proopiomelanocortin (POMC). POMC is a polypeptide precursor that goes through
enzymatic cleavage and modification to produce not only beta-endorphins, but also
ACTH and MSH.
The fact that beta-endorphin and ACTH are derived from the same precursor suggests
that there may be a close physiological relationship between the stress axis and the
opioid system.
Page 232 of 235
UW: Myotonia:
 Abnormally slow relaxation of muscles.

 Second most common inherited muscle disorder (Duchenne is the most
common).
 Trinucleotide repeat expansion (CTG) of the gene that codes for a myotonia-
protein kinase.
 Autosomal dominant and shows anticipation.
 Symptoms:
1. Difficulty loosening one's grip after a handshake
2. Inability to release the doorknob.
3. Cataracts are seen in almost all patients.
4. Frontal balding.
5. Gonadal atrophy.
 Light microscopy:
1. Atrophy of muscle fibers is prominent. Type 1 fibers are more affected.
2. Unlike Duchenne muscular dystrophy, necrosis of muscle fibers and
fibrofatty replacement are not common in myotonic dystrophy.
Page 233 of 235
 Malformation:
 Primary defect in the cells or tissues that form an organ.
 An intrinsic developmental abnormality.
 Originates very early in fetal life.
 Examples:
 Holoprosencephaly which occurs early in 5th week of fetal life.
 Congenital heart disease, anencephaly, polydactyly and
syndactyly.
 Deformity:
 Fetal structural anomalies that occur due to extrinsic mechanical
forces.
 The pressure applied by the uterus is one of the most common
deforming forces.
 For example, uterine constraint on a fetus in breech position can cause
congenital dislocation of the hip. Clubbed feet are also deformations.
 Disruption:
 Secondary breakdown of a previously normal tissue or structure.
 For example, rupture of the amnion during fetal development may
produce amniotic bands which can compress or even amputate fetal
limbs (amniotic band syndrome).
 Agenesis:
 Complete absence of an organ.
 Renal agenesis is an example of this type of abnormality.
 The most effective treatment for herpes simplex virus encephalitis is

intravenous acyclovir; whose mechanism of action is complete inhibition of the
viral DNA polymerase (synthesizes viral DNA).
Page 234 of 235
UW: Diabetic peripheral neuropathy:
 Mechanisms:
1. Non-enzymatic glycosylation of proteins:
 Leads to increased thickness, hyalinization, and narrowing of the
walls of the arteries.
 These changes lead to diabetic microangiopathy of endoneural
arterioles.
 Ischemic nerve damage follows.
2. Osmotic damage:
 Intracellular hyperglycemia occurs in peripheral nerves.
 Accumulating glucose is converted into sorbitol and fructose by
aldose reductase.
 Sorbitol increases cell osmolarity and facilitates water influx into
the cell.
 The result is osmotic damage to axons and Schwann cells.
UW: The diagnosis of tetanus is clinical. It is based on history of penetrating wound in a patient
who has not been vaccinated, clinical features consistent with tetanus such as trismus, sardonic
smile and muscle spasms, and a high clinical suspicion.
Page 235 of 235
 Lissencephaly
 Neuron action potential P. 11

Q Resting membrane potential: membrane is more permeable to K+ than Na+ at rest. Voltage-gated Na+ and K+
channels are closed.
R Membrane depolarization: Na+ activation gate opens Na+ flows inward.
S Membrane repolarization: Na+ inactivation gate closes at peak potential, thus stopping Na+ inflow. K+ activation
gate gate opens K+ flows outward.
T Membrane hyperpolarization: K+ activation gates are slow to close excess K+ efflux and brief period of
hyperpolarization. Voltage-gated Na+ channels switch back to resting state. Na+/K+ pump restores ions
concentration.
 Cerebral perfusion P. 39
Cushing reflex—triad of hypertension, bradycardia, and respiratory depression in response to I +CP.
 Cerebellum P. 55
 Depolarizing neuromuscular blocking drugs P. 225

Complications include hypercalcemia, hyperkalemia, malignant hyperthermia. risk of prolonged muscle paralysis in
patients with pseudocholinesterase deficiency.
 Tendon reflex grading P. 92
0: absent
1: hypoactive
2: normal
3: hyperactive
4: clonus
 Headaches P. 118
Pain due to irritation of structures such as the dura, cranial nerves, or extracranial structures. Primary headaches
include cluster, migraine, and tension; migraine and tension headaches are more common in females. Secondary
headaches include subarachnoid hemorrhage, meningitis, hydrocephalus, neoplasia, giant cell (temporal) arteritis.
 Restless legs syndrome P. 136

intro Uncomfortable sensations in legs causing irresistible urge to move them; relieved by movement; worse at
rest/nightime.
 Ocular motility P. 190

Blowout fracture—orbital floor fracture; usually caused by direct trauma to eyeball or intraorbital rim. risk of IR
muscle A and/or orbital fat entrapment. May lead to infraorbital nerve injury.
 Local anesthetics P. 223
 Friedreich ataxia P. 61
Outer ear Visible portion of ear (pinna), includes auditory canal and tympanic membrane. Transfers sound waves via
vibration of tympanic membrane.
Middle ear Air-filled space with three bones called the ossicles (malleus, incus, stapes). Ossicles conduct and
amplify sound from tympanic membrane to inner ear.
Inner ear Snail-shaped, fluid-filled cochlea. Contains basilar membrane that vibrates 2° to sound waves.
Vibration transduced via specialized hair cells Ž auditory nerve signaling Ž brain stem.
Each frequency leads to vibration at specific location on basilar membrane (tonotopy):
1. Low frequency heard at apex near helicotrema (wide and flexible).
2. High frequency heard best at base of cochlea (thin and rigid).
 Locus ceruleus: Paired, pigmented, brain stem nucleus found in posterior rostral pons near the lateral
floor of the 4th ventricle It is the main site of NE production in the brain → arousal, ↑↑ in anxiety
Damage to these nuclei in pontine hemorrhage is the cause of deep coma → defective in reticular
activating system.
 Raphe nucleus: Single, midline nucleus involved in sleep & pain modulation.
 Site and action of raphe nucleus:

- It produces serotonin, with its axons project over large areas of brain to control sleep wake cycle,
anxiety, mood, psychosis, sexuality, eating behavior. It present in the midbrain pons, medulla in the
midline.
 Cerebral perfusion
In therapeutic hyperventilation, what is the range of change of PaCo2 to be achievec ? In range of BP 50 –

150 → autoregulation occur, ↓↓ PCo2 → vasoconstriction → ↓↓ CBF, but severe drop in CO2 → ↓ perfusion
→ worsen neurological injury in acute trauma → so PaCO2should be kept ≥ 30 mmHg.
 Grestleman syndrome :
 Due to damage in angular gyrus in dominant parietal lobe
 Part of sensory association area responsible for integration of sensations
 May be isolated, or associated with alexia (inability to read) & aphasia (impaired speech)
 What is the difference between chorea & hemiballismus :

 Chorea: involuntary, low amplitude movements, involving distal limbs. Due to atrophy of the
caudate nucleus
 Hemiballismus: involuntary, large amplitude movement, wild, flinging movement affecting the
proximal limbs, due to damage of the subthalamic nucleus.
 Saccular aneurysms :
 Pcom → compress CN III as it passes between SCA & PCA
 Acom → compress optic chiasm
 Creutzfeldt Jacob dementia (CJD) :
 Most of transmitted cases are iatrogenic in corneal transplant, implantable electrodes, GH
 Other prion diseases : Kuru (seen in New Guinea that eat infected human brain), fatal familial
insomnia
 Common features: long incubation period (with rapidly progressive clinical picture)
 Uhthoff’s phenomena : worsening of neurological symptoms in MA when the body get oer heated in
exercise, fever, hot tubs …etc.
 Effects of solubility on the onset of gas anesthetics

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USMLE ENDPOINT,

REGIONAL SPECIFICATION OF DEVELOPING BRAIN

CENTRAL AND PERIPHERAL NERVOUS SYSTEMS ORIGINS

 Anterior pituitary  from oral ectoderm (Rathke’s pouch) = surface ectoderm.

NEURAL TUBE DEFECTS

 Folic acid antagonists (anti-epileptic drugs, trimethoprim) during pregnancy are

SPINA BIFDA OCCULTA

 Failure of caudal neuropore to close, but no herniation.

SPINA BIFIDA CYSTICA

 Also known as rachischisis.

 Failure of rostral (anterior or cranial) neuropore to

POSTERIOR FOSSA MALFORMATIONS

 Failure of foramen Luscka and Magendie to open  dilated 4th ventricle.

Red arrow  agenesis of

Blue arrow  cystic dilation

ANATOMY AND PHYSIOLOGY

 UW: In the peripheral nervous system:

NEURON ACTION POTENT IALS

What are the Nodes of Ranvier?

What voltage gated channels are concentrated in the nodes of Ranvier?

What is the function of these channels?

What happen to these channels in individuals with demyelinating disease?

TYPES OF NERVE FIBER S

Receptor Sensory neuron fiber type Location Senses

PERIPHERAL NERVE DAMAGE

CENTRAL NERVE DAMAGE

 ~ 4-5 minutes of ischemia  irreversible damage.

CHANGES AFTER INFARCTION

 GABA is largely inhibitory.

 Synthesized in raphe nucleus (pons).

 Synthesized in basal nucleus of Meynert (subcortex).

 Major excitatory neurotransmitter.

PHENCYCLIDINE (PCP) (ANGEL DUST)

NEUROTRANSMITTER CHANGES WITH DISEASE

UW: Tight junctions between nonfenestrated capillary endothelial cells:

CEREBRAL CORTEX REGIONS

 Motor function (initiation of movements), planning movements, thinking, feeling,

PRIMARY MOTOR AREA:

PREMOTOR AREA (AREA 6):

FRONTAL EYE FIELDS

BROCA’S SPEECH AREA

EXNER'S AREA (AREA 45) :

PRIMARY SOMATOSENSORY AREA:

 Damage to right (non-dominant) parietal lobe: spatial neglect:

PRIMARY AUDITORY CORTEX:

AUDITORY ASSOCIATIVE AREA:

WERNICKE’S SPEECH AR EA:

 Visual Sensory Area: for the reception of visual images.

MCA: Upper limb, face.

THE PYRAMIDAL SYSTEM (U.M.N.):

THE EXTRAPYRAMIDAL (EXTRA A) SYSTEM:

THE CEREBELLAR SYSTEM:

THE LOWER MOTOR NEURON (L.M.N.)

UPPER MOTOR NEURONS VS LOWER MOTOR NEURONS

 UMN cross just below medulla.

 Bulbar muscles are supplied by CN in brainstem •

BULBAR VS. PSEUDOBULBAR

CEREBRAL ARTERIES—CORTICAL DISTRIBUTION

 System of anastomoses between anterior and posterior blood supplies to brain.

CEREBROSPINAL FLUID (CSF)

 Ventricles can communicate with each other.

NORMAL PRESSURE HYDROCEPHALUS (NPH)

 Normal opening pressure on LP: