Neuroanatomy: ↑ conduction velocity of signals transmitted down axons → saltatory conduction of action potential at the nodes of Ranvier, where there are high concentrations of Na+ channels synthesized by oligodendrocytes in CNS (including CN I and II) and Schwann cells in PNS (including CN III-XII) wraps and insulates axons: ↑ space constant and ↑ conduction velocity

Myelin COPS: CNS = Oligodendrocytes PNS = Schwann cells

Neurology and Special Senses - First Aid Flashcards by Juan Suazo

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:

CNS Neurons
Ependymal Cells
- inner lining of ventricles
- make CSF
Oligodendrocytes
Astrocytes

Neuroepithelia in Neural Tube

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Central and Peripheral Nervous Systems Origins:

PNS Neurons
Schwann Cells

Neural Crest

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Central and Peripheral Nervous Systems Origins:

Microglia (like macrophages)

Mesoderm

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Neural Tube Defects

Neuropores fail to fuse (4th week) → persistent connection between amniotic cavity and spinal canal.
Associated with maternal diabetes as well as low folic acid intake before conception and during pregnancy.
↑ α-fetoprotein (AFP) in amniotic fluid and maternal serum (except spina bifida occulta = normal AFP).
↑ acetylcholinesterase (AChE) in amniotic fluid is a helpful confirmatory test.

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Neural Tube Defects:

failure of caudal neuropore to close, but no herniation
usually seen at lower vertebral levels
dura is intact
associated with tuft of hair or skin dimple at level of bony defect

Spina Bifida Occulta

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Neural Tube Defects:

meninges (but no neural tissue) herniate through bony defect
associated with spina bifida cystica

Meningocele

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Neural Tube Defects:

meninges and neural tissue (eg. cauda equina) herniate through bony defect

Meningomyelocele

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Neural Tube Defects:

also known as rachischisis
exposed unfused neural tissue without skin/meningeal covering

Myeloschisis

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Neural Tube Defects:

failure of rostral neuropore to close → no forebrain, open calvarium
Clinical Findings: polyhydramnios (no swallowing center in brain)

Anencephaly

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Neurologic Defects:

failure of left and right hemispheres to separate
usually occurs during weeks 5–6
may be related to mutations in sonic hedgehog signaling pathway
moderate form has cleft lip/palate, most severe form results in cyclopia
seen in trisomy 13 and fetal alcohol syndrome
MRI reveals monoventricle and fusion of basal ganglia

Holoprosencephaly

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Posterior Fossa Malformations:

ectopia of cerebellar tonsils (1 structure)
congenital
usually asymptomatic in childhood
manifests in adulthood with headaches and cerebellar symptoms
associated with spinal cavitations (eg. syringomyelia)

Chiari I Malformation

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Posterior Fossa Malformations:

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)

Chiari II malformation

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Posterior Fossa Malformations:

agenesis of cerebellar vermis leads to cystic enlargement of 4th ventricle that fills the enlarged posterior fossa
associated with noncommunicating hydrocephalus, spina bifida

Dandy-Walker Syndrome

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Neurologic Defects:

cystic cavity (syrinx) within central canal of spinal cord
fibers crossing in anterior white commissure (spinothalamic tract) are typically damaged first
results in a “cape-like,” bilateral symmetrical loss of pain and temperature sensation in upper extremities (fine touch sensation is preserved)
associated with Chiari malformations and other congenital malformations
acquired causes include trauma and tumors
most common at C8–T1

Syringomyelia

syrinx = tube, as in syringe

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Tongue Development

1st and 2nd branchial arches form anterior 2/3 (thus sensation via CN V3, taste via CN VII).
3rd and 4th branchial arches form posterior 1/3 (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, “the genie sticks out his tongue”), and styloglossus (draws sides of tongue upward to create a trough for swallowing).
Motor innervation is via CN X to palatoglossus (elevates posterior tongue during swallowing).
Taste—CN VII, IX, X (solitary nucleus)
Pain—CN V3, IX, X
Motor—CN X, XII

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Neuroanatomy:

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—degeneration of axon distal to site of injury and axonal retraction proximally; allows for potential regeneration of axon (if in PNS)
macrophages remove debris and myelin

Neurons

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Neuroanatomy:

most common glial cell type in CNS
physical support, repair, extracellular K⁺ buffer, removal of excess neurotransmitter, component of blood-brain barrier, glycogen fuel reserve buffer
reactive gliosis in response to neural injury
derived from neuroectoderm
GFAP—marker

Astrocytes

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Neuroanatomy:

phagocytic scavenger cells of CNS (mesodermal, mononuclear origin)
activated in response to tissue damage
not readily discernible by Nissl stain
HIV-infected cells fuse to form multinucleated giant cells in CNS

Microglia

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Neuroanatomy:

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)

Ependymal Cells

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Neuroanatomy:

↑ conduction velocity of signals transmitted down axons → saltatory conduction of action potential at the nodes of Ranvier, where there are high concentrations of Na⁺ channels
synthesized by oligodendrocytes in CNS (including CN I and II) and Schwann cells in PNS (including CN III-XII)
wraps and insulates axons: ↑ space constant and ↑ conduction velocity

Myelin

COPS:

CNS = Oligodendrocytes
PNS = Schwann cells

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Neuroanatomy:

myelinates only 1 PNS axon
also promote axonal regeneration
derived from neural crest
injured in Guillain-Barré syndrome

Schwann Cells

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Neuroanatomy:

myelinates axons of neurons in CNS
can myelinate many axons (∼ 30)
predominant type of glial cell in white matter
derived from neuroectoderm
“fried egg” appearance histologically
injured in multiple sclerosis, progressive multifocal leukoencephalopathy (PML), and leukodystrophies

Oligodendrocytes

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Sensory Receptors:

C—slow, unmyelinated fibers
Aδ—fAst, myelinated fibers
all skin, epidermis, some viscera
pain, temperature

Free Nerve Endings

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Sensory Receptors: * large, myelinated fibers * adapt quickly * glabrous (hairless) skin * dynamic, fine/light touch, position sense

Meissner Corpuscles

Sensory Receptors: * large, myelinated fibers * adapt quickly * deep skin layers, ligaments, joints * vibration, pressure

Pacinian Corpuscles

Sensory Receptors: * large, myelinated fibers * adapt slowly * finger tips, superficial skin * pressure, deep static touch (eg. shapes, edges), position sense

Merkel Discs

Sensory Receptors: * dendritic endings with capsule * adapt slowly * finger tips, joints * pressure, slippage of objects along surface of skin, joint angle change

Ruffini Corpuscles

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)

Neuropathology: * reaction of neuronal cell body to axonal injury * changes reflect ↑ protein synthesis in effort to repair the damaged axon * characterized by: * round cellular swelling * displacement of the nucleus to the periphery * dispersion of Nissl substance throughout cytoplasm * concurrent with Wallerian degeneration

Chromatolysis

Neurotransmitter Changes with Disease

Meninges

* Three membranes that surround and protect the brain and spinal cord: * Dura Mater * thick outer layer closest to skull * derived from mesoderm * Arachnoid Mater * middle layer * contains web-like connections * derived from neural crest * 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

Blood-Brain Barrier

* Prevents circulating blood substances (eg. bacteria, drugs) from reaching the CSF/CNS. * Formed by 3 structures: * Tight Junctions between nonfenestrated capillary endothelial cells * Basement Membrane * Astrocyte Foot Processes * Glucose and amino acids cross slowly by carrier-mediated transport mechanisms. * 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 (eg. area postrema—vomiting after chemo; OVLT [organum vasculosum lamina terminalis]—osmotic sensing) or neurosecretory products to enter circulation (eg. neurohypophysis—ADH release). * Infarction and/or neoplasm destroys endothelial cell tight junctions → vasogenic edema. * Other notable barriers include: * Blood-Testis Barrier * Maternal-Fetal Bood Barrier of Placenta

Neuroanatomy: * Maintains homeostasis by: * regulating yhirst and water balance * controlling Adenohypophysis (anterior pituitary) and Neurohypophysis (posterior pituitary) release of hormones produced in the hypothalamus * regulating hunger, Autonomic nervous system, temperature, and sexual urges * areas not protected by blood-brain barrier: * OVLT (senses change in osmolarity) * Area Postrema (found in medulla, responds to emetics)

Hypothalamus **TAN HATS**: * Thirst and water balance * Adenohypophysis * Neurohypophysis * Hunger * Autonomic nervous system * Temperature * Sexual urges

Hypothalamus: * hunger * destruction → anorexia, failure to thrive (infants) * stimulated by Ghrelin * inhibited by Leptin

Lateral Nucleus **L**ateral injury makes you **L**ean.

Hypothalamus: * satiety * destruction (eg. craniopharyngioma) → hyperphagia * stimulated by Leptin

Ventromedial Nucleus **V**entro**M**edial injury makes you **V**ery **M**assive.

Hypothalamus: * cooling * parasympathetic

Anterior Nucleus **A**/**C** = **A**nterior **C**ooling

Hypothalamus: * heating * sympathetic

Posterior Nucleus * **H**eating controlled by **P**osterior hypothalamus (“**H**ot **P**ot”). * If you zap your posterior hypothalamus, you become a poikilotherm (cold-blooded, like a snake).

Hypothalamus: circadian rhythm

Suprachiasmatic Nucleus You need **sleep** to be **charismatic** (chiasmatic).

Hypothalamus: * synthesize ADH and Oxytocin * ADH and Oxytocin are carried by Neurophysins down axons to posterior pituitary, where these hormones are stored and released

Supraoptic and Paraventricular Nuclei

Hypothalamus: * thermoregulation, sexual behavior * releases GnRH * failure of GnRH-producing neurons to migrate from olfactory pit → Kallmann Syndrome

Preoptic Nucleus

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) * Neurokinin (NK-1) * 5-HT3, D2, and NK-1 antagonists used to treat chemotherapy-induced vomiting. * M1 and H1 antagonists used to treat motion sickness and hyperemesis gravidarum.

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). * Two Stages: * Rapid-Eye Movement (REM) * 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.

Sleep Physiology

Neuroanatomy: major relay for all ascending sensory information except olfaction

Thalamus

Thalamus: * Input: * spinothalamic and dorsal columns/medial lemniscus * Senses: * vibration * pain * pressure * proprioception * light touch * temperature * Destination: * 1° Somatosensory Cortex

**V**entral **P**ostero**L**ateral Nucleus * Senses: * **V**ibration * **P**ain * **P**ressure * **P**roprioception * **L**ight Touch * Temperature

Thalamus: * Input: * trigeminal and gustatory pathway * Senses: * face sensation * taste * Destination: * 1° Somatosensory Cortex

Ventral Postero**M**edial Nucleus **M**akeup goes on the **face**.

Thalamus: * Input: * CN II * optic chiasm * optic tract * Senses: * vision * Destination: * Calcarine Sulcus

Lateral Geniculate Nucleus **L**ateral = **L**ight

Thalamus: * Input: * superior olive and inferior colliculus of tectum optic chiasm * Senses: * hearing * Destination: * Auditory Cortex of Temporal Lobe

Medial Geniculate Nucleus Medial = Music

Thalamus: * Input: * basal ganglia * cerebellum * Senses: * motor * Destination: * Motor Cortex

Ventral Lateral Nucleus

Neuroanatomy: * collection of neural structures involved in emotion, long-term memory, olfaction, behavior modulation, and ANS function * Consists of: * Hippocampus * Amygdalae * Mammillary Bodies * Anterior Thalamic Nuclei * Cingulate Gyrus * Entorhinal Cortex * Responsible for: * feeding * fleeing * fighting * feeling * sex

Limbic System **5 F**’s: * **F**eeding * **F**leeing * **F**ighting * **F**eeling * **F**ucking

Dopaminergic Pathways: * ↓ activity → “negative” symptoms (eg. anergia, apathy, lack of spontaneity) * antipsychotic drugs have limited effect

Mesocortical

Dopaminergic Pathways: * ↑ activity → “positive” symptoms (eg. delusions, hallucinations) * 1° therapeutic target of antipsychotic drugs → ↓ positive symptoms (eg. in schizophrenia)

Mesolimbic

Dopaminergic Pathways: * ↓ activity → extrapyramidal symptoms (eg. dystonia, akathisia, parkinsonism, tardive dyskinesia) * major dopaminergic pathway in brain * significantly affected by movement disorders and antipsychotic drugs

Nigrostriatal

Dopaminergic Pathways: ↓ activity → ↑ prolactin → ↓ libido, sexual dysfunction, galactorrhea, gynecomastia (in men).

Tuberoinfundibular

Cerebellum Input

* Contralateral Cortex via Middle Cerebellar Peduncle * ipsilateral proprioceptive information via Inferior Cerebellar Peduncle from spinal cord

Cerebellum Output:

* Purkinje Cells (always inhibitory) → Deep Nuclei of Cerebellum → Contralateral Cortex via Superior Cerebellar Peduncle * Deep Nuclei (lateral → medial) * **D**entate * **E**mboliform * **G**lobose * **F**astigial **D**on’t **E**at **G**reasy **F**oods.

Neuroanatomy: * important in voluntary movements and making postural adjustments * receives cortical input, provides negative feedback to cortex to modulate movement

Basal Ganglia * *D1**-**R**eceptor = **D1R**ect Pathway * *I**ndirect (D2) = **I**nhibitory

Basal Ganglia: Putamen (motor) + Caudate (cognitive)

Striatum

Basal Ganglia: Putamen + Globus Pallidus

Lentiform

Cerebral Cortex Regions

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.

Cerebral Perfusion

* Brain perfusion relies on tight autoregulation. * Cerebral perfusion is primarily driven by * Pco2 (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 Po₂ \< 50 mm Hg. * CPP is directly proportional to Pco₂ until Pco₂ \> 90 mm Hg.

Cerebral Arteries—Cortical Distribution

Watershed Zones

* Between anterior cerebral/middle cerebral, posterior cerebral/middle cerebral arteries (cortical border zones); or may also occur between the superficial and deep vascular territories of the middle cerebral artery (internal border zones). * Damage by severe hypotension → proximal upper and lower extremity weakness (if internal border zone stroke), higher order visual dysfunction (if posterior cerebral/middle cerebral cortical border zone stroke).

Circle of Willis

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

Neuropathology: * 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)

Venous Sinus Thrombosis

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 **L**uschka = **L**ateral * Foramen of **M**agendie = **M**edial * CSF made by ependymal cells of choroid plexus. * Travels to subarachnoid space via foramina of Luschka and Magendie, is reabsorbed by arachnoid granulations, and then drains into dural venous sinuses.

Brain Stem—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.”

Brain Stem—Dorsal View | (cerebellum removed)

* 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).

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 * **L**ateral Nuclei = sensory (a**L**ar plate) * **M**edial Nuclei = **M**otor (basal plate) * Sulcus Limitans—separates the cranial nerve motor nuclei from the sensory nuclei

Cranial Nerve and Vessel Pathways

Cranial Nerves: * eye movement (SO) * motor

Trochlear IV

Cranial Nerves: * mastication * facial sensation (ophthalmic, maxillary, mandibular divisions) * somatosensation from anterior 2/3 of tongue * both sensory and motor

Trigeminal V

Cranial Nerves: * facial movement * taste from anterior 2/3 of tongue (chorda tympani) * lacrimation * salivation (submandibular and sublingual glands) * eyelid closing (orbicularis oculi) * auditory volume modulation (stapedius) * both sensory and motor

Facial VII

Cranial Nerves: * taste and sensation from posterior 1/3 of tongue * swallowing * salivation (parotid gland) * monitoring carotid body and sinus chemo- and baroreceptors * elevation of pharynx/larynx (stylopharyngeus) * both sensory and motor

Glossopharyngeal IX

Cranial Nerves: * taste from supraglottic region * swallowing * soft palate elevation * midline uvula * talking * cough reflex * parasympathetics to thoracoabdominal viscera * monitoring aortic arch chemo- and baroreceptors * both sensory and motor

Vagus X

Vagal Nuclei: * visceral sensory information (eg. taste, baroreceptors, gut distention) * CN VII, IX, X

Nucleus Solitarius **S**olitarius = **S**ensory

Vagal Nuclei: * motor innervation of pharynx, larynx, and upper esophagus (eg, swallowing, palate elevation) * CN IX, X, XI (cranial portion)

Nucleus Ambiguus A**M**biguus = **M**otor

Vagal Nuclei: * sends autonomic (parasympathetic) fibers to heart, lungs, and upper GI * CN X

Dorsal Motor Nucleus

Cranial Nerve Reflexes: * Afferent: * V1 ophthalmic (nasociliary branch) * Efferent: * bilateral VII (temporal branch: orbicularis oculi)

Corneal

Cranial Nerve Reflexes: * Afferent: * V1 (loss of reflex does not preclude emotional tears) * Efferent: * VII

Lacrimation

Cranial Nerve Reflexes: * Afferent: * V3 (sensory—muscle spindle from masseter) * Efferent: * V3 (motor—masseter)

Jaw Jerk

Cranial Nerve Reflexes: * Afferent: * II * Efferent: * III

Pupillary

Cranial Nerve Reflexes: * Afferent: * IX * Efferent: * X

Gag

Mastication Muscles

* 3 muscles close the jaw: * **M**asseter * Te**M**poralis * **M**edial Pterygoid **M**’s **M**unch * 1 muscle opens the jaw: * **L**ateral Pterygoid **L**ateral **L**owers (when speaking of pterygoids with respect to jaw motion) * All are innervated by trigeminal nerve (V3). * “It takes more muscle to keep your mouth shut.”

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).

Neuropathology: * 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

Vertebral Disc Herniation

Spinal Cord—Lower Extent

* In adults, spinal cord ends at lower border of L1–L2 vertebrae. * **S**ubarachnoid **S**pace (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). * "To keep the cord alive, keep the spinal needle between L3 and L5." * Goal of lumbar puncture is to obtain sample of CSF without damaging spinal cord.

Spinal Cord and Associated Tracts

* **L**egs (**L**umbosacral) are **L**ateral in **L**ateral corticospinal, spinothalamic tracts. * Dorsal columns are organized as you are, with hands at sides. * “Arms outside, legs inside.”

\_\_\_\_\_ tracts synapse and then cross.

Ascending

Clinical Reflexes

Reflexes count up in order (main nerve root in bold): * 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”)

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.

Primitive Reflexes: * “hang on for life” * abduct/extend arms when startled, and then draw together

Moro Reflex

Primitive Reflexes: * 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

Plantar Reflex

Primitive Reflexes: stroking along one side of the spine while newborn is in ventral suspension (face down) causes lateral flexion of lower body toward stimulated side

Galant Reflex

Landmark Dermatomes: posterior half of skull

Landmark Dermatomes: * high turtleneck shirt * diaphragm and gallbladder pain referred to the right shoulder via phrenic nerve

C3 C**3**, **4**, **5** keeps the diaphragm alive.

Landmark Dermatomes: low-collar shirt

Landmark Dermatomes: includes thumbs

C6 Thumbs up sign on left hand looks like a **6**.

Landmark Dermatomes: at the nipple

T4 T4 at the **teat pore**.

Landmark Dermatomes: at the xiphoid process

Landmark Dermatomes: * at the umbilicus * important point of referred pain in early appendicitis

T10 belly but**ten**

Landmark Dermatomes: at the inguinal ligament

L1 **I**nguinal **L**igament

Landmark Dermatomes: includes the kneecaps

L4 down on **ALL 4**’s

Landmark Dermatomes: sensation of penile and anal zones

S2, S3, S4 **S2**, **3**, **4** keep the penis off the floor

Common Brain Lesions: * disinhibition and deficits in concentration, orientation, and judgment * may have reemergence of primitive reflexes

Frontal Lobe

Common Brain Lesions: * eyes look toward (destructive) side of lesion * in seizures (irritative), eyes look away from side of the lesion

Frontal Eye Fields

Common Brain Lesions: * eyes look away from side of lesion * ipsilateral gaze palsy (inability to look toward side of lesion)

Paramedian Pontine Reticular Formation

Common Brain Lesions: * internuclear ophthalmoplegia (impaired adduction of ipsilateral eye; nystagmus of contralateral eye with abduction) * Multiple Sclerosis

Medial Longitudinal Fasciculus

Common Brain Lesions: * agraphia, acalculia, finger agnosia, left-right disorientation * Gerstmann Syndrome

Dominant Parietal Cortex

Common Brain Lesions: * agnosia of the contralateral side of the world * Hemispatial Neglect Syndrome

Nondominant Parietal Cortex

Common Brain Lesions: Anterograde Amnesia—inability to make new memories

Hippocampus (bilateral)

Common Brain Lesions: * may result in tremor at rest, chorea, and athetosis * Parkinson Disease * Huntington Disease

Basal Ganglia

Common Brain Lesions: contralateral hemiballismus

Subthalamic Nucleus

Common Brain Lesions: Wernicke-Korsakoff Syndrome * confusion * ataxia * nystagmus * ophthalmoplegia * memory loss (anterograde and retrograde amnesia) * confabulation * personality changes

Mammillary Bodies (bilateral) Wernicke problems come in a **CAN** **O**’ beer. * **C**onfusion * **A**taxia * **N**ystagmus * **O**phthalmoplegia

Common Brain Lesions: * Klüver-Bucy Syndrome * disinhibited behavior * hyperphagia * hypersexuality * hyperorality * HSV-1 Encephalitis

Amygdala (bilateral)

Common Brain Lesions: * Parinaud Syndrome * vertical gaze palsy * pupillary light-near dissociation * lid retraction * convergence-retraction nystagmus * stroke, hydrocephalus, pinealoma

Dorsal Midbrain

Common Brain Lesions: reduced levels of arousal and wakefulness (eg. coma)

Reticular Activating System (midbrain)

Common Brain Lesions: * intention tremor, limb ataxia, loss of balance * ipsilateral deficits * fall toward side of lesion

Cerebellar Hemisphere Cerebellar hemispheres are **lateral**ly located—affect **lateral** limbs.

Common Brain Lesions: * Decorticate (flexor) Posturing * lesion above * presents with flexion of upper extremities and extension of lower extremities * Decerebrate (extensor) Posturing * lesion at or below * presents with extension of upper and lower extremities * worse prognosis

Red Nucleus

Common Brain Lesions: * truncal ataxia (wide-based, “drunken sailor” gait), dysarthria * degeneration associated with chronic alcohol use

Cerebellar Vermis Vermis is **central**ly located—affects **central** body.

Ischemic Brain Disease/Stroke

* Irreversible damage begins after 5 minutes of hypoxia. * Most vulnerable: hippocampus, neocortex, cerebellum (Purkinje cells), watershed areas. Irreversible neuronal injury. * Hippocampus is most vulnerable to ischemic hypoxia (“**vulnerable hippos**”). * Stroke Imaging: * CT Scan * Noncontrast CT to exclude hemorrhage (before tPA can be given) * CT detects ischemic changes in 6–24 hr * MRI * Diffusion-Weighted MRI can detect ischemia within 3–30 min

Histologic Features of Stroke: 12-24 hours

eosinophilic cytoplasm + pyknotic nuclei (red neurons)

Histologic Features of Stroke: 24-72 hours

necrosis + neutrophils

Histologic Features of Stroke: 3-5 days

macrophages (microglia)

Histologic Features of Stroke: 1-2 weeks

reactive gliosis (astrocytes + vascular proliferation

Histologic Features of Stroke: \> 2 weeks

glial scar

Neuropathology: acute blockage of vessels → disruption of blood flow and subsequent ischemia → liquefactive necrosis

Ischemic Stroke

Ischemic Stroke: * due to hypoperfusion or hypoxemia * common during cardiovascular surgeries * tends to affect watershed areas

Hypoxic

Ischemic Stroke: Treatment

* tPA (if within 3–4.5 hr of onset and no hemorrhage/risk of hemorrhage). * Reduce risk with medical therapy (eg. Aspirin, Clopidogrel); optimum control of blood pressure, blood sugars, lipids; and treat conditions that ↑ risk (eg. atrial fibrillation, carotid artery stenosis).

Neuropathology: * brief, reversible episode of focal neurologic dysfunction without acute infarction (⊝ MRI), with the majority resolving in \< 15 minutes * deficits due to focal ischemia

Transient Ischemic Attack

Neuropathology: * bleeding into ventricles * increased risk in premature and low-birth-weight infants * originates in germinal matrix, a highly vascularized layer within the subventricular zone * due to reduced glial fiber support and impaired autoregulation of BP in premature infants * can present with altered level of consciousness, bulging fontanelle, hypotension, seizures, and coma

Neonatal Intraventricular Hemorrhage

Intracranial Hemorrhage: * 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

Epidural Hematoma

Intracranial Hemorrhage: * rupture of bridging veins * can be acute (traumatic, high-energy impact → hyperdense on CT) or chronic (associated with mild trauma, cerebral atrophy, elderly, alcoholism → hypodense on CT) * also seen in shaken babies * Predisposing Factors: * brain atrophy * 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)

Subdural Hematoma

Intracranial Hemorrhage: * bleeding (E, F) due to trauma, or rupture of an aneurysm (such as a saccular aneurysm E) or arteriovenous malformation * rapid time course * patients complain of “worst headache of my life” * bloody or yellow (xanthochromic) spinal tap * vasospasm can occur due to blood breakdown or rebleed 3–10 days after hemorrhage → ischemic infarct * Nimodipine is used to prevent/reduce vasospasm * ↑ risk of developing communicating and/or obstructive hydrocephalus

Subarachnoid Hemorrhage

Intracranial Hemorrhage: * most commonly caused by systemic hypertension * also seen with amyloid angiopathy (recurrent lobar hemorrhagic stroke in elderly), vasculitis, and neoplasm * may be 2º to reperfusion injury in ischemic stroke * hypertensive hemorrhages (Charcot-Bouchard microaneurysm) most often occur in the putamen of the basal ganglia (lenticulostriate vessels G), followed by thalamus, pons, and cerebellum (H)

Intraparenchymal Hemorrhage

Effects of Strokes: Anterior Circulation

Effects of Strokes: Posterior Circulation

Neuropathology: * neuropathic pain due to thalamic lesions * initial paresthesias followed in weeks to months by allodynia (ordinarily painless stimuli cause pain) and dysesthesia on the contralateral side * occurs in 10% of stroke patients

Central Post-Stroke Pain Syndrome

Neuropathology: * 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

Diffuse Axonal Injury

Aphasia: * repetition impaired * nonfluent speech * intact comprehension * patient appears frustrated * insight intact

Broca (Expressive) * Broca Area in inferior frontal gyrus of frontal lobe **B**roca = **B**roken

Aphasia: * repetition impaired * fluent speech * impaired comprehension * patients do not have insight

Wernicke (Receptive) * Wernicke Area in superior temporal gyrus of tempora lobe **W**ernicke = **W**ordy

Aphasia: * repetition impaired * fluent speech * intact comprehension * can be caused by damage to arcuate fasciculus

Conduction (Associative) ar**C**uate fasciculus

Aphasia: * repetition impaired * nonfluent speech * impaired comprehension * Arcuate Fasciculus, Broca and Wernicke areas affected

Global

Aphasia: * repetition intact * nonfluent speech * intact comprehension * affects frontal lobe around Broca area, but Broca area is spared

Transcortical Motor

Aphasia: * repetition intact * fluent speech * impaired comprehension * affects temporal lobe around Wernicke area, but Wernicke area is spared

Transcortical Sensory

Aphasia: * repetition intact * nonfluent speech * impaired comprehension * Broca and Wernicke areas and arcuate fasciculus remain intact * surrounding watershed areas affected

Transcortical, Mixed

Aneurysms: * also known as berry aneurysm * occurs at bifurcations in the Circle of Willis * most common site is the junction of ACom and ACA * associated with ADPKD and Ehlers-Danlos syndrome * Risk Factors: * advanced age * hypertension * smoking * race (↑ risk in African-Americans) * usually clinically silent until rupture (most common complication) → subarachnoid hemorrhage * (“worst headache of my life” or “thunderclap headache”) → focal neurologic deficits. Can also * cause symptoms via direct compression of surrounding structures by growing aneurysm.

Saccular Aneurysm

Saccular Aneurysms: * compression → bitemporal hemianopia (compression of optic chiasm) * visual acuity deficits * rupture → ischemia in ACA distribution → contralateral lower extremity hemiparesis, sensory deficits

ACom

Saccular Aneurysms: rupture → ischemia in MCA distribution → contralateral upper extremity and lower facial hemiparesis, sensory deficits

MCA

Saccular Aneurysms: * compression → ipsilateral CN III palsy → mydriasis (“blown pupil”) * may also see ptosis, “down and out” eye

PCom

Aneurysms: * common * associated with chronic hypertension * affects small vessels (eg. lenticulostriate arteries in basal ganglia, thalamus) and can cause lacunar strokes * not visible on angiography

Charcot-Bouchard Microaneurysm

Seizures: * affect single area of the brain * most commonly originate in medial temporal lobe

Partial (Focal) Seizures

Seizures: * partial * consciousness intact * motor, sensory, autonomic, psychic

Simple Partial

Seizures: * partial * impaired consciousness * automatisms

Complex Partial

Seizures: diffuse

Generalized Seizures

Seizures: * diffuse * 3 Hz spike-and-wave discharges * no postictal confusion * blank stare

Absence (petit mal)

Seizures: * diffuse * quick, repetitive jerks

Myoclonic

Seizures: * diffuse * stiffening

Tonic

Seizures: * diffuse * “drop” seizures (falls to floor) * commonly mistaken for fainting

Atonic

Seizures: continuous (≥ 5 min) or recurring seizures that may result in brain injury

Status epEilepticus

Neuropathology: * pain due to irritation of structures such as the dura, cranial nerves, or extracranial structures * more common in females, except cluster

Headaches

Headaches: * unilateral * 15 min–3 hr * repetitive * excruciating periorbital pain (“suicide headache”) with lacrimation and rhinorrhea * may present with Horner syndrome * more common in males

Cluster

Headaches: * bilateral * \> 30 min (typically 4–6 hr) * constant * steady, “band-like” pain * no photophobia or phonophobia * no aura

Tension

Headaches: * unilateral * 4–72 hr * pulsating pain with nausea, photophobia, or phonophobia * may have “aura” * due to irritation of CN V, meninges, or blood vessels (release of substance P, calcitonin gene-related peptide, vasoactive peptides)

Migraine **POUND**: * **P**ulsatile * **O**ne-day duration * **U**nilateral * **N**ausea * **D**isabling

Headache Treatment: Cluster

* Acute: * Sumatriptan * 100% O₂ * Prophylaxis: * Verapamil

Headache Treatment: Tension

* Analgesics * NSAIDs * Acetaminophen * Amitriptyline for chronic pain

Headache Treatment: Migraine

* Acute: * NSAIDs * Triptans * Dihydroergotamine * Prophylaxis: * lifestyle changes (eg. sleep, exercise, diet) * β-Blockers * Amitriptyline * Topiramate * Valproate

Causes of Headache

* Subarachnoid Hemorrhage * “worst headache of my life” * Meningitis * Hydrocephalus * Neoplasia * Giant Cell (Temporal) Arteritis

Neuropathology: * produces repetitive, 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 * Treatment: Carbamazepine

Trigeminal Neuralgia

Movement Disorders: * restlessness and intense urge to move * can be seen with neuroleptic use or as a side-effect of Parkinson treatment

Akathisia

Movement Disorders: * slow, snake-like, writhing movements * especially seen in the fingers * basal ganglia lesion

Athetosis

Movement Disorders: * sudden, jerky, purposeless movements * basal ganglia lesion * seen in Huntington disease and in acute rheumatic fever

Chorea

Movement Disorders: * high-frequency tremor with sustained posture (eg. outstretched arms) * worsened with movement or when anxious * often familial * patients often self-medicate with alcohol, which ↓ tremor amplitude. * Treatment: * Nonselective β-Blockers (eg. Propranolol) * Primidone

Essential Tremor

Movement Disorders: * sudden, wild flailing of 1 arm +/− ipsilateral leg * contralateral subthalamic nucleus lesion (eg. lacunar stroke) * contralateral lesion

Hemiballismus

Movement Disorders: * slow, zigzag motion when pointing/extending toward a target * cerebellar dysfunction

Intention Tremor

Movement Disorders: * uncontrolled movement of distal appendages (most noticeable in hands) * tremor alleviated by intentional movement * substantia nigra lesion (Parkinson disease) * occurs at rest * “pill-rolling tremor” of Parkinson disease

Resting Tremor

Movement Disorders: * worse at rest/nighttime * relieved by movement * associated with iron deficiency and CKD * Treatment: * Dopamine Agonists * Pramipexole * Ropinirole

Restless Legs Syndrome

Neuropathology: * ↓ in cognitive ability, memory, or function with intact consciousness * must rule out depression as cause of dementia (known as pseudodementia)

Neurodegenerative Disorders

Neurodegenerative Disorders: * pill-rolling tremor at rest * cogwheel rigidity * akinesia or bradykinesia * postural instability * shuffling gait * MPTP, a contaminant in illegal drugs, is metabolized to MPP+, which is toxic to substantia nigra * loss of dopaminergic neurons (ie. depigmentation) of substantia nigra pars compacta * Lewy Bodies: * composed of α-synuclein (intracellular eosinophilic inclusions)

Parkinson Disease Parkinson **TRAPS** your body: * **T**remor (pill-rolling tremor at rest) * **R**igidity (cogwheel) * **A**kinesia (or bradykinesia) * **P**ostural instability * **S**huffling gait

Neurodegenerative Disorders: * autosomal dominant trinucleotide (CAG)_nrepeat expansion in the huntingtin (HTT) gene on chromosome 4 * symptoms manifest between ages 20 and 50: * chorea * athetosis * aggression * depression * dementia * sometimes initially mistaken for substance abuse) * anticipation results from expansion of CAG repeats * caudate loses ACh and GABA * atrophy of caudate and putamen with ex vacuo ventriculomegaly * ↑ dopamine, ↓ GABA, ↓ ACh in brain * neuronal death via NMDA-R binding and glutamate excitotoxicity

Huntington Disease **hunt**ingtin = chromosome 4 (**4 letters**) **CAG** repeats = **C**audate loses **A**Ch and **G**ABA

Neurodegenerative Disorders: * most common cause of dementia in elderly * Down syndrome patients have ↑ risk * APP is located on chromosome 21 * ↓ ACh * 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 * widespread cortical atrophy, especially hippocampus * narrowing of gyri and widening of sulci * senile plaques in gray matter: * extracellular β-amyloid core * may cause amyloid angiopathy → intracranial hemorrhage * Aβ (amyloid-β) synthesized by cleaving amyloid precursor protein (APP) * Neurofibrillary Tangles * intracellular, hyperphosphorylated tau protein = insoluble cytoskeletal elements * number of tangles correlates with degree of dementia

Alzheimer Disease

Neurodegenerative Disorders: * also known as Pick disease * early changes in personality and behavior (behavioral variant), or aphasia (primary progressive aphasia) * may have associated movement disorders (eg. parkinsonism) * frontotemporal lobe degeneration * inclusions of hyperphosphorylated tau (round Pick bodies) or ubiquitinated TDP-43

Frontotemporal Dementia

Neurodegenerative Disorders: * visual hallucinations * dementia with fluctuating cognition/alertness, REM sleep behavior disorder, and parkinsonism * cognitive and motor symptom onset \< 1 year apart, otherwise considered dementia 2° to Parkinson disease * intracellular Lewy bodies primarily in cortex

Lewy Body Dementia “ha**Lewy**cinations”

Neurodegenerative Disorders: * result of multiple arterial infarcts and/or chronic ischemia * step-wise decline in cognitive ability with late-onset memory impairment * 2nd most common cause of dementia in elderly * MRI or CT shows multiple cortical and/or subcortical infarcts

Vascular Dementia

Neurodegenerative Disorders: * 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 * spongiform cortex * prions (PrPc → PrPsc sheet [β-pleated sheet resistant to proteases])

Creutzfeldt-Jakob Disease

Neuropathology: * also known as pseudotumor cerebri * ↑ ICP with no apparent cause on imaging (eg. hydrocephalus, obstruction of CSF outflow) * risk factors include female gender, tetracyclines, besity, vitamin A excess, and Danazol * headache, tinnitus, diplopia (usually from CN VI palsy), no change in mental status * impaired optic nerve axoplasmic flow → papilledema * visual field testing shows enlarged blind spot and peripheral constriction * lumbar puncture reveals ↑ opening pressure and provides temporary headache relief * Treatment: * weight loss * Acetazolamide * invasive procedures for refractory cases (eg. CSF shunt placement, optic nerve sheath fenestration surgery for visual loss)

Idiopathic Intracranial Hypertension **Female TOAD**: * **Female** * **T**etracyclines * **O**besity * Vitamin **A** excess * **D**anazol

Hydrocephalus: ↓ CSF absorption by arachnoid granulations (eg. arachnoid scarring post-meningitis) → ↑ ICP, papilledema, herniation

Communicating Hydrocephalus

Hydrocephalus: * communicating * affects the elderly * idiopathic * CSF pressure elevated only episodically * does not result in increased subarachnoid space volume * expansion of ventricles distorts the fibers of the corona radiata → triad of urinary incontinence, gait apraxia (magnetic gait), and cognitive dysfunction (sometimes reversible) * symptoms potentially reversible with CSF shunt placement

Normal Pressure Hydrocephalus “**Wet**, **wobbly**, and **wacky**.” * urinary incontinence * gait apraxia (magnetic gait) * cognitive dysfunction

Hydrocephalus: caused by structural blockage of CSF circulation within ventricular system (eg. stenosis of aqueduct of Sylvius; colloid cyst blocking foramen of Monro; tumor)

Noncommunicating Hydrocephalus

Hydrocephalus: * appearance of ↑ CSF on imaging, but is actually due to ↓ brain tissue and neuronal atrophy (eg. Alzheimer disease, advanced HIV, Pick disease, Huntington disease) * normal pressure hydrocephalus triad is not seen

Ex Vacuo Ventriculomegaly

Neuropathology: * autoimmune inflammation and demyelination of CNS (brain and spinal cord) with subsequent axonal damage * Findings: * acute optic neuritis (painful unilateral visual loss associated with Marcus Gunn pupil) * brain stem/cerebellar syndromes (eg. diplopia, ataxia, scanning speech, intention tremor, nystagmus/INO (bilateral \> unilateral) * pyramidal tract weakness * spinal cord syndromes (eg. electric shock-like sensation along spine on neck flexion [Lhermitte phenomenon], neurogenic bladder, paraparesis, sensory manifestations affecting the trunk or one or more extremity) * symptoms may exacerbate with increased body temperature (eg. hot bath, exercise) * relapsing and remitting is most common clinical course * most often affects women in their 20s and 30s * more common in Caucasians living farther from equator

Multiple Sclerosis

Neuropathology: * ↑ IgG level and myelin basic protein in CSF * oligoclonal bands are diagnostic * MRI is the gold standard * periventricular plaques (areas of oligodendrocyte loss and reactive gliosis) * multiple white matter lesions disseminated in space and time

Multiple Sclerosis

Multiple Sclerosis: 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 (baclofen, GABA_B receptor agonists), and pain (TCAs, anticonvulsants).

Demyelinating and Dysmyelinating Disorders: * also known as Central Pontine Myelinolysis * massive axonal demyelination in pontine white matter 2° to rapid osmotic changes, most commonly iatrogenic correction of hyponatremia but also rapid shifts of other osmolytes (eg. glucose) * acute paralysis, dysarthria, dysphagia, diplopia, and loss of consciousness * can cause “locked-in syndrome”

Osmotic Demyelination Syndrome Fast Serum Na+ Correction: * “**from low to high, your pons will die**” (Osmotic Demyelination Syndrome) * “**From high to low, your brains will blow**” (Cerebral Edema/Herniation)

Demyelinating and Dysmyelinating Disorders: * most common subtype of Guillain-Barré syndrome * autoimmune condition associated with infections (eg. *Campylobacter jejuni*, viruses [eg. Zika]) 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 * results in symmetric ascending muscle weakness/paralysis and depressed/absent DTRs beginning in lower extremities * facial paralysis (usually bilateral) and respiratory failure are common * may see autonomic dysregulation (eg. cardiac irregularities, hypertension, hypotension) or sensory abnormalities * almost all patients survive * majority recover completely after weeks to months * ↑ CSF protein with normal cell count (albuminocytologic dissociation) * respiratory support is critical until recovery * Disease-Modifying Treatment: * plasmapheresis * IV immunoglobulins * no role for steroids

Acute Inflammatory Demyelinating Polyradiculopathy

Demyelinating and Dysmyelinating Disorders: * multifocal inflammation and demyelination after infection or vaccination * presents with rapidly progressive multifocal neurologic symptoms and altered mental status

Acute Disseminated (Postinfectious) Encephalomyelitis

Demyelinating and Dysmyelinating Disorders: * also known as Hereditary Motor and Sensory Neuropathy * group of progressive hereditary nerve disorders related to the defective production of proteins involved in the structure and function of peripheral nerves or the myelin sheath * typically autosomal dominant inheritance pattern and associated with foot deformities (eg. pes cavus, hammer toe), lower extremity weakness (eg. foot drop), and sensory deficits * most common type, CMT1A, is caused by PMP22 gene duplication

Charcot-Marie-Tooth Disease

Demyelinating and Dysmyelinating Disorders: * demyelination of CNS due to destruction of oligodendrocytes (2° to reactivation of latent JC virus infection) * seen in 2–4% of patients with AIDS * rapidly progressive, usually fatal * predominantly involves parietal and occipital areas * visual symptoms are common * ↑ risk associated with Natalizumab and Rituximab

Progressive Multifocal Leukoencephalopathy

Neurocutaneous Disorders: * 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 * affects small (capillary-sized) blood vessels → port-wine stain of the face (nevus flammeus, a non-neoplastic “birthmark” in CN V1/V2 distribution) * ipsilateral leptomeningeal angioma → seizures/epilepsy * intellectual disability * episcleral hemangioma → ↑ IOP → early-onset glaucoma

Sturge-Weber Syndrome **STURGE**-Weber: * **S**poradic * port-wine **S**tain * **T**ram track calcifications (opposing gyri) * **U**nilateral * **R**etardation (intellectual disability) * **G**laucoma * **G**NAQ gene * **E**pilepsy

Neurocutaneous Disorders: * TSC1 mutation on chromosome 9 or TSC2 mutation on chromosome 16 * tumor suppressor genes * autosomal dominant, variable expression * hamartomas in CNS and skin * angiofibromas * mitral regurgitation * ash-leaf spots * cardiac rhabdomyoma * autosomal dominant * mental retardation (intellectual disability) * renal angiomyolipoma * seizures * Shagreen patches * ↑ incidence of subependymal giant cell astrocytomas and ungual fibromas

Tuberous Sclerosis **HAMARTOMAS**: * **H**amartomas in CNS and skin * **A**ngiofibromas * **M**itral regurgitation * **A**sh-leaf spots * cardiac **R**habdomyoma * **T**uberous sclerosis * autosomal d**O**minant * **M**ental retardation * renal **A**ngiomyolipoma * **S**eizures * **S**hagreen patches

Neurocutaneous Disorders: * also known as von Recklinghausen disease * mutation in NF1 tumor suppressor gene on chromosome 17, which normally codes for neurofibromin, a negative regulator of RAS * autosomal dominant, 100% penetrance * café-au-lait spots ,cutaneous neurofibromas, optic gliomas, pheochromocytomas, Lisch nodules (pigmented iris hamartomas)

Neurofibromatosis Type I Chromosome 17 = **17 letters** in “von Recklinghausen”

Neurocutaneous Disorders: * mutation in NF2 tumor suppressor gene on chromosome 22 * autosomal dominant * Findings: * bilateral acoustic schwannomas * juvenile cataracts * meningiomas * ependymomas

Neurofibromatosis Type II NF**2** affects **2** ears, **2** eyes, and **2** parts of the brain.

Neurocutaneous Disorders: * deletion of VHL gene on chromosome 3p * autosomal dominant * pVHL ubiquitinates hypoxia-inducible factor 1a * characterized by development of numerous tumors, both benign and malignant * hemangioblastomas (high vascularity with hyperchromatic nuclei) in retina, brain stem, cerebellum, and spine * angiomatosis (eg. cavernous hemangiomas in skin, mucosa, organs) * bilateral renal cell carcinomas * pheochromocytomas

von Hippel-Lindau Disease Chromosome **3**p = VHL has **3** letters **HARP**: * **H**emangioblastomas * **A**ngiomatosis * bilateral **R**enal cell carcinomas * **P**heochromocytomas

Adult Primary Brain Tumors: * grade IV astrocytoma * common, highly malignant 1° brain tumor with ~ 1-year median survival * found in cerebral hemispheres * can cross corpus callosum (“butterfly glioma”) * astrocyte origin * GFAP ⊕ * “pseudopalisading” pleomorphic tumor cells border central areas of necrosis, hemorrhage, and/or microvascular proliferation

Glioblastoma Multiforme

Adult Primary Brain Tumors: * relatively rare * slow growing * most often in frontal lobes * “chicken-wire” capillary pattern * oligodendrocyte origin * “Fried Egg” Cells * round nuclei with clear cytoplasm * often calcified

Oligodendroglioma

Adult Primary Brain Tumors: * common, typically benign * females \> males * most often occurs near surfaces of brain and in parasagittal region * extra-axial (external to brain parenchyma) and may have a dural attachment (“tail”) * often asymptomatic * may present with seizures or focal neurologic signs * treated with resection and/or radiosurgery * arachnoid cell origin * spindle cells concentrically arranged in a whorled pattern * psammoma bodies (laminated calcifications)

Meningioma

Adult Primary Brain Tumors: * most often cerebellar * 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

Hemangioblastoma

Adult Primary Brain Tumors: * may be nonfunctioning (silent) or hyperfunctioning (hormone producing) * most commonly from lactotrophs (prolactinoma) → 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 * 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 ↓ bone density due to suppression of estrogen * prolactinoma in men classically presents as low libido and infertility * Treatment: * Dopamine Agonists (eg. Bromocriptine, Cabergoline) * transsphenoidal resection

Pituitary Adenoma

Adult Primary Brain Tumors: * classically at the cerebellopontine angle involving both CNs VII and VIII, but can be along any peripheral nerve * often localized to CN VIII in internal acoustic meatus → vestibular \_\_\_\_\_ * bilateral vestibular _____ found in NF-2 * treated with resection or stereotactic radiosurgery * Schwann cell origin, S-100 ⊕ * biphasic * dense, hypercellular areas containing spindle cells alternating with hypocellular, myxoid areas

Schwannoma

Childhood Primary Brain Tumors: * low-grade astrocytoma * most common 1° brain tumor in childhood * usually well circumscribed * in children, most often found in posterior fossa (eg. cerebellum) * may be supratentorial * benign, good prognosis. * glial cell origin, GFAP ⊕ * Rosenthal fibers—eosinophilic, corkscrew fibers * cystic + solid (gross)

Pilocytic Astrocytoma

Childhood Primary Brain Tumors: * most common malignant brain tumor in childhood * commonly involves cerebellum * can compress 4th ventricle, causing noncommunicating hydrocephalus → headaches, papilledema * can send “drop metastases” to the spinal cord * form of primitive neuroectodermal tumor (PNET) * Homer-Wright rosettes, small blue cells

Medulloblastoma

Childhood Primary Brain Tumors: * most commonly found in 4th ventricle * can cause hydrocephalus * poor prognosis * ependymal cell origin * characteristic perivascular pseudorosettes * rod-shaped blepharoplasts (basal ciliary bodies) found near the nucleus

Ependymoma

Childhood Primary Brain Tumors: * most common childhood supratentorial tumor * may be confused with pituitary adenoma (both cause bitemporal hemianopia) * derived from remnants of Rathke pouch (ectoderm) * calcification is common * cholesterol crystals found in “motor oil”-like fluid within tumor

Craniopharyngioma

Childhood Primary Brain Tumors: * tumor of the 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)

Pinealoma

Herniation Syndromes

① Cingulate (subfalcine) * herniation under falx cerebri * can compress anterior cerebral artery ② Transtentorial (central/downward) * caudal displacement of brain stem → rupture of paramedian basilar artery branches → Duret hemorrhages * usually fatal ③ Uncal * uncus = medial temporal lobe * compresses ipsilateral CN III and contralateral crus cerebri against Kernohan notch (causes contralateral CN III palsy and/or ipsilateral hemiparesis, ie. a false localizing sign) ④ Cerebellar Tonsillar * herniation into the foramen magnum * coma and death result when these herniations compress the brain stem

Motor Neuron Signs: * Weakness + * Reflexes ↑ * Tone ↑ * Babinski + * Spastic Paresis + * Clasp Knife Spasticity +

Upper Motor Neuron * everything **up** (tone, DTRs, toes)

Motor Neuron Signs: * Weakness + * Atrophy + * Fasciculations + * Reflexes ↓ * Tone ↓ * Flaccid Paralysis +

Lower Motor Neuron * everything **low**ered (less muscle mass, ↓ muscle tone, ↓ reflexes, downgoing toes)

Spinal Cord Lesions: * congenital degeneration of anterior horns of spinal cord * LMN lesions only, symmetric weakness * “floppy baby” with marked hypotonia (flaccid paralysis) and tongue fasciculations * autosomal recessive inheritance of mutation in SMN1 * type 1 is called Werdnig-Hoffmann disease

Spinal Muscular Atrophy 3 F's: * “**F**loppy baby” * **F**laccid paralysis * tongue **F**asciculations

Spinal Cord Lesions: * combined UMN (corticobulbar/corticospinal) and LMN (medullary and spinal cord) degeneration * no sensory or bowel/bladder deficits * can be caused by defect in Superoxide Dismutase 1 * 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) * fatal * commonly known as Lou Gehrig disease * Treatment: Riluzole

Amyotrophic Lateral Sclerosis

Spinal Cord Lesions: * spares dorsal columns and Lissauer tract * midthoracic ASA territory is watershed area, as artery of Adamkiewicz supplies ASA below T8 * 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), and loss of pain and temperature sensation below the lesion (spinothalamic tract

Complete Occlusion of Anterior Spinal Artery

Spinal Cord Lesions: * caused by 3° syphilis * results from degeneration (demyelination) of dorsal columns and roots → progressive sensory ataxia (impaired proprioception → poor coordination) * ⊕ Romberg sign and absent DTRs * associated with Charcot joints, shooting pain, and Argyll Robertson pupils

Tabes Dorsalis

Spinal Cord Lesions: * 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

Syringomyelia

Spinal Cord Lesions: * Subacute Combined Degeneration (SCD) * demyelination of spinocerebellar tracts, lateral corticospinal tracts, and dorsal columns * ataxic gait, paresthesia, and impaired position/vibration sense

Vitamin B12 Deficiency Subacute Combined Degeneration: * **S**pinocerebellar tracts * lateral **C**orticospinal tracts * **D**orsal columns

Spinal Cord Lesions: * compression of spinal roots L2 and below, often due to intervertebral disc herniation or tumor * unilateral radicular pain, absent knee and ankle reflex, loss of bladder and anal sphincter control, saddle anesthesia * Treatment: * emergent surgery * steroids

Cauda Equina Syndrome

Neuropathology: * caused by poliovirus (fecal-oral transmission) * replicates in oropharynx and small intestine before spreading via bloodstream to CNS * infection causes destruction of cells in anterior horn of spinal cord (LMN death) * Signs of LMN Lesion: * asymmetric weakness * hypotonia * flaccid paralysis * fasciculations * hyporeflexia * muscle atrophy * respiratory muscle involvement leads to respiratory failure * Signs of Infection: * malaise, headache, fever, nausea, etc. * CSF shows ↑ WBCs (lymphocytic pleocytosis) and slight ↑ of protein (with no change in CSF glucose) * virus recovered from stool or throat

Poliomyelitis

Brown-Séquard Syndrome

Hemisection of spinal cord.: 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.

Neuropathology: * autosomal recessive trinucleotide repeat disorder (GAA)_n on chromosome 9 in gene that encodes frataxin (iron binding protein) * leads to impairment in mitochondrial functioning * degeneration of lateral corticospinal tract (spastic paralysis), spinocerebellar tract (ataxia), dorsal columns (↓ vibratory sense, proprioception), and dorsal root ganglia (loss of DTRs) * staggering gait, frequent falling, nystagmus, dysarthria, pes cavus, hammer toes, diabetes mellitus, hypertrophic cardiomyopathy (cause of death) * presents in childhood with kyphoscoliosis

Friedreich Ataxia **F**riedreich is **F**ratastic (**frataxin**): he’s your favorite frat brother, always **staggering** and **falling** but has a **sweet, big heart**. Ataxic **GAA**it

Common Cranial Nerve Lesions: jaw deviates toward side of lesion due to unopposed force from the opposite pterygoid muscle

CN V Motor

Common Cranial Nerve Lesions: * uvula deviates away from side of lesion * weak side collapses and uvula points away

CN X

Common Cranial Nerve Lesions: * 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 XI

Common Cranial Nerve Lesions: * LMN lesion * tongue deviates toward side of lesion (“lick your wounds”) due to weakened tongue muscles on affected side

CN XII

Neuropathology: * most common cause of peripheral facial palsy * usually develops after HSV reactivation * Treatment: Corticosteroids ± Acyclovir * most patients gradually recover function, but aberrant regeneration can occur * other causes of peripheral facial palsy: * include Lyme disease * herpes zoster (Ramsay Hunt syndrome) * sarcoidosis * tumors (eg. parotid gland) * diabetes mellitus

Bell Palsy

Facial Nerve Lesions: * Location: * motor cortex * connection from motor cortex to facial nucleus in pons * Affected Side: * contralateral * Muscles Involved: * lower muscles of facial expression * Forehead: * spared, due to bilateral UMN innervation

Upper Motor Neuron Lesion

Facial Nerve Lesions: * Location: * facial nucleus * anywhere along CN VII * Affected Side: * ipsilateral * Muscles Involved: * upper and lower muscles of facial expression * Forehead: * affected * Other Symptoms: * incomplete eye closure (dry eyes, corneal ulceration) * hyperacusis * loss of taste sensation to anterior tongue

Lower Motor Neuron Lesion

Auditory Physiology: * visible portion of ear (pinna) * includes auditory canal and tympanic membrane * transfers sound waves via vibration of tympanic membrane

Outer Ear

Auditory Physiology: * air-filled space with three bones called the ossicles (malleus, incus, stapes) * ossicles conduct and amplify sound from tympanic membrane to inner ear

Middle Ear

Auditory Physiology: * 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)

Inner Ear

Hearing Loss: * Weber Test: localizes to affected ear * Rinne Test: abnormal (bone \> air)

Conductive Hearing Loss

Hearing Loss: * Weber Test: localizes to unaffected ear * Rinne Test: normal (air \> bone)

Sensorineural Hearing Loss

Hearing Loss: * damage to stereociliated cells in organ of Corti * loss of high-frequency hearing first * sudden extremely loud noises can produce hearing loss due to tympanic membrane rupture

Noise-Induced Hearing Loss

Hearing Loss: * 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)

Presbycusis

ORL Pathology: * overgrowth of desquamated keratin debris within the middle ear space * may erode ossicles and mastoid air cells → conductive hearing loss * often presents with painless otorrhea

Cholesteatoma

ORL Pathology: * sensation of spinning while actually stationary * subtype of “dizziness,” but distinct from “lightheadedness”

Vertigo

Vertigo: * more common * inner ear etiology (eg. semicircular canal debris, vestibular nerve infection, Ménière disease [triad: sensorineural hearing loss, vertigo, tinnitus], benign paroxysmal positional vertigo [BPPV]) * Treatment: * antihistamines * anticholinergics * antiemetics (symptomatic relief) * low-salt diet ± diuretics (Ménière disease) * Epley maneuver (BPPV)

Peripheral Vertigo

Vertigo: * brain stem or cerebellar lesion (eg. stroke affecting vestibular nuclei or posterior fossa tumor) * Findings: * directional or purely vertical nystagmus * skew deviation * diplopia * dysmetria * focal neurologic findings

Central Vertigo

Eye Anatomy

Ophthalmic Pathology: * inflammation of the conjunctiva → red eye * Allergic * itchy eyes * bilateral * Bacterial * pus * treat with antibiotics * Viral * most common * often adenovirus * sparse mucous discharge * swollen preauricular node * self-resolving

Conjunctivitis

Ophthalmic Pathology: * common cause of impaired vision * correctable with glasses

Refractive Errors

Refractive Errors: * also known as “farsightedness” * eye too short for refractive power of cornea and lens → light focused behind retina * correct with convex (converging) lenses

Hyperopia

Refractive Errors: * 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

Myopia

Refractive Errors: * abnormal curvature of cornea → different refractive power at different axes * correct with cylindrical lens

Astigmatism

Refractive Errors: * 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)

Presbyopia

Ophthalmic Pathology: * painless, often bilateral, opacification of lens , often resulting in glare and ↓ vision, especially at night * Acquired Risk Factors: * ↑ age * smoking * excessive alcohol use * excessive sunlight * prolonged corticosteroid use * diabetes mellitus * trauma * infection * Congenital Risk Factors: * Classic Galactosemia * Galactokinase Deficiency * Trisomies (13, 18, 21) * ToRCHeS Infections (eg. rubella) * Marfan Syndrome * Alport Syndrome * Myotonic Dystrophy * Neurofibromatosis 2

Cataract

Aqueous Humor Pathway

Ophthalmic Pathology: * optic disc atrophy with characteristic cupping (thinning of outer rim of optic nerve head versus normal), usually with elevated intraocular pressure (IOP) and progressive peripheral visual field loss if untreated * treatment is through pharmacologic or surgical lowering of IOP

Glaucoma

Glaucoma: * associated with ↑ age, African-American race, and family history * painless * more common in US * Primary—cause unclear * Secondary—blocked trabecular meshwork from WBCs (eg. uveitis), RBCs (eg. vitreous hemorrhage), retinal elements (eg. retinal detachment)

Open-Angle Glaucoma

Glaucoma: * 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 and impeding flow through trabecular meshwork * Secondary * hypoxia from retinal disease (eg. diabetes mellitus, vein occlusion) induces vasoproliferation in iris that contracts angle

Closed- or Narrow-Angle Glaucoma

Closed- or Narrow-Angle Glaucoma: often asymptomatic with damage to optic nerve and peripheral vision

Chronic Closure

Closed- or Narrow-Angle Glaucoma: * true ophthalmic emergency * ↑ IOP pushes iris forward → angle closes abruptly * very painful, red eye, sudden vision loss, halos around lights, frontal headache, fixed and mid‑dilated pupil * mydriatic agents contraindicated

Acute Closure

Ophthalmic Pathology: * inflammation of uvea * specific name based on location within affected eye * anterior = Iritis * posterior = Choroiditis and/or Retinitis * may have hypopyon (accumulation of pus in anterior chamber) or conjunctival redness * associated with systemic inflammatory disorders (eg. sarcoidosis, rheumatoid arthritis, juvenile idiopathic arthritis, HLA-B27–associated conditions)

Uveitis

Ophthalmic Pathology: * degeneration of macula (central area of retina) * causes distortion (metamorphopsia) and eventual loss of central vision (scotomas)

Age-Related Macular Degeneration

Age-Related Macular Degeneration: * \> 80% * deposition of yellowish extracellular material in between Bruch membrane and retinal pigment epithelium (“Drusen”) with gradual ↓ in vision * prevent progression with multivitamin and antioxidant supplements

Dry (Nonexudative)

Age-Related Macular Degeneration: * 10–15% * rapid loss of vision due to bleeding 2° to choroidal neovascularization * treat with anti-VEGF (vascular endothelial growth factor) injections (eg. Bevacizumab, Ranibizumab)

Wet (Exudative)

Ophthalmic Pathology: retinal damage due to chronic hyperglycemia

Diabetic Retinopathy

Diabetic Retinopathy: * damaged capillaries leak blood → lipids and fluid seep into retina → hemorrhages and macular edema * Treatment: blood sugar control

Nonproliferative

Diabetic Retinopathy: * chronic hypoxia results in new blood vessel formation with resultant traction on retina * Treatment: * peripheral retinal photocoagulation * surgery * anti-VEGF

Proliferative

Ophthalmic Pathology: * retinal damage due to chronic uncontrolled HTN * flame-shaped retinal hemorrhages, arteriovenous nicking, microaneurysms, macular star (exudate), cotton-wool spots * presence of papilledema requires immediate lowering of BP * associated with ↑ risk of stroke, CAD, and kidney disease

Hypertensive Retinopathy

Ophthalmic Pathology: * blockage of central or branch retinal vein due to compression from nearby arterial atherosclerosis * retinal hemorrhage and venous engorgement (“blood and thunder appearance”) * edema in affected area

Retinal Vein Occlusion

Ophthalmic Pathology: * separation of neurosensory layer of retina (photoreceptor layer with rods and cones) from outermost pigmented epithelium (normally shields excess light, supports retina) → degeneration of photoreceptors → vision loss * may be 2° to retinal breaks, diabetic traction, inflammatory effusions * visualized on fundoscopy as crinkling of retinal tissue and changes in vessel direction * breaks more common in patients with high myopia and/or history of head trauma * often preceded by posterior vitreous detachment (“flashes” and “floaters”) and eventual monocular loss of vision like a “curtain drawn down” * surgical emergency

Retinal Detachment

Ophthalmic Pathology: * acute, painless monocular vision loss * retina cloudy with attenuated vessels and “cherry-red” spot at fovea (center of macula) * evaluate for embolic source (eg. carotid artery atherosclerosis, cardiac vegetations, patent foramen ovale)

Central Retinal Artery Occlusion

Ophthalmic Pathology: * inherited retinal degeneration * painless, progressive vision loss beginning with night blindness (rods affected first) * bone spicule-shaped deposits around macula

Retinitis Pigmentosa

Ophthalmic Pathology: * retinal edema and necrosis leading to scar * often viral (CMV, HSV, VZV), but can be bacterial or parasitic * may be associated with immunosuppression

Retinitis

Ophthalmic Pathology: * optic disc swelling (usually bilateral) due to ↑ ICP (eg. 2° to mass effect) * enlarged blind spot and elevated optic disc with blurred margins

Papilledema

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 **short**en the pupil diameter.

Pupillary Control: Pupillary Light Reflex

* Light in either retina sends a signal via CN II to pretectal nuclei (dashed lines in image) in midbrain that activates bilateral Edinger-Westphal nuclei. * Pupils constrict bilaterally (direct and consensual reflex). * Result: illumination of 1 eye results in bilateral pupillary constriction.

Pupillary Control: Mydriasis

* dilation * Sympathetic: * 1st neuron: hypothalamus to ciliospinal center of Budge (C8–T2) * 2nd neuron: exit at T1 to superior cervical ganglion (travels along cervical sympathetic chain near lung apex, subclavian vessels) * 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 **long**er.

Ophthalmic Pathology: * 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.

Marcus Gunn Pupil

Horner Syndrome

* Sympathetic denervation of face (**PAM** is **horn**y.): * **P**tosis (slight drooping of eyelid: superior tarsal muscle) * **A**nhidrosis (absence of sweating) and flushing of affected side of face * **M**iosis (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)

Ocular Motility

* The “chemical formula” LR₆SO₄R₃. * CN **VI** innervates the **L**ateral **R**ectus * CN **IV** innervates the **S**uperior **O**blique * CN **III** innervates the **R**est * The strongest action of the superior oblique is depression when the eye is adducted. The further the eye is abducted, the more the superior oblique acts to intort the eye toward the nose. * **O**bliques go **O**pposite (left SO and IO tested with patient looking right). * **IOU**: **IO** tested looking **U**p

CN III, IV, VI Palsies: * has both motor (central) and parasympathetic (peripheral) components. * Common Causes: * ischemia → pupil sparing * uncal herniation → coma * PCA aneurysm → sudden-onset headache * cavernous sinus thrombosis → proptosis, involvement of CNs IV, V1/V2, VI * midbrain stroke → contralateral hemiplegia

CN III damage

CN III, IV, VI Palsies: eye moves upward, particularly with contralateral gaze (→ going down stairs, head may tilt in the opposite direction to compensate)

CN IV damage Can’t see the **floor** with CN **IV** damage.

CN III, IV, VI Palsies: affected eye unable to abduct and is displaced medially in primary position of gaze

CN VI damage

Visual Field Defects

1. Right Anopia 2. Bitemporal Hemianopia (pituitary lesion, chiasm) 3. Left Homonymous Hemianopia 4. Left Upper Quadrantanopia (right temporal lesion, MCA) 5. Left Lower Quadrantanopia (right parietal lesion, MCA) 6. Left Hemianopia with Macular Sparing (PCA infarct) 7. Central Scotoma (eg. macular degeneration) * Meyer **L**oop * **L**ower retina * **L**oops around inferior horn of **L**ateral ventricle * Dorsal Optic Radiation * superior retina * takes shortest path via internal capsule

Cavernous Sinus

* collection of venous sinuses on either side of the pituitary * blood from eye and superficial cortex → cavernous sinus → internal jugular vein * CNs III, IV, V1, VI, and V2 plus postganglionic sympathetic pupillary fibers en route to orbit all pass through cavernous sinus * cavernous portion of internal carotid artery is also here

Ophthalmic Pathology: * presents with variable ophthalmoplegia, ↓ corneal sensation, Horner syndrome and occasional decreased maxillary sensation * 2° to pituitary tumor mass effect, carotid-cavernous fistula, or cavernous sinus thrombosis related to infection * CN VI is most susceptible to injury

Cavernous Sinus Syndrome

Internuclear Ophthalmoplegia

Medial Longitudinal Fasciculus (MLF): * 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) * lesions may be unilateral or bilateral (latter classically seen in multiple sclerosis) Internuclear Ophthalmoplegia (INO) * lesion in MLF * a conjugate horizontal gaze palsy * lack of communication such that when CN VI nucleus activates ipsilateral lateral rectus, contralateral CN III nucleus does not stimulate medial rectus to contract * abducting eye gets nystagmus (CN VI overfires to stimulate CN III) * convergence normal * 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 * directional term (eg. right INO, left INO) refers to which eye is paralyzed * **INO** = **I**psilateral adduction failure, **N**ystagmus **O**pposite

Epilepsy Drugs: * used for Status Epilepticus * 1st line for recurrent seizure prophylaxis * ↑ GABA_A action * causes sedation, tolerance, dependence, respiratory depression * also for eclampsia seizures (1st line is MgSO₄)

Benzodiazepines

Epilepsy Drugs: * commonly used for partial (focal) seizures * used for GTC * blocks Na⁺ channels * causes diplopia, ataxia, blood dyscrasias (agranulocytosis, aplastic anemia), liver toxicity, teratogenesis (cleft lip/palate, spina bifida), induction of cytochrome P-450, SIADH, Stevens- Johnson syndrome * 1st line for trigeminal neuralgia

Carbamazepine

Epilepsy Drugs: * commonly used for absence seizures * blocks thalamic T-type Ca²⁺ channels * causes fatigue, GI distress, headache, itching (and urticaria), and Stevens-Johnson syndrome

Ethosuximide **EFGHIJ**: **E**thosuximide causes **F**atigue, **G**I distress, **H**eadache, **I**tching (and urticaria), and Stevens-**J**ohnson syndrome.

Epilepsy Drugs: * used for partial (focal) seizures * primarily inhibits high-voltage-activated Ca²⁺ channels * designed as GABA analog * causes sedation and ataxia * also used for peripheral neuropathy and postherpetic neuralgia

Gabapentin

Epilepsy Drugs: * used for partial (focal), absence and GTC seizures * blocks voltage-gated Na⁺ channels * inhibits the release of glutamate * causes Stevens-Johnson syndrome (must be titrated slowly)

Lamotrigine

Epilepsy Drugs: * used for partial (focal) and GTC seizures * unknown MOA * may modulate GABA and glutamate release * causes neuropsychiatric symptoms (eg. personality change), fatigue, drowsiness, and headache

Levetiracetam

Epilepsy Drugs: * used for partial (focal) seizures, GTC seizures and status epilepticus * ↑ GABA_A action * causes sedation, tolerance, dependence, induction of cytochrome P-450, and cardiorespiratory depression * 1st line in neonates

Phenobarbital

Epilepsy Drugs: * commonly used for GTC * used for partial (focal) seizures and status epilepticus * 1st line for recurrent seizure prophylaxis * blocks Na⁺ channels * zero-order kinetics * causes P450 induction, hirsutism, enlarged gums, nystagmus, yellow-brown skin, teratogenicity (fetal hydantoin syndrome), osteopenia, inhibited folate absorption, neuropathy * rare adverse reactions include Stevens-Johnson syndrome, DRESS syndrome, and SLE-like syndrome * toxicity leads to diplopia, ataxia, and sedation

* Phenytoin * Fosphenytoin **PHENYTOIN**: * **P**450 induction * **H**irsutism * **E**nlarged gums * **N**ystagmus * **Y**ellow-brown skin * **T**eratogenicity * **O**steopenia * **I**nhibited folate absorption * **N**europathy

Epilepsy Drugs: * used for partial (focal) seizures * ↑ GABA by inhibiting reuptake

Tiagabine

Epilepsy Drugs: * used for partial (focal and GTC seizures) * blocks Na⁺ channels * ↑ GABA action * causes sedation, mental dulling, word-finding difficulty, kidney stones, weight loss, and glaucoma * also used for migraine prevention

Topiramate

Epilepsy Drugs: * commonly used for GTC seizures * used for partial (focal) and absence seizures * ↑ Na⁺ channel inactivation * ↑ GABA concentration by inhibiting GABA transaminase * causes GI distress, rare but fatal hepatotoxicity (measure LFTs), pancreatitis, neural tube defects, tremor, and weight gain * contraindicated in pregnancy * also used for myoclonic seizures, bipolar disorder, and migraine prophylaxis

Valproic Acid

Epilepsy Drugs: * used for partial (focal) seizures * ↑ GABA * irreversible GABA transaminase inhibitor * causes permanent visual loss (black box warning)

Vigabatrin

Neurologic Drugs: Barbiturates

* Phenobarbital * Pentobarbital * Thiopental * Secobarbital

Neurologic Drugs: * facilitate GABA_A action by ↑ duration of Cl⁻ channel opening, thus ↑ neuron firing * used for sedation for anxiety, seizures, insomnia, and induction of anesthesia (thiopental) * causes respiratory and cardiovascular depression (can be fatal), CNS depression (can be exacerbated by alcohol use), dependence, and drug interactions (induces cytochrome P-450) * overdose treatment is supportive (assist respiration and maintain BP) * contraindicated in porphyria

Barbiturates Barbi**durat**es = ↑ **durat**ion

Neurologic Drugs: Benzodiazepines

* Diazepam * Lorazepam * Triazolam * Temazepam * Oxazepam * Midazolam * Chlordiazepoxide * Alprazolam

Neurologic Drugs: * facilitate GABA_A action by ↑ frequency of Cl⁻ channel opening. ↓ REM sleep * most have long half-lives and active metabolites (exceptions [**ATOM**]: **A**lprazolam, **T**riazolam, **O**xazepam, and **M**idazolam are short acting → higher addictive potential). * used for anxiety, spasticity, status epilepticus (Lorazepam, Diazepam, Midazolam), eclampsia, detoxification (especially alcohol withdrawal–DTs), night terrors, sleepwalking, and general anesthesia (amnesia, muscle relaxation), hypnotic (insomnia) * causes ependence and 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 withdrawal

Benzodiazepines * **Fre**nzodiazepines = ↑ **fre**quency * Benzos, barbs, and alcohol all bind the GABA_A receptor, which is a ligand-gated Cl⁻ channel. * **O**xazepam, **T**emazepam, and **L**orazepam are **O**K for **T**errible **L**ivers: they can be used to treat alcohol withdrawal in patients with liver disease due to minimal first-pass metabolism.

Neurologic Drugs: Nonbenzodiazepine Hypnotics

These **ZZZ**s put you to sleep. * **Z**olpidem * **Z**aleplon * Es**Z**opiclone

Neurologic Drugs: * act via the BZ1 subtype of the GABA receptor * effects reversed by Flumazenil * sleep cycle less affected as compared with benzodiazepine hypnotics * used for insomnia * causes ataxia, headaches, and confusion * 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

Nonbenzodiazepine Hypnotics

Neurologic Drugs: * orexin (hypocretin) receptor antagonist. * used for insomnia * causes CNS depression, headache, dizziness, abnormal dreams, and upper respiratory tract infection * contraindicated in patients with narcolepsy * not recommended in patients with liver disease * no or low physical dependence * contraindicated with strong CYP3A4 inhibitors

Suvorexant

Neurologic Drugs: * melatonin receptor agonist * binds MT1 and MT2 in suprachiasmatic nucleus * used for insomnia * causes dizziness, nausea, fatigue, and headache * no dependence (not a controlled substance)

Ramelteon

Neurologic Drugs: * 5-HT1B/1D agonists * inhibit trigeminal nerve activation * prevent vasoactive peptide release * induce vasoconstriction * used for acute migraine and cluster headache attacks * causes coronary vasospasm (contraindicated in patients with CAD or Prinzmetal angina), mild paresthesia, serotonin syndrome (in combination with other 5-HT agonists)

Triptans (Sumatriptan) A s**um**o wrestler **trip**s **an**d falls on your **head**.

Parkinson Disease Drugs

Parkinsonism is due to loss of dopaminergic neurons and excess cholinergic activity. **BALSA**: * **B**romocriptine * **A**mantadine * **L**evodopa (with Carbidopa) * **S**elegiline (and COMT Inhibitors) * **A**ntimuscarinics

Parkinson Disease Drugs: Dopamine Agonists

* Ergot * Bromocriptine * Non-Ergot (preferred) * Pramipexole and Ropinirole * toxicity includes impulse control disorder (eg. gambling), postural hypotension, and hallucinations/confusion

Parkinson Disease Drugs: ↑ dopamine availability

Amantadine * ↑ dopamine release and ↓ dopamine reuptake * toxicity = ataxia, livedo reticularis

Parkinson Disease Drugs: ↑ L-DOPA availability

Agents prevent peripheral (pre-BBB) l-DOPA degradation → ↑ L-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.

Parkinson Disease Drugs: prevent dopamine breakdown

Agents act centrally (post-BBB) to inhibit breakdown of dopamine. * Selegiline and Rasagiline * Block conversion of dopamine into DOPAC by selectively inhibiting MAO-B. * Entacapone * Blocks conversion of dopamine to 3-methoxytyramine (3-MT) by inhibiting central COMT.

Parkinson Disease Drugs: curb excess cholinergic activity

Benztropine and Trihexyphenidyl * antimuscarinic * improves tremor and rigidity but has little effect on bradykinesia in Parkinson disease **Park** your Mercedes-**Benz**.

Neurologic Drugs: * ↑ 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 * used for Parkinson disease * causes nausea, hallucinations, and postural hypotension from ↑ peripheral formation of catecholamines * long-term use can lead to dyskinesia following administration (“on-off” phenomenon) and akinesia between doses

Levodopa/Carbidopa * 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.

Neurologic Drugs: * selectively inhibit MAO-B (metabolize dopamine) → ↑ dopamine availability * adjunctive agent to L-DOPA in treatment of Parkinson disease * may enhance adverse effects of L-DOPA

* Selegiline * Rasagiline

Neurologic Drugs: * inhibit vesicular monoamine transporter (VMAT) dopamine → ↓ vesicle packaging and release * used for Huntington chorea and tardive dyskinesia

* Tetrabenazine * Reserpine

Neurologic Drugs: * ↓ neuron glutamate excitotoxicity * used for ALS * ↑ survival

Riluzole For Lou Gehrig disease, give Ri**lou**zole.

Alzheimer Disease Drugs: * NMDA receptor antagonist * helps prevent excitotoxicity (mediated by Ca²⁺) * causes dizziness, confusion, hallucinations

Memantine

Alzheimer Disease Drugs: * AChE inhibitors * causes nausea, dizziness, and insomnia

**Don**a **Riva** dances at the **gala**. * **Don**epezil * **Riva**stigmine * **Gala**ntamine

Anesthetics—General Principles

* CNS drugs must be lipid soluble (cross the blood-brain barrier) or be actively transported. * drugs with ↓ solubility in blood = rapid induction and recovery times * drugs with ↑ solubility in lipids = ↑ potency = 1/MAC * **MAC** = **M**inimal **A**lveolar **C**oncentration * inhaled anesthetic required to prevent 50% of subjects from moving in response to noxious stimulus (eg. skin incision) * Nitrous oxide (N₂O) has ↓ blood and lipid solubility, and thus fast induction and low potency. * Halothane, Propofol, and Thiopental, in contrast, have ↑ lipid and blood solubility, and thus high potency and slow induction.

Inhaled Anesthetics

* Desflurane * Halothane * Enflurane * Isoflurane * Sevoflurane * Methoxyflurane * N₂O

Anesthetics: * mechanism unknown * causes myocardial depression, respiratory depression, nausea/emesis, ↑ cerebral blood flow (↓ cerebral metabolic demand) * causes **h**epatotoxicity (**H**alothane), **neph**rotoxicity (**Meth**oxyflurane), proconvulsant (**E**nflurane, **e**pileptogenic), expansio**n** of trapped gas in a body cavity (**N**₂O)

Inhaled Anesthetics

Neuropathology: * rare, life-threatening condition in which inhaled anesthetics or Succinylcholine induce fever and severe muscle contractions * susceptibility is often inherited as autosomal dominant with variable penetrance * mutations in voltage-sensitive ryanodine receptor (RYR1 gene) cause ↑ Ca²⁺ release from sarcoplasmic reticulum * Treatment: * Dantrolene—ryanodine receptor antagonist

Malignant Hyperthermia

Intravenous Anesthetics: * facilitate GABA_A (barbiturate) * induction of anesthesia * short surgical procedures * ↓ cerebral blood flow * high lipid solubility * effect terminated by rapid redistribution into tissue and fat

Thiopental

Intravenous Anesthetics: * facilitate GABA_A (benzodiazepine) * procedural sedation (eg. endoscopy) * anesthesia induction * may cause severe postoperative respiratory depression, ↓ BP, and anterograde amnesia

Midazolam

Intravenous Anesthetics: * potentiates GABA_A * rapid anesthesia induction * short procedures * ICU sedation

Propofol

Intravenous Anesthetics: * NMDA receptor antagonist * causes dissociative anesthesia * sympathomimetic * ↑ cerebral blood flow * emergence reaction possible with disorientation, hallucination, and vivid dreams

Ketamine

Local Anesthetics

* Esters * Procaine * Tetracaine * Benzocaine * Chloroprocaine * Amides (**2 I**’s in name) * L**I**doca**I**ne * Mep**I**vaca**I**ne * Bup**I**vaca**I**ne * Rop**I**vaca**I**ne

Anesthetics: * block Na⁺ channels by binding to specific receptors on inner portion of channel * most effective in rapidly firing neurons * 3° amine anesthetics penetrate membrane in uncharged form, then bind to ion channels as charged form * can be given with vasoconstrictors (usually epinephrine) to enhance local action—↓ bleeding, ↑ anesthesia by ↓ systemic concentration * in infected (acidic) tissue, alkaline anesthetics are charged and cannot penetrate membrane effectively → need more anesthetic * 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 * used for minor surgical procedures and spinal anesthesia * if allergic to esters, give amides * causes CNS excitation, severe cardiovascular toxicity (Bupivacaine), hypertension, hypotension, arrhythmias (Cocaine), methemoglobinemia (Benzocaine)

Local Anesthetics

Neurologic Drugs: * used for muscle paralysis in surgery or mechanical ventilation * selective for Nm nicotinic receptors at neuromuscular junction but not autonomic Nn receptors

Neuromuscular Blocking Drugs

Neuromuscular Blocking Drugs: * strong ACh receptor agonist * produces sustained depolarization and prevents muscle contraction * Reversal of Blockade: * Phase I * prolonged depolarization * no antidote * block potentiated by cholinesterase inhibitors * Phase II * repolarized but blocked * ACh receptors are available, but desensitized * may be reversed with cholinesterase inhibitors * complications include hypercalcemia, hyperkalemia, and malignant hyperthermia

Depolarizing Neuromuscular Blocking Drugs * Succinylcholine

Neuromuscular Blocking Drugs: * competitive with ACh for receptors * Reversal of Blockade: * Neostigmine * must be given with atropine or glycopyrrolate to prevent muscarinic effects such as bradycardia * Edrophonium

Nondepolarizing Neuromuscular Blocking Drugs * Atracurium * Cisatracurium * Pancuronium * Rocuronium * Tubocurarine * Vecuronium

Neurologic Drugs: * prevents release of Ca²⁺ from the sarcoplasmic reticulum of skeletal muscle by binding to the ryanodine receptor * used for malignant hyperthermia (a toxicity of inhaled anesthetics and succinylcholine) and neuroleptic malignant syndrome (a toxicity of antipsychotic drugs)

Dantrolene

Neurologic Drugs: * skeletal muscle relaxant * GABA_B receptor agonist in spinal cord * used for muscle spasticity, dystonia, and multiple sclerosis

Baclofen

Neurologic Drugs: * skeletal muscle relaxant * acts within CNS * used for muscle spasms * anticholinergic side effects * causes sedation

Cyclobenzaprine

Analgesics: * act as agonists at opioid receptors (μ = β-endorphin, δ = enkephalin, κ = dynorphin) to modulate synaptic transmission—close presynaptic Ca²⁺ channel, open postsynaptic K⁺ channels → ↓ synaptic transmission * inhibit release of ACh, norepinephrine, 5-HT, glutamate, and substance P * used for moderate to severe or refractory pain, cough suppression (Dextromethorphan), diarrhea (Loperamide, Diphenoxylate), acute pulmonary edema, maintenance programs for heroin addicts (Methadone, Buprenorphine + Naloxone) * causes nausea, vomiting, pruritus, addiction, respiratory depression, constipation, sphincter of Oddi spasm, miosis (except Meperidine → mydriasis), and additive CNS depression with other drugs * tolerance does not develop to miosis and constipation * toxicity is treated with Naloxone (\_\_\_\_\_ receptor antagonist) and relapse prevention with Naltrexone once detoxified

Opioid Analgesics * Full Agonists: * Morphine * Heroin * Meperidine * Methadone * Codeine * Partial Agonist: * Buprenorphine * Mixed Agonist/Antagonist: * Nalbuphine * Pentazocine * Antagonist: * Naloxone * Naltrexone * Methylnaltrexone

Neurologic Drugs: * κ-opioid receptor agonist and μ-opioid receptor weak antagonist or partial agonist * analgesia for moderate to severe pain. * can cause opioid withdrawal symptoms if patient is also taking full opioid agonist (due to competition for opioid receptors)

Pentazocine

Neurologic Drugs: * κ-opioid receptor agonist and μ-opioid receptor partial agonist * used for evere 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

Butorphanol

Neurologic Drugs: * very weak opioid agonist * also inhibits 5-HT receptors * used for chronic pain * adverse effects are similar to opioids * decreases seizure threshold * causes serotonin syndrome

Tramadol

Ophthalmic Pathology: ↓ IOP via ↓ amount of aqueous humor (inhibit synthesis/secretion or ↑ drainage)

Glaucoma Drugs

**BAD** humor may not be **P**olitically **C**orrect. * **β**-Blockers * **α**-Agonists * **D**iuretics * **P**rostaglandins * **C**holinomimetics (M3)

Glaucoma Drugs: * ↓ aqueous humor synthesis * no pupillary or vision changes

β-Blockers * Timolol * Betaxolol * Carteolol

Glaucoma Drugs: * ↓ aqueous humor synthesis via vasoconstriction (Epinephrine) * ↓ aqueous humor synthesis (Apraclonidine, Brimonidine) * causes mydriasis (α1) * do not use in closed-angle glaucoma * causes blurry vision, ocular hyperemia, foreign body sensation, ocular allergic reactions, and ocular pruritus

α-Agonists * Epinephrine (α1) * Apraclonidine * Brimonidine (α2)

Glaucoma Drugs: * ↓ aqueous humor synthesis via inhibition of carbonic anhydrase * no pupillary or vision changes

Diuretics * Acetazolamide

Glaucoma Drugs: * ↑ outflow of aqueous humor via ↓ resistance of flow through uveoscleral pathway * darkens color of iris (browning) * causes eyelash growth

Prostaglandins (PGF2α) * Bimatoprost * Latanoprost

Glaucoma Drugs: * ↑ outflow of aqueous humor via contraction of ciliary muscle and opening of trabecular meshwork * use Pilocarpine in acute angle closure glaucoma—very effective at opening meshwork into canal of Schlemm * causes miosis (contraction of pupillary sphincter muscles) and cyclospasm (contraction of ciliary muscle)

Cholinomimetics (M3) * Direct: * Pilocarpine * Carbachol * Indirect: * Physostigmine * Echothiophate