Somatosensory Pathways

• Dorsal Column/Medial Lemniscus - discriminative touch, vibration, pressure, conscious, proprioception
• Anterolateral Pathways - Pain and Temperature, broad projections, A delta and C fibers
• Anterolateral Pathways - spinothalamic - fast, sharp, well localized
• anterolateral pathways - spinoreticulothalamic - slow, burn, ache; diffuse
• spinocerebellar: non conscious, left side cerebellum to left side of body 

Vestibulo-ocular Reflex

• allows visual fixation while head moves
• reflex - can assess brainstem in unconscious pt

Auditory Pathway Lesions

• damage periphery, VIII nerve, cochlear nuc - unilateral loss of sensitivity
• Damage central - pathway is bilateral, so deficit not limited to one eary - hearing "impaired", especially in contralateral sound field

Acetylcholine Diseases

• Senile dementia of Alzheimer's type - Loss of cholinergic neurons in laeral horn of the spinal cord
• Amyotrophic Lateral Sclerosis (ALS) - degeneration of cholinergic neurons in lateral horn of the spinal cord
• Huntington's Dz - Degeneration of ACh neurons in striatum 

Dopaminergic Pathways

• Mesolimbic Pathway - reward pathway - addiction - schizophrenia (pos Sx)
• Mesocortical pathway - cognitive func, motivation, thought organization, emotion, schizophrenia (neg Sx)
• Nigrostriatal Pathway - basal ganglia motor loop - initiation and control of movts - PD
• Tuberoinfundibular Pathway - prolactin release; antipsychotics are D2 antagonists

Glutamate

• glutamate and aspartate are excitatory a mino acid NTs - depolarization
• participate in Long Term Potentiation (LTP) needed from learning and memory
• Ionotropic rec - NMDA, AMPA, Kainate (KA)
• excitotoxicity/neurotoxicity - apoptosis, cell death - trauma, ischemia, stroke
• PCP - NMDA antagonist - hallucinogen; pschosis
• Antagonists used in treatment of seizures

Amphetamine, Methamphetamine

• inc release of DA and NE
• Powerful CNS stimulation - diminish fatigue, inc alertness, suppress appetitie
• insomnia, psychosis, agitation, HTN, hyperthermia, resp stimulation
• Dopaminergic neurotoxicity w/ prolonged use
• meth mouth - dental decay
• withdrawal Sx - fatigue, depression, cognitive impairment

Narcolepsy (Hypersomnia)

• Narcolepsy is char by excessive daytime sleepiness and irresistible sleep attacks 
• Narcoleptic syndrome may include other Sx
• Cateplexy - a sudden short lived loss of muscle tone and paralysis of voluntary muscle induced by strong emotions
• Sleep paralysis - transient episodes of complete paralysis that occur while falling asleep or during waking respiration is unaffected
• Hypnagogic  - hallucinations - vivid auditory or visual hallucinations while falling asleep
• CNS stimulants - amphetamine, methylphenidate (also modafinil and armodafinlwl dif MOA)
• TCAs and MAO inhibitors

Atomoxetine

• Used to treat ADHD
• selective NE reuptake inhibit (NET blocker); not as eeffective as stimulants
• uses: pts w/ drug abuse histories or parents want to avoid stimulants
• second line treamtnet - when pts do not adequately respond to stimulants or have adverse reaction to them

Cervical Spine Fracture

Intracerebral Hemorrhage (ICH)

• Also called inraparenchymal Hemorrhage (IPH)
• Arteriovenous malformation (AVM) - younger ages
• Hypertension (HTN): middle ages -> basal ganglia
• Amyloid angiopathy: older ages -> cortical/parenchymal (lobar)

Giant Cell Arteritis (GCA)

• the mean age at Dx is approx 72 yrs; essentially never occurs in individuals younger than 50
• New headache plus one of the following: abrupt, onset of visual disturbances (blurry vision, double vision); jaw claudication
• Diagnostic test: ESR/CRP is highly 
• definitive dx - temporal artery biopsy - inflammation of the arterial wall w/ fragmentation and disruption of the internal elastic lamina

Migraine Headaches

• recurrent episodic attacks of head pain and sometimes other neurologic and/or systemic Sx w/ or w/o headache 
• vulnerability to migraine an inherited tendency (genetics)
• migraine is more common in US than asthma+diabetes
• phases/Sx: premonitory, aura (25%; lasts 5min - 1hr), headache, resolution (about 1-2 days)
• headache sx - unilateral, throbbing, moderate to severe, nausea/vommiting, photophobia and noise sensitivity
• pain in migraine from dura, vessels, soft tissue via trigeminal nerve and upper cervical roots (c2-c3)

Prophylactic Tx for Migraines

• beta blockers (propranolol, nadolol, timolol
• Ca channel blockers (verapamil)
• Seizure medication - topiramate (Na channels), valproic acid (inc GABA; Ca and Na cahnnels), and gabapentin (inc GABA)
• TCAs - amitriptyline (5HT n NE), Nortriptyline (NE): inh reuptake of NE, 5HT or both
• SSRI - fluoxetine, paroxetine, citalopram
• SNRI - venlafaxine, duloxetine, desvenlafaxine

Triptans

• Serotonin (5HT) agonists -> 5HT-2B + 5HT1-B
• gold standard abortive treatment for migraines
• Sumatriptain, rizatriptan, almotriptan(adolesence)
• CI - pregnancy, ischemic heard dz, cerebrovascular dz, severe peripheral vascular dz, uncontrolled HTN, severe liver Dz
• Triptans can be used if pt is on SSRIs/SNRIs

Calcitonin Gene Related Peptide (CGRP)

• CGRP is a potent neuropetpide expressed in trigeminal system
• it is released in to the jugulary system during a MIGRAINE attack: ain NT from trigeminovascular system
• CGRP infusion evokes migrain
• CGRP rec antagonists effectively abort a migrain attack: monoclonal Ab

Hearing and Aging

• dec in hearing loss is normal part of hearing
• presbycusis: bilateral high freq hearing loss, inc problem in noisy surrounding, dec speech and pitch discrimination
• When talking to someone w/ hearing loss: get closer and face them so they can read your lips, speak slowly and use lower pitched voice
• shouting is more difficult to understand; dont yell or shout

Impact of Aging on Pharmacodynamics

• Benzo - assoc w/ inc risk of falls and function decline, worsening of delirium Sx, dpeendence - use oxazepam and lorazepam in elderly
• Anticholinergics (TCAs, antipsych, antihist, antichol, antiemetics, muscle relaxants) - worsen dementia, contribute to delirium, contributes to falls (vision changes), cause slowing of urinary and GI tract (constipation and urinary retention)

MASTER Strategy

Principles of prescribing that avoid polypharmacy

• Minimize the numbe of drugs used - select one drug that may help other co-morbid conditions
• Alternatives to drugs should be considered
• start low and go slow (dosing)
• educate pt and family, review regularly 

Variants of Multiple Sclerosis 

• MS remitting; MS acute
• Neuromyelitis optic (Devic)
• Optic Neuritis, transverse myelitis
• Concentric Sclerosis (Balo): svere progressive form of MS; shows target-like picture of demyelination alternation w/ myelin
• Schilder Disease - Progressive Severe form of MS: caues confluent demyelination of usually both hemispheres; more common in children and young

Progressive Multifocal Leukoencephalopathy

(PML)

• JC polyoma virus; opportunistic - AIDS/immunosupr
• Fatal in a few months; rapidly evolving deficits
• Lytic infection of oligodendroglia (not schwann cells)
• Demyelination - happens in random spots along myelin and then spreads out (looks patchy)
• Non-lytic infection of astrocytes: become enlarged/atypical and almost look neoplastic but isnt
• no inflammation

Stroke Risk Factors

• blacks at higher risk than whites; also stroke belt
• age (>), 25% higher in men, HTN, smoking, heavy alcohol use, diabetes, high cholesterol, obstructive sleep apnea
• Heart dz: MI, myopathy, valvular abnormlaities, arrhythmias

Wallenburg Syndrome

(Lateral Medullary Syndrome)

• stroke involving PICA or vertebral artery w/ damage to the lateral medulla
• contralateral sensory loss in the body (spinothalamic tract) - pain and temp sensations
• Ipsilateral Facial Sensory Loss (trigeminal tract) - pain and temp 
• Ipsilateral horner's syndrome (sympathetic tract)
• ataxia, loss of gag reflex, difficulty swallowing and difficulty in articulation
• nausea, vomiting, vetigo (vestibular nuc)
• Dysphagia (vagal nuc)

Subarachnoid Hemorrhage

• saccular (berry) aneurysms - 50% fatality rate
• usually healthy midle aged individuals
• Nausea, stiff neck, someitmes coma/stupor, photo and phonophobia, cranial nerve palsies
• abrupt, severe, "worst headache of my life"
• 25% have warning leak 1-2 wks prior to major rupture
• should undergo CT and if neg, CSF analysis
• early identification and clipping of the aneurysm will prevent bleeding and vasospasm

Ischemic Penumbra

Ischemic Cascade II

• dec ATP leads to depolarization (inc Na in and K out) and lactic acid H+ inc leading to inc Free Fe2
• inc membrane depolarization and failed homeostatic mech from dec ATP leads to inc Ca in 
• inc free Fe2 leads to inc free radicals and glial cell injury
• Inc Ca in leads to dmg to structural proteins, DNA damage, free radical damage to organells and DNA

Optic Neuritis 

• commonly caused by MS plaque on optic nerve
• Mononuclear loss of central vision; afferent pupillary defect on exam
• 25-40% of MS pts experience w/ Sx
• 30% have w/ Sx (detectable only w/ testing)
• If isolated first neurologic Sx, 30-50% go on to develop MS

Acute Disseminated Encephalomyelitis

• monophasic demelination (idiopathic)
• Post viral infection - rubella, rubeola, influenza
• Post Vaccinal - Pertussis, vaccinia, influenza
• Post inoculation - rabies

Hypoxic-Ischemic Encephalopathy 

(HIE)

• most commonly due to lack of cerebral perfusion (cardiac arrest) or severe shock
• lack of energy - Ca Influx - NO syn - cell injury
• histo: neurons become shrunken, eosinophilic and have dark, pyknotic nuc (red, dead neurons)
• Reperfusion - free radicals, lactic acid, cerebral edema
• neurons more sens than glial cells; hippocampus, 3-5 cortical layers and perkinje neurons even more so
• CA-1 region of hippocampus particularly susceptible to HIE
• pseudolaminar necrosis - loss of neurons in cortical layers 3 and 5

Cerebral Amyloid Angiopathy

• amyloid deposited in vessel walls: get stiff and prone to hemorrhage
• can cause dementia by white matter degeneration and infarcts, ~ hypertensive small vessel change
• Lobar hemorrhage (not thalamus or Basal Ganglia)

Venous Infarction

• clinical: risk factors, dec LOC, tumor like presentation, non focal
• called tumor like because presents diff then an arterial infarction
• dont present w/ focal deficit; have headaches, seizures and dec LOC
• post partum, alcoholics and pts w/ IBD are predisposed to venous infarctions
• dense venous structures (CT), hemorrhage, process transgresses arterial boundaries (does not obey them)
• does not present as well defined wedge like arterial infarction

Non-Traumatic Hemorrhage

Aneurysm

• SAH, cisterns + sylvian fissures, +/-ICH and IVH
• anterior and posterior commmunicating arteries is most common spot for brain aneurysm; berry aneurysm
• Vasospasm way more common in non-traumatic SAH from aneurysm rupture than form traumatic SAH
• ruptured aneurysm are 2:1 female to male

Meniere's Disease

• vertigo w/ deafnesss and tinnitus 
• abrupt attacks - lasts mins to hours; incapacitaiotn
• nausea, vomiting and full feeling in ear
• nystagmus is rotary or horizontal
• slow component to side of the problem
• chronic disequilibrium state
• assoc w/ anxiety; equal sexes, onset in 50s
• patho: dilation of the endolymphatic system, degeneration of cochlear hair cells, excess endolymph in the inner ear
• Tx: Na restriction and diuretics; intra-tympanic gentamicin

Vestibular Neuronitis

• vertigo w/o tinnitus or deafness
• usually occurs in oung people; abrupt onset 
• severe vertigo w/ nausea and vomitting
• unilateral vestibular paresis
• Nystagmus w/ SAE
• normal hearing; benign disorder - subsides in a few days
• location is unsure

Treatment of Vertigo

• many vertigo disorders are self limiting
• Anticholinergic antihistamines - suppress central vestibular pathwys; meclizine, cyclizine and dipheyhydramine
• Anticholinergic phenothiazines - relieve nausea and vomiting - promethazine
• Scopolamine - anticholinergic; psychiatric and cardiac effects
• vertigo Tx only helps vertigo 

Nominal Aphasia (Anomic)

• primary deficit is word finding or naming: linked by grammatical types or by their semantic category
• speech is fluent but w/ numerous pauses
• pauses may be filed w/ circumlocutions: describing func of object
• auditory comprehension, reading and writing intact
• often residual after recovery from other aphasias
• less psecific in lesion localization
• typical language deficit in pts w/ ealry alzheimer dz

Trans-Cortical Sensory Aphasia

• similar to Wernicke's aphasia BUT repetition intact: severe deficit in comprehension;can produce fluent speech, but it is often empty and paraphasic
• lesion posterior and inferior to wernicke's area
• can repeat but dont understand
• Echolalia: automatic repitition of vocalizations made by another person
• seen in advancing Alzheimer dz and other progressive dementias, but it is also seen w/ lesions in the left temporo-occipital cortex

Audiogram

• sounds are presented at a range of frequencies and intensities
• pt reports what sound they can hear and an audiogram is compiled to map out the hearing threshold of the listener
• top of line graph (Y axis) is normal and bottom is profound hearing loss
• top is -10 and bottom is 120 so inc in hearing lvl (dBHL) is worse hearing
• in conductive hearing loss the threshold is inc across the whole hearing range indicating there is a transmition/amplification problem

Weber and Rhine Test Results

Weber Test Results (localization)

• normal heard at midline
• Sensorineural heard at normal ear
• conductive heard at affected ear

Rhine Test Results (Conductive)

• Normal and sensorineural: Air > bone 
• Conductive: bone > air

Otitis Media Characteristics

• Resolving Otitis media: air layer visible above the fluid indicating that the otitis media is resolving spontaneous; no intervnetion needed
• Serious Otitis Media: char by presence of a thin straw colored clear transudate in the middle ear - tympanic membrane shows orange discoloration from the fluid which fills the middle ear cleft; clear nature of fluid allows examiner to look into depths of middle ear

Tympanometry

• assesses the mobility of the tympanic membrane and the conduciton properties of the ear
• pure tone played into ear; measure tone reflected
• Type A trace: if hearing is normal then the loudest sound should be recorded when the air pressure in the ear canal is normal
• Type B: flat trace, no sound bounded back - indicates that there is fluid in middle ear or tympanic membrane is perforated
• Type C: sig negative pressure in the middle ear, possibly indicative of pathology - seen just piror to or during resolution of otitis media w/ effusion or eustachian tube dysfunction

Large or Small Axon Neuropathies

• Large Axon: weakness, loss of vibtration, position sense
• Small axon: loss of pain and temp sensation, autonomic dysfunction

Guillain-Barre Syndrome

(AIDP-CIDP)

• most common acute, inflam, demyelinative neuropathy
• autoimmune: -against own myelin and axons
• treated w/ plasma exchange, IVIg
• C jejuni, CMV, EBV, mycoplasma
• Sx: parethesias, sensory loss, generalized paralysis, autonomic disturbances, nerve conduction abnormalities, abnormal CSF
• perivenous lymphoctic infiltration in spinal roots and peripheral nerves

Charcot - Marie Tooth Disease

• most common inherited neuropathy
• autosomal dominant hypertrophic neuropathy
• stork legs, atrophy of hands, action tremors in some cases
• PMP22 overexpression (17p) - 3 copies of normal gene causes peripheral myelin to be unstable and breakdown
• demyelination, loss of axons, hypertrophic changes
• nerves thicken from collagen deposition (hypertrophic)

Neonatal Hypotonia

• muscular dystrophy - dystrophinopathy
• Multisystem disorder
• CTG trinucleotide repeats 19q; CCTG repeats 3q
• Autosomal dominant, myofiber atrophy, ring fibers, internal nuclei

Rhabdomyolysis

• weakness, soreness, markedly elevated CK, myoglobinuria
• Drugs, toxins: alcohol, glucocorticoids, lipid lower agents, cocaine, antimalarial drugs, antipsychotics
• Causes: trauma, extreme exertion, seizures, hyperkinetic states, metabolic myopathies, infections, inflammatory myopathies

Giloblastoma Multiforme (GBM)

• most common primary brain tumor of adults
• found in cerebral hemispheres (intra-axial)
• Highly malignant: cytologic atypia, mitosis, microvascular proliferation
• Necrosis w/ pseudopalisading (border of pleomorhic tumor cells)
• can cross corpus callosum - butterfly glioma

Meningioma 

• common primary benign tumor (20% ofbrain tumors
• 22-BANF
• found in adults; women 2x higher risk then men
• arise from arachnoid cap cells
• extra-axial - anywhere along brain, spinal cord
• can be spindled or epithelioid; whorls of spindle cells
• psammoma bodies; intranuclear pseudoinclusions

Oligodendroglioma

• fried egg cells (round monotonous nuc, clear cytoplasm
• rare, slow growing; most often in frontal lobes
• most tend to calcify
• chicken-wire capillary pattern; fine vascularity
• char by loss 1p and 19q; implies good prognosis; chemosensitive

Schwanoma

• benign tumor of peripheral nerves; extra axial
• tumor of schwann cells: spindle cells
• usually found at cerebellopontine angle
• when localized to CN VIII - acoustic schwannoma
• Bilateral acoustic schwannomas = NF-2
• Verrocay bodies; antoni A/B - hypercellular/hypocellular areas
• S-100+

Pilocytic Astrocytoma

• common brain tumor of children; arise in cerebellum of hypothalamus
• benign, well cricumscribed, solid + cystic
• cyst w/ contrast enhancing mural nodule
• biphasic - hypo/hypercellular w/ microcysts
• usually found in posterior fossa - cerebellum 
• rosenthal fibers - eosinophillic, corckscrew fibers
• granular eosinophilic droplets, no anaplasia, low grade, typically dont become malignant
• GFAP+

Medulloblastoma

• common embryonal brain tumor of children
• malignant form of primitive neuroectodermal tumor
• usually found in posterior fossa - cerebellum
• small round blue cell tumor
• homer-wright rosettes
• can send drop metastases tos pinal cord
• seeds the subarachnoid space - Dx subarachnoid space dissemination via CSF cytology (high protein, low glucose, meduloblastoma cells)

Ependymoma

• ependymal cell tumor
• usually found in posterior fossa - 4th ventricle, spinal cord
• can cause hydrocephalus
• perivascular pseudorosettes: rod shaped blepharoplasts found near nuc, surround central vessel
• poor prognosis 

Neurofibromatosis Type I

• autosomal dominant mutation in NF1 tmor suppressor in Chr17
• neurofibromas in skin, nerves - derived from neural crest cells, rubbery
• optic gliomas
• optic nerve astrocytomas, plexiform neurofibromas
• PCC
• Cafe au lait spots
• lisch nodules - pigmented iris hamartomas
• juvenile pilocytic astrocytoma

Neurofibromatosis Type II

• autosomal dominant mutation in NF2 on chr22
• normally encodes schwannomin or merlin
• bilateral acoustic schwannomas
• juvenile cataracts - lenticular opacities
• miningiomas, ependymomas

Tuberous sclerosis

• autosomal dominant mutation in TS1 (hamartin) or TS2 (tuberin)
• hamartomas - CNS, skin
• cardiac rhabdomyoma, mitral regurgitation
• mental retardation, seizures
• ash leaf spots, shagreen patches
• angiofibromas, renal angiomyolipoma
• inc risk of subependymal giant cell astrocytomas (SEGA), ungual fibromas

Posterior Fossa Tumors in Children

• Ependymoma, pilocytic astrocytoma, medulloblastoma, choroid plexus papilloma
• causes obstructive hydrocephalus
• morning headache, vomiting, blurred vision and papilledema
• LP can cause herniation, death

Nightmares and Night Terrors

• Night Terrors: children; deep NREM sleep, arousal - autonomic outburst - inconsolable, confused, amnestic - no dream recall, asleep immediatly after - assoc w/ sleep walking, enuresis; first 1/2 of night
• Nightmares: REM sleep, last third of night; immediate awakening, clear, good recall of dream - all ages, inc w/ psychopathology

Non-REM Sleep

• N1 - drowsiness, light sleep - theta waves
• N2 - deeper sleep, bruxism, sleep spindles + k complexes
• N3 - deepest non-REM sleep, delta waves (lowest freq, highest amplitude), sleepwalking, bedwetting, night terrors (first 1/3 of night), muscle tone present, dec brain metabolism, regular vitals

REM Sleep

• beta waves (paradoxical sleep), PPRF (extraocular movts)
• occurs every 90 mins
• loss of muscle tone (paralysis)
• inc  brain metabolism, O2 use
• Irregular vitals; dreaming
• nightmares - last 1/3 night (all ages, immediate awakening and good recall)
• penile/clitoral tumescence
• memory processing function

Sleep Apnea

Nocturnal Hypoxia Complications

• systemic/pulmonary HTN
• arrhythmia (a-fib)inc EPO -> erythropoiesis, polycythemia
• Right heart failure and also ?sudden death?
• avoid alcohol, benzos and barbiturates (sedatives) because assoc w/ dec REM sleep)
• weight loss usually first line Tx

Narcolepsy

• disordered regulation of sleep-wake cycles
• excessive daytime sleepiness (onest in teens/20s)
• cataplexy - sudden loss of muscle tone following emotional stimulus
• sleep paralysis and hypnagogic hallucinations
• HCRT/orexin - cells active during wake, REM sleep and inactive in NREM - dec number of HCRT cells and fibers in narcolepsy
• Dx - sleep latency < 10min, SE > 80%; REM latency < 30 min, no significant apnea; MSLT (5 naps)
• Tx - amphetamines, gamma hydroxybutyrate (GHB)

Restless Leg Syndrome

• often assoc w/ PLMS - uncomfortable leg sensations when lying down, worse at night
• Primary (idiopathic) - yong onset (AD)
• secondary - diabetes, renal failure, iron or B12 def, parkinson's and MS
• Tx - dopaminergics - l dopa, D agonists (pramipaxole, ropinorole)
• Tx - benzo - clonazepam
• Tx - antidepressants, antiepileptics, opiates

Non-benzodiazepine Hypnotics

• used to treat Primary insomnia
• Zolpidem, Zaleplon, ESzopiclone
• GABA agonists - BZ1 subtype
• Modest day-after psychomotor depression
• adv effects - ataxia, headaches, confusion

Mononeuropathy

• carpal tunnel syndrome (most common) - median nerve, sensory loss (thumb, 2nd, middle, radial half of 4th digit on volar aspect of hand, atrophy/weakness of abductor pollicis brevis
• Saturday night palsy - radial nerve, wrist drop causes compression of radial nerve 

Myasthenia Gravis

• most common NMJ disorder; ACh receptor Ab - block ACh from binding to NMF and cause rec destruction
• fluctuating weakness - gradually worsens thru day
• ocular variant - fluctuating diplopia, dysphagia - assoc w/ AI dz, thymomas and may or may not progress
• myasthenia crisis - may lead to respiratory failure, death
• Tx - ACh - esterase inh - Neostigmine, pyridostigmine

Myotonic Dystrophy 

• autosomal dominant - CTG repeat w/ anticipation
• Myotonia - pts cannot relax grip
• cataracts, frontal baldness, gonadal atrophy
• atrophy of type 1 fibers

Acid Maltase Deficiency

• glycogen storage disease Type II
• Pompe's Disease - infantile form, rapidly fatal by 6 mo age
• Calf hypertrophy - muslces fill w/ glycogen: other early sine is toe walking around age 2; usually fatal in adolescence/early 20s
• proximal muscle weakness in benign adult form

Myophosphorylase Deficiency and PFK Deficiency

• metabolically different, cinically the same
• muscles normal at rest
• exercise leads to severe cramping and contractions that can cause rhabdomyolysis
• Rhabdomyolysis -> myoglobinuria -> renal failure

Gait Types and Causes

• Cerebellar ataxia: wide base, unsteady irr steps (alcoholism, tumor/stroke, MS, spinocereb atrophy)
• Frontal lobe apraxia: die based, slow initiation, forward flexion, feet glued to floor (NPH, Alz, dementia)
• Circumduction: leg swings in an outward arc to assure ground clearance, avoid trippping (stroke, hemiplegia)
• Scissoring: bilateral circumduction gait (myelopathies)
• Festinating: narrow base, slow, symmetric foot shuffling; flexed posture, dec arm swing (parkinson's)
• Sensory ataxia: wide base, unsteady, foot stomping, looks at ground

Lysosomal Storage Diseaes (LSDs)

Overview

• most enzymes involved in LSDs are glycosidases
• most autosomal recessive
• pathology develops when enzyme lvls fall below 15-20%
• most severely affected cells and tissues: neurons, phagocytic cells (histocytes)
• Dx - lysosmal enzyme genes expressed in many cells and tissues
• LSD phenotypes - neuronal lipidosis, leukodystrophy, mucopolysaccharidosis and Storage histiocytosis

Lysosomal Storage Disease (LSD)

Phenotypes

• Neuuronal Lipidosis: storage in neuronal body - neuronal ballooning, neuronal loss, cortical atrophy; seizures, neurological regression, blindness, persistent - Tay- Sachs Dz
• Leukokdystrophy: storage in myelin-producing, demyelination, ipaired myelin formation, neuroligcal regresion, spasticity, peripheral neuropathy
• Mucopolysaccharidosis - storage in extraneural tissues; visceromegaly, skeletal dysplasia, soft tissue swelling, corneal opacity, heart dz; often combined w/ neuronal lipidosis
• Storage Histiocytosis - hepatosplenomegaly, hematopoietic abnormalities; Gaucher Dz
• Gaucher Dz - hypersplenism, anemia, thrombocytopenia, bone dz

Most Common Mitochondrial Disorders (MTDs)

• Leigh Syndrome - nDNA, few mtDNA; autosomal recessive; no RRFs
• MEERF - mtDNA; maternal genetics, RRFs
• MELAS - mtDNA, maternal genetics, RRFs
• KSS-PEO - mtDNA, sporadic genetics, RRFs
• LHON - mtDNA, maternal genetics, no RRFs
• key biochem abnormality: blood and CSF lactate > 2.5mM/dl; L/P ratio > 25

Peroxisomal Biogenesis Disorder

• Zellweger Syndrome - dysmorphic features, liver dz, neurologic abnormalities (hypotonia, seizures, neurological regression); neuropatholog - neuronal migration defects, VLCFA accumulation in histiocytes, myelin abnormalities 
• XALD (AMN -Childhood XALD) - behavioral changes, dementia, aataxia, visual loss, adrenal insufficiency, accumulaiton of VLCFAs in glial cells (oligos), incorporation into myelin (myelin breakdown, leudkodystrophy); metabolic and I immune-mediated pathology 

Diffuse Axonal Injury

• angular acceleration/deceleration of mobile cerebral hemispheres around fixed brainstem
• creates shearing forces in brain parenchyma
• immediae loss of consciousness -> prolonged comoa or persistent vegetative state
• concussion
• stretching of axolemma at nodes of ranvier
• axonal swellings, wallerian degeneration, loss of axons
• hemorrhages- corpus callosum, brainstem

Types of Brain Herniations

• Subfalcine herniation - cingulate gyrus moves under falx cerebri to other cise; can compress ACA
• Transtentorial/uncal herniation - medial temporal lobe moves under tentorium cerebelli - CNIII palsy, ophthalmoplegia (down n out gaze), ipsilateral paralysis, compression of PCA, chyne strokes respiraitons, coma
• Tonsilar Herniation - cerebellar tonsils move under foramen magnum; compress brainstem -> inhibit respiration, coma, death

Creutzfeldt-Jakob Disease (CJD)

• anormal prion protein PRP^SC -> beta pleated sheets
• Familial prion dz - AD mutation in PRNP gene
• rapidly progressive dementia +/- movt disorders (except fatal familial insomnia (FFA))
• myoclonus - startle myoclonus
• micro - spongiform degeneration - white holes on biopsym amyloid plaques
• gross - brain atrophy (ventricles can be huge)
• fatal - no treatment 

Pick's Disease

(FTDP)

• frontotemproal dementia w/ motor neuron disease
• gross severe "knife-edge" atrophy
• corticobasal degeneration
• progressive supranuclear palsy
• clinical pres: dementia, aphasia, and change in personality
• frontotemproal autrophy - Pick bodies - tau accumulation; and pick cells (purple cell surrounded by white w/ nuc in corner)

Spinal Muscular Atrophy

• most common fatal recessive disorder in children after Cystic Fibrosis; most AR
• degeneration of anterior horns: LMN lesion (flaccid paralysis, atrophy), floppy baby (hypotonia, tongue fasciculations)
• mutation in spinal motor neuron gene (SMN)
• SMA 1(infantile spinal muscular atrophy) - werdnig-hoffmann dz; begins in infant dead at 2
• SMA3 (Juvenile spinal muscular Atrophy) - kugelberg-welander dz; begins in adolescence, long survival in wheelchair
• poliomyelitis - poliovirus desseminated to CNS - destruction of anterior horn (LMN death + fever)

Friedreich's Ataxia

• most frequent inherited ataxia
• Autosomal recessive Sensory Ataxia - GAA repeats in FXN gene
• Frataxin - iron metabolism - causes impaired mitochondrial func, oxidative stress
• degen of multiple spinal cord tracks - muscle weakness, areflexia, loss of vibration, proprioception, sensory neuropathy
• cerebellar cortex normal, but degeneration of dentate nuc and sup CB peduncle
• staggering gait, frequent falling, nystgmus, dysarthria
• pes cavus (high arch), hammer toes
• presents in childhood w/ kyphoscoliosis
• cause of death usually hypertrophic cardiomyopathy

Risk Factors of Dementia

• age and gender (female)
• other medical disorder - Down Syndrome has early onset
• Alcohol abuse, head trauma, mood disorder, low education attainment, MCI
• HTN (other vascular risk factors)
• Family history - 15-30% risk of AD in first degree relative

Alzheimer's Genetics

• Chr 21 - APP (Trisomy 21) - assoc w/ earlier onset
• Chr 14 - Presenilin 1 
• Chr 1 - Presenilin 2
• Chr 19 - ApoE4 (late onset Alzheimer's) - 4 and 3 bad and 2 is protective 
• early onset familial AD: Chr 1, 14, 21
• Alzheimer's has widespread cortical atrophy - temporal > parietal > frontal

Frontotemporal Dementia

• picks disease first recognized subtype
• focal atrophy of frontal and/or temporal lobes in absence of Alzheimer's Disease
• clinicall presents w/ language abnormalities (aphasia) and behavioral disturbances (frontal) - memory problems come later
• age of onset 35-75; male = female
• as many as 50% have positive family history of dementia - Autosomal dominant and may be assoc w/ tau gene on Chr 17
• insidious onset and gradual progression, early decline in social interpersonal conduct

Normal Pressure Hydrocephalus

(NPH

• inc in intracranial pressure (ICP) due to abnormal accum of CSF in ventricles - thought to be form of communicating hydrocephalus
• pressure returns to high normal range: thus no HA; vomiting or loss of consciousness
• can be idiopathic or secondary (SAH, CNS infection, mass)
• expansion of ventricles
• Triad = Wakcy, wobbly, wet - dementia, ataxia (magnetic gait), urinary incontinence
• Dx - MRI/CT, LP (large volme tap, lumbar drain)
• Tx - ventriculoperitoneal (V-P shunt; success ranges (20-80%): gait > incontinence > dementia

Pain Pathways

(peripheral nociceptors)

• alpha-delta fibers: small myelinated, fast - activated by noxious, heat, mech stimuli
• C-fibers - unmyelinaed, slower - activated by chemical, thermal, mech stimuli
• dorsal horn of spinal cord - high conc (GPCRs) of opioid rec - u, delta, k
• opioid agonists directly inhibt dorsal horn pain transmission from the primary afferent neurons

Codeine, Oxycodone

• mild-moderate phenanthrene - less potent than morphine 
• combo w/ acetaminophem, ibuprofen or aspirin for short term Tx of mild to moderate pain
• can build up causing dangerous side effects when used chronically or acutely in high dose in in pts w/ renal impairment
• CYP2D6 convers to more potent metabolites (codeine to morphine; oxycodone to oxymorphone)
• black box warning: CI - codeine in children after tonsillectomy, adenoidectomy; due ot inc incidence of death in children w/ sleep apnea because of the genetic predisposition for ultra rapid metabolism to morphine

Methadone

• phenyleptylamines (opioid); potent u agonist and NMDA rec antagonist; SNRI - serotonin and NE reuptake inh
• clinical use - maintenance programs for heroin addicts
• long half life (25-52 hrs); liophilic nature leads to build up in tissues, becoming reservoir for blood lvls
• no known active metabolites - good for pts w/ renal impairment
• risk of prolonged QTc
• drug interactions w/ CYP3A4 can lead to dangerous side effects due to dramatic changes in drug levels

Phenylpiperidines

(opioid)

• STRONG: Fentanyl, sufentanil, alfentanil, remifentanil - lipophilic; sufentanil most potent and longest duration (then fentanyl), drug interactions w/ CYP3A4 dangerous
• STRONG: Meperidine - antimusc effects (cause tachycardia); neurotoxic metabolite (normeperidine); CI- renal impairment (metabolite leads to seizures unresponsive to antagonists)
• Mild-Moderate: Diphenoxylate, loperamide - cannot cross BBB; used for Diarrhea

Morphinians

(opioids)

• strong - Levorphanol
• Mild: Dextromethorphan - Clinical use - cough suppression
• Mixed activity - Butorphanol - k agonist + possible u agonist or antagonist - treats severe pain (labor, migrain) w/ less respiratory depression

MOA of Opioids

• bind GPCR (u, delta, k)
• close presynaptic voltage gated Ca2+ channels on presynaptic nerve terminals - dec excitatory NT release and inh of glutamate, ACh, NE, 5-HT, substance P release
• Open postsynaptic K channels - hyperpolarizes the cell and inh synaptic transmission
• overdose Tx w/ naloxone (short acting) and Naltrexone or Nalmefene (longer acting)

Inhaled Anesthetics

• lower the MAC the higher the potency
• Nitrous Oxide - Central NMDA antagonist - low potency (MAC 105) but high analgesia; adv effect is expansion of trapped gas in body cavity
• Halothane - multiple ion channel activation leading to hyperpolarization; highly potent but poor analgesic; adv effect - hepatotoxicity
• Methoxyflurane - GABA_A rec activation, causing hyperpolarization - highly potent and analgesic; adv effect nephrotoxicity and hepatotoxicity

Facts of Anesthetics

• lower the MAC the more potent the anesthetic
• The higher the lipid solubility the more potent and the slower onset/recovery
• lipophilic - more able to cross BBB
• low solubility - faster onset of anesthesia

IV anesthetics

• Thipental - barbiturate - induction anesthsia; adv effect - dec cerebral blood flow
• Midazolam (diazepam and lorazepam) - Benzo - preanesthetic, sedative, common for endoscopy, used w/ gaseous anesthetics, severe resp depresion, dec BP, anterograde amnesia
• Ketamine - NMDA antagonist - induciton, maintenance, sedation - CV stimulants - causes disorientation, hallucination, bad dreams and inc cerebral blood flow
• Opioids - morphine, fentanyl - analgesia - no amnesia
• Propofol - potentiates GABA_A rec - used for sedation in ICU - rapid anesthesia induction 
• Dexmedetomidine - alpha agonist - sedation, dec dose of inhaled, analgesia - no amnesia and minimal resp depression

Local Anesthetics

• MOA - inhibit voltage gated Na channels - preferentially bind activated/open Na channels (rapid firing neurons)
• Adm w/ vasoconsrictors -enhance local action and dec systemic conc
• Infected (acidic) tissue requires more anesthetic because alkaline and cannot penetrate membrane
• Esters (metabolized by plasma esterases)- cocaine, procaine (novocaine) (short duration), tetracaine (long duration, mostly spinal), benzocaine 
• Amides (metabolized in liver) - lidocaine (risk of TNS), mepivacaine (vasoconstriction), bupivacaine (risk of cardiotoxicity)
• Adverse effects - systemic effects (cardiotoxicity and seizures), local toxic effects, hypersensitivity, transient neurologic sx (TNS)

Periventricular Leukomalacia (PVL)

• HIE in preterm infants; periventricular white matter infarcts
• Infarcted white matter has more reddish, lighter tint - lesions cavitate and brain tissue around cavity devleops glial scarring
• Calcification common in brain injury of newborns and children; gives chalky white color
• PVL lesions are bilateral and symmetric
• Cystic PVL - ischemic infarction of deep white matter - most susceptible ebcause vascular develop goes from outside in; also cause they contain oligodendroglial precursors suscuptible to HIE
• Diffuse PVL - damage to oligodendroglial precursors in areas that surround the cystic PVL because ischemia not enough to fully kill but can damage

Interventricular Hemorrhage 

(IVH)

• Prematurity, HMD; also called germinal matrix hemorrhage
• usually wraps into lateral ventricles - arises in the germinal matrix
• Hypoxia from ARDS leads to dmg of U turn vein walls making way for them to break
• exsanguination, autonomic failure, periventricular infarction, hydrocephalus
• aqueductal atresia hydrocephalus - from clot and scar tissue in aqueduct - leads to severe hydrocephalus
• Grade I - germinal matrix; Grade II - intraventricular; Grade III - ventricular dilation; Grade IV - periventricular white matter extension

Anticholinergics and Parkinson's

• benztropine, procyclidine, trihexyphenidyl
• ACh is under tonic inh by dopamine; dopamine degen leads to inc striatal cholinergic activity -> inc cholinergic activity causes tremors, dystonia
• treats tremors, rigidity; limited usefulness for bradykinesia
• preferably used in younger pts - tolerate Side effects 
• Adverse Effects: blured vision, confusion, sedation, altered mental status, constipation, dry mouth, mydriasis w/ loss of accomidatino, flushing and fevere

MAO-B Inhibitor

(selective MAO inh)

• Selegiline, rasagiline
• selectively inhibits MAO-B, prevents degradation of D
• Slows progression of Dz; dec oxidative stress and free radicals
• initiation monotherapy in early stages; use adjunct w/ L-dopa later
• Adv effects- may enhance adv effects of LDopa, hypertensive crisis (tyramine rich foods) 

COMT Inhibitor

• entacapone, tolcapone
• COMT degrades catecholamines such as Epi and D
• Enhances central bioavailability of L-Dopa
• used as adjunct w/ L-dopa (no use in absence of L-Dopa)
• Adv effects: Tolcapone - hepatotoxicity

Dopamine Agonists

• apomorphine - non selective D agonist
• Ergot - bromocriptine; pergolide (withdrawn, causes cardiac fibrosis)
• Non-ergot - pramipexole, ropinirole, rotigotineinitiation 
• monotherapy in mild-moderate parkinsons
• preferred in younger pts - use LDopa in older
• Adv effects: nausea, confusion, hallucinations, psychosis, postural hypotension
• Less common adv effect: compulsive behaviors (gambling, shopping)

Atypical Parkinsonian Disorders

• Char by rapid evolution, early postural instability, poor response to D
• Multiple System Atrophy (MSA) - ED (most common 1st feature in males), Glial cytoplasmic inclusions (parkinsonian or cerebellar variant), Hot cross bun appearance of pons in pontine hyperintensity
• Dementia w/ Lewy Bodies (DLB): early dementia, visual hallucinations, parkinsonism
• Progressive Supranuclear Palsy (PSP): 7th decade (never before 40), early postural instability, falls, vertical gaze palsy; speech and swallowing probs
• Corticobasal degeneration: eventually alien limb

Dystonias

• involuntary sustained muscle contractions causes abnormal postures
• causes - primary, D responsive dystonias, brain injury, Parkinsons, Wilsons(ATP7B mutation)
• childhood onset - legs first; Adult - upper body first
• Blepharospasm - periocular dystonia(blinking) - if assoc w/ lower face its Meige's Syndrome
• Cervical dystonia -muscles of the neck and shoulders
• occupational dystonias (task specific) - writers cramp
• Tx - anticholinergics; chemodenervation (Botox)

Gilles de la Tourette's Syndrome

• multiple motor tics; one or more vocal tics
• more or less consistent; cant be absent for more than 3 months; onset before age 21
• coprolalia - involuntarily swearing obsenities (10%)
• assoc behavioral abnormalities - OCD (63%), ADD (75%)
• pathophys- unclear, slightly smaller caudate and lenticular nuc volumes
• Genetics suggest AD w/ vriable expression
• Tx - Atypical neuroleptics (tics); stimulants (ADD), SSRIs (OCD)

Phenytoin

• blocks voltage gated Na channels; inhibits spread of abnormal electrical discharge from seizure focus
• 1st line therapy - Tonic-Clonic Seizures
• Treats - partial, complex seizures and status epilepticus
• NOT for absence seizures (may worsen)
• adv effects: nystagmus, diplopia, ataxia, sedation, gingival hyperplasia, hirsutism, peripheral neuropathy, megoblastic anemia, teratogen
• Adv effect - Steven johnson syndrome - prodrome (malaise, fever, erythematous macules)

Carbamazepine

• also oxcarbazepine, eslicarbazine
• Blocks voltage gated Na Channels - inhibit spread of abnormal electrical discharge from seizure focus
• 1st line therapy - Tonic clonic seizures, partial seizures
• also treats complex seizures
• NOT for absence seizures
• adv efects - diplopia, ataxia, hepatotoxicity, teratogen, blood dyscrasias, SIADH, steven johnson syndrome

Rufinamide

• blocks voltage gated Na channels - inhibits spread of discharge from seizure focus
• uses - refractory epilepsy, adjunct Tx for lennox-gastaut synd

Gabapentin, Pregabalin

• blocks voltage gated  Ca channels (a2d subunit)
• adjunct tx - partial seizures and generalized tonic clonic seizure
• Adv effects - sedation and ataxia

Ethosuximide

• dec low threshold thalamic T type Ca current
• 1st line therapy for absence seizures
• Adv effects: GI, fatigue, headache, uriticaria, Steven johnson syndrome

Lamotrigine

• block votage gated Na and Ca channels
• dec synaptic release of glutamate
• uses - all seizure types
• adv effects - steven johnson syndrome (must titrate slowly), skin rash, life threatening dermatitis (progress to epidermal necrosis/sloughing)

Other types of Anti-epileptics

• topiramate - block Na, Ca channels, block AMPA, kainate rec (glutamate release), potentiates inh effects of GABA
• zonisamide - block voltage gated Na and Ca channels
• Ezogabine - activates K channels
• Levitiracetam - binds synaptic vesicular protein, modifies synaptic release of glutamate and GABA
• Lacosamide - block voltage gated Na channels, bind CRMP-2 and block BDNP on axonal/dendritic growth
• felbamate - block NMDA rec
• Tiagabine - GABA uptake inh, pref inh transport isoform 1 (GAT-1)
• Vigabatrin - irr inh of GABA-T, prevents GABA degradation

Barbiturates and Benzodiazpeines

Seizures

• barbiturates - phenobarbital, primidone, phentobarbital, thiopental
• Benzo - clonazepam, diazepam, lorazepam
• MOA - activate GABA_Arec - Cl influx (hyperpolarization)
• uses - partial siezures and tonic clonic
• Status epileptics - Diazepam and lorazepam

Valproic Acid

• Block voltage gated Na channels and Ca channels
• Block NMDA rec
• inhibit GABA transaminase (GABA-T) and GABA transporter (GAT-1)
• facilitate glutamate decarboxylase (enzyme for GABA syn)
• inh histone acetylation - epigenetic mech
• uses - all seizure types

Teratogenicity 

• Anticonvulsants - may lower lvls of oral contraceptives (unplanned pregnancies)
• Carbamazepine, phenytoin - fetal hydantoin syndrome
• Lamotrigine and valproate - may reduce folate levels (spina bifida)

Generalized Seizure

• Affect entire brain; loss of consciousness
• Absence (petit mal) - no postictal confusion; blank stare - Tx w/ ethosuximide (1st), valproate, lamotrigine
• myoclonic - quick repetitive jerks w/ slow relaxation
• tonic - stiffening
• Clonic - repetitive movts w/o relaxation
• Tonic-clonic (grand mal) - alternating stiffening and repetitiveness movt
• atonic - drop seizures, falls to floor (mistaken for fainting)

Levels of Brain Functioning in Coma

• Cortical level coma - respirations normal or chyne storke resp, normal pupil, intact corneal reflexes, cough, gag and withdrawal from noxious stimuli
• Diencephalic level coma - often bithalamic injury, ehtylene glycol, CO poison; Cheyne storke respirates, eye position variable (weird conjugations), small reactive pupils, intact corneals, cough and gag, withdrawal to pain or bilat rigidity/akinesis
• Midbrain level coma - central hypervent, 3rd nerve palsy (dilated pupil, intact corneals, cough, gap, decorticate posturing on affected sides
• Pontine lvl Coma - apneustic breathing, pinpoint pupils, 6th nerve palsy, intact cough/gag; no corneal reflex, decerebrate posturing
• Medullary lvl coma - ataxic breath, fixed midposition pupils (no symp or parasym inerv), flaccid paralysis of all limbs, intact cough/gag

Important Early signs of Herniation

• paratonic rigiditiy (lead pipe rigidity)
• ipsilateral dilated blown pupil (UNCAL) - 3rd nerve by tentorium
• Cerebellar shivers (tonsillar herniation) - all of the body becomes spastic and tremulous at once - leads to quadraplegic
• Paradoxical ipsilateral hemiparesis (kernehan's notch phenomenon) - paraxocial cause ipsilateral side gets paralyzed from way brainstem twists
• paraparesis (subfalcial)

Alpha agonists

Eye pharm

• apraclonidine and brimonidine
• selective agonists of alpha 2 rec
• not mydriatic agents
• dec aqueous prod in ciliarly bodies
• Brimonidine also inc uveoscleral outflow
• Side effects: tearing, burning, ocular discomfort, blurred vision

Beta Antagonists

IOP lowering drugs

• selective blocker (beta 1 rec) - betaxolol
• Nonselective blocker - timolol, levobunolol, careolol
• MOA: inh of Cl/HCO3 exchange and prevent cAMP production
• have no effect on accommodation or pupil size 
• Timolol also used to treat secondary glaucoma ins elected pts (can cause hallucinations)
• betaxolol indicated for open angle glaucoma and ocular HTN and DOC for pts w/ pulmonary dz because it is selective for only beta1
• Side effects non selective - bronchospasm, bradycardia, confusion, insomnia, weakness, resp difficulties, depression, ataxia, edema

Carbonic Anhydrase Inh

IOP lowering Drugs

• dorzolamide, brinzolamide, acetazolamide
• dec aqueous humor sec due to lack of HCO3
• lack of HCO3 prevents reverse reaction, production of Carbond dioxide (a well knwon vasodilator)
• Side effects - bitter taste, stinging, redness, dry eye

Mast Cell inhibitors and Anti-Histamines

• drug treatment for allergic conjunctivitis 
• Mast cell stabilizers/inh - cromolyn sodium, lodoxamide thromethamide, pemirolast - stabilize mast cell by blocking Ca influx (preents degranualtion)
• Histamine Rec (H1) antagonist - emedastine, levocabastine - block H1 rec 
• Combo drugs - olopatadine HCl, azelastine HCl, nedocromil sodium , ketotifen fumarate

Keratitis

• corneal inflammation
• can occur at any lvl of the cornea - epithelium, subepithelium stroma and endothelium
• Sx - extreme pain and pthophobia
• Noninfectious - poor eyelid closure UV exposure
• Infectious - bacteria (staph, pseudomonas), Virus (HSV, Zoster), acanthamoeba (contact wearers), fungi (fusarium, candida, spergillius, parasite (onchocerca volvulus causes river blindness)
• severe infections w/ corneal ulcers require urgent care due to threat to vision

Red Eye - Eye Lid Disorders

• stye/hordeolum - sebaceous glands of Zeis or paocrine sweat glands of moll; present at lid margin, less painful
• Chalazion - blocked MGD, painful, present on under surface
• Blepharitis - chronic inflam of lid margin; staphy, seborrheic, rosacea
• Tx for stye/chalazion - compress/massage; may require drainage for chronic lesions
• Tx for Blepharitis - lid scrubs, tears for dry eye, antibiotics and/or steroid for short course

Red Eye Disorders: Conjunctiva and Sclera

• subconjunctival hemorrhage
• conjunctivitis: acute, chronic
• Pterygium/pinguecula - elastic degen of conjunctiva; destruction of bowman's layer, wind and UV exposure; interpalperbral location
• Episcleritis/scleritis - inflammation of episclera, sclera, epi less painful; scleritis more painful, redness can be diffuse or nodular; may be assoc w/ systemic dz, Tx w NSAIDs/steroids
• foreign body

Neonatal Ophthalmia

• neonatal conjunctivitis; exposure during vaginal delivery to infectious etiology 
• chemical conjunctivitis was form silver nitrate 
• Gonococcal - most severe, very purulent, seen 3-7 days; one of few organisms that can penetrate intact cornea; rapid corneal perforation, permanent vision loss; IV cefriaxoneas well as topical antibiotics
• Chlamydia- less purulent appearingl most common, tx erythromycin

Red Eye Disorders: Orbit/Lacrimal System

• dacryocele - bluish mass due to enlargement of lacrimal sac w/ fluid/amniotic
• NLD obstruction - most common eye condition of childhood, spontaneous resolution usually
• Dacryocystitis - pain, redness, tearing, swelling (under eye and medial)
• Orbital cellulitis - ocular emergancy - redness, swelling, dec motility, vision dec, +APD
• Preseptal Cellulitis - lid swollen, red, have normal eye movt and vision

Red Eye Disorders

• Vision Threatening - corneal infections, hyphema, iritis, acute glaucoma, orbital cellulitis, scleritis
• Treatment indicated - stye, chalazion, blepharitis, conjunctivitis, subconjunctival hemorrhage, dry eyes
• Vision Sx requiring referral - dec visoin, ocular pain, photophobia, circumlimbal redness, halos, flashes/new floaters, abnormal pupil, elevated IOP
• Referral indicatinos - URGENT (orbital cellulitis, acute glaucoma, corneal infections) and also (episcleritis/scleritis, hyphema, iritis)

Amblyopia

• most comomn cause of vision loss in childhood 
• unilateral or bilateral; treatable
• causes - imbalance btw the two eyes
• Unilateral cataracts more difficult to treat than bilateral
• Stabismic amblyopia - if eyes not straight, brain can not use the two images together - adults get diplopia and children supress
• strabismus -> suppression -> amblyopia -> loss of vision
• Treat w/ eye patch

Strabismus

• eyes do not move together; one or both eyes may wander in, out, up or down
• estropia: eyes in - congential children corss fixates, less amblyopia; accomodative/refractive - 85% treatablew/ glasses for hyperopia
• Extropia: eyes out - most common misalignment at birth which resolves spontaneously, less dangerous to visual system then estropia

Age Related Macular Degeneration

(ARMD)

• elderly, fair complexion, norwegian descent, smoking, HTN, poor diet, UV exposure
• Dry-Drusen: discrete orange blobs, macular area, signify death of RPE, accum of waste products of metabolism, slow dec in vision, no cure, amsler grid monitoring
• Wet: 5% of pts, new vessel growth; results in bleeding, fluid leakage, scarring - choroidal neovascularization (CNV)
• Tx includes focal laser, anti-VEGF

Retinal Detachment

• Sx: flashes, floaters, dec vision, shadows, distortion, curtain progressing across vision
• vision normal if macula not involved, relative scotoma, pigment in vitreous
• Rhegmatogenous Retinal Detachment - break in retina allows fluid beneath retina; rate of progression and amount of vision loss depends upon location
• Tractional Retinal Detachment - traction from prolif retinopathy of any cause: usually diabetes, sickle cell dz, vascular occlusions
• Serous Retinal Detachment - chronic inflammation, central serous retinopathy, wet macular degen, choroidal mass lesions

Diabetic Retinopathy

• most common cause of blindness < 65 yrs
• Background diabetic retinopathy - microaneurysms, dot/blot hemorrhage, exudates - most common casue of visual loss in diabetic is cystic macular edema
• Pre-proliferative diabetic retinopathy - cotton wool spots, extensive hemorrhages, venous bleading, intraretinal microvasc abnormalities
• Proliferative Diabetic Retinopathy - affects 5-10% of diabetes; IDDM at inc risk, NV of disc or elsewhere (NVD or NVE)
• End stage Dz - fibrosis, traction, detachment

Grading for Hypertensive Retinopathy

• Grade 1: arteriolar narrowing and vein concealment - Mild HTN changes
• Grade 2: severe arteriolar narrowing w/ AV nicking
• Grade 3: arteriolar copper wiring, hemorrhages, CWS, exudates
• Grade 4: allof the above plus silver wriing and optic disc swelling

Pseudotumor Cerebri

• inc intracranial pressure w/ no pathology found
• young btw 20-45; overweight women
• headaches 90% - most common sx, diplopia (6th nerve)
• transient vision lossl visual field loss - can progress to blindness from optic atrophy if Dx missed
• Tx w/ carbonic anhydrase inh, LASIK, steroids
• monitor optic nerve swelling and visual fields
• if vision threatened, may need VP shunt or optic nerve sheath fenestrations

Anterior Ischemic Optic Neuropathy

• elderly, unilateral: painless vision loss, altitudinal field cut
• Non Arteric - eldelry (60s), systemic Dz (HTN, DM, athersclerosis), infarction of short posterior ciliary arteris caused by vascular dz - pts at higher risk fo cardiac event, stroke
• Arteritis - usually early sign of anorexia myalgias, may have hx of TIAs, 70s, short posterior ciliary, central retial arteries can be compromised
• Dx - important to Dx quickly, second eye at risk of blndness
• treat w/ high dose steroids immediatly - IV if vision loss
• Temporal artery biopsy

Arnold Chiari II 

Malformations

• Meningomyelocele assoc - incomplete closure of caudal end of neural tube
• Tonsils of cerebellum is going to go down and sit in cervical canal; area of posterior fossa is small
• compression of brainstem
• hydrocephalus - third and lateral ventricle dilates because 4th ventricle is compressed and blocked
• lateral ventricle enlargement stretches corticalspinal tract, compression of leg area (stiffness of leg)
• third ventricle enlargement presses on tectle area leads to setting sun (always looking down)
• macrocephaly (big head) and open fontanel (soft spot on top of head)

Migration Defects

• Lissencephaly - smooth brain surface w/ only 1 or 2 clefts - cognitive delay, seizures, hypotonia, microcephaly w/ big ventricles
• Pachygyria/agyria - dec or absent gyri
• Hetrotopias - abberant neurons; gray matter sits in the white matter; failed migration to the peripher

Treatment of PTSD

• Non-pharm: prolonged exposure, cognitive processing therapy, trauma focused cogntive behavioral therapy, epxosure relaxation and rescripting, eye movement desensitizaiton and reprocessing
• pham: SSRI (1st line) - sertaline and paroxetine; non SSRIs (venlafaxine, nefazodone, trazodone, mirtazepine)
• other meds - MAOIs, TCAs, anticonvulsants (when w/ bipolar), benzo (short term), atypical antipsychotics (for paranoia and flshbacks), beta blockers (prazosin for nightmares and anxiety)

Schizophrenia Symptoms

• Positive Sx - presence of something not usually there - dellusions and hallucinatinos
• Disorganized Sx - formal thought disorder
• Negative Sx - absence of something usually there - 5 As - affecting flattening, alogia (poverty fo thought), avolition (lack of motivation), abulia (lack of will), anhedonia (loss of pleasure)
• Cognitive sx - impaired info processing, abstract categorization and executive func; issue of anosognosia

Dopaminergic Pathways in 

Schizophrenia

• Mesolimbic Pathway - ventral tegmental area to nuc accumbens; reward pathway - inc activaiton leads to positive Sx
• Mesocortical Pathway - ventral tegmental area to frontal cortex - cognitive func, motivation, emotional response - dec activaiton leads to neg Sx
• Nigrostiratal pathway - body movt - basal ganglia - Extrapyramidal side effects
• Tuberoinfundibular pathway - Hypothalamus to pituitary, dec D leads to prolactin sec and hyperprolactinemia

First Generation Antipsychotics

Typicals

• extrapyramidal side effects: D2 antagonism - nigrostriatal pathway - akathisia, pseudoparkinsonism, dystonia, tardive dyskinesia
• strong D2 antagonist - effective in Tx positive schizophrenia Sx
• Phenothiazine - chlorpromazine, thioridazine - D2, M1, H1, alpha1
• Butyrophane -haloperidol - D2, alpha1  - used for acute psycosis, tourettes (tics, coprolalia)
• Azepine - loxapine - D2, 5HT2, alpha 1 and 2

Second Generation Antipschotics

Atypicals

• 5HT2 rec: mesocortical - improves neg Sx; nigrostriatal - alleviates extrapyramidal Sx
• possess D2 as well as 5HT2 antagonist - effective in Tx both pos and neg Sx; does not produce severe movt disorders
• adv effects agranulocytosis, weight gain, cardiac arrhythmias
• Azepine: clozapine, olanzapine, quetiapine
• Benzisoxazole: risperidone, ziprasidone
• Aripiprazole
• clozapine worst offender w/ weight gain and metabolic side effects
• Quetiapine used for psychosis, mania/bipolar, OCD, PTSD, tourette, autism, anxiety and sleep dz
• ziprasidone - lenghtens GTc interval on EKG - cardiac arrhythmias

Somatiform Disorder

• Body dysmorphic Disorder - excessive preoccupation w/ slight or imagined defect in appearance
• Conversion disorder - sx affect motor or sensory func that caues sig distress, impairs functioning or warrents medical evaluation
• Hypochondriasis - preoccupation w/ fear of having a serious dz for at least 6 mo
• Pain Disorder 
• Somatization Disorder - multiple physical complaints causing impairment in func or Tx being sough beginning before age 30 and continuing over a period of several yrs (cannot be fully explained)
• Somatoform Diosrd NOS - 
• Undifferentiated somatoform disorder 

Tricyclic Antidepressants 

(TCAs)

• blockade of M1, H1 and alpha 1 rec; SRI and NRI
• amitriptyline, nortriptaline, imipramine, desipramine, clomipramine 
• Toxicity - overdose fatal, narow therapeutic, excitement and seizures; coma w/ depressed respiration, hypoxia, hypothermia, hypotension, cardiac arrhythmia (wide QRS tachycardia)

Monoamine Oxidase Inhibitors

(MAO I)

• Phenelzine, tranylcypromine: irreversible inh of MAO-A and B
• Moclobemide - reversible inh of MAO-A
• Selegiline, rasagiline - irr inh of MAO-B - parkinsons dz
• clinical us - depression, agoraphobia (social anxiety), migraine prophylaxis and parkinsons
• Hypertensive crisis - sympathomimetic amines (amphetamines, epi) or tyramine rich food

SSRIs

• fluoxetine, fluvoxamine, paroxetine(sedation), sertraline, citalopram, escitalopram
• adv effects - nausea, vomiting, dairrhea, headache, dizziness, insomnia, nervousness, sexual dysfunction, suicidal thoughts?
• clinical use - depression, panic disorders, eating disorders, social anxiety
• Wide therapeutic effect and much safer than TCAs and MAOIs
• Fluoxetine converted to active metabolite norfluoxetine - impair glucose reg in diabetes, SIADH, treats bulimia nervosa
• Fluvoxamine - may cause sedation, treats OCD

Second Generation Antidepresants

• Bupropion - Norepinephrine-Dopamine Reuptake inh (NDRI)
• Mirtazepine - Noradrenergic and specific serotonergic agents (NaSSA) - antidepressant and antianxiety effects
• Trazodone - Serotonin Antagonist Reuptake inhibitor (SARI)
• Venlafaxine, desvenlafaxine - Serotonin Norepinephrine Reuptake Inhibitor (SNRI)

Anxiety Treatment Considerations

• Acute anxiety disorder - benzo and propranolol
• Panic Disorder - Benzo (alprazolam, clonazepam), SSRI (fluoxetine)
• Phobic Disorders - benzos for acute relief, antidepressants - SSRI, TCA; cognitive behavior therapy
• Generalized Anxiety Disorder - Benzo for short term and then buspirone (presynp 5HT-1A partial agonist)

Agoraphobia

• marked fear of at least 2 of the following: public transport, open spaces, being in enclosed spaces, standing in line or being in a crowd,, being outside of home
• person fears or avoids situations becasue escape ma be difficult or help may be unavailable ine event of panic attack
• fear out of proporiton ot actual danger; persistent: >6 mo
• peaks in late adolescence, early adult hood; female twice as likely as males
• typically persistent and chronic; higher rates of depression and substance abuse
• more than 1/3 w/ Dx are homebound and unable to work

Major Depressive Disorder

(MDD)

• five or more Sx present for at least 2 wks; one Sx needs to be either depressed mood or loss of interest in pleasure (anhedonia)
• Sx cause sig distress or impairment in func and never in presence of manic or hypomanic episode
• very common 15-25% lifetime prevalence; women 2x
• tends to be chronic w/ relapses -> episodic; where as persistent depressive disorder is less overall severity than MDD but longterm chronic (continuous)

Screening Tools for

Elderly Depression

• Geriatric depression screen - 5 item GDS: 2/5 needed; 15 item GDS: 5/15 needed
• Patient health questionnaire - PHQ-2 for screening and PHQ-9 for severity and response to Tx
• PHQ-4 screening tool for depression and anxiety

Buproprion

• inc the activity of NE and dopamine; mild anticholinergic effects
• considered an activating agent - used in pts w/ lethargy, fatigue, daytime sedation
• favorite board question: lowers seizure threshold, less sexual side effects
• lack risk foa buse, physical dependency and withdrawal, potentiation of drugs or alcohol
• may not be as effect if pt has already used a BZD

Confusion Assessment Method

(CAM)

• best way to identify delirium in hospitalized pt
• If CAM is okay but mini mental is positive - high risk for developing delirium
• Requires features 1 and 2 and either 3 or 4:
• 1) acute change in mental status and fluctuating course
• 2) inattention - evaluation b reciting days or months backwards, spell name b ackwards, digit span or substract serial sevens
• 3) disorganized thinking
• 4) altered level of consciousness

Risk Factors for Delirium

• interaction btw predisposing factors and precipitating factors
• predisposing - chornic factors - adv age (80), dementia, Hx stroke, PD, multiple co-morbid conditions, impaired vision and/or hearing, func impairment, Hx of alcohol abuse, male sex
• Precipitating factors - acute conditions that initiate delirium - new acute medical problem/sepsis, exacerbation of chronic problem, surgery, new psychoactive med, acute stroke, electrolyte disturbance, dehydration, env change, urine/fecal retention, pain

Cyclothymic Disorder

• for a TWO year period, periodic presence of hypomanic Sx and periodic presence of depressive Sx
• but, criteria for a hypomanic or major depressive episode are not met

Bipolar Disorder - Neuroscience

Lithium

• Bipolar disorer pts chornically treated w/ lithium or valproate acid do not show reduced subgenual prefrontal cortex volumes
• BPD pts chronically treated w/ Li have larger AC volume than BPD pts that were not treated
• BPD pts chronically treated w/ Li or valproic acid do not show reduced glial number or glial/neuron ratios in the aygdale 
• Li inc Gray matter volume
• Li and valproate regulate PKC activity which can block the biochem and behavioral responses to amphetamines and cocaine (manic bipolar pts act like they are on amphetamines and cocaine)
• Li protects against glutamate, NMDA toxicity, Ca toxicity; protects agianst beta amyloid and aging toxicity

Nicotine

• activaiton of cholinergic nicotine rec
• epinephrine release in adrenal medulla; dopamine release in nuc accumbens - dependence; addition
• MAO inhibition
• Mild euphoria, inc arousal and conc, improved memory, appetitie, suppression- stimulant 
• resp stimulaiton, skeletal muscle relaxation, inc BP, HR, CO
• Withdrawal sx - anxiety, difficulties conc, irritability, restlessness, cravings - days to months
• only 3% abstinent at 6 mo mark
• Tx - main is nicotine replacement
• Bupropion SR - antidepressant - NE-Dopamine reuptake inhibitor
• Varenicline - partial agonist - selective bidning at α4β3 nicotine ACh rec

Marijuana

• cannabinoids - THC - highly lipophilic
• Cannabinoid rec- CB1 (brain) and CB2 (immune cells) - anandamide (endogenous ligand) - inh of A/C and cAMP production - modulate NT release
• dec in short term memory, impaired motor skills, dry mouth, tachycardia
• amotivational syndrome - lack of desire to work or excel in life
• dec sperm count and motility, inc number of abnormal sperm
• no physical dependence or withdrawal syndrone - chronic low dose
• Dronabinol (marinol) - chemo induced nausea, anorexia in HIV/AIDS pts
• Nabilone - chronic pain management 

Pharmacologic Management of 

Alcohol Dependence

• Disulfiram - aldehydre dehydrogenase inhibitor
• Acamprosate Ca - modulator at NMDA rec- restores balance btw excitation-inhibition
• Naltrexone - opioid antagonist
• Benzodiazepines (chlordiazepoxide, diazepam)

Mirtazepine

• works presynaptically to release NE and Serotonin
• Exploited for its good side effects on inc appetite and sedation - used in pts w/ weight loss and insomnia
• Sedation is more common at low doses thorugh H1 antagonism
• given to old people and anorexics

Type II (Complex) PTSD

• childhood trauma?
• chronic and recurrent
• PTSD + other psychiatric disorders
• more profound changes in brain
• more profound changes in personality

Stress Categories

• positive - brief inc in HR, mild inc in stress hormones
• Tolerable - serious temporary stress responses; buffered by supportive relationships
• Toxic Stress - prolonged activation of stress response system in absence of supportive relationships
• Traumatic stress - physical/emotional responses to threatening situations; overwhelms childs ability to cope, elicts feelings of terror
• traumic stress may affect perceptions of self, others, world, future, ability to trust, sense of personal safety, effectiveness in navigating life change