test 2 key part 2 Flashcards
factors for hypertension
SNS activation, vasoconstriction, increase Na+ and renin
hypertension mechanism
- Increased resistance and tone, hypertrophy and hyperplasia of smooth muscle, arteriosclerosis, deposit ECM, release less vasodilatory NO
kidneys in hypertesnion
- Kidneys: become hyperreactive to vasoactive stimuli, arteriosclerosis
- Increased pressure in kidneys increased salt and water loss (takes higher pressures to attain same level of salt loss)
o Most arterioles constrict in response to increase pressure to reduce flow
The resetting of baroreceptors in hypertension does what
; for a given BP there is increased SNS activation
o Alpha 1 receptors; vasoconstrict
o ADH release; water retention
o Renin and AT II release
leukocytes migrate into kidneys and vascular walls; activated by what in hypertension
o Activated by increased extracellular Na+
o Th17 cells and ILC3
2 main causes of secondary hypertesnion
kidneys or SNS
hypertension diagnosis
- Need multiple visits to diagnose unless >180/110 mm Hg
hypertensive urgency
elevated BP to treat urgently to minimize likelihood of end organ damage (i.e. stroke, IHD)
systolic >180 or diastolic >120
hypertensive emergency
hypertension with signs/symptoms that suggest end organ damage
o i.e. blurry vision, headache, stroke, angina, polyuria
malignant hypertension
> 180/120, end organ damage (hypertensive emergency), fibrinoid necrosis, hyperplastic arteriosclerosis
difference between hypertensive urgency and emergency
urgency has bp of systole >180 or disstole >120 but no end organ damage
emergency has end organ damage
ca2+ channel blocker for hypertension
o Smooth muscle relax and dilate, negative dromotropy and chronotropy
o Could cause heart block or heart failure (from dromo and chrono)
ACE inhibitors for hypertension
AT1 –> AT II inhibited
o Less aldosterone = less Na+
o Increase bradykinin: Vasodilate, NO
angiotensin II (ARB) blockers for hypertension
o Block AT1 receptors = dilate and block aldosterone secretion
alpha receptor blockers block what in hypertension and effect
(NE and E)
o Lower BP and peripheral resistance
o Adverse: reflex tachycardia, postural hypotension
vasculitis
Inflammation and necrosis of blood vessels
primary vasculitis vs secondary vasculitis
- Primary vasculitis = no underlying disorder
- Secondary vasculitis i.e. medications, autoimmune (lupus, RA), infection (hepatitis B and C)
what T cells are activated in vasculitis
- T lymphocyte activation and form granulomas
o T helper cell (TH1/TH17) and giant cells
what type of hypersensitivity reaction is vasculitis
- Type III hypersensitivity (immune complex formation) complement activation, polymorphonuclear leukocyte (PMN) damages tissue
what antibodies are in vasculitis
- Anti-neutrophil cytoplasmic antibodies ANCAa
2 types of ANCAs
o P-ANCA in neutrophil nucleus; bind myeloperoxidase
o C-ANCA in cytoplasm; bind proteinase 3
where are p-ANCA? where do they bind?
P-ANCA in neutrophil nucleus; bind myeloperoxidase
where are c-ANCA? where do they bind?
C-ANCA in cytoplasm; bind proteinase 3
how are neutrophils in vasculitis activated
o Neutrophil activation express myeloperoxiade/proteinase 3 on cytoplasm antibody binds and increase neutrophil and cytokines endothelial damage
ANCA antigens are usually found _____ but in infection and inflammation they increase expression on _______
- ANCA antigens usually in neutrophil cytoplasm but in infection and inflammation they increase expression on cell surface
temporal arteritis affects which artery
large arteies
polyarteritis nodosa affects which arteries
small and medium arteries
thromboangitis obliterans affects which arteries
small and medium
granulomatosis with polyangitis affects which vessels
small and medium sized arteries and veins
what is the most common cause of vasculitis in elders
temporal arteritisi
how to diagnose temporal arteritis
ESR/CRP and ultrasound of temporal artery
treatment of temporal ateritis
glucocorticoids
cause of temporal arteritis
HLA-DR4
symptoms of temporal arteritis
temporal headache
-scalp tenderness
-tongue and jaw claudication
-eyes ; vision loss, double vission
-fever, fatigue, polymyalgia rheymatica (pain in proximal muscles i.e. hip and shoudler)
pathophysiology of temporal arteritis
-patchy granulomatous inflammation with giant cells and t cells
-usually carotid artery branches in temporal and opthalamic arteries
polyarteritis nodosa affects many organs but rarely the
lungs
pathophys of polyarteritis nodosa
patchy vessel
-neutrophils – fibrinoid necrosis
-thrombosis infarct or aneurysm
which organs is polyarteritis nodosa most common in
- kidney (renal failure, hypertension)
-MSK (arthritis, myalgia)
-peripheral neuropathies (mononeuritis multiplex)
Minority is bowel infarct, areursym, CNS bleed, cholecystitis
skin symptoms in polyarteritis nodosa
purpura, nodule, raynauds
cause of polyarteritis nodosa
HEP B
diagnosis of polyarteritis nodosa
angiogram, CRP, neutrophils, hypergammaglobulinemia
thromboangitis obliterans
In distal legs and arms occlusion and ischemia
who is htromboangitis obliterans common in
men, smokers
symptoms in thromboangitis obliterans
-claudication, ulcers on hands and toes
-smoking; abnormal vasodilation
-neutrophils thrombus
diagnosis for Granulomatosis with polyangiitis
c-ANCA and biopsy
symptoms in Granulomatosis with polyangiitis
flaring disease
-fatigue, arthralgia, weight loss
-sinus pain and discharge, hemoptysis, dyspnea
common sites for Granulomatosis with polyangiitis
kidney (glomerulonephritis), URT (sinusitis, otitis(, LRT (pulmonary infiltrate, pleuritis)
- skin and eye lesions and neuropathy
pathophys of Granulomatosis with polyangiitis
-necrotizing vasculitis with intravascular or extravascular granuloma formation
raynauds
- Intermittent bilateral asymmetric ischemia of fingers and toes
- Caused by transient vasospasm
what is raynauds usually in
- Usually in immunologic disorders (lupus)
what makes raynauds worse
cold and stress
raynauds progression
Digits first turn white (vasoconstriction), then blue (cyanosis), then bright red (hyperemia) when blood flow is restored
ECG lead placement
- Coronal view (left and right arms, left leg)
- Cross sectional view (precordial leads)
- Bipolar leads: compare voltage changes between leads (i.e. leg and arm)
- Unipolar (precordial leads): compare voltage changes between lead (surface of chest) and center of heart
how to determine rate in an ECG
a. Divide 300 by number of large boxes between R-waves (R-R interval) = rate
what is a normal sinus rhythm
pacemaker is SA node, no abnormal conduction
i. Regular or regularly irregular
findings in normal sinus rhythm
ii. Each p wave is followed by QRS (<100ms, 2.5 small boxes), PR interval is constant
iii. Each QRS complex is followed by P wave
regularly irregular
can be normal; HR varies with respiration
irregularly irregular
tachycardia, like atrial fibrillation and is abnormal
intervals problems
widened or shortened?
PR interval problem
usually prolongation = AV nodal dysfunction
i. Abnormal connection between atria and ventricles
QRS interval problem
delay in ventricular excitation
QT interval problem
repolarization abnormalities (torsades de pointes)
normal QRS, QT, PR
e. Normal QRS= normal interventricular conduction pathways
f. Normal QT= normal ventricular repolarization
g. Normal PR= no abnormal delays/ consuctions at AV node
QT interval varies with
heart rate
how to finds QT corrected
i. QT corrected = QT / square root of (R-R interval)
ii. If less than half of R-R is usually good
ST segment isn’t looked at under interval category its under
waves
abnormal Q wave
current or prior MI
ST segmenet elevation or depression?
rule out infarct
depression: NSTEMI, digoxin, hypokalmeia, RVH, LVH, RBBB, etc
elevation: STEMI, pericarditis, LBBB, LVH, hyperkalemia, raised intracranial pressure
T waves normal and problem
- should be upright in all leads except V1
i. Tall: hyperkalemia, early MI
ii. Small: hypokalemia
iii. Inverted: MI, ventricular hypertrophy
P waves problems
i. Change beat to beat= pacemaker not the same
ii. Absence- atrial fibrillation
iii. More P waves than QRS complexes= heart block
3 types of general pathophysiology of dysrhythmias
- re-entry
- ectopic foci or abnormal automaticity
- triggered activity
re=entry
a. Normal depolarization wave enters a pathological space in the heart; contraction can’t occur but may allow slower conduction of wave to healthy tissue
b. Healthy tissue completes refractory period
re-entry causes
tachycardia
areas with XX cause re-entry
d. Area with a block slowing conduction OR conditions that slow refractory period cause re-entry (i.e. atrial fibrillation, atrial flutter, paroxysmal supra ventricular tachycardia, premature ventricular contraction)
ectopic foci
Scar tissue changes local plasma electrolyte concentrations or their movements across channels resulting in occurrence of automaticity in previously non pacemaker cells
what is inhibited in ectopic foci
i. Inhibit Na/K pump causes accumulation of Na and Ca which partially depolarizes
automaticity in previously non pacemaker cells from changes in electrolyte concentration or channel movement from scar tissue
ectopic foci
abnormal automaticity
i. Decrease K+ conductance at rest (catecholamines, hyperkalemia, hypercalcemia)
ii. Increase intracellular Ca2+
iii. Cardiac metabolism; IR K+ channels inactivated by intracellular ATP, activated by ADP allowing K+ efflux and reduced refractory period
what is triggered activity
a. Ventricular arrhythmia; normal AP followed by abnormal depolarization
what causes triggered activity (ventricular arrhythmia; normal AP followed by abnormal depolarization)
i. Premature ventricular contractions
ii. Bradycardia and reduced or prolonged phase 3
iii. Tachycardia and increases Ca2+
chronic inflammation from
fibrosis via cytokines
what do cardiac fibroblasts turn into in fibrosis and via what?
- Cardiac fibroblasts turn into myofibroblasts via AT II, aldosterone, catecholamines, TGF beta, inflammatory cytokines, ROS
cardiac fibroblast vs myofibroblasts in firborisi
- Myofibroblasts produce more ECM and cause fibrosis
fibrosis leads to
remodelling of myocardial collagen
o Local delay in portion of the heart
o Promotes re-entry
fibrosis promotes
re-entry
what is the most common arythmia
atrial fibrillation
risks for atrial fibrilation
age, hypertension, alcohol, sleep apnea
what happens when atrial fibrillation occurs
turbulent blood flow, reduce heart effectiveness, increased thrombus risk
symptoms of atrial fibrillation
asymptomatic OR chest pain, palpitations, tachycardia, dizzy, diaphoresis, fatigue
pathophysiology of atrial fibrillation
atrial structure (ECM, fibrous tissue) and electrical (shorten refractory period, tachycardia) –> remodelling
dysrhythmias in atrial fibrilation
ectopic foci
re entry
prognossis of atrial fibrillation
leading cardiac cause of stroke
ECG in atrial fibrillation
narrow complex “irregular irregular” with no distinguishable p wave
symptoms of atrial flutter
fatigue, palpitation, syncope
what dysrhythmia in atrial flutter and pathophysiology
re entry due to fibrosis fast and slow conductions AND different refractory period
ECG in atrial flutter
fast atrial rate >300bpm with fixed or variable ventricular rate
Flutter waves without an isoelectric line in between QRS complex
sinus tachycardia effects on heart rate and cardiac output
Normal rhythm, heart beats faster and increased cardiac output
what can cause sinus tachycardia
From stress or exercise (catecholamines); concerning if at rest
(myocarditis or other cardiac or non cardiac like infection, pulmonary embolism, hypoglycemia, shock)
Paroxysmal supraventricular tachycardia is
Intermittent (paroxysmal) episodes of supraventricular tachycardia with sudden onset and stop
cause of Paroxysmal supraventricular tachycardia
hyperthyroid, coffee, cocaine, anxiety, heart disease
prognosis of Paroxysmal supraventricular tachycardia
ok unless heart disease
symptoms of Paroxysmal supraventricular tachycardia
dizzy, palpitations, nausea, anxiety
dyrhytmia in Paroxysmal supraventricular tachycardia
Re-entry sometimes due to increased automaticity or trigger
ECG in Paroxysmal supraventricular tachycardia
-often narrow QRS complex
where does the problem orginate in Paroxysmal supraventricular tachycardia
Originate from atria or AV nodes regular or irregular rhythms
what initiates the heart beat in Premature ventricular contraction
Heartbeat is initiated by Purkinje fibers
is Premature ventricular contraction common?
yes
types of Premature ventricular contraction
isolate or double or triplet
cause of Premature ventricular contraction
caffeine, excess catecholamines, anxiety, electrolyte imbalance, hyperthyroid
symptoms in Premature ventricular contraction
-skipped heartbeat, chest pain, lightheaded, dyspnea
prognosis of Premature ventricular contraction
ok unless heart disease
ECG in Premature ventricular contraction
Abnormal and wide QRS complex occurring earlier than expected
dysrhythmia in Premature ventricular contraction
ectopic nodal automaticity
-re-entry
-triggered activity
what isn’t working in idioventricular rhythm
SA node (and AV) isn’t working, ventricle takes over
cause of idioventricular rhythm
heart block, electrolytes, medication, reperfusion after MI
symptoms in idioventricular rhythm
asymptomatic or palpitations, lightheaded, fatigue
heart rate in idioventricular rhythm
Slow regular ventricular rhythm <50bpm
ECG in idioventricular rhythm
P wave absent, prolonged/ wide QRS interval
common cause of ventricular tachycadia
Commonly from ischemic heart disease
preload and SV and cardiac output in ventricular tachycadia
Reduced preload and stroke volume leads to low cardiac ouput
symptoms in ventricular tachycadia
palpitations, chest pain, dyspnea, syncope, cardiac arrest
prognosis of ventricular tachycadia
Potentially life threatening (hypoperfused progress to ventricular fibrillation cardiac death)
heart rate in ventricular tachycardia
> 3 consecutive ventricular beats w rate of 100-250bpm
ECG in ventricular tachycadia
wide QRS complex
Ventricular tachycardia causes a wide QRS complex because the impulse originates in the ventricles (instead of the atria or AV node) and spreads slowly through the ventricular myocardium rather than the specialized Purkinje fibers.
dysthymia present in ventricular tachycadia
Re entry (most common)
-triggered activity and enhanced automaticity
ventricular tachycarid
The abnormal electrical impulses originate from an ectopic focus within the ventricles, rather than from the sinoatrial (SA) node or the atrioventricular (AV) node.
The focus of the arrhythmia may be a scarred area (e.g., from previous myocardial infarction (MI)) or an area of electrical instability within the myocardium.
ventricular fibrilation cause
From MI, electrolyte, alcohol, hypothermia, cardiomyopathies
ventricular fibrillation presentation
Irregular electrical activity, ventricular rate >300bpm, reduced cardiac output sudden cardiac death in minutes
symptoms in ventricular fibrilation
Chest pain, dyspnea, vomit, unconscious
ECG in ventricular fibrillation
No identifiable P wave, QRS complex, T wave, HR 150-500bpm,
dysrhythmia in ventricular fibrillation
Increased automaticity of purkinge cells
Triggered acitivity
Possible re entry
Torsades de pointes is a form of
ventricular tachycardia
Torsades de pointes
Form of ventricular tachycardia rhythm may terminate spontaneously or progress into ventricular fibrillation
causes of Torsades de pointes
Congenital or acquired from meds
which electrolyte in Torsades de pointes
Prolonged repolarization from delay in K+ efflux
symptoms of Torsades de pointes
Asymptomatic OR syncope, palpitation, dizzy
10% of Torsades de pointes can result in
cardiac death
QTc in Torsades de pointes
QTc prolongation
ECG in Torsades de pointes
Twisting ECG, polymorphic, vary amplitude of QRS
what differentiated ventricular tachycardia from other supraventicular arrhythmias
The wide QRS complex of Ventricular Tachycardia helps differentiate it from other supraventricular arrhythmias, which typically have narrow QRS complexes (because the impulse is conducted normally through the His-Purkinje system).
what is a conduction block
- Arrythmia caused by delay or complete block of heart, esp AV node or bundle branches
where are conduction blocks commonly found
AV NODE or bundle branches
conduction blocks lead to
inadequate HR, dizzy, fatigue, syncope
3 types of conduction block
-1st degree AV block
-2nd degree AV block
-3rd degree AV (complete heart block)
first degree heart block cause
Caused by increased vagal tone or fibrotic changes
symptoms in first degree heart block
none
impulse conduction in first degree heart block
good- Every impulse conducted to the ventricles
PR interval in first degree heart block
Prolonged PR interval (slow conduction through AV node)
second degree AV block symptoms in type 1 vs type 2
Type I: asymptomatic
Type II: bradycardia, cardiac arrest
second degree AV block: type 1 vs type 2 ECG finidngs
Type i: prolonged PR interval until QRS complex is dropped
Type II: consistent PR interval with sudden drops of QRS (more serious – can progress to 3rd degree)
cause of second degree AV block symptoms
High vagal tone
third degree AV block effect on ECG and cardiac output
Cardiac output reduced
Regular P waves and QRS but no coordination between
third degree AV block impulse conduction?
No impulse from atria reaches the ventricles, independent atrial and ventricular rates
third degree AV block symptoms
Bradycardia, syncope, heart failure; need pacemaker
third degree AV block cause
Fibrosis or heart disease, electrolytes, meds
cardiac ishcemia impat on ECG
inverted T wave
- ST elevation in leads near injury
4 classes of anti arrhythmic medications
Class 1 antiarrhythmic
- Bind Na+ and prevent influx
- Inhibit K+
- Block Ca2+
o Negative dromotropy (slow conduction) and increase refractoriness (interfere with Ca2+ repolarization)
Class 2 antiarrhythmic
- Beta blocker reduce phase 4 and HR and prolong AV conduction and reduce contractility
- Treat arrhythmias causes by increased SNS activity
Class 3 antiarrhythmic
- Block K+ channels reducing efflux and prolong AP and refractory period
Class 4 antiarrhythmic
- Block Ca2+ and reduce influx, phase 4, and spontaneous depolarization
- Slow down conduction
o Side effects: bradycardia, hypotension, peripheral edema
use of class 2 antiarrhytmic med
beta blockere
- Treat arrhythmias causes by increased SNS activity
which sleep is most important for cognitive performance
N3 deep sleep
which sleep has less psychologic consequences
REM
polysomnography for sleep study 4 parts
E_G
- EMG (electromyogram) – face and leg muscle
- EOG (electrooculogram)- eye movements
- ECGs and pulse oximeters – oxygenation and cardiac function
- EEG (electroencephalogram)- skull/ cortex
EEG measures which cells
pyramidal cells
EEG measure the difference in
o Measure difference in potential between dendrite and cell body; not directly measuring APs
o Measures frequency of potential (waves in Hz) and size of waves (uV)
frequencies in EEG sleep
o Alpha= eyes closed and mind wanders- 8-13Hz, medium amplitude waves
o Beta= eyes open and wide awake- 13-30Hz, low amplitude waves
o REM and Awake= dys-synchronized /random patterns
o Alpha block/arousal/alerting response: when focused; decrease alpha wave
what is alpha block/ alerting response
when focused; decrease alpha wave
alpha is
eye closed and mind wanders, relaxed wakefullness
beta is
eyes open and wide awake, thinking, stressed
theta is
drowsy, light sleep
delta is
deep N3 sleep
frequency in alpha, beta, theta and delta
Beta- 13-30Hz
Alpha- 8-13 Hz
Theta- 4-8 Hz
Delta- 0.5-4 Hz
amplitude in 4 waves
Delta- high
Theta- med to high
Alpha- Med
beta- low to high
N1 sleep
transition from wake to sleep
which wave in N1 sleep
theta
EMG and EOG in N1 sleep
rolling slow eye movements
move in N1?
large axial muscle movements
N2 slee
light sleep
2 key findings in N2 sleep
- K complexes – intermittent high amplitude spikes
- Sleep spindles- 7-15Hz groups of waves
eyes and legs in N2 sleep?
- Limited to no eye movement
- Large movements of axial muscles
eyes and legs in N4 sleep
- Minimal eye movement
- Large movements of axial muscles
eye movements in which sleep stages
N1 has rolling slow eyes
REm has rapid eyes
which has axial limb movement and which sleeps tables dont
REM doesnt, other do
N4 is
stage 3 and 4= deep sleep
wave in N4 sleep
delta= low frequency, high amplitude
o Oscillations in activity between thalamus and cortex
eyes and legs in N4 sleep?
- Minimal eye movement
- Large movements of axial muscles
REM sleep EMG and EOG findings
- Rapid eye movement on EOG
- EMG flatline- no MSK movement
wave in N1 and REM
theta
wave in REM
- Theta= Low amplitude, high frequency like N1 but lower amplitude and not synchronized
which sleep stage do u remember dreams in
REM
which sleep stage are u easily awakened in
REM
what causes the few movements in REM
- GABA to activate spinal inhibitory neurons paralyzed, few movements
which sleep period is the longest? how long?
- 1st sleep period is the longest: 90-110 minutes
which population gets most deep sleep? at what point in the night?
- Kids/ young adults get most N3 deep sleep early, soon after falling asleep
progression of sleep stages
N1,N2,N3, REM
what sleep stage is last
- Never go from wake to REM, its last
- REM occurs near end of sleep session
elders and sleep
- Elders have less N3 and more awakenings
arousal system; brain areas involved
open the gate of thalamus to allow input from outside world to cortex
o Communicates with hypothalamic areas
brainstem nuclei in the arousal system
Locus coeruleus- norepinephrine
Raphe nucleus- serotonin
Tuberomammillary body- histamine
Acetylcholine- multiple brainstem nuclei
Periaqueductal gray- dopamine
locus coerulus- what neurotransmitter?
NE
raphe nucleus- what neurotrasnmitter
serotonin
tubermamillary body- which neurotransmitter
histamine
where is acetylcholine found in the brainstem
multiple brainstem nuclei
periaqueductal grey- which neurotransmitter
dopamine
which part of the brain is sleep promoting
ventrolateral pre-optic nucleus VLPO
what does the ventrolateral pre-optic nucleus VLPO release
galanin and gaba
2 things that promote sleep
galanin and gaba
what 2 things regulate REM
REM on and REM off
where is REM off
pons
where is REM on
lateral pontine
what does SCN communicate with
o SCN communicates with retina for circadian rhythm via light dark
what are the 2 stabilizing nuclei in the lateral hypothalamus that allow for stable sleep (or fully awake)
- orexin
- melanin concentrating hormone MCH
orexin projects where?
– projects to arousal system and VLPO
inhibits VLPO and makes us awake
melanin concentrating hormone MCH projects to where
aoursal system
inhibits it to make us sleepy
orexin and melanin concentrating hormone where they project to
MCH to arousal system (inhibits it) = sleepy
orexin to arousal system and VLPO (inhibits VLPO) = awake
what makes us sleepy (2)
o Homeostatic signal
o Circadian rhythm
what wakes us
o Arousal system inhibits VLPO
o Orexin increases
o Orexin + inhibit VLPO = durable wake state
what makes us sleepy
o VLPO activated
o Inhibit arousal and orexin
o MCH released during REM inhibits monoaminergic arousal system (i.e. dopamine, serotonin)
where is melatonin made and stimulated by what?
- Made in pineal gland in darkness
which fibers work in the absence of light
- In the absence of light→ retinohypothalamic fibres relay “dark info” to the SCN→ lifting of the inhibition of the PVN by the SCN
o Absence of light PVN activates SNS intermediolateral horn excite superior cervical ganglion release NE from pineal gland make melatonin
what is released by the pineal gland to make melatonin
NE
which amino acid starts melatonin synthesis
tryptophan
what does tryptophan become in melatonin path
serotonin
how does serotonin become melatonin
- Metabolite of serotonin (from tryptophan)
o With catecholamine (NE) stimulation the activity and production of AANAT make melatonin
Withdrawal catecholamines = degrade AANAT by proteosomes
which melatonin receptors are entrain SCN to 24 hour light dark cycle
MT-2
MT1 vs MT2 melatonin receptors
- Melatonin can decrease sleep latency (MT-1) and increase amount of sleep (MT-2)
what else does melatonin entrain
core body temperature, HR variability, cortisol and TSH secretion
what enzyme to turn serotonin into n-acetylserotonin then into melatonin
AANAT (rate limiting) (arylalkylamine n-acetyltransferase)
HIOMT
what builds up if you go without sleep and helps with homeostatic drive
adenosine
what is an adenosine receptor (A2a) antagonist
caffeine
A1 and A2a adenosine receptors
- A1 inhibit arousal, A2a facilitate sleep
what is allostasis
response to stressors
o I.e. psychologic stress causes sleep problems -overactivated monoaminergic arousal system
narcolepsy
- Excessive daytime sleepiness
- Intrusion of REM into wakefulness
symptoms in narcolepsy
- Cataplexy, sleep paralysis, dream like hallucinations while awake
which neurons are lost in narcolepsy and cataplexy
orexigenic neurons
what is the cause of loss of orexigenic neurons in cataplexy and narcolepsy
o Usually autoimmune
o Molecular mimicry of orexin from influenza and strept
cataplexy
muscle weakness without loss of consciousness
which type of narcolepsy has cataplexy
type I narcolepsy
hypnagogic vs hypnopompic hallucinations
- Hypnagogic hallucinations- sleep paralysis and hallucinations when falling asleep
- Hypnopompic hallucinations- upon wakening
sleep architecture in narcolepsy
- Enter REM quickly at night, fragmented sleep, naps
treatment of narcolepsy
antidepressants to increase NE or serotonin stimulate REM off neurons
o methylphenidate or modafinil to increase dopamine at synapse
restless leg syndrome vs periodic limb movement
- RLS: compulsion to move legs that’s triggered by rest
- PLMD: occurs during sleep- large movements of legs/ kicking, can occur with RLS
causes of periodic limb movement disorder
o Iron deficiency – iron transport/metabolism
o Abnormal dopaminergic signaling in susbstantia nigra
o Treat: dopamine agonist (excess in AM and inadequate at PM)
o Movement disorders from basal ganglia and substantia nigra
needed to diagnose OSA
- 5+ episodes of OA or hypoapnea in 1 hour of sleep
apnea vs hypopnea
- Apnea= cessation of airflow for > 10 seconds
- Hypoapnea= >30% reduction in airflow for at least 10 seconds with oxygen desaturation or waking
severe OSA
> 15 episodes/hour
symptoms in OSA
- Gasp, snore, choke, awaken, daytime sleepiness, fatigue, morning headaches
inspiration in OSA
- Inspiration –> negative pressure in pharynx collapse bc of decreases muscle tone in sleep
which sleep stage is OSA most severe in
REM
risk factors for OSA
- Upper body adiposity, septal deviation, nasal polyps, small jaw, genes, male, diabetes, hypertension
where should tongue go when mouth closed
seal to soft palate
CO2 sensitivity in OSA
- CO2 sensitivity increase ventilatory drive in OSA stiffens upper airway muscles patent pharynx
hypercarbia and OSA
- Hypersensitive to hypercarbia increase pharyngeal stiffness
how to diagnose OSA
polysomnogrpahy
parasomnia
- Abnormal behaviours or experiences in sleep
sleepwalking
automatic motor activity, mostly in N3 (early evening), mostly in kids
which sleep stage for sleep walking
N3
sleep terror in which sleep stage
N3
sleep terrors
kids awaken screaming, N3, tachycardia, hyperventilate, sweat,
how to avoid sleep walking and sleep terrors
ensure adequate sleep
REM sleep behaviour disorder
act out dreams; kicking, punching, increases with age, usually develop neurodegenerative disorders
what is the endoneurium in the PNS
CT encasing individual nerve fibers, contains blood vessels
axon microtubular apparatus function in PNS
- Transport NTs and structural support
2 types of nerve fiber damage in PNS
- axonal degeneration
- segmental demyelination
distal axon degeneration
distal portion of long nerve fibers; cell bodies and proximal axons unaffected
wallerian degeneration
degeneration beyond where its compressed or severed. If close to origin can regenerate.
- Deterioration of axis cylinder and myelin and central chromatolysis
neuronopathy (type of axonal degeneration)
neuronal cell body and axon degenerated; i.e. autoimmune
segmental demyelination
myelin sheath deteriorate, but underlying axon still functional
primary vs secondary demyelination
o Primary demyelination: direct injury to schwann cell or myelin sheath
o Secondary demyelination: underlying axonal abnormalities
what invades in segmental demyelination
o Macrophages invade and eliminate myelin debris
functional recovery in segmental demyelination
degeneration followed by schwann cell proliferation then remyelination
Remyelinated section have reduced internode lengths (less efficiencet)
hypertrophic neuropathy (type of segmental demyelination)
repeated episodes of segmental peripheral nerve demyelination and remyelination – accumulation of supernumerary Schwan cells that encircle the axons (onion bulbs)
PNS vs CNS
PNS fibers can regenerate and remyelinate
is peripheral neuropathy typically axonal degeneration of segmental demyelination?
- 90% axonal
o If demyelinating its hereditary or immunological
large vs small diameter fibers for what
- Large diameter sensory fibers- proprioception and vibration
- Small diameter myelinated and unmyelinated fibers- pain and temperature
pain and temperature
- Small diameter myelinated and unmyelinated fibers-
proprioception and vibration
- Large diameter sensory fibers
main causes of peripheral neuropathy
DIABETES
: metabolic (diabetes, thyroid), nutritional (B12 deficient), systemic (HIV, lyme, hepatitis), toxic (alcohol, chemo)
features of peripheral neuropathy
muscle weakness and atrophy, sensory loss, paresthesisa, pain, autonomic dysfunction
polyneuropathy
weak symmetrical bilateral, lose reflexes in ankles, decreased sensation in distal extremities
radiculipathy or polyradiculopathy
asymmetrical, sporadic distribution, weak, sensory loss, pain; nerve root distribution (compression of nerve root)
mononeuropathy
weak and sensory loss in single peripheral nerve
multiple mononeuropathies (mononeuropathy multiplex)
many mononeuropathies ; difficult to differentiate from polyneuropathy
plexopathy (involvement of multiple nerves in a plexus)
brachial or lumbosacral plexus. Single limb impacted, but motor, sensory and reflex deficits don’t align with pattern of multiple nerves
neuronopathy (motor or sensory) which cells effected?
ganglion cells effected sensory deficits proximally and distally
autonomic symptoms in peripheral neuropathy
- Autonomic: impaired sweat, heat intolerance, bladder incontinence, BP not regulated, GI
motor symptoms in peripheral neuropathy
- Motor: weak, spasm, wasting, reflexes
sensory symptoms in peripheral neuropathy
o Large fibers (with myelin): reduced sensation, reflexes, limb position
o Small fibers (no myelin sheath): compromised perception of pain and temperature
what type of neuropathy is diabetic neuropathy?
- Polyneuropathy: distal symmetric sensory or sensorimotor polyneuropathy, autonomic neuropathy, diabetic neuropathic cachexia, polyradiculoneuropathies, cranial neuropathies, and other mononeuropathies.
risk for developing diabetic neuropathy
inadequate DM managing
high blood sugar increae which pathway
polyol pathway
what 2 sugars accumulate in nerves and damage them
fructose and sorbitol
diabetic neuropathy pathophysiology
- High blood sugar increases polyol pathway activity accumulate fructose and sorbitol in nerves damage
blood glucose > XX affects polyol pathway
o Blood glucose >7 mmol/L augments glucose flow in polyol pathway
what is the key regulating step in the polyol pathway to prevent diabetic neuropathy
Glucose –> sorbitol by aldose reductase and NADPH
immune in diabetic neuropathy? what type of antibodies?
antineural autoantibodies, antiphospholipid antibodies = nerve damage and vascular irregularities
why is there endoneural vascular insufficiency in diabetic neuropathy?
- Endoneural vascular insufficiency from reduced NO and compromised Na+/K+ ATPase and elevated homocysteinemia vascular permeability and hindered endoneural blood flow
pattern in diabetic neuropathy
- Stocking and glove pattern; sensory loss, dysesthesia, painful paresthesia, lower limbs
symptoms in diabetic neuropathy
- Tingle, prick, numb, burn or freeze, sharp pain, sensitive to touch, muscle weak
increaed oxidative stress in diabetic neuropathy does what
increased AGES advanced gylcation end products
increased sorbitol in diabetic neuropathy does what
decreased Na+/K+ ATPase activity and decreases free carnitine and myoinostiol
____ nitric oxide and ____ homocysteine in diabetic neuropathy impaired endothelial function
decreased NO and increases HC
what causes cobalamin (B12) deficiency
pernicious anemia
o Also vegetarian, by-pass surgery, IBD, pancreatic insufficiency, PPIs…
vitamin B12 deficiency neuropathy is
- Autoimmune antibodies target parietal cells and intrinsic factor
autoimmune antiboedies in B12 deficiency neuropathy target what 2 things
intrisnci factor and parietal cells
what helps with digestion is decreased in vitmain B12 defiiency neuronopathy
- Atrophic gastritis, achlohydria (no gastric acid secretion)
neurological symptoms in vitmain B12 defiiency neuronopathy
peripheral neuropathy and cognitive
what does B12 play a role in
- B12 role in 1 carbon cycle: coenzyme for methionine synthesis; needed for RNA and DNA production
B12 is needed for
DNA and RNA synthesis
B12 is a coenzyme for
methionine sysnthesis
B12 defiicency causes the accumulation of what
homocysteine accuualtes (because u need b12 to turn homocysteine in methionine)
B12 impacts ___ metabolism
folate metabolism
B12 converts _____ into _______ which is needed for myelin sysntehsis and stability
methylmalonyl CoA into succinyl CoA
if b12 defienct and cant turn methylmalonyl CoA into succinyl CoA what happens to myelin
abnormal fatty acids and demyelinate
what type of neuropathy is b12 defieicny ; axonal or demyleianting
- Majority have axonal involved, some have demyelinating changes
symptoms in b12 deficiency neuropathy
numb hands 1st then progress to paresthesia in lower extremities
o Hyperreflexia, unsteady gait, no Achilles reflex
which fibers are impacted and which are spared in b12 deficient neuropathy
- Impact large fibers; proprioception and vibration
o Small fibers are spared
symptoms in chemotherapy induced peripheral neuropathy ? which axons affected?
- Glove and stocking, affects longer axons
changes in chemotherpay induced peripheral neuropathy
- disturbances in microtubules, oxidative stress-induced mitochondrial damage, changes in ion channel function, injury to the myelin sheath, DNA damage, immunological responses, and neuroinflammation
chemotherpay induced peripheral neuroapthy is dose dependent; what is effecting the tissu e
platinum
which chemo meds in peripheral neuropathy
- paclitaxel and docetaxel for ovarian cancer cause neurotubule depolymerization
hypothyroidism is what type of peripheral neuropathy
proximal myopathy
hypothyroid changes that cause peripheral neuropathy
mucopolysaccharides, chondroitin sulfate and hyaluronic acid accumulate in interstitial spaces= water retention and weight gain and compress nerves
carpal tunnel is common in
hypothyroid induced peripheral neroopathy
weight gain in hypothroid effects
nerve conduction
hypothyroid has energy defiecient from nutrient oxidation; how does it cause neuropathy
; less ATP and Na+/K+ pump and accumulation of glycogen deposits can cause neuropathy
changes in hypothyroid neuropathy
- primary axonal degeneration, characterized by axon shrinkage, disintegration of neurofilaments and neurotubules, and active axonal breakdown.
shingles is causes by? what cells does it effect?
- herpes varicella zoster infection
o latent infection in perineuronal satellite cells of dorsal root ganglia
symptoms of shingles
- rash, pain, paresthesia on dermatomal region
- weak muscles
- postherpetic neuralgia
who gets shingles
- in elders and impaired cell mediated immunity
most common area that lyme effects
- facial palsy most common, then cervical or lumbar
what is concurrent with Lyme disease
aseptic menhingoradiculitis
triad of lyme disease and peripheral neuropathy
cranial nerve palsies, radiculitis, and aseptic meningitis
changes in Lyme disease
- perivascular inflammation and vascultic changes
what is the most common hepatitis
hepatitis C
hepatitis C causes
o cryoglobulin deposits in vasa nervorum and HCV-mediated vascultitis
o cryoglobulinemia peripheral neuropathy
hepatitis deposits what
cryoglobulin
how does hepatitis C cause peopheral neruoapthy
- liver effected which metabolized drugs and toxins which can accumulate and damage nerve cells
- chronic liver disease, like in hep B and C can cause B12 and folate deficiencies (which nerves also need to function)
leporsy is cause by
- acid-fast bacteria Mycobacterium leprae
leprosy effects
skin and peripheral nerves
types of leprosy
: tuberculoid leprosy to lepromatous leprosy and borderline leprosy
which type of leprosy is neuropathy most common in
borderline leprosy
tuberculoid leprosy
o asymmetric neuropathy and confined to nerves under the skin lesion
lepromatous leprosy
o slow progression but extensive; bilateral symmetrical distal polyneuropathy
borderline leprosy
o most severe, rapid and multiple nerves effected
which leprosy is most severe
borderline leporsy
HIV causes what type of neuropathy
distal symmetric polyneuropahty
axonal degeneration in distal nerves
HIVother tytpes of neuropathy
- inflammatory demyelinating polyradiculoneuropathy
- vasculitic neuropathy; mononeuropathy or mononeuropathy multiplex
drugs for HIV AIDS can resemeble
distal symmetric polyneuropathy
lymphocyte infiltrates in HIV and neuropathy
- diffuse infiltrative lymphocytosis syndrome; axonal polyneuropathy
- CD8+ lymphocytic infiltrates
alcoholism causes deficiency in
- Thiamine (B1), B6, B12, folic acid
ethanol effects
nerve function
alcohol and peripheral neuropathy
- Impaired blood flow to extremities
- Inflammation
- Metabolic changes to glucose metabolism and insulin resistance
- ROS
Which of the following statements accurately describes the pathophysiology of peripheral neuropathy associated with vitamin B12 deficiency?
A) Vitamin B12 deficiency neuropathy is primarily caused by dietary deficiencies alone.
B) Impaired absorption, parasite infections, and dietary deficiencies are unrelated to the pathophysiology of vitamin B12 deficiency neuropathy.
C) Pernicious anemia, resulting from impaired intrinsic factor production, can contribute to vitamin B12 deficiency neuropathy.
D) Vitamin B12 deficiency neuropathy is exclusively caused by parasite infections.
C) Pernicious anemia, resulting from impaired intrinsic factor production, can contribute to vitamin B12 deficiency neuropathy.
2) Which microbial infection is primarily associated with peripheral neuropathy due to direct nerve damage?
A) Shingles (Herpes zoster)
B) Lyme disease (Borreliosis)
C) Hepatitis B virus (HBV)
D) Leprosy (Hansen’s disease)
E) HIV (Human Immunodeficiency Virus)
D) Leprosy (Hansen’s disease)
3) Which of the following mechanisms best explains the association between alcoholism and the pathophysiology of peripheral neuropathies?
A) Elevated levels of vitamin B12 and folate
B) Enhanced neuronal regeneration and repair
C) Impaired metabolism of thiamine and other essential nutrients
D) Increased production of nerve growth factors
C) Impaired metabolism of thiamine and other essential nutrients
clock genes are
- Intracellular time system, regulates 24 hour circadian rhythm
clock genes are
- Entrained by light dark cycles, exercise and eating
zeitgebers
- Entrained by light dark cycles, exercise and eating
examples of clock genes
Clock, Bmal1, the “period” genes (Per1, Per2, Per3), Cry1, and Cry2
what are clock genes synchronized by
- Increase and decrease over 24 hours; synchronized via melatonin fluctuations
clock genes ARE NOT responsible for
SCN intrinsic rhythms
clock geners ARE responsible for
for intrinsic rhythms of rest of body (i.e muscle, brain, leukocytes) and are modified by sleep and hormones
clock genes regulate ___% of human genome
25%
clock genes are metabolic…
cell growth, body temp, metabolism, immune…
what type of molecule is melatonin
amphipathic
melatonin is carried by
albumin
melatonin_____ by blue light
suppressed
blind and melatonin
abnormal
live in dim light effects melatonin
more sensitive to light and secrete more melatonin in response to it
type of signling for melatonin to retina
paracrine signal
melatonin increases the expression of which antioxidant enzymes
superoxide dismutase and glutathione peroxidase
melatonin blocks
- Blocks Bax proapoptotic activity and reduce caspase 3
melatonin is anti inflammatory via
inhibit cyclooxygenase (COX) enzyme reduce prostaglandin and leukotriene
analgesic effect of melatonin
MT1 and MT2 reduce pain transmission in dorsal horn neurons
melatonin as an antioxidant
(protect against cancer, reduced BP, neuroprotectant
melatonin is found where
- Localized in mitochondria in many tissues
if melatonin fluctuates properly in a day what effect does it have of sugars and fats
insulin sensitive and decrease fat mass and hyperglycemia
cardiometabolic conseuqeunces of disrupted sleep
- Increase visceral fat, decrease insulin sensitivity, obese/ metabolic syndrome, dyslipidemia
complications of obstructive sleep apnea
- Premature death; respiratory events increase SNS hypertension
- Intrathoracic negative pressure swings alter preload and afterload cardiac remodeling
- Hypoxia vasoconstrict, increase RV afterload
- Increase thrombosis and free radicals atherosclerosis
- Atrial fibrillation and atrial flutter
sleep deprivation has what effect on mens reproductive health
decrease testosterone
sleep deprivation and wehich sleep hormone have what effect on Womens health
- Melatonin in ovarian follicular fluid; protect oocytes from oxidative stress
o Low levels = infertility
which homrones increase in sleep
- TSH, GH, prolactin increases in sleep
o GH and prolactin increase T cell proliferation and promote Th1
which homrones decrease in sleep
- Cortisol, NE and E decrease in sleep
increased melatonin in kids helps to suppress____
- Increased melatonin levels in children help to suppress GnRH secretion from the pituitary
o Decline of melatonin production during adolescence is linked to onset of puberty
immune and sleep
- Increase Il2 and IFN gamma
- Decrease IL10
- TH1 adaptive immunes response at 3am
- NK increase in late AM (blocked if sleep problem)
- IL6 and TNF (pro inflame) increase in night
- More Th1 than Th2 in sleep
sleep disorders and cancer
increase prostate cancer
shift workers and circadian
circadian genes affect genes for cell division and DNA repair
circadian rhythm and gut microbiome
- Microbes don’t express clock genes
- Microbes may be able to regulate circadian rhythm
- High fat diet changes clock gene (per2, ARNTL) in liver via butyrate
seizures are
- sudden, uncontrolled electrical disturbance in the brain
o changes in behavior, movements, feelings, and levels of consciousness
seizures are a _____ burst in large cortical region
- hypersynchronized excitatory burst in large cortical region
o individual neuron: paroxysmal depolarization shift (long lasting influx of ca2+ triggers Na+ VGC for influx and repeat APs)
o spike discharge: summation of field APs
spread activation to surrounding neurons in seizure by
o increased K+ (RMP more positive and easier to reach threshold)
o Accumulate Ca2+ in presynaptic terminals
o NMDA receptor additional Ca2+ influx
4 classifications of seizures
- focal seizures
- generalized seizures
- motor onset
- non motor
focal seizures
a. from 1 brain region- structural problem
i. Intact or impaired awareness
ii. Motor or nonmotor at onset
generalized seizures
from both cerebral hemisphers
motor seizures
tonic-clonic
non motor seizures
a. absence seizure, sensory, autonomic or emotional symptoms
focal seizures with intact awareness
- EEG in non-seizure period is normal or brief epileptiform spikes or sharp waves
- From medial temporal lobe or inferior frontal lobs
- i.e. motor cortex spread from fingers to hands
- paresis after seizure
- Sensory changes or emotional experiences (déjà vu, fear, detachment)
focal serizures with impaired awareness
- Not loss of consciousness, but cant respond to environment (i.e. convo) and poor recollection
- Aura, automatism
- Full recovery of consciousness in seconds or > hours
general seizures with typical absence seizures
o Sudden brief (seconds) loss of consciousness without loss of postural control
o Kids
o 100x/day “day dream”
generalized seizures with atylical absence seizures
o Gradual longer lapse of consciousness
o Focal and motor symptoms
o Diffuse or multifocal structural abnormalities; neurological complications
generalize tonic-clonic seizures
o From metabolic problems
o Tonic phase: contract muscles, impair respiration (cyanosis), jaw clench for 10-20 seconds
o Clonic phase: muscle relax for 1 min
o Post-ictal phase: unresponsive, muscles flaccid, salivate, incontinence
o Regain consciousness mins to hours
o Headache, fatigue, muscle pain after
**most comon
hat is the most common type of seizure
generalized tonic clonic seizure
atonic seizure
o 1-2 secs of postural muscle loss
o Impaired consciousness, no post-ictal confusion
o i.e. head drop or body collapse
myoclonic seizure
o Muscle contraction
o From metabolic, CNS degeneration, anoxic brain injury
epileptic spasms (generalized seizure)
o In infants; flex or extend proximal or truncal muscles
- Epileptogenesis in seizures
transform normal brain tissue into network that’s hyperexcitable
o i.e. congenital, head trauma, stroke, infection
epileptogenic factors
promote lowering of seizure threshold
precipitating factors for seizures
trigger a seizure i.e. hormones, toxic, meds, photic stimulation, stress, sleep deprivation
ages and seizures
- neonate/ infant: congenital CNS abnormal, hypoxic ischemic encephalopathy, perinatal injury, inborn errors in metabolism (ie. Pyridoxine deficiency), CNS infection
- early child: febrile seizure
- child: idiopathic or genetic
- adults: CNS lesion, infection, head trauma, tumor, illicit drugs,
- older adults: cerebrovascular disease, degenerative
- any age: metabolic (electrolyte, hypo/hyperglycemia), renal failure, hepatic failure, endocrine, medications
sleep depirvation and epilespsy
- increase cortical excitability generalized epilepsy
- epilepsy affects sleep quality: increase wake time after sleep onset, reduce REM, change nREM
taenia and worm infestations
- cattle or pigs – humans eat uncooked meat
- invades muscles
- abdominal symptoms
o proglottids pass in stool
cysticerosis
is infection of muscle by larval cysts of taenia solium (pork tape worm)
o penetrates intestinal wall and disseminate (muscle and brain
neurocysticerosis
brain infection causing adult seizure in low income countries
o CNS parasite
o Minimal symptoms then seizures and increased intracranial pressure (or death)
o MMP-polymorphism
Increase BBB permeability
trypanosoma brucie is from
parasite from bite of tse-tse fly (s.s. Africa)
Trypanosoma brucei and sleeping sickness
- Sleeping sickness; 3 years, fatal
- Early: Fevers, headache, pruritic, lymph, hepatosplenomegaly
- Later phase: invade CNS- disturb sleep and neuropsychiatric disorders
o Median eminence and hypothalamus
changes in sleep from Trypanosoma brucei and sleeping sickness
o No change in total sleep time (increase daytime sleep and insomnia at night)
o Similar to narcolepsy
SOREM episodes; sudden wake to sleep
Excess daytime sleepiness
Sleep fragmented
