MBB TOLO – Week 4

Lecture 23 – Vestibular System

 Overview
o 2 Sacs and 3 semicircular canals
 Utricles and Saccule
 Sacs = linear acceleration, and static position
 Semicircular canal – head rotation – keeps eyes steady
o Goes to the vestibular nuclei
o Purpose: adjust posture to maintain balance (saccule/utricle) and keep eyes
steady as we move (canal)
o Hair cells  has tip links which opens VGCa channels
 Towards the kinecilium will depolarize
 Saccule and utricle
o Utricle is filled with endolymph
o The hair cells receptors in sac and utricle are located in the macula
o On top of the hair cell receptors are otoliths to increase the movement
 If these otoliths go to semicircular canals by getting loose, then you will probably get vertigo
o If you tilt to one side, the utricle on that side gets activated and the other side gets inhibited
 Semicircular canals
o Fluid movement pends the ampulla and the hairs are in the CRISTA
o The fluid staying behind when you move the head will bend the hair cells
o Rotating to is excitatory, and away is inhibited

 Vestibular Pathways
o Visual stability – CN8 nerve from
semi-circular canals go to vestibular
nuclei, then to the oculomotor nuclei
via medial longitudinal fasciculus
o Balance – CN8 from utricle and
saccule go to vestibular nuclei and
down to LMN via vestibulo-spinal
tracts
 Body tilt head - sacs
o Vestibular hair cells of utricle and
saccule  vestibular nerve 
vestibular nuclei  vestibule-spinal
tract  extensor motor neurons
activate ipsilateral  legs extends to
maintain upright
 Lesion of utricle or
vestibular nuclei or nerve on
one side  tendency to fall
towards side of the lesion
 Semicircular canals
o Endolymph inside lags behind because of inertia
o Head rotation activates vestibule-ocular reflex (VOR) –
rotate head one way, the eyes go other way
 Slow phase eye movement opposite to direct of
head rotation for stable visual image
 When the limit of rotation is reached, the eyes
snap back with corrective fast phase
 With continued rotation, slow and fast phases
alternate, pattern called nystagmus
o When you rotate your head towards right, it stimulates the
right vestibular nuclei and activates the VOR pathway
 Contract left lateral rectus and right medial rectus
so you get slow compensatory, conjugate eye
movement to the left
 MLF communicates between CN 6 ( in the pons) and CN3 (in midbrain)
 When you look around, there is no jumping seen because the vision is suppressed during the rapid eye
movement
o If you lesion the left side, then the right side will be relatively sending more signals, which the brain will interpret
as you turning your head to the right, so you will get slow phase nystagmus towards the left, which is the lesioned
side
 If you put ice water in one ear, you will produce a temporary lesion on that side – chloric nystagmus
 What is dizziness – patient word that can mean vertigo, presyncope, truncal ataxia, or others
o If you have vertigo, it is probably because vestibular apparatus, vestibular division of nerve, or vestibular nuclei
in dorsolateral medulla/caudal pons , or maybe vestibular potion in cerebellum
 If you have no other symptoms, then probably lesion of the nerve of labyrinth vs the brainstem
 If you have spinning vertigo – it is semicircular canal organs
 Your slow phase eyes will go towards the lesion
 If it is tilting/falling, you have utricular or saccular problems
 You fall towards the side of the lesion because no right side means overactive left so left will
side will be extended so you fall to the right
 If you have slow phase to right, and fast phase to the left – it is left beating nystagmus
 Vestibular nuclei project to area postrema and parasympathetic nucleus of vagus (which can go to GI) and
you can sweat more and have pallor because of sympathetic compensatory activity because of increased
vagal output
 Misc
o For CN7 – facial weakness can be facial motor nucleus in caudal pons, fascicles of facial motor nucleus in caudal
pons, or in facial nerve
o If you cannot feel face – trigeminal nerve before dividing into three branches, trigeminothalamic tract so pain and
touch are affected, VP of thalamus
 Drugs: scopolamine, diphenylhydramine, and lorazepam
o Scopolamine – blocks Muscarinic cholinergic receptors on vestibular afferents, emetic center, and NTS
 Good to prevent and treat motion sickness, and has a lot of anti-M side effects
o Diphenydramine – H1 antihistamine blocks H1 receptors on vestibular afferents, emetic center, and NTS. Also
has muscarinic antagonist effects
 Goo for prevent and treat motion sickness but has more side effects because it acts on everyething
o Lorazepam – GABA will suppress vestibular response – but will get drowsy
Lecture 24 – Visual System
Overview
o Move fovea to the center of your target for the highest acuity
 Retina is upside down because of the lens
o Optic chiasm merges two images together – only the medial aspect of both eyes
 The lateral aspect does not cross and just goes directly into the LGN
o Projects then to the calcarine sulcus which has the visual field processing and
there is a lot of analysis for just the fovea – the ventral stream (pattern
recognition)
 Ventral stream – you see what you want to, and what you have seen before affects what you will see now
- see colors, shapes, faces, words, objects
 Dorsal stream – where is it- motion and spatial relationships

o Eyeball
 Retina receptors go into optic disk to optic nerve
 Cornea has a lens, then iris has a hole (pupil)
 Then another lens that has ciliary muscles attached to
it for accommodation
 The ganglion cells go to the optic nerve
o Optic disk is 15 degrees medial to fovea
 Eye and Optics
o Focal length – distance from center of lens to point where
parallel light rays come to focus
 Higher refractive (light bending) power means
shorter focal length
 Refractive power is measured in diopters = 1/F (m)
 Resting eye has 60 D of strength but you can add 10-
12 D by adjusting the lens

o Accommodation
  Ciliary muscle – contract which increases lens contractive power. Contraction of ciliary muscle brings
ciliary muscle closer and relaxes tension of zonule fibers that normally pulls on lens. The lens will then
balloon out and become thicker
 Ability to accommodate decreases with age because loss of elasticity – PRESBYOPIA
o Pathway for near response:
 Lens need to accommodate, eyes converge, pupil constrict
 Retina  LGN  Visual Cortex  III complex
o Refractive Errors in the Eye
 Emmetropia (normal eye), hyperopia –
farsighteded, eyeball is too short relative to
focal length
 Myopia – eyeball too long
 Physiology of Visual Pathways
o Photopigments (Rhodopsin absorbs light)  2nd
messenger and affects sodium channels
 This hyperpolarizes the receptor – so presence of light is signaled by hyperpolarization of receptor
o 4 different types of photoreceptor – with own photopigament
 1 Rod, 3 cones (red, green, blue)
 Rods = dim lights sensitive in moonlight – MORE NUMEROUS 20x more - rhodopsin
o Rods are everywhere except fovea so peripheral retina is sensitive to dim lights
 Cones – works in bright light and provides color vision
o Sometimes cannot tell difference between green and red cone
 Protanope – no red, deuteranope – no green
o Fovea only has cones – lots of cones
o Retinal ganglion cells respond to little circles in ur vision vs cortical cells respond to lines in ur vision
 Binocular vision and lesions of pathways
o Optic chiasm because upside down so if you cannot see
bottom part of temporal field, it is superior optic chiasm
problem
o B – tumor in pituitary
o Homonymous – vision loss in same side in both eyes
o D = ventral-lateral temporal - the upside down bunny –
temporal lobe lesion
o E = Dorsal Medial Parietal – parietal lobe lesion
o Glaucoma – compress the optic nerve as it is leave the disk
o Congruous hemianopia – identical in the two eyes indicates
lesion of visual cortex!!!! Cortex is where the points
converge on the same cell so its identical spots
o Middle part of visual field – macula could be spared during
lesions
Lecture 25 - Eye movement control systems
 Eye movement control systems: either stabilize gaze or shift gaze – 6 different ones total
o 1. Visual fixation – eye move to hold an image stable on the fovea
o 2. Vestibular eye movements – hold image steady on retina as head moves slowly
 Involuntary but can be suppressed
 If head rotation is more than 20-30 seconds – VOR adapts since semicircular canal signal suppressed
 Peripheral vestibular sensory organs activate ipsilateral vestibular nuclei  contralateral abducens for
horizontal movement, and bilaterally oculomotor and trochlear for vertical eye movements
o 3. Optokinetic – eye move to hold image steady while heading is moving quickly
o 4. Smooth pursuit – hold image of moving target on fovea and moves eyes to follow object moving off fovea –
eye move to track a moving target smooth motion
 Voluntary control
 Vestibular nucleus are also used
 Need to see what you are tracking (retina, LGN, visual cortical area), and have to create 3D space in
which this object is moving
o 5. Saccadic eye movement – fast eye movements that occur at fixed velocity – you know where to look – fixed
target
 Active during reflex nystagmus, REM sleep, or voluntary movements to move eye to a different point in
space. Vision is suppressed during a saccade
 Reflex saccades – the nystagmus fast phase is abolished in patients with decreased consciousness and it
has to decrease A LOT for the slow phase to also not work
o 6. Vergence – keep image of single object on both fovea – can converge eyes to see nearby object and diverge
eyes to look at distance. – only time when eye movements are not conjugate
 vergence center is probably at midbrain retricular formation and projects to medial rectus of each
oculomotor nucleus
 Abducens nucleus – center for ipsilateral conjugate horizontal eye movements – everyone has to talk to this
 Right CN 6 tells right lateral rectus to pull right eye right and left eye medially CN3
o If you lesion CN6, you do not get contralateral medial eye movement, but if you lesion the abducens nucleus, you
lose all conjugate movements
o Lesion will affect ipsilateral horizontal gaze for all eye movement control systems
 Lesion = internuclear opthalmoplegia (INO)
o There is nothing that affects vertical conjugate gaze because multiple things affect this

 Saccadic eye movements

o Horizontal saccades made in pontine paramedian retricular formation, which is near abducens nuclei
 Contralateral frontal eye field intiates the movement, the right eye is like, I want to look at that thing to
the left, and then the left PPRF figures out how to do that to affect ipsilatearl LR and contralateral MR
o Right frontal eye field  left PPRF  left abducens nucleus  horizontal saccade to the left
 Frontal eye field is small region of frontal cortex anterior to premotor cortex
o The eye fields are in a battle, and the right eye field wants to move to the left and the left eye field wants to move
to the right. IF you lesion the right eye field, the eyes will deviate to the left. Eye looks at the side of the lesion.
Cannot saccade to the left, but if the eyes are on the left side, they can move to the right. The muscles are fine.
o
o Vertical saccades – bilateral frontal eye fields  rostral midbrain retricular formation  bilateral oculomotor and
trochlear nuclei
o These pathway also have the caudate involved, and also are bilateral so there can be recovery if lesion
 Disorders of dem eyeballs – mostly will get diplopia
 o Eyes need to move together
 If they are mis-aligned vertically, you get images on top of each other
 If they are mis-aligned horizonally, you get images side by side
o Lesion of the right frontal eye field
 cannot activate left PPFR so cannot look left, natural
deviation to the right because the left and the right are
competing against each other
 At normal, the R frontal eye field and L frontal eye field are
evenly pushing
 Since they are naturally looking to the right, if you tell them
to do that, nothing will happen. But if you get their eyes to
the right, then they can move to the right
 You can get the eyes to go the left, just not through the
saccade system – maybe through the VOR, or put water in
the left ear
o Lesion of left PPRF
 The tonic pushing should be fine so maybe midline resting
state. There could be tonic gaze but maybe not
 If you have patient look to the right, nothing bad happens because you need your left eye field, to activate
right PPFR, to activate right abducens LR and left oculomoter MR
 If you want patient to look to the left, you need the right eye field to turn on, which will activate left
PPFR, to activate left abducens and right oculomoter MR wand left PPFR is broken.
 Need VOR, or move their head to get the eye back to midline
o Lesion left abducens nucleus
 Looking straight ahead, maybe tonic gaze, but no saccade
 If you want them to look to the right, it will be fine.
 If you want them to look to the left, left eye nothing happen, and .. since left abducens controls the right
oculomoter, then nothing can happen
 So is there any way to get the right oculomoter to move???- so all the systems VOR, smooth
pursuit, all the eye movement control systems will have trouble with this movement
o Left CN6 lesion
 Right eye looks to the left, but the left eye cannot
 At rest, maybe tonic is fine. Or maybe the left eye is looking medially
o Lesion the MLF
 Tonic – probably fine
 Looking to the right is fine, looking to the left, the right eye will stay constant
 Nystagmus – involuntary movement of the eye that begins with slow phase
o Typically slow phase is away from the desired target and the fast phase is a reflex saccade the returns the eyes to
the desired position of the gaze
 Nystagmus can be horizontal, vertical, torsional, or combination
o Sometimes nystagmus is normal (vestibular / end-point nystagmus)
 VOR movement keeps eye fixed in direction of space so this is not helpful if you are trying to look right,
but your eyes move left because of VOR. So then you will do corrective saccadic eye movement to move
the eye in the correct direction
o Nystagmus is sometimes a sign of a problem, but not the problem itself – inner ear lesion
 Destructive lesion of labyrinth of vestibular nerve will lead to horizontal nystagmus with slow phase
towards the lesion – eyes point towards the lesion
o Sometimes nystagmus is the problem (gaze-evoked nystamus, often drug induced)
 Prevents maintaining gaze in position away from center of gaze – cannot overcome the natural elastic
forces that put eyes to neutral position so you get a slow drift of eyes from desired eccentric position to
neutral position and there is a saccade that jerks the eyes back to where it wants to be
 Drugs that CNS depressant or diffuse lesion on vestibulocerebellum can cause this
Lecture 26 – internal Homeostasis Systems, Thermoregulation; Emotion
 Thermoregulation
o Brain – determines set point for core body temperature
o Anterior hypothalamus – heat dissipation region that activates heat loss, LOSE
o Posterior hypothalamus – heat generation region that activates heat production, GAIN HEAT
 Projections from anterior hypothalamus pass through the posterior hypothalamus so lesions in posterior
hypothalamus affect both
o Fever – typically because brain has raised the set point (probably because of prostaglandins) so COX inhibitors
become anti-pyretics
 Benefit of fever is unclear
 Pyrogens (fever producing substances) enter brain through OVLT which doesn’t have BBB and is very
close to the anterior hypothalamus
 Entrainment of circadian rhythm
o SCN is running at 25 hrs and retina corrects this to 24 hours
so blind people this training is hard
o Melatonin acts on MT2 receptors to fix the 24 hours
 MT1 receptors help with sleep
 Emotion
o Emotion – bodily state – determined by PNS, ANS, endocrine, and motor
 Feeling – cerebral cortex including cingulate gyrus and prefrontal cortex
 Amygdala – anterior in medial temporal – under the uncus – lots of olfactory
 Special role in fear, anxiety and other negative emotions, some in positive emotions
o Mood = internal emotional experience of a person – try to infer mood from history and exam but you have to ask
to be sure
o Affect = external expression of emotion
o Typically mood and affect are usually the same, but could be dissociated in
neurological disorders or depression
 Disorders of mood – depression, mania, fear, anxiety
 Depression: mood that is down – might be related to decreased NE
or serotonin
 Often primary psychiatric disorder but could be because of
neurological lesion – PD, ictal, left frontal lobe lesion (more
common)
o SN degradation, the NE projection in locus cerelus
also degrades in Parkinson’s
o Ictal (during seizure) – one phase of the seizure is
feeling depressed
 Mania – mood that is up: often be because of primary psychiatric disorder
 Stimulants, steroids, antiparkinsonism drugs can increase mood
 Fear and anxiety – amygdala is crucial in fear and fear response
 Stimulation can lead to fear, bilateral lesions can lead to loss of fear
 Different nuclei of amygdala and cerebral cortex are important for anxiety
 Drugs for anxiety and for anxiety disorders
o Five classes of drugs:
 1. Benzodiazepines – symptoms of anxiety (GABAa)
 2. Buspirone – several anxiety disorders
 Does not treat symptom of anxiety, works after 1-4 after few weeks, and does not have a lot of
the side effects of the Benzos
 3. Serotonin boosting drugs – SSRI (fluoxetine), SNRI (duloxetine), dirty SNRI (amitriptyline)
o if the patient feels anxiety, you can target with alcohol/benzos but there is potential for substance abuse
 Disorders of affect
 Too much affect – epileptic seizure can lead to affect without underlying mood, like laughing
 Pseudobulbar affect – spontaneous or exaggerated expressions of affect that do not agree with mood –
mostly because of bilateral corticobulbar tract lesions because you release the normally inhibited
responses
 Lesions in brainstem lead to laughing and crying and burst out, or very small stimulus they cry
really bad or something makes them sad, and they start laughing – BILATERAL LESION
 Happens in ALS, and multiple sclerosis !!!!
 Too little affect – decreased facial expression in parkinsonism / CN7 lesion
 Aprosodia – type of dysarthria in which melody of speech that normally conveys emotional
content is lost – they feelz but the tone of voice doesn’t come out so only can EDUCATE these
patients and tell them its okay
 Drugs for pseudobulbar affect
o Dextromethorphan (cough suppressant too) – serotonergic, NMDA recepctor antagonist, sigma-1 receptor
agonist – decreases by 50%
o Quinidine – low dose inhibits first pass metabolism of dextromethorphan so more gets into brain
o Adverse effects: nausea, headache, diarrhea, fatigue, dizziness, risk of serotonin syndrome
 Reward
o Ventral tegmental area (VTA) – located in midbrain tegmentum close to the substantia nigra
 Dopaminergic projects to limbic systems
 Blocking these projections help with schizophrenia but unclear if these are cause of schizophrenia
o Nucleus accumbens – located ventral to junction of caudate and
putamen, one target of VTA
o Dopaminergic projects from VTA to nucleus accumbens is CRUCIAL
for rewards so positive reinforcement
 However, this system can be hijacked and animals can
stimulate this pathway can ignore all other activites to the
point of death
 Stimulants, opioids, and other addicting drugs act on these
reward pathways which enhance dopamine release or effects of
dopamine in nucleus accumbens
o Dopamine agonists can lead to compulsive gambline, compulsive shopping – 10-20% in parkinson’s disease
 Theoretically Give dopamine antagonist to people with bad behavior but typically, patients do not have
focal lesions that affect specifically reward and a lot of patients who get dopamine agonist do not develop
some addictive disorder
 Drugs for alcohol and other substance use disorders – talk therapy is more important but these are just supplements
o 3 disorders
 1. Ethanol: naltrexone, acamprosate
 Naltrexone- opiod receptor antagonist, inhibit reward and decrease craving, need LFT
 Acamprosate – GABA analog, attenuates “protracted” withdrawal, renal excretion
o This helps with alcohol withdrawal that lasts for longer and the patient needs one more
drink and then they get addicted again
 Disulfiram (probably no memorize)- inhibit aldehyde dehydrogenase so if they drink they die
 2. Opioids: methadone, buprenorphine (sometimes add naloxone), naltrexone
 Methadone – mu agonist, long duration of action, suppresses withdrawal, opioid side effects
 Buprenorphine – suppreses withdrawal symptoms, mu partial agonist
o add naloxone –to prevent patients who want to inject which will make it awful
 3. Nicotine: nicotine, varenicline, bupropion – will get them away from tobacco which is good
 nicotine – nAChR – wont get tobacco products that hurt them
 Bupropion – nicotinic receptor blocking activity
o Both of these therapies can increase smoking sessation by 50-70%
o Combined therapy of these two more effective than monotherapy
 Varenicline – nAChR partial agonist – same as combo therapy nicotine bupropion
 Start 1-2 weeks before cessation date and continue and taper off for 3-6 months
Lecture 27 – Drugs for Depessive, Bipolar, and Related disorders
Other uses for antidepressants
 Treatment of depression
o Biogenic amine theory of mood disorders
 Depressed is caused by decrease synaptic availability of monoamines (NE and 5-HT)
 Evidence: VMAT inhibitor (reserpine) depletes vestibular stores of NE, 5-HT and causes
depression. Increasing NE and 5-HT decrease depression
o Classes of antidepressant drugs
 Presynaptic receptors normally decrease
synaptic release so drugs can inhibit these
receptors to increase transmission as well
 TCA – also block mAChR, H1, and a1
 SSRIs can have antidepressant effects but in
the gut, there are also receptors
 Two side effects: other targets, or same
target in other regions
o General treatment considerations
 All antidepressants are equally efficacious –
around 50-60% benefit regardless of which
drug you choose. If the first drug doesn’t work, then use another drug.
 Slow onset of action – could be weeks-month before benefit, but if no help for 2-3 weeks, do another drug
 This is because you need down-regulation of presynaptic receptors. If you give drugs, the NT
increase but you wont see the effects till the presynaptic receptors also go down
 Or could be change in BDNF – neurotrophic factors (can regulate transcriptions and affect amount
of synapses, increase arborization of dendrites)
 Choice of antidepressant – different drugs have different adverse effects
 So choose based on what else the patient has, or if relatives responded to something then they try
the same – so start with the one with least side effects
o Depression and suicide
 Depression – increase risk of suicides, so theoretically antidepressants should help
 However, antidepressants may increase risk of suicide, especially in children, adolescent, young energy
 So basically, it is not because you are getting sadder. The drugs give you more energy so you can
actually act on the suicidal thoughts
Antidepressant drugs
o Tricyclic antidepressants – amtripytline
 Inhibit SERT > NET, not primary
choice because lots of off target
effects – mAChR, Histamine, A1
receptors (constipation, urinary
retention, do not give to BPH)
 H1 – drowsiness, increase
appetite, weight gain, A1 –
postural hypotention
 Also get sinus tachycardia – risk
of arrhythmia, prolonged QT interval
 Problem = very low Therapeutic index – 10:1 – risk of accidental poisoning
o SSRI – typically first line – Fluoxetine (approved for children)
 Lack off target effects with cardiac toxicities – so much safer. Not more efficacious, just less side effects
 Serotonin is important for sexual dysfunction so all these drugs can cause sexual dysfunction as offtarget
 Can be helpful for premature ejaculation
 Can also cause GI bleeding and diarrhea
 Basically, different drugs in the same class has varying levels of how it is metabolized or where it acts so
you can change between classes
 If you discontinue with SSRI abruptly, you get dizziness, headache, insomnia
 Serotonin syndrome – too much serotonin at a high dose or multiple drugs
 Dual action antidepressants – duloxetine (SNRI), bupropion (NDRI)
o
 Same efficacy – but do not have offtarget effects and cardiac problems
 Some patients who do not respond to SSRI can response to SNRI
 Adverse effects: drowsiness, GI problems
 Bupropion – can cause seizures so if you have preexisting seizures, no
Bueno
 However, it is unlikely to cause weight gain or sexual
dysfunction
 SNRI – monitor BP because you affect NE which increases
o Presynaptic blocker – misc heterocyclic AD
 More off target effects than the SSRI
o MAOIs (Segeiline)
 Increase NE, Serotonin, Dopamine
 Adverse effects: interact with dietary tyramine – monitor diet but segiline should be okay
 Do NOT combine with other serotonergic drugs
 Other antidepressants
o In general, if you combine antidepressants, it can increase efficacy in some patients, but polypharmacy should be
avoided because maybe you get serotonin syndrome or other
 Some drugs can increase efficacy of antidepressants
 St John’s wort (plant) may be effective for mild depression and also induces CYP , so lots of drugs
interactions
 Ketamine(NMDA receptor) – general anaesthetic – offlabel refractory depression, quick level of onset
 There is area in brain – lateral hebenulum (negative reinforcement area) so if this area is active,
you sad, unlike the nucleus accumbens when that is active, you happy

 Mood stabilizers
o Diverse drugs – MOA poorly understood, can treat acute or prevention
o 1. Lithium
 Narrow therapeutic window (must monitor serum levels)
 Adverse effects: tremor, nausea, diarrhea, weight gain, polydipsia and polyuria (Affects actions of ADH)
 Kidney problems long term
o 2. Antiepileptic drugs: Divalproex, carbamazepine, lamotrigine
o 3. 2nd Gen Antipsychotics - quetiapine
Lecture 28- Seizures and Epilepsy
 Overview
o Seizure – overall event – Increased electrical activity and repetitive – change in behavior
o Epilepsy – abnormal predisposition to having seizures, maybe congenital or traumatic/vascular past
o Prodrome – feeling that the patient can report when they feel they are more likely to have a seizure that hour-day
o Aura – very beginning of a seizure, especially if seizure starts in one place in the brain
 Typically gets the same feeling before all seizures, it can either happen or end, or escalate
 Very quickly, like a few seconds and then seizure
o Ictus – the actual event of the seizure, and aura is part of the ictal event
o Post-ictal – when electrical signal stops but the behavior is still not normal, gradiation over many minutes so progress from
ded lethargic, confused, to normal again
 Todd’s phenomenon – depending on which part of the brain it starts in, period of depression / weakness in that
particular structure
 If seizure started in motor cortex, maybe when you wake up, could have hemiparesis
 Pathophysiology
o There is a focus – where it begins (some looks like it start everywhere – probably started in deep part of brain)
 Could stay localize, spread, or start everywhere
o Descriptions for seizures:
 Baseline EEG – moment to moment variations are normal
 Interictal – Have normal rhythm until you get spikes in the same spot repetitively could
suggest that the patient has susceptibility to seizures
 Ictal – record during the seizure – waves are insane and you can see postictal it is still
different for all the leads
o When patient is presenting with seizures, you have to see if it is a reaction to anything like intoxication,
withdrawal, metabolic derangement
 Can lower the threshold for the seizure, or meditations like tramadol or bupropion
 Withdrawal – alcohol, benzos, stopping of these can increase the likelihood of seizure again because the seizure risk
with these agents decreased before and if you stop taking it, or seizure drugs stop taking, then you get increased risk for
seizures
 Metabolic deficit- could get a seizure because anyone would
 Seizure classifications
o 1. Focal onset
 Normal or impaired awareness
 Motor symptoms vs non-motor symptoms (often eyes stay open)
 Spread to bilateral tonic/clonic
 Tonic – steady stiffness of both parts
 Clonic – jerking repetitively
o 2. Generalized Onset
 Tonic clonic vs absence (happens a lot to kids)
 Look like they stop what they are doing, and quick blinking. Usually does not have post-ictal phase so young kids have
no idea what happened and just continue what they were doing
o Status Epilepticus – ongoing steady seizure – if you start seizure but you just don’t stop, or when you stop seizing, then before
you go into post-ictal, you seize again and this is bad we must stop it
 Contracting muscles, thermos problems, airway problems, kidney dying
 Triggers
o Increase risk
 Cessation of an anti-epileptic drug, Alcohol/drug use withdrawal, sleep deprivation (only for patients who is epileptic,
not enough to make normal person have seizure), stress, menstrual
o Reflex stimuli – strobes, tactile/aural stimulus
 Treatment of seizures
o Avoid triggers- don’t tell people to quit their job
o Support therapy – move all the hard things away, don’t let them bang head on floor
 Do not stick fingers in month, because mouth clenches
 Do not grab patient – because when they wake up they might be confused, call for 911
o Anti-epileptic drugs
o Ketogenic diet – will increase their seizure threshold – drink a cup of olive oil – usually only possible in children who cannot
feed themselves so they do not care if its nasty so you feed them through other means
o Vagal nerve stimulation
o Resection – take out specific tumor that causes the epilepsy
Lecture 29 – Antiepileptic Drugs
 Overview – how do antiepileptic drugs work – epilepsy is just overactive electrical activity
o Can Block Na channels, block T type Ca channels (go from thalamus to cortex), enhance inhibitory GABA
transmission, or inhibit excitatory glutamatergic transmission
 Mechanisms
o 1. Na Channel blockage
 Can prolong the inactivation resting period of the Na
 Phenyltoin, Carbazepine, Oxcarbazepine, Valproic acid, Felbamate, Lamotrigine, topiramate,
Zonisamide, ESL
o 2. T-Type Ca blockage ( in the thalamus) – most useful for generalized seizure (like absence seizure)
 Rapid threshold pacemakers in the thalamus, and allows rhythmic waves of excitation and inhibition
 Ethosuximide, divalproex, Lamotrigine, zonisamide
 Absence seizures only in children and because they everywhere, using Ca blocking will be good
o 3. Enhancing inhibitory GABAergic Transmission
 Prevent reuptake by GAT - Tigabine
 GABA agonist – Benzos, topiramate, phenobarbital
 Unclear but increase Transmission – Gabapentin, pregabalin
o 4. Glutamergic blocking
 AMPA receptor blocker – topiramate, perampanal
 NMDA receptor blocker - felbamate
 Presynaptic vesicle binding blocking – lamotrigine (which also blocks VGNa channels, and ca channels
too)
o Lamotrigine is some powerful stuffs
 Pharmacology
o Oral absorption – all are good except gabapentin (which has ceiling)
o Half-life – determines dosing frequency (do not want the seizure to breakthrough)
 Gabapentin – short halflife needs to give more often – Pain might be okay, but hard to do for seizures
 Phenobarbital, zonisamide, ethosuximide long
o Elimination – renal vs hepatic, linear vs non-linear
 If you have a kidney problem, then gabapentin (which only gets excreted with kidney)
 All 1st order, except phenytoin (so regardless of how much drug you have, metabolism is constant and this
is a problem with narrow therapeutic index and you need to constantly check blood levels)
 Carbamazepine (tegretol) and divalproex can auto-induce metabolism
 At higher concentrations, body gets better at metabolizing these drugs and over time as well
o Drug Interactions
 All old drugs, and lamotrigine have pure hepatic metabolism – which can affect metabolism of other
drugs
 Lamotrigine – Estrogen increases how quickly your body removes lamotrigine and birth control
contraceptives may not work as well
 Active metabolites
 Primidone (mysoline), carbamazepine, oxcarbazepine
 Therapeutic ranges
 Narrow for older drugs, presumed wider for newer drugs
 Principles of Treatment
 Get the seizure type right – most important for absence seizure
 Titrate up to mid-therapeutic or effects – easiest for high frequency events (have seizures 1st a week)
o Do not use tiniest pill – want to stop having seizures – move to therapeutic level
 Add 2nd drug if necessary and taper the first if not working
 Don’t suddenly discontinue – will precipitate more events
o Taper the drug by lowering the dose, not lowering the frequency
 Choice of drug
o Focal onset seizures
 Carbamazepine, phenytoin, some others (hard to do new studies), do not choose ethosuximide
o Generalized Seizures
 Absence – without confusion afterwards
 Ethosuximide, Divalproex (toxic for little livers), lamotrigine
 Other generalized – maybe general convulsions
 Divalproex, phenytoin, lamotrigine, others, not ethosuximide (sometimes get worse or better)
o Among non-absence drug – topiramate – probably broadest spectrum, along with felbamate
 Divalproex, lamotrigine – have efficacy everywhere
 Bad things that could happen
o Reasons for failure
 Maybe you do not have epileptic seizures – psychiatric, or provoked (metabolism, alcohol)
 Inadequate dosing, wrong type of medication, nonadherence, alcohol and drugs, progressive lesion (brain
tumor is getting worse so increased seizures), or medically refractory
o Adverse events
 Dose related, long term, idiosyncratic, teratogenicity, drug drug interactions
o Side effects
 GI upset, dizziness, sedation, nystagmus, cognitive blunting
 Dose related- specific
 Phenobarbital – sedated adults and hyperactive kids
 Phenytoin – ataxia
o Long term – get gingival hyperplasia (needs to go to dentist all the time), osteoporosis
(needs supplementation)
 Carbamazepine – diplopia/blurred vision
o Long term – hyponatremia
o Idiosyncratic – neutropenia (less neutrophils), aplastic anemia
 Divalproex – tremor
o Long term Alopecia (spot baldness), weight gain, pancreatitis
o Idiosyncratic: hepatic failure (in kids), pancreatitis
 Topiramate – paresthesia (tingling) because blocked carbonix anhydrase, cognitive impairment
o Long term – kidney stones
 Lamotrigine, zonisamide
o Idiosyncratic – rash
o No cognitive impact, no teragenicity, but has a lot of drug interactions so cannot use with
old people with lots of meds
 Felbamate
o Idiosyncratic: liver failure, aplastic anemia (blood stops producing new RBC)
 Teeratogenicity – first trimester to first generation drugs increase malformations
 Cleft palate, neural tube defects, congenital heart defects
o Drug interactions
 If you combine drugs that have low Therapeutic index, and induce CYP, other drug metabolisms will
increase
 Divalproex inhibits metabolism of other drugs and increases them – like lamotrigine
 Phenytoin, divalproex, tiagabine, Benzo, carbamazepine – all protein bound and can be displaced
 Pharmacodynamic – synergy or antagonism at receptor sites and unclear
 Summary
o Know general mechanism, T-Ca only drugs for absence seizures, drugs that block the channels will not work.
o Drugs with more than one mechanism are better, and choose drugs based on individual tolerability
o GOAL: SEIZURE FREE
 First gen antiepileptic drug
o Carbamazepine – Inactivate VG Na channels, also used for neuropathic lacinating pain
 Adverse effects: diplopia, blurry vision, ataxia, rash, leukopenia, hyponatremia, tetratogenic, drug
interaction
 Types of seizures: partial and secondarily generalized tonic-clonic seizure
o Divalproex- blocks T-type channels
 Adverse: weight gain, alopecia, tremor, teratogenic
 Type of seizures: primary generalized tonic-clonic seizures, partial and secondarily generalized tonic-
clonic, Inactivate VG Na channels, and absence seizures
o Phenobarbital – GABAa receptors
 Adverse: like Benzo, sedation, drowsiness, amnesia
 Type of seizure: partial and secondary generalized tonic-clonic seizure
o Phenytoin- Inactivate VG Na channels
 Adverse: Jingivial hyperplasma, cerebellar, teratogenic
 Type of seizure: partial and primary or secondarily generalized tonic-clonic seizure but not first line
o Primidone – Barbituate, GABAa binding, - also maybe prolonh inactivated VG Na
 Adverse: benzos
 Type of Seizure: partial and secondarily generalized tonic-clonic seizures but not first line
 2nd gen antiepileptic drug
o Gabapentin – 2nd gen bind to A2d subunit of Ca channels – facilitate GABA transmission
 Adverse: ataxia, drowsiness, headache, weight gain, and hyperactivity (kid)
 Uses: Adjunct for partial seizure or secondarily generalized tonic-clonic
 Excreted unchanged by kidney
o Lamotrigine – t type calcium channel, block VG sodium, and inhibit glutamate transmission
 Adverse: rash, headache, ataxia, diplopia
 Uses: partial and secondarily generalized tonic-clonic seizure, and myoclonic seizure
o Levetiracetam – modify exocytosis of glutamate and GABA
 Adverse: psychosis, hallucaination, irritability
 Uses: primarily generalized tonic-clonic , partial and secondarily generalized tonic-clonic, and myoclonic
o Topiramate – VG sodium channels, enhance GABA, blocks AMPA
 Adverse: metallic, cognition, ocular, teratogenic
 Uses: primary generalized, partial and secondarily generalized tonic-clonic seizures
 Treatment of absence seizures:
o Divalproex, Ethosuximide, Lamotrigine
 Not teratogenic meds
o Every one is teratogenic
 First gen is more teratogenic than second.. but ded baby is more likely if parent has seizure than if parent
takes medicine
 Should just take more folate, and divalproex probably causes more abnormalities than others

 First generation antiepileptic drugs
o 1. Carbamazepine – VG Na block – also treat neuropathic pain and bipolar disorder
o 2. Phenytoin – neuropathic pain – also prolong Na inactivation – good for sharp lacinating pain
o 3. Divalproex + valproic acid – also used to treat bipolar disorder
o 4. Ethosuximide
o 5. Phenobarbital – barbiturate like primidone
o 6. Primidone – essential tremor
o 7. Benzo – Also for essential tremor, spastcity, vertigo
 2nd generation antiepileptic drugs – less likely to have interactions, adverse effects, or less teratogenic effects, less
therapeutic index
o 1. Lamotrigine – also used for bipolar disorder
o 2. Topiramate – also used for essential tremor and neuropathic pain
o 3. Gabapentin – essential tremor and neuropathic pain
o 4. Levetiracetam (keppra)
Lecture 30 – Consciousness, Sleep and Attention System; Delirium, Stupor
 Overview:
o Arousal – reticular activating system (thalamus, and in front of 4th ventricle) talks to your diffuse cortex
 In pons – single midline structure, in thalamus – need bilateral lesion, cortex – need bilateral diffuse lesion
o Consciousness – arousal and content
o Sleep – active, recurrent, physiologic, awake vs alert, sleep stages
 Stage 1 – Slow rolling eye movements, would alert to noises and calling name, almost asleep
 Stage 2 – asleep, and would wake up if you touched them, k-complexes, sleep spindles, no more eye
movements
 Stage 3 – Slow wave sleep – big slow waves – deep sleep yay – pick kids up
 If you wake up now, you get groggy
 REM sleep – Dreaming – cortex look like they are awake, and Rapid
eye movements, and absolutely no motor activity – easy to wake up
and no groggy
 Cycles get shorter – start with 90 minutes, kids have more deep sleep,
when older then you need 5 hours and with fragments
 Mechanisms of Sleep
o Wakefulness : Locus cerelus, TMN, Raphe – LETS BE MORE AWAKE
o Sleep: VLPO – lets be asleep via Gabaergic neurons
o Build up of sleep: adenosine, NO, prostaglandins D2 – usually activate Wake stuff
 Disorders of sleep
o Narcolespsy – excessive daytime sleepiness
 Cataplexy – inappropriately turn on paralysis – a stimulus triggers extreme
weakness – So REM sleep paralysis turns on
 Early REM – they fall asleep and enter REM quickly
 You need sleep, you don’t need REM, perform normally
cognitively
 Hypnagogic hallucinations, Sleep Paralysis, Very low hypocretin levels
 Treatment: Stimulants, Sodium oxybate (promotes deep sleep), SSRI,
TCA
o REM behavior disorders – punch people and choke people
 Loss of normal atonia of REM
 Common in older men and with parkinsonism, treat with clonazepam (klonopin)
o Insomnia disorder – greater than 3 nights/week of difficultly – non-restorative sleep (sleep apnea)
 Treat with CBT and short acting sedative – fix sleep hygiene
 Exclude alternate pathology
 Attention – shifts to focus from one relevant stimuli to another – shift too easily or too slowly bad
o Delirium – inattention, cannot control what they are paying attention to
 Disturbance of level and content of consciousness – marked by inattention and fluctuation
 Can use MOCA – count back from 20 and forget what to do
 Decreased level of consciousness due to pathologic processes
o Alert – once you wake up, they will stay awake
o Lethargic – just sleep, and /or provided them stimulus , and they continue to fall back asleep even tho you so
interesting
o Stupor – be basically asleep unless you actively stimulate them noxious – you are really loud
o Coma – no matter how much you harass, they will not awake, can do reflex but cant get interactions
o Lesions
 Bilateral lesion diffuse, hemisphere, then you might be lethargic, and if the lesion is worse, coma
 Thalamic lesion on both sides – decrease level of consciousness because reticular formation in bilateral
 Mild lesion lethargic, severe lesion coma
 Lesion in midbrain, or pons in reticular activating system  sad
 To induce stupor and coma, you need bilateral cortex lesion, or RAS inactivation
 Neither of these are in the medulla (but breathing is  so get diffuse lesion to brain so get
decreased consciousness then
 So awful things on one side should not lead to decreased consciousness
o Things that look like coma but are not
  Locked-in state – lesion in basis pontis that damages all the upper motor neurons so cannot make any
voluntary movements of legs, pharynx, or face or horizontal eye movements
 If it preserves tegmentum – the sensory stimuli is fine
 This can happen with hypertention, or meth use and have bad things happen to pons
 Vegetative state – can spontaneously be asleep or awake but in other way, do not interact with world and
are not aware – catrophobic happen to cerebral cortex, but the diencephalon and the brainstem are fine
 Akinetic mutism – not moving, not talking, bilateral frontal lobe bad – things that make you want to move
and talk but you just sit there unless you are super stimulated
 Herniation syndrome
o With herniation under the tentorial cerebellum, you can hit CN3 and the brainstem so get hemiparesis
o As someone is pushing down:
 Thalamus  will be sleepy, and will still have pupils recreation and try to react to pain
 Late diencephalic – react
 Midbrain – no sympathetic input, get VOR through abducens, but no MLF
Lecture 31 – CNS Depressants and Drugs that Promote Sleep
 Overview
o Hypnotic drug – produces a feeling of need to sleep – sleepiness, drowsiness
o Anxiolytic drug – reduces emotion of anxiety
o Sedative drug – produces feeling of sedation (decreased activity, excitement,
calm)
o CNS depressants
 Drugs that have sedative, hypnotic, and some anxiolytic actions –
include benzos, barbiturates, ethanol
 Alcohol and barbiturates – have linear relationship so easily to OD
 Benzos are safe because of ceiling effects – so if someone OD with benzos, then probably had alcohol as
well
 Have additive or synergistic effects, get tolerance to it, and physical dependence on the drug
 Can get substance use disorder
 Insomnia and treatment – difficulty to fall asleep, or stay asleep (maintenance)
o Rule of thumb – if there is a secondary cause of insomnia, you should take care of the primary problem
o If someone works shift hours, or lost loved one, or loud noises, short term uses
 Drugs for insomnia:
o 1. Benzodiazepines – end in “-pam, -lam”:
 MOA: bind to allosteric site (different site) on GABAa receptor, and
changes conformation, and get increased affinity of the receptor for
GABA – depend on gaba to be around so that’s why there is ceiling
 Potentiation of GABAergic inhibition of neuronal activity
 Can be used for insomnia, anesthesia, anxiety, seizures,
essential tremor and spasticity
o First line drug for long seizure over 5 minutes that will
not start
 Adverse effects: drowsy, confusion, anterograde amnesia, psychomotor
impairtment, substance use disorder
 Pharmacokinetic properties – theres difference in routes of metabolism
 3 drugs: oxazepam, temazepam, lorazepam (OTL)
 Go directly to phase II, so if patients are on other drugs that
inhibit CYP, or liver function problems
o Phase II is generally not a liver problem, and because they
skip one, it doesn’t say anything about the half-life
 Biological half-life
o Depends on sleep maintenance vs sleep onset
 Treatment principle
 Same drugs can be used for insomnia and anxiety and choosing is depending on pharmokinetic
differences Use benzos for the shortest amount of time and if you use for more than one month,
taper the dose down to avoid rebound insomnia or anxiety
 Will decrease time for sleep onset, REM sleep, sleep longer
 Antagonist – Flumazenil – give to Benzo overdose, or anesthesiology to reverse the effects
o 2. Novel benzo receptor agonists – Z-compounds! Zolpidem
 Bind to specific GABA site – used only for sleep
 Adverse effects: less because used only for sleep , eszopiclone has bitter aftertaste
 Less bad effects on sleep cycle , less problems but do still have same problem, good for long term
o 3. Melatonin receptor agonist: Ramelteon
 MOA: Agonist at MT1 and MT2 melatonin receptors
 MT1 – regulation of sleepiness
 MT2 – regulation of circadian rhythm
o Tasimelteon works more on MT2 so good for blind people
 Less efficacious than benzo
o 4. Orexin receptor antagonist – involved in maintaining wakefulness - SUVOREXANT
 MOA: antagonist at OX1 and OX2 orexin receptor
 Can use only for sleep but it is super expensive
 Adverse effects: daytime sleepiness, impaired driving, substance use disorder
 o 5. Other sedative-hypnotics
 Barbiturates – phentobarbital (have dose dependent , no ceiling like benzos)
 At high doses, they can just be GABA agonists, Use for insomnia or seizures
 MOA: Bind to allosteric different GABAa site like benzos so higher affinity for Benzos
 Treatment principles:
o Other drugs are better because this one has bad tolerance, dependence, addition, low
therapeutic index, induced CYP and have long half life
 H1 antihistamine: Diphenhydramine
 MOA: antagonist at H1, used for insomnia but maybe decrease sleep latency
 Adverse: definitely have daytime sedation, and anticholinergic effects

 Psychostimulants and other drugs that promote arousal,

attention and wakefulness
o These drugs improve mental and physical function – increase attention, mood, motor performance, breathing,
decrease appetite
o Purpose: Treatment of excessive sleepiness (narcolepsy) and fatigue, and improvement of attention (ADHD)
 Drugs of abuse – can cause euphoria, students, weight loss
o Drugs: indirect acting sympathomimetic drugs
 Increase NE, dopamine
 1. Amphetamine-like stimulants
 Kicks out dopamine out of the vesicles and
brings it directly out
 MOA: block DAT, NET, SERT
 Uses: ADHD, nacolepsy
 Adverse: insomnia, HR increases, growth
inhibition (dopamine – bad for kids
suppresses GRH but kids eventually catch up), serotonin - do not want to eat
 2. Reuptake inhibitors
 Cocaine
o MOA: block DAT and NET, increase DA and NE
o Use: ADHD, Narcolespsy, or local anesthetic
o Adverse: similar to amphetamine
 Modafinil
o May block NET and DAT
o Use: Narcolepsy – less use for abuse
o Adverse: less than other psychostimulants, anxiety, delusions, hallucinations
 Other reuptakes are not used for this, with similar MOA but these drugs have faster onset of
action!! Bupropion can be used as well, Atomexetine – inhibits NET but gives abdominal pain
and nausea
 Sodium oxybate – GABA analog agonist at GABAb – get sedation and sleepiness but use for nacolepsy
whut…??