Lecture 5 (neuro)-Exam 3

Question 1

Answer 1

Question 2

Tension HA:
* Common or rare?
* What is the etiology? (2)
* More common in who? (gender)
* How to dx it?

Answer 2

• Most common type of headache
• Etiology - stress / dehydration
• F>M
• Dx: clinical

Question 3

Tension Headaches
* What is the criteria? (6)

Answer 3

• Bilateral
• Pressing / tightness (band-like)
• Mild to moderate pain
• Not aggravated by usual physical activity (walking / climbing stairs)
• NO nausea / vomiting (can r/o if they have this)
• NO more than one of photophobia or phonophobia (one of these, not both)

Question 4

Tension headache – Acute Therapy
* What is the first line therapy? (3)

Answer 4

• NSAIDs (ibuprofen / naproxen)
• Aspirin
• Acetaminophen

Question 5

Tension headache – Acute Therapy
* What are the goals? (4)

Answer 5

• Pain free / functioning after treatment
• Consistent efficacy
• Limited disability
• Minimal medication side effects

Question 6

Tension headache – Acute Therapy
* What is the adjuvtive therapy? (3)

Answer 6

• Caffeine 100 to 200mg PO with first-line therapy (if not effective alone)
• Biofeedback
• Massage

Question 7

Tension headache – Acute Therapy
* What is not recommended? (2)

Answer 7

• Triptans
• Muscle relaxants

Question 8

Tension headaches – Prophylactic therapy
* What is acute?
* What is chronic?
* What are the goals? (3)

Answer 8

Acute: 1 to 14 HA days/month
Chronic: ≥ 15 HA days/month (I think this is when you start prophylactic therapy)

Goals:
* Decrease the frequency, severity and duration of HA
* Increase response to acute treatments
* Increase function / decrease disability

Question 9

Tension headaches – Prophylactic therapy
* What is the first line? (4)

Answer 9

First-line – tricyclic antidepressants
* Amitriptyline (MC)
* Nortriptyline
* Imipramine
* Doxepin

DANI

Second-line
* Mirtazapine
* Venlafaxine
* Acupuncture
* Trigger point injections

Question 10

NSAID mechanism of action
* What is the pathway of thromboxane, and prostaglandins

Answer 10

Phospholipase A2 released in response to inflammation

Converts phospholipids into arachidonic acid

Arachidonic acid is a substrate for two enzymes
* 5-lipoxygenase (5-LOX)
* Cyclooxygenase (COX-1 and COX-2)

Question 11

NSAID Mechanism of action
* What is always circulating and active?
* What does thromboxane promote?
* What does Prostaglandins and prostacyclin cause?

Answer 11

Question 12

NSAID Mechanism of action
* When is COX 2 activated? What does it mediate?

Answer 12

COX-2 activated at sites of inflammation
* Mediates inflammation, pain, and fever

Question 13

NSAID Mechanism of action
* What does NSAIDS block and cause?

Answer 13

NSAIDs block COX-1 and COX-2
* Reduce prostaglandin, thromboxane, prostacyclin synthesis
* Reduce inflammation, pain, and fever

Question 14

NSAID classification
* What is the example of irreversible COX inhibitors?
* What does non-selective and selective reversible cox inhibitors do?

Answer 14

Irreversible COX inhibitors
* Aspirin

Reversible COX inhibitors
* Non-selective: Inhibit COX-1 and COX-2
* Selective: Inhibit COX-2

Question 15

Answer 15

Question 16

NSAID adverse effects
* Whatis the MC SE?
* Why does this happen?

Answer 16

Question 17

NSAID adverse effects
* What are the other GI SE? (besides gastric ulcer)

Answer 17

Other gastrointestinal adverse effects
* Dyspepsia
* Abdominal pain
* Nausea / vomiting

Question 18

Nsaid adverse effects
* Why is there an increased bleeding risk?
* Strongest effect with What?

Answer 18

Increased bleeding risk
* Inhibition of thromboxane -> decrease in platelet aggregation

Strongest effect with:
* Aspirin – irreversible inhibition
* Increased COX-1 selectivity

Question 19

Nsaid adverse effects
* Why is there an increased clotting risk and CV events?
* MC with increased what?

Answer 19

• MC with increased COX-2 selectivity
• Less COX-1 inhibition = less inhibition of thromboxane A2
• More COX-2 inhibition = more vasoconstriction

Question 20

NSAIDs - Adverse Effects
* What are the kidney effects?

Answer 20

NSAIDs inhibit prostaglandins -> VASOCONSTRICTION

Decrease renal blood flow
* Kidneys think blood pressure is low and retain fluid ->
increase blood pressure / peripheral edema

Increase risk of renal injury
* Effect more pronounced with underlying decrease in renal perfusion

Question 21

NSAIDs - Adverse Effects
* What can happen to the skin?

Answer 21

Rash – hypersensitivity reactions rare / cross sensitivity

Question 22

NSAIDs: Black box warnings
* What are the serious Cardiovscular events? When is it contraindicated?

Answer 22

Serious cardiovascular events
* Increased risk of embolic events including myocardial infarction and stroke
* Contraindicated in the setting of coronary artery bypass surgery

Question 23

NSAIDS: black box warning
* What are the Increased risk of serious gastrointestinal adverse events?

Answer 23

• Bleeding, ulceration, perforation
• Elderly at greatest risk

Question 24

NSAIDS: black box warning
* When it is contraindated? (4)

Answer 24

• Aspirin allergy – watch for patients with Samter’s triad
• Peptic ulcer. GI bleed or perforation
• Advanced renal impairment
• Cerebrovascular bleeding

Question 25

NSAIDs: Black box warning * What are the pregnancy considerations?

Answer 25

Avoid if possible; especially in first and third trimesters

Question 26

Most important: Know the dose for ibuprofen

Answer 26

Question 27

What is unique about meloxicam and celecoxib?

Answer 27

Question 28

ketorolac * More _ * What is the indication for keterolac IV/IM? * **Do not recommend use of what?**

Answer 28

* More potent * Short-term management of moderate to severe acute pain requiring opioid-level analgesia * **Do not recommend use of oral product for home use** (causes a lot of issues like renal disorders)

Question 29

ketorolac * Do not use more than how many days? * What are the contraindications? (4)

Answer 29

Warning * Do not exceed 5 days combined (inj + tabs) therapy Contraindications * Hypovolemia * Incomplete hemostasis * Bleeding disorders or high risk of bleeding * Concomitant epidural or intrathecal injections

Question 30

Acetaminophen mechanism of action * What is the MOA? What are the effects? (3)

Answer 30

Inhibits COX-1 and COX-2 in the central nervous system * Decreases pain and fever * No anti-inflammatory effects because it does not inhibit peripheral COX receptors * No effects on platelets

Question 31

Acetaminophen mechanism of action * Preferred for patients with what? (5)

Answer 31

* Bleeding disorders * Peptic ulcer disease * Cardiovascular disease * NSAID allergy * Children < 6 months of age

Question 32

Acetaminophen * **What is the adult dosages?** * What are the children dosage?

Answer 32

Adult Dosage: * **650mg to 1000 mg every 4 to 6 hrs** Children Dosage: * 12.5 to 15 mg/kg/dose every 4 to 6 hours * (Max 5 doses daily – 75 mg/kg/day)

Question 33

Acetaminophen * **What are the daily doses (short term, elderly, chronic use and alcohol?**

Answer 33

* Short term (≤10 days): 4 grams/day * Elderly or debilitated: 3 grams/day * Chronic use: 3 grams/day * Alcohol intake ≥ 2 ounces daily: 2.5 grams/day

Question 34

Acetaminophen * What are the dosage forms?

Answer 34

* Tablets / capsules * Oral suspension * Suppositories * Intravenous

Question 35

Acetaminophen * What is the MC side effect? Who is high risk of this SE? (5)

Answer 35

Hepatotoxicity MC * Preexisting liver disease * Concurrent hepatotoxic medications * Poor nutrition * Regular alcohol consumption * Chronic overuse

Question 36

Acetaminophen * What is the metabolism? What is toxic?

Answer 36

## Footnote NAC = N-aceylcysteine

Question 37

What are the symptoms of migraines?

Answer 37

Question 38

Migraine pathophysiology * Begins with activation of what? * Patients can be predisposed how? * Imbalance between what? * What is the result?

Answer 38

A migraine headache begins with activation of the trigeminal nerve * Patients with migraines genetically predisposed to hyperresponsiveness to environmental circumstances or triggers * Imbalance between excitatory and inhibitory signals * Result = TN activation leads to irritation of nociceptors in the meninges

Question 39

Migraine pathophysiology * What does nociceptor irritation cause? (3) * NP release causes what?

Answer 39

Nociceptor irritation causes release of specific neuropeptides (NP): * Vasoactive inhibitory peptide (VIP) * Substance P * Calcitonin gene regulated peptide (CGRP) NP release causes neurogenic inflammation of meningeal vasculature

Question 40

Migraine pathophysiology * Inflamationn results in what? (3)

Answer 40

Vasodilation of meningeal capillaries Increased meningeal capillary membrane permeability Mast cells degranulation * Release histamine – vasodilation, increased capillary permeability * Release prostaglandin - proinflammatory

Question 41

Migraine pathophysiology * What are the end results? (2)

Answer 41

* Activation of meningeal nociceptors * PAIN

Question 42

Migraine treatment * What are the general principals? (4) * What is not be recommended?

Answer 42

* Avoid triggers * Regular sleep pattern * Treat early – first symptoms * Treat aggressive * **Opioids and barbiturates not recommended**

Question 43

Migraine * What are the common triggers?

Answer 43

Question 44

Migraines – **acute / abortive treatment** * What is first line? * What is second line?

Answer 44

First-line * NSAIDS / acetaminophen * May be adequate for **mild to moderate migraines** Second-line * Triptans if NSAIDS / acetaminophen not effective and for Moderate to severe migraines (super bad and need both)

Question 45

# Low yield Migraines – **acute / abortive treatment** * What is third line?

Answer 45

* Ergots * Ditans * Grepans

Question 46

Triptan-MOA * What type of agonist? * Binds to what? * What does it inhibit and decrease (5)? * Reduce activation of what?

Answer 46

Serotonin agonists Bind to pre-synaptic 5-HT1 B and D receptors Inhibit the release of neuropeptides (decrease down cascade) * Decrease mast cell degranulation * Decrease prostaglandin release * Decrease vasodilation * Decrease cell permeability Reduce activation of nociceptors

Question 47

Triptans – general principals * What are pros (5)? * Patients who do not respond to triptans may what? * Recommend trial of how long? * Best results seen when?

Answer 47

* Common MOA; different does, pharmacokinetics, costs, routes * Patients who do not respond to one triptan may respond to others * Recommend trial of single agent x 3 attempts before switching agents (gettings better with each dose) * Best results seen when started with initiation of pain (not aura aka visual changes)

Question 48

Triptans – general principals * Variable evidence regarding what? * Few what? * What is the oldest and most studied? * Specific agent chosen often depends on what?

Answer 48

* Variable evidence regarding benefits from concomitant NSAIDS * Few head-to-head comparisons exist * Sumatriptan oldest and most studied; NNT SQ for complete pain relief at two hours = 2 * Specific agent chosen often depends on insurance / cost

Question 49

Know routes because you need to be careful if pt is vomiting

Answer 49

Question 50

Triptans * What are the SE? (6)

Answer 50

* Fatigue * Dizziness * Nausea * Somnolence * Chest discomfort * Paresthesias, flushing, tingling, neck pain, chest tightness (triptan sensation) | Last two because of vasospasm

Question 51

Triptans * What are rare SEs? (3)

Answer 51

* Myocardial infarction * Arrythmias * Stroke

Question 52

What are the contraindications of triptans? (9)

Answer 52

* History of MI * Coronary artery disease * Angina * History of stroke * Uncontrolled hypertension * Peripheral vascular disease * Hemiplegic migraines * Severe renal or hepatic dysfunction * Age > 65 years ## Footnote Because of the side effects

Question 53

Triptans * Use in pregnancy? * Administration with what? Iimited info with what?

Answer 53

* All triptans except sumatriptan are CI during pregnancy * Administration with ergot alkaloids or MAOIs; limited information with SSRI coadministration

Question 54

Ergots * Ergotamine / dihydroergotamine: What type of the agonist? (2)

Answer 54

* 5HT agonists – not specific to 5-HT1 (more adverse effects-> why it is not first line) * Alpha 1 agonist – peripheral vasoconstriction

Question 55

Ergots * What are the SE? (5)

Answer 55

* Nausea and vomiting – 5HT-3 agonism * Vasoconstriction * Leg weakness * Extremity muscle pain * Uterine contractions

Question 56

Ergots * What is the BBW? * Administration during or within what?

Answer 56

* BBW: administration with strong CYP3A4 inhibitors has been associated with life-threatening peripheral ischemia (protease inhibitors, macrolide antibiotics) * Administration during or within 14 days of an MAOI or triptan; limited evidence for coadministration with SSRIs

Question 57

Ergots * What are the contraindications? (8)

Answer 57

* History of MI * Coronary artery disease * Angina * History of stroke * Uncontrolled hypertension * Peripheral vascular disease * Severe renal or hepatic dysfunction * **Pregnancy**

Question 58

Ergots

Answer 58

No oral * The time you would use this is because status migrainosus or resistance to triptian

Question 59

Status migrainosus * Severe migraine lasting how long? * Refractory to what? * R/o other? * No standard what?

Answer 59

* Severe migraine lasting > 72 hours * Refractory to standard treatment * Rule out other diagnoses (usually need to get scan of head) * No standard treatment approach

Question 60

Status migrainosus * What is the first line therapies? (7)

Answer 60

## Footnote Make a cocktail

Question 61

Migraine – acute medication over use * _ of patients with migraines * Frequent use of what? * Leads to what? * Progression to what?

Answer 61

15% of patients with migraines * Frequent use of acute migraine treatments * Leads to increased attack frequency * Progression to chronic migraines

Question 62

Migraine – acute medication over use * How do you dx it?

Answer 62

≥ 3 months of the following: * ≥ 10 days per month triptans or ≥ 15 days per month NSAIDS or acetaminophen ## Footnote Need a good medical hx

Question 63

Migraine – acute medication over use * What is the tx?

Answer 63

Wean medications

Question 64

Prophylactic therapy * Migraine attacks that interfere with what? * What is the criteria for prophylactic therapy? (4)

Answer 64

Migraine attacks that interfere with function, are frequent, or debilitating * ≥ 6 headache days per month * ≥ 4 headache days per month with some impairments * ≥ 3 headache days per month with severe impairment * Lack of efficacy with acute treatments

Question 65

Migraine Prophylactic Therapy Goals * 50% reduction in what? * Significant decrease in what? * Improved response to what? * Improved what?

Answer 65

* 50% reduction in days of migraine frequency * Significant decrease in duration or severity of migraines * Improved response to acute therapy * Improved QOL

Question 66

Migraine Prophylactic Therapy Goals * Dimished what? * Specific therapy dependent on what? * Equivalent what?

Answer 66

* Diminished migraine disability * Specific therapy dependent on patient comorbidities and adverse effects * Equivalent efficacy – 1 to 3 fewer migraine days on average

Question 67

Migraine prophylaxis * What are the non-pharm treatment? (8)

Answer 67

* Avoid triggers * Adequate hydration (2 liters in adults) * Biofeedback * CBT-stress reduction * Neuromodulation devices * Relaxation / imagery techniques * Acupuncture * Massage | Usually with pharm therapy

Question 68

Answer 68

Be careful about propranolol because it can cause depression therefore if you have a depressed patient on it then need to look at hx.

Question 69

Answer 69

Question 70

Cluster headaches * Cluster when? * HA begins when? (2)

Answer 70

Clustered” at same time of day, and often during a season * HA begins 2-3 hours after going to bed and lasts 30-90 min * Mornings in spring

Question 71

Cluster HA: * Attacks are without what? * Escalate how? * Individual attacks last how long? * Occurs how often? * Typically precipitated by what?

Answer 71

* Attacks are without prodrome (or aura) * Escalate rapidly within 15 minutes, * Individual attacks last 15-180 minutes if untreated * Occur from once every other day to 8x/day * Typically precipitated by ETOH ## Footnote Male > Female: (2-3:1)

Question 72

Answer 72

Question 73

Cluster Headache - pathophysiology * What are the triggers? (3)

Answer 73

* Smoking * Red wine * Stress

Question 74

Cluster Headache - pathophysiology * What becomes activated and what does that stimulate?

Answer 74

* Dysfunctional hypothalamus becomes activated * Stimulates parasympathetic nervous system

Question 75

Cluster Headache - pathophysiology * Since PNS is activated what happens? (3)

Answer 75

Lacrimal glands – tearing Nasal glands – congestion/rhinorrhea Vessels – vasodilation * Neuroinflammation – activation of nociceptors of trigeminal nerve – PAIN (periorbital) * Conjunctival hyperemia

Question 76

Cluster Headache - pathophysiology * What happens to cavernous sinus? * No what?

Answer 76

* Inflammation cavernous sinus – miosis, ptosis (sympathetic inflammation) * No anhidrosis (Not full Horner’s syndrome)

Question 77

Cluster Headache * What is first line **acute treatment**?

Answer 77

Oxygen: 100% @ 6-12 L/min x 15min, via nonrebreather mask * High efficacy – 75% patients with pain relief * Lack of adverse effects * Initial acquisition may be difficult

Question 78

Cluster Headache * What can be used after if oxygen does not work?

Answer 78

Sumatriptan 6mg SC

Question 79

Cluster HA: Sumatriptan * Efficacy? * What is possible? * Greater than what? * What has some benefit? * No role for what?

Answer 79

* High efficacy – 75% patients with pain relief within 15 minutes * Adverse effects possible * Greater than recommended doses possible * Intranasal with some benefit – longer time to pain relief * **No role for oral therapy**

Question 80

Cluster Prophylaxis * When do you start it?

Answer 80

Start immediately with acute treatments to prevent reoccurrence

Question 81

Cluster Prophylaxis * What are all the options?

Answer 81

* Verapamil (1st line) * Lithium * Topiramate

Question 82

Cluster prophylaxis ## Footnote 6

Answer 82

Question 83

Cluster prophylaxis ## Footnote 5/3

Answer 83

Question 84

Cluster headache – transitional treatment * Started concurrently with what? * Onset of effects more what? * Prevents what?

Answer 84

* Started concurrently with prophylactic medication titration (a brigde between acute and prophylactic txt) * Onset of effects more rapid * Prevent recurrent cluster headaches while prophylactic therapy is titrated

Question 85

Cluster headache – transitional treatment * Benefits are limited how? * What are the options?

Answer 85

Benefits are uaully limited-weeks to months * Prednisone * Greater occipital nerve injection->Lidocaine and / or bupivacaine

Question 86

Bacterial Meningitis * Most likely organism varies by what? * What is key to decrease long-term sequelae? * What should be done before antibiotic txt? Do not delay initiation for what?

Answer 86

Most likely organism varies by age Rapid diagnosis and treatment is key to decrease long-term sequelae Ideally blood cultures and lumbar puncture should be completed before antibiotic treatment * Do not delay initiation of therapy for LP / neuroimaging

Question 87

Bacterial Meningitis * Neuroimaging (CT) indicated for patients with what?

Answer 87

Neuroimaging (CT) indicated for patients with focal neurologic deficits, seizures, immunocompromised, papilledema, altered consciousness to rule out mass or increased ICP

Question 88

Bacterial Meningitis * Empiric therapy should be based on what? * Empiric therapy should continue when?

Answer 88

* Empiric therapy should be based on most likely organism and antibiotic ability to penetrate the CNS * Empiric therapy should continue for 48 to 72 hours; until bacterial meningitis is ruled out – culture or PCR

Question 89

Bacterial Meningitis * Tailor therapy when? * Treatment duration varies with what?

Answer 89

* Tailor therapy once pathogen is identified * Treatment duration varies with pathogen but generally 7 to 21 days of intravenous antibiotics

Question 90

BBB penetration * What are the factors that increase antibiotic pentration into CNS? (5) * Maximize antibiotic dose for what?

Answer 90

Inflammation of the meninges – causes gaps in tight junctions and decreases activity of efflux pump Antibiotics with: * Low molecular weight * Non-ionized state at physiologic pH * Low protein binding * High lipid solubility Maximize antibiotic doses to optimized CNS penetration

Question 91

Answer 91

Question 92

Meningitis: empiric therapy for newborn to 1m * What are the most likely organisms (4) * What is the empiric therapy? * What is the typical regimen?

Answer 92

Question 93

Meningitis: empiric therapy for 1m to 50 years * What are the most likely organisms (4) * What is the empiric therapy? * What is the typical regimen?

Answer 93

Question 94

Meningitis: empiric therapy for 50 years or co-morbidities * What are the most likely organisms (4) * What is the empiric therapy? * What is the typical regimen?

Answer 94

Question 95

Neonatal HSV Encephalitis * What is the etiology? * What is the presentation?

Answer 95

* Etiology: perinatal transmission of HSV (1 or 2); often no history of maternal herpes infection; maternal disease may be asymptomatic * Presentation: fever, lethargy, poor feeding, **seizures, increased liver enzymes**, herpes lesions uncommon; most commonly seen within **first month of life**

Question 96

Neonatal HSV Encephalitis * How do you dx it? * What is the txt?

Answer 96

Diagnosis: HSV PCR of CSF; high sensitivity PCR required Treatment: * Acyclovir 20mg/kg/dose IV Q8H until HSV ruled-out or 21 days minimum * Test for cure via CSF PCR at 21 days; if positive treat 7 more days * Suppressive therapy with acyclovir continued for 6 months

Question 97

Viral Meningitis (Aseptic) * Acute meningeal inflammation with no what? * More common than what? * Peaks when? (what time of year) * Occurs how? * Cannot be distingusihed clinically from what?

Answer 97

* Acute meningeal inflammation with no identifiable bacteria in the CSF * More common than bacterial meningitis in pediatric population, RARE in elderly * Peaks in late summer – early fall * Occurs in outbreak and sporadic forms * Cannot be distinguished clinically from bacterial

Question 98

Viral Meningitis (Aseptic) * >90% are caused by what? What are the other causes?

Answer 98

>90% are caused by enterovirus (Coxsackie virus A or B, echoviruses) family. Others are herpes Simplex 2 and arthropod-borne viruses

Question 99

Answer 99

Question 100

What is the biofire meningitis/encephalitis panel? What happens if HSV is negitive on it?

Answer 100

If it is negative, would do a high sen. HSV test

Question 101

Meningitis-Bacterial * What are the classic signs? (2) * What do you need to remember about with elderly and infants?

Answer 101

Classic: * + Brudzinski sign * + Kernig sign Remember: * Elderly: subtle findings, often include confusion * Infants: irritability, lethargy, poor feeding

Question 102

Reyes syndrome * Encephalopathy associated with what? * MC in who? * Associated with what?

Answer 102

Encephalopathy associated with liver damage and liver failure * MC in children 4 to 12 years of age * Associated with viral infections (influenza, chicken pox) and aspirin / salicylate ingestion

Question 103

Reyes syndrome * What is damaged on a cellular level? * What does it mostly effect? * Increased what? (2) * What happens with sugar?

Answer 103

Mitochondrial damage – cells can’t make energy and die * Mostly effects liver cells * Increased ammonia – encephalitis (swelling and increased ICP) * Increased AST, ALT, PT/INR * Hyper or hypoglycemia

Question 104

Reyes syndrome * What is the txt? (2)

Answer 104

* Supportive – mostly aimed at decreasing intracranial pressure * Hyperventilation / mannitol

Question 105

Answer 105

Question 106

Essential tremors * What is the txt? * What is the goal? * Sxs still generally worsen when? * Avoid what?

Answer 106

* Treatment is symptomatic * Goal is to reduce symptoms * Symptoms still generally worsen over time and may require additional treatments * Avoid substances that worsen it

Question 107

Essential tremors * What can help? * Treatment should be considered for who?

Answer 107

* Modest amounts of alcohol may help (60 to 70%) * Treat should be considered for patients with daily symptoms or with intermittent symptoms that cause patient distress

Question 108

What are the substances that may exacerbate essential tremor?

Answer 108

Question 109

Essential tremor – treatment * What are two options?

Answer 109

* Propranolol (MC in most pts) * Primidone

Question 110

Answer 110

# induces hepatic enzymes ## Footnote (*)Lower doses in elderly patients (#)induces hepatic enzymes

Question 111

Answer 111

Question 112

Parkinson Disease (PD) * Occurs in who? Starts when? * Dengeneration of what? * Essential features of what? (4) * What type of impairment?

Answer 112

* Occurs in all ethnicities; 45-65 years start * Degeneration of dopamine-producing neurons in the substantia nigra causing deficiency of dopamine * Essential features resting tremors, bradykinesia, rigidity, and unstable posture * Depression and cognitive impairment

Question 113

Parkinson’s pathophysiology * Complex interplay between what?

Answer 113

Complex interplay between excitatory and inhibitory neurons in the basal ganglia that regulate desired and undesired motor movements

Question 114

Parkinson’s pathophysiology * What is the direct pathway?

Answer 114

Direct pathway – movement stimulation * Glutamate neurons stimulate GABA neurons striatum * Stimulation of GABA neuron -> inhibition of GABA in GPI * Inhibition of GABA second motor neuron in GPI -> less inhibition on thalamus * Thalamus receives and sends signal for movement to the cerebral cortex * **DA from the SN binds to D1 receptors -> enhances activity of pathway**

Question 115

Parkinson’s pathophysiology * What is the indirect pathway?

Answer 115

Indirect pathway – movement suppression * Glutamate neurons stimulate GABA neurons in striatum * Stimulation of GABA in striatum -> inhibition of second GABA neuron in GPE * Inhibition of GABA in GPE -> less GABA released in subthalamic nucleus * Less GABA released in subthalamic nucleus ->less inhibition of glutamate * Glutamate stimulates GABA in GPI * GABA stimulation in GPI ->inhibitory signals sent to thalamus * Inhibitory signals sent to cortex to decrease muscle movement * **DA from the SN binds to D2 receptors in striatum ->opposes the activity of pathway -> less inhibitory effects**

Question 116

Parkinson’s pathophysiology * Loss of what? * What does that cause with the direct pathway?

Answer 116

Parkinson’s = loss of DA in SN Decreased DA in direct pathway * Less DA binding to D1 receptor -> less excitation of the GABA motor neuron in the striatum * Less GABA release from striatum -> less inhibition on GABA motor neuron in GPI * Increase GABA release from GPI ->inhibitory effect on motor neuron

Question 117

Parkinson’s pathophysiology * Overall excess inhibitory stimulation to thalamus causes what?

Answer 117

bradykinesia / akinesia / mask face / postural instability ## Footnote * T = tremor * R = rigidity * A = akinesis / bradykinesia * P = postural instability

Question 118

Parkinson’s pathophysiology * What happens in the indirect pathway due to loss of DA

Answer 118

Decreased DA in indirect pathway * Less DA binding to D2 receptor -> less inhibition of GABA motor neuron in striatum * GABA neuron overactive -> releases more GABA * Inhibits second GABA motor neuron -> cannot release GABA and inhibit glutamate release * Glutamate released and stimulates GABA neurons in GPI -> inhibitory effect on motor movement

Question 119

Parkinson’s pathophysiology * What does cholinergic neurons oppose? * What happens with direct and indirect pathway?

Answer 119

Cholinergic neurons oppose the activity of D1 and D2 receptors Direct pathway * D1 receptors – excitatory / cholinergic activity inhibitory Indirect pathway * D2 receptors – inhibitory / cholinergic activity excitatory

Question 120

Parkinson’s pathophysiology * What is the overall effect of cholinergic motor neurons?

Answer 120

Overall effect = unopposed cholinergic activity * Tremors and rigidity

Question 121

PD treatment * What is the goal? * What are the examples of medications? (5)

Answer 121

Decrease symptoms by increasing dopamine or restoring balance between dopamine and acetylcholine * Levodopa * Dopamine agonists * MAO type B inhibitors * Amantadine * Anticholinergics

Question 122

Dopamine synthesis * What are the steps?

Answer 122

* Tyrosine is absorbed from the GI tract * Readily crosses the BBB and into the CNS * Synthesized into dopamine which is packaged into vesicles * Released by stimulus into synaptic cleft

Question 123

Dopamine synthesis * What happens after DA is release?

Answer 123

* Pumped back into the presynaptic cleft and repackaged into vesicles or * Sent to glia cells and is metabolized by monoamine oxygenase type B (MAO-B) and catechol-O-methyltransferase (COM-T

Question 124

PD treatment: MAO-B inhibitors * Decreases what? * Often used alone for who? What are the examples (3)

Answer 124

Decrease DA metabolism in the CNS Often used alone for early treatment of mild symptoms * Selegiline * Rasagiline * Safinamide

Question 125

PD treatments: MAO-B inhibitors * May help with what? * Interactions with what is rare?

Answer 125

May help with wearing “OFF” symptoms with patients also taking levodopa in late disease Interactions with SSRIs and SNRIs and MAOB inhibitors is rare * Can use together with caution

Question 126

PD treatments: MAO-B inhibitors * What are the SE? (7)

Answer 126

* **Nausea and headache (MC)** * Confusion * Hallucinations * Excitement * Anxiety * Insomnia * Dyskinesia

Question 127

PD treatments: Amantadine * What is the mechanism? * What does it increase (2) and decrease (1)? * Minimal what?

Answer 127

Antiviral, unknown mechanism * Increase DA synthesis * Increase DA release * Decrease DA reuptake Minimal effects

Question 128

PD treatments: Amantadine * Used for what?

Answer 128

Used for initial treatment with mild symptoms or with levodopa to decrease motor complications

Question 129

PD treatments: amantadine * Best for who? * What are the SEs? (4)

Answer 129

Best for patients < 70 years * Effects last 1 to 2 years Adverse Effects * Lethargy * GI effects * Strange dreams * All mild and rare

Question 130

PD treatments: * What is the DA / acetylcholine balance issue?

Answer 130

* Decreased DA causes unopposed acetylcholine (Ach) effects * Ach stimulates muscarinic receptors responsible for smooth motor control * Excess Ach causes tremors and rigidity

Question 131

PD treatments: Antimuscarinic agents * Blocks what? * What does it decrease? * What are the examples (2)

Answer 131

Block muscarinic receptors and restore the balance between DA and Ach Reduce tremors / rigidity * Benztropine * Trihexyphenidyl

Question 132

PD treatments: Antimuscarinic agents * What are the SE? * Best for who?

Answer 132

* **Anticholinergic** * Best for patients ≤ 65 years

Question 133

PD treatments: DA agonist * WHat is the MOA? * What are the examples? (4)

Answer 133

Binds to DA receptors and stimulates them * Pramipexole * Ropinirole * Rotigotine (transdermal) * Bromocriptine

Question 134

PD treatments: DA agonist * What are the se? (7)

Answer 134

* Nausea / vomiting * Somnolence * Orthostatic hypotension * Peripheral edema * Hallucinations * Confusion * Impulse control disorders

Question 135

PD treatments: DA agonist * What do you need to caution with? What crisis? * CI in who?

Answer 135

Caution: do not discontinue abruptly * Hyperkinetic crisis – mimics neuroleptic malignant syndrome CI: breast feeding mothers – decrease prolactin – decrease milk production

Question 136

PD treatments * What can and cannot cross the BBB?

Answer 136

Dopamine * Cannot cross the blood brain barrier (BBB) Levodopa * Crosses BBB readily and gets converted to DA via DOPA decarboxylase (DDC)

Question 137

PD treatments: levodopa * What is the challenge? What are the SE?(5)

Answer 137

Peripheral DOPA decarboxylase can convert levodopa to DA before it can cross BBB Peripheral DA accumulates causing unwanted adverse effects: * Nausea / vomiting * Anorexia * Orthostatic hypotension * Tachycardia * Arrythmias

Question 138

PD treatments: levodopa * What is the solution to the challenge one aka increased peripheral DA ?

Answer 138

Carbidopa * PERIPHERAL DDC inhibitor * Inhibits levodopa conversion to DA outside the CNS

Question 139

Levodopa/carbidopa (Sinemet) * How do you dose it? * What are the SEs? (4)

Answer 139

Dosing * Start low and titrate to effect * Use immediate release products to titrate Adverse effects * Nausea * **Dyskinesias** * Hallucinations * Confusion

Question 140

Levodopa/carbidopa (Sinemet) * CI in who? * Caution?

Answer 140

* CI: patients with psychosis; during or within 14 days of MAOIs * Caution: do not stop abruptly

Question 141

General dosing recommendation: levodopa/carbidopa * What is the initial dose? Titrate how? * What is the usual dose? Consider conversion when?

Answer 141

Initial dose: * 25mg carbidopa/100mg levodopa PO TID with meals (dec. nausea) * Titrate as tolerated to lowest levodopa dose the produces clinical response Usual dose: * 300 to 600mg of levodopa/day * Consider conversion to controlled release products once stable * Absorption 30% less that IR tablets

Question 142

Answer 142

Question 143

PD progression * What will happen over time? What will happen with treatment?

Answer 143

PD is progressive with a continuous decline in DA over time * Effects of levodopa will begin to decrease * 30 to 40% of patients see effects of levodopa decrease 3 to 4 hours after the dose after 5 years; 60% by 10 years * “ON” – levodopa response * “OFF”- PD symptoms return

Question 144

PD progression * What is wearing off? * What is on/off phenomenon? * What is dyskinesia?

Answer 144

Wearing off * Happens first, MC; decreasing effect of LD at the end of the dosing interval On/off phenomenon * Medication works one second and not the next (random-not based on doses) Dyskinesia * Less DA available the higher levodopa doses are needed; over excitation can result in dyskinesia

Question 145

PD treatments * What is the second challenge with levodopa? * What is the solution?

Answer 145

Challenge #2 * Peripheral levodopa and central DA metabolized by catechol-o-methyltransferase (COM-T) COM-T inhibitors * Inhibit the break down of peripheral levodopa and / or central DA

Question 146

PD treatments * What is entacapone? What happens with levodopa? * What is tolcapone? What does that cause?

Answer 146

Entacapone: peripheral COM-T inhibition only (prevents levodopa breakdown) * More levodopa enters the brain Tolcapone: central and peripheral COM-T inhibition (prevents both levodopa and DA breakdown) * More levodopa enters the brain * More constant, stable DA levels * Less DA break down in CNS

Question 147

PD treatments-COM-T inhibitors * Used with what? * What does it cause? (3)

Answer 147

Used with levodopa * Stabilizes levodopa concentrations in the blood * Can improve motor complications * Reduce wearing off phenomenon

Question 148

PD treatments-COM-T inhibitors * What are the SE of Entacapone / tolcapone (4)

Answer 148

* Nausea * Orthostatic hypotension * Hallucinations * Confusion

Question 149

PD treatments-COM-T inhibitors * What is the BBW of tolcapone? Closely monitor what? Reserved for what?

Answer 149

* BBW: Liver toxicity / failure * Closely monitor AST/ALT * Reserved for last-line therapy

Question 150

PD treatment General overview

Answer 150

Question 151

PD treatment General overview

Answer 151

Question 152

PD treatment General overview

Answer 152

Question 153

Huntington Disease (HD) * What atrophy? What enlarges? * What is the genetics? * When is the onset?nFatal when?

Answer 153

* Caudate nucleus atrophy and ventricle enlargement * Inherited autosomal dominant (short arm of chromosome 4), progressive, neurodegenerative * Insidious after age 30 years; fatal within 15 to 20 years

Question 154

Huntington Disease (HD) * What is the mvt, mood/cognitive changes?

Answer 154

* Movement disorders – chorea, dystonia, akathisia, athetosis * Mood /cognitive changes – depression, personality, dementia

Question 155

HD treatment (symptomatic) * Regions of the brain impacted by HD have what? (3)

Answer 155

Decrease of GABA Decrease of Ach Increase of DA * Medications decrease or antagonize DA

Question 156

HD treatment (symptomatic) * For moderately severe chorea, there is an increased risk of what?

Answer 156

Increased risk of falls, poor sleep, difficulty with speech / swallowing

Question 157

HD treatment (symptomatic) * What is first line? * What is second line?

Answer 157

First-line * VMAT-2 inhibitors – DA depletors * Tetrabenazine, deutetrabenazine Second-line * **Patients with depression / suicidality (this will be moved to first line with patients of depression)** * Atypical antipsychotics

Question 158

HD treatment (symptomatic): VMAT-2 inhibitors * What do they deplete and improve? * What happens presynaptic and postsynaptic?

Answer 158

First-line - VMAT-2 inhibitors * Deplete DA by two primary mechanisms * Improve symptoms of chorea Presynaptic * Inhibit vesicular monoamine transporters (VMAT) * Vesicles cannot release DA Postsynaptic * Weak DA receptor antagonists

Question 159

HD treatment (symptomatic): VMAT-2 inhibitors * What are the SE? (3)

Answer 159

* Sedation * Pseudoparkinsonism * Increased depression and suicide risk

Question 160

HD treatment (symptomatic) * What is second line and when is it used?

Answer 160

Patients with depression / suicidality Atypical antipsychotics * Olanzapine, risperidone

Question 161

Tourette Syndrome (TS) * What is it? * What is txt for mild, nondebilitating tics?

Answer 161

* Tourette syndrome (TS) is a neurological disorder manifested by motor and phonic tics with onset during childhood * Mild, nondebilitating tics – no therapy, watch and wait

Question 162

Tourette Syndrome (TS) * What is first and second line?

Answer 162

First-line: * Habit reversal training where available Second-line * VMAT-2 inhibitors (tetrabenazine) * Atypical antipsychotics (aripiprazole) * Other: alpha agonists (clonidine, guanfacine) with ADHD-> will go to first line with ADHD patients