Neuro exam 2 Flashcards
Theories for development of MS
environment (away from equator)
genetic (twins)
autoimmune (attack CNS)
viral/microbial
Pathophysiology of MS
demyelination (decrease oligodendrocytes)
inflammatory response (t-cell breakdown BBB)
both
Primary symptoms of MS
visual complaints/optic neuritis
gait problems and falls
paresthesia
pain, spasticity, weakness, ataxia, speech
Secondary symptoms of MS
recurrent UTI, urinary calculi
decubiti and osteomyelitis
osteoporosis
respiratory infections
poor nutrition
depression
Tertiary symptoms of MS
financial
person/social
vocational
emotional
What is expanded disability status scale (EDSS)
0 no disability 10 death from MS
Factors for MS that are reported to aggravate symptoms or lead to acute attack
infections
anemia
fever
sleep deprivation
stress
malnutrition
childbirth
organ dysfunction
exertion
Diagnosis of MS
MRI (lesions)
CSF (IgG elevations)
What is an MS attack classified as
new symptoms lasting at least 24 hours and separated from other symptoms by at least 30 days
What is relapsing-remitting (RRMS)
no disease progression between relapses
clearly defined disease relapses
What is secondary progressive (SPMS)
develops after initial RRMS course
50% of RRMS pt develop it
What is primary progressive (PPMS)
disease progression from onset, with continuous worsening
What is progressive-relapsing (PRMS)
progressive disease from onset
continuing progression between relapses
Favorable prognosis of MS
<40 yo
female
optic neuritis or sensory symptoms
low attack frequency
relapsing/remitting disease course
Unfavorable prognosis of MS
> 40 yo
male
motor or cerebellar symptoms
high attack frequency
progressive disease course
What is mild MS
do not produce functional decline and may not require any tx
some clinicians may use PO steroids
What is moderate MS
functional ability is affected
high dose corticosteroids shorten duration of acute exacerbations
What is severe MS
manifested by hemiplegia, paraplegia, quadriplegia
no response to steroid therapy
plasma exchange every other day x7 treatments
Optic neuritis tx for MS
visual loss, blurring, hazy vision
onset of symptoms sudden and progressive
lesions on optic nerve
IV methylprednisolone
What do corticosteroids do for MS
improve recovery by decrease edema, BBB abnormality, IgG synthesis
Methylprednisolone (500-1000) 3-10 days duration
Avonex: MOA, indications
interferon 1a
suppress t cell proliferation
decrease BBB permeability
for RRMS (non-FDA: SPMS)
Avonex: warnings, ADRs
depression, seizures, albumin allergy
flu-like, inj rxn, leukopenia, depression
decrease of 1 pt EDSS
Betaseron: MOA, indications
interferon 1b
suppress t cell proliferation
decrease BBB permeability
RRMS, SPMS w/ relapses
(non-FDA: SPMS w/out replases)
Betaseron: warnings, ADRs
depression, seizures, albumin allergy
flu-like, inj rxn, leukopenia, depression
Copaxone: MOA, indications
glatiramer acetate
suppress T-cell activation
reduce inflammation, demyelination, axonal damage at MS lesion
RRMS (non-FDA: PPMS)
Copaxone: warnings, ADRs
not for IV use
inj rxn, skin rash, transient chest pain
Natalizumab for MS
pt who cant take ABC
UTI, depression, joint pain, ab discomfort, infusion rxn
TOUCH program (REMS)
baseline MRI
pt evaluated at 3 and 6 months
risk of progressive multifocal leukoencephalopathy
risk factors: >24 months tx, prior use of immunosuppressives, h/o JCV
SP1s for MS
oral for RRMS
first dose bradycardia, need ECG at baseline
cause macular edema, need eye exam
fetal harm
Fingolimod DDI
ketoconazole
admin live vaccines before drug or 2 months after discontinuation
Siponimod requires genetic screening prior to _________
initation
CI in CYP2C19*3 genotype
Ozanimod is contraindicated in what
severe untreated sleep apnea and MAO-I use
Ponesimod is a ______ half-life than other S1P agonists
shorter (leaves body in about 1 wk)
Teriflunomide for MS
reduce activated lymphocytes in CNS decreasing inflammation and demyelination
for relapsing form of MS
BBW: hepatotxicity, tertogenicity (avoid pregnant for 2 years after stopping)
What are the nuclear factor-like 2 activators for MS and their MOA
dimethyl (texifdera)
diroximel (vumerity)
monomethyl (bafiertam) - active form
activate the nuclear factor (NrF2) pathway involved in cellular response to oxidative stress
nuclear factor-like 2 activators considerations for MS
CBC prior to therapy, w/in 6 months, then annually
cause flushing: pretreat with 325 mg ASA 30 min prior to dose
take with food
Alemtuzumab (lemtrada) for MS
anti-CD-52; deplete T and B cells
for RRMS
high inf rxns and malignancies (REMS program)
Ofatumumab (kesimpta) for MS
anti-CD-20; selctively depletes B cells
for RRMS and active SPMS
hep B screening, increase risk of infections (PML)
Ocrelizumab (ocrevus) for MS
anti-Cd-20; humanized version of the rituximab monoclonal antibody
for RRMS, and PPMS
hep B screening, increase risk of infections (PML)
Mitoxantron for MS
decrease neurologic disability +/- frequency of relapse
SPMS, PRMS, RRMS
cause alopecia, dysmenorrhea, URI, UTI, cardiac toxicity
Cladribine for MS
impairs DNA synthesis resulting in dose dependent depletion of B and T cells
RRMS and active SPMS
2 courses 1 yr apart
increase risk of infections and malignancies
teratogenicity up until 6 months after dose
How to manage MS gait and spasticity
baclofen (somnolence and confusion)
tizanidine (cause less weakness, can cause sedation, dizziness, dry mouth, hypotension)
gabapentin
Drugs for MS urgency, frequency, incontinence (hyper-reflexic bladder)
anticholinergics (oxybutynin, tolterodine, can cause falls or decrease cognition
antimuscarinic agents (trospium, solifenacin, darifenacin)
TCA
Drugs for MS hesitance, retention, overflow (sphincter destrusor dyssynergia)
beta adrenergic blockers like prazosin
Drugs for MS sensory symptoms
trigeminal neuralgia: carbamazepine
neuropathic pain: TCA, pregablin, gabepentin, duloxetine
Drugs for MS fatigue
amantadine
methylphenidate or dextroamphetamine
modafanil or armodafinal
(maybe fluoxetine)
Drugs for MS sexual dysfunction
if also depression use bupropion
Drugs for MS tremor
propranolol, primidone, isoniazid
What is epilepsy
neuro disorder that is an enduring predisposition to generate epileptic seizures
What causes provoked seizures
toxins: alcohol, benzo, barbiturate w/drawal
neuro inj: stroke, intracranial hemorrhage
electrolyte: hypocalcemia, hypoglycemia, hyponatremia
illness: eclampsia, fever, uremia
What are the 4 non-provoked epilepsy type seizures
genetic
structural
infectious
metabolic/immune
Dravet syndrome (genetic seizure)
sodium channel mutation at volt gated, type 1 alpha subunit
Childhood absence epilepsy (genetic seizure)
t-type calcium channel and GABA receptor mutations
Juvenile myoclonic epilepsy (genetic seixure)
EF-hand containing protein-1 (EFHC1) and intestinal kinase (ICK) mutations
What are some structural seizures
cortical dysplasia
mesial temporal lobe epilepsy (sclerosis of hippocampus)
post-traumatic epilepsy (brain lesions)
What are the most common acquired infectious epilepsy in neurocysticercosis (infections)
parasitic infection of brain (tapeworm eggs, pork)
damage from parasite leading to structural injury
What are metabolic/immune seizures
lafora disease (glycogen metabolism)
NMDA encephalitis (tertoma tumors cause the nuronal tissue to make antibodies against NMDA)
What are the 2 principle neurotransmitters in the majority of seizures
GABA (inhibitory)
Glutamate (excitatory)
Generalized vs Partial Seizure
generalized: entire cerebral cortex of both hemispheres
partial: circumscribed area of cortex (focal)
General Action of anticonvulsants: reuce currents through __________ calcium channels
t-type
(generate spikes and bursts of energy in thalamic neurons)
What are L-type calcium channels
need strong depolarization for activation
long lasting
blocked by dihydropyridines and phenylkylamines
What are N, P, Q type calcium channels
need strong depolarization for activation
blocked by various snail and spider venoms
found in neurons
Barbiturates like phenobarbital are useful in treating what seizures
focal onset and generalized onset
phenobarbital MOA
increase Cl- conductance
block non-NMDA receptors
block N, P, L type Ca channels
Hydantoins like phenytoin are useful in treating what seizures
focal onset and generalized onset
phenytoin MOA
block voltage-gates Na+ channels by selectively binding to the channel in the inactive state (hyperpolarizes neurons)
blocks Ca2+ influx directly and indirectly
Carbamazepine is useful for treating what kind of seizures
focal and general
Carbamazepine MOA
block voltage-gated Na+ channels
Valproic Acid is useful for treating what kind of seizures
all focal and general
Valproic Acid MOA
inhibits GABA transaminase
block Na+ channels
block T-Type Ca2+ channels
Gabapentin is useful in treating what kind of seizures
focal onset
Lamotrigine is useful in treating what kind of seizures
focal and general
Lamotrigine MOA
block Na+ channels
Topiramate is useful in treating what kind of seizures
focal and general
Topiramate MOA
block Na+
may increase frequency of Cl- by binding to GABA
may act as AMPA antagonist
Tiagabine used for and MOA
focal onset
block reuptake of GABA
Benzos like diazepam, clonazepam, and lorazepam are used for treating what type of seizures
ACUTE therapy for focal and generalized
(need to be in combo with something else)
Benzos like diazepam, clonazepam, and lorazepam MOA
enhance inhibitory effect of GABA
Phenytoin MOA
prolongs Na+ channel opening
prevent spread of ectopic signals to normal tissue
Phenytoin FDA approved indications
partial
status epilepticus
tonic clonic
seizure ppx
Fosphenytoin FDA approved indications
partial
status epilepticus
tonic clonic
seizure ppx
Levetriacetam FDA approved indications
myoclonic
status epilepticus
tonic clonic
Phenytoin Sodium Injection
S = 0.92
insoluble in water
dissolved in 40% propylene glycol and 10% ethanol
pH adjusted to 10-12 with sodium hydroxide to maintain solubility
Max rate of phenytoin admin for adult <60 yo and >60 yo
<60: 40-50 mg/min
>60 yo: 20-25 mg/min
(flush line with 50 mL NS after each admin)
Oral Phenytoin Formulations S values
1: chew, suspension, elixir
0.92: capsules
How long does it take fosphenytoin sodium to change into phenytoin
hydrolysis to active phenytoin: 8-15 min
S = 0.92
diluted to 1.5-25 mg in D5W
max rate of 150 mg PE/min
What is hypoalbuminemia categorized as
albumin <3.5 g/dL
max single PO dose of phenytoin
400 mg
What is the Vmax and Km value
Vmax: 7
Km: 4
What increases Vmax
enzyme induction:
fever, pregnancy, trauma
phenobarbital, carbamazepine
What decreases Vmax:
hepatic cirrhosis
-decreased hepatocytes
-decreased enzyme activity
non-competitive inhibition
What increases Km
competitive inhibition
-amiodarone
-cimetidine
-chloramphenicol
What decreases Km
change in protein binding
protein displacement:
valproic acid, salicylates, penicillin, bilirubin, p-HPPH, fatty acids
What is the therapeutic range for phenytoin
10-20
(>15 cause 88% decrease in seizures)
Phenytoin adverse effects
death
ams, coma
ataxia
What is the typical level for phenytoin LD
15-20 mg PE/kg
What is the typical level for phenytoin MD
4-6 mg/kg/day
VPA MOA
chemically related to free fatty acids
inhibits voltage-gated sodium channels in the CNS
decrease neuronal excitability and rate of signal transduction
increase GABA
Therapeutic range for VPA
50-100
(only relevant when used as an AED)
What are the hepatic mechanisms that VPA is eliminated
glucuronidation
beta oxidation
alpha hydroxylation
What is carbamazepine used for
monotherapy and adjunctive therapy in tonic clonic and focal seizures
carbamazepine MOA
enhance inactivation of voltage-gated sodium channels
carbamazepine therapeutic monitoring
4-12 mcg/mL
(needs to be titrated over 2-3 wks)
carbamazepine ADE
derm
blood dyscrasia
hyponatremia (SIADH)
osteoporosis
carbamazepine dose adjustments
CTP score >8 = reduce by 25-50%
pregnancy in 3rd trimester
hemodialysis
Clonazepam used for
monotherapy or adjunctive for myoclonic, akinetic, and absence seizures
Clonazepam MOA
competitively binds the GABA-A receptor and potentiates the effect of GABA via modulation of chloride efflux
Benzo BBW
respiratory depression w/ opioids
Clonazepam clinical pearls
physiological dependence and w/drawal common
CNS depression effects
cause hallucinations, worsen ICU delirium, increase aggression
Ethosuximide used for
monotherapy or adjunctive for absence seizures
DOC
Ethosuximide MOA
inhibition of T-type Ca2+ channels
Ethosuximide drug monitoring
40-100 mcg/mL
Ethosuximide interactions and ADE
VPA, phenytoin, carbamazepine, phenobarbital, phenytoin
Ethosuximide clinical pearls
worsens tonic clonic seizures
causes hiccups
Phenobarbital used for
generalized and focal seizures
Phenobarbital MOA
binds GABA-A receptor and potentiates GABA via modulation of chloride efflux
Phenobarbital drug monitoring
20-40 mcg/mL
Phenobarbital ADE
other AED
SJS and TEN
Phenobarbital clinical pearls
not FDA approved for anything
off-label for alcohol w/drawal
Primidone used for
tremor
(Prodrug of phenobarbital, Converted to active intermediary metabolite phenylethylmalo-n-amide)
Phenytoin used for
Focal seizures, tonic-clonic seizures
Seizure prophylaxis post-operatively and in traumatic brain injury
Phenytoin MOA
Enhances inactivation of voltage-gated ion channels
Phenytoin significant interactions and adverse drug effects
SJS/TEN
DDI w/ warfarin
purple glove syndrome
Fosphenytoin used for
Focal seizures, tonic-clonic seizures
Seizure prophylaxis post-operatively and in traumatic brain injury
Fosphenytoin MOA
Enhances inactivation of voltage-gated ion channels
Phosphorylated pro-drug of phenytoin, activated by serum esterases
VPA used for
Focal seizures, general seizure disorders
Most utilized drug for absence seizures in patients >10
VPA interactions and ADE
Black Box Warning for hepatoxicity
Hyperammonemia
Associated with nail bed abnormalities, hirsutism, alopecia
VPA clinical pearls
Contraindicated in urea cycle disorders
Pregnancy Category D
Used off-label for migraines, mood/behavioral augmentation
Felbamate used for
Focal onset seizures with or without tonic-clonic seizures
Felbamate MOA
Antagonizes N-methyl-D-aspartic acid receptors as well as GABA-A receptors
Felbamate drug monitoring
30-60 mcg/mL
Felbamate BBW
Black Box Warning for aplastic anemia and hepatoxicity
Aplastic anemia risk = >100-fold increase from general population
Felbamate clinical pearls
Only indicated for super-refractory seizures
Gabapentin used for
Adjunctive therapy in most seizure types, with the exception of absence
seizures and tonic-clonic seizures
Gabapentin MOA
Binds to alpha-2 subunit of calcium channel, with unknown effects on
seizures
Gabapentin drug monitoring
2-20 mcg/mL
Gabapentin clinical pearls
Rarely utilized in seizure disorders
Commonly utilized in:
* Neuropathic pain
* Restless leg syndrome
* Post-herpetic neuralgia
* Alcohol withdrawal
* Chronic refractory cough
Lamotrigine used for
Adjunctive therapy for focal-onset seizures without tonic-clonic motion
Lamotrigine MOA
Enhances fast inactivation of voltage-gated sodium channels
Lamotrigine drug monitoring
4-20 mcg/mL
Lamotrigine ADE
Significant interaction with valproic acid:
* Max dose of lamotrigine if on VPA: 500 mg
* Max dose if on VPA: 200 mg
Black Box Warning for dermatologic reactions (SJS/TEN)
Lamotrigine clinical pearls
Utilized for bipolar disorder, headaches, and trigeminal neuralgia
Levetiracetam used for
Workhorse of modern anti-epileptic agents
Utilized in focal-onset, myoclonic, JME, tonic-clonic seizures
* Second or third line for absence seizure
Levetiracetam MOA
inhibits synaptic vesicle SV2A which prevents neurotransmitter release
Levetiracetam drug monitoring
10-66 mcg/mL
Not correlated with clinical efficacy or safety
* Not routinely measured other than to confirm adherence
Levetiracetam ADE
Minimal drug-drug interactions
Negative behavior effects
Levetiracetam clinical pearls
100% oral bioavailability
Can be administered as an undiluted IV push
* Useful in status epilepticus
Oxcarbazepine used for
Focal-onset seizures
Oxcarbazepine MOA
Enhances inactivation of voltage-gated sodium channels
Oxcarbazepine ADE
Inhibitor of CYP 2C19 and inducer of CYP 3A4
Oxcarbazepine clinical pearls
Structural analog of carbamazepine with fewer adverse effects
* Considered safer alternative with regard to dermatologic reactions
Eslicarbazine (Aptiom) and oxcarbazepine are metabolized to same intermediary compound
Lacosamide used for
Focal-onset seizures, generalized tonic-clonic, and status epilepticus
Post-injury prophylaxis in neurologic injury/traumatic brain injury
Lacosamide MOA
Mediates voltage-gated ion channels
Lacosamide ADE
Substrate of CYP 3A4, 2C9, 2C19
Requires dose adjustment in hepatic impairment
Lacosamide clinical pearls
May be necessary to decrease doses of concomitant agents by up to 20%:
* Carbamazepine
* Phenytoin
* Phenobarbital
* Primidone
Perampanel used for
Focal-onset seizures, tonic clonic seizures
* Commonly as adjunctive therapy
Perampanel MOA
Non-competitive antagonist of glutamate receptors on post-synaptic neurons
Perampanel ADE
Black Box Warning for significant psychiatric events, including suicidal and homicidal ideation
Dose-dependent CYP enzymatic inducer
Perampanel clinical pearls
Schedule III controlled substance
Associated with weight gain
Clobazam used for
Adjunctive therapy for non-absence seizure classifications
Clobazam MOA
Binds GABA-A receptors and potentiates GABA via modulation of chloride conductance
Clobazam drug monitoring
0.03 – 0.3 mcg/mL
Clobazam ADE
BBW for profound sedation and respiratory depression in combo w/ BZD and opioids, addiction, inhibitor of CYP 2C9, inducer of CYP3A4
Clobazam clinical pearls
Schedule IV controlled substance
Moderate association with dermatologic reactions
Cannabidiol used for
Primarily used in Dravet syndrome and Lennox-Gastaut Syndrome
* More commonly being prescribed for refractory status epilepticus, NORSE, and FIRES
Cannabidiol ADE
Increases lamotrigine levels
Increases clobazam metabolite concentration by 300%
Cannabidiol MOA
Hepatotoxicity and respiratory failure are significant
May be associated with ICU delirium and poor sleep hygiene
Why is status epilepticus a medical emergency
associated w/ brain damage and potentially death
long term consequences after 30 minutes of ongoing seizure activity
status epilepticus definition
cont seizure activity for 5 minutes or multiple seizures w/out return to baseline over 5 min
(pharm resistance and mortality increase w/ prolonged duration)
Type 1 vs Type 2 SE
1: absence of structural lesions
2: presence of structural lesions
Type 1 SE causes
alcohol
systemic infection
CNS infection
metabolic dysregulation
subtherapeutic AED levels
Type 2 SE causes
anoxia/hypoxic brain injury
CNS malignancy
CVA/TIA (ischemic or hemorrhagic)
Drug overdose
TBI
pathophysiology of SE what decreases
GABA
adenosine, K, neuropeptide Y, opioid peptides, galanin
pathophysiology of SE what increases
glutamate
Ca, Na, substance P, neurokinin B
What is phase 1 of SE
0-30 min
active: E, NE, insulin, cAMP
presentation: hypertensive, tachycardia, hyper then hypoglycemia, tracheal secretions
What is phase 2 SE
> 30 min
active: lactic acid, insulin, temp, dysregulation, hypoxia, acidosis
presentation: hypotension, shock, hypoglycemia, azotemia
What labs to order before SE tx
CBC, BMP, UDS, blood cultures, ABG, drug levels
What is SE stabilization phase
ABCDE (airway, breathing, circulation, disability, exposure)
vitals
time of onset
oxygen
ECG
blood glucose (adults thiamine then dextrose)
IV assess and collect electrolytes, CBC, tox, ASM
Initial tx for SE (5-20 min)
lorazepam IV 0.1 mg/kg/dose (max 4 mg) x2
midazolam IN 0.15-0.3 mg/kg (max 10 mg) x2
midazolam IM 0.2 mg/kg/dose (max 10 mg) x2
diazepam IV 0.15-0.2 mg/kg/dose (max 10 mg) x2
diazepam IN or PR
Midazolam buccal
Second phase tx for SE (20-40 min): first line tx
Fosphenytoin IV 20 mg PE/kg (max 1500) x1
VPA IV 40 mg/kg (max 3,000 mg) x1
keppra IV 60 mg/kg (max 4,500 mg) x1
Second phase tx for SE (20-40 min): 2nd and 3rd line tx
2: Phenobarbital IV 15 mg/kg x1
3: Lacosamide IV 5-10 mg/kg (max 400 mg) x1
Third phase tx for SE (40-60 min)
begin EEG monitoring
Midazolam IV 0.2 mg/kg bolus, 0.05-2 mg/kg/hr
Phentobarbital IV 5-15 mg/kg, 0.05-5 mg/kg/hr
Propofol IV 1-2 mg/kg, 20 mcg/kg/min
BZD for SE
first line for first 30 min
diazepam is lipophilic and shirt half life (bad)
lorazepam hydrophilic (protect for 24 hr)
midazolam short half life need bolus or cont IV
Phenytoin for SE
Considered second-line agent to benzodiazepine-
refractory or recurrent seizures
ADE: bradycardia, hypotension, phlebitis
Alternatives for AED for SE
Fosphenytoin
Levetiracetam: 60 mg/kg max 4500 mg IV
Valproate: 40 mg/kg max 3000 mg IV
What is considered refractory SE
Up to 15% of patients will fail benzodiazepine + 1 ASM, and are considered refractory
What is considered super-refractory SE
seizure activity for >24 hours
Anesthetic Medications for SE
midazolam (Versed): caution w/ respiratory depression and hypotension, avoid flumazenil
Pentobarbital (Nembutal): need vent produces coma min 72 hr get neuro exam
Propofol (Diprivan): need vent, produce coma
Propofol-Related Infusion Syndrome risk factors
dose >4 mg/kg/hr
duration: >48 hr
low glycogen stores
neuro compromise (traumatic brain injury)
underlying hyper-TGL
liver disease
Potentially Useful Agents in Status Epilepticus
Ketamine (Ketalar): 0.5-3 mg/kg bolus followed by 0.1-4 mg/kg/h (increases BP and HR, increased secretions and hallucinations) use BZD
Topiramate: may use NG
New Onset Refractory Status Epilepticus: (NORSE)
No previous history of seizures or neurological disorder with out a clear metabolic or toxic cause
present w/ fever -> febrile infection-related epilepsy syndrome (FIRES)
autoimmune or infection
Goal for NORSE
keep patient stable and stop seizure activity
-Typically burst suppression on EEG with IV anesthetics is required
-May start immunotherapy early
NORSE drugs to use
Monotherapy: pentobarbital
Combination therapy: midazolam and propofol
Patient should be seizure free for 24-48 hours before weaning
IV steroids, immunoglobulin, plasmapheresis
