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Benitez CNS 1C
Benitez Epilepsy and Seizures
| Question | Answer |
|---|---|
| Seizures are? | Not a disease, but signs and/or symptoms that can result from many stimuli or disorders resulting in excessive neuronal brain activity |
| Think of a seizure as a sign/symptoms, a manifestation resulting from any number of potential stimuli or disorders that results in _____ ____ _____. | excessive brain activity.; |
| We can classify the type of seizure based on: | location, symptoms, and duration |
| Epilepsy is a ________, typically diagnosed by at least 2 unprovoked seizures | disease |
| When we broadly classify seizures we can distinguish them as being either: | “unprovoked” or “provoked”. |
| Provoked seizures have a suspected _____ ______ | underlying cause *For example, seizures can occur in patients going through alcohol withdrawal. *These seizures would be classified as provoked since we know that alcohol withdrawal is the underlying cause and provoking factor. |
| Other examples of "Provoked seizures could arise from: | Alcohol/benzodiazepine withdrawal, acute neurologic illness (eg. brain hemorrhage), or systemic illness (eg. hypocalcemia, hypoglycemia, uremia, high temperature fever), medications |
| To summarize…think of seizures as a __/______ and epilepsy as a_____ All patients with epilepsy will experience seizures, but not all patients that experience seizures have epilepsy (remember that many factors can cause provoked seizures). In fact, seizures are much more common than epilepsy and about 1 in 10 people will experience a seizure at some point during their life | sign/symptom; disease |
| First way to classify a seizure is based on the _______ of onset | location *Seizures can either occur in just one hemisphere of the brain or they can quickly spread to both hemispheres |
| The correct terminology for a seizure limited to ONE HEMISPHERE is a: | Focal (Partial) Onset |
| Seizures affecting both hemispheres are classified as: | Generalized Onset |
| Next we can classify based on symptoms the patient is experiencing during the seizure. One thing we look at is whether or not ______ or _______ is maintained | awareness or consciousness *Patients experiencing focal onset seizures may be able to maintain awareness through the seizure which we would classify as a “focal aware seizure”. |
| If a patient loses consciousness or awareness this is termed “impaired” so the patient would have a: | “focal impaired seizure”. |
| Generalized seizures will result in _____ _______, so classification based on awareness is more important for focal seizures. | impaired consciousness |
| We can also classify seizures based on whether the symptoms experienced during the seizure are predominantly ____ or __-_____ symptoms | motor or non-motor |
| Benitez wants us to be aware that “tonic-clonic seizures” (also called “grand mal” seizures) are an example of a generalized _____ _____ and that “absence seizures” are generalized ___-_____ _____ | motor seizure; non-motor symptoms. |
| Classification Vocabulary: Tonic is? | sustained increase in muscle contraction (stiffening) |
| Classification Vocabulary: Atonic is? | sudden loss of muscle tone |
| Classification Vocabulary: Clonic is? | sustained rhythmic jerking of limbs, and often head, face, and trunk (also called muscle contractions or convulsions) |
| Variance of Seizures: Absence Seizures are: | Generalized onset, non-motor seizures, patient unresponsive; Characterized by sudden interruption of ongoing activities, a blank stare, and possible a brief upward deviation of the eyes; Duration of a few seconds to 30 seconds *Benitez note: may commonly go undiagnosed as someone may view the patient as zoning-out or not paying attention, when in fact a seizure is occurring. |
| Variance of Seizures: Tonic-Clonic | -Generalized onset, motor seizure, patient unresponsive (Grand mal seizure) -Characterized by a sequence consisting of a tonic (muscle contraction) followed by a clonic phase (sustained rhythmic jerking) -Duration of 1-3 minutes Notice the duration is much longer than Absence seizures but still short overall, lasting 1-3 minutes. |
| Notice the duration is much longer in Tonic-Clonic seizures than Absence seizures but still short overall, lasting 1-3 minutes. Again, consciousness/awareness has been _____ as these are generalized seizures. Here you can see the muscle contraction and rhythmic jerking movements that are characteristic of tonic-clonic seizures. | LOST |
| Variance of Seizures-Focal Aware: | -Focal onset, patient aware/conscious (previously called “simple partial”), can be further classified as motor or nonmotor onset (video shows motor onset) -Person maintains awareness during seizure, though may be “frozen” or unable to respond -Focal seizures can be accompanied by cognitive symptoms (feelings of déjà vu, hallucination, or forced thinking) or emotional symptoms (anxiety, fear, anger, joy, laughing, or crying) -Duration of < 2 minutes |
| Even though awareness is maintained in focal aware seizures, it does not necessarily mean the patient will be able to respond. Patients may be _______ during the seizure but upon completion of the seizure they are able to recall the event. These seizures can be associated with cognitive and emotional _____ as well. Duration remains brief and is comparable to tonic-clonic seizures | Frozen; symptoms |
| Duration of Seizures can vary based on: | the type of seizure Seizures are typically brief and most do not exceed 2 minutes |
| *Status epilepticus is any seizure that last over __ minutes Classifued as either ______ or _______. **especially dangerous and is considered a medical emergency -Death or extensive brain damage can occur without prompt treatment | 5; (or multiple consecutive seizures that occur over 5 minutes without recovery) Convulsive; Nonconvulsive |
| Complexity of Seizure Classification: | 1. Not all seizures are easy to recognize 2. Diagnosis/classification is multifactorial 3. Focal onset seizures can sometimes precede generalized onset seizures 4. The same patient can experience multiple types of seizures |
| Diagnosis/Classification is multifactorial for Seizure classification: Subjective (1) Objective (2) | Subjective: Medications (including OTC or illicit substances) and alcohol use -Eyewitness description of seizure -Patient description of seizure (if aware), or events preceding/ following seizure Objective: Neurologic exam Electroencephalogram (EEG): measures the electrical activity in the brain Neuroimaging (MRI or CT scan) Blood testing (eg. blood glucose levels) |
| Why is it important to classify seizures? | important as it helps to guide treatment; *For example, patients with focal onset seizures are often candidates for surgical resections while those with generalized onset are not. There are also certain medications where use is based on the type of seizure. For example, ethosuximide is indicated specifically for Absence seizures and is usually ineffective for other seizure types. |
| Epilepsy can also be classified and is largely dependent on? | SEIZURE CLASSIFICATION |
| Epilepsy is a disease characterized by _____ _______ to generate epileptic seizures | enduring predisposition |
| Epilepsies are clinically interpreted as: | 1. At least 2 unprovoked (or reflex) seizures occurring > 24 hours apart 2. One unprovoked (or reflex) seizure and a probability (≥ 60%) of further seizures occurring over 10 years 3. Diagnosis of epilepsy syndrome *"Reflex” indicates a tendency to respond repeatedly to a given seizure-inducing stimuli (eg. photic stimulation of seizures) *maintain enduring predisposition and *no reversible factor |
| Epidemiology of Epilepsy: | -4th most common neurologic disorder (following stroke, migraine, and Alzheimer’s disease) -Prevalence between 1%-3% -Highest number of new cases occur in childhood (under age 5) and in the geriatric population |
| Etiology of Epilepsy: | Unknown for about 50% Genetic Structural/functional change or damage to the brain (i.e. present at birth, scarring from infection (meningitis, viral encephalitis), head injuries 2/2 motor vehicle accidents), CVA/TIA, Brain tumor, Alzheimer's, Autism spectrum disorder) |
| Provoked Seizures also called ____ _____ or acute symptomatic seizures. *Transient Factor acting on an otherwise normal brain to ______ _____ the seizure threshold. | “reactive seizures;" temporarily lower |
| Many factors could potentially cause a provoked seizure: Acute neurologic illness (eg. brain hemorrhage); Acute systemic illness (eg. hypocalcemia, hypoglycemia, uremia, high temperature fever): Medications such as: | **Alcohol/benzodiazepine withdrawal Medications that lower the seizure threshold *Reversible factor is present |
| Lowering the Seizure Threshold--> Medications such as: | *Analgesics (tramadol, meperidine) *Antibiotics & antivirals (eg. penicillins, cephalosporins, fluoroquinolones, carbapenems, amantadine, ganciclovir) *Anticholinergics (eg. diphenhydramine overdose) *Antipsychotics (eg. *clozapine, olanzapine, quetiapine) *Antidepressants (*bupropion, SNRIs, TCAs, and SSRIs) Drugs of abuse (cocaine, amphetamines, ketamine) *Abrupt discontinuation of alcohol, benzodiazepines, other sedatives, or medications used to treat seizures |
| Lowering the Seizure threshold Conditions are: | Sleep deprivation Stress Alcohol intoxication Menstruation Infection and fever |
| Greatest risk with medications that may lower the seizure threshold are: | High doses/overdose (except tramadol) Renal/hepatic impairment Elderly Multiple medications that lower threshold History of seizures or predisposing risk factors |
| Treating Provoked Seizures: Treating the underlying cause | Treat acute illness (neurologic or systemic) If medication induced: lower dose, discontinue medication (tramadol), dose adjust per renal/hepatic impairment In patients with epilepsy: If possible, avoid medications that can lower the seizure threshold Adjust accordingly if suspected that seizures are worsening due to medication Provide appropriate treatment for alcohol/benzodiazepine withdrawal |
| Treatment of Epilepsy & Antiepileptic Medications: Pharmacologic options include Levetiracetam which can? | Inhibit NT release (synaptic vesicle protein) |
| Treatment of Epilepsy & Antiepileptic Medications: Pharmacologic options such as Topiramate or Zonisamide which can act as? | Carbonic Anhydrase inhibitors |
| Treatment of Epilepsy & Antiepileptic Medications: Pharmacologic options for inhibiting Na+ channels which include what drugs? | Carbamazepine Oxcarbazepine Lacosamide Lamotrigine Phenytoin Topiramate |
| Treatment of Epilepsy & Antiepileptic Medications: Pharmacologic options for AMPA Blockade including which drugs? | Topiramate Perampanel |
| Treatment of Epilepsy & Antiepileptic Medications: Pharmacologic options for inhibiting Ca2+ channels such as which drugs? | Ethosuxamide Gabapentin/Pregabalin |
| Treatment of Epilepsy & Antiepileptic Medications: Pharmacologic options for inhibiting Na+ and Ca2+ channels? | Valproic Acid Zonisamide |
| Treatment of Epilepsy & Antiepileptic Medications: Pharmacologic options for GABA activity include which drugs? | Benzodiazepines Phenobarbital Tiagabine/Vigabatrin Topiramate Valproic acid Zonisamide |
| Selection of Therapy for drug choices comes down to? | Safety (AE, Pt-specific factors related to safety) Efficacy (Type of seizure, Pt-specific efficacy) |
| Levetiracetam (Keppra) is what kind of dinosaur? Dose to remember? | Brachisaurus; **initial: 500 mg BID or 1,000 mg daily (XR); increase by 500 mg per dose (IR) or 1,000 mg per dose (XR) every 2 weeks up to max of 3,000 mg/day, can be given IV as well |
| Warnings for Levetiracetam (Keppra, XR) are? | **Behavioral abnormalities and psychotic symptoms (highest risk in children) Severe skin reactions (SJS/TEN) and Drug Reactions with Eosinophilia and Systemic Symptoms (DRESS) reactions (rare compared to other antiepileptic medications) Hematologic abnormalities **Remember B for brachiosaurs; (Behavioral abnormalities and psychotic symptoms) |
| Adverse Effects of Levetiracetam (Keppra) are? | Drowsiness, fatigue, behavioral problems (highest risk in children, include agitation, anger, anxiety, emotional lability, irritability), headache, weakness, GI-related effects (highest risk in children), diplopia (low risk) |
| Gabapentin and Pregabalin are what kind of dinosaur? Its an Antiepileptic drug but used more commonly for other indications. Don't worry about dosing but what is the CrCl dosing cut-off for the 2 drugs? | Mosasaurus; <60 |
| Warnings for Gabapentin (Neurontin) (1) and Pregabalin (Lyrica) (2) to know are: AE are (3): | 1. multiorgan hypersensitivity (DRESS) reactions (rare) 2. angioedema (rare), **peripheral edema 3. *Drowsiness,*dizziness, *fatigue, *peripheral edema (highest with pregabalin), mood changes, weight gain, diplopia, blurred vision, dry mouth *Think Water or Fluid with Gabapentin and Pregabalin (only water-dwelling dinosaur "Mosasaurus (Peripheral edema, renal dose adjustments) |
| Topiramate (Topamax) is what kind of dinosaur? Dosing? | Stegosaurus; requires SLOW DOSE DITRATION (initial 25 mg BID, increasing by 50 mg *WEEKLY to max of 400 mg/day *Higher dosing than for migraine prophylaxis (max recommended generally 100 mg/day) |
| Warnings for Topiramate are? | -Metabolic acidosis (22 CAI (consider dose reduction/DC if chronic) -Oligohydrosis (reduced perspiration/Hyperthemia), children -Nephrolithiasis (kidney stones) -Hyperammonia -Visual field defects and ophthalmic effects (reversible and may require discontinuation) -Weight loss/anorexia |
| Adverse effects of Topiramate are? | Paresthesia (especially in adults), *somnolence, *dizziness, *fatigue, psychomotor slowing, *cognitive problems (difficulty with memory/concentration/attention) GI effects (abdominal pain, nausea, diarrhea) Dietary considerations--> ketogenic diet may increase risk of acidosis and/or kidney stones |
| Remember Topiramate Think of MOHAWK--> All on top like the spine of a stegosaurus | M: Migraine Prophylaxis O: Oligohydrosis & hyperthemia H: Hyperammonia A: Acidosis (metabolic acidosis) W: Weight loss/anorexia K: Kidney stones (nephrolithiasis) |
| Lamotrigine (Lamictal) is what kind of dinosaur? Dosing is based on concimitant medications (comes in 3 starter kits that are color coated? Orange (1) Blue (2) Green (3) | Triceratops; Requires SLOW DOSE TITRATION; 1. No interacting medications 2. Valproic Acid (inhibitor) 3. Carbamazepine, Phenytoin, phenobarbital, or primidone (inducer) |
| Lamotrigine (Lamictal, XR) Orange has no concerning medications and has a dose during week 1 and 2 at (1)? Maintenance dose of orange? (2) | 1.) 25 mg daily 2.) 225 to 375 mg daily in 2 divided doses |
| Lamotrigine (Lamictal, XR) Blue is given with Valproic Acid (inhibitor) Week 1 and 2 dose is (1)? Usual maintenance dose (2)? | 1.) 25 mg every other day 2.) 100 to 200 mg daily in 1-2 divided doses |
| Lamotrigine (Lamictal, XR) Green (Carbamazepine, etc) week 1 and 2 dose is (1)? Usual maintenance dose (2)? | 1. 50 mg daily 2. 300 to 500 mg daily in 2 divided doses |
| Boxed warnings of Lamotrigine are? | Boxed Warning: Serious Skin Rashes (including SJS/TENS) Risk may be increased if *higher initial dose or *faster dose titration. Higher risk in *pediatric patients Benign rashes can occur; not possible to reliably predict if rash will be serious/life-threatening Recommended that drug be *immediately discontinued at first sign of rash (unless clearly not drug related) |
| General warnings of Lamotrigine are? | Blood dyscrasias, multiorgan hypersensitivity (DRESS) reactions, aseptic meningitis |
| Side effects to know for Lamotrigine are? | N/V, *drowsiness/*insomnia *(associated with less daytime sleepiness than other AEDs), rash (incidence of non-serious rash around 7%)*, ataxia, impaired coordination, dizziness, changes in mood, ophthalmic changes |
| Remember Lamotrigine (Lamictal) think of __ horns and S for SICK. | 3 (representing a dosing strategy based on concomitant meds) SICK--> SERIOUS SKIN RASHES (careful with dosing due to boxed warning) |
| Oxcarbazepine (Trileptal, Oxtellar XR) is what kind of dinosaur? Dosing? | Tyrannosaurus Rex; increase weekly up to max of 2,400 mg/day Dose adjust for CrCl < 30 mL/min |
| Warnings for Oxcarbazepine are? | **SJS/TEN (consider screening patients of Asian descent for *HLA-B*1502 prior to initiating) Multiorgan hypersensitivity (DRESS) reactions **Hyponatremia Hypothyroism |
| Adverse effects of Oxcarbazepine to know are? | **Dizziness (12-36%), drowsiness (20-49%), N/V (15-29%), abdominal pain (10-13%), diplopia/visual disturbances (10-40%), ataxia (2-31%), tremor (4-16%) |
| Remember Oxcarbazepine--> think "little arms" and can't reach SALTY snacks--> | Hyponatremia (bolded warning from Benitez) |
| Carbamazepine (Tegretol) is what kind of dinosaur? Dosing requires? | Indominus Rex **Remember weekly intervals--> 200 mg BID; max 1600 mg/day (increase dose by 200 mg/day in weekly intervals) |
| Boxed warning for Carbamazepine is? | *Serious dermatologic reactions and HLA-B*1502 allele (patients of Asian descent should be tested for HLA-B*1502 prior to initiating); If positive, carbamazepine should not be used *Aplastic anemia and agranulocytosis |
| Warnings for Carbamazepine to know (1)? AE (2)? | 1. HEPATOXICITY 2. Dizziness (44%), drowsiness (32%), N/V (18-29%), ataxia (15%), dry mouth (mild anticholinergic effects), blurred vision, rash, increased LFTs Changes in mood/thinking (may activate latent psychosis and/or cause confusion/agitation) |
| Dose conversion of Carbamazepine to Oxcarbazepine? | 1.2-1.5 x carbamazepine dose |
| Remember Carbamazepine (Tegretol) think LAB since its created in a lab and A for apex predator. Lab for? | 1. Lab= Liver (hepatotoxicity) 2. HLA*B 1502 allele testing recommended (serious dermatologic reactions) – boxed warning A for apex predator = Aplastic Anemia & Agranulocytosis - boxed warning |
| Comparison of Carbamazepine (1) vs Oxcarbazepine (2) | 1. -Generally, more adverse effects and *less tolerable -Risk of hepatotoxicity (think “lab” = “liver” -HLA-B1502 testing *RECOMMENDED* (greater risk of severe skin rxns) -Lower risk of hyponatremia 2. -Generally, less adverse effects and more tolerable -Low risk of hepatotoxicity, may increase liver enzymes -HLA-B1502 testing *CONSIDERED* (lower risk of severe skin rxns) -Higher risk of hyponatremia* |
| Phenytoin (Dilantin) is what kind of dinosaur? Dosing considerations for Phenytoin (Dilantin)/ Fosphenytoin (Cerebyx)? | Dilophosaurus; Doses should only be *adjusted every 7-10 days* Fosphenytoin available as *IM/IV only; *dosed in phenytoin equivalents (PE): 1 mg PE = 1 mg phenytoin (fosphenytoin 1.5 mg = 1 mg PE)* |
| Boxed warnings for Phenytoin? | *Cardiovascular risk associated with rapid infusion* (injection) Rate of IV administration should not exceed *50 mg/min in adults (risk of *severe hypotension and cardiac arrhythmias)* *Fosphenytoin should not exceed *150 mg PE/min or 2mg PE/kg/min |
| General warnings to know for Phenytoin and Fosphenytoin? | -*Blood dyscrasias* (wide spectrum) -*Cardiovascular events*: cardiac monitoring recommended during and after IV administration (use oral when possible), slow infusion -*SJS/TEN*: caution in Asian patients, avoid use if + HLA-B1502 allele (screening prior to initiation not required) -Extravasation: inject slowly and into large vein -*Hepatotoxicity* -Lymphadenopathy -Multiorgan hypersensitivity reactions |
| AE of Phenytoin and Fosphenytoin? | *CNS effects: ataxia, poor coordination, drowsiness, slurred speech, confusion, mood changes (dose related) *GI effects: constipation, nausea, vomiting **Gingival hyperplasia** *Dermatologic effects: (bullous dermatitis, exfoliative dermatitis, hypertrichosis *(excessive hair growth) *Rash (5-10%) *Ocular effects: nystagmus, diplopia/blurred vision (dose related) |
| Toxicity with Phenytoin and Fosphenytoin? | Levels above optimal range: *nystagmus, *ataxia, *blurred vision, confusion, delirium, psychosis |
| Phenytoin and Fosphenytoin may cause drug induced Hyperplasia caused with what agents? | -Antiepileptics (phenytoin) -Immunosuppressants (cyclosporine) -Calcium channel blockers (nifedipine) |
| Remember Phenytoin (dilantin): Think “lab” since Dennis was escaping from the lab, “head”, and “heart” | 1. Lab= Liver (hepatotoxicity) 2. For head we think of… -Gingival hyperplasia -Hair growth 3. Heart = CV risks with rapid infusion – boxed warning |
| Valproic Acid and Derivatives, we think of what dinosuars? Dosing reqirements? | Velociraptors **Weekly intervals--> 10-15 mg/kg/day; max 60 mg/kg/day (oral and IV formulations) Titrate by 5-10 mg/kg/day at weekly intervals; use actual body weight for dosing Not recommended for use in hepatic disease |
| Valproic Acid/Valproate (Depakene,Stavzor, Depacon) Divalproex (Dapakote, Depakote DR/ER)--> formulation considerations? | Depakote available in delayed-release (DR) & extended-release (ER) Conversion from DR to ER requires dose adjustment (not bioequivalent): increase total daily dose by 8-20% when converting to ER) |
| Efficacy and Safety of Valproic Acid and derivatives?Formulations? | Efficacy: all formulations have similar efficacy, with variance between patients If specific formulation is working, best not to switch between formulations Safety: divalproex generally better tolerated than valproic acid (GI effects) and DR/ER formulations better tolerated |
| Boxed warnings of Valproic Acid and derivatives? | Hepatotoxicity (first 6 months of tx (especially high in children <2); Monitor symptoms (may be non-sepcific); Jaundice, abdominal pain, faitgue, weakness, facial edema, anorecia, decreased appeteite, V; LFTs obtained prior to initiation then at regular intervals (frequent during FIRST 6 months) |
| Other Boxed warnings for Valproic acid and derivatives include? | Fetal risk Major congenital malformations (esp. neural tube defects), decreased IQ scores Pancreatitis Life-threatening pancreatitis (range from shortly after initiation to after years of use) Monitor symptoms: abdominal pain, nausea, vomiting, anorexia Mitochondrial disorders (increased risk of liver failure in pts with mitochondrial disorders) |
| CI of Valproic Acid and derivatives? | *Hepatic disease* (not recommended in mild-mod; contraindicated in severe) Urea cycle disorder or known mitochondrial disorders (mutations in DNA polymerase gamma) **Pregnant women if indication of migraine prophylaxis** |
| General warnings to know of Valproic acid and derivatives? | -Blood disorders: dose-related thrombocytopenia, inhibition of platelet aggregation, bleeding -Hyperammonemia/encephalopathy (CI in urea cycle disorders) |
| AE of Valproic Acid and derivatives include? | drowsiness (7-30%), dizziness (12-25%), *Thrombocytopenia (1-27%, dose related); *AST/ALT elevations; *Tremor (≤57%), weakness; *Visual disturbances: diplopia, blurred vision |
| Remember Valproic acid and derivatives: Think “P for Pack” since raptors are pack hunters and think “kids”; Think LAB, since raptors are always in the lab; Think Jealous since raptors like being the star of the show--> Jealous = envious of the stegosaurus (topiramate) and it’s “mohawk” and steals the "M" and "H" | *1. Pack= Pancreatitis (boxed warning) and Platelets (thrombocytopenia) *2. Kids = not kid friendly (boxed warning for fetal risk) *3. LAB= LIVER (hepatotoxicity (boxed warning) *4. Jealous: M--> migraine prophylaxis; H--> hyperammonemia |
| Phenobarbital Warnings include? Adverse effects of Phenobarbital? | 1. *CNS depression (impaired mental/physical abilities), *respiratory depression, *abuse risk 2. rash (SJS), *drowsiness, dizziness |
| Zonisamide (Zonegran): dose? Warnings? | 100 mg/day, increase after 2 weeks; max of 600 mg/day (no evidence of improved response > 400 mg/day) *use not recommended if GFR < 50 mL/min* 2. metabolic acidosis, *caution if sulfonamide allergy* (low risk of cross-reactivity) |
| Adverse effects of Zonisamide (Zonegran)? | *Drowsiness, *dizziness, *anorexia, *rash *(SJS/TENs), *nephrolithiasis (kidney stones), oligohydrosis/hyperthermia (primarily in children) *carbonic anhydrase inhibitor, adverse effects similar to topiramate |
| Ethosuxamide (Zarontin) AE incliude? | N/V, abdominal pain, anorexia,/weight loss, blood dyscrasias *caution in renal or hepatic impairment |
| Tiagabine (Gabitril) AE? | Dizziness, drowsiness, tremor, accidental injury, rash (SJS) *caution in hepatic impairment |
| Lacosamide (Vimpat) warnings? AE? | 1. CV effects (prolong PR interval, arrhythmias) *not recommended in severe hepatic impairment 2. Dizziness, headache, nausea |
| Eslicarbazepine (Aptiom) Warnings? AE? | 1. Hyponatremia 2. Dizziness, drowsiness, HA, Nausea, diplopia; *Active metabolite of oxcarbazepine; similar adverse effects |
| Antiepileptic medications carry considerable ___ ___ Careful monitoring and follow-up are essential to maintaining patient safety Therapeutic drug monitoring used for certain medications | safety risks |
| Warnings associated with Antiepileptics: Common AE? | CNS depression; Blood dyscrasias/hematologic changes; Drug rxn w/ Eosinophilia and Systemic Symptoms (DRESS) |
| Warnings associated with Antiepileptics: Monitoring? | Symptoms from pt when medication is initiated or titrated; CBC count w/ differential; Fever, rash, lympadoenopathy; signs of other organ system involvement (hepatitis, hematologic abnormalities) |
| Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) seen with which drugs? | Lamotrigine, levetiracetam, carbamazepine, oxcarbazepine, phenytoin, lacosamide, valproic acid, ethosuximide, eslicarbazepine, zonisamide |
| Blood dyscrasias/hematologic changes seen with which drugs? | Carbamazepine, oxcarbazepine, phenobarbital, lamotrigine, phenytoin, valproic acid, eslicarbazepine, ethosuximide, zonisamide |
| CNS depression seen with which meds? | Class effect but extent of impairment can vary between patients |
| Warnings associated with Antiepileptics: Common AE: SJS/TEN seen with which antiepileptics? | Highest risk with: carbamazepine, phenytoin, phenobarbital, and lamotrigine |
| Warnings associated with Antiepileptics: Common AE: Suicidal Ideation (FDA issued warning) seen with which drugs? | Warning given as class effect, risk appears to be greatest with topiramate and lamotrigine |
| Warnings associated with Antiepileptics: Common AE: Decreased bone mineral density (hypocalcemia, low vitamin D) monitor for (1)? Which drugs? | 1. Bone health every 2-5 years including Vit D levels. Recommend daily Ca2+ and Vit D intake 2. General class effect, risk is greatest with enzyme inducing agents (phenytoin, phenobarbital, and carbamazepine) and valproic acid |
| Warnings associated with Antiepileptics: Common AE: Vision-related AE in which drugs? | most antiepileptics have been associated with ophthalmic-related adverse effects |
| Unique AE/Warning of: Metabolic acidosis, nephrolithiasis, oligohydrosis? | Topiramate; Zonisamide |
| Unique AE/Warning of: Weight loss/anorexia? | Topiramate, zonisamide, ethosuximide |
| Unique AE/Warning of: Hyperammonia? | Topiramate, valproic acid |
| Unique AE/Warning of: Hyponatremia? | Oxcarbazepine and eslicarbazepine (metabolite of oxcarbazepine), and to a lesser extent carbamazepine |
| Unique AE/Warning of: Cardiovascular concerns? | Carbamazepine (conduction abnormalities) Pregabalin (peripheral edema) Phenytoin (CV risk associated w/ rapid infusion) Lacosamide (prolong PR interval, arrhythmia risk) |
| Unique AE/Warning of: Gingival hyperplasia & excessive hair growth? | Phenytoin |
| Unique AE/Warning of: Pancreatitis? | Valproic Acid |
| Unique AE/Warning of: Hepatotoxicity? | Valproic acid, phenytoin, carbamazepine |
| Drug-induced Hematologic Changes: Blood Dyscrasias (generic term for blood abnormalities) seen in which drugs? Agranulocytosis (loss of WBC, esp neutrophils) (2)? Thrombocytopenia (loss of platelets) (3)? Aplastic anemia (loss of all cell lines) (4)? | 1. Carbamazepine; Valproic acid 2. Carbamazepine 3. Valproic Acid 4. Carbamazepine |
| SJS and TEN are? | Severe skin reaction characterized by hemorrhagic erosions, erythema, and epidermal detachment *Considered medical emergency with mortality rates of 1-5% for SJS and 25-35% with for TENS *Most common cause = medications* |
| List of High risk Long-term Medications for SJS and TEN? | Carbamazepine; Phenytoin; Phenobarbital; Lamotrigine; Valproic acid and oxcarbazepine (Lower risk) |
| Counseling on SJS and TEN? important during DRUG INITIATION--> | -Highest incidence within the first 2 months of treatment -Risk may be increased if higher initial dose/faster titration -If SJS/TEN is suspected, stop causative drug immediately -Causative drug should NOT be reinitiated |
| Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) can be? | Potentially fatal (mortality rate around 10%) Presentation can vary widely between patients: General symptoms: fever, rash, lymphadenopathy, facial swelling Signs of specific organ involvement: hepatitis, nephritis, hematologic abnormalities (eosinophilia), myocarditis -Onset typically 2 – 8 weeks after medication initiation -If DRESS is suspected, stop causative drug immediately |
| Tips to remember AED class effect Think DINO ATTACK--> | Eyes (vision related AE); Skin (Skin rxn/hypersensitivty rxns); Blood (Hematologic changes); Bones (decreased bone mineral density and fracture risk); Depressed (CNS depression/Suicidal ideation) |
| TDM: Carbamazepine--> Therapeutic range? | 4-12 mcg/mL |
| TDM: Phenytoin--> Therapeutic range? | 10-20 mcg/mL (total); 1-2 mcg/mL (free) **Highly protein bound, if albumin is low ; total levels will underestimate the amount of free/unbound drug |
| TDM: Valproic Acid: | 50-100 mcg/mL (total) **Highly protein bound, if albumin is low ; total levels will underestimate the amount of free/unbound drug |
| TDM: Level typically taken as a trough, prior to next dose (may check random if concerned for toxicity). Circumstances where levels are commonly checked include: | Following medication initiation (can be difficult to predict steady state) Carbamazepine checked within 3-5 days and again at 4 weeks (autoinduction)** -dosage changes or changes in route of administration -medication interaction -concern for toxicity -concern for decreased efficacy (i.e increased seizure frequency) |
| Phenytoin PK exhibits? | -Michaelis-Menten kinetics (saturable, zero-order) -*Increase in dose will disproportionately increase drug concentration at steady state Dose adjustments should be made in **small increments** |
| Antiepileptic medications are associated with: | significant drug interactions Interactions occur between different antiepileptic medications as well as with medications in other classes |
| Carbamazepine? Enzymatic effects? Interactions? | 1. Inducer of 1A2, 2C19, 2C8/9, 3A4 (strong), P-gp, and an autoinducer 2. Extensive, including other antiepileptic medications and oral hormonal contraceptives* *avoidance of oral hormonal contraceptives is recommended |
| Oxcarbazepine? Enzymatic effects? interactions? | 1. Inducer of 3A4 (weak) and substrate, NOT an autoinducer 2. Less extensive than carbamazepine, *can decrease concentration of oral hormonal contraceptives* *Strong 3A4 inducers decrease oxcarbazepine concentrations **avoidance of oral hormonal contraceptives is recommended |
| Phenytoin? Enzymatic effects? Interactions? | 1. Inducer of 2B6, 2C19, 2C8/9, 3A4 (strong), P-gp 2. Extensive, including other antiepileptic medications and oral hormonal contraceptives* *avoidance of oral hormonal contraceptives is recommended |
| Phenobarbital? Enzymatic Effects? Interactions? | 1. Inducer of 1A2, 2A6, 2B6, 2C9, and 3A4 (strong) 2. Extensive, including other antiepileptic medications and oral hormonal contraceptives* *avoidance of oral hormonal contraceptives is recommended |
| Topiramate? Enzyme Effects? Interactions? | 1. Inhibitor of 2C19 (weak), inducer or 3A4 (weak) 2. Less extensive than other strong inducers, decrease concentration of oral hormonal contraceptives* *avoidance of oral hormonal contraceptives is recommended |
| Enzyme Inhibitor--> Valproic Acid? Enzyme Effects? Interactions? | 1. Inhibitor of 2C9 (weak) 2. Less extensive, but can increase levels of lamotrigine, phenobarbital, phenytoin, and warfarin Hormonal contraceptives can decrease serum concentrations of valproic acid (monitor levels when starting or stopping) *Hormonal contraceptives can also decrease Lamotrigine levels* |
| Interactions b/w medications: Majority of antiepileptic medications either _____ or _______ various CYP enzymes or they are susceptible to the effect of DI (Lamotrigine | inhibit; induce -Extensive interactions exist between various antiepileptic medications -ALWAYS run an interaction check and adjust/monitor accordingly -Many interact with hormonal contraceptives |
| Monitoring for interactions between medications is essential: Safety? Efficacy? | 1. Adverse events associated with increased serum conc. 2. Loss of seizure suppression (associated with decreased conc. *Lamotrigine (Keppra)--> lower drug interaction concern* |
| The majority of antiepileptic medications are associated with _____ _______. | significant teratogenicity |
| Remember Valproic Acid: Pregnancy risk factor? | X (migraine prophylaxis)/D (all other indications). Risk of major congenital malformations including neural tube defects (spina bifida), cardiac & limb malformations, and decreased IQ scores |
| Pregnancy risk factor letter for 1. Topiramate? 2. Phenobarbital? 3. Phenytoin? 4. Oxcarbazepine? 5. Carbamazepine? | 1. D 2. D 3. D 4. less available data 5. D |
| Pregnancy Considerations: Counsel women of: | child-bearing age (use of contraception & teratogenic effects) -Avoiding oral hormonal methods of contraception preferred |
| Pregnancy considerations: If antiepileptic medication is needed: | Monotherapy preferred (risk of teratogenicity highest with polypharmacy) Medication with lower associated risks preferred -recommend Folic Acid (risk of neural tube defects) |
| AAN (American Academy of Neurology) Pregnancy Recommend avoidance of: | Valproic acid (Level B) -Phenytoin (Level C) -Phenobarbital (Level C) -Antiepileptic polytherapy (Level B) -Avoidance is recommended during entire pregnancy and especially during the first trimester |
| Antiepileptic medications should always be adjusted/titrated slowly. Rapid dose increases can increase risk of: | AE and rapid dose decreases can increase risk of seizures |
| Dose Titration and D/C: Follow the recommended dosing titration for each medication--> As medication increases, patient should monitor for: | -Adverse effects or toxicity -Decrease in seizure frequency |
| Dose Titration and D/C: As medication decreases, patient should monitor for: | -Increase or recurrence in seizure frequency |
| Patients may consider discontinuing antiepileptic medication if seizure free ≥2 years, if this is done--> | -Medication should be tapered slowly (over at least 3 months) -If on multiple medications, only one medication should be tapered at a time |
| Certain antiepileptic medication can be administered in the inpatient setting as *IV loading doses *for various indications (status epilepticus, seizure prevention post traumatic brain injury, etc.), these include: | Phenytoin; Valproic acid; Phenobarbital; Levetiracetam |
| Summary of AED lessons--> | -Dangerous (adverse effects, warnings, toxicity) -Drug interactions -Teratogenicity -Slow dose adjustments **Remember Keppra (Fewer safety concerns, DI concerns, and Safer in pregnancy** |
| Selection of Therapy: First unprovoked Seizure: | -Early initiation of antiepileptic shown to reduce recurrence in the first 2 years -Highest risk of recurrence in the first 2 years; Decision to initiate therapy after a first unprovoked seizure is based on estimations of individual risk of seizure recurrence -*1st unprovoked seizure = may or may not require treatment -*2nd unprovoked seizures = typically requires treatment |
| Selecting an Antiepileptic Medication: Based on--> | Seizure Type and Pt-specific factors; AE and warnings (safety and tolerability); CI; DI |
| General rules of Tx: | 1. Monotherapy preferred; -If no response to initial medication (after titrating), try monotherapy with a different medication -New medication is often titrated up gradually while the first medication is titrated down gradually; 2. Adjunctive therapy considered if 2 monotherapy trials are unsuccessful 3. Preference given to medications with fewer adverse effects/warnings 4. Always take drug interactions into consideration |
| When selecting a medication, recognize that some options are considered broad spectrum and work for a wide-range of seizure types such as (1): -while others are considered narrow-spectrum and have more limited scope of use (2): | 1. i.e. Valproic Acid and Lamotrigine 2. Ethosuximide |
| Pediatric population--> Febrile seizures are common in children between ages | 6 months to 5 years (2-5%) -Provoked seizures (antipyretics will not prevent occurrence but may improve comfort) Generally benign and do not require treatment with antiepileptic medication |
| Most common types of epilepsy in the pediatric population are? | Benign Childhood Epilepsy with Centro-Temporal Spikes (BECT) and Childhood Absence Epilepsy (CAE) *Attention and learning problems are common among children with epilepsy *Around 50% of children will outgrow their epilepsy |
| Pediatric population--> Medications may affect pediatric patients differently such as which drugs? | Topiramate and zonisamide can cause reduced sweating in young children (limit exposure to the sun) Risk of lamotrigine-induced rash, including SJS/TENS is highest in young children Always check medications for pediatric-specific concerns and counsel patient/caregiver |
| Pediatric patients may have difficulty swallowing pills. If needed, recommend: | easy to swallow formulations (ODT, oral solution, chewable tablets, etc) |
| Treatment resistant Epilepsy--> 2/3 of patients will be seizure free following the 1st or 2nd antiepileptic medication however: | 1/3 of patients will have treatment resistant epilepsy *Only 5-10% achieve control with more/alternative medications *Alternative strategies should be considered in treatment resistance |
| Alternative options to Tx Resistant Epilepsy: (1) Ketogenic diet; (2) Surgical Intervention: (3) Neurostimulation (vagus Nerve Stimulation) | 1. *pediatric patients who have not responded to medications (highly restrictive diet) 2. Generally reserved for patients with *focal epilepsy* who have *not responded to medications* (options do exist for generalized, but are much more limited) 3. Considered as adjunctive therapy in patients with *focal epilepsy who have *not responded to medications* and are *not suitable for surgical intervention* |
| Alternative options for Tx resistant epilepsy: Medical Marijuana -Epidiolex (Cannabidiol, CBD) FDA approved in 2018--> | Bottom line: use is controversial, more studies are needed. Try FDA approved pharmacologic options first and always consult with your physician if considering use. Currently FDA approval of Epidiolex is limited to specific epilepsy syndromes |
| Tx Resistant Epilepsy--> If meds don't work, explore more options. Uncontrolled seizures can increase risk for harm, physical injury, accidental death, and: | sudden unexpected death in epilepsy (SUDEP) |
| SUDEP (sudden unexpected death in epilepsy)--> | -1 in 1,000 adults & 1 in 4,500 children with epilepsy die from SUDEP each year |
| Risk factors for SUDEP include? | -Frequent seizures, especially generalized tonic-clonic -Not taking medications as prescribed -Stopping or changing medications suddenly |
| First Aid for Seizures includes: | 1. Stay calm! Many seizures are brief and do not require emergency services 2. TIME THE SEIZURE. If seizure lasts ≥ 5 minutes (or multiple seizures occur close together) or if the person has trouble breathing, appears to be injured, or has an unusual recovery, call 911 |
| First Aid for Seizures: What NOT to do: | 1. Do not hold the person down or attempt to stop their movements 2. Do not put anything into the person’s mouth (they cannot swallow their tongue) 3. Do not attempt artificial respiration unless the person does not start breathing after the seizure has stopped 4. Do not offer food, water, or medication until the person is fully alert |
| Status Epilepticus what to do (1) | 1. Look for seizure lasting ≥ 5 minutes and get medical emergency since it requires immediate treatment |
| Treatment approaches to Status Epilepticus incudes: | Secure airway, give oxygen, assess cardiac & respiratory function, check blood glucose levels, and secure IV access if possible Administer benzodiazepine **IV lorazepam** is first line if IV access available If no IV access, use alternative options: IM, intranasal, or buccal midazolam or Rectal diazepam *remember cutoff time for Status epilepticus is 5 minutes |
| Other First Aid Options for Seizures (not underlined or bolded) | -Ease the person onto the floor -Turn the person gently onto one side -Clear the area of anything hard or sharp -Put something soft and flat under their head -Remove eyeglasses and anything around neck that might impair breathing -Stay with them until the seizure ends and they are fully awake |
| 2024 Updated AAN Guideline on pregnancy —> Encourage thinking about pregnancy as early as possible. Use drugs with less fetal risk in pts with child-bearing potential. Consider use of _____, _____, and _______ when appropriate. Associated with the lowest rates of major congenital malformations (monotherapy) | Lamotrigine, Levetiracetam, Oxcarbazepine *Recommending daily folic acid dose of at least 0.4 mg daily during pregnancy and preconceptionally |
| Focal seizures first line therapy is—> | Lamotrigine; Levetiracetam; 2nd line monotherapy—> Oxcarbazepine; carbamazepine, Zonisamide |
| Generalized Tonic-Clonic (Grand Mal) First line therapy is? | Valproic Acid; Lamotrigine; Levetiracetam |
| Absence Seizures First line and Additional monotherapy options are? | Ethosuximide; Valproic acid, Lamotrigine |
| For absence seizures, DO NOT OFFER which medications? | Carbamazepine, Gabapentin, Oxcarbazepine, Phenytoin, Phenobarbital, Pregabalin, Tiagabine, Vigabatrin |
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