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What is the primary characteristic required to diagnose epilepsy?

Two unprovoked seizures occurring more than 24 hours apart (correct)

Continuous seizures occurring over a 48-hour period

At least one unprovoked seizure occurred at any time

Two unprovoked seizures occurring less than 24 hours apart

What percentage of epilepsy cases are classified as idiopathic?

11%

70% (correct)

Which of these statements accurately describes a simple focal seizure?

The patient retains consciousness and may include motor involvement. (correct)

It occurs with a blank stare and involves a small region of the brain.

It involves impaired consciousness and may include an aura.

It affects the entire brain resulting in loss of consciousness.

Which term describes the time period when the actual seizure occurs?

Ictus Signup and view all the answers

What neurotransmitter is primarily associated with inhibition in the brain?

GABA Signup and view all the answers

Which type of seizure can turn into generalized seizures?

Complex focal seizures. Signup and view all the answers

What characterizes the interictal period in epilepsy?

The time between seizures which may include confusion and headaches. Signup and view all the answers

Which population is least likely to be affected by epilepsy, according to the U-shaped curve of prevalence?

Middle-aged adults Signup and view all the answers

What is the primary concern regarding the use of anti-amyloid monoclonal antibodies?

Potential for infusion reactions Signup and view all the answers

Which of the following is a common adverse drug effect associated with memantine?

Dizziness Signup and view all the answers

What precaution should be considered for patients on memantine?

Seizure disorders Signup and view all the answers

In combination therapy for Alzheimer's dementia, what is memantine predominantly used with?

Donepezil Signup and view all the answers

Which diagnostic tool is essential prior to the infusion of anti-amyloid monoclonal antibodies?

Brain MRI Signup and view all the answers

What adverse imaging effect is commonly associated with anti-amyloid antibody treatment?

Amyloid-related imaging abnormalities (ARIA) Signup and view all the answers

What is the mechanism of action of aducanumab?

Reduces amyloid brain levels Signup and view all the answers

Which of the following is NOT a common drug-drug interaction with memantine?

Beta-blockers Signup and view all the answers

What is a key characteristic of barbiturates regarding their therapeutic window?

Very small therapeutic window, making them potentially lethal Signup and view all the answers

Which of the following statements is true regarding phenobarbital?

It is 100% bioavailable and is strongly protein bound. Signup and view all the answers

What does the term 'non-linear pharmacokinetics' imply for drugs?

Drug concentration variations may not correspond predictably with dosing. Signup and view all the answers

Which anti-seizure medication is known for having a short half-life?

Lorazepam Signup and view all the answers

Which of the following medications is known to be a strong CYP2C and CYP3A4 inducer?

Phenobarbital Signup and view all the answers

What is a common adverse drug event associated with phenobarbital?

Nystagmus and ataxia Signup and view all the answers

What describes the mechanism of action for primidone?

Modulation of GABAa receptors and depresses glutamate excitability Signup and view all the answers

What issue does gabapentin's GI transport raise concerning its pharmacokinetics?

It can decrease bioavailability due to saturable transport mechanisms. Signup and view all the answers

Which benzodiazepine is noted for having the longest half-life?

Clonazepam Signup and view all the answers

Which of the following drugs is characterized by its ability to induce the metabolism of WARFARIN?

Phenobarbital Signup and view all the answers

What is a recommended precaution before initiating treatment with Lecanemab?

APOE E4 testing Signup and view all the answers

Which of the following is considered an adverse effect of both Lecanemab and Donanemab?

Micro hemorrhage Signup and view all the answers

Which condition is NOT categorized as a non-cognitive symptom of dementia?

Cognitive impairment Signup and view all the answers

What should be monitored over 1-3 months after discontinuation of pharmacotherapy in dementia patients?

Evidence of decline Signup and view all the answers

What is a key component of nonpharmacologic approaches to dementia care?

Cognitive stimulation activities Signup and view all the answers

What is the appropriate management strategy for non-cognitive symptoms of dementia?

Go low and slow with documentation Signup and view all the answers

Which statement about the Montreal Cognitive Assessment (MoCA) is true?

Scores below 24 warrant follow-up. Signup and view all the answers

Which of the following conditions is considered a common comorbidity in geriatric dementia patients?

Diabetes Signup and view all the answers

What should be avoided when prescribing sleep aids for dementia patients?

Benzodiazepines Signup and view all the answers

What is a realistic therapy expectation for dementia treatment?

Slow decline and delayed long-term care placement Signup and view all the answers

What is the recommended action for a patient experiencing SJS or TEN due to ASM?

Discontinue immediately and provide hospitalization. Signup and view all the answers

Which of the following ASMs is associated with the highest risk of fractures?

Carbamazepine Signup and view all the answers

What risk is associated with the use of estrogen in women with epilepsy?

Increased seizure frequency Signup and view all the answers

What condition is characterized by targeted lesions and may involve mucous membranes?

Erythema multiforme Signup and view all the answers

What should be the main treatment approach for non-life threatening rashes due to ASMs?

Discontinue quickly and start a new ASM with rapid titration Signup and view all the answers

What is the primary concern regarding SAEs (sudden unexplained deaths) in epilepsy patients?

Abrupt death with no evident medical cause Signup and view all the answers

Which of the following is NOT a recommended practice for women of childbearing potential on ASMs?

Switch ASMs if pregnancy is confirmed Signup and view all the answers

What percentage of patients may develop osteopenia or osteoporosis while on ASMs?

38-60% Signup and view all the answers

Which drug is associated with potentially causing a hemorrhagic disease in newborns?

Valproate (VPA) Signup and view all the answers

What is the appropriate vitamin D supplementation for adults on ASMs?

4000 IU daily Signup and view all the answers

What complication is associated with polytherapy in terms of teratogenicity risks?

Higher teratogenicity risks Signup and view all the answers

Which type of dementia affects the frontal and temporal lobes and is often misdiagnosed?

Frontotemporal dementia Signup and view all the answers

What is the ideal duration of seizure freedom before considering changing treatment in epilepsy?

2 years Signup and view all the answers

What is a crucial safety consideration for individuals with epilepsy?

Seizure-free periods of 3-12 months for driving Signup and view all the answers

Study Notes

Epilepsy

Epilepsy is a chronic condition marked by recurrent, unprovoked seizures.
At least two unprovoked seizures occurring more than 24 hours apart are required for diagnosis.
A seizure is an abnormal excessive cerebral neuronal discharge, with or without a change in level of consciousness.
Convulsions are abnormal, involuntary muscle contractions seen with certain seizure disorders.
Prodrome refers to symptoms that may occur in the hours or days preceding a seizure.
Aura indicates the beginning of the seizure, lasting seconds to minutes.
Ictus refers to the actual seizure, from its first symptom to the end.
Interictal refers to the period between seizures, which may include deep sleep, headaches, vomiting, confusion, and other symptoms.
Most seizures start in small groups of injured, hyper-excitable neurons, referred to as “foci.”

Epilepsy Causes

70% of cases are idiopathic (primary).
11% are linked to cardiovascular disease.
5% stem from developmental issues.
4% are caused by head injuries.

Epilepsy Pathophysiology

Glutamate is the primary excitatory neurotransmitter.
GABA is the primary inhibitory neurotransmitter.
Alterations in glutamate and GABA balance can lead to seizures.
Epileptic brain activity on an EEG is substantially different from normal physiological brain activity.

ILAE Seizure Classification

Focal Seizures (Partial): Affect one part of the brain.
- Simple Focal: Patient remains conscious.
  - Affects a small brain region.
  - May involve motor activity.
  - Simple activities.
  - Typically last 15 seconds to 3 minutes.
- Complex Focal: Consciousness impaired.
  - May start as simple focal.
  - May include an aura.
- Secondarily Generalized: Consciousness impaired.
Generalized Seizures: Involve the entire brain.

Anti-Seizure Medications (ASMs)

Most ASMs are not very soluble and are lipophilic.
ASMs interact with the GABAa receptor, a chloride channel modulator.

Barbiturates

Phenobarbital (Luminal)
- MOA: GABAa receptor modulator (positive allosteric).
- Indications: focal, tonic-clonic seizures.
- PK: About half protein-bound, renal excretion of unmetabolized drug. 100% bioavailable.
- Strong CYP2C and CYP3A4 inducer.
- ADE: Sedation (tolerance develops), nystagmus, ataxia, learning difficulties.
- DDI: Induces the metabolism of other drugs (Warfarin).
Primidone (Mysoline)
- MOA: GABAa receptor modulator, depresses glutamate excitability, affects Na, K, Ca conductance.
- Indications: Focal, generalized tonic-clonic seizures, essential tremor.
- PK: Metabolized by CYP2C19, strong CYP2C and CYP3A4 inducer.
- ADE: Similar to phenobarbital.
- Primidone is metabolized into phenobarbital.

Benzodiazepines

Diazepam (Valium, Diastat)
Lorazepam (Ativan)
Midazolam (Dormicum)
Clonazepam (Klonopin)
MOA: GABAa receptor modulators.
Indication: All seizure types, including status epilepticus.
ADV: Tolerance (limits long-term use), CNS depression, sedation, lethargy, aggressiveness, withdrawal, rebound effects.
DDI: Common - induction of CYPs - can cause DDIs.

Anti-Seizure Medication Pharmacokinetics

Non-linear PK: Kinetics resulting from saturable drug transfer, leading to variation of kinetic parameters with drug concentration.
- Phenytoin is a perfect example.
- Drug concentration changes more or less than expected.
- Non-linear kinetics occur commonly at high concentrations following overdose, and in disease states.
Non-linear PK: Capacity Limited:
- Gabapentin is an example of a medication that has problems with GI transport.
Dose-Dependent:
- Doses may need to be adjusted due to non-linear kinetics.

Rash in ASMs

3% of patients taking ASMs experience rash.
Risk is greatest when multiple ASMs are used concurrently.

Risk Factors for Different Types of Rash

Carbamazepine: Patients with HLA-B1502 (testing recommended) and HLA-A3101.
Lamotrigine: High initial dose, rapid dose increases, co-administration with valproic acid (VPA).

Types of Rash

Maculopapular (Morbilliform): Begins 3-20 days after starting medication, itchy, resolves within weeks of stopping.
Urticaria (Hives): Wheals with pale centers and red borders, migratory, can be associated with anaphylaxis or angioedema.
Erythema Multiforme: Targeted lesions, may involve mucous membranes, is self-limiting.
Stevens-Johnson Syndrome (SJS)/Toxic Epidermal Necrolysis (TEN): 7-21 days after starting medication, sheet-like skin and mucosal sloughing.
- Less than 10% body surface area (BSA) - SJS.
- 10-30% BSA - SJS/TEN.
- Greater than 30% BSA - TEN.
- Mortality rate 10-30%.
Drug-induced Hypersensitivity Syndrome (DIHS)/Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): 2-6 weeks after starting medication.
- Includes fever, generalized rash, lymphadenopathy, facial edema, multiorgan failure.
- 10% mortality.

Rash Treatment

SJS, TEN, DIHS, DRESS: Discontinue medication immediately, hospitalization with systemic corticosteroids, burn unit care.
Non-life-threatening rash: Discontinue quickly, start a new ASM with rapid titration or load in the hospital, use benzos for breakthrough seizures.

Bone Health & ASMs

38% to 60% of patients taking ASMs experience osteopenia or osteoporosis.
Increased risk of fractures.
ASMs inhibit osteoblasts and/or activate osteoclasts.
Increased vitamin D metabolism.
Inhibition of calcium absorption.
Injuries can be caused by the seizures themselves.

Fractures and ASMs

The risk of fractures increases with the duration of ASM treatment.
Most common culprits: carbamazepine, clonazepam, phenobarbital, phenytoin, VPA.
Monitor vitamin D and bone mineral density (BMD).

Treatment

Vitamin D supplementation: 4000IU for adults, 2000IU for children.
Estrogen: May trigger seizures in some women.

Safety Precautions in Epilepsy

Avoid heavy machinery, heights, swimming/bathing, and driving (most states restrict driving until seizure-free for 3-12 months).
Be prepared to administer first aid in case of a seizure.

Suicidality

Patients with epilepsy have twice the risk of suicidal behavior/ideation.
The FDA requires a black box warning for all ASMs.
No difference in suicidal risk exists between different ASMs.

Sudden Unexplained Death in Epilepsy (SUDEP)

Abrupt death in patients with epilepsy without apparent medical cause.
1 in 1000 in adults.
Risk factors:
- Tonic-clonic seizures.
- High seizure frequency.
- Nocturnal seizures.
- Sleeping alone.

Women with Epilepsy and Contraception

Progesterone has anti-seizure effects, while estrogen has pro-seizure effects.
Catamenial epilepsy affects 1/3 to 1/2 of women with epilepsy.
Treatment for catamenial epilepsy: ASMs, benzos, acetazolamide, progesterone.
Menstrual cycle dysfunction and polycystic ovary syndrome (PCOS) are associated with VPA.
Decreased fertility is common; there are more anovulatory cycles, and prolactin can decrease libido.
Enzyme inducing ASMs can decrease the effectiveness of oral contraceptives.
Intrauterine devices (IUDs) are a safe contraceptive option due to a lack of interaction with ASMs.
Lamotrigine decreases lamotrigine concentrations.

Pregnancy and Postpartum

Caution regarding PK changes during and after pregnancy (everything is faster, leading to decreased serum drug levels).
Breastfeeding is encouraged.
Pregnancy categories:
- A-D
- X: Drug is contraindicated in pregnancy.
Fetal hydantoin syndrome, hemorrhagic disease of the newborn, and spina bifida are potential risks.
Most ASMs are category C in pregnancy.
Levitiracetam or lamotrigine are often preferred.

Teratogenicity Risks

Higher risks with polytherapy and VPA usage.
Phenytoin, phenobarbital, and topiramate are also associated with teratogenicity.
More than five seizures during pregnancy may lower verbal IQ in the child.

Pregnancy Recommendations

Prioritize seizure control.
Changing ASMs during pregnancy is generally not recommended due to the risk of seizures.
All women of childbearing potential should take at least 1mg folic acid per day.
Serum concentrations should be used to guide dose adjustments.

Advanced Age

Decreased metabolism and clearance of drugs.
Increased serum drug concentrations.
Decreased protein binding.

Goals of ASM Therapy

Seizure-free for at least 2 years.
Normal EEG.
Slow tapering.
If there are multiple seizure types, it might be impossible to achieve seizure freedom.

Dementia

Frontotemporal Dementia (FTD):
- Affects frontal and temporal lobes.
- Often mistaken for a psychiatric illness.
- Occurs between ages 45 and 65.
- Characterized by cerebral atrophy, tau deposits, and Pick bodies.
- Hallmark symptom: Socially inappropriate behavior.

Treatment for Alzheimer’s disease

Memantine (Namenda):
- MOA: NMDA receptor antagonist. Blocks toxic effects associated with excess glutamate.
- ADE: Dizziness, headache, constipation, confusion.
- DDI: Nicotine, ranitidine, cimetidine.
- Precautions: CVD, hepatic/renal dosing, seizure disorders, alkaline urine (decreases clearance)
- DDI: Carbonic anhydrase inhibitors, sodium bicarbonate, trimethoprim.
- ADE: CNS effects.
- Monitoring: Mental status.
- Used as an add-on or monotherapy.
- Combined Therapy: Memantine XR/donepezil (Namzaric) for moderate to severe Alzheimer's dementia.
Anti-amyloid Monoclonal Antibodies:
- Very effective in removing amyloid plaques.
- Early treatment is key. Removing amyloid from a brain heavily laden with plaques can cause significant inflammation.
- MOA: Not clearly defined. They are given by IV infusion, and clear amyloid from the body and the brain.
- May become first-line therapy for Alzheimer's disease.
- Precautions: Appropriate use.
- DDI: Efgartigimod alpha, rozanolixizumab.
- ADE: Amyloid-related imaging abnormalities (ARIA), diarrhea, confusion, infusion reactions (pre-medicate).
- Monitoring: Confirm beta-amyloid pathology via PET scan or spinal tap, brain MRI before infusions, MRI changes, ARIA, mental status.
- ARIA: Mostly asymptomatic. May cause cognitive decline, headache, seizures, falls.
  - Risk factors: High medication dose, APOE status, pre-treatment micro-hemorrhage.
  - Treatment: Corticosteroids, may stop treatment.
Aducanumab (Aduhelm):
- IV solution.
- MOA: Reduces amyloid brain levels.
- Efficacy is debated.
- Indication: Mild cognitive impairment, mild AD dementia.
- ADE:
  - ARIA-E (brain edema)
  - ARIA-H (micro-hemorrhage, bleeding)
  - BBB leakage
  - Headache
  - Confusion, delirium
- FDA approval:
  - Only approved for Medicare.
Lecanemab (Leqembi):
- IV.
- Most widely used anti-amyloid antibody.
- Indication: Mild cognitive impairment, AD with mild dementia.
- Same ADEs as Aducanumab.
- Boxed warnings. APOE E4 testing recommended. MRI required.
- Increased risk of bleeding in patients taking anticoagulants or thrombocyte agents.
- Slightly safer than Aducanumab.
Donanemab (Kisunla):
- IV.
- MRI required.
- May need to premedicate for infusions.
- Boxed warning: APOE E4 testing recommended.
- Increased risk of bleeding.
- Very expensive.
- Therapy may be stopped once plaques are removed.

Realistic Therapy Expectations for Dementia

Slow decline.
Possible delay in long-term care placement.
MMSE decline of 2-4 points per year without treatment.

Discontinuation of Pharmacotherapy

Patient/family decision.
Intolerable adverse effects.
Comorbidities make use risky or futile.
Rate of decline greater on treatment than before.
Dementia has progressed to the point where medication is no longer beneficial.
Patient non-adherence.
Always taper before stopping.
Monitor over 1-3 months for signs of decline.

Non-Cognitive Symptoms of Dementia

Agitation/combativeness.
Sleep disturbances.
Wandering.
Depression.
Seizures.
Anxiety.
Psychosis (sundowning).

Pharmacological Therapy for Non-Cognitive Symptoms

Go low and slow, meticulously document.
Weigh risks versus benefits.
Atypical antipsychotics: For psychosis and agitation.
- Black box warning: Increased risk of mortality in dementia-related psychosis.
Sleep aids:
- Avoid hypnotics, benzos, and antihistamines if possible.
- Melatonin is a better option.
Antiseizure drugs: Monitor for sedation and increased confusion.
Antidepressants:
- Avoid anticholinergics (paroxetine, TCAs).

Comorbidities in Dementia

Very common in geriatric patients.
HTN, depression, epilepsy, pain, stroke, urinary tract infections (UTIs).

Nonpharmacologic Approaches to Dementia

Cognitive stimulation.
Social interactions.
Healthy diet.
Adequate sleep.
Proper personal hygiene.
Physical exercise.
Safety inside and outside the home.
Long-term planning for health care.
Medical Power of Attorney (POA) or regular POA (best to establish early).
Effective communication.

Caring for Dementia Patients

Speak slowly and clearly, using short sentences.
Maintain eye contact.
Give them time to respond.
Offer simple choices.
Use a positive, friendly tone.
Acknowledge what they say.

Adherence and Dementia

Memory aids for pill planners.
Reduce pill burden (polypharmacy is a problem).
Reduce medication frequency if possible.

Alzheimer’s Disease Prevention

Good quality education.
Get hearing aids when needed.
Treat depression effectively.
Head protection.
Reduce smoking.
Prevent/reduce high blood pressure (HTN).
Maintain a healthy weight.
Treat high LDL cholesterol.
Treat vision loss.
Reduce air pollution exposure.

Severity of Dementia and Treatment

Montreal Cognitive Assessment (MoCA): Requires about 10 minutes to administer, useful for early detection.
- Range 0-30, follow up if score less than 24.
  - 18-25: Mild cognitive impairment.
  - 10-17: Moderate cognitive impairment.
  - Less than 10: Severe cognitive impairment.

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