Epilepsy Module 5 PDF

Epilepsy **Epilepsy **is an overarching term for a brain disorder that leads to recurrent, unprovoked seizures. The therapies discussed here are primarily for patients with epilepsy. **Seizures** can occur because of a specific provocation, such as a fever, head trauma, or low blood glucose. Patie...

Epilepsy **Epilepsy **is an overarching term for a brain disorder that leads to recurrent, unprovoked seizures. The therapies discussed here are primarily for patients with epilepsy. **Seizures** can occur because of a specific provocation, such as a fever, head trauma, or low blood glucose. Patients whose seizure has a definite cause do not generally require long-term anti-epileptic therapy.  Therapy is indicated when there is a high risk of recurrence. Only about 2% of adults have at least one seizure in their lifetime. Only about one third of those will have a second seizure. **Epilepsy affects over 60 million people worldwide. Some patients have refractory epilepsy, or failure to be seizure-free for 12 months despite optimal medical management. This leads to increased risk of physical injury or death over time.** **Seizure Classification** The classification of the seizure is important as it will **dictate effective therapies**. It is possible to have a mixed seizure disorder where the patient experiences more than one seizure type. Partial Seizures Partial seizures generally last less than three minutes and are often less than one minute. Partial seizures can also occur secondary to a generalized seizure. **Partial Seizures** Partial seizures generally last less than three minutes and are often less than one minute. Partial seizures can also occur secondary to a generalized seizure. Types of partial seizures include: - - **Generalized Seizures** Types of generalized seizures include: - - - - - **Anticonvulsants** **Anticonvulsants**, or **antiepileptics**, are used to treat patients with epilepsy who are at **risk of another seizure**. There are many mechanisms of action, and therapy often requires trial and error. Anticonvulsant drugs **selectively modify the excitability of neurons** in order to **inhibit seizure-related firing** without inhibiting normal neural activity.  The mechanism of action of anticonvulsants can be described as: - - - **Examine the images below to view the mechanism of action of anticonvulsant medications affecting GABA and glutamate receptors.** A diagram of a cell division Description automatically generated **Anticonvulsant mechanism of action at the GABA receptor.**  **Anticonvulsant mechanism of action at the Glutamate receptor.** **Drug Selection** While we can characterize some of the chemical actions of these drugs, it is not firmly established that these effects are what stop seizure activity. Many drugs are effective for many different seizure types, therefore it is primarily the other considerations that drive drug selection.    **Only about 50% of patients respond to the first drug. Of those remaining, 20% eventually respond to some combination of antiseizure medications, but 30% never achieve a complete response.** When choosing a medication, consider the following: - - - - - - - **Drug Levels** Many anticonvulsants, particularly older agents, require **therapeutic drug monitoring**. When possible, collect drug levels if the patient is experiencing a seizure or toxicity to guide therapy.    **It is important to note that, although we have a therapeutic range for these medications, the "therapeutic level" is the level at which the patient has seizure control without side effects. Treat the patient, not the number!** Indications for a level include: - - - - - - **Partial and Generalized Tonic-clonic Seizure (GTC) Medications** Nearly all drugs used to treat **partial seizures** can be used to treat most different subtypes of partial seizures, including simple and complex. These drugs would also be used to treat **generalized tonic-clonic seizures (GTC)**.  They are divided into **classic** and **modern** medications. **Classic Medications ** - - - - - - **Modern Medications ** - - - - - - - - - - - - - Let's examine some of the** most common** anticonvulsant medications in more detail. **Phenytoin (Dilantin®)** **Mechanism of Action** - - - - - **Therapeutic Level** - - - - - - **Dosing ** - - - - - - - - - **Adverse Effects** - - - - - - - - - - - - - - - **General Considerations:** - - **Fosphenytoin (Cerebyx®)** Fosphenytoin is a prodrug of phenytoin that is dosed in "phenytoin equivalents." Unlike IV phenytoin, it\'s less likely to have rate-related hypotension, infusion-site reactions, or concern for extravasation/purple-glove syndrome. Other adverse effects are the same as phenytoin, including cardiotoxicity.   **Other advantages include:** - - **Carbamazepine (Tegretol®, Carbatrol®)** **Mechanism of Action** - - **Therapeutic Level ** - **Dosing ** - **Other** - - - -  ** Adverse Effects** - - - - - - - - - - - - **General Considerations** - - **Oxcarbazepine (Trileptal®)** **Mechanism of Action** - - **Therapeutic Level** - **Dosing** - **Other** - - - **Phenobarbital (Luminal®)** **Mechanism of Action** - - **Therapeutic Level** - **Dosing** - - **Other** - - - - **Adverse Effects** - - - - - - - **General Considerations** - **Gabapentin (Neurontin®)** **Mechanism of action** - - **Therapeutic Level** - **Dosing** - **Other** - - - - - **Adverse Effects** - - - - - **Pregabalin (Lyrica®)** **General** - - - - **Dosing** - **Adverse Effects** - - - - - **Topiramate (Topamax®)** **Mechanism of Action** - - - **Moderate CYP3A4 Drug Interactions** - **Dosing**  - **Other** - - - - -  **Adverse Effects** - - - - - - - - - - - - - - - **General Considerations** - - **Levetiracetam (Keppra ®)** **Mechanism of Action** - **Dosing** - **Other** - - - - **Adverse Effects** - - - - - - **Lacosamide (Vimpat ®)** **Mechanism of Action** - - **Dosing ** - **Other** - - - - **Adverse Effects** - - - - **Generalized Seizure Medications** It is important to note that, for generalized seizures, only specific drugs are effective for specific subtypes, including: - - - - **Myoclonic is usually accompanied by another primary seizure type. Treatment should be directed at controlling primary seizure disorder while choosing drugs that are unlikely to exacerbate myoclonus.** The headings will show you more about medications used for each subtype.  **Absence** - - - - - **May exacerbate absence seizures:** - - - **Myoclonic\*\ ** - - - - \*Doesn't require treatment itself as it coexists with other types. **May exacerbate myoclonic seizures:** - - - - - **Atonic\*\ ** - - - - \*Often treatment resistant. Treatment for generalized tonic-clonic seizures follows treatment for partial seizures, as discussed above.  Let's examine each of the subtype medications in more detail. **Ethosuximide (Zarontin®) ** **Use** - **Mechanism of Action** - **Dosing** - - **Therapeutic Level** - **Other** - **Adverse Effects\*** - - - - - - - - \*Most ADEs are transient, may improve over time or with a dose-reduction. **Felbamate (Felbatol®)** **Use** - - **Mechanism of Action** - **Dosing** - **Therapeutic Level** - **Adverse Effects** - - **Lamotrigine (Lamictal®)** **Use** - **Mechanism of Action** - **Dosing** - - **Other** - **Therapeutic Level** - **Adverse Effects** - - - - - - - - - - - - **General Considerations** - - - **Valproic Acid (Depakote®, Depakene®)** **Use** - **Mechanism of Action** - **Dosing** - - **Other** - - - **Therapeutic Level** - **Adverse Effects** - - - - - - - - - - **General Considerations** - **Zonisamide (Zonegran®)** **Use** - **Mechanism of Action** - **Dosing ** - **Other** - **Therapeutic Level** - **Adverse Effects** - - **Benzodiazepines** **Use** - **Mechanism of Action** - **Dosing**  - - - - **Other** - **Adverse Effects** - - **Clobazam (On®)** **Use** - - - **Mechanism of Action** - **Dosing** - **Adverse Effects** - - **All antiseizure medications include a black box warning regarding risk of suicide. The FDA has reported an increased risk of suicidality: 1 in 500. Medication guides must be dispensed for all antiseizure medications per the FDA REMS program.** **Status Epitilepticus and Emergent Seizure Management** It is important to understand that the treatment of **status epilepticus**, or an **acute seizure**, is an **emergency** and follows a specific recommendation in terms of therapy. The recommended progression of medication therapy is as follows: - - - - **Emergent Seizure Management** **Step 1 ** Position person on their side to prevent aspiration.  A person doing cpr Description automatically generated **Step 2 ** Prevent injury: Remove dangerous objects or move the patient away from dangerous environments.  **Step 3** Place a pillow or jacket under their head if possible A blue and white image of a person and a baby Description automatically generated **Step 4 ** Call 911 if the seizure persists for more than five minutes.   **Step 5 ** Do not hold them down.  A blue and white graphic of a person pushing a person Description automatically generated Step 6  Do not place anything in their mouth, including medications.   **Anticonvulsants Considerations** Anticonvulsant use in patients of childbearing potential is something really important to consider. Most anticonvulsants are **teratogenic**, but a seizure during pregnancy can also be detrimental to the fetus. **Combination Oral Contraceptive Interactions** These medications **reduce the effectiveness **of oral contraceptives: - - - - - These medications** do not interact** with oral contraceptives: - - **Prior to conception** - - - - **Major Congenital Malformations** Below is a table from a research study in North America looking at the rates of major congenital malformations in neonates exposed to these antiepileptic medications. The study population consisted of pregnant patients enrolled in the North American AED registry (1997 -- 2011). A table with numbers and symbols Description automatically generated In addition to the table above, the following malformations are seen most commonly in the following: - - - - **Seizures During Pregnancy** 25 to 30% of patients experience increased seizure frequency during pregnancy, probably related to changing kinetics. For example, pregnancy may decrease phenytoin, lamotrigine, and carbamazepine levels, and increase levetiracetam and oxcarbazepine levels. Seizures while pregnant can result in **miscarriage**, **trauma**, **fetal hypoxia**, or **fetal acidosis**.  Therefore, during pregnancy it is important to consider the following: - - - **Antiepileptic Medication Considerations** Unfortunately for pregnant patients suffering from epilepsy, there is a lack of available evidence for the "best" antiepileptic drug (AED) for preventing teratogenesis or negative perinatal outcomes. However, over 90% of patients on AEDs for epilepsy have successful pregnancy outcomes.  It is important to be aware of the different antiepileptic medication choices, keeping in mind the following: - - - - Supplementation considerations include: - - - **Withdrawal of Anticonvulsant Medication** Some patients may benefit or request to withdraw their anticonvulsant medication. There is no standard recommendation and may be considered if the patient has been seizure free for at least two to five years. About 60% of patients who are seizure free for at least two years and go off medication will relapse. Alternatively, 75% will continue to be seizure free if they stay on the medication that is controlling their seizures. Generalized tonic-clonic and partial seizures are more likely to relapse. Also, patients with longer duration of disease and abnormal EEG are at increased risk of relapse. **Summary Study Guide Answers** **Black Box Warning** - All anticonvulsants carry a **black box warning** for an increased risk of suicidal ideation and behavior. - This risk highlights the importance of monitoring patients for mood changes and signs of depression, especially during the initial months of treatment. **Classic Anticonvulsant Medications** - Examples: **Phenobarbital**, **Phenytoin**, **Carbamazepine**. - Characteristics: - Require **therapeutic drug monitoring**. - Associated with **numerous drug-drug interactions** due to effects on CYP3A4 enzymes. - Highly protein-bound (e.g., phenytoin), meaning small dose changes can significantly alter drug levels. - Dosing adjustments should be done **slowly** with close monitoring of drug levels to avoid toxicity. **Modern Anticonvulsant Medications** - Examples: **Levetiracetam**, **Lamotrigine**, **Topiramate**. - Characteristics: - Do not generally require **therapeutic drug monitoring**. - Have **more predictable pharmacokinetics**, making dosing simpler. - Fewer drug-drug interactions compared to classic anticonvulsants. - Effective for a broad range of seizure types. **Status Epilepticus** - Defined as a **seizure lasting more than 5 minutes** or **recurrent seizures without recovery in between**. - **Treatment Steps**: 1. Administer **benzodiazepines** (e.g., lorazepam or diazepam) as first-line therapy to stop the acute seizure. 2. Follow with **longer-acting anticonvulsants** (e.g., phenytoin, levetiracetam) for sustained seizure control. **Teratogenicity in Pregnancy** - Many anticonvulsants are **teratogenic** and may harm fetal development. - Risks must be carefully weighed against the benefits of seizure control. - Considerations: - **Valproate** has a high teratogenic risk and is generally avoided in pregnancy. - **Levetiracetam** and **lamotrigine** are often preferred due to lower teratogenic risks. - Use the **lowest effective dose** and ensure appropriate **folic acid supplementation** to reduce neural tube defects. **Summary Study Guide Answers** **Review Common Anticonvulsant Medications** - **Classic Anticonvulsants**: - Examples: **Phenytoin**, **Carbamazepine**, **Phenobarbital**. - Require therapeutic drug monitoring. - Associated with significant drug interactions (e.g., CYP3A4 induction). - Small dose changes can result in large serum level fluctuations​. - **Modern Anticonvulsants**: - Examples: **Levetiracetam**, **Lamotrigine**, **Topiramate**. - Minimal need for drug level monitoring. - Fewer drug-drug interactions. - Broader spectrum of seizure type coverage​. **Propose an Appropriate Anticonvulsant Regimen in a Given Patient Case** 1. **Partial Seizures**: - First-line: **Levetiracetam** (500--3000 mg daily divided into two doses). - Alternative: **Lamotrigine** (requires slow titration to minimize rash risk). 2. **Generalized Tonic-Clonic Seizures**: - First-line: **Valproic Acid** (monitor for hepatotoxicity). - Alternative: **Lamotrigine** or **Topiramate**​. **Examine Emergency Management of Seizures** - **Status Epilepticus**: - Step 1: Administer **Lorazepam** (4 mg IV push). - Step 2: Follow with **Phenytoin**, **Fosphenytoin**, or **Valproic Acid** for sustained seizure control. - Step 3: Consider **Phenobarbital** or newer agents (e.g., levetiracetam) if refractory​. - Non-Pharmacological Steps: - Position the patient on their side to prevent aspiration. - Do not restrain the patient or place objects in their mouth. **Treatment Considerations for Epilepsy in Patients Who May Become Pregnant** - **Preferred Medications**: - **Levetiracetam** and **Lamotrigine** have lower teratogenic risks. - Avoid **Valproic Acid**, **Phenytoin**, and **Phenobarbital** due to high teratogenicity​. - **Monitoring**: - Adjust dosing based on altered drug clearance during pregnancy. - Monitor serum drug levels more frequently. - **Supplementation**: - Ensure folic acid supplementation (at least 4 mg daily) three months prior to conception. - Consider Vitamin K supplementation if using phenytoin or phenobarbital​. **Strategies for Withdrawing Anticonvulsant Medications** 1. Ensure the patient has been seizure-free for **2--5 years**. 2. Assess seizure type and risk factors: - Generalized tonic-clonic and partial seizures are more likely to relapse. - Patients with abnormal EEGs or longer disease duration are at higher risk. 3. Taper the medication slowly over several months to reduce withdrawal seizures. 4. Educate the patient on relapse risk: - 60% of patients off medication may relapse. - 75% remain seizure-free if they continue their regimen​.