Understanding Seizures and Epilepsy

Overview

• Discovery session prepares for Interactive Lecture 1.1 & 1.2 in the unit
• Total time to complete is approximately 2 hours
• Activities include reading/viewing (90 mins), tasks (20 mins), and a learning quiz (10 mins)

Learning Outcomes

• Define seizures and epilepsy and understand their relationship
• Understand seizure type classification
• Describe symptoms for each seizure type and relate to brain regions affected
• These seizure types include absence, mesial temporal lobe, medicine-induced, pseudo-seizures and status epilepticus
• Understand the consequences of uncontrolled seizures
• Describe the epidemiology of epilepsy
• Discuss disease state management for epilepsy types
• Describe symptoms for seizure types (tonic-clonic, absence, myoclonic, clonic, tonic, atonic, focal aware, focal impaired awareness), relating to brain regions
• Identify seizure trigger factors including medications that can lower the seizure threshold
• Explain the mechanism of action of antiepileptic medications used to control and treat seizures
• Examples include carbamazepine, valproate, phenytoin, levetiracetam, brivaracetam, lamotrigine, pregabalin, gabapentin, topiramate, lacosamide, perampanel, felbamate, clobazam, clonazepam, midazolam
• Integrate knowledge of antiepileptic pharmacokinetics and patient-specific factors to identify management options
• Identify medications requiring plasma drug concentrations monitoring and how to interpret results
• Create a medication management plan incorporating clinical guidelines and a review of medicine-related problems
• Compare anticonvulsant medication side effects, their impact on medication selection, and how to manage them
• Identify patient groups requiring extra precaution
• Including women of child bearing age, and patients ceasing antiepileptic medicines and driving when managing seizure disorders
• Know when referral is required due to lack of efficacy or adverse effects of anticonvulsant medications
• Discuss the impact of epilepsy on an individual's lifestyle
• Use a multidisciplinary healthcare team approach to develop appropriate clinical and communication strategies for seizure disorder treatment

Prerequisite Knowledge

• Familiarity with brain regions and neurotransmitters involved in the nervous system
• Knowedge of CYP450 enzymes and their drug interaction implications
• Understanding of the MMOC framework

Key Concept Tasks

• Consider prevalence of seizures/epilepsy, definitions, classifications, symptoms, causes, brain parts affected and consequences
• Consider neurotransmitter alterations and antiepileptic drug effects
• Common seizure triggers and medications that lower seizure threshold should be thought of
• Important to know first aid for seizures; assess impact on patient quality of life
• Understand when to initiate antiepileptic drugs for epilepsy/seizure disorders
• Know first and second-line antiepileptic medicines recommended for main seizure types
• Know the mechanism of action of antiepileptic drugs introduced in the unit
• Know precautions, contraindications, drug-drug interactions, side-effects of antiepileptics
• Understand the role of Therapeutic Drug Monitoring (TDM) including considerations for using and interpreting TDM results
• Be able to offer main counseling points for starting antiepileptic drug therapy
• Know how to manage a patient presenting with status epilepticus

Treatment

• Untreated seizures cause central nervous system injury, noncardiogenic pulmonary edema, rhabdomyolysis, acidosis, kidney failure, hyperthermia, aspiration, trauma, increased SUDEP risk, and lower quality of life
• Weigh risks against potential antiepileptic medication side effects
• Status epilepticus is continuous seizure activity/repetitive seizures for ≥5 minutes without recovery
• Convulsive type (generalized tonic-clonic) requires urgent intervention to prevent brain injury/death
• Non-convulsive type is subtler, presenting as altered consciousness, behavior, or cognition, and can last days/weeks
• Status epilepticus is common in children and adults >60 years, often from abrupt withdrawal/non-adherence
• Status epilepticus is usually initially treated with benzodiazepines, followed by an antiepileptic drug
• Pharmacists must understand the management of status epilepticus and recommend medications

Treatment - Activity 1

• Refer to Neurology Therapeutic Guidelines: Acute Management of Seizures
• Navigate to Acute Management of Seizures, starting with Give Supportive Care
• Read Treat Status Epilepticus, focusing on Steps 1, 2, and 3
• Note treatment options, forms, treatment routes, pharmacology, mechanisms of action, side effects to determine perfect treatment

Ongoing Management of Seizures

• Ellie fits International League Against Epilepsy criteria for diagnosis of epilepsy
• Assess medication history and explore concerns about antiepileptic medication
• Obtain medications, allergy and swallowing information
• Grandmother used sodium valproate, experiencing hair loss/weight gain
• Ellie concerned about cosmetic effects, fogginess, and long-term antiepileptic consequences
• Antiepileptic drugs control seizures in ~2/3 of patients, but don't cure it (CDC, 2019)
• Monotherapy is preferred, with additional medications added when necessary, but consider less effectiveness against increasing side effects
• 2+ monotherapy failures and polytherapy requires reassessment for resective epilepsy surgery (BMJ Best Practice, 2018)
• Surgery is considered when seizures are drug-resistant, debilitating, or from a surgical cause
• Surgical goals include resecting, disconnecting, or stimulating the affected area to reduce/stop seizures
• Post-surgery, antiepileptic drugs are usually continued temporarily, followed by potential withdrawal
• Other treatments for include vagus nerve stimulation and ketogenic diet.

Treatment- Activity 2

• Decisions regarding antiepileptic therapy is important when treating patients.
• Short section Decide When to Treat Epilepsy and Choosing an Antiepileptic Drug is to be read under Therapeutic guidelines: neurology, in chapter Choosing an Antiepileptic Drug
• The section Choosing an Antiepileptic Drug should put priority on Figure 7.4, initial management of tonic-clonic seizures
• It needs to be decided if therapy should commence for Elly or change if she has only one seizure to date

Treatment Activity 3

• Seizure type, safety profile, adherence likelihood guide the choice of AED therapy
• Resources that guide your choice for Ellie are Therapeutic Guidelines: Neurology which includes choosing an antiepileptic drug and factors affecting selection, and Australian Medicines Handbook
• The table Choice of Antiepileptic Drug in AMH should be reviewed
• You need to especially consider first and second-line medication for seizure types
• AMH should also be reviewed, especially the considerations for Lamotrigine
• Additional factors need to be considered for each AED which is hightlighted by reading until Acetazolamide and sulthiame

Treatment

• Cannabidiol gel is available through SAS for future epilepsy treatment
• Review the Australian Prescriber spot lights summaries on newer medications (perampanel and brivaracetam)

Drug Interactions

• Patients may have comorbidities treated with medications interacting with antiepileptics
• Most common cause of drug interactions for antiepileptics are CYP enzyme and UGT mediated enzyme induction/inhibition
• The task relates to Topic Level Learning Outcome 10
• Reference Antiepileptic Drug Interactions - Principles and Clinical Implications which is relevant to read through

Task 1 Focus

• Pharmacokinetic interactions
• CYP enzyme and drug interactions
• UGTs and drug interactions
• Tables 2/3 on pages 258/259 outline antimicrobials and antidepressants that have multiple comorbidities with medications and can be used as a hand to consider cases
• It is also optional to refresh memory with material learnt in PHR1022 How Medicines Work II on CYP interactions
• Look at particular drug interactions in workshops

Side Effects

• Potential side effects of antiepileptic medicines should be a concern
• These concerns include fogginess and long-term use
• Antiepileptics agents should be chosen on factors which may affect patient compliance, including there side effects profiles
• Start of treatment may cause lethargy, drowsiness, dizziness which may decrease over time
• If problematic, the doctor should be consulted for alternative options
• The Epilepsy Foundation offers clear information on drug side effects and common questiosn
• These is useful for the pharmacists

Significant Side Effects

• Osteoporosis and fractures can be a result
• Especially drugs that cause increased vitamin D metabolism such as with those ones that induce CYP450
• This can result in decreased calcium absorption, secondary hyperparathyroidism, increased bone resorption, and accelerated bone loss
• Those with epilespy can also easily have fractures
• There is a 2–6 higher risk the normal population

Optional Side Effects Activity

• Antiepileptics and bone health are factors to be mindful of
• Influence of antiepileptic drugs on bone metabolism should be focused on in Table 1
• Up until page 241 on the text Practial Procedure should be focused on
• Prophylactic measures against osteoporosis is outlined in Table 2
• Allergic reactions can relate to antibiotics
• Severe cutaneous adverse reactions, SCAR, can be present with medications where Stevens-Johnson syndrome, SJS, Toxic epidermal necrolysis, TENs, and Drug reaction with eosinophilia and systemic symptoms, DRESS Stevens-Johnson syndrome, SJS, and toxic epidermal necrolysis, TEN must be noted
• Characteristics: Rare, life-threatening mucocutaneous diseases with epidermal and mucosal necrosis
• Causes: Often triggered by new drugs, especially carbamazepine, lamotrigine, and phenytoin
• Risk Factors: Increased risk with HLA-B*15:02 allele, particularly in Han Chinese

Drug Reaction

• Severe skin eruptions, fever, hematologic abnormalities, and internal organ involvement
• Onset: Typically 2-6 weeks after starting the drug

Monitoring

• Efficacy of drug treatment is is better judged by clinical response over target serum concentration
• Therapeutic drug monitoring can be useful though

Monitoring - Task 2

• According to Therapeutic Drug Monitoring of Antiepileptic Drugs in Epilepsy: A 2018 Update which is what the summary is derived from, a reference range is often misunderstood and an individual therapeutic concentration is better
• Reference range is the concentration therapeutic responses are unlikely below an one that may cause toxicity above, however population data may vary
• A patient's steady state concentration is needed to be stablilized for the regimen
• Individual therapeutic concentration is when the patient's response is a good one and allows good management decisions
• Reasons for monitoring are found in Indications for AED TDM on the page
• From the material the differences between the reference range and therapeutic range can be learnt and why TDM should be considered of antiepileptic medicinces

Other Aspects to Monitor

• LFT's and FBE's need to have baseline check before commencemeng AED
• Changes to liver function needs to be monitored during AED and with dyscrasias
• Clotting should be studied before a suergy
• Such as with sodium valproate
• Tests for bone metabolism are also baselined and monitored 2–5 yearly
• Calcium and alkaline phosohatase are examined

Phenytoin

• The antiepileptic medication should be reviewed a minimum of annually
• Arrangement and spcialist arrangements can be changed between 3–12 months

Task 3 - Phenytoin Monitoring

• You need to read the references that is critical in the workshop to understand both interpreation and patient level monitoring
• These references include Phenytoin: A Guide to Therapeutic Drug Monitoring along with When to measure serum concentrations of antiepileptic drugs

Pharmacokinetics

• The increasements of dose with phenytoin is decreased because hepatic metabolism becomes saturated
• Can result into low dose increasements that can cause large increasements in the drug level
• Therapeutic range is in between efficacy and is needed to allow balance, which can be a difficult thing to find
• The half life increasement makes a steady state impact a thing to watch
• Less fluctuation in drug means once daily dosing is something to consider
• Cessaation of drug will need to be carefully planned as drug levels remain elevated

Albumin Binding

• Only free Phenytoin is able to cross, exert the blood brain barrier
• Conditions include burns and cirrhosis and needs to be accounted for
• Conditions like renal failure should be looked at as albumin as it binds the free drug concentration
• There should be consideration for modified sheer tozer equation

Clinical Implications

• Blood levels are guides and are varied on the patient level Higher levels in the bloods can be accepted with no side effects
• Individualized dosing can be needed to make sure adequate seuizure control is maintained

Dosing

• Figure three relates to the saturatuion where steady state phenytoin concentrations are shown with increased dosing
• With a minnute 5mg/L increase values used in individualy epilepsy is increased
• The data is used to reflect accurate saturation with a 10-20mg/L limit

Alternative for Task

• Pharmokenetics can be made very simple by following the link provided

Albumin

• Sheer tozer will follow modified levels
• Modified level will count the total blood albumin levels
• Not every blood level can count as they are not a "true level"

Clinical Case

• John is 75 year old man in emergency for consultation
• He shows slurry in his speech , as well as nuasea, tremors
• He has hypertension issues, hypercholesterolemia, epilepsy problems and depression
• Doctors consider his issues and make a interview with the wife for consideration
• All medication is reviewed except ibuphrofen which was started recently for achy tooth
• There where worries of depression, which now is exacerbated by the use of alcohol, he cant have a specialist since there is some lack of doctors since more are oversea

Task Four - Clinical Study

• Doctors look over medication to review how long each date and quantity where dispenced
• He has daily: atrova, ramiprili, phenytoin, aspirin, and metformi
• He has as needed: Sertraline and ibuprophen
• He has some amount of confusion with the new disponsials
• Dilantin is now taken four times a day, where it should be once daily

Sodium Valproate Monitoring

• Valproate doesn't correlate well as levels are used to toxicity and compliance
• Hypermmonemic Encephalopathy can result It has shown the potential to cuase many different side effects and toxicity

HYperammonemic Encephalopathy

• Valproate runs the potential to risk this condition
• This can relate to vomitting, and loss of cognition
• Can still run the risk with normal dosage as it also can change the levels
• Treatment will involve immediate cessation
• Levels for sodium help see how compliant people where when seeing toxic levels

Task five

• Sodium is studied to show levels in body
• An interactive lecture 1.2 will show and open to see levels in a sodium person

Check Your Learning

• Some steps that help guide, prepare, and give an ability to check lecture topics
• After going over lectures the topics need to be seen a minimium to make sure they can be clearly understood

Where To From Here

• You Can Follow Steps With Lectures to Learn More
• Lecture content is given to follow scenarios and different case studies

Steps

• Assessments should be checked for

• There is a forum of questions for extra help

• There are other helpful links to see

• Stimulation and Ketogenics are options

• There are links for medication updates