14 - Seizure Disorders Flashcards
1
Q
Define seizure
A
Abnormal, paroxysmal, excessive firing of CNS neurons – transient event
2
Q
Define epilepsy
A
Chronic condition characterized by recurrent seizures which aren’t provoked by systemic or acute neurologic insults
3
Q
Define status epilepticus
A
Seizure lasting >/ 30 minutes or >/ 2 sequential seizures w/o return to normal mental baseline
4
Q
Initial evaluation of seizure
A
- When pt presents w/ first seizure, need to rule out physiologic (and possibly treatable) causes before beginning therapy for seizure disorder, or epilepsy
- This evaluation will help determine the likelihood of future seizures and assist w/ deciding if anti-seizure therapy is warranted
- Hx and physical exam, lab tests (CBC, electrolytes, glucose, hepatic and renal function, etc.), blood/urine tox screen for drugs (to rule out provoked seizure), EEG, CT/MRI to rule out brain tumour or bleeding
5
Q
Diagnosing epilepsy
A
- At least 2 unprovoked (or reflex) seizures occurring > 24 h apart
- Unprovoked = a cause that we can’t fix
- Can also diagnose after 1 seizure based on px hx & risk factors (> 60% chance of having another seizure)
6
Q
Types of seizures
A
- Focal = seizure activity starts in one area of the brain
- Generalized = seizure activity involves both hemispheres of the brain
- Tonic = stiff/flexed; tend to fall backwards
- Clonic = convulsions
- Myoclonic = short muscle twitches
- Atonic = relaxed; tend to fall forward
- Tonic-clonic = tonic phase + clonic phase (alternates between flexion and convulsion)
- Absence = “spaced out”
7
Q
Physiology applicable to seizures
A
- In normal synaptic transmission, there is a balance between inhibitory and excitatory transmission
- Inhibitory = GABA binds to post-synaptic GABAa receptor to open Cl- ion channels & allow influx (hyperpolarized postsynaptic neuron = less likely to “fire”)
- Excitatory = glutamate binds to glutamate receptor (NMDA or non-NMDA type); net result is excitatory postsynaptic potential (ready to “fire)
8
Q
Target for most anti-epileptic drugs (AEDs)
A
- Enhanced excitation (glutamate)
- Membrane depolarization (affecting ion channel Na+, Ca2+, K+ currents)
- Reduced inhibition (GABA)
9
Q
Goals of therapy for seizure disorders
A
- Eliminate seizures (reduce frequency and severity)
- Minimize side effects
- Optimize QOL – address comorbid anxiety, depression
10
Q
Natural hx of treated epilepsy
A
- 60-65% are seizure free (most are w/ one drug but some require more than one)
- Remission: complete cessation of seizures (seizure-free) for at least 1 year
- 30-40% are not controlled
- Refractory: 2 or more AEDs failed to control seizures (appropriate drug, appropriately dosed, tolerated)
- *Majority of px are controlled w/ their first monotherapy, but some require second or third monotherapy or more than 1 drug simultaneously
11
Q
General principles for tx of seizure disorders
A
- Verify diagnosis and determine etiology if possible
- Review seizure description to ensure correct classification
- Match choice of AED to seizure type and to specific pt
- Use monotherapy if possible; polytherapy if necessary
- When adding an AED start low and go slow, but if needed push to max tolerated dose
- Consider changing the timing of dosing to reduce toxicity
- Use clinical response and PK principles to fine-tune dose
- Adjust doses for drug-drug interactions (**AEDs have many interactions)
- Don’t give up
12
Q
Justifying your selection fo AED **know this
A
- Is a drug indicated? (if pt is diagnosed w/ epilepsy)
- Is the selected drug effective? – evidence vs. clinical experience
- Is the selected drug safe? – most common/ serious SE, drug interactions, comorbidities
- Is the selected drug convenient? – available, affordable, relatively easy to take
- Do you have money to pay for this if it isn’t covered?
- Are you likely to remember to take this medication every day?
13
Q
How to determine if an AED is indicated for a pt
A
- Generally, once a pt meets the criteria for diagnosis of epilepsy tx is indicated
- Clinical decision process to treat first-time unprovoked seizures not diagnosed as epilepsy is very pt specific and depends on multiple clinical factors
- Weigh risk of seizure recurrence against adverse effects of AEDs (and consider pt preferences)
14
Q
Recommended drug therapy for different seizure types to know**
A
- Focal (adult) – carbamazepine, levetiracetam, valproic acid
- Generalized tonic-clonic (adult) – carbamazepine, lamotrigine, oxcarbazepine, valproic acid
- Absence (children) – ethosuximide, valproic acid
15
Q
Most common SEs for all AEDs
A
- CNS side effects
- Drowsiness, sedation, fatigue
- Incoordination
- Dizziness
- Cognitive impairment (mental dulling, memory, concentration)
- Diplopia (double vision)
- *May be comparatively worse w/ phenobarbital, carbamazepine, & topiramate
- GI side effects -> diarrhea, cramping
- Toxicities are additive (ie: worse w/ each additional AED added)
16
Q
Dose related SE of AEDs
A
- Associated w/ AED initiation or dose increase
- Usually corelate w/ blood concentration
- Reversible on lowering or discontinuing AED
- Predictable – AED selection based on SE profile
17
Q
Some examples of dose related SEs of AEDs
A
- Carbamazepine -> benign leukopenia
- Valproic acid -> GI, benign elevation of liver enzymes, weight gain, hair loss, hirsutism
- Topiramate -> weight loss, mood changes
18
Q
AED idiosyncratic reactions
A
- More serious and potentially life-threatening
- Not dose-related
- No lab test/ level identifies risk for these reactions
- Risk factors = hx of previous drug reactions, liver/kidney function, conditions affecting hematopoiesis, metabolic disorders
- Mechanism of reaction:
- Immune-mediated reaction to the drug
- Genetics – unusual sensitivity to drug
- *Less likely w/ gabapentin, pregabalin, topiramate, oxcarbazepine, and levetiracetam
19
Q
Hypersensitivity reactions to AEDs
A
- Rare, idiosyncratic reactions that can be life threatening – SJS, TEN (toxic epidermal necrosis), DRESS (drug rash w/ eosinophilia and systemic sx)
- SJS and TEN most often associated w/ carbamazepine, oxcarbazepine, lamotrigine; less w/ VPA and topiramate
- Highest risk of occurrence during first 2 months of therapy
20
Q
Other idiosyncratic reactions from AEDs
A
- Agranulocytosis (rare w/ carbamazepine)
- Aplastic anemia (VPA, CBZ)
- Hepatotoxicity (VPA)
- *Increased suicide risk (especially w/ other psych conditions)
21
Q
AED considerations in pregnancy**
A
- *Never use VPA in pregnancy or women of child bearing age
- Greater risk of malformation and possible neurodevelopmental impairment w/ VPA
- VPA has highest risk of teratogenicity and neurodevelopmental outcomes than any other seizure med
- All females on AEDs should receive folic acid before any possibility of pregnancy
22
Q
Drug interactions w/ AEDs
A
- CYP P450 inducers = carbamazepine, phenytoin, phenobarbital, topiramate, oxcarbazepine
- Results in increased drug metabolism of drug metabolized by the same pathway = reduced plasma concentrations & altered pharmacologic effect (ex: warfarin, oral contraceptives)
- CYP P450 inhibitor = valproate
- Results in decreased drug metabolism of drug metabolized by the same pathway = increased plasma concentrations (and potential increases in toxicity)
- *Drugs less likely to interact = gabapentin, levetiracetam
23
Q
Serum level monitoring for AEDs
A
- *Only done if clinically indicated
- To assess non-adherence
- Suspected toxicity
- Management of PK interactions
- Special clinical conditions = status epilepticus, organ failure, pregnant while on lamotrigine or phenytoin (levels affected by pregnancy)
- Used as a guide rather than rule for clinical decision making; therapeutic and toxic ranges are individualized
24
Q
Pt counselling on new AEDs **know this
A
- Will the drug work? – probability of efficacy
- *How will they assess efficacy? – record seizure frequency (so efficacy can be quantified and compared among AEDs)
- Will they tolerate it? – be open about SEs & discuss titration; develop monitoring plan; pt to document adverse effects on a calendar/ journal
- Non-pharm interventions? – record precipitating factors (ex: menses, sleep, stress)
- Monitoring required? – blood work (CBC, electrolytes, LFTs) before starting AED and regular intervals during first months of use
25
Managing adverse effects of AEDs
- Factors affecting tolerability and safety:
1. Dose escalation rate (too fast = SE risk)
2. Habituation period (time to allow adverse effects to occur – varies btwn px)
3. Blood levels (rate of increase, peaks)
4. Timing of doses (single vs. spread out vs. ER formulation)
5. PK interactions (drug interactions – change in metabolism)
6. PD interactions (additive or synergistic adverse effects)
26
SE management strategies for new AEDs
- Use a test dose HS
- If SE, delay next dose
- If SE recur, reduce dose
- Increase dose as tolerated
27
SE management strategies for peak blood levels of AEDs
- Administer w/ food (to slow rate of absorption)
- Change dosing interval
- Give larger dose at bedtime, smaller doses during the day
- XR formulation if available
28
SE management strategies for PK interactions of AEDs
- Adjust co-therapy (ex: reduce dose of one drug)
| - Gradual dose escalation
29
SE management strategies for PD interactions of AEDs
Reduce co-therapy if possible or change to an alternative therapy w/ fewer additive SEs
30
Approach to managing recurrence
- Includes evaluation for progressive pathology and avoidable precipitant (stress, sleep, hypoglycemia, drug-induced causes)
- If on AED – compliance, PK (absorption, metabolism), increased dose needed?, change in medication needed?
31
Outcome and expected time frame for monitoring efficacy
- Seizure frequency/ severity
- Daily by pt and at follow-ups
- Improvement = 1-2 weeks
- Significant benefit = 1 month
32
Outcome and expected time frame for monitoring safety
- Dose-dependent CNS effects (sedation, ataxia) -- daily by pt and at follow-up; pharmacist to follow-up by phone after about 1 week
- AED-specific effects (ex: rash, liver toxicity) -- daily by pt and pharmacist follow-up; blood work drug dependent
33
Outcome and expected time frame for monitoring convenience
- Dose and titration schedule -- for most q1-2weeks; escalate dose based on tolerability
- Therapeutic drug monitoring -- if indicated (ex: at 1 week and q3days for dose changes)
- CBC, LFT, electrolytes -- baseline and q3-6months initially
34
Guidelines for d/c of AEDs
- Seizure free period of >/ 2 years implies overall > 60% chance of successful withdrawal in some epilepsy syndromes
- Favourable factors:
- - Control achieved easily on one drug at low dose
- - No previous unsuccessful attempts at withdrawal
- - Normal neurologic exam and EEG
- Consider relative risk/ benefit (driving, pregnancy, toxicity vs. psychosocial/ vocational consequences of seizure)
- To be done slowly – at least 2-3 months, one drug at a time
35
Status epilepticus
- Any seizure lasting > 30 mins +/- impaired consciousness, OR
- Recurrent seizures w/o period of consciousness between seizures
- Neurologic emergency
- - Associated w/ brain damage, tx resistance, and death
- - Poorer outcomes increase w/ increased seizure duration
- Immediate emergency care if:
- - Seizure lasting > 5 mins
- - Repeated convulsive seizures (3 or more in 1 h)
36
Status epilepticus supportive tx
- Pt stabilization
- Adequate oxygenation
- Preservation of cardiorespiratory function
- Management of systemic complications
- Aggressive assessment of underlying causes
37
Status epilepticus abortive tx
- BZD (lorazepam, diazepam; buccal midazolam if IV not available)
- - 1st line for active seizures including SE
- - Effective in terminating seizures in 75-90% of px
- Anticonvulsant (phenobarbital, phenytoin)
- - 2nd line if BZD doesn’t terminate seizure
