IC6&7: Seizures and Epilepsy

Question 1

Define an acute seizure

Answer 1

result from some immediately recognisable stimulus of cause (occuring in the presence or close timely association (about a week) with an acute brain insult (metabolic, toxic, structural, infectious, hypoxic)

Question 2

Define a remote seizure

Answer 2

seizures that occur longer than 1 week following a disorder

Question 3

Define epilepsy

Answer 3

At least 2 unprovoked seizures occuring > 24h apart

Question 4

What are the two key concepts in the pathophysiology of seizures

Answer 4

Hyeprexcitability → enhanced predisposition of a neuron to depolarise (mediated by ion channels)

Hypersynchronisation → promoting the generation of epileptiform activity in a self-perpetuating cycle

Question 5

What are the 5 classes of epilepsy etiology?

Answer 5

1. Structural
   - Hippocampal sclerosis, brain tumours, vascular malformations, glial scarring (including stroke and traumatic brain injury)
2. Genetic or presumed genetic
   - Dravet syndrome with SCN1A mutations
3. Neurodegenerative
   - Alzheimer’s disease
4. Metabolic
   - Inborn errors of metabolism, mitochondrial disorders
5. Infectious
   - Bacterial meningitis, encephalitis, neurocysticercosis

Question 6

What are focal onset seizures

Answer 6

seizures that begin only in one hemisphere, may spread to the contralateral hemisphere, where they will then be known as secondary generalised seizures

Question 7

What are generalised onset seizures

Answer 7

seizures that begin in both hemispheres

Question 8

Describe the presentation of a generalised tonic-clonic seizure (Grand mal)

Answer 8

beginning with limb stiffening (tonic phase) followed by jerking of limbs and face (clonic phase)

Question 9

Describe the presentation of a generalised absence seizure (Petit mal)

Answer 9

basic lapse in awareness that begins and ends abruptly, sometimes mistaken as persistent staring

Question 10

What are the 4 symptoms that come with focal onset seizures?

Answer 10

• Motor symptoms → clonic movements (eg. twitching or jerking) of the arm, shouldder, face or leg; speech arrest
• Sensory symptoms → feeling of numbness or tingling; visual disturbances (flashing lights); rising epigastric sensation
• Autonomic symptoms → sweating, salivation, pallor, changing BP and HR
• Psychic (somatosensory) → flashbacks; visual, auditory, gustatory or olfactory hallucinations; affective symptoms include fear (most common), depression, anger and irritability

Question 11

What investigations can be conducted to confirm seizures? (3)

Answer 11

1. Scalp EEG (positive proves, negative does not mean seizures are absent)
2. MRI (help identify focal lesions)
3. Biochemical/toxicology (electrolyte abnormalities, serum prolactin, CK levels)

Question 12

What are the 4 means of non-pharmacological management for epilepsy?

Answer 12

1. Ketogenic diet (low carb high fat to induce ketosis)
2. Vagus nerve stimulation
3. Responsive neurostimulator system (stimulator implanted in skill w leads to the brain for continuous monitoring)
4. epilepsy surgery

Question 13

What are examples of seizure triggers? (8)

Answer 13

• Hyperventilation
• Photostimulation
• Physical and emotional stress
• Sleep deprivation
• Sensory stimuli
• Infection
• Hormonal changes (time of menses, puberty or pregnancy)
• Drugs (eg. theophylline, alcohol, high-dose phenothiazines, antidepressants especially bupripion, tramadol, carbapenems)

Question 14

What are the 1st gen ASMs? (4)

Answer 14

carbamazepine
phenobarbital
phenytoin
valproate

Question 15

What are the 2nd gen ASMs? (5)

Answer 15

lamotrigene
levetiracetam
gabapentin
pregabalin
topiramate

Question 16

What drugs can be used for new onset focal seizures? (4)

Answer 16

carbamazepine
phenytoin
lamotrigene
levetiracetam

(CP, LL)

Question 17

What drugs can be used for refractory focal seizures? (2)

Answer 17

clobazam, pregabalin

Question 18

What drugs can be used for new onset generalised seizures? (4)

Answer 18

carbamazepine
vaproate
lamotrigene
topiramate

(CV, LT)

Question 19

What drugs can be used for refractory generalised seizures? (2)

Answer 19

clobazam, levetiracetam

Question 20

Of the 1st generation ASMs, which drugs are CYP inducers and inhibitors

Answer 20

Inducers: carbamazepine, phenytoin, phenobarbitone
Inhibitors: valproate

Question 21

Which drug undergoes autoinduction?

Answer 21

Carbamazepine

Question 22

Which drug follows non-linear kinetics?

Answer 22

Phenytoin

Question 23

What 4 classes of drugs commonly have DDIs with ASMs?

Answer 23

1. antidepressants
2. antipsychotics
3. immunosuppressive therapy
4. chemotherapy drugs

Question 24

Under what circumstances should phenytoin dosing regime be altered? (2)

(think absorption and DDI)

Answer 24

If patient taking >400mg, split dose for better absorption

Space 2h apart from enteral feeds

Question 25

How should phenytoin concentration be calculated for in albumin <40g/L

Answer 25

Winter-Tozer eqn

Question 26

What phenomenon is valproate subjected to?

Answer 26

Saturable protein binding within therapeutic range (lower protein binding at higher drug concentrations)

Question 27

When does maximum autoinduction occur after initiating carbamazepine

Answer 27

2-3 weeks Hence start at a dose below the maintenance dose

Question 28

What are the 4 broad classes of general SEs in ASMs?

Answer 28

1. CNS (somnolence, dizziness, ataxia) 2. GI (n&V, especially w CBZ and VPA) 3. Psych (behavioural disturbances, especially with levetiracetam) 4. Cognition (slurred speech, especially with topiramate)

Question 29

What should be tested for for hypersensitivity reactions

Answer 29

- HLA-B*1502 genotyping prior to starting carbamazepine - **HLA-B*1502** positive patients should avoid carbamazepine and phenytoin

Question 30

Which is considered the "clean and easy to use" drug

Answer 30

Levetiracetam

Question 31

How should ASM treatment be assessed (when to discontinue)? (4)

Answer 31

- If the patient achieves seizure freedom but has intolerable side effects, decrease ASM dose and monitor - If the patient achieves seizure freedom and has optimal QoL for more than 2 years, consider withdrawing ASM - If the patient is unable to achieve seizure freedom with monotherapy, lower the dose of the first ASM and add on a second ASM - If the patient is still not seizure free, remove the least effective ASM and add another second ASM

Question 32

What are indications for TDM? (4)

Answer 32

- **To establish an individual’s “therapeutic range”** → this is usually a lab reported reference range which may not be effective for all; once the patient is stable, document effective level which controls seizures while minimising side effects, which helps in subsequent changes (anticipated PK changes, DDIs and medical conditions) - **To assess lack of efficacy** → fast metabolisers, adherence issues, other problems; helps in deciding when to change drugs vs when to rework diagnosis (eg. is this the right drug for the right disease?) - **To assess potential toxicity** → changing physiology, slow metabolisers, changes in disease or drugs (eg. renal (uremia, hypoalbuminemia), liver (CYP enzymes)) - **To assess loss of efficacy (breakthrough seizures)** → changes in physiology (age, pregnancy), changes in pathology, changed formulation (brand vs generic, dosage forms), drug interactions

Question 33

What are there reference ranges for the the 4 first generation drugs?

Answer 33

- Carbamazepine → 4-12 mg/L - Phenytoin → 10-20 mg - Phenobarbital → 15-40 mg/L - Valproate → 50-100 mg/L

Question 34

-

Answer 34

-

Question 35

Which is the drug of choice in seizures in pregnancy?

Answer 35

Levetiractam, lamotrigene

Question 36

What should be taken note for women on lamotrigene?

Answer 36

OCs may lower lamotrigene contraceptions resulting in breakthrough seizures