Epilepsy Flashcards
How to differentiate between seizure and epilepsy?
Seizure - transient occurence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain
Epilepsy - brain disorder characterised by an enduring predisposition to generate epileptic seizures
Describe the underlying pathophysiology processes in seizures and epilepsy
Hyperexcitability and hypersynchronisation of neurons within the cortex
Etiology of epilepsy
- Genetic - gene or chromosome
- Structural - eg traumatic brain injury, tumours
- Metabolic - mitochondrial disorders, glucose transporter 1 deficiency
- Immune - antibody mediated
- Infectious - bacterial meningitis, HIV, meningo-TB
- Unknown
Discuss common clinical presentation of focal seizures without dyscognitive features
(motor, sensory, autonomic, psychic)
- Motor symptoms (twitching, speech arrest)
- Sensory (feelings of numbness or tingling, visual disturbances - flashing lights, rising epigastric sensation)
- Sweating, salivation, or pallor
- BP,HR increase
- Flashbacks
- Visual, auditory, gustatory or olfactory hallucinations
- Fear, depression, anger, irritability
Describe laboratory tests and investigations that are used in the diagnosis and management of seizures
Scalp electroencephalography
MRI
Biochemical/toxicology
What toxic substances or drugs can provoke seizures?
Illicit drugs (cocaine, amphetamine)
Drugs (TCA, carbapenems, baclofen)
ETOH (withdrawal and intoxication)
Benzodiazepine withdrawal
Describe appropriate first aid for a person with seizures
Ease person to the floor
Turn patient gently onto one side
Clear the area around the person of anything hard or sharp
Put something soft under his or her head
Remove eyeglasses
Loosen ties or anything around teh neck that may make it hard to breathe
Time the seizure. Call 911 if the seizure lasts longer than 5 minutes.
Describe common psychosocial challenges in people with epilepsy
Social stigma (marriage, starting a family)
Employment (PwE may require more time away from work for medical follow up, higher medical costs borne by employer)
Prohibited from driving
Caregiver burden
Discuss the non-pharmacological options available for epilepsy?
Ketogenic diet
Vagus nerve stimulation
Responsive neurostimulator system
Surgery
How is epilepsy classified?
- Based on mode of onset (focal onset - seizures only begin in one hemisphere, generalised onset - seizures begin in both hemispheres)
- Impairment of consciousness - loss of awareness to external stimuli or inability to respond to external stimuli in a purposely and appropriate manner - described as “with or without dyscognitive features”
What are focal onset seizures without dyscognitive features called?
Simple partial seizures
What are focal onset seizures with dycognitive features called?
Complex partial seizures
How is epilepsy classified?
- Based on mode of onset (focal onset - seizures only begin in one hemisphere, generalised onset - seizures begin in both hemispheres)
- Impairment of consciousness - loss of awareness to external stimuli or inability to respond to external stimuli in a purposely and appropriate manner - described as “with or without dyscognitive features”
- Other features of the seizure
Discuss common clinical presentation of focal seizures with dyscognitive features
Motor, sensory, autonomic, psychic symptoms (as with non-dyscognitive seizures)
Impaired consciousness
Automatisms - lip smacking, chewing or picking at their clothing unpurposefully
Discuss common clinical presentation of generalised onset tonic-clonic seizures
- stiffening of the limbs, followed by jerking of limbs and face
- cyanosis of nail beds, lips and face
- incontinence may occur, along with biting of the tongue or inside of the mouth; breathing may be noisy and appear to be laboured
- following the seizure, patient may have a headache and appear lethargic, confused or sleepy
- full recovery takes several minutes to hours
What is diagnosis based on?
History taking (description of onset, duration and characteristics of seizure) - positive identification of classical characteristics
Neurologic examination
Concomitant medical conditions
What are some classical characteristics that help to confirm the diagnosis of epilepsy
Aura Cyanosis Loss of consciousness Motor manifestations Generalised stiffness of limbs and body Jerking of limbs Tongue biting Urinary incontinence Post-ictal confusion Muscle soreness
What are some differential diagnoses of epilepsy that must be ruled out?
Syncope
Transient ischemic attack
Migraine
Psychogenic nonepileptic seizures
How can scalp electroencephalography help in the diagnosis and classification of seizures?
if diagnosis of seizures or epilepsy is considered, epileptiform discharges on EEG confirm diagnosis
A normal EEG does not exclude possibility of epilepsy
What are limitations of scalp EEGs?
Not all epileptic patients have an abnormal EEG
EEG can be abnormal in normal persons (false positives)
When would an MRI be ordered?
For adult patients who presents with first seizure, patients with focal neurologic deficits, suggestion of focal onset seizure
Identify focal lesions.
When would biochemical/toxicology investigations be useful?
To rule out electrolyte abnormalities
CK - raised after GTC
Risk of second seizure is higher in the presence of
- Epileptiform abnormalities on EEG
- prior brain insult (eg stroke, brain trauma)
- structural abnormality in brain imaging
- nocturnal seizure
Do we start all patients on AEM after first seizure?
No, only if they have risk factors that put them at higher risk of second seizure
Treatment goals for epilepsy
- Absence of epileptic seizures
- absence of AED-related side effects
- attainment of optimal quality of life
How should AED treatment strategy be individualised?
According to seizure type, co-medication and comorbidity
What considerations if patient has history of migraine or depression/anxiety?
Migraine - topiramate
Depression/anxiety - use levitiracetam with caution
What should you choose in women with child bearing potential?
Avoid valproate, consider levetiracetam/lamortrigine
Do we start all patients on AEM after first seizure?
No, only if they have risk factors that put them at higher risk of second seizure
Risk of recurrent seizures after 2 unprovoked seizures at 4 years ~70% - start treatment
Algorithm for initiation of treatment
Start with low doses of 1st line AED appropriate for the particular seizure type
If seizures continue but no side effects occur, gradually increase dose of AED
If seizures continue despite maximum tolerated dose of 1st line AED:
-diagnosis should be reviewed
-ensure that patient has received the appropriate drug for seizure type/epileptic syndrome
-check adherence
When should we consider substitution?
If the first AED produces an adverse drug reaction or is not tolerated at low doses or does not improve seizures
When should we consider combination therapy?
If patient tolerates the first or second AED but with a suboptimal response
Factors to consider when combining AEDs
Patients previous clinical response to each drug alone
Drugs mechanism of action
Drugs tolerability profile
Drugs PK profile
What is drug resistant epilepsy?
Failure of adequate trials of two tolerated, appropriately chosen and used antiepileptic drug schedules
In which population does ketogenic have evidence in?
Young children
Seizure triggers
Hyperventilation Photostimulation Physical and emotional stress Sleep deprivation Electrolytes imbalance Sensory stimuli Infection Hormonal changes (time of menses, puberty or pregnancy) Drugs (eg theophylline, alcohol, high dose phenothiazines, antidepressants esp bupropion, tramadol, carbapenems)
What to log in seizure diary?
Seizure frequency and types How long they last Changes in AEDs AED side effects Seizure triggers
If status epilepticus, what kind of drugs do we avoid?
Avoid drugs that require slow titration - lamotrigine and topiramate
We want to give a drug that can be given fast and titrate dose fast enough
What influences the choice of ASM?
- Seizure type
- Drug drug interactions
- Comorbidity
- Route of elimination
- Special populations (eg pregnancy)
- Patient’s lifestyle and preference (dosage form/formulation, dosing frequency, lifestyle, occupational considerations)
- National/institutional guidelines, availability, costs, financial subsidy
What are the first line treatments for new onset focal onset epilepsy? (ILAE)
Carbamazepine Levetiracetam Valproate Lamotrigine Oxcarbazepine
What are the first line treatments for new onset generalised tonic clonic epilepsy? (ILAE)
Lamotrigine
Valproate
Carbamazepine
What are the agents used for refractory focal onset epilepsy? (ILAE)
Clobazam
Pregabalin
what are the agents used for refractory generalised tonic-clonic epilepsy? (ILAE)
Clobazam
Levetiracetam
NICE guidelines: what are the recmomended first line AEDs for generalised tonic clonic seizures?
Carbamazepine
Lamotrigine
Oxcarbazepine
Sodium valproate
NICE guidelines: what are the recommended first line AEDs for focal seizures?
Carbamazepine Lamotrigine Levetiracetam Oxcarbamazepine Sodium valproate
1st generation antiepileptic drugs
Carbamazepine
Phenobarbitone
Phenytoin
Sodium valproate
2nd generation antiepileptic drugs
Gabapentin Lamotrigine Levetiracetam Pregabalin Topiramate
Which drugs act on voltage gated Na+ channels?
Phenytoin
Carbamazepine
Lamotrigine
What is the mechanism of acton of levitiracetam?
Synaptic vesicle glycoprotein 2A
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Whats the difference between 1st generation ASMs and newer ASMs in terms of PK characteristics?
newer ASMs have less of a protein binding issue, elimination comparatively is more via renal route, less concern for DDIs
Problems with 1st generation ASMs (carbamazepines, phenobarbital, phenytoin, valproate)
Poor water solubility
Extensive protein binding
Extensive oxidative metabolism
Multiple DDIs
Key players involved in drug interactions
CYP-P450
UGT
Transporters
What are the effects of First gen ASMs on drug metabolism?
Potent enzyming inducers:
- Carbamazepines - CYP (1A2, 2C, 3A4), UGTs
- Phenytoin -CYP (2C, 3A), UGTs
- Phenobarbital/primidone - CYP (1A, 2A6, 2B, 3A), UGTs
Potent enzyme inhibitor:
- Valproate - CYP2C9, UGT
No effect on CYPs:
-ethosuximide
Which second generation ASM is a moderate inducer?
Topiramate (CYP3A) - for patients who require more than 200mg a day, have to be aware that there could potentially be clinically significant DDIs
What should be done during discontinuation of carbamazepine?
Activity of affected enzymes will return to baseline - CYP1A2, 2C, 3A4
Dose adjustments for drugs that are metabolised by the affected enzymes. (should titrate down)
What are issues with enzyme-inducing ASMs?
Drug drug interactions
- Antidepressants and antipsychotics
- Immunosuppressive therapy
- antiretroviral therapy
- chemotherapeutic agents
Reproductive hormones, sexual function, OC in women (rendered inadequate)
Sexual function and fertility in men
Bone health - osteopenia and osteomalacia
Vascular risk - affects metabolism of cholesterol
How does albumin affect phenytoin dosing?
Phenytoin is highly albumin bound
Low albumin increases free phenytoin
Protein binding can be altered by displacement - uraemia
-→ need to correct for albumin level
Implication of kinetics of phenytoin on dosing
Zero-order kinetics
Capacity-limited clearance (clearance will decrease with increasing concentration)
Unlike first-order kinetics, concentration increment is NOT proportional to dose increment
Formulations of phenytoin
Capsules, syrup and IVa
How does albumin affect phenytoin dosing?
Phenytoin is highly albumin bound
Low albumin increases free phenytoin
Protein binding can be altered by displacement - uraemia
-→ need to correct for albumin level
Formulations of valproate
IV, tablet, enteric coated, syrup
How does albumin affect valproate?
Valproate is highly albumin bound
- Saturable protein binding within therapeutic range (decreased protein binding with higher concentration, higher free fraction of drug with low albumin)
- Displacement by endogenous compounds (uremia, hyperbilirubinemia)
- Competition for binding: PHT, warfarin, NSAIDs
What is the difference between valproate and phenytoin?
Capacity limited clearance in phenytoin
Valproate - protein binding is saturable, leading to higher free fraction
Implication of saturable protein binding in valproate?
Total valproic acid concentrations increase in a nonlinear fashion with dosage increases (solid line), unbound or “free” valproic acid concentrations increase in a linear fashion with dosage increases (dashed line)
Implication: interpreting VPA level for patients with hypoalbuminemia
Formulation of carbamazepine
Tablets (immediate release and CR)
Is carbamazepine highly protein bound?
Yes, to albumin and alpha1-acid glycoprotein
Metabolism of carbamazepine
By CYp3a4
Carbamazepine-10,11-epoxide is active
Kinetics of carbamazepine
Undergoes autoinduction (induces its own metabolism) Clearance increase and half-life shorten → carbamazepine concentration decline and stabilise in accord with the new clearance and half life Maximal autoinduction usually occurs 2-3 weeks after dose initiation Implication: do not start with desired maintenance dose at the first dose, but gradually increase over the initial few weeks
Adverse effects of ASMs
CNS: somnolence, fatigue, dizziness, visual disturbances,
GI: nausea, vomiting (carbamazepine, valproate)
Psychiatric: behavioral disturbances (levitiracetam)
Cognition: usually speech fluency (topiramate)
How to minimise occurence and severity of dose-related adverse effects
Initiating therapy at a low dose and slowly increasing the dose
Avoiding large dosage changes
Restricting therapy to one drug only (if clinically feasible)
Adjusting the administration schedule (administration of largest dose at bedtime, dividing a daily dose into smaller doses given more frequently, use of sustained-release formulations, reducing the total daily dose)
Plasma concentration-related adverse effects of ASMs
CNS: somnolence, fatigue, dizziness, visual disturbances,
GI: nausea, vomiting (carbamazepine, valproate)
Psychiatric: behavioral disturbances (levitiracetam)
Cognition: usually speech fluency (topiramate)
Serious idiosyncratic reactions related to ASMs (except some 2nd generation ASMs)
Blood dyscrasia (aplastic anemia, agranulocytosis)
Hepatotoxicity (1st gen ASMs - phenytoin, valproate, carbamazepine)
Pancreatitis
Lupus-like reaction
Exfoliative dermatitis
Toxic epidermal necrolysis/SJS
Chronic adverse effects (drug-specific) - 11
Gingival hyperplasia (phenytoin)
Hirsutism (phenytoin)
Alopecia (sodium valproate)
Encephalopathy (phenytoin, phenobarbitone)
Peripheral neuropathy (phenytoin, carbamazepine, phenobarbitone)
Increased weight gain (valproate)
Anorexia and weight loss (topiramate)
Osteomalacia (phenytoin, phenobarbitone, carbamazepine) - potent enzyme inducers
Blood dyscrasias - ALL
Megaloblastic anemia (phenytoin)
Neonatal congenital defects (phenytoin, phenobarbital, topiramate)
What adverse effects are related to phenytoin?
gingival hyperplasia hirsutism encephalopathy peripheral neuropathy osteomalacia blood dyscrasia megaloblastic anemia neonatal congenital defects
Which ASM is related to anorexia and weight loss?
Which ASM is related to weight gain?
Weight loss - topiramate
Weight gain - valproate
Which adverse effects are related to carbamazepine, phenobarbitone and phenytoin?
Osteomalacia
Peripheral neuropathy
Risk management strategies for hypersensitivity reaction
Pharmacogenetic testing (carbamazepine) Follow dosing guidance (lamotrigine) Identify potential cross-sensitivity reaction (ASMs with aromatic rings)
What is the recommendation for pharmacogenetic testing?
Recommendations for HLA-B*1502 genotype testing prior to initiation of carbamazepine in new patients
Positive HLA-B*1502 should avoid…
Phenytoin and carbamazepine
Dosing recommendations for lamotrigine
Slow titration
Risk of serious cutaneous reaction higher with high starting doses, rapid dose escalation, concomitant valproate
25mg every other day vs 50mg/day - which one is for carbamazepine and which one is for valproate?
25mg every other day - valproate (inhibitor)
50mg/day - carbamazepine
Which ASMs have an aromatic ring?
Carbamazepine, lamotrigine, phenytoin, phenobarbital
Options for mdm Fc
Option1: Levetiracetam
Pros: predictable pharmacokinetics, minimal DDI, available data for use in pregnancy
Cons: higher risk possible mood changes, agitation, hostility in comorbid psychiatric
disorders
Option 2: Lamotrigine
Pros: less DDI, available data for use in pregnancy
Cons: slow titration schedule (to prevent severe cutaneous reaction)
Option 3: Carbamazepine
Pros: cheap, established efficacy in focal onset epilepsy
Cons: potent enzyme inducer, pharmacogenetic test done (HLA B*1502) required
before initiation
Indications for ASM TDM
- to establish an individual’s “therapeutic” range
- to assess lack of efficacy
- to assess potential toxicity
- to assess loss of efficacy
Reference ranges for phenytoin and valproate
10-20mg/L
50-100mg/L
Ref ranges for carbamazepine and phenobarbitone
4-12mg/L
15-40mgL
Special considerations for women of childbearing age
- Counselling on importance of early discussion on family planning
- Potential risk to fetus - Uncontrolled seizures and teratogenic potential of antiepileptic drugs
- Use of oral contraceptives (OC) may be rendered ineffective by potent enzyme inducers
- For patients on lamotrigine, OC may lower lamotrigine concentrations, resulting in breakthrough seizures
Can women breastfeed while taking ASM?
No, they are encouraged to breastfeed
When can ASM discontinuation be considered?
After a minimum of two years without a seizure
In patients with an increased risk of seizure recurrence, it is advisable to wait longer than two years before considering antiepileptic drug discontinuation
Definition of status epilepticus
SE is a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms which lead to abnormally prolonged seizures
At when should we trigger treatment for Status epilepticus?
after the 5 minute mark
When will a seizure cause irreversible long term consequences like neuronal injury, neuronal death, alteration of neuronal networks and functional deficits?
30 mins
What is the initial therapy of choice for SE?
Benzodiazepines
IM midazolam, IV lorazepam, IV diazepam
2nd line therapy of choice for SE?
IV phenytoin
IV valproic acid
IV levetiracetam
