epilepsy Flashcards
What is SUDEP?
Sudden unexplained death in epilepsy
What are the risk factors for SUDEP?
1) Presence and frequency of generalised tonic-clonic seizures
2) Nocturnal seizure
3) Lack of seizure freedom
What is a seizure?
A seizure is a transient occurrence of signs and symptoms due to synchronous or abnormally excessive neuronal activity in the brain
What is epilepsy?
A brain disorder characterized by an enduring predisposition to generate epileptic seizures
What are the conditions that define epilepsy?
Defined by any of the following condition
1) At least two separate unprovoked seizures episodes occurring > 24 hours apart
2) Diagnosis of an epilepsy syndrome
3) One unprovoked seizure and a probability of further seizures similar to general recurrence risk (60%) after two unprovoked seizure, occurring over the next 10 years
What events can provoke seizures?
1) Electrolyte imbalances
2) Toxic substance/ drugs
3) Structural insults
4) Infectious reasons (CNS infection, Febrile illness)
5) Inflammation
What are some of the electrolyte imbalance that can lead to seizure?
1) Hypoglycaemia
2) Hyponatremia
3) Hypocalcaemia
4) Hypomagnesemia
ALL Hypo
What are some of the structural insults that can lead to seizure?
1) Traumatic brain injury
2) Stroke
What are some of the toxic substances/ drug that causes seizure?
1) Illicit drug (Cocaine, Amphetamines)
2) Drugs (TCA, Carbapemen, Baclofen)
3) Alcohol
4) BZD withdrawal
What are main processes in the pathophysiology of a seizure?
1) Hyperexcitability
2) Hypersynchronization
Seizure activity is characterized by?
Synchronised paroxysmal discharge occurring in a large population of neurons within the cortex
What is hyperexcitability?
Enhanced deposition for a neuron to depolarize
What are main ion channels involved in depolarisation?
1) Voltage gated Na+ channel
2) Voltage gated Ca2+ channel
3) Voltage gated K+ channel
4) Voltage gated Cl- channel
What are the neurotransmitters that can lead to hyperexcitability?
1) Glutamine
2) Acetylcholine
3) Histamine
4) Cytokines
Insufficiency of which neurotransmitters can result in hyperexcitability
Inhibitory neurotransmitters such as
1) Dopamine
2) GABA
What can lead to hypersynchronization?
Intrinsic organization of local circuits can contributed to synchronization and promote generation of epileptiform activity
What cause is significant for childhood epilepsy
Genetic causes (e.g. Fragile X syndrome)
How many mode of onset are there in epilepsy?
2, focal and generalized
Describe “focal onset”
Seizures begins only in one hemisphere. May spread to the contralateral hemisphere
Describe “generalized onset”
Seizure begins in both hemisphere
What is significant in a seizure described to have dyscognitive feature?
Impairment of consciousness
How is impairment of consciousness described as?
Loss of awareness to external stimuli or inability to respond to external stimuli in a purposeful and appropriate manner
How are seizure types classified?
Based on 3 keys features
1) Where does the seizure begin in the brain
2) Level of awareness during the seizure
3) Other features of the seizure
Focal onset seizure without dyscognitive features are classified as?
Simple partial seizure
Focal onset seizure with dyscognitive feature are classified as?
Complex partial seizure
The clinical characteristics of a seizure will depend on?
1) Site of focus
2) Degree of “irritability” of the areas of the brain surrounding the focus
3) Intensity of the impulse
How are the clinical presentation of simple partial seizures classified?
1) Motor symptoms
2) Sensory symptoms
3) Autonomic symptoms
4) Psychic (or somatosensory) symptoms
What are the motor symptoms of simple partial seizures?
1) Clonic movement of the arm, shoulder, leg, face
2) Speech arrest
What are the sensory symptoms of a simple partial seizure?
1) Tingling sensation, feeling of numbness
2) Rising epigastric sensation
3) Visual disturbances
What are the autonomic symptoms of a simple partial seizure?
1) Increased HR and BP
2) Sweating, salivation or pallor
What are the psychic symptoms of a simple partial seizure?
1) Hallucinations
2) Flashbacks
3) Affective symptoms including fear, depression, anger, irritability
What are the clinical presentation of complex partial seizures?
1) Aura
2) Impaired consciousness
3) Automatisms
What are the some of the characteristics of the clinical presentation of complex partial seizures?
1) For Aura, visual disturbances (flashing lights) are similar to that of simple partial seizure
2) Impaired consciousness leads to amnesia to the event
3) Automatisms includes lip smacking/ chewing, picking at their clothing unpurposefully and
What are the type of seizures in generalized onset seizures?
1) Tonic-clonic, “Grand-Mal”
2) Clonic (Jerking)
3) Tonic (Stiffness)
4) Myoclonic
5) Absence, “Petit Mal”
6) Atonic (Rag-doll)
What are some characteristics seen during a tonic-clonic seizure?
1) Cyanosis
2) Stiffening of limbs (Tonic), jerking of limbs and face (Clonic)
3) Incontinence
4) Biting of the tongue, inside of mouth
5) Noisy breathing
What are some characteristics seen after a tonic-clonic seizure?
1) Patient has a headache and appear lethargic, confused or sleepy. Sore muscles
2) Full recovery can take hours or several minutes
What is a myoclonic seizure?
A seizure that involves rapid, brief contractions of bodily muscles on both sides of the body
What is the characteristic EEG pattern seen in Absence seizure?
“3Hz Spike waves”
During history taking what are some of the important things to ask?
Description of onset, duration and characteristics of the seizure
Ask patient for details of aura, preservation of consciousness and post-ictal state
What are some of the investigational tools used in the diagnosis of Epilepsy?
1) Scalp/ Video Electroencephalography (EEG)
2) MRI with gadolinium
3) Biochemical/toxicity labs
What are the limitation of EEG?
Not all epileptic patients have an abnormal EEG.
EEG can be abnormal in normal persons
What are the treatment goals for epilepsy?
1) Absence of epileptic seizure (Seizure freedom)
2) Absence of ADR
3) Attainment of optimal QoL
What are the non-pharmacological option for treatment of epilepsy?
1) Ketogenic diet
2) Vagus nerve stimulation
3) Responsive neurostimulator system (RNS)
4) Surgery
Anti epileptic drug (AED) should be individualised according to …?
1) Seizure type, epilepsy syndrome
2) Co-medication and co-morbidity
3) Patient’s lifestyle and preference
4) National/Institutional guidelines
What are the co-morbidities that we should take note of when giving AEDs?
1) Depression - Use levetiracetam with caution
2) Renal/liver impairment necessitating dose adjustment
3) Pregnancy
4) Migraine - consider topiramate, valproate
What are the advantages of monotherapy?
1) Lower incidence of ADR
2) Absence of DDI
3) Reduced risk of birth defects
4) Lower cost
5) Easier to correlate response and ADR
6) Better adherence
Is monotherapy preferred for AEDs?
Yes
How do we initiate AED treatment?
Start with low doses of an appropriate 1st line AED for a particular seizure type
If seizure continue but there no AED SEs, what do we do?
Gradually increase dose
If seizure continues despite maximum tolerate dose of 1st line AED, what do we do?
1) Review diagnosis
2) Ensure pt has received the appropriate drug for seizure type/ epileptic syndrome
3) Check adherence
When do we consider combination AED therapy?
When the patient tolerates the first and second AED but with a suboptimal response
When do we consider substitution monotherapy?
When first AED produces an ADR/ not well tolerated at low doses/ does not improve seizures
What are the factors to consider when combining AEDs?
1) Patient’s previous clinical response to each drug alone
2) Drug’s MOA
3) Drug tolerability profile
4) Drug PK
What does a ketogenic diet consist of?
Low carbs, high fat
When do we recommend ketogenic diet?
When patient cannot tolerate/ have not responded well to AED treatment
What type of seizure is Vagus nerve stimulator (VNS) indicated for?
Only for intractable focal seizure
How does VNS work?
During a seizure, the subcutaneously implanted stimulator delivers cyclical “on-demand” stimulation to the vagus nerve by placing a magnet next to it
Responsive neurostimulator system (RNS) are indicated for what group of patients?
1) Patient with partial-onset seizures
2) 2 or less epileptogenic foci has been localized
3) Refractory to 2 or more AED
4) Have frequent and disabling symptoms
How does RNS work?
Continuously monitors electrical activity in the brain, detects patient-specific patterns and deliver brief pulses of stimulation when it detect activity that can lead to seizure
What are the epileptic syndromes indicated for epilepsy surgery
1) Temporal lobe epilepsy
2) Frontal lobe epilepsy
What is the appropriate seizure first aid?
1) Ease the person on the floor and turn the person gently onto one side. Put something soft under his/her head
2) Clear the area
3) Remove eyewear and loosen ties/ anything around the neck
4) Time the seizure
5) Call emergency hotline if seizure episode > 5 mins
What are some treatment options for a new onset of focal onset epilepsy?
1) Carbamazepine
2) Valproate
3) Phenytoin
4) Gabapentin
5) Lamotrigine
6) Levetiracetam
7) Topiramate
8) Oxcarbazepine (FYI)
9) Zonisamide (FYI)
What are some treatment options for a new onset of generalized onset epilepsy?
1) Lamotrigine
2) Topiramate
3) Valproate
Which drugs are useful in elderly with new onset of focal onset epilepsy?
1) Lamotrigine
2) Gabapentin
What are some treatment options for refractory (stubborn) generalized onset epilepsy?
1) Clobazam
2) Levetiracetam
What are some treatment options for refractory (stubborn) focal onset epilepsy?
1) Clobazam
2) Lacosamide
3) Pregabalin
4) Perampanel
How can the cost of a drug affect treatment outcomes?
Affects adherence to treatment
Which AED can lead to teratogenicity?
1) Valproate
2) Phenytoin
3) Topiramate
Which AED inhibits voltage gated Na+ channel?
1) Carbamazepine
2) Phenytoin
3) Lamotrigine
4) Lacosamide
5) Oxcarbazepine (FYI)
6) Zonisamide (FYI)
Which drug inhibits SV2A? What is SV2A?
1) Levetiracetam
Synaptic vesicle glycoprotein 2A
What is the MOA of Valproate?
Block voltage gated Na+ and Ca2+ channels.
Also inhibits GABA transaminase
What are some common 1st generation AEDs?
1) Carbamazepine
2) Phenobarbitone/ Phenobarbital
3) Phenytoin
4) Sodium valproate
What are some common 2nd generation AEDs?
1) Gabapentin
2) Lamotrigine
3) Levetiracetam
4) Pregabalin
5) Topiramate
Which drugs are more commonly used for neuropathic pain?
1) Gabapentin
2) Pregabalin
What is the usual maintenance dose for phenytoin?
300-400mg/day
or
5-7 mg/kg/day
What is the usual maintenance dose for sodium valproate?
600 - 2000 mg/day
or
20-30 (max:60) mg/kg/day
What is the usual maintenance dose for carbamazepine?
800-1200 mg/day
What is the usual maintenance dose for phenobarbitone?
60-180 mg/day
What is the usual maintenance dose for lamotrigine?
100-200 mg/day
What is the usual maintenance dose for topiramate?
200-400 mg/day
What is the usual maintenance dose for levetiracetam?
1000-3000 mg/day
What are the PK issues with 1st generation AEDs?
1) Poor water solubility
2) Extensive protein binding
3) Extensive oxidative metabolism
4) Multiple DDRs
What are the protein binding % of the 1st gen AEDs?
1) Carba: 75-85
2) Phenobarbital: 50
3) Phenytoin: 90
4) Valproate: 75-95 (non-linear)
Which AED undergoes autoinduction?
Carbamazepine
What is the main route of elimination for 1st gen AED?
Hepatic elimination
Which 1st gen AED are CYP inducers
1) Carbamazepine
2) Phenytoin
3) Phenobarbital
Which 1st gen AED is CYP inhibitor?
Valproate
How does high protein binding lead to clinical implications?
Total drug level may not be reflective of drug effect. Patient with hypoalbuminemia leads to higher % of free drug, more effect
Does ESRF affect 1st gen AEDs? Why?
Yes, kidney produce albumin. Affect protein binding
What is the main route of elimination for Gabapentin?
100% renal
What is the main route of elimination for Pregabalin?
90% renal
What is the main route of elimination for Lamotrigine?
100% hepatic
What is the main route of elimination for Levetiracetam?
66% renal
What is the main route of elimination for Topiramate?
30-55% renal
What is the main route of elimination for Clobazam?
82% renal
Which AED has minimal protein binding?
1) Gabapentin (0%)
2) Pregabalin (0%)
3) Levetiracetam (<10%)
4) Topiramate (15%)
What are the key players for AED DDIs?
1) CYP-450
2) UGT
3) Transporters
Which AEDs does not have an effect on CYP?
1) Gabapentin
2) Levetiracetam
3) Pregabalin
What must be performed when AEDs that induce CYP are discontinued?
Dose adjust the drugs that are metabolized by the affected enzymes
What are the issues with enzyme-inducing AEDs?
1) DDIs
2) Affects reproductive hormones, sexual function, and Oral contraceptive effectiveness in women
3) Sexual function and fertility in men
4) Bone health
5) Vascular risk
What are the drug classes affected enzyme-inducing AEDs?
1) Antidepressants
2) Antipsychotics
3) Chemotherapeutic agents
4) Antiretroviral therapy
5) Immunosuppressive therapy
For Phenytoin, what PK factor is reduced at dose > 400 mg?
Absorption
What affects absorption of Phenytoin?
1) Dose > 400mg
2) NGT & feed interaction (Space 1-2 hours apart between feed and dosing)
What affects protein binding of Phenytoin?
1) Uraemia
2) Hypoalbuminemia
3) Other protein-binding drugs (NSAIDs, Valproate, Warfarin)
Describe the PK of phenytoin
1) Zero-order kinetics
2) Capacity-limited clearance (i.e. clearance is dependent on concentration, clearance decreases with increased concentration)
What does zero order kinetics of Phenytoin implies?
Concentration increment is not proportional to dose increment. Hence, phenytoin has a narrow therapeutic window
What are the dosage forms available for Phenytoin?
1) Syrup
2) IV
3) Capsules
What are the dosage forms available for Valproate?
1) Injection
2) Tab
3) Syrup
Describe the PK of Valproate
Saturable protein binding. Decreased protein binding at a higher concentration
What is the clinical implication of saturable protein binding?
Interpreting VPA level for patients with hypoalbuminemia.
The total levels of valproate does not accurately reflect clinical efficacy as clinical efficacy is directly correlate with the free drug level, not total levels
What are the dosage forms available for Carbamazepine?
Tablets (Immediate/ CR)
What is the active metabolite of Carbamazepine?
Carbamazepine-10,11-epoxide
Describe the PK of Carbamazepine
Undergo autoinduction. Maximal autoinduction occurs 2-3 weeks after dose initiation
What is the implication of autoinduction?
Do not start with desired maintenance dose at the first dose, but gradually increase over the initial few weeks.
What are the CNS SE of AEDs?
1) Somnolence
2) Fatigue
3) Dizziness
4) Visual disturbances
5) Nystagmus
6) Ataxia
What are the GI SE of AEDs?
1) Nausea/ Vomiting
Especially in Carbamazepine and Valproate
What are the psychiatric SE of AEDs?
1) Behavioural disturbances especially in levetiracetam
What are the cognitive SE of AED?
Affect speech fluency (Topiramate), start low go slow to mitigate cognition SE
What causes more SEs for combination therapy?
Additive neurologic effects of combining AEDs
How do you minimise occurrence and severity of dose-related SEs?
1) Initiating therapy at a low dose and slowly increasing the dose
2) Avoiding large dosage changes
3) Restricting therapy to only one drug (if clinically feasible)
4) Adjusting the administration schedule
How can you adjust the administration schedule of AEDs?
1) Administration of largest dose at bedtime
2) Dividing daily dose into smaller doses, given more frequently
3) Use of sustained release formulations
4) Reducing total daily dose
What are the idiopathic/ hypersensitivity related SEs of AEDs?
1) Steven-Johnson syndrome/ Toxic epidermal necrolysis
2) Exfoliative dermatitis
3) Lupus-like rxn
4) Pancreatitis (Valproate)
5) Hepatotoxicity (1st gen AED)
6) Aplastic anemia
How would you describe the chronic SEs of AED?
1) Tend to be drug specific, but no directly related to plasma concentration of AED
2) Not life threatening, but affect QoL
3) Can be avoided or minimised by appropriate preventive measure
What are some of the chronic SE of AEDs affecting connective tissue? What drug causes it?
1) Gingival hyperplasia / Phenytoin
2) Hirsutism / Phenytoin
3) Alopecia / Sodium valproate
What are some of the neurological SE of chronic AEDs use? What drug causes it?
1) Encephalopathy, commonly associated with prolonged phenytoin tx, may also occur with phenobarbitone
2) Peripheral neuropathy, associated with long-term phenytoin tx, may also be associated with carbamazepine and phenobarbitone
What are some of the GI SE of chronic AEDs use? What drug causes it?
1) Weight gain, often associated with sodium valproate
2) Anorexia and weight loss, associated with topiramate and felbamate
What are some of the endocrine SE of chronic AEDs use? What drug causes it and how?
1) Osteomalacia, associated with enzyme inducers
Increased hepatic metabolism of Vit D and/or inhibition of calcium absorption
What are some of the haemoatological SE of chronic AEDs use? What drug causes it ?
1) Blood dyscrasias, associated with nearly all AEDs
2) Megaloblastic anaemia (rare), occurs predominately in pt receiving phenytoin, also associated with carbamazepine and phenobarbitone
Which AED causes neonatal congenital defects?
1) Phenytoin
2) Phenobarbitone
3) Topiramate
4) Valproate (Cognition)
Can AEDs cause suicidality?
Yes, monitor symptoms
What must be tested for before initiating Carbamazepine?
HLA-B*1502 genotyping, relevant for Han Chinese and other Asian Ethnic group
What is the risk of combining lamotrigine and valproate
Risk of serious cutaneous reaction
What is the risk of starting high dose/ rapid dose escalation for lamotrigine?
Risk of serious cutaneous reaction
Recommendation for starting lamotrigine?
Slow dose titration
What are the common SE of carbamazepine?
1) Nystagmus
2) N/V, Dizziness, Drowsiness, headache
3) Lethargy
4) Blurred vision
5) Diplopia
6) Unsteadiness, incoordination
7) Ataxia
What are the common SE of Phenytoin?
Same as Carbamazepine
What are the common SE of valproate?
1) N/V
2) Weight gain
3) Ataxia
4) Tremor
What are the common SE of Phenobarbitone?
1) Sedation and drowsiness
What are the common SE of Levetiracetam?
1) Somnolence
2) Dizziness
3) Asthenia
4) Coordination difficulties at first 4 weeks
5) Headache
6) Irritability, aggression
What are the common SE of Lamotrigine?
1) Somnolence
2) Dizziness, N/V
3) Asthenia (abnormal physical weakness or lack of energy)
4) Incoordination
5) Headache
6) Tremor
What are the common SE of Topiramate?
1) Somnolence
2) Ataxia
3) Fatigue
4) Cognitive dysfunction
5) Weight loss
6) Nausea
What are the common SE of Pregabalin and gabapentin?
1) Drowsiness
2) Ataxia
3) Weight gain
4) Dizziness
What are the indications for AED therapeutic drug monitoring?
1) To establish an individual’s “therapeutic range”
2) To assess lack of efficacy
3) To assess potential toxicity
4) To assess loss of efficacy
What are the special population to take note of in AED treatment?
1) Women of childbearing age
2) Pregnancy and lactation
Is it contraindicated to breastfeed while on AEDs?
Not an absolute contraindication to breastfeeding. Refer to specialist care
Define status epilepticus
A condition resulting from either a failure of the mechanisms responsible for seizure termination or from the initiation of mechanism which lead to abnormally long seizures
What are the initial treatment option for status epilepticus?
1) IM Midazolam (Not IV)
2) IV Lorazepam
3) IV Diazepam
If IM/IV Benzodiazepines not available:
4) IV Phenobarbital
5) Rectal diazepam
6) Intranasal midazolam
Why are oral drugs not preferred for status epilepticus?
Risk of choking
What are the secondary treatment option for status epilepticus?
1) IV Fosphenytoin
2) IV Valproic acid
3) IV Levetiracetam
4) IV Phenobarbital
