treatment of epilepsy Flashcards
Epilepsy epidemiology
Bimodal age distribution: < 1y and > 60y
Mean age of onset = 11.1y
Mortality risk of epilepsy
Increased 2-3 fold Highest within first 12m in diagnosis Sudden Unexplained Death in Epilepsy (SUDEP) Status epilepticus Unintentional injuries Suicide
Characteristics of SUDEP
Peak at 20-40y
Mostly unwitnessed and sleep related
Risk factors: Presence and frequency of generalised tonic-clonic seizures; nocturnal seizures; lack of seizure freedom
Seizure definition
Transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain
Epilepsy definition
Any of:
- At least 2 unprovoked seizures occurring > 24h apart
- One unprovoked seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10y
- Diagnosis of an epilepsy syndrome
Provoked seizures (Acute symptomatic seizure)
Events occurring in close temporal relationship with an acute CNS insult with varying intervals according to underlying condition
- metabolic
- toxic
- structural
- infectious
- inflammation
Pathophysiology
Hyperexcitability and hypersynchronisation
Can be traced back to instability in a single neuronal cell membrane or group of cells around it
Synchronised paroxysmal discharges occurring in a large population of neurons within the cortex
Causes of hyperexcitability
Voltage/ligand-gated K+, Na+, Ca2+ and Cl- ion channels
Abnormalities in intra/extracellular substances
Excessive excitatory neurotransmitters
Insufficient inhibitory neurotransmitters
Etiology of epilepsy
Genetics Structural Metabolic Immune Infectious Unknown
Classification of seizures
Based on mode of onset:
- Focal onset (begins in one hemisphere)
- Generalised onset (begins in both hemispheres)
Impairment of consciousness (with or without dyscognitive features)
Generalised tonic-clonic (grand-mal) seizures
Stiffening of limbs (tonic phase), then jerking of limbs and face (clonic phase)
Clonic phase lasts 1min
Incontinence with biting of tongue or inside of mouth
May have headache and appear lethargic, confused or sleepy after seizure
Full recovery takes several minutes to hours
Generalised clonic seizures
Clonic jerking that is asymmetrical and irregular
Most common in neonates, infants or young children
Generalised tonic seizures
Sudden loss of consciousness and rigid posture of entire body, lasting 10-20s
Occurs at all ages, associated with diffuse cerebral damage and learning disabilities
Characteristic and defining in Lennox-Gastaut syndrome
Generalised myoclonic seizures
Rapid, brief contractions of bodily muscles, usually on both sides concurrently
May involve just one arm or one foot
Generalised absence (petit mal) seizures
Basic lapse in awareness that begins and ends abruptly
Lasts only a few seconds, no warning, no after-effects
Often undetected
More common in children, 4-12y
Differences between generalised absence and complex partial seizures
Never preceded by auras
Lasts seconds
Begin frequently and end abruptly
Produce characteristic EEG pattern “3Hz spike waves”
Generalised atonic seizures
Classic drop attack, all postural tone suddenly lost
Short episode followed by immediate recovery
Occurs at any age, associated with diffuse cerebral damage and learning disabilities
Common in severe symptomatic epilepsies
Risk of seizure recurrence
Within the next 5y: ~30%, higher in the 1st 2y
Higher risk in the presence of:
- epileptic abnormalities on EEG
- prior brain insult
- structural abnormality in brain imaging
- nocturnal seizure
Risk of recurrent seizures after 2 unprovoked seizures at 4y ~70%
When is treatment not initiated?
First unprovoked seizure None of the following: - epileptic abnormalities on EEG - prior brain insult - structural abnormality in brain imaging - nocturnal seizure
Treatment goals
Absence of epileptic seizures
Absence of ASM-related side effects
Attainment of optimal QOL
2/3 can achieve seizure freedom
Non pharmacological treatment
Keto diet
Vagus nerve stimulation
Responsive neurostimulator system
Surgery
Factors for ASM choice
Seizure type, epilepsy syndrome
Co-medication and comorbidities
Advantages of monotherapy
Likely lower incidence of AE Easier to correlate response and AE Absence of DI Reduced risk of birth defects Lower cost Better adherence
Initiation of treatment with 1st line ASM
Start with low dose of 1st line appropriate ASM
Gradually increase dose if not seizure free and no SE
Review of diagnosis and medication of max tolerated dose; check adherence
If failure of therapy
Substitution if AE or not tolerated at low doses or no improvement
Combination if tolerated first/second gen ASM but with suboptimal response
Seizure triggers
Hyperventilation Photostimulation Physical and emotional stress Sleep deprivation Electrolytes imbalance Sensory stimuli Infection Hormonal changes Drugs
Investigations
MRI with gadolinium for: - adult patients who presents with first seizure - pts with focal neurologic deficits - suggestion of focal onset seizure Biochemical/toxicology
Treatment options for new onset focal onset epilepsy
A - Carbamazepine* A - Levetiracetam* A - Phenytoin A (E) - Lamotrigine* A (E) - Gabapentine B - Valproate* C - Topiramate A - Zonisamide
Treatment options for new onset generalised tonic clonic epilepsy
Carbamazepine*
Lamotrigine*
Valproate*
Topiramate
Treatment options for refractory focal onset epilepsy
Clobazam
Lacosamide
Pregabalin
Perampanel
Treatment options for refractory generalised tonic clonic epilepsy
Clobazam
Levetiracetam
Considerations in epilepsy treatment
Migraine - topiramate, valproate
Depression/anxiety - use levetiracetam with caution
Women w child-bearing potential - avoid valproate consider levetiracetam/lamotrigine
1st generation AEM
Carbamazepine Phenobarbitone/Phenobarbital Phenytoin Sodium Valproate Primidone
2nd generation AEM
Gabapentin Lamotrigine Levetiracetam Pregabalin Topiramate Clobazam Vigabatrin
1st gen AEM PK
Highly protein bound
Hepatic elimination
Many DDI
2nd gen AEM PK
Reduced protein binding
Mostly renal elimination except lamotrigine
Fewer (no) DDI except lamotrigine
1st gen AEM effects on metabolism
Inducers: carbamazepine, phenytoin, phenobarbital
Inhibitor: valproate
Issues with enzyme-inducing ASMs
DDI - antidepressants and antipsychotics - immunosuppressive therapy - antiretroviral therapy - chemotherapeutic agents Reproductive hormone, sexual function, OCPs Sexual function and fertility in men Bone health Vascular risk
Phenytoin
Slow but complete absorption, reduced at higher (>400mg) doses, NGT and feeds interactions Highly albumin bound Zero-order kinetics Capacity limited clearance AE: osteomalacia
Valproate
F = 1.0
Highly albumin bound; saturable protein binding with higher conc
Competition with binding: PHT, warfarin, NSAIDs
AE: NV, weight gain, alopecia
Carbamazepine
Not available in IV formulation
F = 0.8
Highly protein bound
3A4 metabolised
Autoinduction; max 2-3w after dose initiation
Not to be started at desired maintenance dose
AE: NV, osteomalacia
AEs of ASMs
CNS - somnolence, fatigue, dizziness, visual disturbances, nystagmus, ataxia
Topiramate AE
Weight loss
Reduced speech fluency
Managing AEs
Initiating therapy at low dose, slowly increasing
Avoiding large dosage changes
Restricting to monotherapy
Adjusting administration schedule
Idiopathic AEs
Blood dyscrasia (aplastic anemia, agranulocytosis) Hepatotoxicity (1st gen) Pancreatitis (valproate) Lupus-like reaction Exfoliative dermatitis TEN/SJS
Neurological AEs
Encephalopathy (high dose phenytoin, phenobarbitone) Pheripheral neuropathy (long term phenytoin, carbamazepine, phenobarbitone)
Indications for ASM TDM
Establish individual’s therapeutic range
Assess lack of efficacy
Assess potential toxicity
Assess loss of efficacy (breakthrough seizures)
Women of childbearing age
Potential risk to fetus via uncontrolled seizures and teratogenic potential
Lamotrigine
Pregnancy and lactation
Referred to specialist care
Not an absolute contraindication to breastfeeding
Discontinuation
Considered if min 2y seizure free
Longer than 2y if increased risk of seizure recurrence
Tapering schedule to be individualised
Status Epilepticus windows
GTC: seizure > 5min, neuronal damage if > 30min
Treatment for SE once past 5min to prevent progression to > 30min
SE Treatment
5-20min IV Midazolam IV Lorazepam IV Diazepam 20-40min IV Fosphenytoin IV Valproic acid IV levetiracetam IV Phenobarbital
