Epilepsy Flashcards
What is the Aim of Therapy?
Complete suppression of seizures (reduction in seizures) without adverse effects/complications
There are different types of epilepsy, what does this mean for treatment?
The specific type of epilepsy will have an impact upon the choice of anticonvulsant
When should treatment start?
- After 2 seizures if both severe
- If seizures occurred within 6-12 months
- If patient wishes to start treatment
- Considered after first seizure when:
- Epileptiform abnormalities on EEG
- Abnormal neurological examination
- Lesion on neuroimaging
What are some lifestyle advice points?
- Identify triggers that bring on seizures (e.g. sleep deprivation, illicit drugs, stress)
- Avoid dangerous situations like driving, swimming, climbing, long bath, operating machinery
- Legal obligations (drivers licence may be taken away)
- Concomitant Prescription Drugs
- Known to provoke seizures (e.g. tramadol, lithium, clozapine)
- Lower seizure threshold (e.g. TCA)
- Enzyme induction/inhibition
Management of an Unprovoked First Seizure in Adults: What is the Risk for Seizure Recurrence?
50% of patients with first unprovoked seizure who aren’t treated will never have a 2nd seizure and therefore defer treatment until after seizure recurrence as AED treatment carries with it a substantial risk of S/Es – remaining 50% = risk of having a 2nd seizure within the 1st 2 years increased 4 times
Management of an Unprovoked First Seizure in Adults: Does immediate treatment with an AED change the short term (2 years) prognosis for seizure recurrence?
- If single seizure at random = not a huge difference if treated early
- If multiple seizures at random = better if treated early
Management of an Unprovoked First Seizure in Adults: Does immediate treatment with an AED compared with delay pending a seizure recurrence influence prognosis over the longer term (>3 years)?
- Every time an individual has a seizure, portion of brain dies = accumulating damage if you don’t treat
- Not a huge increase in incidence of sustained remission
- Don’t matter in the long term but in the short term, best to treat early
What are the Factors that Influence the Choice of AED?
- Select drug most appropriate for the type of seizure/syndrome
- Age
- Gender
- Adverse Effects
- CYP enzymes Interactions
- Drug-Drug Interactions
- Pharmacokinetics
- Presence of Comorbidities
- Formulations available
- Cost
What are the Factors that Influence the Choice of AED: Age
- In the elderly
- Increased vulnerability
- Titration and Tapering
- Infants
- WCBP
- Elderly
- Increased vulnerability to develop A/Es
- Different ADME profile
- Drugs slowly metabolised by liver or slowly excreted in the kidneys (check for normal kidney and liver function)
- Increased sensitivity to dose-related A/Es
- CNS or Non-CNS A/Es
- Different ADME profile
- Titration and tapering: start low, go slow
- More likely receiving polypharmacy to manage other health conditions (DDIs)
- Increased vulnerability to develop A/Es
- Infants
- Under developed livers and associated CYP enzymes
- WCBP
What are the Factors that Influence the Choice of AED: Gender - Women
- Bone loss (manage with prophylactic measures against osteoporosis)
- Reduction in bone density
- Reduction in Vitamin D
- Teratogenicity of AEDs
What are the Factors that Influence the Choice of AED? CYP Enzymes Interactions
- Inducers of CYP450
- Inhibitors of CYP450
-
Inducers of CYP450: phenytoin, carbamazepine, phenobarbital
- Can lead to therapeutic failure e.g. CBZ and COC – CBZ will induce CYP3A4 which also acts on COC – enzyme induction will bring about increased metabolism of estrogen in the pill hence becomes ineffective for intended purpose
- Inhibitors of CYP450: valproate
What are the Factors that Influence the Choice of AED - Drug Drug Interactions
- Lamotrigine with CBZ
- Lamotrigine with Valproate
- Lamotrigine with CBZ: induces activity of enzyme which means the t1/2 life of lamotrigine will decrease as more gets cleared
- Lamotrigine with Valproate: inhibits activity of enzyme, increasing the t1/2 life of lamotrigine
What are the Factors that Influence the Choice of AED - Pharmacokinetics
- Time to achieve therapeutic dose
- Phenytoin: can start at low therapeutic dose
- Lamotrigine: cannot start at therapeutic dose due to risk of idiosyncratic drug reactions à start low and up-titrate
- TDM
What are the Advantages of Monotherapy?
- Reduced frequency of adverse effects
- No DDIs
- Reduced risk of birth defects (valproate)
- Improved compliance
- Lower cost
- Equal or superior efficacy to many 2 or 3 drug regimens
Which Dose to Pick?
Unless immediate seizure control required, start low and up titrate as this reduces the risk of A/Es
What are the Reasons for Treatment Failure?
- Inappropriate diagnosis
- Poor compliance (especially if A/Es)
- Inappropriate drug choice (including wrong choice for type of seizure)
- Inappropriate dose
- Discontinuation due to idiosyncratic reaction
- Rash in response to Carbamazepine
- Potential for cross-reactivity with other aromatic AEDs (phenytoin, lamotrigine, phenobarbital)
- Rash in response to Carbamazepine
Discuss Transitional Polytherapy?
If patients experience adverse effects during titration?
If patients are seizure free and at risk of breakthrough seizures?
- Period when new AED is added and uptitrated while the existing baseline AED is tapered and withdrawn
- Baseline AED held at current dose to limit breakthrough seizures while new AED is titrated to a protective target dose followed by baseline AED tapered and withdrawn
- If patients experience adverse effects during titration: taper initial AED more rapidly and in larger doses
- If patients are seizure free and at risk of breakthrough seizures: taper initial AED slower in smaller doses
What is Drug Resistant Epilepsy?
Failure of adequate trials of two tolerated, appropriately chosen and used AED schedules
How are AEDs Discontinued?
- Discontinuation of AED treatment might be considered after at least 2-3 years of seizure freedom
* This also depends on what drug they’re on and how long process of tapering is going to take
When is Epilepsy Resolved?
- Past applicable age of an age-dependent epilepsy syndrome
- Seizure free for minimum past 10 years and off AED at least the last 5 years
What may reduce the level and efficacy of COCs, vaginal ring, oral progestogen-only contraceptives and etonogestrel implant?
- CYP3A4 inducers
- E.g. carbamazepine induces CYP3A4 enzyme – this induction increases the activity of the enzyme which causes increased metabolism of estrogen and progesterone in these forms of contraceptive methods and therefore there isn’t sufficient amount to give you cover for contraceptions
- Progestin-releasing IUD, medroxyprogesterone depot or copper IUD if possible as they are unaffected by enzyme inducing AEDs
What AEDs don’t affect hormonal contraception?
- Gabapentin, lacosamide, lamotrigine, levetiracetam, valproate, tiagabine and zonisamide
- Choose these if a patient is already on COC, then diagnosed with epilepsy
What should a patient do before pregnancy?
- Withdrawal of antiepileptic treatment in women planning pregnancy who have been seizure-free for at least 2 years
- If that’s not possible, they should be treated with the least teratogenic but most efficacious antiepileptic drug for their particular type of epilepsy at the lowest effective dose
What are Principles for AED use in pregnancy?
- Treatment should be continued only if it’s required to prevent seizures
- Monotherapy used where possible, minimise dose
- Avoid valproate unless other drugs unlikely to prevent seizures
- Changes to the treatment regimen, including attempts to withdraw medication, are best done well before planned conception
What AED dose adjustment and monitoring during pregnancy is recommended?
- Before conception, or as early as possible in pregnancy – establish a baseline
- Measure the serum concentration at least every 2 months during pregnancy and adjust the dose according to the baseline
- After child birth, maternal serum concentration should return back to normal value
Discuss the Teratogenicity of AEDs?
- Balance risk of congenital malformation from AEDs against dangers to mother and foetus of uncontrolled epilepsy
- Contraception is very important
- Gabapentin probably the safest in pregnancy
Discuss AED and Breastfeeding?
- Antiepileptic drugs do pass into breast milk, but the ratio of child to maternal plasma concentration is low
- Breastfeeding often aggravates sleep deprivation and this may provoke seizures
Discuss AED in Geriatric Patients?
- What may require lower doses?
- Newer AEDs are what?
- Gabapentin?
- Decreased renal or hepatic clearance may require lower doses
- Newer AEDs are better tolerated and less likely to cause drug interactions
- Gabapentin has no drug interactions so desirable, however completely renally cleared
What is Anticonvulsant Hypersensitivity Syndrome?
- What is it?
- What is the interval?
- What is it characterised by?
- Drug-induced, multi-organ syndrome which is potentially fatal
- Interval between first drug exposure and symptoms is usually 2-4 weeks
- Characterised by fever, rash, internal organs involvement (e.g. hepatitis, splenomegaly)
Anticonvulsant Hypersensitivity Syndrome: What drugs?
- Carbamazepine
- Primidone and phenobarbitone
- Lamotrigine
Cross reactivity of about 75% - if it occurs with one drug, then the others should be avoided
