1. Anticonvulsant Therapy
Dr. Sia Michoulas
Pediatric Epilepsy Fellow
BC Children’s Hospital

2. Outline Introduction Why do we treat seizures
How do we select anticonvulsant medications
Adverse Effects
Drug Interactions
Anticonvulsants and Pregnancy

3. Epidemiology of Epilepsy
1- 2 % of Canadians
40, 000 people in BC
Cerebral Palsy – 20%
Autism – 20-30%
Mental Retardation - >20%
3rd most common neurologic disorder
After Stroke and Alzheimer’s
Cause of epilepsy is also cause of MR

4. What was the cause of the seizure?
Epileptic seizures are symptoms due to a variety of causes
Determining the underlying cause has implications for both treatment and prognosis

5. Seizure Occurrence
Up to 10% of the population will experience a seizures during there lifetime
majority due to an acute reversible cause: fever, metabolic changes, drug intoxication/withdrawal.
Since seizures don’t reoccur in these patients after the provoking factor has been corrected, they don’t have a diagnosis of epilepsy.
A diagnosis of epilepsy is made after a patient has had 2 or more unprovoked seizures
Epilepsy is defined as 2 or more unprovoked seizures.

6. Causes epileptic seizures
Idiopathic (Genetic) % of cases
Childhood and Juvenile absence epilepsy
Benign rolandic epilepsy of childhood
Juvenile myoclonic epilepsy (JME)
Symptomatic - 50% of cases
Malformations of brain developmental
Tuberous Sclerosis
Brain Infection
Stroke
Traumatic brain injury
Tumor
Approximatley 50% of patients with epilepsy do not have a brain lesion and genetic factors predispose them to recurrent seizures. The term idiopathic has been used to describe this genetic predisposition to epileptic seizures.
Approximatley 50% of patients with epilepsy have an underlying brain abnormality. This is called symptomatic when the underlying cause is shown and is called probably symptomatic or cryptogenic when an underlying leison is suspected but not demonstrated.

7. Clinical Factors Associated with Idiopathic versus Symptomatic Epilepsy
Determining the underlying cause of the epilepsy will influence treatment, treatment duration and prognosis.

8. Seizure Manifestations
A seizure is a sudden disruption of the brain's normal electrical activity. This may result in motor activity, sensory symptoms, behavior changes and or altered conciousness depending on which area(s) of the brain are involved.

10. Why Do We Treat Seizures?
Prevent Falls & Injuries
Employment & Education
Psychosocial well-being
Anxiety
Embarrassment
Loss of self-control
Driving
Life-style restriction
It is not to prevent brain damage. Seizures do not cause brain amage unless > 30 min. Give BREC---don’t treat.

11. AED Very Old Old New Even Newer The Newest Bromides (1861)
Phenobarbital (1912)
Phenytoin (DilantinR)(1936)
Diazepam (ValiumR)(1960’s)
Carbamazepine (TegratolR) (1974)
Valproic Acid (DepakoteR) (1978)
New
Clobazam (FrisiumR)
Lamotrigine (LamictalR)
Topiramate (TopamaxR)
Vigabatrin (SabrilR)
Even Newer
Levetiracetam (KeppraR)
Oxcarbazepine (TrileptalR)
The Newest
Lacosamide (VimpatR)
Rufinamide (BanzelR)

12. When do you consider starting treatment?
After first unprovoked seizure 50% of patients will have a 2nd seizure. This needs to be balanced against the potential side-effects and cost of medication.
In general treatment is started after the 2nd seizure.
Clinical trials have demonstrated that early treatment (after 1st seizure) significantly reduces the risk of 2nd seizure but does NOT affect natural history and overall prognosis

13. How effective are medications?
70% of patients will respond
(1st or 2nd drug)
If 2 appropriate drugs fails
3rd drug: approximate 5% success rate
If 3rd drug fails: “refractory epilepsy”
Other treatments
Ketogenic diet
Epilepsy Surgery

14. Goals of Anticonvulsant Treatment
Complete Suppression of Seizures
with NO side-effects
Maintain/Restore patients lifestyle
Anticonsulsant medication do NOT cure epilepsy. They suppress the seizure, but the underlying cause of the seizures is not treat the underlying cause (eg brain malfornation).

15. Case #1
Mark is an 7 year boy seen in the neurology clinic accompanied by his mom. Teachers have noticed “staring spells” at school.

16. Principles of AED therapy
Select most appropriate drug
Seizure type
Epilepsy Syndrome
Individual patient factors
adverse effect, cost, patient-lifestyle
dosing schedule
Co-morbidities
Epilepsy Syndrome: Expected response; duration of treatment; pronosis.
Headache, mood disorder, weight, sleep disturbance

17. Principles of AED therapy
2. Optimize Dosage
start low dose, titrate up to maximum dose
Minimize initiation related side-effects
End Point:
seizures controlled or side-effects occur
Side effects more common when using high doses or multiple anticonvulsant medication.

18. Principles of AED therapy
Drug level monitoring
Target blood drug level
Helpful in guiding dose adjustments
Treat the INDIVIDUAL
NOT the therapeutic range
Should be restricted to answering a specific clinical question for that person
Unexpected loss of seizure control
Unexpected occurrence of side-effects
The addition of a drug that may interact and alter blood levels.
Exception is dilantin, more frequent monitoring.

19. Adverse Effects

20. Adverse Effects Initiation & Dose related adverse effects
Chronic adverse effects
Idiosyncratic “allergic” reactions
Thus given warning if skin rash, fever, lethargy, jaundic, loss of appetite, or easy bruising/bleeding contact doctor.
Drowsiness, GI, balance, sleep disorbance, mood disorder

21. Case #1
Mark’s mom calls your office 2 weeks later. Patient has been increasing the medication every 5 days but noticing that she is more “sleepy” during the day.

22. Adverse Effects Initiation & Dose related adverse effects
Important to recognize
Seldom are serious – reversible
Decreasing medication
Discontinuing medication
Change titration schedule to every week, to minimize side effects.
Psychiatric co-morbidity.

23. Case # 2
Sarah 14 year old girl. She has experience 2 brief generalized tonic-clonic seizures.
Decision is made start anticonvulsant medication.
She is started on lamotrigine (LamictalR)

24. Lamotrigine (LamictalR)
Advantages
Effective
Well-tolerated
Twice daily
Disadvantages
Allergic Rash
Titrate Slowly
Mild drowsiness, titration/dose dependent

25. Case #2 Sarah returns to your office 3 weeks later.
She has developed a rash and fever.

26. Most rashes are NOT caused by medication
Most rashes are NOT caused by medication. 9 out 10 times the rashes we see are due to other causes. Mostly viral rashes.

29. Idiosyncratic “allergic” reactions
Unpredictable
NOT dose-dependent
Usually occur early in the course of treatment
Range: Mild-> severe
Rare: 1 in 20,000 – 50,000
Manifest as severe skin reaction, liver failure, pancreatitis,and even psychosis
May be underlying genetic differences, resulting in difference in drug metabolism, leading to the accumulation of toxic metabolic products.

30. Idiosyncratic “allergic” reactions
Skin Rash
Usually within 4 – 6 weeks
Titrate dose up slowly
Mild - Severe
Reversible if discontinued early!!
AED: lamotrigine 1:
Others: phenytoin, carbamazepine, phenobarbital

31. Idiosyncratic “allergic” reactions
Liver
Usually occurs early in treatment
Can be reversible if medication is stopped early
Blood
Symptoms:
Bleeding, bruising, persistent infections
Up to 30% if cases can be fatal, if not detected and medication stopped early
Usually occurs early in treatment
AED: all except gabapentin, lamotrigine, topiramate, levateracetam
Symptoms:
Lethargy, loss of seizure control, vomiting, loss of appetite
Rash and fever >80%

32. Carbamazepine (TegratolR)
Advantages
Effective
Well tolerated
Min sedation, behavioral side-effects
Disadvantages
“allergic” reaction
Skin
Aplastic anemia
Drug Interactions
May exacerbate seizures
Myoclonic, absence

33. Carbamazepine Rare serious & potentially fatal skin reactions:
1 to 6 per 10, 000 patient
Asian Ancestry: risk 10 times higher

34. Carbamazepine Genetic Marker Asian Ancestry: prevalence of this allele
Inherited variant of a gene (HLA-B 1502 allele)
Patients with this variant are at a higher risk
It is possible to screen: blood test
Asian Ancestry: prevalence of this allele
High Risk: (10-15%)
China (Han Chinese), Thailand, Malaysia, Indonesia, Philippines, Taiwan
Moderate Risk: (5-10%)
South Asia
Low Risk: ( <1%)
Japanese or Korean
Studies has found a stron association between certain serious skin reaction and an inherited variant of a gene, HLA-B, an immune system gene, found almost exclusively in people with Asain ancestry.

35. Carbamazepine Note If already on carbamazepine for months
Unlikely to experience serious reaction
Patients with positive results may not get this reaction
Serious skin reactions can still occur in patients who test negative
Regardless of ethnicity
Monitor for signs and symptoms
Advances in science is now letting us individualize treatment based on how bodies may react to a medication.
Studies has found a stron association between certain serious skin reaction and an inherited variant of a gene, HLA-B, an immune system gene, found almost exclusively in people with Asain ancestry.

36. Anticonvulsant Medications

37. Valproic Acid (DepakoteR)
Advantages
Well tolerated
Broad spectrum
No effect on BCP
Disadvantages
Weight gain
Essential tremor
Hair thinning
Platelet dysfunction
Neural tube defects
Drug interactions
“allergic” reactions

38. Phenytoin (DilantinR)
Advantages
Effective
Broadspectrum
Chew tabs, capsules
Intravenous
Inexpensive
Once daily
Disadvantages
Therapeutic levels
Drug interactions
“Allergic” reactions

39. Topiramate (TopamaxR)
Effective
Migraine
No “allergic” reactions
Twice daily
Cognitive effects
Kidney Stones
Weight Loss

40. Levetiracetam (KeppraR)
Advantages
Effective
No drug interactions
Including OCP
Well tolerated
No “allergic” reactions
Can titrate fast
Disadvantages
Mild fatigue
Psychosis (0.6%)
Cost

41. Clobazam (FrisiumR) Advantages Disadvantages Effective Well tolerated
Once or twice daily
Disadvantages
Drowsiness
Headache
Unsteadiness
Rare
Behavior changes

42. Lacosamide (VimpatR) Advantages Disadvantages
Effective for focal seizures
Well tolerated
Disadvantages
Drowsiness
Headache
Unsteadiness
Rare
Heart arrhythmia
Rash
Suicidal behavior

43. Rufinamide (BanzelR) Advantages Disadvantages
Effective in Lennox-Gastaut Syndrome
Well tolerated
Disadvantages
Drowsiness
Headache
Unsteadiness
Loss of appetite
Rare
Heart arrhythmia
Rash
Suicidal behavior

44. Drug Interactions

45. Why do drug interactions occur?
Increase breakdown of other drugs
Decrease breakdown of other drugs

46. Drug Interactions: Birth Control Pill
Reduce Effectiveness
Carbamazepine
Oxcarbazepine
Phenobarbital
Phenytoin
Topiramate
Lamotrigine
No Effect
Clobazam
Clonazepam
Ethosuximide
Gabapentin
Levetiracetam
Valproic Acid
Numerous drug interaction can occur with other medication aside from AED’s, including antibiotics, antidepressant, chemotherapies. A number of anticonvulsant can reduce the effectiveness. Barrier methods, IUD’s
The following medication have been shown to induce the metabolism of the estrogen/progestron compontents of BCP. Thus in women receiving AED..the efficacy of the pill may be reduce. Anticoagulation, has narrow therapeutic window…leading to serious complications (clots/strokes or bleeding) particularily when stopping the drug (0-10 fold change in warfain dose). Phenytoin interaction is more complex, may involve increase of decrease warfarin level. Careful monitoring of the INR needed when comedication

47. When do you stop anticonvulsant medications
Need to continue AED therapy should be re- evaluated after 2 years seizures free.
Factors favoring low risk recurrence
Minimum 2 years seizure free
Normal EEG
Normal Neurological Examination
Ease of controlling seizures
Slow withdrawal of medications:
over 2-3 months

48. Anticonvulsant Medication and Pregnancy

49. Anticonvulsants and Pregnancy
> 90% of women with epilepsy will have a healthy baby
Slightly higher risk for major congenital malformation
General population: 2-3%
Untreated epilepsy: 2-5%
All anticonvulsant drugs: 4-7%
Issues: Seizure control and risk of drugs and seizure to the fetus.
Lamotrigine 3-4%, CBZ 2-5%; VPA 8-16%; DPH 4-11%
Other risk factors for congenital malformation. Include alcohol, malnutrition (folic acid) and genetics.

50. Anticonvulsants and Pregnancy
Planned Pregnancy
Talk to doctor
Ideally one drug at lowest possible dose
Monotherapy: 4.5% vs polytherapy 7%
Folic Acid
0.4mg/day all women of child baring age
Higher dose (4-5mg/day): women with epilepsy of child baring age
Vitamin K
Start 10mg orally at 36 weeks
1mg intramuscular to newborn
40% of all pregnancy are unplanned. NTD occur in the first 4 weeks.

51. Conclusion Epilepsy is common
We treat seizures to prevent injury and maintain active lifestyle
We select anticonvulsant medications
Seizure types, drug profile, individual factors
Adverse Effects
Drug Interactions
Anticonvulsants and Pregnancy 51