Doctor Interview
| An Interview with Dr J M K Murthy, on "Treatment of Epilepsy" | |
Ans. The basic principles of epilepsy treatment include
- Complete seizure control
- No or minimal side effects
- Optimal quality of life
Treatment with antiepileptic drugs (AEDs) should always begin with monotherapy. Seizure remission can be achieved with monotherapy in about 70% of patients with epilepsy. In a recent study seizure remission with first monotherapy was 47% and with alternate monotherapy another 21% patients had seizure remission. The seizure remission rates were similar with both conventional AEDs and newer AEDs. Of the remaining patients, addition of second AED achieved seizure remission in only 23% of patients. Achieving further remission with the addition of third AED seems negligible. In this study, the overall seizure remission with monotherapy or two-drug therapy was 63%.
The other advantages of monotherapy include: fewer side effects, no drug interaction, reduced cost or medication, reduced teratogenic effects, better drug compliance, and improved quality of life.
Q2. How long should anti-epileptic drugs (AEDs) be administered?Ans. Duration of AED therapy and discontinuation AEDs should be individualized. Antiepileptic drug therapy controls seizures and improves the quality of life people with epilepsy, but has no influence on the natural course of the disease. Type of epilepsy or epilepsy syndrome determines the natural course of seizures.
Example: The chance of achieving seizure remission in a patient with temporal lobe epilepsy with the available AEDs is only 10%, often with polytherapy. However in patients with juvenile myoclonic epilepsy seizure remission with sodium valproate is very good and these patients require the drug for almost lifetime.
In majority of people with epilepsy, other than specific syndromes, discontinuation of AED therapy can be considered once a patient has been seizure free for more than 2 – 5 years. In children AED discontinuation can be considered if the child has been seizure free for 2 years.
The profile least likely to relapse is
- Seizure free for 2 – 5 years (mean 3.5 years) on AEDs
- Normal neurological examination and IQ
- Single type of seizure – partial or generalized
- EEG that normalized on treatment (American Academy of Neurology)
On AED withdrawal the chance of relapse is about 30% in children and 40% in adults. The best predictors of recurrence of seizures are older age, symptomatic epilepsy, and many seizures before therapy or inadequate response to initial AED therapy.
Q3. What are the steps involved while reducing the dose of AEDs?Ans. Individualize the drug withdrawal protocol based on the estimated risk of recurrence off treatment type.
Patient's life style and occupation should also be taken into consideration. For persons for whom driving is important may require drugs for lifetime.
Most drugs should be withdrawn slowly over a period of 3 to 6 months.
Drug withdrawal in patients receiving barbiturates and benzodiazepines should be very slow and over several months as these drugs are most likely to lead to withdrawal seizures.
In patients receiving polytherapy, sedating drugs such as barbiturates or benzodiazepines should be withdrawn first.
Q4. In your opinion when should an epileptic patient be admitted in the hospital?Ans. The indications for hospitalization for people with epilepsy include
- Seizure clusters
- Status epilepticus
- Severe adverse drug reactions
- Accidental or otherwise drug overdose
- While rescheduling drug therapy from poly therapy to mono or two drug therapy, when difficult to do on out patient basis.
Ans. The EEG provides specific information about epileptogenesis. The objectives of obtaining EEG in people with suspected epilepsy are: 1) to support the clinical diagnosis of epilepsy; 2) to aid in the syndromic classification of epilepsy, 3) to localize the epileptogenic zone, especially in presurgical candidates. Normal EEG findings, however, do not exclude the possibility of epilepsy.
An awake standard EEG record will record interictal epileptiform discharges (IEDs) in ~50% of adults with epilepsy. The chance of recording IEDs increases with multiple EEGs and it is 92% with four recordings. The yield substantially increases by recording during sleep, more so after overnight sleep deprivation. A single wake and sleep EEG provide information supportive of diagnosis and also classification of epilepsy in ~80% of patients.
The recording of IEDs depends on the seizure type, localization of epileptogenic zone, recording methodology, age at seizure onset, frequency of seizure activity, and not much on AED therapy. In an established case of epilepsy one should not stop AEDs, at times it is dangerous and may precipitate status epilepticus or seizure clusters. In patients with epilepsy on AEDs, the EEG yield will be high with multiple awake and sleep EEGs with activation procedures However in patients with new onset epilepsy, it will be appropriate to take EEG before starting AED therapy.
Q6. According to you do "control release formulations" have advantages over plain formulations? Can you explain?Ans. Yes, control release formulations have some distinct advantages. A controlled release dosage form is a system in which the rate of release is regulated and is supposed to be constant during GI transit. The advantage of controlled-release dosage formulations are 1) reduction in blood drug level fluctuations, 2) enhanced patient convenience and adherence, 3) reduction in adverse side effects, and 4) reduction in health care costs.
Tertogenic effects are likely to be more when the fetus is exposed to fluctuating drug levels It has been shown in experimental animals that the teratogenic effect of sodium valproate will be less with control release formulation.
Q7. When a patient is presented with focal seizures how would you treat?Ans. Currently for focal-onset seizures in adults virtually all first-line AEDs, carbamazepine, phenytoin, valproic acid, phenobarbital, and primidone and most of the new AEDs, are equally effective.
However phenobarbital and primidone produce higher number of side effects.
My first line drug for patients with complex partial seizures in adults is carbamazepine. The alternative drugs are phenytoin valproic acid. For adults with focal-onset seizures with generalization, carbamazepine or phenytoin are the drugs. I will be hesitant to use phenytoin in women for its side effects such as hirsutism. I use rarely valproic acid as first line drug in patients with focal-onset seizures with generalization.
In children carbamazepine or valproic acid appear reasonable in most of cases. I will be careful to use phenytoin in children for its unpredictable pharmocokinetics and cosmetic side effects such as hirsutism and gingival hyperplasia.
All newer AEDs have been found equally effective in adults with focal-onset seizures. The experience with the newer drugs in children with focal-onset seizures is also similar.
Q8. How does sodium valproate compare to carbamazepine in focal epilepsy?Ans. In Veteran Affairs (USA) study carbamazepine and valproic acid worked equally well against secondarily generalized tonic-clonic seizures. Carbamazepine had greater efficacy against partial complex seizures.
Q9. For optimal management of epileptic seizures during pregnancy what therapy would you recommend?Ans. While treating women with epilepsy and pregnancy many issues need to be considered. These include
- Effect of pregnancy on epilepsy
- Effect of epilepsy and epilepsy treatment on pregnancy
- Tertogenic and other effects of AEDs on the fetus
Effect of Pregnancy on Seizures
About a quarter of pregnant women with epilepsy will have an increase in seizures during pregnancy and a quarter will have a decrease. When seizures increase during pregnancy, it is usually in the last trimester or peripartum. Possible causes of increased seizures are
- Decreasing AED levels
- Elevated estrogen levels
- Water retention
- Stress, anxiety
- Sleep deprivation
Decrease in AED levels during pregnancy is due to
- Increase clearance
- Poor compliance
- Decreased protein binding
- Decreased absorption
- Increased volume of distribution
AEDs and Teratogenicity
The risk of malformations or anomalies in the fetuses exposed to AEDs is two to three - fold high when compared to fetuses not exposed to AEDs. Maximum risk is in the first four weeks of gestation at which most of the mothers may be unaware of the pregnancy. All AEDs have some potential risk. Valproic acid carries a 1 - 2% risk of producing major malformation like spina bifida and carbamazepine is associated with 0.5 - 1.0% risk. The relative risk of for malformations with exposure to either valproic acid or carbamazepine compared to healthy mother controls is 4.9. Risks of spina bifida are increased with
- Family history of or prior child with spina bifida
- Folate deficiency
- High doses or fluctuating blood levels during the day
- Polytherapy
Other Effect of AEDs on the Fetus
All conventional and some of the newer AEDs induce vitamin K metabolism and deficiency of vitamin K dependent clotting factors. This can result in hemorrhagic disease of the newborn. It tends to occur in the first 24 hours and is associated with a high mortality.
All the above factors should be considered while prescribing AEDs with women with epilepsy. The guidelines proposed by American Academy of Neurology are
- AED therapy for WWE should be optimized before conception if possible
- If AED withdrawal is planned, this should be completed at least 6 months before conception
- Change to an alternate AED should not be undertaken during pregnancy for the sole purpose of reducing teratogenic risk.
- WWE, especially those treated with carbamazepine, divalproex sodium, or valproic acid should be offered prenatal testing with alpha-fetoprotein levels at 14 to 16 weeks gestation. Level II (structural) ultrasound at 16 to 20 weeks' gestation, and, if appropriate, amniocentesis for amniotic fluid alpha-fetoprotein and acetyl cholinesterase levels
- Breastfeeding is not contraindicated in WWE taking AEDs, however, for WWE taking sedating AEDs, the neonate should be monitored for sedation.
Ans. The prerequisites to start antiepileptic drug medication in children are similar to adults. They include
Decision to start AEDs should be made once the risks of further seizures outweigh the risks of treatment. For this it is prudent to define the epilepsy and epilepsy syndrome more precisely.
Recurrent disabling seizures are uncommon in certain type of childhood epilepsies or epilepsy syndrome (eg., Benign epilepsy with centrotemporal spikes). In such situation the decision to treat or not treat should be made jointly by the medical care providers and the family after careful discussion.
Majority of children with a first un-provoked seizure do not have additional seizures. The decision to treat or not after first seizure must be based on the relative risks and benefits of therapy compared with the risks of further seizures. Overall, irrespective of etiology, abnormal EEG is associated with increased risk of recurrence. In children with cryptogenic seizures, abnormal EEG and seizure while asleep are associated with increased risk of recurrence. While in the remote symptomatic epilepsies prior febrile seizures and first un-provoked seizure before the age of four years are the risk factors for recurrence.
Q11. What are the general principles to be followed when a child is started on an antiepileptic drug?Ans. The principles include
- Define the epilepsy and epilepsy syndrome
- The benefit of treatment should outweigh the risk of recurrence of seizures
- Use a single appropriate antiepileptic drug (monotherapy) whenever possible
- Build the drug dose slowly to either seizure control or toxicity (decreasing the dose if toxicity occurs)
- If a drug fails to achieve seizure control switch to an alternate appropriate monotherapy
- Drug selection:
- Epilepsy with partial seizures - carbamazepine, valproic acid, topiramate
- Epilepsy with generalized seizures - valproic acid, lamotrogine, topiramate
- West syndrome - Vigabatrine, ACTH
- Absence epilepsy - Ethosuximide, valproic acid
- Juvenile myoclonic epilepsy - Valproic acid
- Lenox-Gestaut syndrome - Valproic acid, lamotrogine, topiramate
- Severe myoclonic epilepsy - Avoid lamotrogine, it can precipitate status myoclonicus
- Avoid carbamazepine in infants. Focal seizures may be presenting feature of some epilepsy syndromes. Institution of gabanergic drugs like carbamaxepine may aggravate absences and myoclonic jerks
- Avoid phenobarbital in children with behavioral problems
- Avoid valproic acid in child aged less than two years and taking multiple antiepileptic drugs. The chance of valproic acid induced liver injury is very high in these children.
- Be aware of drug interactions among AEDs and between AEDs and other drugs
Ans. Imaging facilities - Most of the major cities today have high resolution MRIs with all the soft ware for proper imaging of people with chronic epilepsy. MRI is the imaging modality for patients with chronic epilepsy.
Video-EEG facilities - Major cities like Delhi, Mumbai, Hyderabad, Trivandrum, etc., are having facilities for video monitoring facilities. Video-EEG monitoring is of help to characterize the seizure semiology, to differentiate pseudoseizures from true seizure, and also to determine epileptic zone presurgically.
Epilepsy surgery - Quite good number of centers have established epilepsy surgery facilities. The cities with such centers include Delhi, Trivendrum, Hyderabad, and Mumbai. With the present day available AEDs, seizure remission can be achieved in about 75% of patients. Of the remaining 25% of patients, in significant proportion of patients seizure remission can be achieved by surgery. Surgery can be cure. For patients with temporal lobe epilepsy surgery is the treatment of choice.
