REVIEWARTICLE

Rational Management of Epilepsy

Venkataraman Viswanathan

Received: 2 March 2014 /Accepted: 30 April 2014# Dr. K C Chaudhuri Foundation 2014

Abstract Management of epilepsies in children has im-proved considerably over the last decade, all over theworld due to the advances seen in the understanding ofthe patho-physiology of epileptogenesis, availability ofboth structural and functional imaging studies alongwith better quality EEG/video-EEG recordings and theavailability of a plethora of newer anti-epileptic drugswhich are tailormade to act on specific pathways. Inspite of this, there is still a long way to go before oneis able to be absolutely rational about which drug to usefor which type of epilepsy. There have been a lot ofadvances in the area of epilepsy surgery and is certainlygaining ground for specific cases. Better understandingof the genetic basis of epilepsies will hopefully lead toa more rational treatment plan in the future. Also, a lotof work needs to be done to dispel various misunder-standings and myths about epilepsy which still exists inour country.

Keywords Rational management . Epilepsy . Anti-epilepticdrugs . Epilepsy surgery . Genetic epilepsies

Introduction

Significant advances have been made both in the under-standing of the pathogenesis of seizures and the thera-peutic armamentarium over the last decade. New

concepts about the mechanisms of seizures and theirpropagation have led to the development of epilepticnetworks [1]. Better understanding of the excitatoryand the inhibitory neuro-transmitters in the brain hasled to the development of precisely acting drugs whichcan be used rationally rather than empirically. The ad-vances in the understanding of specific ion channeldefects in certain genetic epilepsies have added a newdimension to the treatment of certain epileptic syn-dromes. Epilepsy surgery in children has gained groundover the last decade with the ability to clearly delineatethe epileptogenic zone with advanced imaging tech-niques. The availability of structural and functional im-aging of the brain has made the diagnosis more precise.Good quality electroencephalography (EEG) and video-EEG recordings have added to the better understandingof the seizure characteristics and thus being able tomore clearly and rationally decide the treatment plans.

Key Factors That Makes Rational ManagementImportant in Children

1. The child’s brain is more prone to epileptogenesisand has higher tendency to spread to the wholebrain.

2. The main etiologies of early onset epilepsies (suchas perinatal brain injury and developmental struc-tural brain abnormalities) are highly epileptogenic[2].

3. Severe seizure activity may in turn be responsiblefor additional functional or structural brain impair-ment [3].

4. Cognitive impairment is common in epilepsies but canbe made considerably worse by some anti-epilepticdrugs or combinations of drugs [4], and this will

V. ViswanathanDepartment of Pediatric Neurology, Kanchi Kamakoti Childs TrustHospital, Chennai, Tamil Nadu, India

V. Viswanathan (*)Flat - 2, Srikrupa Apartments, 21, 3rd Seaward Road, Valmiki Nagar,Thiruvanmayur, Chennai 6000041, Tamil Nadu, Indiae-mail: vishneuro@gmail.com

Indian J PediatrDOI 10.1007/s12098-014-1482-8

certainly be an important consideration in the manage-ment of epilepsies in children.

Diagnosis of Epilepsy

The precise diagnosis of epilepsy and classification is animportant element in the management. A careful and detailedhistory taking remains the corner stone of accurate diagnosis[5]. Clearly, the best way to get to a diagnosis is the detaileddescription of the event from the family or the eye-witness. Ifthe seizures are more frequent, we now have more familieswilling to video the event at home and show it to the physicianto understand the exact nature of the event.

Key Points in the History

1. Family history of seizures2. Antenatal history3. Birth history4. Development history5. Age at first seizure6. Seizure characteristics: Time– occurs during awake

period, sleep, early mornings only etc.; Seizure onset,aura’s if any; Involvement of the part of the body atonset and then progression; Duration of seizures–details about the actual episode of twitching, if anyfollowed by the duration of the period of loss ofawareness and time to come back to normalcy;Associated features– frothing at the mouth, vomiting,tongue biting, incontinence of bowel or bladder, fever,pallor, cyanosis at the lips; Post seizure state–confused, agitated, aggressive, drowsy, crying etc.

7. Did the child require hospitalization for the seizure? If so,was the child in the intensive care unit? Was the childventilated?

8. What anti-epileptic medications were given and what wasthe dose?

9. School performance

History During Follow Up Visit

1. Date of last visit2. Date of last seizures3. Drugs–names with exact dosages4. Any compliance issues–vomiting/bad taste/forgetting

doses frequently5. Any side effects noticed–excess hair growth, gum

hypertrophy, poor appetite, weight gain, issues withlearning/concentration at school, aggressive behav-ior, excessive drowsiness etc.

6. Any inter-current illnesses

Role of EEG in Diagnosis

Electro-encephalography is mainly useful to confirm the na-ture of the epileptic seizure and also helps to classify theepilepsy. Occasionally, an EEG may help in identifying apossible cause such as focal slow waves suggesting a struc-tural lesion. Standard EEG recordings in children shouldinclude sleep as well as awake state. Sleep EEG and the useof routine facilitating maneuvers like intermittent photic stim-ulation and hyperventilation increase the positivity rate ofroutine EEG from 60 % to roughly 90 % [6]. It is importantto remember that various types of epileptic paroxysms can beobserved in 5–8 % of inter-ictal EEG in non-epileptic childrenwhen an adequate sleep record is obtained. This precludesmaking a diagnosis of epilepsy solely on the basis of EEGfindings in the absence of convincing clinical manifestations.Conversely, a normal inter-ictal EEG recording does not ex-clude the diagnosis of epilepsy, when the clinical history isconvincing [1]. Video-EEG recordings have added to thebetter understanding of the seizure onset in children andlocalization of the epileptic focus which is particularly impor-tant if one is considering epilepsy surgery as an option for thechild.

Differential Diagnosis

Jeavons found that 20–25 % of patients referred to his epilep-sy clinic did not have epilepsy [7]. Similarly, Metrick et al.reported that 10–20 % of children referred to their epilepsyclinic with a diagnosis of refractory epilepsy had non-epilepticevents [8]. Non epileptic seizures are events resembling epi-leptic attacks but lacking their characteristic clinical andelectrographic features. These non-epileptic seizures can co-occur in patients with true epilepsy [9]. Video-EEG remainsthe gold standard in diagnosis of non-epileptic seizures and noother procedure appears to show equal sensitivity or specific-ity [10]. Imprecise diagnosis and treatment can have gravelong-term consequences for the child and the family.

Role of Neuro-Imaging in Pediatric Epilepsy

Computed tomography (CT) scans of the brain appear to bethe most easily available and cost effective mode of imagingin a child with first episode of seizure, unless a structuralmalformation in the brain is contemplated. In developingcountries, the transitional phase of neuro-cysticercosis is prob-ably the most common cause of acute symptomatic seizures inolder children and adults [11, 12]. Magnetic resonance imag-ing (MRI) of the brain is the preferred choice of imaging inbabies and younger children as structural malformations areidentified much more clearly. At present, in our country func-tional imaging modalities like SPECT, functional MRI andPET are not easily available and are too expensive but they

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may play a larger role in the future in the management ofrefractory partial epilepsies [13].

When Do I Treat a Child with Epilepsy?

Once you are sure that it is a clinical seizure and the chance ofrecurrence of seizure is high, treatment should be initiated. In ahuge country like ours, it is sometimes necessary to rationalizethe decision to treat or not, depending on the availability ofmedical facilities locally in the event of a seizure. Childrenwho show abnormal neurological signs or developmentaldelay have a much higher chance of recurrence of seizuresas compared to children whose neurological examination isnormal and have normal development. It is, therefore, impor-tant that one considers commencing medications in childrenwith developmental delay. It is also true that when a child hasrecurrent seizures within 24 h or when the first episode ofseizure itself is prolonged for more than 10 min then thosechildren can develop further seizures and it would be better tocommence medications in these children.

Choice of Anti-Epileptic Drugs

A large number of drugs are currently available in the Indianmarket and this makes the rational choice of anti-epilepticdrugs even more difficult for a doctor who does not prescribethem regularly. The ultimate choice of an anti-epileptic drug(AED) for any individual patient with newly diagnosed oruntreated epilepsy should include consideration of theevidence-based efficacy for each AED, safety and tolerabilityprofile, pharmacokinetic properties, available formulations,and cost of treatment. International League Against Epilepsyrecently conceded that when selecting a patient’s AED, phy-sicians and patients should consider all relevant variables andnot just efficacy and effectiveness [14]. In a survey conductedby World Health Organization in partnership with theInternational League Against Epilepsy and the InternationalBureau for Epilepsy, it was identified that the median cost ofthe daily defined dose of the first line AED in internationaldollars is 0.14 for phenobarbital and is three times more forphenytoin, 11 times more for carbamazepine and 16 times forvalproic acid [15]. Consideration of an easily available andless expensive drug for treatment improves the compliancefrom the families. The prohibitive costs of some of the neweranti-epileptic medications should make one think a little be-fore prescribing the medications although in certain cases thebenefits from using the newer drugs far outweighs the burdenof costs on the family.

In most cases a single drug is all that is required in themanagement of the epilepsy. It is better to start with low dosesand then titrate upwards depending on the response. The

appropriate dose for a given child is the dose at which thechild remains seizure-free. Further dose increments are neededin about one-fifth patients who do not respond to averagedoses. Switching or adding another AED may be necessaryfor one in five patients who do not respond to the first AED. Itwould be prudent to continue with the first AED until thesecond drug has had time to reach reasonable serum levels andthen consider weaning off the first AED. While consideringcombination therapy in epilepsy management, it is importantto look for synergistic efficacy and possible additive toxicity.For example, using carbamazepine with lamotrigine may re-sult in undesirable central nervous system side effects whilevalproate with lamotrigine has favorable effects. Combinationof three or more drugs is rarely indicated and their efficacyremains to be demonstrated [16]. The typical scenarios where-in a child requires multiple AEDs include severe myoclonicepilepsy of childhood, Lennox Gastaut syndrome, cerebralpalsy with extensive neuronal injury in the brain etc.

A simplified scheme for choice of AEDs is given in (Fig. 1)which may guide the patient-tailored selection of AEDs.

Remember that it would be important to use less sedatingdrugs in children as it helps cognition and learning.Topiramate has been used in children with refractory myo-clonic seizures showing partial onset, with good effect.Similarly, lamotrigine has also been shown to be useful asadjunctive drug in partial seizures. The choice of anti-epilepticmedications should ideally take into consideration the follow-ing factors 1. Age of the child, 2. The identification of epilep-tic syndromes such as Rolandic epilepsy or absence seizures?3. Associated issues like liver, renal or electrolyte abnormal-ities 4. EEG abnormalities, 5. Neuro-imaging findings, 6.Long-term availability/affordability of the medications forthe family.

Seizures in the New Born

Phenobarbitone and Phenytoin still remain the drugs of choicefor neonatal seizures. Clonazepam may be added in certaincircumstances. Levetiracetam is being used more often inneonatal seizures particularly when an underlying neuro-metabolic disorder is suspected. It is found to be quite safeand well tolerated but as with any new drug, caution isadvisable [17]. Drugs like Sodium Valproate andCarbamazepine should be used cautiously due to concernsabout underlying neuro-metabolic disorders. One should re-member that in the newborn hypoglycemia, hypocalcemia,hypomagnesemia may all present with seizures and it wouldbe important to diagnose these and correct beforehand.Biotinidase deficiency can also present with seizures in thenewborn. These children do well with biotin supplements ifdiagnosed and treated appropriately [18]. Pyridoxine is yetanother simple but effective drug for management of neonatal

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seizures at a dose around 100 mg per day and should beconsidered in any baby with recurrent seizures in spite of firstline anti-epileptic medication. This is an example of yet an-other simple treatment that can, not only control seizures butprevent long term morbidity for the child [19].

Febrile Seizures

Simple febrile seizures are brief seizures in a previously nor-mal child between the ages of 6 mo to 6 y of life. The mostimportant treatment in simple febrile seizures is to try tocontrol the fever quickly with either paracetamol or tepidsponging the child. Intermittent prophylaxis with clobazamin a dose of 0.75 mg/kg for 2–3 d in two divided doses duringfever is useful to prevent recurrence [20].

Complex febrile seizures are characterized by partial onsetof seizures, duration more than 15 min or multiple episodeswithin 24 h. Late-onset febrile seizures beyond the age of 6 y,febrile status epilepticus, and febrile seizures with generalizedepilepsy (GEFS+) are part of the spectrum of febrile seizures[21, 22]. These are the children who require further investiga-tions including EEG, neuro-imaging and continuous prophy-laxis with anti-epileptic medications. Any prophylaxis withanti-epileptic medications reduces the chance of recur-rence of seizures but does not reduce the risk of futureepilepsy. Drug that is commonly used for long termprophylaxis is Sodium Valproate in children for a periodof two years. Although Phenobarbitone may be equallybeneficial in the younger child, the side effects likesedation or hyperactivity in some children need consid-eration in a school going child.

Other indications, when long term prophylaxis may beconsidered is when there is a strong family history of a closerelative with complex febrile seizures and when there is back-ground of developmental delay or abnormalities on neurolog-ical examination.

Some Points of General Interest

& Routine drug level monitoring of anti-epileptic drugs isnot required unless there are concerns about compliancewith the medications or adverse reactions suggesting ex-cess dosages.

Routine monthly checking of liver function tests–is notneeded. Twice yearly investigations may be done whileusing drugs like Sodium Valproate. Each drug has specificmechanisms of action and so, appropriate investigationsare beneficial such as monitoring pH while usingTopiramate or hyponatremia while using Oxcarbazepine.

& Avoid macrolide antibiotics while using Carbamazepineor Phenytoin

& Drugs like Metronidazole/Tinidazole may also interactwith Carbamazepine and Phenytoin

& Advice the parents not to stop anti-epileptic drugs whenthe child is not well or while giving other medicines

How Long Do We Continue Anti-Epileptic Drugs?

Approximately 50 % of the children who have childhoodonset epilepsy will have remission of their epilepsy and an-other 20 % remission after a relapse [23].

The most important prognostic factor is the epilepsy syn-drome with relapse rates being very low for children withrolandic epilepsy, relatively rare in typical absence epilepsy,intermediate in cryptogenic or symptomatic partial epilepsyand high in juvenile myoclonic epilepsy. In childhood epilep-sy, age of onset above 12 y of age is an important risk factorfor recurrence [24]. Children with structural lesions in thebrain or children with well known epileptic syndromes likeWest syndrome or Lennox Gastaut syndrome may requirelong term treatment. Children with remote symptomatic etiol-ogy, mental impairment and localization related epilepsy are

Epileptic seizure

Absence seizuresSodium Valproate

LamotrigineClobazam

Myoclonic seizuresSodium Valproate

LamotrigineClonazepam

Primary Generalizedseizures

Sodium ValproateLamotrigine

Phenobarbitone

Sodium Valproate

Generalized seizures

OxcarbazapineTopiramatePhenytoin

Carbamazapine orSodium Valproate

Partial seizures

Fig. 1 Scheme for choice of anti-epileptic medications in children

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prone to have difficult to control epilepsy and are more likelyto relapse after a seizure free period. It would be prudent to getan EEG performed before discontinuing medications, as therisk of recurrence is higher for children who had paroxysmalEEG abnormalities than those with normal EEG tracings [25].

Ketogenic Diet in Epilepsy

All children above the age of one year with drug resistantepilepsy may be tried on ketogenic diet [26]. Although itinvolves a lot of parental counseling and time in making thespecific diet for the child, the benefits of the seizure control andimprovement in alertness and concentration over a period oftime makes the family stick to the diet [27].

Surgical Treatment for Epilepsy

More children are being considered for epilepsy surgerynow than in the past. When a lesion in a child has beenidentified as the epileptogenic focus with concordance onneuro-imaging and EEG, these children are good candidatesfor surgery. No patient with epilepsy should be operatedwithout attempting to treat with drugs but the consequencesof years of disabling seizures and high doses of anti-epileptic medications during a period of rapid neuronalmaturation in the child should be weighed against the risksof surgery. Many authors agree that making a decision onsurgical therapy for epilepsy should not exceed 1 to 2 y[28].

More centers in India are now available where a compre-hensive work up of the child can be performed before epilepsysurgery is considered.

Epilepsy and Genetics

There are a number of genetically determined epilepsies thathave been recognized over the years. These can be broadlydivided into two groups: one, where the genetic defects di-rectly result in functional abnormalities in the neurons suchas benign familial neonatal convulsions where the geneticdefect is in the voltage gated potassium channel genesKCNQ3 [29]. The other group is associated with structuralbrain abnormalities such as Tuberose sclerosis—TSC1/TSC2genes. One of the reasons why it is interesting and importantto understand these is the fact that the future researchers maybe able to tailor drug therapy to specific subtypes dependingon which ion channel is defective and thus achieve a muchbetter success rate in “curing” some of these epilepsies. Thissort of understanding may also help us to counsel families andpredict the genetic susceptibility in families in the future.

General Patient Management

When we speak about rational management of epilepsy, oneneeds to also take in to account misunderstandings, erroneousopinions and prejudices which still exist in our society. Theparents of these children need to be provided enough infor-mation and should also be taught how to deal with the child inthe event of a seizure. There needs to be a lot of awarenesscreated in schools so that these children do not get excludedfrom a number of the usual activities at school. There alsoneeds to be a huge stress on using the media to educate thepublic about the common misconceptions and dispel a lot ofmyths about epilepsy.

Acknowledgement The author would like to thank Kanchi KamakotiChilds Trust Hospital and Childs Trust Medical Research Foundation.

Conflict of Interest None.

Source of Funding None.

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