Indian J Pediatr DOI 10.1007/s12098-014-1482-8
REVIEW ARTICLE
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 improved considerably over the last decade, all over the world due to the advances seen in the understanding of the patho-physiology of epileptogenesis, availability of both structural and functional imaging studies along with better quality EEG/video-EEG recordings and the availability of a plethora of newer anti-epileptic drugs which are tailormade to act on specific pathways. In spite of this, there is still a long way to go before one is able to be absolutely rational about which drug to use for which type of epilepsy. There have been a lot of advances in the area of epilepsy surgery and is certainly gaining ground for specific cases. Better understanding of the genetic basis of epilepsies will hopefully lead to a more rational treatment plan in the future. Also, a lot of work needs to be done to dispel various misunderstandings and myths about epilepsy which still exists in our country. Keywords Rational management . Epilepsy . Anti-epileptic drugs . Epilepsy surgery . Genetic epilepsies
Introduction Significant advances have been made both in the understanding of the pathogenesis of seizures and the therapeutic armamentarium over the last decade. New V. Viswanathan Department of Pediatric Neurology, Kanchi Kamakoti Childs Trust Hospital, Chennai, Tamil Nadu, India V. Viswanathan (*) Flat - 2, Srikrupa Apartments, 21, 3rd Seaward Road, Valmiki Nagar, Thiruvanmayur, Chennai 6000041, Tamil Nadu, India e-mail: [email protected]
concepts about the mechanisms of seizures and their propagation have led to the development of epileptic networks [1]. Better understanding of the excitatory and the inhibitory neuro-transmitters in the brain has led to the development of precisely acting drugs which can be used rationally rather than empirically. The advances in the understanding of specific ion channel defects in certain genetic epilepsies have added a new dimension to the treatment of certain epileptic syndromes. Epilepsy surgery in children has gained ground over the last decade with the ability to clearly delineate the epileptogenic zone with advanced imaging techniques. The availability of structural and functional imaging of the brain has made the diagnosis more precise. Good quality electroencephalography (EEG) and videoEEG recordings have added to the better understanding of the seizure characteristics and thus being able to more clearly and rationally decide the treatment plans.
Key Factors That Makes Rational Management Important in Children 1. The child’s brain is more prone to epileptogenesis and has higher tendency to spread to the whole brain. 2. The main etiologies of early onset epilepsies (such as perinatal brain injury and developmental structural brain abnormalities) are highly epileptogenic [2]. 3. Severe seizure activity may in turn be responsible for additional functional or structural brain impairment [3]. 4. Cognitive impairment is common in epilepsies but can be made considerably worse by some anti-epileptic drugs or combinations of drugs [4], and this will
Indian J Pediatr
certainly be an important consideration in the management of epilepsies in children.
Diagnosis of Epilepsy The precise diagnosis of epilepsy and classification is an important element in the management. A careful and detailed history taking remains the corner stone of accurate diagnosis [5]. Clearly, the best way to get to a diagnosis is the detailed description of the event from the family or the eye-witness. If the seizures are more frequent, we now have more families willing to video the event at home and show it to the physician to understand the exact nature of the event. Key Points in the History 1. 2. 3. 4. 5. 6.
Family history of seizures Antenatal history Birth history Development history Age at first seizure 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 at onset and then progression; Duration of seizures– details about the actual episode of twitching, if any followed by the duration of the period of loss of awareness 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 child ventilated? 8. What anti-epileptic medications were given and what was the dose? 9. School performance
Role of EEG in Diagnosis Electro-encephalography is mainly useful to confirm the nature of the epileptic seizure and also helps to classify the epilepsy. Occasionally, an EEG may help in identifying a possible cause such as focal slow waves suggesting a structural lesion. Standard EEG recordings in children should include sleep as well as awake state. Sleep EEG and the use of routine facilitating maneuvers like intermittent photic stimulation and hyperventilation increase the positivity rate of routine EEG from 60 % to roughly 90 % [6]. It is important to remember that various types of epileptic paroxysms can be observed in 5–8 % of inter-ictal EEG in non-epileptic children when an adequate sleep record is obtained. This precludes making a diagnosis of epilepsy solely on the basis of EEG findings in the absence of convincing clinical manifestations. Conversely, a normal inter-ictal EEG recording does not exclude the diagnosis of epilepsy, when the clinical history is convincing [1]. Video-EEG recordings have added to the better understanding of the seizure onset in children and localization of the epileptic focus which is particularly important if one is considering epilepsy surgery as an option for the child. Differential Diagnosis Jeavons found that 20–25 % of patients referred to his epilepsy clinic did not have epilepsy [7]. Similarly, Metrick et al. reported that 10–20 % of children referred to their epilepsy clinic with a diagnosis of refractory epilepsy had non-epileptic events [8]. Non epileptic seizures are events resembling epileptic attacks but lacking their characteristic clinical and electrographic features. These non-epileptic seizures can cooccur in patients with true epilepsy [9]. Video-EEG remains the gold standard in diagnosis of non-epileptic seizures and no other procedure appears to show equal sensitivity or specificity [10]. Imprecise diagnosis and treatment can have grave long-term consequences for the child and the family. Role of Neuro-Imaging in Pediatric Epilepsy
History During Follow Up Visit 1. 2. 3. 4.
Date of last visit Date of last seizures Drugs–names with exact dosages Any compliance issues–vomiting/bad taste/forgetting doses frequently 5. Any side effects noticed–excess hair growth, gum hypertrophy, poor appetite, weight gain, issues with learning/concentration at school, aggressive behavior, excessive drowsiness etc. 6. Any inter-current illnesses
Computed tomography (CT) scans of the brain appear to be the most easily available and cost effective mode of imaging in a child with first episode of seizure, unless a structural malformation in the brain is contemplated. In developing countries, the transitional phase of neuro-cysticercosis is probably the most common cause of acute symptomatic seizures in older children and adults [11, 12]. Magnetic resonance imaging (MRI) of the brain is the preferred choice of imaging in babies and younger children as structural malformations are identified much more clearly. At present, in our country functional imaging modalities like SPECT, functional MRI and PET are not easily available and are too expensive but they
Indian J Pediatr
may play a larger role in the future in the management of refractory partial epilepsies [13].
When Do I Treat a Child with Epilepsy? Once you are sure that it is a clinical seizure and the chance of recurrence of seizure is high, treatment should be initiated. In a huge country like ours, it is sometimes necessary to rationalize the decision to treat or not, depending on the availability of medical facilities locally in the event of a seizure. Children who show abnormal neurological signs or developmental delay have a much higher chance of recurrence of seizures as compared to children whose neurological examination is normal and have normal development. It is, therefore, important that one considers commencing medications in children with developmental delay. It is also true that when a child has recurrent seizures within 24 h or when the first episode of seizure itself is prolonged for more than 10 min then those children can develop further seizures and it would be better to commence medications in these children.
Choice of Anti-Epileptic Drugs A large number of drugs are currently available in the Indian market and this makes the rational choice of anti-epileptic drugs even more difficult for a doctor who does not prescribe them regularly. The ultimate choice of an anti-epileptic drug (AED) for any individual patient with newly diagnosed or untreated epilepsy should include consideration of the evidence-based efficacy for each AED, safety and tolerability profile, pharmacokinetic properties, available formulations, and cost of treatment. International League Against Epilepsy recently conceded that when selecting a patient’s AED, physicians and patients should consider all relevant variables and not just efficacy and effectiveness [14]. In a survey conducted by World Health Organization in partnership with the International League Against Epilepsy and the International Bureau for Epilepsy, it was identified that the median cost of the daily defined dose of the first line AED in international dollars is 0.14 for phenobarbital and is three times more for phenytoin, 11 times more for carbamazepine and 16 times for valproic acid [15]. Consideration of an easily available and less expensive drug for treatment improves the compliance from the families. The prohibitive costs of some of the newer anti-epileptic medications should make one think a little before prescribing the medications although in certain cases the benefits from using the newer drugs far outweighs the burden of costs on the family. In most cases a single drug is all that is required in the management of the epilepsy. It is better to start with low doses and then titrate upwards depending on the response. The
appropriate dose for a given child is the dose at which the child remains seizure-free. Further dose increments are needed in about one-fifth patients who do not respond to average doses. Switching or adding another AED may be necessary for one in five patients who do not respond to the first AED. It would be prudent to continue with the first AED until the second drug has had time to reach reasonable serum levels and then consider weaning off the first AED. While considering combination therapy in epilepsy management, it is important to look for synergistic efficacy and possible additive toxicity. For example, using carbamazepine with lamotrigine may result in undesirable central nervous system side effects while valproate with lamotrigine has favorable effects. Combination of three or more drugs is rarely indicated and their efficacy remains to be demonstrated [16]. The typical scenarios wherein a child requires multiple AEDs include severe myoclonic epilepsy of childhood, Lennox Gastaut syndrome, cerebral palsy 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 sedating drugs in children as it helps cognition and learning. Topiramate has been used in children with refractory myoclonic seizures showing partial onset, with good effect. Similarly, lamotrigine has also been shown to be useful as adjunctive drug in partial seizures. The choice of anti-epileptic medications should ideally take into consideration the following factors 1. Age of the child, 2. The identification of epileptic syndromes such as Rolandic epilepsy or absence seizures? 3. Associated issues like liver, renal or electrolyte abnormalities 4. EEG abnormalities, 5. Neuro-imaging findings, 6. Long-term availability/affordability of the medications for the family.
Seizures in the New Born Phenobarbitone and Phenytoin still remain the drugs of choice for neonatal seizures. Clonazepam may be added in certain circumstances. Levetiracetam is being used more often in neonatal seizures particularly when an underlying neurometabolic disorder is suspected. It is found to be quite safe and well tolerated but as with any new drug, caution is advisable [17]. Drugs like Sodium Valproate and Carbamazepine should be used cautiously due to concerns about underlying neuro-metabolic disorders. One should remember that in the newborn hypoglycemia, hypocalcemia, hypomagnesemia may all present with seizures and it would be important to diagnose these and correct beforehand. Biotinidase deficiency can also present with seizures in the newborn. These children do well with biotin supplements if diagnosed and treated appropriately [18]. Pyridoxine is yet another simple but effective drug for management of neonatal
Indian J Pediatr Fig. 1 Scheme for choice of antiepileptic medications in children
Epileptic seizure Generalized seizures
Partial seizures
Sodium Valproate
Carbamazapine or Sodium Valproate
Absence seizures Sodium Valproate Lamotrigine Clobazam
Myoclonic seizures Sodium Valproate Lamotrigine Clonazepam
Oxcarbazapine Topiramate Phenytoin
Primary Generalized seizures Sodium Valproate Lamotrigine Phenobarbitone
seizures at a dose around 100 mg per day and should be considered in any baby with recurrent seizures in spite of first line anti-epileptic medication. This is an example of yet another simple treatment that can, not only control seizures but prevent long term morbidity for the child [19].
Some Points of General Interest &
Febrile Seizures Simple febrile seizures are brief seizures in a previously normal child between the ages of 6 mo to 6 y of life. The most important treatment in simple febrile seizures is to try to control the fever quickly with either paracetamol or tepid sponging the child. Intermittent prophylaxis with clobazam in a dose of 0.75 mg/kg for 2–3 d in two divided doses during fever is useful to prevent recurrence [20]. Complex febrile seizures are characterized by partial onset of seizures, duration more than 15 min or multiple episodes within 24 h. Late-onset febrile seizures beyond the age of 6 y, febrile status epilepticus, and febrile seizures with generalized epilepsy (GEFS+) are part of the spectrum of febrile seizures [21, 22]. These are the children who require further investigations including EEG, neuro-imaging and continuous prophylaxis with anti-epileptic medications. Any prophylaxis with anti-epileptic medications reduces the chance of recurrence of seizures but does not reduce the risk of future epilepsy. Drug that is commonly used for long term prophylaxis is Sodium Valproate in children for a period of two years. Although Phenobarbitone may be equally beneficial in the younger child, the side effects like sedation or hyperactivity in some children need consideration in a school going child. Other indications, when long term prophylaxis may be considered is when there is a strong family history of a close relative with complex febrile seizures and when there is background of developmental delay or abnormalities on neurological examination.
& & &
Routine drug level monitoring of anti-epileptic drugs is not required unless there are concerns about compliance with the medications or adverse reactions suggesting excess dosages. Routine monthly checking of liver function tests–is not needed. Twice yearly investigations may be done while using drugs like Sodium Valproate. Each drug has specific mechanisms of action and so, appropriate investigations are beneficial such as monitoring pH while using Topiramate or hyponatremia while using Oxcarbazepine. Avoid macrolide antibiotics while using Carbamazepine or Phenytoin Drugs like Metronidazole/Tinidazole may also interact with Carbamazepine and Phenytoin Advice the parents not to stop anti-epileptic drugs when the child is not well or while giving other medicines
How Long Do We Continue Anti-Epileptic Drugs? Approximately 50 % of the children who have childhood onset epilepsy will have remission of their epilepsy and another 20 % remission after a relapse [23]. The most important prognostic factor is the epilepsy syndrome with relapse rates being very low for children with rolandic epilepsy, relatively rare in typical absence epilepsy, intermediate in cryptogenic or symptomatic partial epilepsy and high in juvenile myoclonic epilepsy. In childhood epilepsy, age of onset above 12 y of age is an important risk factor for recurrence [24]. Children with structural lesions in the brain or children with well known epileptic syndromes like West syndrome or Lennox Gastaut syndrome may require long term treatment. Children with remote symptomatic etiology, mental impairment and localization related epilepsy are
Indian J Pediatr
prone to have difficult to control epilepsy and are more likely to relapse after a seizure free period. It would be prudent to get an EEG performed before discontinuing medications, as the risk of recurrence is higher for children who had paroxysmal EEG abnormalities than those with normal EEG tracings [25].
Ketogenic Diet in Epilepsy All children above the age of one year with drug resistant epilepsy may be tried on ketogenic diet [26]. Although it involves a lot of parental counseling and time in making the specific diet for the child, the benefits of the seizure control and improvement in alertness and concentration over a period of time makes the family stick to the diet [27].
Surgical Treatment for Epilepsy
General Patient Management When we speak about rational management of epilepsy, one needs to also take in to account misunderstandings, erroneous opinions and prejudices which still exist in our society. The parents of these children need to be provided enough information and should also be taught how to deal with the child in the event of a seizure. There needs to be a lot of awareness created in schools so that these children do not get excluded from a number of the usual activities at school. There also needs to be a huge stress on using the media to educate the public about the common misconceptions and dispel a lot of myths about epilepsy. Acknowledgement The author would like to thank Kanchi Kamakoti Childs Trust Hospital and Childs Trust Medical Research Foundation. Conflict of Interest None. Source of Funding None.
More children are being considered for epilepsy surgery now than in the past. When a lesion in a child has been identified as the epileptogenic focus with concordance on neuro-imaging and EEG, these children are good candidates for surgery. No patient with epilepsy should be operated without attempting to treat with drugs but the consequences of years of disabling seizures and high doses of antiepileptic medications during a period of rapid neuronal maturation in the child should be weighed against the risks of surgery. Many authors agree that making a decision on surgical therapy for epilepsy should not exceed 1 to 2 y [28]. More centers in India are now available where a comprehensive work up of the child can be performed before epilepsy surgery is considered.
Epilepsy and Genetics There are a number of genetically determined epilepsies that have been recognized over the years. These can be broadly divided into two groups: one, where the genetic defects directly result in functional abnormalities in the neurons such as benign familial neonatal convulsions where the genetic defect is in the voltage gated potassium channel genes KCNQ3 [29]. The other group is associated with structural brain abnormalities such as Tuberose sclerosis—TSC1/TSC2 genes. One of the reasons why it is interesting and important to understand these is the fact that the future researchers may be able to tailor drug therapy to specific subtypes depending on which ion channel is defective and thus achieve a much better success rate in “curing” some of these epilepsies. This sort of understanding may also help us to counsel families and predict the genetic susceptibility in families in the future.
References 1. Arzimanoglou A, Guerrinni R, Aicardi J. Aicardi’s epilepsies in children. 3rd ed. Philadelphia: Lippincott Williams and Wilkins; 2004. p. 1–6. 2. Guerrini R, Andermann E, Avoli M, Dobyns WB. Cortical dysplasias, genetics and epileptogenesis. Adv Neurol. 1999;79:95–121. 3. Holmes GL, Stafstrom CE. Effects of seizures on the developing brain. In: Tuxhorn I, Holthausen H, Boenigk H, et al., editors. Pediatric epilepsy syndromes and their surgical treatments. Paris: John Libbey; 1997. p. 489–504. 4. Loring DW, Meador KJ. Cognitive side effects of anti-epileptic drugs in children. Neurology. 2004;62:872–7. 5. O’Donohoe NV. Epilepsies in childhood. 2nd ed. London: Butterworth-Heinemann; 1985. 6. Mirzrahi EM. Electroencephalographic/polygraphic/video-monitoring in childhood epilepsy. J Pediatr. 1984;105:1–9. 7. Jeavons PM. Non epileptic attacks in childhood. In: Rose CF, editor. Research progress in epilepsy. London: Pitman; 1983. p. 224–30. 8. Metrick ME, Ritter FJ, Gates JR, Jacobs MP, Skare SS, Loewenson RB. Non epileptic events in childhood. Epilepsia. 1991;32:322–8. 9. Ramsay RE, Cohen A, Brown MC. Co-existing epilepsy and nonepileptic seizures. In: Rowan AJ, Gtes JR, editors. Non epileptic seizures. Boston: Butterworth-Heinemann; 1993. p. 47–54. 10. Cuthill FM, Espie CA. Sensitivity and specificity of procedures for the differential diagnosis of epileptic and non-epileptic seizures: a systematic review. Seizure. 2005;14:293–303. 11. Guidelines for epidemiologic studies on epilepsy. Commission on epidemiology and prognosis of the International League Against Epilepsy. Epilepsia. 1993;34:592–6. 12. Murthy JM. Seizures due to solitary cysticercus granuloma. In: Singh G, Prabhakar S, editors. Taenia solium cysticercoids: from basic to clinical science. Oxon: CABI publishing; 2002. p. 251–6. 13. Koepp M, Woermann FG. Imaging structure and function in refractory focal epilepsy. Lancet Neurol. 2005;4:42–53. 14. Glauser T, Ben-Menachem E, Bourgeois B, Cnaan A, Chadwick D, Guerreiro C, et al. ILAE treatment guidelines: evidence-based analysis of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia. 2006;47:1094–120.
Indian J Pediatr 15. World Health Organization. Atlas—epilepsy care in the world. Andheri, Mumbai: Michael Fernandez, Medica Press International; 2005. p. 40–3. 16. Reynolds EH, Shorvon SD. Monotherapy or polytherapy for epilepsy. Epilepsia. 1981;22:1–10. 17. Ramantani G, Ikonomidou C, Walter B, Rating D, Dinger J. Levetiracetam: safety and efficacy in neonatal seizures. Eur J Paediatr Neurol. 2011;15:1–7. 18. Venkataraman V, Balaji P, Panigrahi D, Jamal R. Biotinidase deficiency in childhood. Neurol India. 2013;61:411–3. 19. Rajesh R. Pyridoxine dependant seizures: a review. Indian Pediatr. 2003;40:633–8. 20. IAP Expert Committee Guidelines. Guideline for diagnosis and management of childhood epilepsy. Indian Pediatr. 2009;46:681–98. 21. Singhi PD, Srinivas M. Febrile seizures. Indian Pediatr. 2001;38: 733–40. 22. Sadlier LG, Scheffer IE. Febrile seizures. BMJ. 2007;334:307–11. 23. Silanpaa M, Schmidt D. Natural history of treated childhood onset epilepsy, prospective long term population based study. Brain. 2006;129:617–24.
24. Shinnar S, Berg AT, Moshé SL, Kang H, O’Dell C, Alemany M, et al. Discontinuing antiepileptic drugs in children with epilepsy: a prospective study. Ann Neurol. 1994;35:534–45. 25. Berg AT, Shinnar S. Relapse following discontinuation of anti-epileptic drug: a meta-analysis. Neurology. 1994;44:601– 8. 26. Freeman JM, Kosoff EH, Hartman AL. The ketogenic diet:one decade later. Pediatrics. 2007;119:535–43. 27. Lefervre F, Aronson N. Ketogenic diet for the treatment of refractory epilepsy in children: a systematic review of efficacy. Pediatrics. 2000;105:e46. 28. Mohammed A, Wyllie E, Ruggieri P, Kotagal P, Babb T, Hilbig A, et al. Temporal lobe epilepsy due to hippocampal sclerosis in pediatric candidates for epilepsy surgery. Neurology. 2001;56:1643–9. 29. Castaldo P, del Giudice EM, Coppola G, Pascotto A, Annunziato L, Taglialatela M. Benign familial neonatal convulsions caused by altered gating of KCNQ2/KCNQ3 potassium channels. J Neurosci. 2002;22:RC 199.
REVIEW ARTICLE
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 improved considerably over the last decade, all over the world due to the advances seen in the understanding of the patho-physiology of epileptogenesis, availability of both structural and functional imaging studies along with better quality EEG/video-EEG recordings and the availability of a plethora of newer anti-epileptic drugs which are tailormade to act on specific pathways. In spite of this, there is still a long way to go before one is able to be absolutely rational about which drug to use for which type of epilepsy. There have been a lot of advances in the area of epilepsy surgery and is certainly gaining ground for specific cases. Better understanding of the genetic basis of epilepsies will hopefully lead to a more rational treatment plan in the future. Also, a lot of work needs to be done to dispel various misunderstandings and myths about epilepsy which still exists in our country. Keywords Rational management . Epilepsy . Anti-epileptic drugs . Epilepsy surgery . Genetic epilepsies
Introduction Significant advances have been made both in the understanding of the pathogenesis of seizures and the therapeutic armamentarium over the last decade. New V. Viswanathan Department of Pediatric Neurology, Kanchi Kamakoti Childs Trust Hospital, Chennai, Tamil Nadu, India V. Viswanathan (*) Flat - 2, Srikrupa Apartments, 21, 3rd Seaward Road, Valmiki Nagar, Thiruvanmayur, Chennai 6000041, Tamil Nadu, India e-mail: [email protected]
concepts about the mechanisms of seizures and their propagation have led to the development of epileptic networks [1]. Better understanding of the excitatory and the inhibitory neuro-transmitters in the brain has led to the development of precisely acting drugs which can be used rationally rather than empirically. The advances in the understanding of specific ion channel defects in certain genetic epilepsies have added a new dimension to the treatment of certain epileptic syndromes. Epilepsy surgery in children has gained ground over the last decade with the ability to clearly delineate the epileptogenic zone with advanced imaging techniques. The availability of structural and functional imaging of the brain has made the diagnosis more precise. Good quality electroencephalography (EEG) and videoEEG recordings have added to the better understanding of the seizure characteristics and thus being able to more clearly and rationally decide the treatment plans.
Key Factors That Makes Rational Management Important in Children 1. The child’s brain is more prone to epileptogenesis and has higher tendency to spread to the whole brain. 2. The main etiologies of early onset epilepsies (such as perinatal brain injury and developmental structural brain abnormalities) are highly epileptogenic [2]. 3. Severe seizure activity may in turn be responsible for additional functional or structural brain impairment [3]. 4. Cognitive impairment is common in epilepsies but can be made considerably worse by some anti-epileptic drugs or combinations of drugs [4], and this will
Indian J Pediatr
certainly be an important consideration in the management of epilepsies in children.
Diagnosis of Epilepsy The precise diagnosis of epilepsy and classification is an important element in the management. A careful and detailed history taking remains the corner stone of accurate diagnosis [5]. Clearly, the best way to get to a diagnosis is the detailed description of the event from the family or the eye-witness. If the seizures are more frequent, we now have more families willing to video the event at home and show it to the physician to understand the exact nature of the event. Key Points in the History 1. 2. 3. 4. 5. 6.
Family history of seizures Antenatal history Birth history Development history Age at first seizure 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 at onset and then progression; Duration of seizures– details about the actual episode of twitching, if any followed by the duration of the period of loss of awareness 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 child ventilated? 8. What anti-epileptic medications were given and what was the dose? 9. School performance
Role of EEG in Diagnosis Electro-encephalography is mainly useful to confirm the nature of the epileptic seizure and also helps to classify the epilepsy. Occasionally, an EEG may help in identifying a possible cause such as focal slow waves suggesting a structural lesion. Standard EEG recordings in children should include sleep as well as awake state. Sleep EEG and the use of routine facilitating maneuvers like intermittent photic stimulation and hyperventilation increase the positivity rate of routine EEG from 60 % to roughly 90 % [6]. It is important to remember that various types of epileptic paroxysms can be observed in 5–8 % of inter-ictal EEG in non-epileptic children when an adequate sleep record is obtained. This precludes making a diagnosis of epilepsy solely on the basis of EEG findings in the absence of convincing clinical manifestations. Conversely, a normal inter-ictal EEG recording does not exclude the diagnosis of epilepsy, when the clinical history is convincing [1]. Video-EEG recordings have added to the better understanding of the seizure onset in children and localization of the epileptic focus which is particularly important if one is considering epilepsy surgery as an option for the child. Differential Diagnosis Jeavons found that 20–25 % of patients referred to his epilepsy clinic did not have epilepsy [7]. Similarly, Metrick et al. reported that 10–20 % of children referred to their epilepsy clinic with a diagnosis of refractory epilepsy had non-epileptic events [8]. Non epileptic seizures are events resembling epileptic attacks but lacking their characteristic clinical and electrographic features. These non-epileptic seizures can cooccur in patients with true epilepsy [9]. Video-EEG remains the gold standard in diagnosis of non-epileptic seizures and no other procedure appears to show equal sensitivity or specificity [10]. Imprecise diagnosis and treatment can have grave long-term consequences for the child and the family. Role of Neuro-Imaging in Pediatric Epilepsy
History During Follow Up Visit 1. 2. 3. 4.
Date of last visit Date of last seizures Drugs–names with exact dosages Any compliance issues–vomiting/bad taste/forgetting doses frequently 5. Any side effects noticed–excess hair growth, gum hypertrophy, poor appetite, weight gain, issues with learning/concentration at school, aggressive behavior, excessive drowsiness etc. 6. Any inter-current illnesses
Computed tomography (CT) scans of the brain appear to be the most easily available and cost effective mode of imaging in a child with first episode of seizure, unless a structural malformation in the brain is contemplated. In developing countries, the transitional phase of neuro-cysticercosis is probably the most common cause of acute symptomatic seizures in older children and adults [11, 12]. Magnetic resonance imaging (MRI) of the brain is the preferred choice of imaging in babies and younger children as structural malformations are identified much more clearly. At present, in our country functional imaging modalities like SPECT, functional MRI and PET are not easily available and are too expensive but they
Indian J Pediatr
may play a larger role in the future in the management of refractory partial epilepsies [13].
When Do I Treat a Child with Epilepsy? Once you are sure that it is a clinical seizure and the chance of recurrence of seizure is high, treatment should be initiated. In a huge country like ours, it is sometimes necessary to rationalize the decision to treat or not, depending on the availability of medical facilities locally in the event of a seizure. Children who show abnormal neurological signs or developmental delay have a much higher chance of recurrence of seizures as compared to children whose neurological examination is normal and have normal development. It is, therefore, important that one considers commencing medications in children with developmental delay. It is also true that when a child has recurrent seizures within 24 h or when the first episode of seizure itself is prolonged for more than 10 min then those children can develop further seizures and it would be better to commence medications in these children.
Choice of Anti-Epileptic Drugs A large number of drugs are currently available in the Indian market and this makes the rational choice of anti-epileptic drugs even more difficult for a doctor who does not prescribe them regularly. The ultimate choice of an anti-epileptic drug (AED) for any individual patient with newly diagnosed or untreated epilepsy should include consideration of the evidence-based efficacy for each AED, safety and tolerability profile, pharmacokinetic properties, available formulations, and cost of treatment. International League Against Epilepsy recently conceded that when selecting a patient’s AED, physicians and patients should consider all relevant variables and not just efficacy and effectiveness [14]. In a survey conducted by World Health Organization in partnership with the International League Against Epilepsy and the International Bureau for Epilepsy, it was identified that the median cost of the daily defined dose of the first line AED in international dollars is 0.14 for phenobarbital and is three times more for phenytoin, 11 times more for carbamazepine and 16 times for valproic acid [15]. Consideration of an easily available and less expensive drug for treatment improves the compliance from the families. The prohibitive costs of some of the newer anti-epileptic medications should make one think a little before prescribing the medications although in certain cases the benefits from using the newer drugs far outweighs the burden of costs on the family. In most cases a single drug is all that is required in the management of the epilepsy. It is better to start with low doses and then titrate upwards depending on the response. The
appropriate dose for a given child is the dose at which the child remains seizure-free. Further dose increments are needed in about one-fifth patients who do not respond to average doses. Switching or adding another AED may be necessary for one in five patients who do not respond to the first AED. It would be prudent to continue with the first AED until the second drug has had time to reach reasonable serum levels and then consider weaning off the first AED. While considering combination therapy in epilepsy management, it is important to look for synergistic efficacy and possible additive toxicity. For example, using carbamazepine with lamotrigine may result in undesirable central nervous system side effects while valproate with lamotrigine has favorable effects. Combination of three or more drugs is rarely indicated and their efficacy remains to be demonstrated [16]. The typical scenarios wherein a child requires multiple AEDs include severe myoclonic epilepsy of childhood, Lennox Gastaut syndrome, cerebral palsy 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 sedating drugs in children as it helps cognition and learning. Topiramate has been used in children with refractory myoclonic seizures showing partial onset, with good effect. Similarly, lamotrigine has also been shown to be useful as adjunctive drug in partial seizures. The choice of anti-epileptic medications should ideally take into consideration the following factors 1. Age of the child, 2. The identification of epileptic syndromes such as Rolandic epilepsy or absence seizures? 3. Associated issues like liver, renal or electrolyte abnormalities 4. EEG abnormalities, 5. Neuro-imaging findings, 6. Long-term availability/affordability of the medications for the family.
Seizures in the New Born Phenobarbitone and Phenytoin still remain the drugs of choice for neonatal seizures. Clonazepam may be added in certain circumstances. Levetiracetam is being used more often in neonatal seizures particularly when an underlying neurometabolic disorder is suspected. It is found to be quite safe and well tolerated but as with any new drug, caution is advisable [17]. Drugs like Sodium Valproate and Carbamazepine should be used cautiously due to concerns about underlying neuro-metabolic disorders. One should remember that in the newborn hypoglycemia, hypocalcemia, hypomagnesemia may all present with seizures and it would be important to diagnose these and correct beforehand. Biotinidase deficiency can also present with seizures in the newborn. These children do well with biotin supplements if diagnosed and treated appropriately [18]. Pyridoxine is yet another simple but effective drug for management of neonatal
Indian J Pediatr Fig. 1 Scheme for choice of antiepileptic medications in children
Epileptic seizure Generalized seizures
Partial seizures
Sodium Valproate
Carbamazapine or Sodium Valproate
Absence seizures Sodium Valproate Lamotrigine Clobazam
Myoclonic seizures Sodium Valproate Lamotrigine Clonazepam
Oxcarbazapine Topiramate Phenytoin
Primary Generalized seizures Sodium Valproate Lamotrigine Phenobarbitone
seizures at a dose around 100 mg per day and should be considered in any baby with recurrent seizures in spite of first line anti-epileptic medication. This is an example of yet another simple treatment that can, not only control seizures but prevent long term morbidity for the child [19].
Some Points of General Interest &
Febrile Seizures Simple febrile seizures are brief seizures in a previously normal child between the ages of 6 mo to 6 y of life. The most important treatment in simple febrile seizures is to try to control the fever quickly with either paracetamol or tepid sponging the child. Intermittent prophylaxis with clobazam in a dose of 0.75 mg/kg for 2–3 d in two divided doses during fever is useful to prevent recurrence [20]. Complex febrile seizures are characterized by partial onset of seizures, duration more than 15 min or multiple episodes within 24 h. Late-onset febrile seizures beyond the age of 6 y, febrile status epilepticus, and febrile seizures with generalized epilepsy (GEFS+) are part of the spectrum of febrile seizures [21, 22]. These are the children who require further investigations including EEG, neuro-imaging and continuous prophylaxis with anti-epileptic medications. Any prophylaxis with anti-epileptic medications reduces the chance of recurrence of seizures but does not reduce the risk of future epilepsy. Drug that is commonly used for long term prophylaxis is Sodium Valproate in children for a period of two years. Although Phenobarbitone may be equally beneficial in the younger child, the side effects like sedation or hyperactivity in some children need consideration in a school going child. Other indications, when long term prophylaxis may be considered is when there is a strong family history of a close relative with complex febrile seizures and when there is background of developmental delay or abnormalities on neurological examination.
& & &
Routine drug level monitoring of anti-epileptic drugs is not required unless there are concerns about compliance with the medications or adverse reactions suggesting excess dosages. Routine monthly checking of liver function tests–is not needed. Twice yearly investigations may be done while using drugs like Sodium Valproate. Each drug has specific mechanisms of action and so, appropriate investigations are beneficial such as monitoring pH while using Topiramate or hyponatremia while using Oxcarbazepine. Avoid macrolide antibiotics while using Carbamazepine or Phenytoin Drugs like Metronidazole/Tinidazole may also interact with Carbamazepine and Phenytoin Advice the parents not to stop anti-epileptic drugs when the child is not well or while giving other medicines
How Long Do We Continue Anti-Epileptic Drugs? Approximately 50 % of the children who have childhood onset epilepsy will have remission of their epilepsy and another 20 % remission after a relapse [23]. The most important prognostic factor is the epilepsy syndrome with relapse rates being very low for children with rolandic epilepsy, relatively rare in typical absence epilepsy, intermediate in cryptogenic or symptomatic partial epilepsy and high in juvenile myoclonic epilepsy. In childhood epilepsy, age of onset above 12 y of age is an important risk factor for recurrence [24]. Children with structural lesions in the brain or children with well known epileptic syndromes like West syndrome or Lennox Gastaut syndrome may require long term treatment. Children with remote symptomatic etiology, mental impairment and localization related epilepsy are
Indian J Pediatr
prone to have difficult to control epilepsy and are more likely to relapse after a seizure free period. It would be prudent to get an EEG performed before discontinuing medications, as the risk of recurrence is higher for children who had paroxysmal EEG abnormalities than those with normal EEG tracings [25].
Ketogenic Diet in Epilepsy All children above the age of one year with drug resistant epilepsy may be tried on ketogenic diet [26]. Although it involves a lot of parental counseling and time in making the specific diet for the child, the benefits of the seizure control and improvement in alertness and concentration over a period of time makes the family stick to the diet [27].
Surgical Treatment for Epilepsy
General Patient Management When we speak about rational management of epilepsy, one needs to also take in to account misunderstandings, erroneous opinions and prejudices which still exist in our society. The parents of these children need to be provided enough information and should also be taught how to deal with the child in the event of a seizure. There needs to be a lot of awareness created in schools so that these children do not get excluded from a number of the usual activities at school. There also needs to be a huge stress on using the media to educate the public about the common misconceptions and dispel a lot of myths about epilepsy. Acknowledgement The author would like to thank Kanchi Kamakoti Childs Trust Hospital and Childs Trust Medical Research Foundation. Conflict of Interest None. Source of Funding None.
More children are being considered for epilepsy surgery now than in the past. When a lesion in a child has been identified as the epileptogenic focus with concordance on neuro-imaging and EEG, these children are good candidates for surgery. No patient with epilepsy should be operated without attempting to treat with drugs but the consequences of years of disabling seizures and high doses of antiepileptic medications during a period of rapid neuronal maturation in the child should be weighed against the risks of surgery. Many authors agree that making a decision on surgical therapy for epilepsy should not exceed 1 to 2 y [28]. More centers in India are now available where a comprehensive work up of the child can be performed before epilepsy surgery is considered.
Epilepsy and Genetics There are a number of genetically determined epilepsies that have been recognized over the years. These can be broadly divided into two groups: one, where the genetic defects directly result in functional abnormalities in the neurons such as benign familial neonatal convulsions where the genetic defect is in the voltage gated potassium channel genes KCNQ3 [29]. The other group is associated with structural brain abnormalities such as Tuberose sclerosis—TSC1/TSC2 genes. One of the reasons why it is interesting and important to understand these is the fact that the future researchers may be able to tailor drug therapy to specific subtypes depending on which ion channel is defective and thus achieve a much better success rate in “curing” some of these epilepsies. This sort of understanding may also help us to counsel families and predict the genetic susceptibility in families in the future.
References 1. Arzimanoglou A, Guerrinni R, Aicardi J. Aicardi’s epilepsies in children. 3rd ed. Philadelphia: Lippincott Williams and Wilkins; 2004. p. 1–6. 2. Guerrini R, Andermann E, Avoli M, Dobyns WB. Cortical dysplasias, genetics and epileptogenesis. Adv Neurol. 1999;79:95–121. 3. Holmes GL, Stafstrom CE. Effects of seizures on the developing brain. In: Tuxhorn I, Holthausen H, Boenigk H, et al., editors. Pediatric epilepsy syndromes and their surgical treatments. Paris: John Libbey; 1997. p. 489–504. 4. Loring DW, Meador KJ. Cognitive side effects of anti-epileptic drugs in children. Neurology. 2004;62:872–7. 5. O’Donohoe NV. Epilepsies in childhood. 2nd ed. London: Butterworth-Heinemann; 1985. 6. Mirzrahi EM. Electroencephalographic/polygraphic/video-monitoring in childhood epilepsy. J Pediatr. 1984;105:1–9. 7. Jeavons PM. Non epileptic attacks in childhood. In: Rose CF, editor. Research progress in epilepsy. London: Pitman; 1983. p. 224–30. 8. Metrick ME, Ritter FJ, Gates JR, Jacobs MP, Skare SS, Loewenson RB. Non epileptic events in childhood. Epilepsia. 1991;32:322–8. 9. Ramsay RE, Cohen A, Brown MC. Co-existing epilepsy and nonepileptic seizures. In: Rowan AJ, Gtes JR, editors. Non epileptic seizures. Boston: Butterworth-Heinemann; 1993. p. 47–54. 10. Cuthill FM, Espie CA. Sensitivity and specificity of procedures for the differential diagnosis of epileptic and non-epileptic seizures: a systematic review. Seizure. 2005;14:293–303. 11. Guidelines for epidemiologic studies on epilepsy. Commission on epidemiology and prognosis of the International League Against Epilepsy. Epilepsia. 1993;34:592–6. 12. Murthy JM. Seizures due to solitary cysticercus granuloma. In: Singh G, Prabhakar S, editors. Taenia solium cysticercoids: from basic to clinical science. Oxon: CABI publishing; 2002. p. 251–6. 13. Koepp M, Woermann FG. Imaging structure and function in refractory focal epilepsy. Lancet Neurol. 2005;4:42–53. 14. Glauser T, Ben-Menachem E, Bourgeois B, Cnaan A, Chadwick D, Guerreiro C, et al. ILAE treatment guidelines: evidence-based analysis of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia. 2006;47:1094–120.
Indian J Pediatr 15. World Health Organization. Atlas—epilepsy care in the world. Andheri, Mumbai: Michael Fernandez, Medica Press International; 2005. p. 40–3. 16. Reynolds EH, Shorvon SD. Monotherapy or polytherapy for epilepsy. Epilepsia. 1981;22:1–10. 17. Ramantani G, Ikonomidou C, Walter B, Rating D, Dinger J. Levetiracetam: safety and efficacy in neonatal seizures. Eur J Paediatr Neurol. 2011;15:1–7. 18. Venkataraman V, Balaji P, Panigrahi D, Jamal R. Biotinidase deficiency in childhood. Neurol India. 2013;61:411–3. 19. Rajesh R. Pyridoxine dependant seizures: a review. Indian Pediatr. 2003;40:633–8. 20. IAP Expert Committee Guidelines. Guideline for diagnosis and management of childhood epilepsy. Indian Pediatr. 2009;46:681–98. 21. Singhi PD, Srinivas M. Febrile seizures. Indian Pediatr. 2001;38: 733–40. 22. Sadlier LG, Scheffer IE. Febrile seizures. BMJ. 2007;334:307–11. 23. Silanpaa M, Schmidt D. Natural history of treated childhood onset epilepsy, prospective long term population based study. Brain. 2006;129:617–24.
24. Shinnar S, Berg AT, Moshé SL, Kang H, O’Dell C, Alemany M, et al. Discontinuing antiepileptic drugs in children with epilepsy: a prospective study. Ann Neurol. 1994;35:534–45. 25. Berg AT, Shinnar S. Relapse following discontinuation of anti-epileptic drug: a meta-analysis. Neurology. 1994;44:601– 8. 26. Freeman JM, Kosoff EH, Hartman AL. The ketogenic diet:one decade later. Pediatrics. 2007;119:535–43. 27. Lefervre F, Aronson N. Ketogenic diet for the treatment of refractory epilepsy in children: a systematic review of efficacy. Pediatrics. 2000;105:e46. 28. Mohammed A, Wyllie E, Ruggieri P, Kotagal P, Babb T, Hilbig A, et al. Temporal lobe epilepsy due to hippocampal sclerosis in pediatric candidates for epilepsy surgery. Neurology. 2001;56:1643–9. 29. Castaldo P, del Giudice EM, Coppola G, Pascotto A, Annunziato L, Taglialatela M. Benign familial neonatal convulsions caused by altered gating of KCNQ2/KCNQ3 potassium channels. J Neurosci. 2002;22:RC 199.
