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SUPPLEMENT TO Journal of the association of physicians of india august 2013 VOL.

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Guest Editorial

Epilepsy - An Update
SV Khadilkar
ndia is home to large numbers of individuals with epilepsy. Epidemiological studies in India have shown epilepsy to rank first or second amongst the neurological diseases seen in India.1,2 The annual incidence of epilepsy in India is approximately 40-50 per 100,000 per year.3,4 While this is lower than some other developing nations, the actual numbers of individuals suffering from epilepsy in India are very high and hence epilepsy assumes public health importance. The dimensions of the medical, social, psychological and financial consequences of epilepsy in India are enormous. 5 Several studies have reported that a large proportion of Indian patients with epilepsy do not get treatment. The causes of this significant treatment gap include high cost of treatment, non availability of anti-epileptic drugs, faith in alternative treatments, superstitions and cultural beliefs. Drug discontinuation is common due to fear of side effects of allopathic medications and ignorance. An Indian study reported 43% discontinuation rate within one year.6 In addition to the disease related disability, the social stigma creates further difficulties in its management. The quality of life of patients with epilepsy is affected, children find it difficult to be accepted in schools, finding suitable employment and arranging marriages also become more difficult. On this background, it is appropriate to take a review of recent happenings in the field of epilepsy. The classification of epilepsy is changing remarkably. After having gone through a phase of being voluminous as a result of splitting, it is becoming user friendly again, and the internists dealing with a variety of epilepsies will find this a welcome change. Several new anti attack agents have recently become available for the management of epilepsy. They are considered to be safer, have less drug interactions and compare well in efficacy with older agents. While availability of newer medicines is not much of an issue in India, the costs of the newer agents are often prohibitive and go beyond the means of common Indians. Hence, scientific knowledge of when and how to use these medicines, is essential. As the plethora of agents has increased, possibilities of combinations have multiplied and the information about which combinations are pharmacologically and therapeutically sound
110, New Wing, Bombay Hospital, 12, New Marine Lines, Mumbai 400 020

is increasingly becoming relevant. Women with epilepsy form a very import subgroup which needs to be dealt with special care and expertise. As neurology work force in India is very limited and distributed mainly in metropolitan cities, in many parts of India, neurological consultations are very difficult to obtain.7 Majority of people with epilepsy in India are hence diagnosed and treated by physicians. Therefore it is very important that physicians and internists are familiar with the newer developments in the field of epilepsy. This special issue on epilepsy deals with all the aforementioned areas. Epilepsy experts from various parts of India have contributed to this issue. I do hope that the readers of JAPI will find this issue helpful in their clinical work. I thank all the contributors and compliment Dr Siddharth Shah, Editor- in- Chief, JAPI, for conceptualizing and facilitating this special issue.

References
1. Gouri-Devi M, Gururaj G, Satishchandra P et al Prevalence of neurological disorders in Bangalore, India: a community based study with a comparison between urban and rural areas. Neuroepidemiology 2004;23:261-268. 2. Razdan S, Kaul RL, Motta A et al. Prevalence and pattern of major neurological disorders in rural Kashmir [India] in 1986. Neuroepidemiology 1994;13:113-119. 3. Mani KS, Rangan G, Srinivas HV et al. The Yelandur study:a community based approach to epilepsy in rural south Indiaepidemiological aspects. Seizure J BR Epilepsy Assoc 1998:7;281-288. Saha SP, BhattacharyaS, Roy BK et al. A prospective incidence study of epilepsy in a rural community of West Bengal, India. Neurol Asia 2008;13:41-48. Bharucha NE. Epidemiology and treatment gap of epilepsy in India. Ann Ind Acad Neurol 2012;15:352-353.

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6. Das K,Banerjee M,Mondal G,et al. Evaluation of socio-economic factors causing discontinuation of epilepsy treatment resulting in seizure recurrence: a study in an urban epilepsy clinic in India. Seizure 2007;16:601-607. 7. Khadilkar S V. Neurology: Scenario in India. JAPI 2012;60:42-44.

SUPPLEMENT TO Journal of the association of physicians of india august 2013 VOL. 61

Classifying Epilepsy : Whats New?


Vibhor Pardasani*, Satish Khadilkar**

Introduction

clear understanding of the classification of seizures and epilepsies is essential for their diagnosis, treatment, and prognostication. The management of a patient with seizuresbegins with an understanding of his/her seizure type based on semiology and, if pertinent, epilepsysyndrome. Specific seizure typesor syndromes often respond better to specificmedications or surgical approaches.Some electroclinical syndromes carry abenign prognosis or high likelihood ofseizure remission by a certain predictable age. Otherseizure syndromes may carry a generally poorerprognosis, and fore-knowledge allows focused treatment and lifestylemodifications for patients and families.

cerebralhemisphere, which may include subcortical structures. For each seizuretype, ictal onset is consistent from one seizure to another. These may consistently propagate alongpreferred network (s) involving the contralateral hemisphere. While emphasizing this conceptual shift, certain specific changes have been suggested to the 1981 classification of seizures3. 1. 2. Neonatal seizures are classified within the classification scheme and not separately. The sub-classification of absence seizures hasbeen simplified. Myoclonic absence seizuresand eyelid myoclonia are now recognized as subtypes of absence seizures. It is now known thatthe so-called infantile spasmsmay continue past or even occur de novo after infancy. 5,6 Therefore, themore generic term epileptic spasms is recommended for use. It is still not possible to classify these as focal or generalized and so they have been placed in their owngroup as unknown mode of onset.

The classification of epileptic seizures haslargely evolved withclinicalobservation, EEG findings and expert opinions. TheInternational League Against Epilepsy(ILAE) first published a classificationsystem in 1960. The last official updatefor seizures was published in 1981,and the last official update for the epilepsieswas published in 19891, 2. However, over the last two to three decades, we have come to know much more about epilepsies due to the advances in neuroimaging, genomics and molecular biology. This Knowing much more has changed our concepts towardsthe causation and phenomenology of seizures. These aspects need to be incorporated in epilepsy classification so as not just to reflect current scientific understanding but also to make the management and clinical decision making easier for even the non-specialized clinician. To this effect, the ILAE commission, in its 2005-2009 term had sought to revise the terminology and concepts for classification of both seizures as well as epilepsies so as to reflect the advances beingmade in basic and clinical neurosciences. Inputsweresought from experts in fields of genetics, neuroimaging, therapeutics, pediatric and adult epileptology, as well as statistics and research design. A report on these inputs was subsequently submitted but is yet to be officially endorsed3. These proposals are not meant to be permanent,but form part of a transition to a system that will ultimatelyallow for meaningful translation of scientific understandingto the classification of the epilepsies for clinical and otherpurposes.4

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4. The traditional classification used the terms simple partial, complex partial, and partial seizures-secondarily generalized. However, the terms simple and complex are often misused ormisunderstood. In addition, this distinction, based on impairment of consciousness or awarenessmay not always be precise and well defined and has therefore been recommended for discontinuation. The mode of onset of seizure is usually of greater practical importance than the mode of spread. The term secondarilygeneralized usually does not add to the management of focal seizures, makes them liable to be confused with generalized seizures and has therefore been eliminated. Since the information required to scientificallyclassifying focal seizures is still inadequate, the ILAE Commission recommends that focal seizure be described according to features that are most useful for a given specific purpose. This may include detailed description of semiology for the purpose of differentiation between epileptic andnonepileptic events and forpresurgical evaluation.7 The myoclonicastatic seizures are now re-classified as myoclonic atonic seizures.3

New Terminologies and concepts


Mode of seizure onset It is now recognized that generalized seizures do not necessarily involve the entire cerebral cortex3. They can be originating at some point within one or more of bilaterally distributed networks. In patients with generalized seizures, including those with known generalized electroclinical syndromes, at times ictal onsets have been noted to be localized and seizure semiologies to be asymmetric. However, unlike focal seizures, the location and lateralization of such seizures are usually not consistent from one event to another. Focal seizures originate within networks limited to one
Consultant Neurologist, Bombay Hospital Institute of Medical Science, Mumbai; **Professor and Head, Department of Neurology, Grant Medical College and sIr J J group of Hospitals, Mumbai; Honorary Neurologist, Bombay Hospital Institute of Medical Science, Mumbai
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Descriptors of focal seizures Even as the commission report discourages the terms simple and complex partial seizures, in order to facilitate continuity with the1981 classification of seizures, descriptors of focal seizuresmay be used, individually or in combination with other features depending on the purpose.3 Chiefly, these include: With observable motor or autonomic components. This corresponds to the concept of simple partial seizure. Involving subjective sensory or psychic phenomena only. This corresponds to the concept of an aura. With impairment of consciousness or awareness. The previously termed complex partial seizure can be referred by this descriptor. The term Dyscognitive has been also been proposed for the alteration in awareness8. Evolving to a bilateral, convulsive seizure (involving tonic,

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clonic, or tonic and clonic components). This corresponds to the previously used term secondarily generalized seizure.

Etiology
The terms idiopathic, symptomatic, and cryptogenic had taken on a variety of meanings and connotations over the years. The commissions report recommends that the terms idiopathic, symptomatic, and cryptogenic be substituted by genetic, structural/ metabolic and unknown.3 Genetic The term idiopathic as defined in the 1989 document implied epilepsies with no underlying cause other than a possible hereditary predisposition and were defined by age-related onset, clinical and electrographic characteristics, and a presumed genetic etiology. 2 The current recommendations strongly require irrefutable evidence for genetic basis. Such evidence may derive from specific molecular genetic studies or from appropriately designed family studies1. The genetic designation does not rule out the possibility of contribution of environmental factors in the expression of disease. Genetic epilepsies would include childhood absence epilepsy, autosomal dominant nocturnal frontal lobe epilepsy,Dravet syndrome, etc. The term idiopathic was also used to convey the idea of a highly benign, self-limited,pharmacoresponsive form of epilepsy, occurring and at times remitting in predictable age groups and generally unaccompanied by other neuropsychiatric consequences or disabilities. We now know a variety of subtle cognitive and behavioral disorders to be occurring in association with these epilepsies.In this context, the use of the word benign can be misleading for physicians, patients, and families.Therefore, the new report recommended that this term should neither be used nor implied when referring to this group of epilepsies. Instead usage of two new terms has been proposed: self-limited and pharmacoresponsive. Self-limited: This is a more precise term to denote epilepsies having a high likelihood of spontaneous remission at a predictable age. Pharmacoresponsive : Designating an epileptic syndrome Idiopathic allowed, within a reasonable certainty, the prediction of rapid seizure control with appropriate medication without significant morbidity.The term pharmacoresponsive may be more meaningful to clinicians as well as families than the term benign or idiopathic. In general, it was felt that cause should notbe equated with prognosis of epilepsy. H o we ve r , e ve n p h a r m a c o r e s p o n s i ve , m a y b e problematicbecause: (1) at least one-third of children with benign epilepsiesdo not need pharmacologic treatment; and (2)patients with the same syndrome may be pharmacoresponsiveor pharmacoresistant and the prediction, almost impossible at the onset of the illness. . Structural/metabolic The term symptomatic as used in the conventional classification is often substituted for the concept of a poor prognosis. The ILAE report recommends the term structural and metabolic to highlight that there is a separate disorder, structural or metabolic, the relationship of which to epilepsy is not as direct as in genetic epilepsies. Structural lesions includeacquired disorders such as stroke, trauma, neoplasia and infection, as well as those of genetic origin (e.g., tuberous sclerosis,many malformations of cortical development). Even when associated with genetic defects, there is a separate disorder

interposedbetween such defect and the epilepsy.It may become necessary to subdivide these causes further, starting with separate groups for structural and for metabolic. Unknown cause The designation Cryptogenic in the previous classification implied an as-yet-unrecognized structural/ metabolic defect or presumed symptomatic2. The new term Unknown is meant to be truly neutral; the epilepsy may have a fundamental geneticdefect at its core or it may be the consequence of a separateas yet unrecognized disorder. It was from among the so-called cryptogenic epilepsies that genetic electroclinical syndromes such as autosomal dominant nocturnalfrontal lobe epilepsy (ADNFLE) and autosomal dominant epilepsy with auditory features (ADEAF) were discovered. 9,10 This group would include electroclinical syndromes like epilepsy of infancy with migrating focal seizures and myoclonic epilepsy in infancy [formerly benign myoclonic epilepsy of infancy]11. It might be reasonable to include some of the traditional idiopathic electroclinical syndromes as well. These include benign rolandic epilepsy,Panayiotopoulos syndrome, and benign occipital epilepsy of the Gastaut type, in the causation of whichgenetic factors may be involved but do not appear to be primary12, 13. Diseases, syndromes, and epilepsies The new report remarks that the 1989 report classification had used the terms syndromes and epilepsies almost interchangeably and the term syndrome took on a broad and very imprecise meaning. Certainhighly specific entities such as childhood absence epilepsy and poorly differentiatedepilepsies like cryptogenic parietal lobe epilepsywere treated as if they represented the same level of diagnostic precision. An electroclinical syndrome, however, is a complex of clinical features, signs, and symptoms that together define adistinctive, recognizable clinical disorder with typical age of onset, specific EEG characteristics, seizure types, and other features which, when taken together, permit a specific diagnosis.Syndrome recognition oftenhas implications for treatment, management, and prognosis. The report recommends to restrict the term syndrome to a group of clinical entities reliably identified by a cluster of electroclinical characteristics. Patients whose epilepsy does not fulfill the criteria for a specific electroclinical syndrome should be described in terms of a variety of clinically relevant factors like etiology and seizure types. In clinical practice, one frequently encounters patients who do not fit precise electroclinical syndromes but whose features represent clinically distinctiveconstellations, based at times on etiology. These are diagnostically meaningful forms of epilepsy and may have implicationsfor clinical management. These include mesial temporal lobe epilepsy, hypothalamic hamartoma with gelastic seizures, epilepsy with hemiconvulsion and hemiplegia, and Rasmussen syndrome.The new report recommends that these constellations are sufficiently distinctive to be recognized as relativelyspecific diagnostic entities. In the current classification, many epilepsies with structural or metabolic defects are grouped together as symptomatic focal epilepsies and distinguished on the basis of localization. The commission recommended that terms such as symptomatic temporal lobe epilepsy be replaced by longer but more precise expressions such as epilepsy with focal seizures secondary to cortical dysplasia in the temporal lobe. Localization is not the primary factor of importance for understanding the cause and prognosis of these epilepsies.

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The commission decided to discard the terms generalized and focal for modifying the epilepsies themselves 3 . Generalizedspasms arising from a focal lesion as occurs in West syndrome and focal seizures arising from a diffuse geneticdisorder as occurs in Dravet syndrome were the examples of why and how these terms do not adequatelyreflect the processes underlying the epilepsies.. The term catastrophicappears emotionally charged and discouraging and has been rejected in the new recommendations. The new ILAE report does not appear to fulfill its intent to modernize the classification by incorporating the advances in the neurosciences3. In fact it has raked up disagreements and controversies among experts while adding some confusion for the clinician. It is infact preferable to continue using the previous ILAE classifications, despite their significant incompleteness. Nevertheless, It may be worthwhile for students as well clinicians managing epilepsy to go through these recommendations and the objections thereto in order to develop a better understanding of seizure and epilepsy classification. The four dimensional classification:Luders et al, while urging the commission to abandon a tentative approach of finding a smooth transition between the old classification and an incomplete new classification, recommend utilization of all the modern diagnostic technologies in the development of a really new classification14. The group has been using and teaching aFour-dimensionalClassification of Epilepsies and Epileptic Seizures the purpose of which has been to classifyindividual cases to help in the selection of therapeuticapproaches and to define prognosis. 1. Seizures. The detailed symptomatologic description of the seizure along with the frequency and the presence or absence of provocative factors. 2. Location.Even though the theoretical differentiationbetween focal and generalized epilepsies isbecoming difficult, when classifying individual cases this may not be as big a problem. Certain simplifying assumptions need to be made considering that the so-called focal seizures, whatever their origin and etiology, tend to respond to similar antiepileptic drugs agents whereas most generalized epilepsies respond to different agents. One also needs to define the epileptogenic zone precisely while considering epilepsy surgery. Etiolog yThe prognosis of epilepsy is often dependent on the etiology. The etiology also often determines the management of epilepsy both medical as well as surgical. 4. Related medical conditionsSpecifying the related medical conditions further clarifies the clnical condition and guides treatment. This four-dimensional approach can be illustrated with examples: Case 1 Location: Left frontal lobe. Seizures: Right hand clonic seizure. Frequency: 2/month.Etiology: Left frontal gliosis. Related Medical Condition: Past history of CNS Tuberculosis. Mild left hand paresis Case 2 Location:Right mesial temporal lobe. Seizures: Left hand tonic seizure evolving to bilateral tonic. Frequency: 1/ month.Etiology:Right mesial temporal sclerosis. Related Medical Condition:Moderatemental retardation Shorvon felt that despite being a major determinant of prognosis, seizure etiology remains neglected as a dimension in

the classification scheme 15. He has proposed an etiology based classification with four broad categories: Idiopathic: epilepsy of predominately genetic or presumed genetic origin Symptomatic: epilepsy associated with gross anatomic or pathologic abnormalities, and/or clinical features, indicative of underlying disease or condition Provoked: epilepsy in which a specific systemic or environmental factor is the predominant cause of the seizures with no gross causative neuroanatomic or neuropathologic changes.This a new category and includes seizures provoked by fever; menstrual cycle and catamenial epilepsy; sleep-wake cycle;metabolic and endocrine-induced seizures; drug-induced seizures, etc. It also includes reflex epilepsies like photosensitive, startle-induced, reading epilepsy, etc. Cryptogenic: epilepsy of presumed symptomatic nature in which the cause has not been identified Suggested scheme for an etiological classification of epilepsy15
Main category Idiopathic epilepsy Symptomatic epilepsy Subcategory Pure epilepsies due to single gene disorders Pure epilepsies with complex inheritance Predominately genetic or developmental causation Childhood epilepsy syndromes Progressive myoclonic epilepsies Neurocutaneous syndromes Other neurologic single gene disorders Disorders of chromosome function Developmental anomalies of cerebral structure Predominately acquired causation Hippocampal sclerosis Perinatal and infantile causes Cerebral trauma Cerebral tumor Cerebral infection Cerebrovascular disorders Provoking factors Reflex epilepsies

Reflexive epilepsy Cryptogenic epilepsies

InShorvonsetiologic scheme, the new terms genetic, structural/ metabolic and unknown have not been followed. It was felt that some of this change in terminology is cosmetic rather than conceptual. The term genetic for example should not be used unless predominant genetic causation is fully established. Some feel that thiscategory should be in addition to idiopathic, cryptogenic,and symptomatic and not a substitute for idiopathic16, 17, 18,19,20. The term structural/ metabolic is imprecise and the change from cryptogenic to unknown purely semantic. From Books to the consulting rooms The nineteenth century scientist John Hughlings Jackson subdivided classification systems into scientific and practical.21 The analogy provided was that of a botanist who classified plants according to the evolutionary place and gardeners who grouped plants according to the color of their flowers, shape of their leaves, growth requirements and characteristics. Thus, for the practicing physician, the classification of epilepsies remains reasonably simple. The first attempt is to differentiate seizures as a symptom of another disease from epilepsy as a disease itself. Further, attention to description

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of attacks, age at onset, family history and accompanying disorders will usually lead to accurate practical information. For the treating clinician, the scheme proposed by Luders carries tremendous practical value as all the four dimensions largely direct the symptomatic as well as disease modifying therapy besides determining the prognosis.Classification being the fundamental step towards understanding and therapy of epilepsy, it is important to spend time on this aspect of the disease. Complex classification systems are more for research purposes and the above discussion will help readers to translate the classification systems to fruitfully apply to the patients.

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Scheffer IE, Bhatia KP, Lopes-Cendes I, Fish DR, Marsden CD, et al. Autosomal dominant nocturnal frontal lobe epilepsy: a distinctive clinical disorder. Brain 1995; 118:6173.

10. Ottman R, Barker-Cummings C, Lee JH, Ranta S. (1999) Genetics of autosomal dominant partial epilepsy with auditory features. In Berkovic SF, Genton P, Hirsch E, Picard F (Eds) Genetics of focal epilepsies. John Libbey& Co Ltd, London, pp. 95102. 11. Engel J. Report of the ILAE Classification Core Group. Epilepsia. 2006; 47:15581568. 12. Taylor I, Berkovic SF, Kivity S, Scheffer IE. (2008) Benign occipital epilepsies of childhood: clinical features and genetics. Brain 131:22872294. 13. Vadlamudi I, Kjeldsen MJ, Corey LA, Solaas MH, Friis ML, et al. Analyzing the etiology of benign rolandic epilepsy: a multicenter twin collaboration. Epilepsia. 2006; 47:550555. 14. Luders HO, Amina S, Baumgartner C, Benbadis D, BermeoOvalle A, et al. Modern technology calls for a modern approach to classification of epileptic seizures and the epilepsies. Epilepsia, 2012; 53(3):405411. 15. Shorvon SD. The etiologic classification of epilepsy. Epilepsia. 2011; 52(6):10521057. 16. Ferrie CD. Terminology and organisation of seizures and epilepsies: radical changes not justified by new evidence. Epilepsia 2010;51:713714. 17. Guerrini R. Classification concepts and terminology: is clinical description assertive and laboratory testing objective? Epilepsia 2010; 51:718720 18. Wolf P. Much ado about nothing? Epilepsia. 2010;51:717718. 19. Shorvon S. Using etiology as one axis of classification. Epilepsia. 2011; 52:12081209. 20. Panayiotopoulos CP. The new ILAE report on terminology and concepts for the organization of epilepsies: Critical review and contribution. Epilepsia, 2012; 53(3):399404. 21. Jackson JH. Selected Writings. 2 vols. London: Hodder& Stoughton, 1931.

References
1. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised clinical and electrographic classification of epileptic seizures. Epilepsia. 1981; 22:489501. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia. 1989; 30:389399. Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia. 2010 Apr;51(4):676-85. Berg AT, Scheffer IE. New concepts in classification of the epilepsies: entering the 21st century. Epilepsia. 2011 Jun;52(6):1058-62. Camfield P, Camfield C, Lortie A, Darwish H. Infantile spasms in remission may reemerge as intractable epileptic spasms. Epilepsia. 2003; 44:15921595. Goldstein J, Slomski J. Epileptic spasms: a variety of etiologies and associated syndromes. J Child Neurol 2008; 23:407414. Luders HO, Burgess R, Noachtar S. Expanding the international classification of seizures to provide localization information. Neurology. 1993; 43:16501655. Blume WT, Luders HO, Mizrahi E, Tassinari C, van Emde Boas W, Engel J. Glossary of ictal semiology. Epilepsia 2001;42:12121218.

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Epilepsy: Diagnostic Evaluation


JMK Murthy*
pilepsy, a common chronic neurological disorder, is a potentially treatable condition. The determinants of seizure remission and long-term outcome include: seizure type, type of epilepsy and epilepsy syndrome, and etiology. The diagnostic evaluation of patients with epilepsy involves essentially these aspects. In patients with drug resistant epilepsy, pre-surgical work-up involves evaluation for the substrate for possible surgery.

firing with paroxysmal depolarization shift and aftergoing hyperpolarization. A large area of cortex, approximately 6 cm,2 must be involved in a spike discharge for that spike to be apparent with scalp recording.2 The epileptiform activity in deep brain structures may not be seen with superficial scalp electrodes. IEDs are rarely seen normal children (1.9-3.5%) and adults (0.2-0.5%).3-6 The EEG may be normal in people with epilepsy. In serial EEG recording, 50% of patients with epilepsy were found to have epileptiform discharges on the first EEG, 84% by the third EEG, and in 92% by the fourth EEG.7 While reviewing interictal EEG particular attention is paid to sharp waves or spikes, focal or generalized slow activity, inappropriate response to stimuli (hyperventilation, photic stimulation), and EEG correlates to changes in state or behavior in addition to background rhythm. Methods that increase the chances of detecting IEDs in the EEG include sleep deprivation, hyperventilation, photic stimulation, and placement of special electrodes like e.g., sphenidal electrodes. Photoparoxysmal response (PPR) consists of spikes or spike waves in response to intermittent photic stimulation. The epileptiform discharge may persist after the end of photic stimulation and majority of the patients have stable photosensitivity range (Figure 2). The International League Against Epilepsy (ILAE) Commission on Classification and Terminology has redefined generalized and focal seizures as occurring in and rapidly engaging bilaterally distributed networks (generalized) and within networks limited to one hemisphere and either discretely localized or more widely distributed (focal).8 EEG has an important role to distinguish between generalized from focal epilepsy. Focal spike and sharp activity generally suggests focal epilepsy and the irritative zone is the area of the cortex that generates interictal focal spike activity. The irretative zone does not coincide but frequently overlaps with epileptogenic zone (Figure 3).9 However, sometimes focal (mesial frontal) onset seizures rapidly generalize, giving the EEG appearance of generalized onset. Spike and sharp wave location indicates the probability of epilepsy. Spikes in the anterior and mid temporal location have high probability of epilepsy. Frontal, central, and occipital spikes have moderate probability of epilepsy.10

Electroencephalography
Electroencephalography (EEG) records electrical current (changing voltage) generated in the large pyramidal neurons of the superficial layers of cerebral cortex. Only synchronized electrical activity occurring across large areas of layered cortex is recorded. Normal rhythmic EEG activity represents the current flow from rhythmic changes in resting membrane potentials (excitatory post-synaptic potentials and inhibitory post-synaptic potentials). In most normal adults, the awake EEG pattern consists of 8-12 Hz alpha activity which is most prominent in the occipital area with attenuation (block) on eye opening (Figure 1). Scalp EEG Inteictal EEG aids: (1) in establishing whether epilepsy is present, (2) in classifying seizure type, (3) in localization of irritative zone and epileptogenic zone, (4) in defining specific epilepsy syndrome, and (5) in selecting appropriate antiepileptic drug (AED) and also helps while withdrawing AEDs. However, EEG is not specific to etiology. Epileptiform discharges (IEDs) are specific for epilepsy (Table 1).1 The duration of spikes is less than 70 msec and that of the sharp waves is between 70-200 msec. Combination of spikes, sharp waves, and slow waves are also epileptiform discharges. Interictal spike or sharp wave is the summated postsynaptic excitatory and inhibitory potentials associated with hypersynchronous neuronal

Fig. 1 : Normal awake EEG showing 10 11 Hz alpha with attenuation (block) on eye opening

Table 1: Characteristics of interictal epileptiform discharges1


Paroxysmal with spiky configuration standing out from the background Duration for spike 20-70 msec and for sharp wave 70-200 msec Abrupt change in polarity and surface negative polarity Should have a physiological field Fig. 2 : EEG showing photo-paroxysmal response at 15 Hz photic stimulation

* Chief of Neurology, Institute of Neurosciences, Continental Hospitals, Hyderabad 500 035

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Epileptogenic Zone Area of the cortex generating seizures, the removal of which is necessary to abolish seizures
Symptomatic Zone

Ictal-onset Zone

Irritative Zone

Epileptogenic Lesion Functional Deficit Zone

Fig. 6 : Awake interictal EEG showing predominantly right occipital transient of sharp-wave activity

Fig. 3 : Shows the concept of epileptogenic zone and different zones (Table 4) and their congruence in a patient with left mesial temporal lobe epilepsy

Fig. 4 : Awake inteictal EEG showing left anterior temporal sharp wave transients with phase reversal at left anterior temporal leads

Fig. 7 : Awake interictal EEG showing generalized polyspike, spikewave activity with normal background activity in a patient with juvenile myoclonic epilepsy

or cure has been reported in 74-92% of such patients following surgical resection.10 The interictal EEG is less useful in localizing the extratemporal epilepsy. In patients with frontal lesions, the IEDs was exclusively frontal in 27.5% (Figure 5) and in patients with parieto-occipital lobe lesions it was exclusively over the lesional lobe in only 12.1% (Figure 6).11 Generalized or multifocal spikes or sharp waves, generalized spike and wave complexes and poly--spikes are reliable indicators of epilepsies with generalized seizures. In combination with a normal awake and sleep background, generalized 3-4 hz and wave complexes and polyspikes are typical for generalized genetic (idiopathic) generalized epilepsies: childhood absence epilepsy (CAE), juvenile absence epilepsy (IAE), juvenile myoclonic epilepsy (JME) (Figure 7), and idiopathic epilepsy with GTC only.

Fig. 5 : Awake interictal EEG showing left frontal spike activity with a field

Video-EEG Video-EEG monitoring refers to continuous EEG recorded for a prolonged period with simultaneous video recording of the clinical manifestations. This permits having correlation of the recorded behavior and the EEG activity. The indications for video-EEG include: (1) to establish the epileptic nature of the attack, (2) to characterize the seizure semiology and thus seizure type, particularly in children; (3) diagnostic evaluation of patients with drug resistant seizures; (4) presurgical evaluation of potential surgical candidates (non-invasive and invasive)

Localization of the focus can be determined by principles of polarity: (1) in the bipolar montages by reversal of polarity, isopotentiality, and end of the chain and (2) in the referential montages by voltage maxim. Interictal EEG abnormalities commonly observed in temporal lobe epilepsy are focal arrhythmic slowing (either theta or delta) and focal IEDs that are often restricted to anterior temporal leads (Figure 4). Bilateral independent discharges are not uncommon. Clear laterality of spikes in patients with mesial temporal lobe epilepsy provides a reliable guide to epileptogenesis and significant improvement

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(a) (b) Fig. 8 : Magnetic resonance imaging (a) FLAIR sequence showing right hippocampal atrophy with hyperintense signal changes suggesting sclerosis and (b) T1-weight sequence showing changes in the floor architecture

Table 2: Structural MR imaging in epilepsy


Hippocampal sclerosis (mesial temporal sclerosis) Malformation of cortical development Focal cortical dysplasia Lessencephaly Hetrotopia (band hetrotopia, nodular hetrotopia) Polymicrogyria Schizencephaly Hemimegalencephaly Tuberous sclerosis Tumors Dysembryoplastic neuroepithelial tumor Ganglio-glioma Gangliocytoma Oligodendroglioma Low grade astrocytoma Hemispherical syndromes Rasmussen encephalitis Sturge-Weber syndrome HHE syndrome Others Fig. 9 : Magnetic resonance imaging, FLAIR sequence showing right frontal focal cortical dysplasia with transmantal sign Cavernoma Hypothalamic hamertoma Vascular malformations Atrophic scars

Invasive EEG Invasive EEG is two types: intracranial EEG recording and intraoperative electrocorticography (ECoG). Intracranial EEG (icEEG) is a technique in which the electrodes are directly implanted on to the surface and depths of the brain. This approach is used in the presurgical evaluation of patients with drug resistant epilepsy, particularly in non-lesional extratemporal, bilateral temporal, and dual pathology. Electrocorticography (ECoG) refers to intraoperative recording of cortical activity, interictal abnormalities, with subdural and less commonly with depth electrodes. ECoG helps in delineating the irritative cortex and thus helps in delineating the extent of surgical resection.

Imaging in Epilepsy
Magnetic Resonance Imaging Advances in neuroimaging particularly with continuous evolution of magnetic resonance imaging (MRI) techniques in the last one decade have a great impact on the management of epilepsy. The application of neuroimaging extends beyond the identification of epileptogenic lesions and refinement of surgical interventions. Presence of structural abnormality and widespread, bilateral abnormalities detected on structural and functional imaging studies are associated with likely antiepileptic drug (AED) resistance. High resolution MRI should be the imaging modality to detect structural lesions in patients with chronic epilepsy. MRI has been

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Table 3 : Indications for MRI in epilepsy14


Onset of seizures at any age with evidence of a partial onset on history or EEG Onset of unclassified or apparently generalized seizures in the first year of life or in adulthood Evidence of focal fixed deficit on neurological or neuropsychological examination Difficulty in obtaining control of seizures with first-line antiepileptic drug treatment Loss of control of seizures with antiepileptic drugs or a change in the seizures pattern that may imply a progressive underlying lesion

brain tissue. Tractography is a post-acquisition processing extension of DTI in which the directional information of the diffusion of water in each voxel is used to infer the orientation of specific white matter tracts. Tractography is the only currently available technique for tracing white matter pathways in vivo. Understanding the configuration of white matter-tracts is fundamental in understanding cerebral function. Tractography can be combined with functional activation studies to delineate white matter tracts connecting eloquent cortex which can assist pre-operative planning to reduce the risk of damaging eloquent cortical function.17

Functional Imaging
Functional imaging with single photon emission tomography (SPECT) and positron emission tomography (PET) reflects seizurerelated changes in cerebral perfusion, glucose metabolism, and neuroreceptor status and thus help in localizing epileptogenic foci even in areas that are morphologically inconspicuous. Neither SPECT nor PET information independently makes the case for surgery in a particular brain area in lesion negative epilepsy and the information from other investigations has to be considered. Ictal SPECT and interictal PET (Figure 10) are useful imaging modalities in the presurgical evaluation of patients with drug resistance epilepsy. The usefulness of interictal SPECT for preoperative localization of ictal onset zone is limited because of low sensitivity, where as ictal SPECT is more sensitive in localizing ictal onset zone. The sensitivity in temporal lobe epilepsy ranges between 7397% and 66% for extratemporal lobe epilepsy.18 Co-registration of the subtracted SPECT images to the patients MRI (SISCOM) can provide further anatomical information on the location the seizure focus PET is of use in lateralizing rather than localizing epileptic focus. In patients with epilepsy the goal of a PET study is to detect areas of relative hypometabolisim, which are presumed to reflect focal functional disturbance of cerebral activity associated with the ictal onset zone. The sensitivity of PET in temporal lobe epilepsy ranges between 70-90%, where as in patients with extratemporal lobe epilepsy it varies between 30-60%.18

Fig. 10 : Interictal PET showing left temporal hypometabolism

shown consistently superior to computed tomography (CT) in identifying the etiology of epilepsy. It identifies mesial temporal sclerosis (Figure 8 a and b) small lesions and abnormalities of malformation of cortical development (Figure 9) (Table 2). Focal structural pathology is identifiable on MRI in 12.7% to 14% patients with newly diagnosed epilepsy.12,13 The reported sensitivity of MRI in identifying surgical proven pathological substrates is approximately 86%.12 However, CT may be useful as complementary imaging technique in the detection of cortical calcification. The indications for MRI in patients with epilepsy are given in Table 3.14 MR-spectroscopy (MRS), functional-MRI (fMRI), and diffusion tensor imaging (DTI) are the other adjunctive MRI techniques used in the presurgical evaluation of patients with drug resistant epilepsy. MRS provides measurement of brain metabolites. In patients with hippocampal sclerosis 1H MRS shows decrease in the ratio of N-acetylaspartate (NAA, neuronal and axonal marker) to creatine (marker of brain energy metabolism) and lateralizes seizure focus in 80-90% of the patients.15,16 Functional MRI (fMRI) is based on the principle that neuronal activity produces regional changes in cerebral blood flow, volume, and oxygenation, therefore leading to variation in the ratio of diamagnetic oxyhemoglobin and paramagnetic deoxyhemoglobin which can be detected as bloodoxygen-level-dependent (BOLD) contrast. fMRI is being used for lateralizing language dominance and also memory deficits thus avoiding the need for invasive intracarotid amobabrbital test (Wadas test). DTI provides the structural integrity of

Drug Resistant Epilepsy and Presurgical Evaluation


Epidemiological data indicate that 20-40% of the patients with newly diagnosed epilepsy become drug resistant. Drug resistant epilepsy is defined as failure of adequate trials of two tolerated, appropriately chosen and used AED schedules (whether as monotherapies or in combination) to achieve sustained seizure sustained seizure freedom. Patients with drug resistant epilepsy should be investigated to determine whether the patient is a possible surgical candidate.19 Presurgical evaluation in patients with drug resistant epilepsy aims at determining the epileptogenic zone. Epileptogenic zone is a theoritical concept and is defined as the area of the cortex generating seizures, the removal of which is necessary to abolish seizures.9 Determining the epileptogenic zone involves identification a number of other zones (Table 4) that if consistently indicative of the same brain area as abnormal (i.e. concordent), provide the best indication of where the true epileptogenic zone might lie.20 Several investigative techniques are done to define the epileptogenic zone. Prolonged video-EEG identifies irritative zone and also ictal onset zone. Analysis of seizure symptoms and signs of the seizures captured during video-EEG identifies the

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Table 4 : Definitions of abnormal brain areas9


Zones Irritative zone Definitions Technique Area of the cortex Electophysiological that generates and invasive and noninterictal spikes invasive) Area of brain where Electrophsiological seizures are generated invasive and non(including areas of invasive) early Structural abnormality Structural imaging of the brain that is MRI and tissue the direct cause of the pathology epileptic seizures Portion of the brain Behavioral observation that produces (video-EEG) and the Initial clinical patient report symptomatology Cortical area of non- Neurological epileptic Dysfunction examination, fMRI, neuropsychological examination, PET and SPECT

electroencephalography, Lipincott Williams and Wilkins, Pheladelphia, Pa, USA, 3rd edition, 2003 2. Cooper R, Winter AL, Crow HJ, et al. Comparison of subcortical, cortical and scalp activity using chronically indwelling electrodes in man. Electroencephalogr Clin Neurophysiol 1965;18:21728. 3. Eeg-Olofsson O, Pe terson I, Sellden U. The development of the electroencephalogram in normal children from the age of 1 through 15 years paroxysmal activity. Neuropediatrie 1971;2:375404.

Ictal onset zones

Epileptogenic lesion

4. Cavazzuti GB, Cappella L, Nalin A. Longitudinal study of epileptiform EEG patterns in normal children. Epilepsia 1980;21:43 55. 5. 6. Bennett DR. Spike-wave complexes in normal flying personnel. Aerosp Med 1967;38:127682. Bridgers SL. Epileptiform abnormalities discovered on electroencephalographic screening of psychiatric inpatients. Arch Neurol 1987;44:3126. Salinsky M, Kanter R, Dasheiff RM. Effectiveness of multiple EEGs in supporting the diagnosis of epilepsy: An operational curve. Epilepsia 1987; 28;331-4. Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizure and epilepsies: Report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia 2010;51:676-85. Luders HO, Engel J Jr, Munari C. General principles, In Engle J Jr (ed), Surgical treatment of the epilepsies, 2nd ed. Raven Press, New York, 1999;137-53.

Symptomatic zone

Functional deficit

7.

8.

symptomaticic zone which in turn can (1) lateralize the seizures to one hemisphere and (2) localize the seizures to a specific brain region in that hemisphere. A variety of neuroimaging techniques are used in the presurgical evaluation to identify various zones: high resolution MRI to determine epileptic lesion zone, fMRI to map the eloquent cortex, EEG-fMRI and MEG to determine irritative zone, PET for functional deficit zone, SPECT to determine ictal onset zone, and fMRI to determine language dominance and memory deficits. Basic preoperative testing includes interictal EEG, structural imaging usung high resolution MRI, video-EEG monitoring, and neuropsychological evaluation. Additional tests are done when the information obtained by these basic testing is insufficient to define the epileptogenic zone. When all the test results are congruent in localizing the epileptogenic zone, the patients can be considered for surgery (Figure 3). Basic preoperative testing (mostly non-invasive) often helps in identifying the epileptogenic zone (surgical substrate), in a significant proportion of patients, particularly in patients with mesial temporal lobe epilepsy. This approach is being used most widely in India while evaluating patients with drug resisting epilepsy for possible surgery. To conclude basic evaluation of a patient with epilepsy involves EEG to define the type of seizure and epilepsy and epilepsy syndrome, video-EEG to characterize the seizure semiology, particularly in patients with multiple seizure types and it also helps to exclude non-epileptic events, and structural imaging with high resolution MRI to establish the cause of epilepsy. Patient with drug resistant epilepsy may require multimodality investigations to determine the epileptogenic zone.

9.

10. Pillai J, Sperling MR. Interictal EEG and the diagnosis of epilepsy. Epilepsia 2006;47(Suppl 1):14-22. 11. Rami J, Vollmar C, de Martinis A, Heinlin J, Peraud A, Noachtar S. Congruence and discrepancy of interictal and ictal EEG with MRI lesions in focal epilepsies. Neurology 2011;77:1383-90. 12. Bronen RR, Fulbright RK, Spencer DD, et al. Refractory epilepsy: Comparison of MR imaing, CT and histopathologic findings in 117 patients. Radiology 1996;20:97-105. 13. Scott CA, Fish DR, Smith SI, et al. Presurgical evaluation of patients with epilepsy and normal MRI: Role of scalp video-EEG telemetry. J Neurol Neurosurg Psychiatry 1999;66:69-71. 14. ILAE Commission Report: Recommendations for neuroimaging of patients with epilepsy. Epilepsia 1997;38:1255-6. 15. Salmenpera TM, Duncan JS. Imaging in epilepsy. J Neurol Neurosurg Psychiatry 2005;76:2-10. 16. Cendes F, Caramarios Z, Andermann F, Dubeau F, Arnold DL. Proton magnetic resonance spectroscopic imaging and magnetic resonance imaging volumetry in the lateralization of temporal lobe epilepsy: A series of 100 patients. Ann Neurol 1997;42:737-46. 17. Duncan JS. Imaging the brains highways-diffusion tensor imaging in epilepsy. Epilepsy Curr 2008;8:85-9. 18. Chong TTJ, Cook M. Neuroimaging in the investigation of epilepsy. In Shorvon S, Guerrini R, Cook M, Lhatoo SD (eds), Oxford textbook of epilepsy and epileptic seizures, Oxford, Oxford University Press, 2013;111-26. 19. Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: Consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 2010;51:1069-77. 20. Lhatoo SD. Principles of epilepsy surgery, In Shorvon S, Guerrini R, Cook M, Lhatoo SD (eds), Oxford textbook of epilepsy and epileptic seizures, Oxford, Oxford University Press, 2013; 291-8.

References
1. Pedley TA, Mendiratta A, Walczak TS. Seizures and epilepsy. In Ebeersole JS, Pedley TA (eds) Current practice of clinical

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15

Treatment Options for Epilepsy in Adults


Manjari Tripathi*, Bhavna Kaul**
pilepsy affects around 50 million people globally. Each year, about 40-190 people are newly affected by this ailment.1 The armamentarium for management of epilepsy in adults consists of both pharmacological and non-pharmacological options. Pharmacological therapy continues to be the mainstay of management of a large majority of persons with epilepsy (PWE). However, several pertinent issues need to be dealt with in the pharmacological treatment of epilepsy in adults. Some of these issues are- when should anti-epileptic AEDs) be started, choice of the first AED, combination therapy, treatment of generalized versus partial seizures. The following sections will deal with the management of epilepsy in adults, both pharmacological and surgical.

Introduction
medications, cost of medication, age and gender of patient (women of childbearing age), psychiatric co-morbidities, and co-medication.4 The proportion of patients who remain on the allocated AED for a period of time, often referred to as effectiveness, provides a combined measure of efficacy and tolerability although this parameter takes into consideration only the adverse effects which lead to drug discontinuation. Some epilepsy syndromes may be responsive to specific anti-epileptic drugs. For example, juvenile myoclonic epilepsy responds to sodium valproate, and infantile spasms in tuberous sclerosis respond to Vigabatrin. Narrow spectrum agents, such as carbamazepine, phenytoin, gabapentin, pregabalin, and oxcarbazepine, can worsen myoclonic jerks and absence seizures. If seizure classification is uncertain or the patient exhibits multiple seizure types, a broad spectrum agent such as sodium valproate, topiramate, levetiracetam, or zonisamide may be the best choice. Levetiracetam is a highly efficacious broad spectrum agent that can be used for a number of seizure types including partial seizures, myoclonic seizures of JME, and generalised tonic-clonic seizures of pharmacokinetics, renal metabolism with minimal drug interactions, and multiple dosing preparations. A word of caution being few reports of seizure aggravation on the drug needing withdrawal.5 Table 2 lists the broad classification for drugs effective in generalized versus focal epilepsy. A systematic review comparing the efficacy and effectiveness of AEDs concluded that there are major weaknesses in the quality of the available evidence.6 It is not surprising, therefore, that recommendations for first line AEDs to be used in the treatment of focal epilepsy in adults differ in different guidelines. Co-morbidities can influence the choice of AEDs in patients by proving efficacious in conditions other than epilepsy. For instance, in patients of migraine, valproate or topiramate may serve as good choice of anti-epileptic agent due to its dual role in epilepsy and migraine prophylaxis. Similarly, in patients of epilepsy with co-existing neuropathic pain, gabapentin or pregabalin may serve as a good anti-epileptic agent. The adverse effects of an agent may compel one to exclude it as a treatment option in certain cases. For instance, sodium valproate, carbamazepine, pregabalin, gabapentin, and vigabatrin are all associated with weight gain and may be best avoided in obese patients or in those with diabetes mellitus. On the other hand, patients wishing to gain weight may benefit from these agents. Table 2 : Efficacy spectrum of antiepileptic drugs against different seizure types in adults
Effective against focal seizures and most generalized seizures Valproate, benzodiazepines, Phenobarbital, primidone, lamotrigine, levetiracetam, topiramate, zonisamide, rufinamide, felbamate. Carbamazepine, phenytoin, gabapentin, lacosamide, oxcarbazepine, eslicarbazepine, pregabalin, tiagabine, vigabatrin. Ethosuximide

Pharmacotherapy: When should AEDs be Started?


AED therapy is typically instituted for several years and sometimes for life. The decision to start AEDs should therefore be taken after considering the risk-benefit equation. After a first unprovoked seizure, the average risk of having a second seizure is 46%.2 However, the risk of subsequent seizures after the first seizure is 70% even in a cohort in which most patients were on treatment after their second seizure.3 On the basis of this increased risk, there is a consensus that treatment is definitely indicated after at least two unprovoked seizures. Risk factors for seizure recurrence include epileptiform electroencephalogram [EEG] discharges, an abnormal neurological examination, or other evidence of a structural CNS abnormality. In the presence of these factors, the risk of recurrence after one seizure may be as high as the risk of recurrence after two seizures. Early treatment might be justified in patients with a high recurrence risk, in particular if the consequences of further seizures are expected to be severe. Patients with a first unprovoked seizure after a stroke or a seizure caused by other identifiable lesions have a high recurrence rate, and fragile elderly patients are also likely to be more vulnerable if seizures recur. The choice to start or not too also has to be offered to the patient as the patient may not be able to risk having another episode.

Choice of the First AED


A number of factors govern the first choice of AED (Table 1). These include- drug efficacy for seizure type or types, adverse effects considering the patient profile, interactions with other Table 1 : Factors that determine the choice of AED in patients with newly diagnosed epilepsy
Patient dependant factors Age, gender, genetic background, comedication, co-morbidity, affordability. Drug-specific issues Specific epilepsy syndrome, dosedependent adverse effects, idiosyncratic reactions, chronic toxicity, teratogenicity, interaction potential, formulation. Non-specific variables Cost, availability
*

Professor Neurology, AIIMS, Delhi; **Assistant Professor Neurology, IHBAS, Delhi

Primarily effective against focal seizures, with or without secondary generalization Effective against absence seizure

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Table 3 : Initial and maintenance daily doses and important side effects of commonly used AEDs
AED Carbamazepine (CBZ) 10-20 mg/kg Starting dose in average adult 100 mg BID Maintenance dose in average adults (mg/day) 400-1000 Important side effects Sedation, dizziness, ataxia, skin rash (occasionally Steven-Johnson syndrome), hyponatremia, weight gain, seizure worsening in some epilepsy syndromes Sedation, ataxia, somnolence, irritability, depression, weight gain, tolerance (reduced anti-epileptic effect) Sedation, ataxia, dizziness, skin rash (occasionally Steven-Johnson syndrome) Somnolence, dizziness, cognitive slowing, psychosis Sedation, dizziness, ataxia, headache, hyponatremia, skin rash Sedation, ataxia, depression, memory problems, skin rash, hyperactivity in children Ataxia, sedation, gum hyperplasia, coarsening of facial features, hirsutism, memory problems, osteomalacia and bone loss, skin rash Anorexia, weight gain, nausea, vomiting, tremors, hair loss, polycystic ovarian syndrome, thrombocytopenia Sedation, somnolence, cognitive problems, weight loss, word finding difficulty, renal stones, seizure worsening Sedation, anorexia, renal stones, forgetfulness, skin rash, weight loss, distal parasthesiae

Clobazam (CLB)

10 mg OD (HS)

10-30

Lamotrigine (LTG) 5 mg/kg with other AEDs 2.5 mg/kg with VPA Levetiracetam (LEV) 20-40 mg/kg Oxcarbazepine (OXC) 15-30 mg/kg Phenobarbitone (PB) 5-8 mg/kg

25 mg OD (HS) Lower dose with VPA 250 mg BID 150 mg BID 60-90 mg OD (HS) 200-300 mg OD (HS)

100-300

1000-3000 600-1800 60-180

Phenytoin (PHT) 5 mg/kg

200-400

Valproate (VPA)

200 mg BID

500-2000

Topiramate (TPM) 2-5mg/kg

25 mg OD

100-400

Zonisamide (ZNS) 4-5 mg/kg

50 mg OD (HS)

200-500

OD: Once daily; BID: Twice daily; HS: At night

Topiramate and Zonisamide increase cachexia and should be avoided in underweight patients. There is a relationship between Valproate intake and polycystic ovarian syndrome and it is essential to take a menstrual history and consider BMI and hirsuitism when introducing this drug in a young woman. Valproate can also cause parkinsonism and tremor and is best avoided in patients with the above movement disorders. Topiramate and zonisamide have been associated with nephrolithiasis, especially in hot environments, so it may be fruitful to advice patients regarding adequate hydration before prescribing these agents. The use of agents like topiramate, zonisamide and levetiracetam has been associated with psychiatric disturbances and so, are best avoided in patients with current or previous psychiatric co-morbidity. Antiepileptic drugs should be chosen with caution in patients with hematological disorders as commonly used first line agents such as phenytoin, carbamazepine, and phenobarbitone and second line agents like oxcarbamazapine, eslicarbazapine, lamotrigine, and ethosuximide can cause bone marrow depression. In patients with prolonged QT syndrome or in those taking medication which can prolong the QT interval, lacosamide, rufinamide, and retigabine should be avoided. In recent years, evidence has accumulated that people with newly diagnosed epilepsy respond to relatively low doses of AEDs 400 mg per day for carbamazepine, 1000 mg per day for

levetiracetam, 125-200mg per day for lamotrigine, and 600-1000 mg per day for Valproate.7,8 Should seizures occur at the selected initial maintenance dose, the dose should be appropriately increased to maximum tolerable doses (Table 3).

What to do when Monotherapy Fails?


Following the institution of the first AED for newly diagnosed epilepsy, about 60% of the patients are well controlled with the first AED prescribed.9 What happens to the remainder? When should AEDs be substituted or added in these patients? If initial monotherapy fails, the subsequent course of action should take into account the reason for failure. For instance, in case of failure due to an idiosyncratic reaction, the AED should be substituted with care, avoiding a drug which may have cross-reactivity with the first one. If the first AED is considered to have failed because of lack of efficacy, non-compliance must be excluded. If a change in AED is indicated, gradual substitution of the second drug must be done with slow withdrawal of the first.10 A second school of thought propounds that combination therapy can be tried earlier in severe epilepsies where the first AED seems to have been partially effective and well tolerated.11 An effort should be made to avoid using drugs with similar mechanisms of action. Often an agent with multiple mechanisms of action and a broad spectrum with minimum interactions will be chosen as first add-on.

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17

Management of Drug Resistant Epilepsy


Patients who fail to attain seizure freedom after an adequate trial of at least two antiepileptics should be managed as drug refractory epilepsy (DRE).12 The rationale for this definition is that the probability of seizure freedom decreases in proportion to the number of drugs tried in the past and is less than 20% after the patient has failed two AEDs. Such patients should be referred to a specialist for reassessment to evaluate the cause of refractoriness and be evaluated for epilepsy surgery. However, disabling seizures should be identified much earlier for surgical candidacy. Likewise, in the presence of an identifiable substrate (like hippocampal sclerosis, cortical dysplasia etc) PWE should be evaluated early for the possibility of a surgical cure. Mesial temporal sclerosis is the commonest indication for resective epilepsy surgery.The available procedures for extra temporal epilepsy account for less than half of all epilepsy surgery and can be either resective or palliative. Surgical procedures include hemispherectomy, corpus callosotomy and multiple sub-pial and lobar resections. Surgery has now become the standard of care for adults with mesial temporal lobe epilepsy (MTLE) syndrome, with anterior temporal resection being the commonest procedure. Results of meta-analyses surveying the literature from 1985 to 2003 indicate that about two-thirds of patients are seizure-free in the first two to three years after surgery for MTLE.13

in seizure frequency. Across all studies, VNS reduced seizure frequency by approximately 45%, although the rate of seizure reduction increased from 36% at the 3- to 12-month follow-up to 51% after > 1 year of therapy. Patients of post-traumatic epilepsy and tuberous sclerosis experienced the greatest seizure reduction following VNS. Hoarseness of voice was the most common side effect reported by 37%62% of patients. Cough, paresthesia, pain, dyspnea, and headache were other side effects. Device site infection occurred in 4-6% cases, requiring device exlpantation. Asystole was reported in 5 cases (<0.1%), although it is unclear if stimulation directly lead to this occurrence.Although not yet approved for use in the pediatric population, VNS has shown efficacy similar to that in the adult population in pediatric series as well.15

Deep Brain Stimulation


Deep brain stimulation is a neurosurgical procedure that enables brain structures to be stimulated electrically by a pacemaker implanted under the skin. Several targets, including the cerebellum, anterior thalamic nucleus, subthalamic nucleus, hypothalamus, caudate and hippocampus have been studied as targets for deep brain stimulation in patients of epilepsy. Despite initial reports of the efficacy of cerebellar stimulation in epilepsy16, a double blind randomized trial consisting of 12 patients failed to show any improvement in seizure control17. The Stimulation of the Anterior Nucleus of the Thalamus in Epilepsy (SANTE) trial, a double-blind trial of anterior nucleus DBS for refractory seizures, has suggested that targeting the anterior nucleus of the thalamus is effective for refractory epilepsy.18 No surgery related complications were reported, although two patients had stimulation induced seizures. A randomized, double-blind multicenter sham stimulation trial of the responsive neurostimulator has been done in the United States. The responsive neurostimulator system is an implanted device designed to detect abnormal activity in the brain and respond, similar to an implantable cardiac defibrillator.

Neurostimulation
There exist multiple types of direct or indirect neurostimulation methods for therapeutically altering brain activity. Such techniques include stimulating the brain indirectly, as with transcranial magnetic stimulation, stimulating the brain directly, as with deep brain stimulation, or affecting the brain indirectly via stimulation of peripheral nerves. Electrical neuromodulatory approaches to extratemporal epilepsy are indicated where epilepsy persists despite resection of epileptogenic foci or in the palliative circumstance where no seizure focus is demonstrated using scalp recording, non-invasive neuroimaging and invasive recording, described elsewhere. Neuromodulatory procedures useful in epilepsy include deep brain stimulation (DBS) and VNS (Vagal nerve stimulation).These however may not be more useful than an added new AED and come at a tremendous side effect of cost.

Ketogenic Diet
Ancient teaching advocates the benefits of fasting and prayer in epilepsy. The ketogenic diet is a high fat, low carbohydrate diet, induces a state similar to fasting. The classical ketogenic diet uses a 4:1 ratio in calories of fat to carbohydrate. The Atkins diet is a popular weight-reducing diet which has a 2:1 ratio in calories of fat to carbohydrate and is considerably less restricted. Although evidence about long term efficacy of the ketogenic diet is lacking and one study reports high attrition rates in the long term, at three months, the efficacy of the ketogenic diet is similar to that of antiepileptic drugs.19 For those with medically intractable epilepsy or those in whom surgery is unsuitable, a ketogenic diet could improve seizure control, but tolerability is poor To summarize, the majority of adult patients (two thirds) with epilepsy can be treated adequately with pharmacotherapy alone, using either a single drug or a rational drug combination. In a small section of patients who are not adequately controlled on medication, surgical options are available. Surgery has now become the standard of care in epilepsy attributable to conditions like hippocampal sclerosis, focal cortical dysplasia and gliotic pathologies. Most of the treatment options are available in centers in India. A timely diagnosis, counseling a PWE to various medical and social aspects of epilepsy, apart from AED therapy are the

Vagal Nerve Stimulation


Stimulation of both the trigeminal and vagus nerves has been shown in multiple clinical trials to be anticonvulsant, and stimulation of these nerves at therapeutic levels does not cause pain or negatively affect brain function. Left sided VNS was approved by the USFDA in 1997 as an adjunctive treatment for medically refractory epilepsy in adults. It is useful in patients who have failed resection or in patients who are poor candidates for resection. The neurobiological mechanisms of VNS in epilepsy are incompletely understood, although it is hypothesized that VNS may desynchronize activity and decrease abnormal spiking patterns on the EEG. A meta-analysis of studies pertaining to VNS in epilepsy identified three blinded randomized controlled trials, two non-blinded randomized controlled trials and 10 studies reporting prospective data.14 Seizure reduction rates were 17%55% after 364 months of VNS therapy, with 21% to 50% of patients experiencing 50% decrease

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cornerstone of good epilepsy management in India. The senior author (MT) strongly recommends physicians are a pillar of support for the management of epilepsy in this country considering the burden and treatment gap a PWE faces. Reading the freely available online version of guidelines of epilepsy management in India will help achieve the goal of reducing the knowledge and practice gap this disease could face too.

10. National Institute for Clinical Excellence. Clinical guideline 20 the epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care. October 2004. http:// www.nice.org.uk/nicemedia/live/10954/29532/29532. pdf (accessed Jan 1, 2011). 11. Kwan P, Brodie MJ. Combination therapy in epilepsy: when and what to use. Drugs 2006;66:181729. 12. Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 2010;51:106977. 13. McIntosh AM, Kalnins RM, Mitchell LA, Fabinyi GCA, Briellmann RS, Berkovic SF. Temporal lobectomy: long-term seizure outcome, late recurrence and risks for seizure recurrence. Brain 2004;127:2018 2030. 14. E n g l o t D J , C h a n g E F , Au g u s t e K I . Va g u s n e r v e stimulationforepilepsy: ameta-analysisof efficacy and predictors of response. J Neurosurg 2011;115:1248-55. 15. Jason S. Hauptman ,Gary W. Mathern. Vagal nerve stimulation for pharmacoresistant epilepsy in children. Surg Neurol Int2012;3(Suppl 4):S269S274. 16. Davis R, Emmonds SE. Cerebellar stimulation for seizure control: 17-year study. Stereotact Funct Neurosurg 1992;58:200-208. 17. Wright GDS, McLellan DL, Brice JG. A double-blind trial of chronic cerebellar stimulation in twelve patients with severe epilepsy. J Neurol Neurosurg Psychiatry 1984;47:769-774. 18. Fisher R, Salanova V, Witt T, et al. Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy. Epilepsia 2010;51:899-908. 19. Levy RG, Cooper PN, Giri P. Ketogenic diet and other dietary treatments for epilepsy. Cochrane Database Syst Rev. 2012 Mar 14;3:CD001903. 19. Guidelines for epilepsy management in India (GEMIND) http:// www.ilae.org/Visitors/initiatives/GEMINDbook.cfm

References
1. 2. Sander JW. The epidemiology of epilepsy revisited. Curr Opin Neurol 2003;16:165170. Berg AT, Shinnar S. The risk of seizure recurrence following a first unprovoked seizure: a quantitative review. Neurology 1991;41:965 72. Hauser WA, Rich SS, Lee JR, Annegers JF, Anderson VE. Risk of recurrent seizures after two unprovoked seizures. N Engl J Med 1998;338:42934. Perucca E, Tomson T. The pharmacological treatment of epilepsy in adults. Lancet Neurol 2011;10:446456. Elaine Wyllie et al. Wyllies treatment of epilepsy. Principles and Practice. Philadelphia: Lippincott Williams & Wilkins; 2011 Glauser T, Ben-Menachem E, Bourgeois B, et al. ILAE treatment guidelines: evidence-based analysis of antiepileptic drug effi cacy and eff ectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia 2006;47:1094120. Brodie MJ, Perucca E, Ryvlin P, Ben-Menachem E, Meencke HJ; Levetiracetam Monotherapy Study Group. Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy. Neurology 2007;68:40208. Kwan P, Brodie MJ. Eff ectiveness of first antiepileptic drug. Epilepsia 2001;42:125560. Patterns of treatment response in newly diagnosed epilepsy. Brodie MJ, Barry SJ, Bamagous GA, Norrie JD, Kwan P. Neurology 2012;78:1548-54.

3.

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19

New Drugs for the Treatment of Epilepsy : A Practical Approach


Debashish Chowdhury*
uelled by exponential developments in basic epileptology, molecular biology and clinical electrophysiology, there has been a steady rise in the availability of new antiepileptic drugs (AEDs) since early 90s, a trend that is continuing till this day (Figure 1). Currently, 7 traditional AEDs and at-least 15 new AEDs are available for treating epilepsy (excluding drugs such as acetazolamide, corticosteroids and other rarely used antiepileptic drugs) (Table 1). With multiple options comes the responsibility of choosing the right drug for an individual patient. Serious considerations must be given for efficacy, tolerability, sustainability, remission after withdrawal, drug interactions, quality of life and the cost of new AEDs. Physicians familiar with the use of traditional AEDs with established track records are faced with the dilemma of choosing a new drug based on deluge of information that may appear daunting. The purpose of present review is therefore to provide a birds eye view on these new AEDs from a practical point of view. For the purpose of this review the AEDs developed in the last 20 years (1993-2012) shall be considered as new in contrast to traditional AEDs. Before proceeding any further, it may be worthwhile to recapitulate the existing principles regarding the use of traditional AEDs as these form the backdrop against which important clinical questions regarding the use of new AEDs can be asked.

Introduction

Side effects of phenobarbital were lesser than bromides but did happen and included sedation, CNS depression, and paradoxical hyperactivity in children. By 1937, Merritt and Putnam developed an electroshock model for epilepsy using a cat and thus the drugs could be tested for their efficacy, at least experimentally.3 In 1938, they introduced phenytoin which over the next two decades became the standard drug for epilepsy treatment despite the increasing recognition of many adverse effects. With increasing knowledge of chemical nature of the AEDs and greater understanding of their mechanism of action, older AEDs were being modified chemically for greater effectiveness and lesser side effects. Modification of phenobarbital resulted in primidone in 1952 whose action however, was found to be Table 1 : List of AEDs
1. Bromide 2. Phenobarbital 3. Phenytoin 4. Primidone 5. Ethosuximide 6. Benzodiazepines 7. Carbamazepine 8. Valproate Traditional AEDs So called Traditional AEDs, these drugs were developed during 1857 to 1978. Some of them like bromides and primidone are rarely used now a day. Only few benzodiazepines are used for chronic treatment.

The Traditional AEDs


Bromides were the first antiepileptic drugs to be used in epilepsy in 1857 by Sir Charles Lacock in patients of catamenial epilepsy.1 There were no formal trials and experience regarding efficacy and adverse effects were gained with their increasing usage for next 65 years or so. Bromides did reduce the seizure frequency but adverse effects were common. Then phenobarbital arrived. Phenobarbital was initially introduced as sedative and hypnotic but subsequently started to be used for epilepsy from 1919 due to pioneering efforts of Hauptman.2 Within next two decades, it became the mainstay of epilepsy treatment. Again, no formal clinical trials were conducted but experience of its efficacy and adverse effects gained through community use.
2010 1990 1970 1950 1930 1910 1890 1870 1850
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1993 1974 1960 1938 1919 1978

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1994 1997

1997 1999

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Introduction / FDA Approval (year)

Fig. 1 : Introduction / FDA approval (year) of AEDs


*

Professor of Neurology, G.B.Pant Hospital, New Delhi

New AEDs 1. Felbamate So called New AEDs, these drugs were developed in last 20 years (19932. Gabapentin 2012). They have been ordered here 3. Lamotrigine from the time they got FDA approval 4. Tiagabine for use in Epilepsy. Some of them were 5. Topiramate used for a much longer time in other countries for example Zonisamide in 6. Levetiracetam Japan and Clobazam. 7. Zonisamide 8. Oxcarbazepine 9. Pregabalin 10. Lacosamide 11. Vigabatrin 12. Rufinamide 13. Clobazam 14. Ezogabine (Retigabine) 15. Eslicarbamazepine Used as AEDs in Special situations only 1. ACTH and First line drug for infantile spasm corticosteroids 2. Acetazolamide Adjunctive therapy for resistant partial and generalized seizures. Intermittent treatment in catamenial epilepsy. Use limited by tolerance and idiosyncratic reactions 3. Pyridoxine Certain infantile epilepsies Rarely used AEDs 1. Mephenytoin Sulthiame is still used in Germany 2. Phenacemide 3. Trimethadione 4. Sulthiame

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Table 2 : Traditional antiepileptic drugs


AED / Introduction Primary indication Mechanism of / FDA approval action Bromide / 1857 No longer used in most of Unknown; the countries potentially stabilize neuronal membranes via hyperpolarization Phenobarbital /1920 Adjunctive/ 1st line therapy Enhance for partial and generalized g-aminobutyric acid seixures (GABA) inhibition 9including myoclonus); ineffective in absence Primidone /1952 Elimination Protein binding Drug Interaction Main disadvantage Many CNS and systemic side effects

Phenytoin / 1938 / 1953

25% excreted unchanged in urine. Rest by glucosiadation and oxidation followed by conjugation Rarely used now a days; Converted to Converted to Phenobarbital and Adjunctive/ 3rd line Phenobarbital which is the active phenylethyltherapy for partial and generalized seizures compound malonamide and including myoclonus); some excreted ineffective in absence unchanged in urine. Blockage of voltage Hepatic oxidation 1st line/ adjunctive for partial and generalized gated sodium and hydroxylation, seizures (except myoclonic channels then conjugation and absence)

45-60%

Common

CNS adverse effects including sedation; hyperactivity in chiildren

10%

Common

Inferior tolerability particularly in children.

90%

Common

Ethosuximide / 1958 1st line/ adjuctive therapy of generalized absence / 1960 seizures Benzodiazepines / 1960s / 1970s 2nd/ 3rd line therapy for partial and generalized tonic-clonic seizures

Reduction of lowthreshold T-type calcium currents in thalamic neurons Potentiation of GABAA mediated inhibition

Primarily by Less than 10% oxidation, catalysed by CYP3A4 85-95%

Common

Many CNS and systemic side effects; unpredictability due to non-linear elimination kinetics Many CNS and systemic side effects

Carbamazepine / 1962 / 1974

1st line/adjunctive partial and generalized tonicclonic seizure

Variable including demethylation, hydroxylation, acetylation, nitroreduction and decarboxylation depending on benzodiazepine. Blockage of voltage Hepatic; CYP3A4 gated sodium channels

Common

Sedation, cognitive dysfunction, tolerance and withdrawal seizures

75%

Common

Valproate / 1978

1st Line in idiopathic generalized epilepsies; 1st line/ adjuctive in cryptogenic or symptomatic generalized epilepsies; valuable for partial seizures

Precise mechanism Hepatic; oxidation unknown; multiple and glucoronide GABA-related conjugation actions

70-90%

Common

Occasional severe toxicity; can aggravate absence and myoclonic seizures; enzyme induction Weight gain, hepatotoxicity; teratogenecity

largely due to metabolically active Phenobarbital.4 But it had inferior tolerability than other traditional AEDs and is rarely used now. About two decades following the introduction of phenytoin, in 1960, a drug called ethosuximide was introduced. It was found to be mainly useful for absence seizures with a fair share of side effects.5 1960s also saw the development of a whole new class of drugs originally intended for psychiatry but later extensively used in epilepsy too. These were benzodiazepines. By 1973, a major review on use of benzodiazepines in epilepsy was published.6 Although very useful for emergency management, their oral long term use is limited by side effects like sedation and development of tolerance. In 1974, carbamazepine was introduced for epilepsy in USA although it was already being marketed for trigeminal neuralgia since 1962. This drug proved to be one of the most efficacious, prescribed and studied AEDs

produced so far.7 After a short time, valproate was introduced (in 1978 in USA although it was already in use in many European countries). In USA, its introduction was led by a campaign by J. Kiffin Penry who had reviewed the drug in 1975.8 It was soon recognized to be a broad spectrum AED and by next three and half decades of its usage, the spectrum of its adverse effects was gradually uncovered.

Lessons Learnt from use of Traditional AEDs


Continued clinical usage for many decades, some head to head randomized double blind trails, many open label randomized trials and post marketing trials have delineated the profiles of traditional AEDs. Based on these, certain facts

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emerged regarding their usage. There are 7 traditional AEDs and one group of AEDs (benzodiazepines) that have been available for use till early 1990s. Of the 7 traditional AEDs, bromides and primidone are no longer considered as agents of first choice because of significant adverse effects and poor tolerability. Benzodiazepines (diazepam, nitrazepam and clonazepam) used occasionally as oral AED for chronic use is not generally considered as standalone therapy (clobazam is considered as a new AED). Ethosuximide is useful exclusively for absence seizures. That left 4 traditional AEDs, namely phenobarbital, phenytoin, carbamazepine and valproic acid for routine clinical use. Two landmark studies have compared these 4 traditional AEDs in terms of efficacy and tolerability.9,10 Salient features of traditional AEDs are tabulated in Table 2. 1. Efficacy of individual AEDs: All the 4 AEDs namely phenobarbital, phenytoin, carbamazepine and valproic acid have been found to be efficacious for partial seizures with or without secondary generalization as well as primarily generalized seizures.9 However, efficacy wise, carbamazepine scores probably better in partial seizures especially in complex partial seizures.10 Valproate emerged as a truly broad spectrum AED which is effective in primarily generalized seizures, absence seizures, myoclonic seizures and partial seizures with or without secondary generalization. Also in some difficult to treat epilepsy syndromes like West syndrome and LGS, valproate was found to be somewhat effective. Ethosuximide is useful for absence seizures. Later, it was found out that some of these agents like carbamazepine, phenytoin and phenobarbital may exacerbate or precipitate certain seizures and hence may not be the best choice in certain generalized seizures even if they may be efficacious (see below). 2. Overall Efficacy: About 50% newly diagnosed epilepsy patients are likely respond to monotherapy when appropriately chosen for seizure type/ epilepsy syndrome.11 Further 20-30% will benefit from another AED or when two drugs are combined.12 20-30% will remain refractory. 3. Efficacy in Severe Childhood epilepsy syndromes: Most of the traditional AEDs are ineffective. Valproate and benzodiazepines can be of some value. 4. Tolerability: In terms of tolerability, valproate and carbamazepine would probably score better than phenobarbital and phenytoin.9,10 However, all the traditional AEDs have large number of CNS and systemic adverse effects. Some of the adverse effects may be potentially life threatening like Steven Johnsons syndrome with phenytoin and carbamazepine and hepatic failure in valproate and occasionally with carbamazepine and phenytoin. But other non-life threatening adverse effects may be quite disabling as well for example, gingival hypertrophy and abnormal bone metabolism in a growing child due to phenytoin, weight gain, tremors and hair loss due to valproate in a female, diplopia and hyponatremia with carbamazepine in an elderly and increased hyperactivity in children with phenobarbital. 5. Mechanism of action: Phenytoin and carbamazepine share same mechanisms (blockage of voltage gated sodium channels)13,14 whereas phenobarbital and valproate possibly have GABA mediated inhibitory actions.15,16 AEDs with similar mechanism of action do not form a good choice for combination polytherapy, if required. Therefore, the choices

for add-ons are limited within the traditional basket. 6. Pharmacokinetics: Phenytoin having nonlinear kinetics may prove to be very difficult for predictable drug adjustments. A small increment or decrement in dosage may produce huge changes in the serum level.17 Carbamazepine can have significant auto induction effect, thereby lowering its blood level.18 7. Drug interactions: Being enzyme inducers (phenobarbital, phenytoin and carbamazepine)/inhibitor (valproate), they can have clinically significant interactions thereby lowering or increasing their blood concentration or their co-medications. All the 4 traditional AEDs have high protein binding thereby increasing the chances of toxicity if they are unbound due to drug interactions. 8. Aggravation of Seizures: With continued use, it has been found that certain AEDs paradoxically precipitated or exacerbated seizures.19,20 Examples include carbamazepine and phenytoin exacerbating absence and myoclonic seizures. Even primary generalized tonic clonic seizure can be exacerbated in a subset of patients with idiopathic generalized epilepsies by carbamazepine. Phenobarbital may aggravate absence seizures. 9. Many adverse events were recognized later: With time many adverse effects of an AED that were not known during preclinical stage or during early phase of its use were recognized. For example, attention was first drawn to hyperactive behavioural disorder due to phenobarbital in children in a study in 1977.21 Similarly, haemorrhagic pancreatitis (1979),22 hyperammonaemic encephalopathy (1981),23 polycystic ovarian syndrome (1990)24 were detected much later with widespread valproate use. 10. Teratogenicity: The prevalence of major congenital malformations with the use of AEDs has ranged from 4% to 10%, corresponding to a 2-4 fold increase compared with expected (25, 26). As per the data from 9 pregnancy registries, the rates are lowest for carbamazepine (2.2-4%) as compared to phenobarbital (6.5%), phenytoin (2.6-6.8%) and valproate (5.8 to 13.3%).27 Risks increase with usage of multiple drugs and there is also a dose effect relationship. 11. Ethnic differences: Studies from resource limited countries have shown that certain adverse effects which were common in developed nations may not occur in patients of these countries. For example, excess behavioural problems in children seen with phenobarbital were not seen when compared to carbamazepine or phenytoin. The study by Pal et al from India illustrates this point.28 12. Quality of life issues: Gradually, clinicians realized that besides the principal aim of seizure control, other issues which affect the quality of life of patients with epilepsy are equally important. Co-morbidities (specially psychiatric), serious adverse effects including potentially life threatening idiosyncratic side effects, chronic adverse effects ( as AEDs are usually continued for years), cognitive changes, reproductive concerns, bone metabolism changes and other endocrinal effects impact the life of epilepsy patients. The question was whether the seizure control with traditional AEDs also resulted in good quality of life. This has remained largely unanswered because of lack of adequate studies. 13. Cost: The cost of AEDs is an important consideration especially in countries with limited resources. For a country like India, traditional AEDs offer low cost treatment options

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Table 3 : New Antiepileptic drugs


AED Felbamate Mechanism of action Add-on treatment of Blockade of LGS and partial and sodium channels, secondary generalized potentiation of seizures in patients GABAA mediated refractory to other agents inhibition and antagonism of NMDA mediated response Adjunctive therapy for structurally partial seizures with related to gammaand without secondary aminobutyric acid generalization in (GABA) but its precise mechanism persons 3 years and older of action in humans is unknown blockade of sodium Broad-spectrum agent. Adjunctive and channels and, to monotherapy of partial- a lesser extent, onset seizures with calcium channels or without secondary generalization, primary generalized seizures and generalized seizures associated with LGS and for conversion to monotherapy. adjunctive treatment of blocking reuptake partial-onset seizures of GABA into in persons 12 years or neurons and glial older cells broad-spectrum agent approved as adjunctive treatment in adults and children 2 years or older with partial seizures, primary generalized seizures, and seizures associated with LGS Primary indication Elimination Protein binding Drug Interaction Common Main disadvantage aplastic anaemia, hepatitis Partly metabolized 20-25% in liver via hydroxylation followed by conjugation. Both inducer and inhibitor No hepatic Negligible metabolism and excreted unchanged in urine

Gabapentin

None

Modest efficacy

Lamotrigine

Primarily by conjugation with glucoronic acid

55%

Pharmacokinetics Slow titration; of lamotrigine occasionally severe can be markedly rash influenced by concomitant medications. Pharmakodynamic ionteractions with other AEDs can occur. Enzyme inducing AEDs can increase the hepatic clearance of tiagabine Enzyme inducing AEDs can lower topiramate concentration by 40% Modest efficacy with poor tolerability may limit its use. May precipitate seizures Adverse effects may be troublesome.

Tiagabine

extensive hepatic oxidation via the cytochrome P450 system

96%

Topiramate

Levetiracetam

Zonisamide

Multiple Primarily excreted 13-17% mechanisms unchanged including sodium through kindneys and calcium ; only a fraction channel blockade, is metabolized by GABA potentiation, cytochrome P450 glutamate receptor antagonism and inhibition of carbonic anhydrase First line and adjunctive Binds to synaptic Primarily excreted <10% therapy in partial onset vesicle 2A (SV2A) unchanged through seizures; adjunctive and protein kidneys first line treatment of generalized tonic clonic seizures and myoclonic seizures associated with generalized seizures; may be useful in other generalized seizures also. adjunctive treatment of Multiple Partly renal 50% partial-onset seizures; mechanisms excretion, partly may be useful as including sodium by metabolism adjunctive treatment in and calcium channel mediated by a variety of generalized (T type) blockade, CYP3A4 seizures also GABA potentiation, inhibition of carbonic anhydrase

Enzyme inducing AEDs can lower levitiracetam concentration by 20-30%

Behavioural disturbance in about 10-15% may be problematic.

Zonisamide levels Some of the are lowered by CBZ, adverse effects like PHT, PB nephrolithiasis, hypersensitivity reactions and hyperthermia may be troublesome. Contd.. 2

whereas new AEDs are invariably costlier. Therefore, the usefulness of new AEDs must also be weighed in the context of price and affordability.

New AEDs

Role of new AEDs can now be discussed in the context of above discussion. First, each new AED is discussed briefly

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Table 3 : New Antiepileptic drugs


AED Oxcarbazepine Mechanism of action Adjunctive and Voltage gated monotherapy of partial- sodium and calcium channels (N and P onset seizures with or without secondary type) blockade generalization; also useful for primary generalized tonic clonic seizures not associated with absence and myoclonic seizures adjunctive treatment modulates of partial- onset neurotransmitter release by binding seizures with or to the alpha-2-delta without secondary generalization subunit of voltage gated calcium channel acts by enhancing adjunctive treatment of partial- onset slow inactivation of seizures with or sodium channels without secondary generalization Monotherapy of infantile spasms and as add-on therapy for refractory partial epilepsy in adults when other options have failed Adjunctive treatment of atonic seizures in LGS irreversible inhibitor of GABA transaminase Primary indication Elimination Protein binding Drug Interaction Main disadvantage Ketoreduction to <40% its 10 monohydro derivatives (MHD) which is excreted unchanged in urine Enzyme inducers Occasional reduce the levels of severe rash and MHD; Can reduce hyponatremia levels of steroid contraceptives and felodipine.

Pregabalin

excreted unchanged nil in urine

negligible

Modest efficacy; caution in renal dysfunction

Lacosamide

Vigabatrin

40% excreted <15% unchanged in urine; rest by demethylation followed by excretion excreted unchanged nil in urine

Enzyme inducers reduce lacosamide level by 25%

Caution in patients with heart disease

May reduce phenytoin levels

Limited indication because of potential irreversible visual filed constriction

Rufinamide

modulation of sodium channels, specifically, prolongation of time spent in the inactive state of the channel

Excretion is 30% largely renal with biotranformation by hydrolysis of carboxamide group

Common

Clobazam

Ezogabine (Retigabine)

N demethylation First line and adjunctive potentiation of and hydroxylation therapy in partial onset GABAA mediated seizures; adjunctive and inhibition first line treatment of generalized seizures adjunctive treatment enhancement of of partial- onset potassium currents seizures with or mediated by a without secondary particular family of generalization ion channels known as KCNQ Voltage gated sodium channels blockade

85-90%

Common

To be avoided in patients with familial short QT interval syndrome and others using drugs which shortens QT interval. Tolerance and withdrawal seizures

Eslicarbamazepine adjunctive treatment of partial- onset seizures with or without secondary generalization

Excreted in urine in 30% free and conjugated forms

Enzyme inducers reduce eslicarbazepine level; it reduces steroid contraceptive levels

Urinary retention, neuropsychiatric symptoms, such as psychotic states associated with confusion and hallucinations Limited experience

followed by a summary statement. Secondly, few broad clinically relevant questions are discussed regarding their use. This is followed by some practical evidence based recommendations. Finally future trends are discussed. I. Currently available New AEDs (Table 3) 1. Felbamate: Felbamate is chemically related to the anti-anxiety drug meprobamate. Its exact mechanism of action is not known. Possible mechanisms include blockade of sodium channels, potentiation of GABAA

mediated inhibition and antagonism of NMDA mediated response. 29 Although it was introduced in 1993 after extensive clinical trials, by mid-1994, serious adverse events like aplastic anaemia and thrombocytopenia were described. This led FDA to issue a warning on 1st August 1994 for further use of this drug (to be used only if it is absolutely necessary). Later, leukopenia, pancytopenia and hepatitis were also reported.30,31 Hence, it is no longer recommended

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as first line agent and the risk of aplastic anaemia and hepatitis must be carefully weighed against the potential benefits. It is currently recommended as add on treatment of LGS and partial and secondary generalized seizures in patients refractory to other agents.32 In adults, it can be initiated at 1200 mg/day in 3-4 divided doses with weekly or biweekly increments to 2400 and 3600 mg/day. The dose of other AEDs should be reduced by 20-30% initially and further reductions with increase in felbamate dose. In children, the starting doses have been 15mg/kg/day with weekly increments up to 45mg/kg/day. Again concomitant AEDs should be reduced and gradually tapered off. Patients should be on constant surveillance clinically, and by measurements of haematological parameters and liver functions. Summary: Felbamate is a reserve drug for patients with LGS or refractory partial seizures with or without secondary generalization where other treatments have failed. 2. Gabapentin: Gabapentin is structurally related to gamma-aminobutyric acid (GABA) but its precise mechanism of action in humans is unknown. It is currently indicated as adjunctive therapy for partial seizures with and without secondary generalization in persons 3 years and older. Four initial add-on trials enrolling more than 700 patients with refractory partial onset epilepsy led to the FDA approval of gabapentin.33-36 Dosages ranged from 1200 to 1800 mg/d with 25% to 33% demonstrating a greater than 50% reduction in seizure frequency from baseline. Gabapentin has also been evaluated in 2 large monotherapy trials.37,38 Gabapentin had modest efficacy as monotherapy in one study in patients with partial seizures and no effect in another study in patients with generalized seizures. Hence, it is not FDA approved for monotherapy. Adverse effects include somnolence, dizziness, and fatigue, modest weight gain but no serious idiosyncratic reactions or organ toxicities have been identified. In addition, gabapentin possesses several desirable pharmacokinetic properties: it does not undergo hepatic metabolism and is excreted unchanged in urine. Also, gabapentin does not affect plasma concentrations of other antiepileptic drugs, oral contraceptives, or probenecid.

in dosages up to 500 mg/d.39-45 2 smaller trials however failed to show statistically significant reductions in seizure frequency from baseline.46-47 In a multicenter conversion to monotherapy study of 156 patients comparing lamotrigine (500 mg/d) with low-dose valproate (1000 mg/d), lamotrigine was found to be efficacious.48 Fifty-eight percent of the patients in the lamotrigine group completed the study vs 31% in the valproate group (P=.001). Active control monotherapy trials (lamotrigine versus phenytoin, carbamazepine and gabapentin) found lamotrigine to have similar efficacy but fewer adverse effects and lower withdrawal rates.49-51 Two studies have evaluated the efficacy of lamotrigine in generalized seizures associated with LGS.52,53 The largest study enrolled 169 patients and demonstrated a 33% responder rate (P=.01) and a 34% decrease in drop attacks. Lamotrigine has also been found to be efficacious in absence seizures but more data is needed.54,55 Pooled clinical trial data showed that adverse effects necessitated withdrawal of lamotrigine therapy in 10.2% of patients (n=3501), with rash being the most common cause for discontinuation (3.8%).56 In addition, there have been reports of lamotrigine-associated rash requiring hospitalization, some progressing to StevensJohnson syndrome. However, a recent review of 73 cases of antiepileptic drugrelated Stevens- Johnson syndrome and toxic epidermal necrolysis found lamotrigine to be associated with a lower relative risk compared with phenobarbital, phenytoin, and carbamazepine.57 Subsequent review of published and unpublished clinical trial data showed that severe rashes occur more often with rapid titration and in pediatric patients as opposed to adults (1% vs 0.3%).58 It has also been recognized that the risk of skin rash is significantly higher when lamotrigine is co-administered with valproate because valproate markedly slows the metabolism of lamotrigine.59 This risk can be reduced with lower initial doses and slower titration schedules. Lamotrigine undergoes hepatic metabolism through glucuronidation but does not induce or inhibit hepatic enzymes and thus has no significant effects on the metabolism of other antiepileptic drugs or oral contraceptives.

Summary: Gabapentin offers the unique advantages of a wide margin of safety with good tolerability in the absence of any significant drug interactions but with modest efficacy. The efficacy may be enhanced by higher doses up to and in some cases exceeding 3600mg/day. 3. Lamotrigine: Lamotrigine exhibits its antiepileptic effect primarily by blockade of sodium channels and, to a lesser extent, calcium channels. Lamotrigine is a broad-spectrum agent for use as an adjunctive treatment in adults with partial- onset seizures. Later approval was granted for use in adults and children aged 2 years and older with generalized seizures associated with LGS and for conversion to monotherapy. Lamotrigines efficacy was demonstrated in seven clinical trials as an adjunctive agent in partial seizures with responder rates ranging from 17% to 67%

Summary: Lamotrigine is a broad-spectrum agent with minimal sedation or drug interactions. Main drawback is a slow titration schedule requiring 8 to 12 weeks to reach therapeutic maintenance doses which becomes even longer when used in conjunction with valproate. 4. Tiagabine: Tiagabine is approved for use as the adjunctive treatment of partial-onset seizures in persons 12 years or older. It has a novel mechanism of action, blocking reuptake of GABA into neurons and glial cells.61 Three multicenter studies evaluated the efficacy and tolerability of tiagabine as adjunctive therapy.62-64 The smallest trial enrolled 154 patients and showed a responder rate of 14%, which was not significantly greater than placebo. However, more than 600 patients enrolled in 2 additional trials showed modest but significant responder rates of 29% and 31% at doses of 56 and 32 mg/d. The most common adverse effects included dizziness, tremor, and impaired concentration, most often seen with twice

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daily dosing and much less frequently with either 3- or 4-times daily dosing. Tiagabine undergoes extensive hepatic oxidation via the cytochrome P450 system.65 Occasionally tiagabine has been reported to precipitate nonconvulsive status epilepticus, in particular, absence status epilepticus.66,67 Summary: Tiagabine offers a novel mechanism of action with modest efficacy in partial-onset seizures but tolerability may limit its use in many patients. 5. Topiramate: Topiramate is a sulphamate-substituted monosaccharide. Multiple mechanisms of action have been shown in preclinical studies including sodium and calcium channel blockade, GABA potentiation, glutamate receptor antagonism and inhibition of carbonic anhydrase.68 Topiramate is a broad-spectrum agent approved as adjunctive treatment in adults and children 2 years or older with partial seizures, primary generalized seizures, and seizures associated with LGS. The efficacy of topiramate as adjunctive therapy is supported by 6 multicenter trials that enrolled 580 patients with refractory partial-onset seizures.69-74 Responder rates were 35% to 48% with daily doses ranging from 300 to 800 mg. The 2 largest trials randomly assigned patients to multiple doses and found no significant increase in efficacy for dosages higher 400 mg. Topiramate has also shown efficacy against generalized-onset seizures including refractory seizures seen in LGS.75,76 In a study of 98 patients with LGS, 33% had a 50% reduction in tonicclonic seizures as well as drop attacks (P=.002).76 A single pseudo-placebo-controlled monotherapy trial in 48 patients demonstrated a 54% completion rate for patients taking 1000 mg/d vs 17% completion rate for those taking 100 mg/d (P=.002).77 Adverse effects that were seen more commonly for patients taking topiramate than placebo in clinical trials included ataxia, decreased concentration, confusion, speech and language specially word finding difficulties dizziness, paresthesias and fatigue, most of which occurred in patients taking more than 600 mg/d or with relatively rapid titration to maintenance dose in 3 to 4 weeks.78 Ocular adverse effects including acute angle closure glaucoma can occur. Hyperammonaemia with or without encephalopathy has been reported following concomitant therapy with valproate. Other clinically relevant adverse effects include nephrolithiasis, with a reported incidence of 1.5%,79 and mild weight loss averaging 1 to 6 kg predominantly in the first 3 months of therapy. Metabolic acidosis and hypohydrosis can also occur. Topiramate exerts no significant effects on other antiepileptic drugs or on serum norethindrone levels but decreases serum estradiol levels by 30% and serum digoxin levels by 12%.

unknown.80 Four multicentre trials with levetiracetam as add-on therapy enrolled more than a thousand patients and showed a responder rate of between 32% and 48% with doses ranging from 2000 to 4000 mg/d.8184 A study employing an extended release formulation also showed favourable result.85 Other studies have also shown its efficacy as adjunctive therapy in refractory partial seizures in children,86 monotherapy in partial onset seizures,87 and adjunctive therapy in refractory generalized epilepsy.88-89 Common adverse effects of levetiracetam in clinical trials included somnolence, asthenia, headache, and infection. The majority of adverse effects occurred in the first 4 weeks of therapy and did not appear to be dose related. In addition, behavioural disturbances such as agitation and anxiety were reported in up to 13% of the study cohort.81-89 The pharmacokinetic profile of levetiracetam is favourable, with absence of hepatic metabolism and low protein binding.90 No significant interaction was reported with co-administration of other antiepileptic drugs, oral contraceptives, digoxin, warfarin, or probenecid. Additionally, levetiracetam has the highest safety margin in animal models compared with all other antiepileptic drugs.91 Summary: Levetiracetam offers the advantage of a favourable pharmacokinetic profile and high safety margin with the capability of rapid dosage titration. 7. Zonisamide: Zonisamide is a broad-spectrum anticonvulsant that has had widespread clinical use in Japan since 1989. It is a sulfonamide derivative that acts by blocking sodium as well as T type calcium channels.92,93 Two multicenter trials carried out in the United States and Europe in 342 patients evaluated the efficacy and tolerability of zonisamide for partial-onset seizures.94,95 The patients randomly assigned to receive zonisamide were titrated up to a dose of 400 to 500 mg/d and had a responder rate of 30% to 43%. Case studies have demonstrated significant improvement with zonisamide in patients with generalized-onset seizures, particularly myoclonus. 96,97 Significant adverse effects included fatigue, dizziness, ataxia, and anorexia. An earlier open-label study reported a 3.5% incidence of renal calculi that initially halted the drugs development, but this finding was not reproduced in subsequent studies.98 In the pediatric population there have been rare reports of high fever secondary to hyperhidrosis.99 Its long half-life, (63 to 69 hours) in healthy volunteers, makes once-daily dosing possible. Low protein binding as well as partial liver metabolism via conjugation contributes to its minimal interaction with other medications. Its use is contraindicated in patients with known sulfonamide allergy for obvious reasons.

Summary: Topiramate offers the advantage of a broad spectrum agent with minimal drug interactions, the absence of serious adverse effects, and the potential for weight loss but with the slight risk of kidney stones and a slow titration schedule (8-12 weeks). 6. Levetiracetam: Levetiracetam was approved for the adjunctive treatment of adults with partial-onset seizures. It binds to the synaptic vesicular protein SV2A but how this binding produces anticonvulsant effect is

Summary: Zonisamide is efficacious as adjunctive therapy for many seizure types, particularly myoclonus, with the advantage of once-daily dosing. 8. Oxcarbazepine: Oxcarbazepine is an analogue of carbamazepine. It was designed to have similar efficacy to carbamazepine but fewer adverse effects, largely due to its lack of formation of the toxic metabolite carbamazepine 10, 11 epoxide.100 It is available for use as monotherapy or adjunctive therapy in the

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treatment of partial-onset seizures in persons aged 4 years and older. Like carbamazepine, its principal mechanism of action is via sodium channel blockade.100 Oxcarbazepine has been evaluated as adjunctive therapy for partial seizures in 3 placebo controlled and high dose versus low dose clinical trials. 101103 The larger trial in adults enrolled 694 patients who were randomly assigned to receive placebo or oxcarbazepine in dosages of 600 mg/d, 1200 mg/d, or 2400 mg/d. Responder rates were 27%, 42%, and 50%, respectively, for the oxcarbazepine groups (P_.001). 2 trials in children and infants also showed favourable efficacy of oxcarbazepine.102,103 Three trials compared oxcarbazepine with carbamazepine and found equal efficacy.104-106 Three additional active-control trials compared oxcarbazepine with phenytoin, or valproate and found similar efficacy but a statistically significant decrease in adverse effects in the oxcarbazepine group.107-109 In the SANAD trial, oxcarbazepine was entered late in the arm but found to have comparable efficacy with carbamazepine, lamotrigine, gabapentin and topiramate. Oxcarbazepine was also evaluated in 4 monotherapy trials with favourable efficacy results.110113 Common adverse effects of oxcarbazepine in clinical trials were dose related and included dizziness, diplopia, somnolence, nausea, and ataxia, particularly in patients receiving 2400 mg/d. Allergic skin reactions occurred less frequently than with carbamazepine, although a cross sensitivity of approximately 30% has been demonstrated in patients with hypersensitivity to carbamazepine.114 Hyponatremia has also been reported, particularly in elderly persons. In a large postmarketing study, 23% of 350 patients receiving oxcarbazepine were found to have a serum sodium level lower than 135 mEq/L, although only 1% required discontinuation of the drug.115 Oxcarbazepine does not induce its own metabolism or hepatic microsomal enzymes and is not affected by concurrent administration of erythromycin, as seen with carbamazepine. Oxcarbazepine has not been shown to interact with other antiepileptic drugs, cimetidine, warfarin, or dextropropoxyphene. However, oxcarbazepine decreases serum levels of oral contraceptives and felodipine. Summary: Oxcarbazepine offers similar efficacy to carbamazepine but with fewer drug interactions and overall fewer adverse effects, with the exception of hyponatremia. 9. Pregabalin: Pregabalin is a structural analogue of GABA. It modulates neurotransmitter release by binding to the alpha-2-delta subunit of voltage gated calcium channel.116 Pregabalins efficacy and safety have been studied in patient with partial epilepsy, with or without secondary generalization as an add-on therapy. Pregabalin was studied in 4 randomized, doubleblind, placebo-controlled trials.117-120 Responder rates (more than or equal to 50%reduction from baseline seizure frequency) across effective pregabalin doses (150-600mg/day) ranged from 14 to 51%. In all these four randomized placebo-controlled parallel trials of pregabalin as an add-on therapy for partial epilepsy, the odds ratio for a >50% reduction in seizure frequency was 3.56 (CI 2.60 to 4.87) for pregabalin (all doses pooled) relative to placebo.121 In one flexible dose study

also, pregabalin (600mg/day and 150-600 mg/day) was found to be significantly better than placebo.122 Experience gained after the marketing of pregabalin also suggested moderate efficacy, cost effectiveness with favourable adverse profile.123-125 Pregabalin has a rapid onset of action. The long-term efficacy of pregabalin as add on therapy in partial epilepsy was studied in four long term open label extension studies of 1480 patients.126-128 Majority of patients received pregabalin >450 mg/day. Over the last 6 and 12 months of pregabalin across these studies, proportion of seizure freedom ranged from 7.4% to 24.2% and from 4.5% to 18.4%. Seizure responder rates were 41% to 60% during the subsequent 6, 12, or 24 months Most common adverse events were somnolence, dizziness, ataxia and weight gain. Summary: Pregabalin is an appropriate option in patients with drug resistant partial epilepsy. It has moderate efficacy with mild to moderate adverse effects. It may not be an appropriate choice for overweight patients and those with renal dysfunction. 10. Lacosamide: Lacosamide is approved as an adjunctive therapy for partial seizures in adults. Among the new AEDs, lacosamide is the only one with both an oral and intravenous formulation. It acts by enhancing slow inactivation of sodium channels in contrast to traditional AEDs such as phenytoin and carbamazepine, which act to block sodium channels in the fast inactivated state.129 The efficacy of lacosamide was established in three 12-week, randomized, double-blind, multicentre studies that enrolled adult patients.130-132 The median percentage reduction of seizure frequency was 35% to 39% in the 3 studies. A 50% reduction in seizure frequency was achieved in one-third of patients taking 200 mg of lacosamide and approximately 40% of those taking 400 mg. Doses higher than 400 mg led to more adverse effects than benefits; thus, 400 mg is the maximum recommended dose. Intravenous lacosamide was also tested in a randomized, double-blind study with 60 patients.133 Efficacy of the intravenous formulation was consistent with the oral drug. The recommended infusion rate is 300 mg for 30 to 60 minutes. Intravenous formulation is interchangeable milligram to- milligram with its oral counterpart. Lacosamides most common adverse effects included dizziness (25%) and ataxia (6%). A small but measurable dose-dependent PR-interval prolongation has been observed in association with lacosamide; therefore, caution of its use is advised for patients with known cardiac conduction problems. In patients with myocardial disease, heart failure, or those taking other drugs known to affect PR interval, an electrocardiogram is required before the start of therapy.

Summary: Lacosamide has a novel mechanism of action and has been found to be efficacious for adults with uncontrolled partial seizures. The intravenous formulation expands options for patients who require an AED and who are unable to receive oral medication. 11. Vigabatrin: Vigabatrin is a new antiepileptic drug with very narrow indications for its use. It is recommended only for 2 forms of severe epilepsy: infantile spasms

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and as add-on therapy for refractory partial epilepsy in adults when other options have failed. In infantile spasms, a severe epilepsy syndrome beginning in the first 2 years of life, treatment options consist of only vigabatrin and corticotropin as the first-line therapies. Vigabatrin is believed to act as an irreversible inhibitor of GABA transaminase which results in increased levels of GABA in the central nervous system.134 A randomized, doubleblind trial meeting Class 1 evidence criteria enrolled a total of 40 patients. At the end of 5 day double blind phase, 35% vigabatrin treated patients were spam free and 25% had resolution of hypsarrhythmia compared to 10% and 5% of the placebo group.135 In another multicentre study involving 142 infants with new-onset infantile spasms, the patients were randomized to low-dose (18-36 mg/kg daily) vs high-dose (100-148 mg/ kg daily) vigabatrin. Seventeen patients in the high dose group achieved a significant spasm freedom compared with 8 patients in the low-dose group.136 Other studies with class 3/4 evidence also suggested good efficacy for vigabatrin.137-139 It was also found that vigabatrin is particularly useful for the treatment of infantile spasms due to tuberous sclerosis complex.140-142 The efficacy of vigabatrin as adjunctive therapy in adults with complex partial seizures was also established in many multicentre, double-blind, placebo-controlled, parallel-group and cross over clinical studies. 143 Vigabatrin can cause permanent, bilateral concentric visual field constriction in 30% or more of patients. Peripheral visual loss can range from mild to severe tunnel vision to within 10 of visual fixation. Visual loss is irreversible, is unpredictable, and can occur any time during treatment. The risk typically increases with dose and cumulative exposure. The estimated risk of developing a visual field defect is 8% per year in adults.144,145 In some cases, vigabatrin may damage the central retina, decreasing visual acuity. A formal ophthalmologic assessment is required at baseline and every 3 months during therapy. Because of the risks to vision, a patient who does not show substantial benefit within 3 months of initiation of treatment should stop using the drug. Other adverse effects of vigabatrin include somnolence and fatigue, peripheral neuropathy, edema, and weight gain. Summary: Vigabatrin is a useful AED for a specific indication (infantile spasm). It can also be used in adults for refractory partial seizures when all other drugs become ineffective. Serious adverse event like peripheral visual loss limits its usage. 12. Rufinamide: Rufinamide is a triazole derivative structurally unrelated to other currently available AEDs. Its exact mechanism of action is not known but the principal action is believed to be due to modulation of sodium channels, specifically, prolongation of time spent in the inactive state of the channel.129,146 It was approved for treatment of atonic seizures in LGS in 2010. Atonic, or drop seizures are often the most disabling seizures in LGS and are usually drug resistant. Choices for AEDs for LGS are limited. The efficacy of rufinamide was established in a single, multicenter, double-blind, placebo-controlled, randomized, parallel-group study involving 138 individuals.147 It was studied as adjunctive treatment for seizures associated

with LGS. Three end points that were addressed were the percent change in total seizure frequency for 28 days, the percent change in atonic seizure frequency in 28 days, and seizure severity based on apparent parent/guardian global evaluation. There was a 32.7% reduction in total seizure frequency in the rufinamide group compared with 11.7% in the placebo group, a 42.5% reduction in tonic seizures compared with 1.4% in the placebo group, and a 53.4% improvement in seizure severity rating from a caretaker. Common adverse effects are similar to those reported with other AEDs and include headache, dizziness, fatigue, and gastrointestinal distress. Of concern is the potential for cardiac conduction disturbances with QT interval shortening. In the placebo-controlled trial, the observed degree of QT shortening was mild; nevertheless, the potential for increased risk of ventricular arrhythmia exists. Rufinamide should be avoided in patients with familial short QT syndrome and used with caution in combination with other drugs that shorten QT interval. Summary: Rufinamide is a limited-spectrum seizure drug, having a narrow therapeutic role in treating patients with LGS. However, for patients with atonic seizures and falls, rufinamide is an appropriate option. 13. Clobazam: Clobazam is a benzodiazepine. Although a benzodiazepine, clobazam is unique because of relatively low tendency to produce sedation and lower incidence of tolerance (loss of therapeutic effect over time), rendering it appropriate for long-term maintenance therapy. It has been in use worldwide for a very long time, although it was recently approved in the United States for adjunctive treatment of LGS in patients 2 years or older. The mechanism of action for clobazam, like other benzodiazepines, is potentiation of GABAergic neurotransmission via binding to the GABAA receptor. Clobazam have been found to be efficacious in many seizure types as an add-on in adults and children. In children, it can also be considered as first line monotherapy. In a large Canadian open label retrospective study (877 patients), clobazam has been found to be efficacious against all seizure types.148 Double blind studies as add-on in partial seizures and as monotherapy in Canadian children have also shown positive results.148-150 One review on use of clobazam as add-on in the management of refractory epilepsy is also available in the Cochrane library.151 Effectiveness of clobazam as add-on therapy for LGS in persons 2 years or older was established in 2 multicenter controlled studies performed specifically to bring the drug to the US market.152-153 The first study was a randomized, double-blind, placebo-controlled study of patients aged 2 to 54 years with LGS. Dosing was determined first based on weight (>30 kg or<30 kg), then with a low, medium, and high dose for each weight-based category. Total seizure reduction was 41% in the low-dose group, 50% in the medium-dose group, and 68% in the high-dose group compared with 12% with placebo. No significant tolerance issues were noted. A second randomized, double-blind study compared high- and low-dose clobazam in patients 2 to 25 years old with LGS. Dosing was again determined first by body weight. Seizure reduction was significantly greater in the high-dose (93%) compared with the

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low-dose group (29%). Summary: Clobazam is efficacious in many seizure types (both primarily generalized including Myoclonic and partial onset seizures) as an add-on in adults and children. In children, it can also be considered as first line monotherapy. 14. Retigabine or Ezogabine: Retigabine also known as Ezogabine has been approved for use as adjunctive treatment of partial epilepsy. Its mechanism of action appears to be enhancement of potassium currents mediated by a particular family of ion channels known as KCNQ. By activating these specific channels on neurons, retigabine is thought to reduce brain excitability. This drug is the first AED to control seizures by modulation of potassium channels.154 It may also potentiate GABAA receptors. Retigabine has been evaluated for efficacy as adjunctive therapy in partialonset seizures in 3 multicenter, randomized, doubleblind, placebo-controlled trials in 1239 adult patients.155157 Patients were randomized to daily maintenance doses of 600, 900, or 1200 mg/d, administered in 3 equally divided doses. Compared with placebo, retigabine reduced seizure frequency at 600 mg/d by 27%, 900 mg/d by 25%, and 1200mg/d by 24%. The main adverse effects of retigabine are urinary retention, neuropsychiatric symptoms, dizziness and somnolence, and QT-interval lengthening. Patients at high risk for urinary symptoms, particularly urinary obstruction, need to be carefully assessed. Neuropsychiatric symptoms, such as psychotic states associated with confusion and hallucinations, are frequently noted in patients taking retigabine. Most psychiatric symptoms resolved rapidly after discontinuation of drug use. Retigabine also has a potential for abuse and dependence. In healthy volunteers, the use of 1200 mg/d of retigabine led to a mean QT prolongation of 7.7 milliseconds. Hence, caution should be used in patients with known pre-existing cardiac conduction abnormalities or using medicines known to increase QT intervals. Electrocardiographic monitoring of QT intervals is advocated. Retigabine also has important drug interactions.

eslicarbazepine 800 and 1200 mg makes eslicarbazepine as a valuable addition in armamentarium of AEDs for refractory partial onset seizures. II. Questions that clinicians need to ask regarding New AEDs 1. Are New AEDs significantly better than placebos in add-on studies?

A recent meta-analysis determined the placebocorrected net efficacy of adjunctive treatment with modern AEDs on the market for treatment resistant epilepsy in more than 11,000 adults and children (161). The overall weighted pooled risk difference in favour of AEDs over placebo was 6% (95% CI: 48%; z = 6.47; p < 0.001) for seizure freedom and 21% (95% CI: 1924%; z = 17.13; p < 0.001) for 50% seizure reduction. Thus, placebo-corrected efficacy of adjunctive treatment with modern AEDs is disappointingly small. There is need to develop better agents. 2. Are New AEDs significantly better than placebos in monotherapy studies? 3. Are the new AEDs better in efficacy than traditional AEDs? The efficacy of new versus old AEDs for the treatment of idiopathic generalized epilepsy was studied in Arm B of the SANAD trial, which compared valproate, lamotrigine, and topiramate for treatment of mostly untreated epilepsy in an un-masked randomized design.162 SANAD was designed to assess whether any of the new AEDs available at the time should become first-line treatment and thereby replace valproate as the existing first-line agent. The result was that valproate was more efficacious than lamotrigine and similar in efficacy to topiramate for the subgroup of patients with idiopathic generalized epilepsy. Multicentre double-blind randomized trial compared treatment with ethosuximide, lamotrigine, or valproate in 453 children with new-onset absence epilepsy of childhood. After 16 weeks of therapy, the freedomfrom-failure rates for ethosuximide and valproate were similar (53% and 58%), but for both the rates were higher than for lamotrigine (29%; p < 0.001 for both comparisons).

Data is inadequate as very few studies are available. A. For generalized onset seizures:

B. For Absence seizures:

Summary: Retigabine may be helpful for patients with partial epilepsy when other medications have failed. Serious adverse effects and multiple drug interactions may limit its use. 15. Eslicarbazepine: Eslicarbazepine acetate was recently licensed as an adjunctive agent in partial epilepsy. It is structurally linked to carbamazepine and oxcarbazepine. It is converted into the major active metabolite S-licarbazepine.158 The exact mechanism of action is unknown, although S-licarbazepine stabilizes the inactive state of voltage-gated sodium channels. It mainly undergoes metabolic hydrolysis followed by glucoronidation with minimum CYP-mediated metabolism.159 In phase III clinical trials (which used eslicarbazepine doses of 400, 800, and 1200 mg/day), eslicarbazepine was well tolerated, with the most common AEs reported to include dizziness, headache, and somnolence.160 Hyponatremia and rash were rare. It can be given as once daily dose with simple titration.

C. For partial onset seizures Arm A of the SANAD trial was designed as a pragmatic trial to assess whether any of the new AEDs (lamotrigine, gabapentin, topiramate or oxcarbazepine should become first-line treatment and thereby replace the existing first-line agent carbamazepine.162 Based on efficacy criteria alone, none of the new AEDs were superior in efficacy to carbamazepine although lamotrigine and oxcarbazepine were considered to be non-inferior in efficacy, while carbamazepine was reported to be more efficacious compared to gabapentin and topiramate. Levetiracetam which entered the market later could not be studied in SANAD. However, a well-controlled non-inferiority trial has shown that, at per-protocol analysis, 73.0% of patients randomized to levitiracetam and 72.8% receiving controlled-release CBZ were seizure free at

Summary: Favourable efficacy and safety profiles of

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Table 4 : Adverse Effects of Traditional and New AEDs


AED Bromides Phenobarbital Traditional AEDs Potential adverse effects Drowsiness, restlessness, headache, acneiform rashes, granulomatous skin lesions, loss of appetite Sedation, depression, and paradoxical hyperactivity in children; neurologic toxicity (such as dysarthria, ataxia, nystagmus) with increasing doses; Nystagmus, ataxia, diplopia, drowsiness, impaired concentration, gingival hyperplasia, hirsutism, acne Nausea, abdominal discomfort, anorexia, drowsiness, dizziness Nausea, dizziness, drowsiness, diplopia, weight gain, rash, hyponatremia Dose-related tremor (less with controlled-release formulations), hair loss, weight gain, nausea, vomiting, lethargy New AEDs Headache, nausea, dizziness; weight loss, Somnolence, dizziness fatigue, weight gain Dizziness, nausea, insomnia, and headache Serious adverse effects Delirium , psychosis Rare hematologic toxicity

Phenytoin

Hepatotoxicity and idiosyncratic reactions including lupuslike reactions and aplastic anemia Numerous idiosyncratic reactions; rare hematologic toxicity Stevens Johnson syndrome, toxic epidermal necrolysis, leucopenia, rare cases of hepatotoxicity, and other idiosyncratic reactions Hepatotoxicity, acute hemorrhagic pancreatitis, thrombocytopenia, and hyperammonemia

Ethosuximide Carbamazepine

Valproate

Felbamate Gabapentin Lamotrigine

Tiagabine Topiramate Levetiracetam Zonisamide

Dizziness, tremor, abnormal thinking, nervousness and abdominal pain Drowsiness, paresthesias, metabolic acidosis, oligohydrosis, impaired language fluency and cognition, weight loss Dizziness, somnolence, asthenia, headache; irritability, behavioural problems, depression Fatigue, dizziness, somnolence, anorexia, abnormal thinking, rash Fatigue, headache, dizziness, ataxia, diplopia, nausea, vomiting, hyponatremia Dizziness, somnolence, weight gain Dizziness, headache, nausea, diplopia Headache, fatigue, dizziness and drowsiness; depression, Fatigue, vomiting, loss of appetite, somnolence, headache Sedation Neuropsychiatric symptoms, dizziness and somnolence Dizziness, headache, and somnolence

Fulminant hepatic failure and aplastic anemia None Hypersensitivity reactions, Stevens Johnson syndrome (increased occurrence with rapid titration); Rare psychosis, rare non-convulsive status epilepticus Renal calculi (most commonly reported idiosyncratic reaction), rare hepatic failure; acute glaucoma (rare) Psychosis Stevens Johnson syndrome, renal calculi, aplastic anemia, oligohydrosis Rash, Stevens Johnson syndrome None PR prolongation Permanent visual field deficits Aggravated seizures, status epilepticus, QT-interval lengthening. None Urinary retention, QT-interval lengthening. Rarely rash

Oxcarbazepine Pregabalin Lacosamide Vigabatrin Rufinamide Clobazam Ezogabine (Retigabine) Eslicarbamazepine

the last evaluated dose (adjusted absolute difference 0.2%; 95% CI: 7.88.2%) for at least 6 months indicating equivalent seizure remission for LEV versus slowrelease carbamazepine.163 4. Are New AEDs better tolerated compared to traditional drugs? There is no straight forward answer to this question. While some of the new AEDs like oxcarbazepine, lamotrigine and levitiracetam are attractive because of fewer adverse effects, some others like topiramate, tiagabine and ezogabine have a number of adverse effects (Table 4). Head to head comparison of Arm A of SANAD trial (partial seizures with or without secondary generalization) showed that, lamotrigine was more effective than carbamazepine largely due to lamotrigines superior tolerability.162 Carbamazepine

therapy was most likely to fail due to AEs, and lamotrigine and gabapentin were least likely to fail due to the presence of AEs. Oxcarbazepine was relatively similar in tolerability and failure rates to lamotrigine, and topiramate fell in between the two extremes. Rash was the AE most associated with treatment failure, and was most commonly reported by those patients receiving carbamazepine and oxcarbazepine. 162 In arm B (for primarily generalized seizures), topiramate was most frequently associated with AE-related discontinuation, followed by valproate. Lamotrigine was less likely to cause treatment failure due to unacceptable side effects. Interestingly a retrospective study involving 461 patients from Spain gives a completely opposite picture.164 In this study the new generation AEDs

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Table 5 : Comparative cost of Traditional and New AEDs


AEDs Lowest cost per tablet (branded) in rupees Average maintenance dose in Indian patients Lowest per day cost of therapy for average maintenance dose in rupees 1.25 -3.75 0.66 1.98 2.88- 3.84 4.08 5.44 15.54 31.08 90 - 270 6-12 30 - 60 30-45 20-30 20-40 12-36 12-18 12-24 10-20 100-300 20-40 Lowest cost per month in rupees

Traditional AEDs Phenytoin 100 mg Phenobarbital 60 mg Carbamazepine 200mg Carbamazepine SR 200mg Primidone 250 mg Ethosuximide 250 mg New AEDs Clobazam 10mg Lacosamide 100 mg Eslicarbzepine 400 mg Gabapentin 300 mg Levetiracetam 500mg Lamotrigine 50 mg Oxcarbazepine 300mg Pregabalin 75mg Topiramate 100 mg Vigabatrin 500 mg Zonisamide 100 mg

1.25 0.66 0.96 1.36 5.18 45 6 15 15 10 10 6 6 6 10 50 10

100-300 mg 60-180 mg 600-800 mg 600-800 mg 750-1500 500-1500 10-20 mg 200-400 mg 800-1200 mg 600-900 mg 1000-2000 mg 100-300 mg 600-900 mg 150-300 mg 100-200 mg 1000-3000 mg 200-400 mg

37.50 - 112.50 19.80 59.40 86..40 - 115.20 122.4 0 163.40 466.20 932.40 2700 - 8100 180 - 360 900 - 1800 900 - 1350 600 - 900 600 - 1200 360- 1180 360- 540 360- 720 300- 600 3000 - 9000 600 - 1200

comprising of gabapentin, lamotrigine vigabatrin, topiramate, tiagabine, oxcarbazepine, levitiracetam were withdrawn due to adverse events in 19.1% patients compared to only 9.3% patients using the traditional AEDs. Tiagabine was worst tolerated of all drugs. Retrospective nature of the study and lack of information on dosage and titration scheme in the paper limit the interpretation of the results. In another study, topiramate and lamotrigine were compared with phenobarbital. Relative Odds ratio for sedation of topiramate compared equally with phenobarbital but was 2.1 4 times worse than that of lamotrigine.165 In a study of children with absence seizures, traditional AEDs, namely valproate and ethosuximide had similar tolerability (but better efficacy) when compared to lamotrigine. Between valproate and ethosuximide, however, valproate was more likely to produce attention deficit syndromes than ethosuximide. Hence, ethosuximide was considered the drug of first choice.166 5. Are New AEDs better tolerated in elderly compared to traditional drugs? There is some evidence that new AEDs like lamotrigine and gabapentin may be better tolerated than nonsustained release carbamazepine in elderly epilepsy patients. In a 24-week double-blind trial, lamotrigine and carbamazepine were compared in 150 patients 65 years and older with newly diagnosed epilepsy. Forty patients on lamotrigine (39%) remained seizure-free during the final 16 weeks and did not discontinue drug treatment compared with 10 (21%) patients taking carbamazepine (p = 0.027). In this study, retention on treatment at the end of the trial was significantly higher in patients treated with lamotrigine than in those treated with carbamazepine (71% vs 42%, respectively), the difference being ascribed primarily to lower rates

of withdrawal because of lower adverse events in the lamotrigine group.167 More recently, 593 elderly subjects with previously untreated or undertreated seizures were randomized in a study to lamotrigine, carbamazepine, or gabapentin.168 Retention in the trial at 12 months was significantly greater in the groups allocated to lamotrigine and gabapentin (56% and 49%, respectively) than in the group allocated to carbamazepine (36%). However, there were no significant differences in seizure free rate at 12 months. 6. Are there potentially life threatening adverse effects of new AEDs? Except for gabapentin, pregabalin, clobazam (and levitiracetam except for severe behavioural disturbance at times), all other new AEDs can have serious adverse effects, some of which can be potentially life threatening too (Table 4). Just like traditional AEDs, assessment of risk benefit ratio must be made before initiating a new AED.

7. Are the pharmacokinetics and pharmacodynamics of new AEDs favourable? Many of the new AEDs have linear kinetics, low protein binding are non-enzyme inducers and have few drug interactions which make them attractive (Table 3).

8. How do the new AEDs fare in terms of titration, formulation and frequency of administration? While some of the new AEDs can be titrated quickly, others like lamotrigine and tiagabine need slow titration to improve tolerability. Most of the new AEDs can be given in convenient BID or OD dose frequency. Some of them are now also available in extended release forms although clinical efficacies of these forms have not been tested adequately.

9. Are the new AEDs better in terms of teratogenicity?

Data regarding most of the new AEDs on teratogenicity

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Table 6 : Potential First line drugs for Partial seizures with or without secondary generalization
AED Advantages Carbamazepine High-level evidence of efficacy, extensive experience, low cost, mood stabiliser Phenobarbital Disadvantages Enzyme inducer, high interaction potential, hyponatraemia (particularly in the elderly)

Table 7 : Potential First line drugs for adult onset primarily generalized seizures
AED Valproate Advantages Best evidence of efficacy, rapid titration Disadvantages Enzyme inhibitor, some interaction potential, weight gain, teratogenic potential Slow titration; dose requirements influenced by interactions with valproate, enzyme inducers, and oestrogen-containing contraceptives; can aggravate myoclonic seizures in some patients Psychiatric adverse effects

Lamotrigine

Extensive experience, Enzyme inducer, high very low cost, once-daily interaction potential, dosing cognitive and behavioural adverse effects Phenytoin High-level evidence of Complicated efficacy, rapid titration, pharmacokinetics, extensive experience, enzyme inducer, high interaction low cost, once-daily potential, cosmetic dosing possible adverse effects Valproate Rapid titration, mood Enzyme inhibitor, some stabiliser interaction potential, weight gain, teratogenic potential Oxcarbazepine Low potential for enzyme Higher risk of induction, lower risk of hyponatremia than for rashes than for carbamazepine, reduces blood carbamazepine concentrations of oral contraceptive steroids Lamotrigine High-level evidence of Slow titration; dose efficacy in the elderly, requirements influenced non-enzyme inducer, by interactions with effective in bipolar valproate, enzyme depression inducers, and oestrogencontaining contraceptives Topiramate Effective for migraine Slow titration, cognitive prophylaxis, low potential adverse effects for enzyme induction Levetiracetam High-level evidence of Psychiatric adverse effects efficacy, rapid titration, non-enzyme inducer, no significant interactions Gabapentin Non-enzyme inducer, Low-level evidence of no interactions, rapid efficacy (except in the titration, effective in elderly), weight gain neuropathic pain

Non-enzyme inducer, effective in bipolar depression

Levetiracetam Non-enzyme inducer, no significant interactions, rapid titration Topiramate Effective for migraine prophylaxis, low potential for enzyme induction

Slow titration, cognitive adverse effects

basket and clobazam, levetiracetam and topiramate from newer basket were prescribed (169-171). 11. Do patients with new AEDs have better chance of sustained remission after drug withdrawal compared to traditional AEDs?

Answer is not available yet. III. How to choose an AED? Major guidelines differ in their first line choice of AEDs. For example, the American Academy of Neurology (AAN) guideline does not state any preference for many old and new AEDs (4 traditional AEDs like phenobarbital, phenytoin, carbamazepine and valproate and 4 new agents like oxcarbazepine, topiramate, lamotrigine and gabapentin) for treating partial epilepsies with or without secondary generalization.172 The UK National Institute for Health and Clinical Excellence (NICE) recommends preferential use of older agents unless there are specific reasons for doing otherwise;173 carbamazepine, valproate, lamotrigine, and oxcarbazepine as first-line agents are recommended by the Scottish Intercollegiate Guideline Network (SIGN)174 and the ILAE recommends phenytoin and carbamazepine because they have the highest quality of evidence for efficacy and effectiveness.175 But efficacy and effectiveness are not the only issues of importance while choosing an AED. Tolerability of a given drug in a given patient, co-morbidities like anxiety, depression, systemic diseases like renal, hepatic or heart diseases, reproductive concerns, age (elderly patients or children), intake of co-medications like contraceptives or oral anticoagulants are also important issues that need to be addressed while choosing an AED. Rare idiosyncratic side effects, teratogenic side effects and chronic side effects are important as well. Tables 6 and 7 highlight the advantages and disadvantages of use of traditional versus new AEDs in partial onset and primarily generalized seizures. One of the aims for development of new AEDs is their possible use in some difficult to treat epilepsy syndromes

are meagre (as only a small number of pregnant women have been initiated on these drugs). However, preliminary data from pregnancy registries show that the rate of major congenital malformations may be comparable to some of the traditional AEDs like CBZ. For example lamotrigine has a rate of major congenital malformations ranging from 1.4 to 4.4%.27 Doses above 200mg were associated with higher risk. 10. Can the cost be an impediment for greater use of new AEDs? Certainly, cost of new AEDs is a limiting factor. For a country like India, this might be the greatest limiting factor for wider use of new AEDs (Table 5). Further, the utilization pattern may reflect the population being treated (rural/urban) and level of care (primary/ secondary/tertiary). Generally in the rural/ primary or secondary setting phenytoin remain the most commonly used drug while in tertiary urban centre, valproate and carbamazepine from the traditional

IV. Role of New AEDs for specific epilepsy syndromes

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Table 8 : Use of Traditional and New AEDs in infantile and childhood epilepsy syndromes
Epilepsy syndromes Infantile Spasm (West Syndrome) 1st line AEDs ACTH, vigabatrin 2nd line AEDs Valproate, clonazepam Uncertain status but may be May worsen seizures useful occasionally Nitrazepam, pyridoxine plus sulthiame, lamotrigine, Zonisamide , felbamate, TRH Carbamazepine, vigabatrin, lamotrigine Carbamazepine, vigabatrin, oxcarbazepine, phenytoin, Tiagabine Carbamazepine, vigabatrin, oxcarbazepine, phenytoin, tiagabine Carbamazepine, vigabatrin, oxcarbazepine, phenytoin, tiagabine Sulthiame Tiagabine, vigabatrin

Severe myoclonic epilepsy of Valproate infancy (Dravets Syndrome) Childhood absence epilepsy Valproate, lamotrigine

clonazepam, Stiripentol, topiramate, bromide Levitiracetam, topiramate, Zonisamide, ethosuximide Topiramate, zonisamide

Juvenile absence epilepsy

Valproate, lamotrigine

Juvenile myoclonic epilepsy Valproate, lamotrigine (preferred in female as 1st line) Benign epilepsy with centro- Carbamazepine, , temporal spikes oxcarbazepine, lamotrigine, valproate, Panayiotopoulos Syndrome Carbamazepine, , (early onset benign lamotrigine, oxcarbazepine childhood occipital epilepsy) valproate Idiopathic occipital Carbamazepine, , lobe epilepsy (late onset lamotrigine, oxcarbazepine childhood occipital epilepsy valproate Gastaut type) Lennox-Gastaut Syndrome Valproate, lamotrigine, topiramate

Topiramate, zonisamide

Levitiracetam, topiramate, gabapentin Levitiracetam, topiramate

Levitiracetam, topiramate

Doose syndrome (Epilepsy with myoastatic seizures)

Carbamazepine, clonazepam, valproate, topiramate Landau-Kleffner syndrome Lamotrigine, valproate, steroids Continuous Spike and wave Clobazam, clonazepam, during slow sleep ethosuximide, lamotrigine, valproate and steroids

Zonisamide, levitiracetam, ketogenic diet, felbamate, clobazam, clonazepam, ethosuximide, rufinamide Lamotrigine, levitiracetam,

Carbamazepine, oxcarbazepine

Levitiracetam, topiramate Levitiracetam, topiramate

Sulthiame -

Carbamazepine, oxcarbazepine Carbamazepine, oxcarbazepine, vigabatrin

(commonly seen in infants and children) which have been usually refractory or sub-optimally treated by traditional AEDs. Table 8 lists such situations where these drugs can be of considerable value. A new AED exclusively reserved for a difficult to treat childhood myoclonic syndrome is described in the following. Rest of the drugs listed in the table have already been described above. Stiripentol: It is a novel compound (aromatic allyl alcohol) which acts by increasing GABAergic transmission. It has been developed during last 30 years and has been used in France and Canada for past 10 years. It was authorized in 2007 by European Medicines agency for the treatment of refractory generalized tonic clonic seizures associated with severe myoclonic epilepsy of infancy (SMEI, Dravets syndrome). The recommended mean dose in children in 50mg/kg/day divided into 2-3 doses taken with meal. Although side effects (CNS and GI) are common, they are usually of milder nature. Main problem is interaction with other AEDs and their doses need to be adjusted. As an adjunct to valproate and clonazepam or clobazam, stiripentol can be very valuable in patients with SMEI. This was demonstrated in a randomized placebo controlled double blind trial in 2000.176

AEDs These are tabulated in the Table 9.

Future Trends
1. AEDs in pipeline: It is evident from above discussion that although we have a large number of AEDs at our disposal, no drug is ideal and the search for better drugs must continue. The following AEDs are in phase II/III trials and may soon become available for clinical use. Brivaracetam: Brivaracetam is a pyrrolidone derivative related to levetiracetam that binds to the synaptic vesicle protein 2A, but with higher affinity; brivaracetam also inhibits sodium channels.177 Following exploratory, phase IIb, double-blind, randomized, parallel-group studies, a number of Phase III clinical trials are currently on-going. Dose range has been 20-150mg/day. Drug may become useful for refractory partial onset seizures. Carisbamate: It is a novel agent under development for treatment of epilepsy.178 One phase II and 2 phase III trials have been completed. It has interactions with other AEDs. Exact mechanism of action is not known but is believed to act blocking voltage gated sodium channels. With tentative

V. Titration, Dose and Frequency of Administration of New

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Table 9 : Titration, dose and frequency of administration of traditional and new AEDs
AED Phenobarbital Suggested titration rate Start with 3050 mg at bedtime and increase, if indicated, after 1015 days Start with 625 mg per day and increase to target dose over about 3 weeks; in patients on enzymeinducing comedication, faster titration can be used Start with 100 mg per day and increase to target dose over 37 days Traditional AEDs Initial target maintenance Usual maintenance doses Frequency of dose (mg per day) (mg per day) administration 50100 50200 Once daily

Primidone

500750

5001500

23 times daily

Phenytoin

200300

200400

Once or twice daily

Ethosuximide Carbamazepine

Valproate

500-750 400600 Start with 100 mg per day or 200 mg per day and increase to target dose over 14 weeks Start with 500 mg per day 5001000 and increase, if indicated, after about 1 week New AEDs 18002400

500- 1500 4001600

23 times daily (twice daily with sustained-release formulations) Twice daily (once daily might be sometimes feasible, especially with sustained release 34 times daily

5002500

Felbamate

Gabapentin

Lamotrigine (and comedication with enzyme inducers associated with valproate) Lamotrigine and enzymeinducing comedication (without valproate)

Tiagabine

Topiramate

Levetiracetam

Zonisamide

Oxcarbazepine

Start with 600 mg per day or 1200 mg per day and increase to target dose over 1021 days Start with 300900 mg per day and increase to target dose over 510 days Start with 25 mg per day for 2 weeks, then increase to 50 mg per day for 2 weeks; further increases by 50 mg per day every 12 weeks) Start with 25 or 50 mg per day for 2 weeks, then increase to 50 or 100 mg per day for 2 weeks; further increases by 50100 mg per day every 12 weeks Start with 5 mg per day and increase by 5 mg increments at weekly intervals Start with 25 mg per day and increase by 25 mg or 50 mg increments every 2 weeks Start with 500 mg per day or 1000 mg per day and increase if indicated after 2 weeks Start with 50 mg per day and increase to 100 mg per day after 1 week; further increases by 50 mg per day every 12 weeks or by 100 mg per day after 2 weeks Start with 300 mg per day and increase to target dose over 13 weeks

18003600

9001800

9003600

23 times daily

100150*

100300

Twice daily (once daily possible

200300

200500

Twice daily

30 (patients on enzyme inducers); 15 (patients not on enzyme inducers) 100*

3050 (patients on enzyme inducers); 1530 (patients not on enzyme inducers) 100400

24 times daily

Twice daily

1000*

10003000

Twice daily

200

200600

Twice daily

600900

6002400

23 times daily

Contd.. 2

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Table 9 : Titration, dose and frequency of administration of traditional and new AEDs
AED Pregabalin Traditional AEDs Initial target maintenance Usual maintenance doses dose (mg per day) (mg per day) Start with 5075 mg per day 150300 150600 and increase to 150 mg over 24 weeks; further increases, if indicated, by increments of 75150 mg every 2 weeks Start with 100 mg per day 200300 200400 and increase by 100 mg after 12 weeks; if indicated, increase further by 100 mg after 12 weeks Start with 250 mg per day 1000 10003000 or 500 mg per day and increase to target dose over 12 weeks Start with 200400 mg 4001800 4003200 per day and increase by 200400 mg per day after 2 weeks; further increases, if indicated, by 400 mg per day every 2 weeks Start with 10 mg per day; if 10 1040 indicated, increase to 20 mg per day after 12 weeks Start with 300mg/day; 600-900 600-1200 increase by 300mg every 2 weeks Start with 400 mg per day 800 8001200 and increase to target dose after 12 weeks Suggested titration rate Frequency of administration 23 times daily

Lacosamide

Twice daily

Vigabatrin

Once or twice daily

Rufinamide

Twice daily

Clobazam

Once or twice daily

Ezogabine (Retigabine)

Thrice daily

Eslicarbamazepine

Once daily

usual dosage of 300-800mg/day, twice daily frequency of dosing and chiefly CNS adverse effects of moderate degree, it has potential for add on therapy in refractory partial seizures. Efficacy however is modest with 30-35% responder rate. Besides these there are a number of experimental drugs which are in pipeline, discussion of which are beyond the scope of this article. Pharmacogenomics is the prediction of drug response or adverse effects based on genetic markers. Although, this discipline can be considered to be in infancy so far as epilepsy is concerned, exciting vistas are opening up with unprecedented developments in molecular biology. It is hoped that drug-resistant epilepsy can be predicted early, AED choices can be refined and likelihood of idiosyncratic reactions can be predicted using these methods. Thus, the treatment can be made highly individualistic. Three main categories of candidate genes have been studied in relation to pharmacokinetics and pharmacodynamics of AEDs. These are genes encoding drug transporters, genes encoding drug metabolizing enzymes and genes encoding AED targets.179 Detailed discussion on this topic is beyond the scope of this review but few examples may be illustrative. Stevens-Johnson syndrome is a serious dermatologic adverse effect that can more likely occur with certain AEDs. Pharmacogenomics has already affected this issue. Certain HLA-B haplotypes predict serious rash when the patient is exposed to carbamazepine. There is a strong association in the Han Chinese and other Southeast Asian populations with Stevens-Johnson syndrome and the

2. Pharmacogenomics

HLA-B*1502 marker.180,181 HLA-A*3101 has subsequently been identified as a risk factor for carbamazepine-induced hypersensitivity reactions in Europeans.182 Several studies have also looked into the genetic variations of the genes encoding CYP2C9 which accounts for 90% of metabolism of phenytoin and found correlation between the maximum dose and *3 allelles.179 Similarly, AED targets may play a role in drug responsiveness. For example, SCN1 genes expressing a mutant auxillary 1subunit produce a reduced response to phenytoin in patients of generalized epilepsy with febrile seizures plus syndrome (GLFS+).179 3. Suicide Behaviour and Ideation Lately, there has been an increasing concern that persons who are on AED may have an increased suicidal rate or ideation.183 This has been particularly brought into focus in 2008 when the FDA issued a safety alert regarding the association of AEDs and suicidal behaviour and ideation. Based on a large pooled analysis composed of 199 randomized controlled trials involving both adjunctive and monotherapy drug trial designs, enrolling 43,892 patients in trials of 11 different AEDs, it was found that there was a doubling of the incidence rate of suicide or suicidal ideation, with 0.43% rate in patients taking AEDs compared with a 0.24% rate in those taking a placebo, representing an increase of approximately 1 case of suicidal ideation for every 530 patients treated. The increased risk of suicidal thoughts or behaviour with the use of AEDs was observed as early as 1 week after starting treatment and persisted for the assessed treatment duration. This issue remains controversial and methodological objections were put forward for the study.184 Subsequent population-based studies have suggested that

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suicide risk may be unique to a subset of patients with preexisting co-morbid depression who were taking an AED.185 In another study evaluating 5 million people in UK, similar conclusions were drawn.186 This underscores the need for the physicians to screen for mood disorders in each and every patient of epilepsy as they are frequent co-morbidities that need to be treated as aggressively as the seizures. 4. Generic Substitution of AEDs There is an on-going debate all over the world including in India regarding generic substitution of drugs. In the field of epilepsy, this has been a very controversial issue. Many physicians, neurologists and epileptologists do not believe in the bioequivalence of generic vesus the branded drug although the cost of the former may be much cheaper.187 A study involving 1000 patients showed that breakthrough seizures happened in as many as 59% of patients who were shifted from branded to generic drugs.188 Subsequently in another study involving 150 physicians, 69 reported that breakthrough seizures occurred in 50 patients without any other provocations except for changing the branded drug with a generic prescription.189 Smaller sample size of these studies and other methodological issues necessitate larger trials to settle this issue. Meantime, physicians treating epilepsy patients must discuss the possibility of breakthrough seizures with their patients if the branded AEDs are changed to generic ones. Also switching between generics may be undesirable.

1955 and 1989 with Special Reference to the Role of the International League Against Epilepsy (ILAE). In: Shorvon SD, Perucca E, Engel Jr J. The Treatment of Epilepsy, 3rd edition: (Special Indian ed.)Wiley Blackwell, 2009: xxi-xxxviii. 8. 9. Simon D, Penry JK. Sodium di-N-propylacetate (DPA) in the treatment of epilepsy: a review. Epilepsia 1975;16:549-573. Mattson RH, Cramer JA, Collins JF, Smith DB, Delgado-Escueta AV, Brown TR, et al. Comparison of carbamazepine, Phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic-clonic seizures. N Engl J Med 1985;313:145-151.

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Conclusion
New AEDs have expanded our therapeutic options for treating difficult to treat epilepsies. Some of them have also emerged as first line treatment options in new onset seizures, both generalized from onset and partial at onset with or without secondary generalization. Compared to traditional AEDs, as a group, they are neither more efficacious nor have lesser adverse effect profile. However, in a given clinical situation, they may be very useful when others have failed or they may have some unique advantages due their pharmacokinetic and pharmacodynamic profiles. Some of them can score over the traditional AEDs in terms of side effect profiles as well. Therefore, their use must be tailored to the needs of an individual patient giving serious thought about risk benefit ratio. Constant vigilance is also needed for identifying new adverse effects of new AEDs as these may unfold with wider use, as happened with traditional AEDs.

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Combination Therapy in Epilepsy : What, When, How and What Not!


Jayanti Mani*
he role of combination therapy as a treatment strategy for epilepsy is undergoing reevaluation. A growing appreciation that all seizures cannot be controlled by monotherapy and the introduction of over 14 new antiepileptic drugs (AEDs) for the adjunctive treatment in refractory epilepsy in the past twenty years has triggered an renewed interest in combination therapy. However, the experimental and clinical evidence in support of rational polytherapy is sparse, with only the combination of sodium valproate and lamotrigine demonstrating synergism. Robust evidence to guide clinicians on how and when to combine AEDs is lacking and current practice recommendations are largely empirical.

Summary

could be successfully treated with a single AED (Reynolds et al 1976) Patients reduced from polytherapy to monotherapy experienced fewer side effects and sometimes better seizure control (Shorvon and Reynolds 1979, Schmidt 1983 Albright 1985) Thus monotherapy became the new dogma for the management of newly diagnosed epilepsy. All the above data belongs to the era of traditional AEDs with limited and overlapping mechanisms of action. But the last two decades have seen the introduction of over fifteen new anti- seizure agents. Many of the newer agents possess broader and sometimes novel mechanisms of action, encouraging investigators to search for a pharmacomechanistic approach to combining AEDs with the goal of achieving synergism. Some newer AEDs have been shown to possess better adverse-effect profiles than their older counterparts thus raising the possibility of better tolerated drug combinations. Both of the above factors have improved the potential for a good outcome with polytherapy regimens. Combining drugs with different mechanisms of action is a common strategy in the treatment of many medical disorders. For instance, in patients with a history of cerebrovascular disease, combination therapy with perindopril (an ACE inhibitor) and indapamide (a diuretic) produced greater risk reductions than did perindopril alone. (PROGRESS trial 2001). In infectious diseases, several antimicrobials are used simultaneously for the treatment of tuberculosis and HIV infection to reduce the risk of drug resistance. Combination therapy is the norm in cancer chemotherapy. Polytherapy is also used routinely in some neurological conditions, even at treatment initiation. Thus, in patients with Parkinsons disease, levodopa is combined with a dopa decarboxylase inhibitor to reduce its systemic breakdown. In epilepsy too all the newer drugs have been introduced because they demonstrated their efficacy as add-on therapy in refractory epilepsy, implying that many patients can and do benefit from polytherapy. Despite this promise of combination therapy, a robust evidence base is lacking, and controversy continues over when and how AEDs should be combined. In a randomized comparison of adjunctive therapy versus alternative monotherapy in patients with partial epilepsy taking a single AED, no difference in seizure freedom was identified between these strategies (Beghi et al 2003) Adverse events were also similar in both treatment arms. A similar observation has been reported in a handful of pragmatic studies (Kwan and Brodie 2000, Mohanraj and Brodie 2005) There is a paucity of controlled studies investigating the question of how combination therapy can be used optimally in the management of epilepsy, particularly when to combine and what agents to use. The ideal way to test for synergism of antiepileptic drugs the clinical setting has not been agreed upon. The most scientifically valid approach to study such potential combinations is the isobolographical method (Figure 1), in which two AEDs are given in various dose proportions to identify the most effective regimen in terms of seizure control (Mawer et al 1995). This approach has been successfully applied in animal studies (Temkin 2001) but presents logistic difficulties in the

Introduction
Epilepsy is a common condition that occurs globally in around 50 million people (Sander 2003). Each year 40190 per 100 000 people are newly affected, with a higher incidence in resource-poor countries. Treatment options have become plentiful as the number of available antiepileptic drugs (AEDs) has swelled worldwide over the last two decades. Appropriate pharmacological management can result in seizure freedom for 6070% of patients.(Kwan and Brodie 2000, Mohanraj 2006, Brodie 2012 ). Overall, however, a substantial minority of patients fare relatively poorly, with around 30% of this population never achieving optimal seizure control (Mohanraj 2006) a figure that appears not to have significantly improved over the previous decade (Loscher 2011), despite the introduction of several new medications. Until the early 1980s, it was accepted clinical practice to initiate treatment in patients of new onset epilepsy with more than one agent [ (Reynolds and Shorvon 1981). Some standard antiepileptic drugs were in fact, available as fixed dose combinations (eg Phenytoin and Phenobarbitone). The probable basis for this practice was the premise that low dose combination therapy was less toxic than high doses of a single drug. All AEDs available at that time, such as acetylureas, barbiturates, benzodiazepines, succinimides and hydantoins, were associated with considerable CNS toxicity, and mechanisms of AED action were not well elucidated. Subsequently, concerns were raised about polytherapy including unfavourable interactions, and difficulty in evaluating individual pharmacological effects. Older AEDs are notorious for their ability to produce pharmacokinetic interactions among themselves as well as with other medications via their effect on the hepatic cytochrome P450 (CYP) enzyme superfamily.(Pastalos and Perucca 2003). It became recognized that combining traditional agents did not necessarily improve seizure outcome and could increase the propensity for side effects (Schmidt 1982). Reynolds et al conducted a series of prospective and retrospective studies to demonstrate that many patients with newly diagnosed epilepsy
*

Consultant Neurologist, Kokilaben Dhirubhai Ambani Hospital; Honorary Consultant Neurologist, Lokmanya Tilak Memorial Municipal Hospital and Medical College

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Table 1: Principles of polytherapy in Epilepsy


Rational polypharmacy in epilepsy involves combining Antiepileptic drugs that Have different mechanisms of action Do not have complex pharmacokinetic interactions Do not have a similar adverse effect profile Can be combined in minimum doses to produce maximum effect 1.

Table 2 : Mechanism of action of antiepileptic drugs


Sodium channel blockers a. Fast-inactivated statephenytoin, carbamazepine, lamotrigine, oxcarbazepine, eslicarbazepine b. Slow-inactivated statelacosamide 2. Calcium channel blockers a. Low voltage activated channelethosuximide b. High voltage activated channelgabapentin, pregabalin 3. GABA-ergic drugs a. Prolongs chloride channel openingbarbiturates b. Increased frequency of chloride channel opening benzodiazepines c. Inhibits GABA-transaminasevigabatrin d. Blocks synaptic GABA reuptaketiagabine 4. Synaptic vesicle protein 2A modulation levetiracetam 5. Carbonic anhydrase inhibition Acetazolamide 6. Multiple pharmacological targets sodium valproate, felbamate, topiramate, zonisamide, rufinamide

clinical setting because of the wide interindividual variation in the pharmacokinetics and pharmacodynamics of different AEDs.

When to Consider Combination Therapy?


In current day practice, every newly diagnosed patient with epilepsy should be initiated on appropriate monotherapy, based on the seizure type and the epilepsy syndrome. This approach is reasonable because in 60% of newly diagnosed epilepsy patients, seizures are controlled on the first monotherapy (Kwan and Brodie 2005). If the first monotherapy cannot be used in full doses because of idiosyncratic side effects, alternative monotherapy should be tried. If on the other hand, the first drug fails to achieve seizure control despite adequate doses, there is a wide variation in the strategies adopted. In a survey conducted among European physicians from different countries the percentage that adopted an add on AED strategy varied from 23% to 67% (BaldyMoulinier et al 1998). On the other hand a survey among epileptologists in the United States, 100% of them preferred to use an alternative monotherapy after the failure of the first drug(Karceski 2005). Evidence from recent trials, are weak but suggest an insignificant trend in favour of add-on therapy over substitution, both in terms of seizure freedom and intolerable side effects (Kwan and Brodie 2000, Beghi 2003) Among 780 newly diagnosed epilepsies, 47% became seizure free with the first monotherapy. Another 10% responded to the second monotherapy. Only 2.3% of the cohort entered remission with the third monotherapy (Mohanraj and Brodie 2006). These observations suggest that when two appropriately chosen monotherapy regimens have failed, the chance of success with a third single agent is slim. Thus the inadequacy of a policy of monotherapy for all has been highlighted in these long-term outcome studies of newly diagnosed epilepsy.

properties of drugs. In epilepsy it implies selection of a combination of antiepileptic durgs that will produce optimum seizure control with minimal adverse effects. This requires extensive knowledge of drug mechanism(s) of action, clinical effects, adverse effects, drug- drug interactions and therapeutic index. Mechanism of drug action There is limited evidence to suggest that mechanism of action may be useful in choosing appropriate combinations (Gilliam 2004, Hakkarainen 1980). Combination therapy with complementary mechanisms of action has generally been recommended (Table 2). There is the theoretical consideration that small effects on multiple drug targets may be more optimal than targeting a single mechanism of action (Bianchi 2009). It has been postulated that selection of AED combinations by mechanism of action may be useful because AEDs with similar mechanisms may have similar side effect profiles. AEDs with similar mechanisms of action may cause an excessive amount of additive side effects when used in combination. Deckers et al (1997) reviewed 39 papers on AED combination therapy with two drugs.. There was a wide variability in the method of reporting with most studies focused only on seizure control. The authors conclude that it may be better to combine drugs with different mechanisms of action (Table 3). They recommend a combination of a sodium channel blocker with a GABA mimetic drug to be superior to a combination of two GABA mimetic drugs which in turn is better that two sodium channel blocker AED combination. However, mechanisms of action have not yet provided meaningful guidelines to aid in the rational choice for polytherapy as there is insufficient evidence to determine whether identical or complementary mechanisms should be targeted. In addition, while it is convenient to conceptualise and categorise the mechanisms of action of AEDs, it is important to bear in mind that our understanding of the pathogenesis of seizure generation and propagation in the individual patient remains rudimentary. It is also likely that some AEDs possess as yet unrecognised modes of action. As we do not understand how seizures are generated and propagated in the brains of individual patients, adding molecules that possess multiple mechanisms of action, such as valproic acid, levetiracetam, topiramate and zonisamide, may be more likely to provide a beneficial pharmacological effect in the setting of refractory epilepsy. (Deckers 2004, Kwan and Brodie 2000)

Choosing the Next Antiepileptic Drug : What Matters?


With at least 15 AEDs available, 105 dual-therapy combinations are possible. Such an overwhelming number of options makes rational polytherapy not only of academic interest but a practical necessity.30Although a number of two-drug combinations have been tested in animals, there is a paucity of data on the comparative efficacy of different AED combinations in clinical practice. For patients in whom substitution or addition of an AED is required, selection of the new agent depends on many factors. These include seizure type or syndrome, adverse effects, comorbidities, interactions with comedication, age, possibility of pregnancy, learning disabilities, adherence, and formulation (French et al 2004) Rational polytherapy The concept of rational polytherapy has evolved as a system for planning treatment (Table 1). The theory is based on what is known and believed of pharmacokinetic and pharmacodynamic

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Table 3 : Pharmacokinetics and drug interactions of anti-epileptic drugs (Kwan 2006)


AED Older AEDs Carbamazepine Clobazam Clonazepam Ethosuximide Phenobarbital Phenytoin Primidone Valporic acid Newer AEDs Felbamate Gabapentin Lamotrigine Levetiracetam Oxcarbazepine Pregabalin Tiagabine Topiramate Vigabatrin Zonisamide
a

Undergoes hepatic metabolism Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes No Yes No Yes Yes No Yes

Affects hepatic cytochrome P450 enzymes Yes No No No Yes Yes Yes Yes Yes No No No Yes No No Yes No No

Affects metabolism of other AEDs Yes No No No Yes Yes Yes Yes Yes No No No Yesa No No Yesa Yesa No

Metabolism affected by other AEDs Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yesa Yes No Yes Yes No Yes

Effect modes, see section 1.2.

Thus, our understanding of seizure mechanisms and antiepileptic effect of drugs is still evolving and antiepileptic drug prescriptions can only be based on the major mechansisms of drugs that are currently known. Drug Interactions during combination therapy The potential for pharmacokinetic and pharmacodynamic interactions is an important consideration when substituting or combining AEDs . Several older AEDs produce pharmacokinetic interactions via their influence on the hepatic cytochrome P450 and other enzyme systems, affecting the clearance of other AEDs and comedications (Table 3)(Kwan 2006). In particular, phenobarbital, primidone, phenytoin, and carbamazepine induce the metabolism of many lipid-soluble drugs including oral contraceptives, cytotoxic agents, antiretrovirals, cardiac antiarrhythmics, immunosuppressants, and warfarin. Enzyme induction can also contribute to the development of chronic adverse effects, such as reduced bone density, sexual dysfunction, and potentially deleterious changes in cholesterol concentrations and other markers of vascular risk (Perucca 2005) Valproic acid is a weak enzyme inhibitor, and as such, can slow the clearance of other AEDs such as phenytoin and lamotrigine (Stephen 2003). (Table 3). The newer drugs are less likely to induce hepatic metabolism Interactions of newer AEDs with CYP enzymes is minimal and they are generally less likely to affect the metabolism of other AEDs to a clinically significant extent (Pastalos and Perucca 2003). Levetiracetam and gabapentin are notable for their lack of drug interactions, a clear advantage in combination AED therapy and with other medication. However, oxcarbazepine, eslicarbazepine, felbamate, rufinamide, and topiramate (at daily doses above 200 mg) can all selectively induce the breakdown of the oestrogenic component of the oral contraceptive pill (Burakgazi 2009). Consideration of these potential interactions must be taken into account when treating patients with drug-resistant epilepsy. The Valproate Lamotrigine Combination therapy The best evidence in favour of a synergism with a particular AED combination is for sodium valproate with lamotrigine (Brodie and Yuen 1997). During a trial in 347 patients designed to

assess the efficacy of lamotrigine in patients failing monotherapy with sodium valproate, carbamazepine, or phenytoin, a better response was demonstrated for the valproate/lamotrigine combination with 64% patients reporting a 50% or greater seizure reduction, compared with 41% taking carbamazepine/ lamotrigine and 38% on phenytoin/lamotrigine, despite similar circulating lamotrigine concentrations. Supportive data for a synergistic interaction came from a study (Pisani 1999) which reported that seizure freedom can be achieved with lower median doses of valproate and lamotrigine . Add retrospective study by Poolos in Neurology about VPA/ LTG combination 2011 Other combination therapies Other small studies and case studies have made claims for pairing sodium valproate with ethosuximide for absence seizures (Rowan 1983), Phenobarbital with phenytoin for tonic clonic seizures (Cereghino 1975), vigabatrin with tiagabine for refractory epilepsy (Leach 1994), lamotrigine with topiramate for a range of seizure types (Stephen 1998) and carbamazepine with valproate or vigabatrin for focal seizures (Brodie and Mumford 1999). Although observational at best, these combinations do all involve drugs with different modes of action (Brodie and Sills 2011). The best studied antagonistic combination is LTG and CBZ. Although it was initially proposed to be a pharmacokinetic effect due to the increase in the toxic epoxy residue of CBZ as a result of LTG administration [56], further studies have found this unfavorable combination is more likely due to a pharmacodynamic effect(Besag 1998, Gidal 1997) Polytherapy in special groups Pregnancy : Risk of teratogenecity Studies have confirmed higher birth defect rates than expected among children of mothers with epilepsy.. Commonly quoted figures are 36% for women with epilepsy compared with 23% in the general population (Morrow 2006). The cause is probably multifactorial, but antiepileptic drugs (AEDs) are the main reason for the increased risk. Fetal risks associated with maternal seizures are less well delineated, but

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generalised tonic-clonic seizures can induce fetal lactic acidosis and hypoxia and status epilepticus can cause fetal death. Frequent tonic-clonic seizures during pregnancy have been associated with poor cognitive performance in childhood. The challenge for clinicians is to balance these risks and to select a treatment that is eff ective in preventing major seizures while minimising adverse fetal drug eff ects. Clarifying the teratogenic potential of a new drug takes a long time, and data comparing the safety of diff erent treatment options have only begun to be available. been scarce. The past decade has seen intensifi ed clinical research on the subject, with several pregnancy registries reporting pregnancy outcomes after maternal use of AEDs (Meador 2008). This meta-analyses and other studies have demonstrated a greater risk of teratogenecity with polytherapy compared to monotherapy. The risk of teratogenicity increases with the doses and number of AEDs taken (Holmes 2001) . Polytherapyis associated with greater risk than monotherapy for both MCMs andcognitiveoutcome (Harden 2008). Recent findings from prospective pregnancy registers suggest a higher risk of foetal malformation in patients taking valproic acid with lamotrigine compared with those receiving lamotrigine alone. (Cunningtion 2005, Morrow 2006). The risks of teratogenecity weigh against the use of polytherapy and current recommendations dissuade the use of polytherapy in pregnancy (Harden CL 2009). A few recent studies suggest that the fetal hazard of AED polytherapy relative to monotherapy may depend more on the degree of exposure to valproate than on the fact of polytherapy per se (Vajda 2010, Holmes 2011) Where pregnancy is a possibility, and the first AED fails, it would seem sensible to substitute rather than combine antiepileptic drugs, and aim for a low dose without compromising seizure control as far as possible. Practice Recommendations Start with Monotherapy Choose AED appropriate for seizure type and epilepsy syndrome, emphasise on safety and tolerability. More than 50% of patients respond to the first appropriately chosen drug in moderate doses. Dose escalation should always be steady and gradual to avoid poor tolerance. If the first drug produces idiosyncratic adverse effects or side effects at low doses, substitute with a suitable alternative drug. If first drug reduces seizures, dose should be escalated to the maximum tolerated dose. If seizure freedom is elusive despite full doses of the first AED, a second drug may be added. The second drug should have a different mechanism of action and should not have an overlapping side effect profile. Drugs with similar mechanisms of action should preferably not be combined. (Refer to Table for mechanisms of action for various AEDs) Combination therapy should also be tried after two monotherapy regimens fail, as chances of seizure control on third monotherapy are slim. Before considering AED change or combination for lack of effective seizure control, the diagnosis of epilepsy, seizure type and syndrome should be reviewed and compliance of the patient with AEDs should also be confirmed. If seizure freedom is achieved on the combination therapy,

dose of the first drug may be reduced gradually, if necessary, to avoid drug overload. If seizure control is good on the combination, but seizure freedom is still elusive a third drug with a different mechanism of action may be tried in small doses. However adding a fourth or a fifth drug is unlikely to be successful. Three drug regimen are generally avoided if possible.80 Indeed, the vast majority of patients reaching seizure freedom do so with two AEDs, and virtually no one achieves seizure freedom with four AEDs.52 If a patient is on four or more AEDs, a concerted attempt should be made to reduce the regimen to two or three AEDs Treatment for each patient is individualized based on seizure type, syndrome, age, gender, co morbid conditions and comedications. When two monotherapies fail or a combination of two AEDs fails to achieve seizure freedom, the patient qualifies to have drug resistant epilepsy. Such patients should be evaluated for alternative therapeutic strategies such as epilepsy surgery. Women who are likely to become pregnant should be maintained on monotherapy in moderate doses as far as possible. . Suboptimal control of seizures other than tonic clonic seizures during this period may be an acceptable trade off, to reduce the risk of teratogenecity from polytherapy or high drug load. Risk of teratogenecity is highest soon after conception and in the first trimester, hence AED therapy has to be rationalized before conception. High dose valproate either alone or in combination therapy is best avoided throughout pregnancy.

Combination Therapy : When Not

References
1. 2. 3. 4. 5. 6. Sander JW. The epidemiology of epilepsy revisited. Curr Opin Neurol 2003;6:165170 Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med 2000;342:314319. Mohanraj R, Brodie MJ. Diagnosing refractory epilepsy: response to sequential treatment schedules. Eur J Neurol 2006;13:277282. Mohanraj R, Brodie MJ. Outcomes in newly diagnosed localisationrelated epilepsies. Seizure 2005;14:318-23 9. Brodie MJ, Barry SJ, Bamagous GA, et al. Patterns of treatment response in newly diagnosed epilepsy. Neurology 2012;78:1548-54 . Loscher W, Schmidt D. Modern antiepileptic drug development has failed to deliver: ways out of the current dilemma. Epilepsia 2011;52:657678.

Combination Therapy : When and How

7. Reynolds EH, Shorvon SD. Monotherapy or polytherapy for epilepsy? Epilepsia 1981;22:110. 8. Schmidt D. Two antiepileptic drugs for intractable epilepsy with complexpartial seizures. J Neurol Neurosurg Psychiatry 1982;45:1119 1124

9. Reynolds EH, Chadwick D, Galbraith AW. One drug (phenytoin) in the treatment of epilepsy. Lancet 1976;307: 923-6 10. Shorvon SD, Reynolds EH. Reduction in polypharmacy for epilepsy. Br Med J 1979;2:10231025. 11. Schmidt D. Reduction on two-drug therapy in intractable epilepsy. Epilepsia 1983;24:368376. 12. Albright P, Bruni J. Reduction of polypharmacy in epileptic patients. Arch Neurol 1985;42:797-9. 13. PROGRESS Collaborative Group. Randomised trial of perindnoprilbased blood pressure lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack. Lancet

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2001;358:1033-41. 14. Beghi E, Gatti G, Tonini C, et al. Adjunctive therapy versus alternative monotherapy in patients with partial epilepsy failing on a single drug: a multicentre, randomised, pragmatic controlled trial. Epilepsy Res 2003;57:113. 15. Kwan P, Brodie MJ. Epilepsy after the first drug fails: substitution or add-on? Seizure 2000;9:464468. 16. Kwan P : Patrick Kwan et al. Combination Therapy in Epilepsy. When and What to Use. Drugs 2006;66:1817-1829. 17. Mohanraj R, Brodie MJ. Pharmacological outcomes in newly diagnosed epilepsy. Epilepsy Behav 2005;6:382387 18. Baldy-Moulinier M, Covanis A, et al. Therapeutic strategies against epilepsy in Mediterranean countries: a report from an international collaborative survey. Seizure 1998;7:513-20. 19. Karceski S, Morrell MJ, Carpenter D. Treatment of epilepsy in adults: expert opinion. Epilepsy Behav 2005;7Suppl.1:S1-64. 20. Beghi E, Gatti G, Tonini C, et al. Adjuctive therapy versusor alternative monotherapy in patients with partial epilepsy failing a single drug: a multicentre, randomised, pragmatic controlled trial. Epilepsy Res 2003;57:1-13. 21. Mohanraj R, Brodie MJ. Diagnosing refractory epilepsy: response to sequential treatment schedules. Eur J Neurol 2006;13:277-82. 22. Mawer CE, Pleuvry BJ. Interactions involving new antiepileptic drugs. Pharmacol Ther 1995;68:209-31. 23. Temkin MR. Antiepileptogenesis and seizure prevention trials with antiepileptic drugs: metanalysis of controlled trials. Epilepsia 2001;42:515-24. 24. French JA, Kanner AM, Bautista J, Abou-Khalil B, Browne T, Harden CL, Theodore WH, Bazil C, Stern J, Schachter SC, Bergen D, Hirtz D, Montouris GD, Nespeca M, Gidal B, Marks WJ Jr, Turk WR, Fischer JH, Bourgeois B, Wilner A, Faught RE Jr, Sachdeo RC, Beydoun A. Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology; Quality Standards Subcommittee of the American Academy of Neurology; American Epilepsy Society. Efficacy and tolerability of the new antiepileptic drugs II: treatment of refractory epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology 2004;62:1261-1273. 25. Gilliam FG, Fessler AJ, Baker G, Vahle V, Carter J, Attarian H. Systematic screening allows reduction of adverse antiepileptic drug effects: a randomized trial. Neurology 2004;62:23-27. 26. Hakkarainen H. Carbamazepine vs. diphenylhydrantoin vs. their combination in adult epilepsy. Neurology 1980;30:354. 27. Bianchi MT, Pathmanathan J, Cash SS. From ion channels to complex networks: magic bullet versus magic shotgun approaches to anticonvulsant pharmacotherapy. Med Hypotheses 2009;72:297305. 28. Deckers CLP, Hekster YA, Keyser A et al Reappraisal of polytehrapy in Epilepsy: A critical review of drug load and adverse effects. Epilepsia 1997;38:570-575. 29. Deckers CLP, Czuczwar SJ, Hekster YA, Keyser A, Kubova H, Meinardi H, et al. Selection of antiepileptic drug polytherapy based on mechanisms of action: the evidence reviewed. Epilepsia 2000;41:136474. 30. Kwan P, Brodie MJ. Epilepsy after the first drug fails: substitution or add-on? Seizure 2000;9:4648. (already quoted above) 31. Perucca E. Clinically relevant drug interactions with antiepileptic drugs. Br J Clin Pharmacol 2005;61:246255. 32. Stephen LJ. Drug treatment of epilepsy in elderly people. Focus on valproic acid. Drugs Aging 2003;20:141152. 33. Patsalos PN, Perucca E. Clinically important drug interactions in epilepsy: general features and interactions between antiepileptic drugs. Lancet Neurol 2003;2:347356.

34. Burakgazi E, Harden C, Kelly JJ. Contraception for women with epilepsy. Rev Neurol Dis 2009;6:E62E67 35. Brodie MJ, Yuen AW. Lamotrigine substitution study: evidence for synergism with sodium valproate? Epilepsy Res 1997;26:423432. 36. Pisani F, Oteri G, Russo MF, et al. The efficacy of valproatelamotrigine comedication in refractory complex partial seizures: evidence for a pharmacodynamic interaction. Epilepsia 1999;40:1141 1146. 37. Rowan AJ, Meijer JW, de Beer-Pawlikowski N, van der Geest P. Valproate ethosuximide combination therapy for refractory absence seizures. Arch Neurol 1983;40:797802. 38. Cereghino JJ, Brock JT, Van Meter JC, et al. The efficacy of carbamazepine combinations in epilepsy. Clin Pharmacol Ther 1975;18:733741 39. Leach JP, Brodie MJ. Synergism with GABA-ergic drugs in refractory epilepsy. Lancet 1994;343:1650. 40. Stephen LJ, Sills GJ, Brodie MJ. Lamotrigine and topiramate may be a useful combination. Lancet 1998;351:958959. 41. Brodie MJ, Mumford JP. Double-blind substitution of vigabatrin and valproate in carbamazepine-resistant partial epilepsy. Epilepsy Res 1999;34:199205. 42. Brodie MJ, Sills GJ. Combining antiepileptic drugs: rational polytherapy? Seizure 2011;20:369375. 43. Besag FM, Berry DJ, Pool F, Newbery JE, Subel B. Carbamazepine toxicity with lamotrigine: pharmacokinetic or pharmacodynamic interaction? Epilepsia 1998;39:183187. 44. Gidal, B.E.; Rutecki, P.; Shaw, R.; Maly, M.M.; Collins, D.M.; Pitterle, M.E. Effect of lamotrigine on carbamazepine epoxide/ carbamazepine serum concentration ratios in adult patients with epilepsy. Epilepsy Res 1997;28:207211. 45. Morrow J, Russell A, Guthrie E, Parsons L, Robertson I, Waddell R,et al. Malformation risks of antiepileptic drugs in pregnancy: A prospective study from the UK Epilepsy and Pregnancy Register. J Neurol Neurosurg Psychiatry 2006;77:193-8 46. Kimford Meador, Matthew W. Reynolds, Sheila Crean, Kyle Fahrbach, Corey Probst, Pregnancy outcomes in women with epilepsy: A systematic review and meta-analysis of published pregnancy registries and cohorts. Epilepsy Research 2008; 81(1): 1-13 47. Harden CL : antiepileptic drug teratogenesis: what are the risks for congenital malformations and adverse cognitive outcomes? Int Rev Neurobiol 2008;83:205-13. 48. Cunnington M, Tennis P, for the International Lamotrigine Pregnancy Registry Scientific Advisory Committee. Lamo-trigine and the risk of malformations in pregnancy. Neurology 2005;64:95560. 49. Harden CL, Meador KJ, Pennell PB, Hauser WA, Gronseth GS, French JA, Wiebe S, Thurman D, Koppel BS, Kaplan PW, Robinson JN, Hopp J, Ting TY, Gidal B, Hovinga CA, Wilner AN, Vazquez B, Holmes L, Krumholz A, Finnell R, Hirtz D, Le Guen C; American Academy of Neurology; American Epilepsy Society. Practice parameter update: management issues for women with epilepsy-focus on pregnancy (an evidence-based review): teratogenesis and perinatal outcomes: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology 2009;73:133-41. 50. Frank JE Vajda, Alison A Hitchcock, Janet Graham, Terence J OBrien, Cecilie M Lander, Mervyn J Eadie. The teratogenic risk of antiepileptic drug polytherapy. Epilepsia 2010;51:805810. 51. Holmes LB, Mittendorf R, Shen A, Smith CR, Hernandez-Diaz S. Fetal Effects of Anticonvulsant Polytherapies: Different Risks From Different Drug Combinations. Arch Neurol2011;68:1275-1281. 52. Holmes LB, Harvey EA, Coull BA, et al. The teratogenicity of antiepileptic drugs. N Engl J Med 2001;344:11321138.

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Phenobarbitone in Modern India


Roop Gursahani* Abstract
Phenobarbital has been in use for a century. Because of its low cost and ease of use as a broad spectrum antiepileptic drug, it is often used in low-cost situations. It has significant adverse effects and can produce learning and behavior problems in children. In addition it is a major inducer of the hepatic Cytochrome P450 system producing many interactions. Because of these issues, the usage of this drug has declined substantially over the past few decades although it remains a therapeutic option in difficult to treat epilepsy patients. henobarbitones role in the management of epilepsy began a century ago, in 1912. The drug had been synthesized a decade earlier and was in use as a sedative. In 1912 Alfred Hauptmann serendipitously discovered that it controlled seizures in epilepsy patients in whom it was used for sedation. Last year the International League Against Epilepsy (ILAE) marked this centenary with a special symposium and a supplement in the journal Epilepsia. In the introduction to the supplement, Bialer1 noted that PHB was the only synthetic drug to have registered more than a century of continuous and ongoing clinical use. Most current practitioners however do not seem to see it as a prominent part of their armamentarium against epilepsy and hence this review.

Basic Pharmacology
PHB is marketed in India as 15-, 30- and 60-mg tablets of phenylbarbituric acid while the sodium salt is used in the syrup (20 mg/5 ml) and parenteral (200 mg/ml) formulations. The standard 60 mg tablet is marketed at about Rs 1 (range Rs. 0.80-1.70). Drug levels can be reliably measured in various body fluids by both chromatography and immunoassay and the recommended target therapeutic range is 15-45 mg/L. The main mechanism of action as an anti-epileptic is through prolongation of the opening of the chloride channel in the GABA-A receptor in the post-synaptic cell membrane, producing hyperpolarization and limiting spread of seizure activity. PHB is nearly completely and rapidly absorbed after oral administration and this is comparable with the intramuscular route. With a long half-life of 3-5 days (adults) once daily administration is acceptable and dose changes result in a steady state after 2-3 weeks. About 60% of the drug in the plasma is protein bound and it is metabolized by hydroxylation through the cytochrome P450 system with the main isoform being CYP2C9. Notably, PHB is also a strong inducer of other isoforms of the microsomal system and thus increases clearance of various drugs, vitamins (D, E) and hormones that undergo hepatic metabolism.2

3-arm controlled study of 95 patients with Alzheimers disease who developed epileptic seizures where PHB was at least as efficacious as the other 2 AEDs.3 The general impression is that PHB is at least as effective against both generalized and partial onset seizures as the other standard AEDs and most of the new AEDs. Absences are the only seizure type not amenable to PHB and these can occasionally be aggravated because of drowsiness. Neonatal seizures are the only situation where PHB is practically a drug of choice. It has also been used in refractory status epilepticus. Thus it can be used to treat all the seizure types usually seen in adolescents and adults. Unlike the Na-channel blockers (phenytoin, carbamazepine) PHB does not aggravate primary (genetic) generalized epilepsy and hence may not require EEG confirmation before starting treatment. PHB has also been successfully used in juvenile myoclonic epilepsy.

Adverse Effects
PHBs notoriety is mainly due to CNS adverse effects. Sedation, cognitive slowing and depressed mood and affect are prominent when the drug is initiated and can be partly mitigated with a slow introduction. In children this may cause learning difficulties. These effects are not easily picked up on routine follow up and can only be identified on sophisticated neuropsychologic testing. A placebo controlled study of PHB (4-5 mg/kg/day) for febrile seizures showed a mean IQ drop of 8.4 after 2 years of treatment in the treatment. Unfortunately even 6 months after stopping the drug the treatment group was still 5.2 points behind.4 Three to five years later, reading skills were still poorer in the PHB treated group as compared to their peers in the placebo group, leading the authors to conclude that there may be a long term adverse cognitive effect of PHB on developmental skills being acquired during the period of treatment.5 Whether these effects can be mitigated with lower doses (2-3 mg/kg/day) is unknown. Nevertheless these studies were hugely influential in sharply restricting the use of PHB in children in developed countries after the early 1990s. It has been presumed that similar considerations may not apply in developing countries, especially not to adults in cognitively non-demanding occupations. This was confirmed by Ding et al6 who compared 144 patients with epilepsy with matched controls from villages in China where scores actually improved (partly explained by the learning effect) on retesting after treatment. Behavioral changes can appear at all ages. Adults can occasionally become irritable and aggressive while children have been reported to paradoxically develop hyperexcitability. Two randomized studiesfrom South Asia studied PHB versus carbamazepine7 and PHB versus phenytoin 8 but could not confirm any disadvantage for the former.

Anti-Epileptic Efficacy of Phenobarbitone and its Indications in Epilepsy Management


Comparisons between the 4 standard AEDs (Phenytoin, Phenobarb, Carbamazepine and Valproate) date to about 2 decades ago or more and do not match up to current methodologic standards. The only direct head-to-head comparison with modern AEDs (lamotrigine and levetiracetam) was in a small
*

Consultant Neurologist And Epileptologist, P.D.Hinduja National Hospital, Mumbai 400016

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Teratogenicity is a major issue impacting AED choice in women of reproductive ages. Since PHB is now hardly used in developed countries, reliable prospective pregnancy registry data is scarce. The best estimate from Tomson 9 suggests a malformation rate of 5.4% with <150 mg/day of PHB monotherapy but 13.7% with higher doses. These figures are higher than the malformation rates with use of carbamazepine, lamotrigine or levetiracetam but still lower than with valproate. PHB usage during pregnancy can cause Vitamin K deficiency (due to hepatic enzyme induction) in the newborn and hence prenatal Vit K1 supplementation (10 mg/day) is mandatory from the 36th week onwards. Symptomatic drug withdrawal (hypotonia, irritability, poor feeding) can also be an issue in infants when the mother is treated with PHB through pregnancy. Increased Vitamin D catabolism is of particular significance in the Indian context where patients are often deficient even before starting AED therapy.10 Folate depletion is a less well known adverse effect. In patients on very long term treatment, PHB has produced Dupuytrens contracture and shoulder-hand syndrome by unknown mechanisms. Idiosyncratic skin reactions are rare but have a 50% chance of cross reactivity with phenytoin and carbamazepine. Zhang et al 11 attempted to address all these concerns in a systematic review. These authors could not find any convincing evidence that PHB caused more adverse events than carbamazepine, phenytoin or valproate but they did note that PHB was associated with a higher rate of drug withdrawal. An accompanying editorial12 questioned the power of this analysis to address concerns about PHBs safety. It was also pointed out that there was no scope for comparing PHB with the whole gamut of modern AEDs! The whole argument reflects the differing perspectives of developing versus developed countries.

The most elaborate of these has been a demonstration project set up between the WHO, the ILAE and the International Bureau for Epilepsy in Hunan province in China which started with a door-to-door survey in 2000. This estimated a treatment gap of 93.4% and was followed by a pragmatic intervention study using PHB monotherapy as the first treatment option. Of 2455 patients recruited, 2-year follow-up was available for 1324 patients with 26% of patients seizure free. Another 45% had a greater than 50% reduction of seizure frequency. The estimated probability of patients remaining on treatment with PHB at 6 years was 0.53 and this is comparable to the retention rate of modern AEDs.15

Using Phenobarbitone in Modern India : An Argument for Pragmatism


PHBs adverse effects are probably more comprehensively documented than that for any other AED. This leads one to wonder whether this is purely due to its prolonged stay in active service. Personal experience can however be more compelling than any published evidence for the individual physician. In 1987, a close friend failed his undergraduate exams in the MBBS course. He had been started on PHB for seizures secondary to neurocysticercosis. He was changed over to carbamazepine and he passed his remaining exams comfortably. Today he is a respected practicing surgical pathologist with an enviable CV. Was the earlier failure due to PHB? Public spending on healthcare in India at 1.4% of GDP is abysmally low as compared not only to developed countries (6.5-8%) but also compared to China (2.3%) or Thailand (3.3%). Per capita, the Indian government spends just $43 as compared to $87 in Sri Lanka, $155 in China and $261 in Thailand.16 Thus expecting adequate epilepsy treatment as part of comprehensive public health care is a distant dream. The only way forward is to tackle epilepsy in mission mode as has been proposed by Tripathi et al13 and this will most likely have to be a public-private partnership operating at the lowest possible cost. Epilepsy is a major and often correctable component of overall neurologic disability. If well controlled and in the absence of behavioral, cognitive or other neurologic problems, it is compatible with a completely normal and fulfilling life. About 50% of patients with new onset epilepsy will become seizure free with a modest dose of an appropriate AED. PHB is the least expensive AED, widely available in government and private pharmacies, easy to store and easy to use with once daily dosing. With a broad spectrum of action, it is not known to exacerbate primary generalized epilepsy: a major concern with phenytoin and carbamazepine, which are the next in order of cost. This is important since initial diagnosis and treatment at the primary level has to be entirely clinical, with no scope for any sophisticated investigations. Vitamin D and folate supplementation are easy to add in vulnerable individuals. Thus there is a compelling argument to make PHB the first monotherapy for epilepsy in all public and charitable health services. As a personal statement, I find it difficult to justify prescribing PHB to anyone who can afford Valproate or any of the modern AEDs. Is it then either ethical or appropriate for me to recommend this drug to school age children just because their parents cannot afford treatment with any of the alternatives? This dilemma cannot be resolved individually and it is my hope that in the future AED choices will be determined by clinical and not economic compulsions.

Phenobarbitone and the Treatment Gap in Epilepsy


A large number of patients with epilepsy in India do not come to medical attention or do not receive treatment for various causes: this is the treatment gap. It has been measured to be just under 40% in the literate and relatively well served population of Kerala while it reaches an alarming 90% in some parts of West Bengal.13 On an average more than 50% of Indian patients with epilepsy receive no treatment and the situation is similar in most developing countries. PHB has been the mainstay of most systematic attempts to address this treatment gap. The Yellandur study in Karnataka by Mani et al14 recruited 135 patients in a non-randomized trial of phenytoin and/or PHB and followed them up for 5 years. Sixty-eight patients with generalized tonni-clonic seizures received PHB monotherapy, 60 were on phenytoin and another 7 received duotherapy. All management was entirely clinical by trained primary-care physicians. Only 3 (4%) of PHB treated patients developed adverse effects. Terminal remission (seizure freedom for 2 years) was analyzed at the end of each of 4 years and ranged from 58-66% for those patients who were compliant and who had a lifetime total of less than 30 seizures. In the words of the authors: In rural areas of less developed countries, epilepsy control in its early stages can be practical and effective with existing resources. The key to success is a combination of trained primary-care physicians, health workers, inexpensive phenobarbital, drug compliance, health education, and follow-up. Similar studies and results have been obtained from Cameroon, Nigeria, Mali and Laos.15

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References
1. 2. Bialer M, Smith PE. Introduction. Epilepsia 2012;53(s8):1-2. Eadie MJ, Kwan P. Phenobarbital and other barbiturates. In Engel J, Pedley TA, eds. Epilepsy: A Comprehensive Textbook, 2nd Edition. Philadelphia, Lippincott Williams Wilkins, 2008;2:1599-1607.

8.

Pal DK, Das T, Chaudhury G, Johnson AL, Neville BG. Randomized controlled trial to assess acceptability of PHN for childhood epilepsy in rural India. Lancet 1998;351:19-23. Tomson T, Battino D. Teratogenic effects of anti-epileptic drugs. Lancet Neurol 2012;11:803-13.

9.

3. Cumbo E, Ligori LD. Levetiracetam, lamotrigine and PHB in patients with epileptic seizures and Alzheimers disease. Epilepsy Behav 2010;17:461-6 4. Farwell JR, Lee YJ, Hirtz DG, Sulzbacher SI, Ellenberg JH, Nelson KB. Phenobarbital for febrile seizures effects on intelligence and on seizure recurrence. N Engl J Med 1990;322:364-369. Sulzbacher S, Farwell JR, Temkin N, Lu AS, Hirtz DG. Late cognitive effects of early treatment with PHB. Clin Pediatr (Phila.) 1999;38:38794 Ding D, Zhang Q, Zhou D et al. Cognitive and mood effects of PHB treatment in people with epilepsy in rural China: a prospective study. J Neurol Neurosurg Psychiatry 2012;83:1139-44 Banu SH, Jahan M, Koli UK, Ferdousi S, Khan NZ, Neville B. Side effects of PHB and Carbamazepine in childhood epilepsy: randomized controlled trial. BMJ 2007;334:1207.

10. Menon B, Harinarayan CV. The effect of anti-epileptic drug therapy in serum 25-hydroxyvitamin D and parameters of calcium and bone metabolism a longitudinal study. Seizure 2010;19:153-8. 11. Zhang L, Zeng L, Li Y. Side effects of PHB in epilepsy: a systematic study. Epileptic Disord 2011;13:349-65. 12. Rheims S. The safety profile of PHB: can meta-analyses tell us the truth? Epileptic Disord 2011;13:366-7. 13. Tripathi M, Jain DC, Devi MG et al. Need for a national epilepsy control program. Ann Indian Acad Neurol 2012;15:89-93. 14. Mani KS, Rangan G, Srinivas HV, Sridharan VS, Subbakrishna DK. Epilepsy control with PHB or phenytoin in rural South India: the Yelandur study. Lancet 2001;357:1316-20. 15. Brodie MJ, Kwan P. Current position of PHB in epilepsy and its future. Epilepsia 2012;53(s8):40-6. 16. Health care spend to rise to 2.5 % of GDP. Indian Express, 1 Mar 2012. Available at http://www.indianexpress.com/news/healthcarespend-to-rise-to-2.5--of-gdp/918380.

5.

6.

7.

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Women with Epilepsy in Reproductive Age Group : Special Issues and Management Strategies
Shehanaaz Begum*, Sanjeev V Thomas** Abstract
Women with epilepsy (WWE) have several gender based problems pertaining to social and biological domains. The stigma of epilepsy and its consequences appear to be more for women than men. They have more difficulty in getting married and sustaining a married life. The cyclical variations in the reproductive hormones can adversely impact the seizure pattern in WWE. Epileptiform discharges in the brain can influence the hypothalamic functions and lead to sexual dysfunction. The Antiepileptic drugs (AED) may alter their metabolic and hormone profile and contribute to this disorder. Most WWE tend to have uneventful pregnancies and healthy babies. Nevertheless, the risk of fetal malformations appears to be increased when AEDs are used during pregnancy. This risk is higher for those who are on polytherapy, or using valproate. Recent studies have also demonstrated that antenatal exposure to AEDs could lead to neurocognitive and developmental impairment, low IQ or language problems in exposed infants. Clinicians need to consider these special issues while initiating AED therapy in adolescent girls. All WWE need to have a detailed pre conception evaluation wherein the need to continue AEDs, the ideal AED and dosage are reassessed. The AED therapy would have to be individualized according to the clinical situations, obstetric background and family concerns. Folic acid should be prescribed to all women who could potentially become pregnant. Detailed screening for fetal malformations by estimation of serum alpha fetoprotein and fetal ultrasonography need to be carried out between 14 - 18 weeks of pregnancy. The dosage of AEDs may have to be escalated in the second half of pregnancy in selected patients. The family should be provided detailed counseling and information on how to cope with the pregnancy, childbirth, lactation, and contraception. Unlike others, the European registry and the UK registry do not include WWE who are not taking any AEDs. KREP, EURAP and the Australian registry collect data from the maximum number of contacts. Of these, the Australian registry collects data over telephone. They also differ in their duration of follow up, outcome ascertainment methods, outcome classification, control selection methods etc. Among the five, KREP is the only one providing pre conceptional counseling. Under KREP, WWE and their children are followed up to the age of 12yrs. KREP has an important role in the Indian scenario as it is generating data from our country. The genetic constitution, socio economic environment and health care delivery system that would influence the foetal and maternal outcome for persons with epilepsy are different in different populations. The final outcome of the disease and the effect of AEDs in different populations may vary based on many such factors. For example, the US registry has found an increase in the incidence of cleft lip and palate in their population1 while the UK or European registries2 have not.

t is estimated that about 50 million people worldwide have epilepsy and women constitute half of this number. In India, about 5.5 million people have epilepsy. 2.5 million of them are women and 1.3 million of these women with epilepsy (WWE) belong to the reproductive age group. There is significant gender based difference in the biological, pharmacological, psycho social and economical profile of epilepsy. The biological variations are attributed to the influence of female reproductive hormones on epileptogenesis and seizure recurrence. Seizure exacerbations with menarche and menopause and catamenial worsening are examples. WWE also suffer a more severe psycho social impact when compared to men with epilepsy. Continuous use of AEDs can increase the risk of sexual dysfunction, infertility and fetal malformations. Most of the recent literature regarding WWE and their reproductive problems has come from the various epilepsy and pregnancy registries. Worldwide, there are 5 registries which follow up WWE.

Introduction

Social issues in WWE


WWE experience a broader spectrum of problems and social stigma associated with epilepsy than their male counterparts.3
KREP 1998 Yes Yes 4 contacts 12 months External Internal EURAP 1999 No No AED change 4 contacts 12 months Internal Australia 2000 No Yes 4 (phone) 12 months Internal External

Table 1 : Characteristics of various epilepsy and pregnancy registries


Year of commencing Pre conceptional evaluation Includes those not on AED Exclusion criteria Data collection Malformation ascertainment at Control selection UK 1996 No Yes AED change 2 contacts <12 wks Internal US 1997 No No 3 contacts < 12 wks External Non epileptic

Abbreviations: UK, United Kingdom; US, United States; KREP, Kerala Registry of Epilepsy and Pregnancy; EURAP = An International Registry of Antiepileptic Drugs in Pregnancy; AED, Anti-epileptic Drug
*

Senior Research Fellow, **Professor of Neurology, Department of Neurology, Kerala Registry of Epilepsy and Pregnancy, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum 695011.

In a comparison of young men and women with JME (Juvenile Myoclonic Epilepsy) or TLE (Temporal Lobe Epilepsy) living in India, it was found that there were significant gender based differences in the profile of epilepsy. WWE were found to have

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higher odds ratio for remaining unmarried (OR 2.81) than men (OR 1.63) across all age groups from 20-44yrs. WWE were also observed to have higher rates of unemployment and divorce.4

Teratogenic Effects
Ante natal use of AEDs has been associated with increased risk of fetal malformations. Various mechanisms have been proposed as to how AEDs exert their teratogenic effects.12 AEDs may lead to folate deficiency and thus predispose to neural tube defects. AEDs that are metabolized by cytochrome P450 enzymes in the liver increase the levels of arene oxide which is a byproduct of this metabolism. Arene oxide is a potent teratogen. Other mechanisms include alteration of homeobox (HOX) genes, retinoic acid signaling pathway, histone deacetylators, polymorphisms involving AED transporters and oxidative stress.13,14 Considerable amount of data has come from the various registries regarding fetal malformations.2,15-17 But it is important to consider the characteristics of the registry, their selection criteria, case ascertainment methods and follow up duration while interpreting their results. Under KREP, malformations are defined as serious defects which interfere with the quality of life unless they are managed. Others which produce only a cosmetic effect and do not interfere with the quality of life are considered as anomalies and do not qualify as major malformations. AEDs can induce malformations in almost all organs. These can be broadly classified into cardiac malformations (tetralogy of Fallot, atrial septal defect, ventricular septal defect, patent ductus arteriosus, pulmonary atresia, single ventricle etc), malformations of the nervous system (neural tube defects), skeletal defects (club foot, hip dislocation etc), cranio facial defects (cleft lip and palate), malformations of the gastro intestinal system (esophageal atresia, congenital hypertrophic pyloric stenosis, inguinal, diaphragmatic and umbilical hernias and omphalocele), malformations of the genitor urinary system (renal agenesis, hydronephrosis, hypospadias and undescended testis) and malformations involving multiple systems. In a prospective study from the UK epilepsy and pregnancy register, 4.2% of live births to WWE had major congenital malformations. The rate of major congenital malformation was more with polytherapy than monotherapy (adjusted OR 1.83).17 In a larger study involving patients from Europe, Australia and India, it was observed that there was a dose dependent increase in the risk of malformations for carbamazepine, lamotrigine, valproate, and Phenobarbital.2

Infertility
Issues regarding reproduction are a major concern in WWE. Earlier studies have indicated that WWE have reduced fertility.5 Infertility is defined as the inability to conceive even after 12 months of unprotected intercourse. A prospective study over 10 years under KREP had shown that WWE have a greater risk for infertility, especially with polytherapy.6 The prevalence of infertility among WWE was more than double (38.4%) that among women in the general population (15.15%). Also, the WWE who conceived had a fewer number of children than the rest. Infertility was least for those who were not on any AEDs (7.1%) while it was 31.8% for those taking one AED, 40.7% for those taking two AEDs and 60.3% for those taking three or more AEDs. Those exposed to Phenobarbital had a significant risk of infertility (OR 1.517 for monotherapy and OR 1.43 for polytherapy) but no such trend was observed with valproate or other drugs in that study.6

Effect of Pregnancy on Epilepsy


Another concern is the recurrence of seizures during pregnancy. In general, 20-30% of WWE may have exacerbation of seizures during pregnancy, 20-30% show improvement and 40-50% experience no change in seizure pattern.7 The cause for seizure recurrence varies with the stage of pregnancy. In the first trimester recurrence is mostly due to mental stress, sleep deprivation, hormonal changes etc. Patients may be apprehensive about the adverse effects of AEDs on the fetus and may tend to discontinue treatment. Another issue is hyperemesis which indirectly results in drug default. Either ways non compliance is a major cause of seizure recurrence in pregnancy. During the second and third trimesters there is significant hemodilution which causes a reduction in the blood levels of AEDs. This compounded with increased elimination of drugs, especially lamotrigine and oxcarbazepine and to some extend leviteracetam can result in break through seizures. Therefore patients on these AEDs can be prescribed to take an increased dose of the same. Of the 1,297 pregnancies in WWE enrolled in KREP, all the three patterns were observed. 47.8% remained seizure free during pregnancy. Seizure relapse was highest during the three peripartum days. Recurrence was more with localization related epilepsy (LRE) than generalized epilepsy (OR-1.6, CI-1.2-2.0). Also, patients with poor seizure control in the pre pregnant month were more likely to have seizure recurrence in pregnancy when compared to those with seizure free pre pregnant period. Polytherapy was significantly associated with seizure relapse than monotherapy.8

Long Term Outcome


Until recently, not much research was directed to the adverse effects of AEDs on the long term language and IQ development of children exposed to AEDs in utero. A long term adverse effect of ante natal use of AEDs is impaired neurocognitive development in infants exposed to AEDs prenatally. A prospective evaluation of 15 month old infants of mothers with epilepsy enrolled in KREP showed that about one third of them had a significantly impaired mental (MeDQ) and motor (MoDQ) development quotient. Those exposed to polytherapy had a significantly lower development quotient than those exposed to monotherapy. Valproate monotherapy was associated with significantly lower MeDQ and MoDQ when compared to carbamazepine.18 In a follow up study under KREP where children of mothers with epilepsy, of age 6 years and above were compared against age and socio economic status matched controls, it was found that the test group scored significantly less than the controls in both full scale IQ test (FSIQ) and language test. It was also observed that children with low MeDQ and MoDQ at one year of age continued to have low FSIQ and MLT at 6 years of age

Effect of Epilepsy on Pregnancy


There is no undue risk of pregnancy and childbirth in WWE.9-11 WWE are found to have an adverse maternal outcome of pregnancy. In a prospective study9 where the complications of 643 completed pregnancies were compared with 18,272 pregnancies managed in a teaching hospital, it was found that WWE had a higher chance for some complications like, anemia, ovarian cyst, fibroid uterus, spontaneous abortions and seizures in the peri partum period. The risk of caesarean section was not increased in WWE.

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ALGORITHM FOR PRECONCEPTION MANAGEMENT OF EPILEPSY IN WOMEN


A / N VISIT << 12 wk

ALGORITHM FOR MANAGING EPILEPSY IN PREGNANT WOMEN

ENTRY
II A / N VISIT

EXCLUDE

NO

16 - 20 Wk

TITRATE AED

EPILEPSY DEFINITE

MALFORM: SCREEN
NO

YES

TERMINATE

FOLIC ACID

<20 Wk

YES NEED FOR AED YES YES CHANGE AED NO NEW AED REGIME FOLIC ACID
LSCS

MTP

YES

NO

INDUCTION

NO
28 Wk. TITRATE AED 28 Wk.

36 Wk.

TITRATE AED

VITAMIN K (Prior to delivery)

TYPE OF DELIVERY VAGINAL

PREGNANCY

BREAST FEEDING

FOLLOW UP

CONTRACEPTION

Fig. 1 : Algorithm for follow up of women with epilepsy during pregnancy

(p value 0.05, 0.05 and 0.02 respectively). Also the polytherapy group had lower mean FSIQ than monotherapy group. Those exposed to higher cumulative load of AEDs had significantly lower FSIQ and MLT scores compared to those exposed to lower drug load.19 The findings were later confirmed in a sample drawn from UK and USA as well as Europe.20,21

Management Approach
The AED therapy in adolescent girls should ideally be tailored considering their reproductive needs. WWE should be advised to consult their neurologist before starting a family. Their diagnosis should be actively re-assessed at this point of time (Figure 1). It is not rare to find women who are inadvertently started on AEDs for non epileptic conditions misdiagnosed as epilepsy. Some are found to be in remission and in them drugs may be withdrawn following the general principles. However, the risk of recurrence of seizures, particularly with the risk of marriage and its impact needs to be addressed. Patients with Juvenile Myoclonic Epilepsy need to be continued on AEDs as they are at high risk of seizure relapse on complete withdrawal. Any changes in the pattern of drug therapy may be planned prior to pregnancy. Reduction of doses, change over to less teratogenic drugs and conversion of polytherapy to monotherapy may be done depending on the disease status of individuals. Pre pregnancy blood levels of AEDs can also be checked.22,23 WWE who are likely to get pregnant may be started on folic acid 5mg/day pre conceptionally. WWE and their families may be counseled regarding the need to continue AEDs in order to remain seizure free, that >90% of infants born to WWE on AEDs are healthy, the risk of a major malformation is 6-8% and that this is seen mostly with WWE taking polytherapy and high doses of AEDs. The need to take folic acid daily has to be reinforced. Under KREP, pregnant WWE are screened for malformations at 16-18 weeks of pregnancy with serum alpha feto protein

levels at 16 weeks as well as a fetal ultra sonogram at 18 weeks of pregnancy (Figure 2). This provides a margin of 2 weeks time for a safe termination before 20 weeks in the event of a malformation. Malformation focused ultrasonography can be done as early as 12 weeks. But it has been found that the expertise regarding malformation detection with an early scan is highly variable among radiologists and in some instances may not be helpful. Therefore an ultra sonogram at 18 weeks is preferred. In the second trimester blood levels of AEDs tend to fall due to hemodilution and other metabolic changes. Periodic monitoring of blood levels especially free blood levels in first, second and third trimesters can guide the physicians in adjusting the dosage of AEDs. Anticipatory increase of AED dose may be done with lamotrigene and oxcarbazepine as their blood levels fall significantly and in most instances lead to break through seizures. With other AEDs, dose is usually increased only if break through seizures occur as most of the WWE go through their second and third trimesters uneventfully even with pre pregnant doses. We advise all WWE to take two doses of vitamin K 10mg IM at 34 and 36 weeks of pregnancy respectively as vitamin K tablets are not available in India. This is to prevent hemorrhagic disease of the newborn. Mode of delivery is generally dictated by the obstetric needs. Routine doses of AEDs must be administered to the lady in the labor room also. If she has an increased propensity to develop seizures an elective caesarean section may be performed.

Fig. 2 : Algorithm for antenatal screening for congenital malformations

Post partum Management


The necessity of contraception and birth spacing in WWE cannot be over emphasized. Oral contraceptives are generally avoided in those taking enzyme inducing AEDs for fear of failure. But if the couple prefers oral contraceptive pills, high estrogen pills may be prescribed, i.e. pills containing 50g of estrogen. Medroxy Progesterone Acetate depot injection once

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every 3 months is another alternative. In an Indian setting, intra uterine contraceptive devices are generally preferred. Child rearing is a physically and emotionally demanding task as far as WWE are concerned. Hence they have to be prepared for this. It is generally seen that WWE either refrain from or are not given an opportunity to look after their infants due to multiple reasons. Upbringing of these children by others may interfere with their development. Therefore, maternal involvement in child rearing has to be fostered. WWE often skip medications or refrain from breast feeding for fear of AEDs finding way into breast milk. But only traces of AEDs are found to pass into breast milk. This exposure is not demonstrated to produce any significant adverse effects in children. According to a recent prospective study no significant difference has been found between children of WWE exposed to AEDs via breast milk and those with no such exposure regarding IQ at 3 years of age.24 There are only anecdotal reports of adverse effects of AEDs in breast fed babies. Moreover, the benefits of breast feeding far outweigh the adverse effects and needs to be fostered. It is recommended that mothers first nurse their babies and then take medicines so that blood levels will not be very high during breast feeding. Sleep deprivation for nursing the child at night may lead to break through seizures especially in those with Juvenile Myoclonic Epilepsy.25 In such cases family members should be adequately counseled and compliance ensured. Mothers can use expressed breast milk during night. Good compliance to AEDs and compensatory sleep during daytime needs emphasis in them. WWE are advised to nurse their babies in such a way that in the event of a seizure she may not drop the baby or fall over and suffocate it.

pregnancy in women with epilepsy. Epilepsia 2012;53:e8588. 9. Thomas SV, Sindhu K, Ajaykumar B, Sulekha Devi PB, Sujamol J. Maternal and obstetric outcome of women with epilepsy. Seizure 2009;18:1636. 10. Borthen I, Eide MG, Daltveit AK, Gilhus NE. Delivery outcome of women with epilepsy: a population-based cohort study. BJOG 2010;117:153743. 11. Veiby G, Daltveit AK, Engelsen BA, Gilhus NE. Pregnancy, delivery, and outcome for the child in maternal epilepsy. Epilepsia 2009;50:21309. 12. Dansky LV, Rosenblatt DS, Andermann E. Mechanisms of teratogenesis: folic acid and antiepileptic therapy. Neurology 1992;42(4 Suppl5):3242. 13. Wells PG, McCallum GP, Chen CS, Henderson JT, Lee CJJ, Perstin J, et al. Oxidative stress in developmental origins of disease: teratogenesis, neurodevelopmental deficits, and cancer. Toxicol Sci 2009;108:418. 14. Deepa D, Jayakumari N, Thomas SV. Oxidative stress is increased in women with epilepsy: Is it a potential mechanism of anti-epileptic drug-induced teratogenesis? Ann Indian Acad Neurol 2012;15:281-6. 15. Holmes LB, Wyszynski DF, Lieberman E. The AED (antiepileptic drug) pregnancy registry: a 6-year experience. Arch Neurol 2004;61:6738. 16. Wyszynski DF, Nambisan M, Surve T, Alsdorf RM, Smith CR, Holmes LB. Increased rate of major malformations in offspring exposed to valproate during pregnancy. Neurology 2005;64:9615. 17. Morrow J, Russell A, Guthrie E, Parsons L, Robertson I, Waddell R, et al. Malformation risks of antiepileptic drugs in pregnancy: a prospective study from the UK Epilepsy and Pregnancy Register. J Neurol Neurosurg. Psychiatr 2006;77:1938. 18. Thomas SV, Ajaykumar B, Sindhu K, Nair MKC, George B, Sarma PS. Motor and mental development of infants exposed to antiepileptic drugs in utero. Epilepsy Behav 2008;13:22936. 19. Thomas SV, Sukumaran S, Lukose N, George A, Sarma PS. Intellectual and language functions in children of mothers with epilepsy. Epilepsia 2007;48:223440. 20. Meador KJ, Baker GA, Browning N, Cohen MJ, Bromley RL, Clayton-Smith J, et al. Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurol 2013;12:244-52. 21. Oyen N, Vollset SE, Eide MG, Bjerkedal T, Skjaerven R. Maternal epilepsy and offsprings adult intelligence: a population-based study from Norway. Epilepsia 2007;48:1731 8. 22. Harden CL, Hopp J, Ting TY, Pennell PB, French JA, Hauser WA, et al. Practice parameter update: management issues for women with epilepsy--focus on pregnancy (an evidence-based review): obstetrical complications and change in seizure frequency: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology 2009;73:126 32. 23. Harden CL, Meador KJ, Pennell PB, Hauser WA, Gronseth GS, French JA, et al. Practice parameter update: management issues for women with epilepsy--focus on pregnancy (an evidencebased review): teratogenesis and perinatal outcomes: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology 2009;73:13341. 24. Meador KJ, Baker GA, Browning N, Clayton-Smith J, CombsCantrell DT, Cohen M, et al. Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs. N Engl J Med 2009;360:1597 605. 25. Saramma PP, Thomas SV. Child rearing knowledge and practice scales for women with epilepsy. Ann Indian Acad Neurol 2010;13:171 9.

Conclusion
Management of epilepsy in women of child bearing age involves close interaction between the clinician, patient and family members. Most women can expect safe pregnancy and healthy babies. Careful planning of pregnancy, folate administration, optimization of AED therapy, close monitoring and screening for fetal malformations are very important. Neurologist, obstetrician and a neonatologist need to work as a team to offer the best medical care for women with epilepsy and their children.

Reference
1. Holmes LB, Baldwin EJ, Smith CR, Habecker E, Glassman L, Wong SL, et al. Increased frequency of isolated cleft palate in infants exposed to lamotrigine during pregnancy. Neurology 2008;70(22 Pt 2):21528. 2. Tomson T, Battino D, Bonizzoni E, Craig J, Lindhout D, Sabers A, et al. Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry. Lancet Neurol 2011;10:60917. Thomas SV, Nair A. Confronting the stigma of epilepsy. Ann Indian Acad Neurol 2011;14:15863. Gopinath M, Sarma PS, Thomas SV. Gender-specific psychosocial outcome for women with epilepsy. Epilepsy Behav 2011;20:447.

3. 4.

5. Herzog AG. Disorders of reproduction in patients with epilepsy: primary neurological mechanisms. Seizure 2008;17:10110. 6. Sukumaran SC, Sarma PS, Thomas SV. Polytherapy increases the risk of infertility in women with epilepsy. Neurology 2010;75:13515. 7. Seizure control and treatment in pregnancy: observations from the EURAP epilepsy pregnancy registry. Neurology 2006;66:35460.

8. Thomas SV, Syam U, Devi JS. Predictors of seizures during

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Refractory Epilepsy
Tapas Kumar Banerjee*, Shyamal Kumar Das** Abstract
Refractory Epilepsy (R.E.) is a condition where all antiepileptic drugs (AEDs) fail to provide adequate seizure control. To diagnose R.E., false cases of refractoriness need to be carefully excluded. There are several predictors of refractoriness. The treatment options in R.E. are resective surgery, ketogenic diet and vagal nerve stimulation. The roles of newer AEDs are also promising. The future therapeutic possibilities include deep brain stimulation, AED containing polymers, stem cells and gene therapy.

p until the late 60s it was widely believed that a vast majority of the people of epilepsy had a refractory disorder. But with the advent of a wide range of anti-epileptic drugs (AED) particularly over the past two decades and development of technology , considerable number of previously untreatable cases of epilepsy can now be successfully brought under control as well as underlying cause can be ascertained..1 In 2000, Kwan and Brodie in their landmark report stated that with single AED around 47% of the newly-diagnosed epilepsy can be made seizure-free. A further 13% of patients can be controlled on their 2nd AED. With 3rd AED or with combination of AEDs a further 4% undergo remission.2 But the remaining 30-35% of the epileptic disorders cannot be made completely seizure-free with medical treatment. The International League Against Epilepsy (ILAE) task force recently defined Drug-resistant Epilepsy as failure of adequate trials of two tolerated, appropriately chosen and used AED schedules as monotherapy or in combination to achieve sustained seizure freedom.3 This is a slightly different condition from Refractory (or Intractable) Epilepsy (R.E.). R.E. is defined as a condition of epilepsy where all drug choices used singly or in combination have failed to provide adequate control of seizure.4 Symptomatic epilepsy particularly complex partial or secondarily generalized tonic-clonic and epilepsy in persons with neurological deficit have the propensity to be R.E. In neonates and children, a wide range of epilepsy syndromes that constitute Epileptic Encephalopathy5 manifest as R.E. These epilepsy syndromes are listed in Table 1. Predictors of R.E.: Clinical determinants for predicting future refractoriness are (A) Epilepsy syndromes, (B) response to initial 2 AEDs, (C) seizure frequency at epilepsy onset, (D) age, (E) inter-ictal spike discharges and (F) co-morbid depressive illness. Table 1 : Refractory Epilepsy in infants and children
Ohtahara syndrome Early myoclonic encephalopathy West syndrome Dravets syndrome Lennox-Gastaut syndrome Epilepsy with continuous spike-wave in slow wave sleep Landau-Kleffner syndrome Myoclonic status in non-progressive encephalopathy Hypothalamic gelastic epilepsy

Introduction

A. Epilepsy syndromes as listed in Table 1 are the typical examples of R.E.6 Among the focal epilepsy cases, R.E. is common in hippocampal sclerosis, cortical dysplasia and cortical hemorrhage.7 The site of epileptogenic zone also is a predictive factor. Temporal lobe is the most epileptogenic area as kindling can easily be elicited by stimulation of amygdala. B . Absence of seizure freedom when 2 appropriate AEDs proved inefficient is a crucial predictor of refractoriness.2 Chance for seizure freedom decreases proportionately as the number of ineffective AEDs increases. Failure after 6 AEDs indicates absolute R.E. (0% seizure freedom).4 C. High seizure frequency (> 1 seizure per month) occurring soon after the diagnosis of epilepsy correlates with refractoriness both in the short term (2-4 years) and in the long term (30-35 years).8 D. Younger age at onset of epilepsy is a predictive factor for R.E. 9 Epileptic seizures occurring in immature brain results in non-pruning of neurons and contribute to the existence of a high number of gap junction communications. This ultimately leads to abnormal neural connectivity in brain, termed as hyper-connected cortex,10 the precursor of R.E. E. There is some association of R.E. with the number of spike discharges as well as with the presence of multi-focal spikes in inter-ictal EEG. F. Co-existent depression is a predictor of R.E. Neurobiological processes that underpin depression may interact with those producing seizure and increase the likelihood of development R.E.11 What is the necessity for early identification of R.E .? Uncontrolled seizures have devastating impact on social functioning and may even lead to psychiatric complications. There is also a heightened risk of mortality due to seizurerelated accidents or due to SUDEP (sudden unexpected death associated with epilepsy).12 Recurrent seizures have long-term adverse effects on cognition and behavior. Early intervention may prevent or minimize the risks of all these complications. Diagnosis of R.E.: At the outset it is very important to exclude cases of pseudo- refractory epilepsy that include the various non-epileptic paroxysmal events, as listed in Table 2. Factors that lower seizure threshold (Table 3) also may present as false R.E. Last but not the least, non-compliance of AED is an important factor for pseudo-refractoriness. In fact, studies have shown that around 30-50% of patients with epilepsy do not comply with their prescribed AED therapy.13 Once the cases with false refractoriness have been excluded, and the patients have more than 1 epileptic attack per month for at least a year in spite of appropriate AEDs in adequate dose, the diagnosis of R.E. is

*Head, Dept of Neurology, National Neuroscience Centre. Kolkata, West Bengal; **Prof and Head, Dept. of Neurology, Burdwan Medical College, Burdwan, West Bengal

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Table 2 : Causes of non-epileptic paroxysmal events


Shuddering attacks in infancy Breath-holding spells in infancy Benign paroxysmal vertigo in childhood Tics and habit spasms Parasomnias Paroxysmal choreo-athetosis Migraine Syncope and cardiac arrhythmias Hyperventilation syndrome Panic attacks Transient global amnesia Transient ischemic attack Acute confusional state Psychogenic seizures

Table 4 : Special investigations to localize epileptogenic focus


Epilepsy-protocol MR scan ( 1.5Tesla) Inter-ictal FDG-PET for hypo-metabolic focus -Ictal SPECT and SISCOM (subtraction ictal SPECT co-registered to MRI) to detect hyper-metabolic focus Magnetoenceophalography - could be useful in extra-temporal epilepsy At times, intracranial EEG is needed

focus for temporal/ extra-temporal lobectomy or lesionectomy. Computer-image guided navigational surgery is the latest surgical technique introduced to excise the focus with precision. Apart from resective surgery of epileptogenic lesions, there are other surgical approaches used in R.E. These are Hemispherectomy: for temporo-parietal resection in Kozhevnikov- Rasmussen syndrome Corpus Callosotomy: where anterior 2/3 rd of corpus callosum is excised to minimize risk of fall and injury, as in intractable drop attacks from atonic, tonic-clonic or tonic seizures. Multiple Subpial Transections: a series of shallow cuts 1/4th inch deep around epileptic focus, when the focus could not be completely resected due to the presence of important cortical function.

Table 3 : Factors lowering seizure threshold


Sleep deprivation Alcohol or barbiturate withdrawal Dehydration Drug interaction-quinolone and carbapenem antibiotics, antihistaminics, phenothiazines, tricyclic antidepressants, etc. Systemic infections Malnutrition Trauma Hyperventilation TV screen malfunction, flashing lights Gastro-intestinal upset

Other treatment modalities: This includes ketogenic diet and vagal nerve stimulation, Ketogenic diet: This high fat, low carbohydrate diet reduces seizures in children with various focal or generalized R.E.. This diet is particularly effective in Doose, Dravets, tuberose sclerosis, etc. This also leads to behavioral improvement. Improvement of seizure frequency starts within 2 weeks. About 40% has at least 50% reduction in seizure frequency16 and 5% actually becomes seizure free. But 10% has side-effects like hypoproteinemia, weight loss, growth failure or renal stones. Fifty percent of subjects have been found to discontinue therapy after 1 year mainly because of unpalatable taste of the diet. Vagal nerve stimulation (VNS): VNS is an implantable device approved for those cases of R.E. who are above 12 years of age. This is useful in diverse seizure semiology -focal, generalized, tonic, atonic or infantile spasms. The device includes a chest pacemaker with electrode in left cervical vagal nerve. The possible complications include vocal cord palsy (1%), infection (1%), cough, diminished figural memory, Horners syndrome and neck pain. On the average about one-third have 50% reduction of seizures. However, seizure freedom rarely occurs.17 Role of newer AEDs. Some authors do not believe that refractoriness or intractability of epilepsy is inevitable if seizure control is not achieved within the first few years of medical treatment.18 According to them, with the introduction of new AEDs (levetiracetam, lamotrigine, topiramate, zonisamide, lacosamide, rufinamide, stiripentol, etc.) there has been improved seizure control in a substantial number of cases. They demonstrated that addition of new AED provides seizure freedom in 17% and a 50-99% seizure reduction18 in about 28%. Levetiracetam is one of the newer AED which is now widely used in the treatment of epilepsy, both in adults and in children. It is a broad spectrum AED with demonstrated significant efficacy as add-on therapy in idiopathic generalized as well as in focal onset refractory seizure, but more effective in the latter group.19,20 Rational polytherapy(combining AEDs of

established. These R.E. candidates need to be evaluated in a specialized center for further diagnostic tests, optimization of pharmacotherapy and for consideration of alternative treatments which include surgery. Surgical treatment of R.E. Once the diagnosis of R.E. is established, the possibility of Resective Surgery to cure or at least adequately control seizures should be explored. The ideal surgical candidates have (i) well-circumscribed MRI lesions, (ii) well-localized inter-ictal discharge, (iii) clinical feature indicative of focal-onset of seizure, (iv) concordance of nos. 2 and 3 findings, (v) low risk of deficit after surgical resection of focus, and (vi) absence of other potentially epileptogenic focus. Temporal lobe lesions, namely, mesial temporal sclerosis, cavernous angioma or low grade tumor have 94% chance of excellent seizure control post-operatively. On the other hand, frontal lobe lesions have post-operative 72% chance of excellent seizure control. These cases should undergo epilepsy surgery evaluation soon after the seizure fails to be controlled with 2nd appropriate AED. Although the number of post-operative seizure-free state diminishes to some extent over the years, still this case could be better managed with AEDs than those who did not undergo surgery.14 The best outcome after resective surgery is in mesial temporal sclerosis.15 Surgery is also indicated in cases of nonlesional extra temporal epilepsy, multiple lesions like multiple cavernous angioma or tubers, bilateral hippocampal atrophy, epileptogenic focus at eloquent cortex, large multi-lobar lesions and in some cases of epileptic spasms and atonic seizures. To localize accurately epileptogenic focus in these latter cases, many sophisticated invasive and non-invasive investigations are now available (Table 4). Concordance of the different diagnostic modalities helps to accurately localize the seizure

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different mechanisms of action) should be considered, because that may have synergistic effect and also a less adverse reaction. 21 For example, the combination of lamotrigine and valproate is found to be very effective for partial seizures. There are a number of newer AEDs currently under investigation, i.e., retigabine (potassium channel opener), perampanel (AMPA receptor antagonist), ganaxolone (GABA A receptor agonist), brivarecetam (SVA-2 ligand antagonist) and so on. So the future of pharmacotherapy in R.E. seems to be promising. Temporal pattern of refractoriness in epilepsy: It is believed that in most cases pharmacoresistance is constitutive and hence fully developed before the first seizure or at least before the start of AED.2 But there are now evidences to show that some patients with initially easily treatable seizures developed R.E. years later.22 Another hypothesis claims that drug resistance may remit and reappear in the course of the disease. But this latter theory is controversial since the temporary remission could be the result of the addition of new AED. Mechanism underlying refractoriness in epilepsy: Two major hypotheses exist, i.e., (A) Target hypothesis, and (B) Transporter hypothesis. According to target hypothesis, there is alteration of the receptor (which binds to the AED) at the neuronal target site, thereby reducing overall drug efficacy. On the other hand, according to transporter hypothesis there is enhancement of blood-brain barrier (BBB) efflux transport, thereby reducing the penetration of AED across BBB to reach the epileptic neurons.23 Therapeutic possibilities of the future: The future therapeutic possibilities for treatment of R.E. are immense. To suppress epileptic seizure, deep brain stimulation at anterior thalamus or at centromedial nucleus is under investigation. A cranially implanted responsive neurostimulator that detect EEG activity of seizure and then trigger delivery of electric pulse to the focus to terminate seizure is being devised. Apart from this, research is under way to create 2-3 mm microspheres containing polymers with AED in it. This micropolymer might be implanted near the cerebral epileptogenic zone.24 The advantage of this micropolymer apart from increased efficacy is that it eliminates the possibility of non-compliance and also bypasses the blood-brain barrier. Hopefully, the future device may be able to predict seizures also and at the same time automatically administer AEDs to prevent occurrence of seizure. Cell transplantation and gene therapy hold great promise but their clinical application will perhaps be in distant future.25

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Engel J Jr. A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: report of the ILAE Task Force on Classification and Terminology. Epilepsia 2001;42:796-803. Mohamed IS, Minassian BA. What intractability information is there in the type of generalized seizure? Adv Neurol 2006;97:141-7. Blume WT. Focal seizures: intractability and semiology. Adv Neurol 2006;97:17-25. Berg AT, Shinnar S, Levy SR, Testa FM, Smith-Rapaport S, Beckerman B. Early development of intractable epilepsy in children: a prospective study. Neurology 2001;56:1445-52. Ko TS, Holmes GL. EEG and clinical predictors of medically intractable childhood epilepsy. Clin Neurophysiol 1999;110:1245-51.

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10. Mikuni N, Nishiyama Km Babb TL, et al. Decreased calmodulin_ NR1 co-assembly as a mechanism for focal epilepsy in cortical dysplasia. Epilepsy Res 2007;75:192-6. 11. Hitiris N, Mohanraj R, Norrie J, Sills GJ, Brodie MJ. Predictors of pharmacoresistant epilepsy. Epilepsy Res 2007;75:192-6. 12. Walczak TS, Leppik IE, DAmelio M, Rarick J, So E, Ahman P. Incidence and risk factors of sudden unexpected death in epilepsy: a prospective cohort study. Neurology 2001;56:519. 13. Faught E, Duh MS, Weiner JR, Guerin A, Cunnington MC. Nonadherence to antiepileptic drugs and increased mortality: findings from the RANSOM Study. Neurology 2008;71:1572-8. 14. Tllez-Zenteno JF, Dhar R, Wiebe S. Long-term seizure outcomes following epilepsy surgery: a systematic review and meta-analysis. Brain 2005;128:118898. 15. Radhakrishnan K, So EL, Silbert PL, Jack CR Jr, Cascino GD, Sharbrough FW et al. . Predictors of outcome of anterior temporal lobectomy for intractable epilepsy: a multivariate study. Neurology 1998;51:46571. 16. Neal EG, Chaffe H, Schwartz RH, Lawson MS, Edwards M, Fitzsimmons G et al. The ketogenic diet for the treatment of childhood epilepsy: a randomized controlled trial. Lancet Neurology 200;7:500-6. 17. Morris GL 3rd, Mueller WM. Long term treatment with vagus nerve stimulation in patients with refractory epilepsy. The Vagus Nerve Stimulation Study Group E01-E05. Neurology 1999;53:1731-5. 18. Luciano AL, Shorvon SD. Results of treatment changes in patients with apparently drug-resistant chronic epilepsy. Ann Neurol 2007;62:375-81. 19. Mbizvo GK, Dixon P, Hutton JL, Marson AG. Levetiracetam add-on for drug-resistant focal epilepsy: an updated Cochrane Review. Cochrane Database of Systematic Reviews 2012, Issue 9, John Wiley and Sons. 20. Incelik F, Hergner MO, Altunbasak S. The efficacy and side-effects of levetiracetam on refractory epilepsy in children. J Pediatr Neurosci 2012;7:19-22. 21. Kwan P and Brodie MJ. Combination therapy in epilepsy: when and what to use. Drugs 2006;66:1817-29. 22. Berg AT, Langfitt J, Shinnar S, Vickery BG, Sperling MR, Walzack T et al. How long does it take for partial epilepsy to become intractable? Neurology 2003;60:186-90. 23. Kwan P, Brodie MJ. Potential role of drug transporters in the pathogenesis of medically intractable epilepsy. Epilepsia 2005;46:225-35. 24. Kwan P, Brodie MJ. Refractory epilepsy: mechanisms and solutions. Expert Rev Neurotherapeutics 2006;6:397-406. 25. Nilsen KE, Cock HR. Focal treatment for refractory epilepsy: hope for the future? Brain Res Rev 2004;44:141-153.

References
1. 2. 3. Stephen LJ, Brodie MJ. Selection of antiepileptic drugs in adults. Neurol Clin 2009;27:967-92. Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Eng J Med 2000;342:314-9. Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Hauser WA, et al. Definition of drug-resistant epilepsy: Consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 2010;51:1069-77. Schiller Y, Najjar Y. Quantifying response to antiepileptic drugs: effect of past treatment history. Neurology 2008;70:54-65.

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Surgery for Drug-resistant Focal Epilepsy


Malla Bhaskara Rao*
pilepsy is a common and a complex neurological disorder that affects health and quality of life. It has been estimated that there are 10 million people with epilepsy (PWE) in India. These PWE have an increased risk of seizure-related death and disability. Effective treatments are available for many types of epilepsy, but timely referrals and access to these treatments fall short. Currently, forty different types of antiepileptic drugs (AED) are available. However, all these drugs together can control seizures in only 60%70% of PWE. The remaining, 30-40% of PEW continues to have seizures in spite y of AED and constitute the drug resistant epilepsy (DRE) group.1 Now we have class 1 evidence2 that epilepsy surgery is significantly more efficacious than continued medical treatment in people with DRE.However, epilepsy surgery is highly underutilized or overly delayed in India. There are several reasons underlying the delay in the referral.National Institutions in India like SCTIMST at Trivandrum,3 AIIMS at New Delhi and NIMHANS at Bangalore and other centers have successfully established cost-effective epilepsy surgery programmes (ESP) over the past two decades. However, considering the magnitude of the patients who are likely to be benefited by epilepsy surgery, several centers which can cater to the needs of these PWE, require to be developed in India in the near future.4, 5During this brief write-up, I will summarize the current status of epilepsy surgery and outline the pre-requisites to establish ESP successfully.

cerebral blood flow, glucose metabolism, or benzodiazepine (BZD) receptors that implicate a more widespread physiologic abnormality.

Clinical Electrophysiology
Electroencephalography (EEG) is the most important test in epileptology. During the past several decades, considerable effort has been devoted to the development of several electrophysiological techniques in pre-surgical evaluation namely visual analysis of inter-ictal and ictal EEG findings obtained during routine scalp and intracranial recording; stereoEEG and magnetoencephalography (MEG) among others.

Surgical Procedures
Epilepsy surgery is the resection or functional manipulation of part of the brain with the aim of alleviating seizures, improving the cognitive function and the quality of life. The principle of epilepsy surgery is to identify and resect or disconnect a single identifiable epileptogenic focus and or lesion without risk of neurological deficit. It has been reported that the success of epilepsy surgery depends upon the accurate localization of the epileptogenic zone, which is defined as the area necessary and sufficient for initiating seizures and whose removal or disconnection is necessary for abolition of seizures.

Pre-surgical Evaluation
People with DRE have to undergo detailed presurgical evaluation to find out the surgery candidacy and the expected outcome. The standard pre-surgical evaluation includes careful analysis of history and clinical features, non-invasive tests consisting of high resolution epilepsy protocol based brain MR imaging, scalp video-EEG telemetry and neuropsychological assessment. Concordance of data obtained from these tests may be adequate to perform surgery with good results, as in the classical mesial temporal epilepsy syndrome (MTLE) with mesial temporal sclerosis (MTS) or circumscribed and discrete neocortical lesions such as dysembryoplastic tumours, low-grade astrocytomas, focal vascular abnormalities and malformations of cortical development like focal cortical dysplasia.

Surgery for Temporal Lobe Epilepsy


MTLE with MTS is most common cause of DRE and anterior temporal lobectomy along with amygdalohippocampectomy is the most common epilepsy surgery procedure.Surgery for MTLE with MTS leads to improvement in seizure control, cognitive function and quality of life.Suitable surgical candidates for ATL can be identified with standardized non-invasive protocols and the outcome will be cost effective. There are a number of surgical techniques, including the standard ATL, tailored ATL and selective amygdalohippocampectomy with different variations. However, it is preferable to perform standard ATL in the majority of cases with modifications based upon cerebral dominance, cortical vasculature and neuropsychological status. We have to take measures to optimize the seizure outcome as well as avoidance of surgical, neurological and neuropsychological deficits.

Neuroimaging
In recent years, tremendous advances in the neuroimaging have had a profound effect on the pre-surgical evaluation and surgical management of people with DRE. High resolution magnetic resonance imaging (MRI) is now capable of identifying the structural pathology underlying DRE in most patients. In clinical situations, where MRI brain is either normal, equivocal, demonstrate multiple lesions or lesion is adjacent to the eloquent cortex, then epileptogenic zone can be reliably predicted by careful correlation of clinical, EEG and functional imaging findings. Functional imaging techniques such as single-photon emission computed tomography (SPECT) or positron emission tomography (PET) may give localizing information about ictal
*

Surgery for Extra-Temporal Epilepsy


In contrast to temporal lobe surgery, extra-temporal epilepsy surgery demands complex pre-surgical evaluation and innovative surgical approaches. Outcome in extra temporal epilepsy surgery was reported to be inferior to temporal lobe surgery. However, recent data suggests that resection of discrete small epileptogenic lesions in the extra temporal regions also leads to good outcome.Frontal lobe epilepsy surgery prevails in this category. Non-lesional extra temporal epilepsy surgery usually requires extensive invasive pre-surgical evaluation, which differs from patient to patient according to the noninvasive findings. Invasive EEG with grid-, strip- and depthelectrodes, often in combination, is necessary, to delineate the epileptogenic seizure onset zone. In non-lesional extra temporal epilepsies circumscribed corticectomies are rarely successful,

Department of Neurosurgery, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore

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more often rather extensive resections are required to render a patient seizure-free. Incomplete resection can be due to poor differentiation of lesion from the normal brain or the extension of the structural abnormalities to a functional area.

needs not be destroyed or resected, except for the tissue directly along the tract of the stimulating electrodes. Stimulation can occur within seconds, enabling patients to turn the stimulator on at the beginning of a seizure.

Lesional Epilepsy Surgery


Lesionectomy for epilepsy is a surgical procedure that is directed at the structural lesion, believed to be the etiology of the seizure disorder. It has been reported that, in the case of isolated structural lesions such as dysembryoplastic tumours, low-grade astrocytomasor focal vascular abnormalities, total macroscopic and radiologic evidence of lesional excision is associated with excellent seizure-free outcome. The extent of the resection may be determined by different criteria: (1) intraoperative visualization of the tissue; (2) radiological margins determined by MRI signal abnormalities; (3) histologic margins based on intra-operative frozen section evaluation of the tissue; (4) electrocorticographic margins based on intra-operative ECoG; and (5) intra-operative MRI or ultrasound evaluation or a combination of these techniques.

Vagal Nerve Stimulation


Though the exact mechanism by which the vagal nerve stimulation controls seizure is still unknown, it was felt that continual stimulation of the vagus nerve by an implantable electrical device might result in wide-spread bilateral activation or de- activation of the brain circuits thought to be involved with epileptic seizures. The efficacy of the vagal nerve stimulation is based on two randomized control trials which reported a modest response of reduced frequency of seizures by 50% or more in 30%40% of patients. This technique is currently being proposed in select cases of non-localized drug resistant epilepsy, where resective surgery is not the option. In comparison to the corpus callosotomy,VNSis expensive, but reversible procedure.

Deep Brain Stimulation in Epilepsy


There are indications that deep brain stimulation (DBS) improves seizure control in a group of patients previously not suitable for resective surgery.Stimulation of the centro medianand the anterior nuclei of the thalamus, sub thalamic nucleus, as well as amygdalo-hippocampal complex have been performed with partial seizure control. Responsive stimulation (RNS), cortical and hippocampal stimulations are other alternatives.

Pediatric Epilepsy Surgery


In the pediatric patients, diagnosis of DRE should be made much earlier, particularly if children present with epileptic encephalopathy, infantile spasms, catastrophic onset of epilepsy, frequent and disabling seizures.Children with specific epilepsy syndromes such as: SturgeWeber syndrome, hemispheric syndromes, Rasmussens encephalitis and hypothalamic hamartoma should be referred for pre-surgical evaluation without delay and if found suitable, surgery should be offered earlier.In children presenting with drug resistant and disabling seizures without delineation of an epileptogenic zone or Lenox Gestaut syndrome, functional procedures such as corpus callosotomy can be performed especially to control the drop attacks.

Need to Establish New Epilepsy Surgery Centers


The International League against Epilepsy (ILAE) working group in surgery suggested a two-tiered structure for the surgical management of epilepsy, with a basic center providing a service to adults with more straight forward surgically remediable epilepsy and an academic reference center offering facilities for invasive recording and the treatment of children and basic scientific and clinical research.

Stereotactic Techniques
Stereotactic techniques have been used in India for both temporal lobe epilepsy as well as generalized seizures.However, since the introduction of image guidance, these techniques are being used currently for the electrode implantation of both depth and subdural electrodes, as well as to localize lesions and facilitate anatomic resections. Stereotactic laser ablation of the hippocampus under MR thermal imaging is an emerging technique.

Basic Epilepsy Surgery Centers


Basic epilepsy surgery units can be developed in all the medical college hospitals in India which cater to a sizable number of people with epilepsy and where the infrastructure and capability to identify people with DRE exists. Among the people with DRE, in order to identify candidates with surgically remediable epilepsy syndromes, the essential requirements are video EEG telemetry and MRI. Since more and more surgically remediable epilepsy syndromes that do not need expensive and invasive pre-surgical work have been identified, these patients can be operated in these new epilepsy centers. These new centers can cater to people with DRE with MTLE and MTS and other circumscribed structural lesions. They should be able to identify ideal surgical candidates for anterior temporal lobectomy where pre-surgical evaluation will be simple through a standardized non-invasive protocol and the surgical outcome will be good. The difficult cases can be referred to the established centers. It is essential to know which patients may benefit from surgery with the limited facilities and which patients will need further studies. This step-wise approach by reserving more difficult to treat patients to a later date as experience develops, or by referring them to a better-equipped center, will help the basic

Radiosurgery
Radiosurgery (RS) for management of DRE has been introduced in the past two decades. Radiosurgery is being proposed in cases of refractory seizure wherein the epileptogenic focus can be well defined radiologically and is smaller in volume. The classical conditions which are being considered are mesial temporal sclerosis, hypothalamic hamartoma and arteriovenous malformations. The outcome of RS has been reported to be at par with surgery. However, the long term neurobiological effects of RS are yet to be identified.

Neurostimulation
Electrical stimulation to treat seizures in patients who are not suitable for resective surgery is a novel idea. Electrical stimulation is reversible. If it does not work, it can be discontinued and the electrodes can be removed. Neuronal tissue

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surgery units to establish very well in India. These units also need to work with and educate the local public and professionals, if their epilepsy surgery programmes were to have a lasting impact.

Referral Centres
In contrast to the basic surgical units, the referral units should have full-fledged facilities for the evaluation and management of people with DRE. In addition to video EEG telemetry and MRI, these centres can have functional imaging such as fMRI, PET and SPECT studies as well as capability for invasive evaluation. These units should be able to perform temporal as well as extra-temporal, multi-lobar and hemispheric resections and functional procedures like corpus callosotomy, multiple subpial transections, neuro-stimulation and radiosurgery.

basic epilepsy surgery units as well as referral centers, a sizable number of people with drug resistant focal epilepsy can now undergo pre-surgical evaluation and surgical management. Physicians could play a major role in reducing the population of people disabled by epilepsy in India by proper identification and timely referral to a comprehensive epilepsy care programme.

References
1. 2. Engel J Jr. Current concepts: Surgery for seizures. NEngl J Med 1996;334:64752. Wiebe S, Blume WT, Girvin JP, et al. Effectivenessand Efficiency of Surgery for Temporal LobeEpilepsy Study Group. A randomized, controlledtrial of surgery for temporal-lobe epilepsy. N Engl JMed 2001;345:31118. Rao MB, Radhakrishnan K. Is epilepsy surgerypossible in countries with limited resources ? Epilepsia 2000;41:S31S34. Cherian PJ, Radhakrishnan K. Selection of idealcandidates for epilepsy surgery in developingcountries. Neurol India [serial online] 2002;50:1116. Chandra PS, Tripathi M. Epilepsy surgery:Recommendations for India. Ann Indian AcadNeurol 2010;13:8793.

Conclusions
In India, national institutions have successfully established comprehensive epilepsy care programmes and proved that surgery for epilepsy is not only feasible, but can be done in a cost effective way. With the establishment of a number of new

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Status Epilepticus
Ramshekar Menon*, Ashalatha Radhakrishnan**, Kurupath Radhakrishnan*** Abstract
Status epilepticus (SE) is a neurological emergency resulting from prolonged clinical or electroencephalographic seizure activity. Refractory SE refers to the persistence of seizure activity despite the initiation of first- and secondline anticonvulsant therapy. Sinister outcomes are often attributed to the etiology of SE. Despite randomized multicentre trials of established and promising therapeutic options, the management and prognostication in SE are fraught with challenges. Neither the duration of SE nor time-delay to initiation of therapy should discourage the aggressive approach to the management of SE. Neurointensive care of patients with SE consists of an algorithmic approach tailored to the etiology and systemic complications that arise as a consequence. This approach is also driven by the persistence of electrographic seizure activity, which is best followed with continuous EEG monitoring. The extent of patient support has to be augmentative to the degree of encephalopathy/coma and impairment of vital functions. Potential interactions of anticonvulsant drugs with other co-medications need to be considered during the course of treatment. This review discusses the existing literature on the epidemiological aspects, clinical approach, treatment and prognostication of SE.

tatus epilepticus (SE) in simple terms is used to describe a series of uninterrupted seizures which result in an impairment of normal brain function, which if not treated as a medical emergency results in high morbidity and mortality.1-3 SE is one of the most common medical emergencies, with an overall annual incidence of 10-41 per 100,000.1-6 The incidence of SE has shown a decreasing trend in both developing and developed countries over the years. Age-specific incidence rates of SE show a U-shaped curve with a bimodal distribution peaking in very young and the elderly.7

Introduction

Convulsive SE
Convulsive SE generally refers to the generalized tonicclonic SE which is the most dangerous type of SE. Generalized convulsive SE classically has been defined as recurrent generalized convulsions without full and complete recovery of consciousness between seizures or as a single prolonged convulsion without the characteristic evolution of a single discrete seizure.11 The definition of duration of convulsive SE has been a subject of controversy over the years. Most authors have suggested a seizure activity lasting 30 minutes for defining SE. However, for practical purposes, a duration of 5 minutes as proposed by Lowenstein et al.11 may be better adopted for adults and children aged above 5 years.

Definition and Classification


The International League against Epilepsy (ILAE) has defined SE as a seizure that persists for a sufficient length of time, or repeated frequently enough that recovery between attacks does not occur.8 However, the definitions and classifications are still evolving and an ILAE task force is currently developing a new draft on a definition and classification of SE.9 For the purpose of this review, we classify SE based on the presence or absence of motor manifestation into convulsive and non-convulsive (Figure 1).10 A third category is often recognized comprising the boundary syndromes including epileptic encephalopathies and acute forms of coma with status-like electroencephalography (EEG) patterns.

Non-convulsive SE
Non-convulsive SE is a state of electromechanical dissociation where the epileptiform discharges evident on the EEG are not accompanied by clinical manifestations other than obtundation, hardly discernible motor manifestations or coma. 12 Nonconvulsive SE has long been subdivided into 2 categories: absence status and complex partial status. Patients with nonconvulsive SE need to be managed as convulsive SE, using EEG as a guide rather than clinical observations as the determinant of response to treatment.

Phases of SE
The physiological changes in SE evolve in two phases: the first is the compensated stage during which cerebral damage is prevented by the physiologic mechanisms which compensate the increased metabolic demands because of seizures. After 30 to 60 minutes of continuous seizures, the patient moves into the second or the decompensated stage when these compensatory mechanisms are overwhelmed and there is potential for neuronal injury with persistence of seizures.13 The cerebral damage is caused by systemic and metabolic disturbances (hypoxia, hypoglycemia, acidosis and raised intracranial pressure) and also by the direct excitotoxic effect of seizure discharges, which result in calcium inux into neurons and a cascade of events resulting in necrosis and

Fig. 1 : Classification of status epilepticus


*

Assistant Professor, **Associate Professor, ***Senior Professor, Department of Neurology, R Madhavan Nayar Center for Comprehensive Epilepsy Care, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum 695 011.

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of the membrane potential.18,19 But once the SE becomes established, only certain drugs remain effective especially those inhibiting the glutamatergic transmission.20 Those acting via potentiating GABAergic transmission have 20 times reduction in potency after 30 minutes of seizure activity.21 Basic pathophysiologic mechanisms which operate during SE are due to changes at the molecular level mainly involving protein phosphorylation. The initial changes occur at the level of the neurotransmitter receptors and neuronal plasticity which Fig. 2 : Etiologies of status epilepticus. Abbreviations: CVT- Cortical vein thrombosis; alter the protein expression. There is also a SOL - Space occupying lesion; CNS - Central nervous system; MELAS - Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes; AED - Antiepileptic drugs; receptor trafficking taking place in the form FIRES - Febrile infection-related epilepsy syndrome of externalization or internalization of the receptors. During SE, there is decrease in the GABA receptor apoptosis. Understanding this concept is pertinent to the timing subunits and increase in the NMDA glutamate receptor of therapeutic interventions in SE. subunits on the membrane surface.22 In addition, recent data have implicated other mechanisms operating at the receptor Duration level like acute down-regulation of adenosine A1activity, which The duration of seizures which qualifies for SE has long been contributes to ovrexcitation.23 Changes in gene expression come a subject of debate. New evidences are now coming up based on to play later and are partly annulled by the inhibition of protein animal research as well as anecdotal evidence from humans. Data synthesis. Maladaptive changes occur in protein expression from animal studies indicated that repetitive seizures become which may contribute to the self-sustaining nature of the self-sustaining and pharmacoresistant and can produce neuronal events There is depletion in hippocampus of the predominantly 14 injury within a period of 15 to 30 minutes. inhibitory peptides dynorphin, galanin, somatostatin, and neuropeptide Y, whereas the expression of the proconvulsant Stages tachykinins, substance P and neurokinin B is increased. SeizureAs there is time-dependent development of pharmacoresistance induced neuronal death continues to occur even when motor and ongoing neuronal injury in SE, it is prudent not to delay the manifestations are absent due to excitotoxic mechanisms which treatment till the status becomes established. The concept of produce cell death.22,23 SE evolving in three sequential stages is useful in deciding the management strategies.15 Etiology Impending SE: This is defined as continuous or intermittent seizures lasting more than 5 minutes without full recovery of consciousness between the seizures. In the study by Theodore et al.,16 it was noted that the duration of a single seizure never exceeded 2 minutes and a cut-off of 5 minutes is 18 standard deviations from the mean duration. In the Richmond study, 40% of seizures lasting between 10 to 29 minutes were shown to stop spontaneously without treatment, thereby indicating that all seizures exceeding the 5 minute mark may not proceed to established SE, but still pose a high risk for it.17 According to etiology, SE can be classified into: 1) Acute symptomatic: SE related to an acute medical or neurological illness; 2) Remote symptomatic: SE owing to conditions resulting in a static encephalopathy or an antecedent insult such as stroke; 3) Cryptogenic: SE presumed to be symptomatic, but the cause is unclear; and 4) On the background of an established epilepsy. The etiologies causing SE is distinctly different in developing and developed countries, although in both scenarios acute symptomatic etiology ranks as the major cause of SE. Cerebrovascular disease is the predominant etiology in developed countries, whereas in developing countries CNS infections accounts for the majority, varying between 20-67% in various studies.24-31 A systematic review by Neligan and Shorovon showed that the most common underlying causes were cerebrovascular disease and low antiepileptic drugs (AED) levels. A relatively good outcome was noted when the etiology is low AED levels, metabolic conditions and alcohol-related SE, whereas a worse prognosis was seen when the etiology was acute symptomatic with cerebrovascular disease or CNS infections especially in the setting of cerebral anoxia.6 The common etiologies are enlisted in Figure 2. In a prospective study from India by Murthy et al31 the etiology was acute symptomatic in 54%, remote symptomatic in 7%, and cryptogenic in 19%. In 20% of patients, it was due to antiepileptic medication non-compliance. Of the acute symptomatic SE, central nervous system infections (neurocysticercosis, encephalitis or menigoencephalitis) were the risk factor in 52% patients.31

Established SE: This is defined as clinical or electrographic seizures lasting more than 30 minutes without full recovery of consciousness between the episodes. Animal data has proven that by 30 minutes, the seizures become self-sustaining; produce distinct seizure-induced neuronal damage and become more pharmacoresistant.18 Subtle SE: When a generalized convulsive SE is prolonged or after treatment in an active manner, both the motor as well as electrographic activity becomes subtle although there is likely to be continuing neuronal damage warranting an active ongoing treatment.19

Pathophysiology
In experimental settings, recurrent seizures exhibit the tendency to become self-sustaining even after the removal of the epileptogenic stimulus in the mature brain. The available data leads us to assume that similar mechanisms operate in human brain. The initial phases of SE can be easily terminated by drugs which augment inhibition or depress excitation

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Table 1 : Antiepileptic drugs used in the treatment of status epilepticus and their doses
Antiepileptic drug First Line (IV) Lorazepam Diazepam Midazolam Second Line(IV) Phenytoin Dose 0.1mg/kg bolus @ 2mg/min 0.2mg/kg bolus @ 4mg/min 0.05-0.2mg/kg @ 2mg/min 15-20mg/kg @ 50mg/min; Maintenance= 4-7mg/kg/day (IV/ PO) 15-20mg/kg PE @ 75-150mg/min Target Phenytoin level= 15-20 g/ ml 20-30 mg/kg bolus over 15 minutes, followed by maintenance dosing 1500 mg BID (IV/PO) 15-30 mg/kg bolus @ up to 6 mg/ kg/min, followed by maintenance dosing 500 mg TID(IV/PO) Target Valproate Level= 50-100 g/ml 20 mg/kg bolus @ 75 mg/min, followed by initial maintenance dosing 60 mg TID (IV/PO) Target Phenobarbitone Level= 20-40 mcg/mL 200mg @50mg/min; 200mg BID (IV/PO) Loading: 0.1-0.2 mg/kg (max, 10 mg at a time) Repeat bolus - If clinical seizures persist 5 min after initial bolus, then administer additional bolus of 0.2 mg/ kg bolus & continue infusion. Repeat bolus every 5 min till total midazolam bolus dose reaches 2 mg/Kg Maintenance cIV dose: 0.05-0.4 mg/kg/h Maximum cIV dose: increase infusion rate (with each bolus)of midazolam by 0.05 to 0.1 mg/kg/ hr to a maximum infusion rate of upto 3 mg/kg/hr). Loading: 3 to 5 mg/kg at 0.2-0.4 mg/kg/min Maintenance cIV dose: 3.0 -5.0 mg/kg/h Maximum cIV dose: 5.0 mg/kg/h Loading: 1-2 mg/kg at 10 mg/min Maintenance cIV dose: 2-10 mg/ kg/h Maximum cIV dose: 15 mg/kg/h 10 mg/kg NG loading dose followed by 5 mg/kg NG divided b.i.d. Dose range: 300 mg -1,600 mg.

Fosphenytoin

Third Line (IV) Levetiracetam

Sodium Valproate

Phenobarbitone (ventilator on stand-by)

Lacosamide Fourth Line (cIV) Midazolam (optional third line treatment if ventilator on stanby)

Fig. 3 : Algorithm for management of status epilepticus [Refer to Table 1 for drug dosing]. Abbreviations: Min - time in minutes; IV- Intravenous; PHT- Phenytoin; fosPHT - Fosphenytoin; BPBlood pressure; EEG - Electroencephalography; AED - Antiepileptic drug; BS - Burst suppression on EEG; cIV- Continuous intravenous infusion therapy

Treatment
The principles of management of recurrent seizures are to identify and correct reversible causes, maintenance of cerebral and systemic homeostasis and prompt termination of SE.

Thiopental sodium

Prehospital Management
The studies which have looked into the prehospital management of SE have shown that rectal diazepam (15-20 mg as rectal gel) to be useful and safe in both adults and children. Other drugs which have been tried are intravenous lorazepam (2 mg) and diazepam (5 mg) which have a relatively good safety profile. Although these drugs are preferred intravenously if possible, intramuscular route is also found to be effective in the prehospital setting.32 However, these should be administered only by trained paramedical personnel. The other alternatives which are being used recently are buccal or nasal midazolam.

Propofol

Topiramate (PO)

IV- Intravenous route of administration; cIV- Continuous intravenous infusion; BID- twice daily; TID- thrice daily; PE Phenytoin equivalent dose (1.5 times of phenytoin dose); PO- Peroral route; NG- Nasogastric route of administration

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General Emergency Measures


The maintenance of airway, breathing and circulation is the priority in patients presenting with SE. The reversible factors which should be kept in mind that include hypoglycemia, hyponatremia, hypocalcemia, hypomagnesemia, acidosis, hyperthermia and hypoxia. If alcoholism is suspected, patient should be given a bolus dose of 100 mg thiamine followed by dextrose infusion. Hypoxia may not be clinically manifest and oxygen supplementation is recommended in all patients in SE. Emergency investigations should include the following: blood gases, glucose, renal and hepatic functions, calcium, magnesium, full blood count, clotting screen, and AED concentrations. Serum should be stored for toxicology or virology or other future analyses. An electrocardiogram should be performed.

one randomized trial and was found to be equally effective in adults.43 Therefore, in the absence of clear rational evidence so far, an experienced physician can choose pragmatically from one among them as the clinical situation warrants. They have to be continued in the oral form once the seizures are controlled.

Refractory SE
There is no single well-accepted definition for refractory SE. For practical purposes, when adequate doses of two intravenous anticonvulsants fail to terminate seizures, the status is said to be refractory. At this stage general anesthetic medications are used for the control of seizures after intubating the patient.33 With the use of these agents, majority of SE will get controlled, and hence the failure of therapy is usually attributable to dose-limiting side effects or due to an inadequate target dose. Withdrawal seizures while tapering the drugs are reported in 0.3% to 9% cases.33 The various drugs used in refractory SE are midazolam, thiopental sodium/pentobarbital and propofol.33,44 Of these, there is a trend towards more preference for midazolam in that the control of seizures, lesser rate of withdrawal seizures and fewer side effects are exhibited by this drug as compared to the other two.44 Propofol is associated with potentially fatal propofol infusion syndrome produced by depression of cellular and mitochondrial functions and is commonly seen in children and patients co-medicated with catecholamines and steroids. Thiopentone anesthesia was more commonly associated with death, which may be a reflection of the severity of the status. The end point of anesthetic treatment in SE is to achieve burstsuppression pattern in the EEG.

Antiepileptic Drug Therapy in SE


All treatment protocols in SE are based on a staged approach (33,34). The AEDs used in SE can be broadly divided into first and second line drugs. The detailed protocol of therapy and the dosages are provided in Figure 3 and Table 1. First-line drugs Randomized controlled trials comparing the efficacy of firstline medications in SE are scarce and hence the protocols for management are heterogeneous. In early SE, the drug of choice is intravenous benzodiazepines.33 Administration of intravenous benzodiazepines, lorazepam or diazepam has shown similar benefits in studies although the safety profile may be slightly in favor of the former. Intravenous midazolam is also being increasingly used, but has not been studied in any double-blind randomized trial.35 Pertinent to the first-line management would be the issue of respiratory or hemodynamic compromise that may be incurred during bolus dosing with benzodiazepines or phenytoin, especially in children and the elderly. Recent studies including an open labelled randomized study from India have emphasized equivalence of efficacy and safety of levetiracetam in comparison to first line AED like lorazepam.36,37 Though cost of therapy is an issue, availability as an intravenous preparation, favourable pharmacokinetic profile and longer duration of action of levetiracetam could make it an acceptable alternative as a first line agent during a cluster of seizures or SE in a hemodynamically unstable patient. Second-line drugs Once the SE is established, intravenous AEDs need to be administered. The agents available are phenytoin, valproate and levetiracetam.33 Intravenous fosphenytoin or phenytoin is generally preferred world-over as first choice if the seizures are not controlled with benzodiazepines. Fosphenytoin is preferred over phenytoin due to the favorable side effect profile especially lack of thrombophlebitis. In a comparative trial of phenytoin, valproate and levetiracetam, phenytoin was not statistically different in efficacy from the other two and levetiracetam was found to be less efficient than valproate to control SE.38 The other parenteral AEDs available recently is lacosamide, but data on its effectiveness and its comparative efficacy with other drugs are not available presently.39,40 There are no head to head comparative prospective trials between them. A few randomized studies from India with either one or two of them displayed almost similar efficacy especially between phenytoin and valproic acid,41,42 although there are no studies comparing levetiracetam or lacosamide with these agents from India. Topiramate orally was compared with phenytoin in

Super-refractory SE
Super-refractory SE is a relatively newer terminology used to define SE that continues for 24 hours or more after the initiation of anesthesia, including those cases in which the SE recurs on the reduction or withdrawal of anesthesia.45 Ketamine infusion was studied in a small group of patients with super-refractory SE and 82% achieved satisfactory control. Inhalational anesthetics, isoflurane and desflurane were also found to be useful for initial control in small case series.45 Intravenous magnesium has excellent efficacy in the treatment of seizures due to eclampsia and in congenital or acquired hypomagnesemia. Serum magnesium level should be done in all patients with refractory SE. Pyridoxine is effective in SE related to pyridoxine deficiency. Immunosuppressive regimens like steroids, intravenous immunoglobulin, and plasma exchange may are effective as many of the refractory seizures have occult immunologic causes. Ketogenic diet has effect in SE related to epileptic encephalopathies. Hypothermia of 32 to 35C, preferably delivered by endovascular cooling is an effective measure and affords neuroprotection as well, but one should be aware of the various systemic complications.45 Neurosurgery has been used in many centers for refractory SE and is mainly targeted against the etiology of the seizures. Resection of cortical dysplasia is the most frequently performed surgery. Magnetic and electrical stimulation therapies like transcranial magnetic stimulation, vagus nerve stimulation, deep brain stimulation and electroconvulsive therapy are experimental forms of treatment used in SE.45

Outcome
Mortality from SE in various studies is up to 20%.1,5,33 Major determinant of the outcome in SE is the underlying etiology and

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is not related to the type of medications used or duration of SE.31,44 In one study which specifically looked into the duration elapsed before instituting correct treatment in SE, a duration of less than 10 hours was associated with a better overall outcome, but this was not significant once etiology, presentation in a comatose state and type of SE were accounted for.46 In a study on convulsive SE from India by Murthy et al.,31 the overall mortality was 10.5%, with lack of response to first-line treatment being a predictor of mortality (p < 0.001). Also, longer duration of seizures was associated with increased morbidity (p=0.001).31 These facts reflect on the importance of emergent treatment of SE by medical/ para-medical staff at the primary health care contact point. Study of SE in 84 patients from our Institute over a period of 10 years showed the distribution of types of SE as convulsive SE in 90.7%, non-convulsive SE in 6.5%, and myocloinc SE in 2.8%. Majority (60%) events were remote symptomatic. Mean delay between onset of SE and initiation of treatment was 12.8 hours and only in 11% events, appropriate treatment was started within 1 hour of onset of SE. In 79% of events, SE could be aborted with use of first- and second-line drugs. Case fatality rate was 11%, 22% developed neurological sequelae and 67% returned to baseline. Acute symptomatic SE, older age, sensorium at the time of admission and delayed hospitalization were predictors of poor outcome.

status epilepticus of different causes: A systematic review. Arch Neurol 2010;67:931-40. 7. Chin RF, Neville BG, Peckham C, Bedford H, Wade A, Scott RC. Incidence, cause, and short-term outcome of convulsive status epilepticus in childhood: prospective population-based study. Lancet 2006;368:2229. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 1981;22:489501. Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, Engel J, French J, Glauser TA, Mathern GW, MosheSL,Nordli D, Plouin P, Scheffer IE. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 20052009. Epilepsia 2010;51:67685.

8.

9.

10. Trinka E, Hfler J, Zerbs A. Causes of status epilepticus. Epilepsia 2012;53:12738. 11. Lowenstein DH, Bleck T, Macdonald RL. Its time to revise the definition of status epilepticus. Epilepsia 1999;40:120-2. 12. Husain AM, Horn GJ, Jacobson MP. Non-convulsive status epilepticus: usefulness of clinical features in selecting patients for urgent EEG. J Neurol Neurosurg Psychiatry 2003;74:189-91. 13. Shorvon S. The management of status epilepticus. J Neurol Neurosurg Psychiatry 2001;70(suppl II):227. 14. Mazarati AM, Wasterlain CG, Sankar R, Shin D. Self-sustaining status epilepticus after brief electrical stimulation of the perforant path. Brain Res 1998;801:2513. 15. Chen J, Wasterlain C. Status epilepticus: pathophysiology and management in adults. Lancet Neurol 2006;5:24656. 16. Theodore WH, Porter RJ, Albert P, Kelley K, Bromfield E, Devinsky O, Sato S: The secondarily generalized tonic-clonic seizure: a videotape analysis. Neurology 1994;44:1403-7. 17. Delorenzo RJ, Garnett LK, Towne AR, DeLorenzo RJ, Garnett LK, Towne AR, Waterhouse EJ, Boggs JG, Morton L, Choudhry MA, Barnes T, Ko D. Comparison of status epilepticus with prolonged seizure episodes lasting from 10 to 29 minutes. Epilepsia 1999;40:164 9. 18. WasterlainCG, Mazarati AM, Naylor D, Niquet J, Liu H, Suchomelova L, Baldwin R, Katsumori H, Shirasaka Y, Shin D, Sankar R. Short-term plasticity of hippocampal neuropeptides and neuronal circuitry in experimental status epilepticus. Epilepsia 2002;43(suppl 5):209. 19. Treiman DM, Walton NY, Kendrick C. A progressive sequence of electroencephalographic changes during generalized convulsive status epilepticus. Epilepsy Res 1990;5:4960. 20. Mazarati AM, Wasterlain CG. N-methyl-D-asparate receptor antagonists abolish the maintenance phase of self-sustaining status epilepticus in rat. Neurosci Lett 1999;265:18790. 21. Kapur J, Macdonald RL. Rapid seizure-induced reduction of benzodiazepine and Zn2+ sensitivity of hippocampal dentate granule cell GABAA receptors. J Neurosci 1997;17:753240. 22. Naylor DE, Liu H, Wasterlain CG. Trafcking of GABA(A) receptors, loss of inhibition, and a mechanism for pharmacoresistance in status epilepticus. J Neurosci 2005;25:772433. 23. Hamil NE, Cock HR, Walker MC. Acute down-regulation of adenosine A(1) receptor activity in status epilepticus. Epilepsia 2012;53:177-88. 24. Aminoff MJ, Simon RP. Status epilepticus: causes, clinical features and consequences in 98 patients. Am J Med 1980;69:65966. 25. Lowenstein DH, Alldredge BH. Status epilepticus at an urban publichospital in the 1980s. Neurology 1993;143:4838. 26. DeLorenzo RJ, Pellock JM, Towne AR, Bogges JG. Epidemiologyof status epilepticus. J ClinNeurophysiol1995;12:31625.

Conclusions
For the general physician, recognition of SE in both its convulsive and non-convulsive or subtle forms is of paramount importance. Prompt initiation of first- and second-line therapy is critical for management of this devastating condition and early referral is important when ventilatory care and intravenous anesthesia are anticipated. The role of emergent EEG cannot be overemphasized not only in the recognition of non-convulsive SE but also when continuous intravenous therapy is to be initiated with midazolam or barbiturates. Diagnosis and management of the precipitating event are likely to determine the outcome of SE related to acute symptomatic etiologies. Primary health care centers should be equipped with basic facilities for the initial management of SE. With more and more governmental and nongovernmental ambulance service facilities becoming available in major cities and towns, pre-hospital treatment of SE needs emphasis. These measures, hopefully, will improve the outcome of SE in terms of both the morbidity and mortality during the coming years.

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