2014

Guidelines for Diagnosis and

Management of Childhood Epilepsy

Expert Committee on Pediatric Epilepsy, Indian Academy of Pediatrics

Neurology Chapter of IAP Office Bearer 2013-14

Vol.-3, Issue-II, Nov. - 2013

Dr KMP Suresh, Hubli

Dr TM Ananda Kesavan, Thrissur

Dr K. P. Sarbhai, Raipur

Treasurer & Editor in Chief

Executive Board Members

Dr Vijay Jain, Gaya Dr Nitin Maheshwari, Gurgaon

Dr Anju Agrawal, Delhi Dr Kundan Mittal, Rohtak

Dr Sanjeev Joshi, Yawatmal

National Coordinator Dr Arun Agrawal, Gaziabad

National Advisory Board Dr Jaya Kumar, Madurai

Dr Vrajesh Udani, Mumbai Dr C.P. Bansal, Gwalior

Dr Anoop Verma, Raipur

2014 Chairperson Prof PAM Kunju Trivendrum

Vice President

Secretary

Dr Kiran Makhija. Raipur

Webmaster

From The Desk Of The Neurology Chapter….

2014

We are extremely happy to present to you the “Current IAP Guidelines for Diagnosis and Management of Childhood Epilepsy”. It was all possible by inputs and hard work by learned contributors. We wish to congratulate Prof Dr Sheffali Gulati for her great effort in bringing up the

current guidelines.

I am confident that the present guidelines are an update, which will be extremely helpful for general pediatricians, practitioners and practicing neurologist in dealing effectively the childhood epilepsy. We wish to thank and congratulate National President Dr Vijay Yewale and the IAP National Executive Board 2014 for accepting the neurology chapter dedicated work as IAP National Guide lines.

With warm regards

DR PAM Kunju National Chaiperson Neurology Chapter

DR K.P Sarbhai National Secretary Neurology Chapter

Published in Indian Pediatrics 2009 ; 46 : 681-698 : Revised and updated by Dr Sheffali Gulati, Dr Biswaroop Chakrabarty, Dr Rachana Dubey, Dr Jaya Shankar Kaushik, Division of Child Neurology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi.

Dr Mohammed Kunju (Chairperson Neurology Chapter 2013) Dept. of Pediatric Neurology Medical College Trivandrum, Dr Anoop Verma (chairperson Neurology chapter 2012) Consultant pediatrician , Raipur Address for correspondence: Dr SheffaliGulati, Professor, Chief, Child Neurology Division, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi. Justification : Seizures constitute the most common neurological problem in children and the majority of epilepsy has its on set in childhood. Appropriate diagnosis and management of childhood epilepsy is essential to improve quality of life in these children. Evidence-based clinical practice guidelines, modified to the Indian setting by Epinal of experts, are not available. Process : The Indian Academy of Pediatrics organized a consensus meeting on the diagnosis and management of childhood epilepsy on 22, 23 of July 2006 at Mumbai. An expert committee was formed consisting of Pediatricians, Pediatric epileptologists, Pediatric and Adult Neurologists, Electrophysiologists, Neuro- Radiologists, Neurosurgeons and intensivists. A consensus was reached during the discussion that followed presentation by each of these experts. The consensus recommendations have been updated till2013. Objectives : To develop practice guidelines for diagnos is and management of childhood epilepsy. Recommendations : Recommendations for diagnosis and management of following childhood seizures and epilepsies are given : Neonatal seizures, acute symptomatic seizures, neurocysticercosis, febrile seizures, focal and generalized epilepsies, first unprovoked seizure, newly diagnosed epilepsy, epileptic encephalopathy, refractory epilepsies of older children and adolescents, epilepsy with cognitive deterioration and status epileptic us. Keywords : Childhood Epilepsy, Diagnosis, India, Management, Refractory epilepsy Seizures constitute the commonest neurological problem in children with significant epilepsy having its on set in childhood. A considerable treatment gap exists in developing countries due to poverty, stigmatization, and lack of trained manpower (1). Evidence-based clinical practice guideline scan improve the quality of care (2). An expert consensus meeting was held at the PD Hinduja National

1

Hospital, Mumbai on July22-23rd 2006 under the IAP 2006 action plan. The aim was to produce a practice parameter for diagnosis and management of epilepsy in the Indian context. All 22 experts (AnnexureI) had several years of experience and publications in epilepsy. Epilepsy sub topics were assigned to each expert with a format of five common questions faced by a practicing pediatrician. A man script and presentation were prepared by each expert, using evidence from the medical literature. Emphasis was placed on the resource-poor Indian context, which of ten makes guidelines from developed countries difficult to apply. The consensus statement was prepared in 2006 and has been updated till 2013. Objectives : To provide easy, quick and practical guidelines for diagnosis and management of acute symptomatic seizures ; and newly diagnosed and refractory childhood epilepsy to the practicing pediatrician. Recommendations : 1. Neonatal Seizures : Neonatal seizures are often acute symptomatic due to

underlying brain insults. Focal clonic, multi focal clonic, and focal tonic seizures are usually accompanied by ictal EEG activity while subtle, generalized tonic and my aclinic episodes are not associated with electro graphic ictal activity (3). True seizures are often accompanied by open eyes (4). Non-epileptic phenomena like jitteriness and benign sleep my oclonus should be identified. Serum glucose, electrolytes, calcium and magnesium must be done in all (5,6). CSF studies and culture must be done in all except when the diagnosis is definite. g. hypoxic ischemic encephalopathy. A portable 60minute EEG by a trained technician and interpreter is useful in recognizing subclinical seizures, epileptic encephal opathies and prognostication. Amplitude integrated EEG is increasingly being used in neonatal intensive care setting for monitoring patients with neurological damage, picking up seizures and prognostication (7).A cranial ultrasound is the minimum imaging required, butanin-house MRI with diffusion tensor imaging is the modality of choice, done immediately for aetiology done immediately for aetiology and at 3-6 months for prognosis (6). Management should be done asper figure 1 (5,6,8-11).

Once seizure is controlled attempt is made to continue the neonate on only oral phenobarbitone 3-5 mg/kg/day. If the neonate continues to be seizure free, then antiepiletics are discontinued at discharge if the neurological examination is normal irrespective of etiology and EEG. In case of an abnormal neurological examination, baby is seen again at 1 month. At this point of time if there are no seizures and neurological examination is normal, AED is tapered, however on an abnormal examination, EEG is done. If EEG is not overtly abnormal, AED is tapered and stopped, otherwise the baby is seen again at 3 months and in similar fashion 3 monthly thereafter (6)

2

Maintain ABC and temperature.

With draw blood for biochemistry

Immediate glucose by dextrostix

Correct glucose and calcium/ sodium/magnesium

Administer IV- phenobarbitone 20mg/kg.

Repeat in 5mg/kg bol use still a maximum of 40mg/kg every15minutes if seizure continues, 5mg/kg/day in two divided doses as maintenance dosage; if seizure persist, any of the 3 below mentioned drugs can be used sequentially

IV Phenytoin15-20mg/kg Levetirecetam 50 mg/kg i.v. Lidocaine 2mg/kg i.v. diluted in equal volume of Loading followed by maintenance bolus, then 6mg/kg/hr, normal saline at a maximum rate 40mg/kg/day in 2 divided doses taper 12 hrly by 2mg/kg of 1 mg/kg/min over 35-40 minutes until off, also start phenytoin/ levetirecetam

IV Lorazepam (0.05to0.1mg/kg) or Diazepam (0.25mg/kgbolusor0.5mg/kgrectal)

Or IV Midazolamasa continuous in fusion (an initia lIV bol us of 0.15mg/kg, followed by continuous in fusion (1µg/kg/min) increasing by 0.5to1µg/kg/min every 2 minutes until a favorable response or a maximum of 18µg/kg/min

Consider pentobarbital/ lidocaine drip (if not tried previously)

3

If no apparent risk factor (HIE, CNS infection), metabolic work up should be considered and tailored according to the clinical scenario

· Arterial lactate and pH · CSF glucose/ lactate · Blood TMS · Urine GCMS · Serum and CSF glycine

Consider pyridoxine 100 mg i .v. preferably under EEG monitoring

2. Acute Symptomatic Seizures : A seizure occurring in close temporal relationship with an acute CNS insult is called an acute symptomatic seizure. The time period varies for temporal association; 1 week in stroke, head trauma and anoxic encephalopathy, persistent ongoing active phase in CNS inflammation and infection and within 24 hours of severe metabolic derangement (12). Future risk of unprovoked seizure is to the tune of 17% in structural and encephalopathic causes and it increases to 41% if the the acute symptomatic episode was a status epilepticus. Risk of unprovoked seizures in repetitive acute symptomatic seizures needs to be ascertained by further studies (13). Serum calcium, magnesium, electrolytes and glucose should be estimated for all children. Lumbar puncture should be done in febrile infants and in those with suspected meningoencephalitis. A plain CT scan is indicated in traumatic brain injury and a contrast enhanced CT scan is indicated in children above 2years, especially those presenting with convulsive seizures, focal seizures, cluster of seizure or focal neurological deficit s to rule out granuloma. However under ideal circumstances, in non emergent and non traumatic cases, MRI (with contrast whenever indicated) is preferred. EEG should be considered after ruling out a granuloma by neuroimaging. EEG helps in localization in those with normal MRI Brain, recurrence prediction and identification of epilepsy syndrome (13,14).

In a hypocalcemic breast feed infant, an underlying vitamin D deficiency statein the child and the feeding mothers should be corrected (15). Anti- epileptic drugs (AED) are required in the acute phase and can be withdrawn in a week in acute traumatic brain injury (16) or in 3months in illnesses with parenchymal involvement (e.g. CNS tuberculosis or pyogenic meningitis with parenchymal involvement).

3.FebrileSeizures : Febrile seizures are the most common form of childhood epileptic seizures. They occur between the age of 6 months to 5 years. A simple febrile seizure is generalized, lasts for <15 minutes, doesn't cause focal neurological deficits and usually doesn't recur in the same febrile episode or within 24 hours. Complex febrile seizures are characterized by focal on set, duration > 15 minutes, associated focal neurological deficits or multiple episodes in the same illness (17). Late onset febrile seizures, persistent febrile seizures, generalized epilepsy and febrile seizure plus (GEFS+) and febrile status epilepticus (FSE) are part of the spectrum of febrile seizures (18). A recent concept of simple febrile seizure plus has emerged which signifies recurrent episodes of febrile seizures within 24 hours which otherwise behaves like simple febrile seizures (19). Indications for Lumbar puncture in the first episode of simple febrile seizure are : • Any child who has meningeal signs and symptoms or in any child whose

history or examination suggests meningitis or intracranial infection.

4

• Any infant 6-12 mths, LP is an option when the child is considered deficient in Hib or Streptococcus pneumoniae immunizations or when immunization status cannot be determined.

• LP is an option in the child is pre treated with antibiotics. EEG and neuro imaging have no role in simple febrile seizures (17,18, 20, 21).

Management includes definitive diagnosis, treatment of an acute episode, prophylax is for future episodes and family counseling (17,20). There is no evidence that defervescene prevents occurrence of febrile seizures, but it should anyways be done to decrease discomfort of the patient (17,18).Parents can be taught to use rectal liquid diazepam (0.5mg/kg) or buccalor nasal midazolam (0.3mg/kg) for acute termination of seizures that last for two minutes or more (20,22).

Any prophylaxis of febrile seizures reduces the recurrence of seizures but does not reduce the risk of future epilepsy. Intermittent prophylax is with oral clobazamina dose of 0.75 to 1mg/kg/day for2-3days in 2 divided doses during fever is useful to prevent recurrence (23,24). Febrile status, complex and recurrent febrile seizures (>4/year inspite of intermittent prophylaxis) may need EEG, neuro imaging and continuous prophylax is with AED. Phenobarbitone and Valproate may be used in infants and older children respectively, for 1- 2 years. Carbamazepine and phenytoin are not useful (17,20).

4. Granuloma in Children : New-on set partial or generalized convulsive seizures occurring in clusters in an otherwise normal childish the common- est presentation of single small contrast enhancing CT lesion (SSECTL); necessitating neuro imaging, except when an idiopathic epilepsy syndrom eis established with EEG (25). The common estetiology is neuro cysticercosis (NCC) followed by tuberculomas. Parenchymal NCC cysts should be classified as an active vesicular form (cystic, with out enhancement or edema, with occasional eccentric hyper dense nodule signifying scolex), a transitional colloidal / granular - nodular form (ring /discenhancement with edema) or an in active form (non-enhancing calcified lesions with out edema). Active lesions when accompanied by edema of ten producea focal background asymmetry on the EEG (26,27). NCC versus Tuberculoma : On neuro imaging, the presence of an eccentric scolex in a cystic lesion with ring pattern of enhancement, with size less than 2cm is quite characteristic of NCC. On the other hand larger (>2cm) multiple lesions with iso to hypointense core on MRI with irregular margins on contrast administration favour a diagnosis of tuberculoma. MRSpectroscopy and magnetization transfer MRI may help differentiate the two (28-30).

5

Cysticidal treatment is beneficial and recommended strongly in live cysts and transitional granulomas. Albendazole for aperiod of 7 or 28 days in a dose of 15mg/kg/day in 2 divided doses is the treatment of choice. Prednisone (1mg/kg/day) or dexamethasone (0.6 mg/kg/day in 3 to 4 divided doses) is given 3days be fore starting albendazole and continued for a total of 5-7days to reduce the risk of cerebral edema at the time of cyst breakdown. An ophthalmo scopic examination should be performed before use of cysticidal drugs as ophthalmic lesions are an absolute contraindication for medical therapy (27,31,32). Repeat imaging should be done to check there solution of lesion after 6month if the child is clinically well, or earlier, if the initial diagnosis was in secure or if the child is symptomatic.

AEDs are given in acute symptomatic seizures due to active lesions (cystic lesions, granulomas) till such time that they disappear, usually for a period of 6months. In active calcified lesions should be considered remote symptomatic and should be treated till a 2 year seizure free period is achieved (27,33).

5. Idiopathic Partial Epilepsies in Childhood Benign epilepsy with cento-temp oral spikes (Benign rolandic epilepsy, BECT) : This should be considered when a normal school aged child presents with brief and infrequent, partial, nocturnal, hemi-facial, sensory or motor seizures. An a wake-cum-sleep EEG is necessary, as it displays a characteristic pattern of sleep activated runs of centro-temp oral spikes or sharp waves. The syndrome has an excellent prognosis with remission in most cases by the age of 15-16years (34, 35). AED treatment can be avoided in most cases however those with frequent seizures, particularly generalized may require short period of anti epileptic therapy preferably carbamazepine (35).

Panayiotopoulos syndrome (Early - onset childhood epilepsy with occipital paroxysms, CEOPs) : CEOP should be considered when a normal pre school (3-5 years) child presents with severe nocturnal vomting, followed by eye deviation and status epilepticus, usually hamiclonic. This syndrome has an excellent out come(35,36). A later age Gastaut variant of CEOPS is usually characterized by diurnal simple partial seizures with visual hallucinations or amaurosis and migraine like headaches. This has a variable prognosis and can persist in to adult life. Neuroimaging is considered in cases with an abnormal perinatal history or examination, atypical EEG, or poorly controlled seizures.

6

Treatment with AED is not required when seizures are in frequent, but parental counseling is a must. In long term therapy, carbamazepine or valproate are preferred. The syndrome may evolve atypically with frequent refractory seizures, scholastic deterioration and / or behavioral changes; more often with the use of carbamazepine, emphasizing the need of clinical monitoring (35,37).

6. Idiopathic Generalized Epileptics : Childhood absence epilepsy (Petit-mal, CAE) : This should be suspected in a normal school age child with frequent absence seizures of ten up to a hundred per day. These occur in the awake state with sudden staring, unresponsive ness and minor brief automatisms, leading to Interruption of ongoing activity and unassociated with any postictal abnormality (34).GTC seizures are unusual. Precipitation of seizure by hyperventilation is a simple clinical diagnostic test. A typical absence seizures are prolonged, seen usually in catastrophic pediatric syndromes.

An EEG showing a typical pattern characterized by frontally predominant generalized bursts of 3Hz spike wave complexes with abrupt onset is diagnostic. There is no role for routine neuroimaging.

Valproate and ethosuxsimide (presently unavailable) followed by lamotrigine and the benzodiazepines are the drugs of choice. Response to AEDs should be confirmed by repeat EEG with hyperventilation to check the disappearance of typical EEG pattern. Treatment is for a minimum seizure free period of 2 years with a normal EEG at discontinuation. An EEG may be repeated after 6-8 weeks of stopping AEDs to look for reappearance of spike wave discharges (38,39).

Idiopathic generalized epilepsies of adolescence : When a patient presents with absence, myoclonic or generalized tonic clonic seizures for the first time after 10 years, a diagnosis of idiopathic generalized epilepsies of adolescent on set is considered. EEG shows generalized paroxysms of spike or polyspikes wave discharges. Photo sensitivity is common. Juvenil emyoclonic epilepsy (JME), juvenile absence epilepsy (JAE) and epilepsies with only GTC seizures should be considered in diagnosis (40).

JME presents in adolescents with history of early morning pre dominant upper limb myoclonic jerks leading to dropping of objects by the patients. This occurs often in sleep-deprived individuals, especially if suddenly awakened. JAE is similar to CAE, though the numbers of absences are much less and the onset is usually later. GTC seizures typically occur on awakening gorin the evening (34).

7

Sodium valproate is the most effective drug in most cases of idiopathic generalized epilepsies (41), but it may cause weight gain, hair loss, and menstrual irregularities and has a higher incidence of fetal teratogenicity. Therefore, lamotrigine may be preferable in adolescent girls. Due to its lower cost, phenobarbitone may be used in poor patients with resource constrains, with only generalized tonic clonic seizures, but will not control my oclonic or absence seizures. Carbamazepine and phenytoin may worsenthe syndromes. Life style adjustments include avoiding precipitating factors like sleep deprivation and alcohol consumption.

Seizure control is achieved in 80% with mono therapy. Withdrawal of AEDs results in relapse in more than 90%, especially in JME and JAE,and often need low dose life time medication (39).

7.Investigations for Epilepsy : Electroencephalography (EEG) When should an EEG be done ? EEG is recommended as a part of the initial evaluation in all children presenting with an epileptic event. Epileptiform abnormalities support a clinical diagnosis of seizure, help in the diagnosis of specific syndromes and predict seizure recurrence (30); how-ever, a normal EEG does not rule out epilepsy. The EEG interpretation is reliable only when it is well recorded and interpreted by an experienced EEG reader with at least one year of training in the same.

In the child with un controlled epilepsy, a repeat EEG helps in reclassifying the syndrome. Before AED discontinuation, an EEG aids in predicting the risk of recurrence in most syndromes barring a few e.g. BECTS. In children with unexplained cognitive, neuro behavioral or scholastic deterioration; an EEG may help in diagnosis of specific disorders like SSPE, or epilepti cencephalopathies like electrical status in slow wave sleep (ESES), and non-convulsive status epilepticus.There is no place for routine follow-up EEGs in patients who are doing well.

EEG is desirable under following circumstances (42) : First unprovoked seizure General anaesthesia during status epilepticus management Suspected non convulsive status epilepticus Uncontrolled epilepsy Unexplained cognitive and neuro behavioral decline Before AED discontinuation

8

How should an EEG be done (43) ? EEG should be done as early as possible after seizure (44). An EEG after sleep deprivation should be part of all routine recordings in

children above the age of two years (44). Minimum activation procedures like hyperventilation and photic stimulation

should be used. Omission of AED prior to EEG recording is not recommended. Simultaneous video-EEG is useful in differentiating non-epileptic events from

true seizures and for pre-surgicalevaluation. EEG in status epilepticus (SE): A portable EEG can be done in children with convulsive SE who do not regain consciousness as expected, so as to exclude a non going non convulsive status epilepticus (NCSE).Continuous EEG monitoring is desirable in refractory SE when pentothal or propofol are being used for dose titration. Continuous EEG (cEEG) Monitoring in SE (45) : 1.The use of cEEG is usually required for the treatment of SE. 2.Continuous EEG monitoring should be initiated within1 h of SE onset if

ongoing seizures are suspected. 3.The duration of cEEG monitoring should be at least 48 h in comatose patients

to evaluate for non-convulsive seizures Neuro imaging : MRI is more sensitive than CT and is the modality of choice. CT retains a role in detecting calcification and in acute situations like head trauma, status epilepticus, and epilepsy, where granulomas are a possibility. MRI protocol should be adapted to the age of the child and the type of epilepsy syndrome (46). Neuro imaging is not recommended in benign epilepsies. High resolution MRI with special techniques is recommended for delineating the epileptogenic zone and the eloquent cortex in pre-surgical evaluation. The preferred sequences are T1W (preferably, inversion recovery),T2W and PD fast spin echo, Fluid-Attenanted Inversion Recovery (FLAIR), 3DT1acquisitions with1-2mm partitions (better an atomy and morphometry). Children with epilepsy should be advised neuro imaging if one or more of the following are present (47): 1. Any evidence to suggest the epilepsy is localization related (e.g., focal), with

the exception of benign partial epilepsies of childhood. 2. Abnormal neurologic examination, including focal deficits, stigmata of neuro

cutaneous, cerebral malformation syndrome, or a history of significant developmental delay, arrest, or regression.

9

3. Children younger than 2 years, excluding those with simple febrile seizures. 4. Children with characteristics of a symptomatic generalized epilepsy syndrome,

including infantile spasms or early Lennox-Gastaut syndrome, as focal MRI findings may be found in a substantial proportion of these children.

5. Poorly controlled epilepsy, worsening seizures, changes is seizure manifestations, or developmental regression also merit neuroimaging if not previously performed.

6. New-onset seizures/epilepsy presenting as medical emergency such as increased intracranial pressure or status epilepticus merit emergency imaging.

8. Management of First Unprovoked Seizure : A good history is most important for diagnosis of a seizure. Open eyes, eye and head deviation, incontinence, tongue-bite are fairly specific for a seizure, where as unresponsiveness, confusion, clonic / tonic movements are suggestive, though these may be prominent in non - ep ileptic events as well (48). If the child is less t h a n 6 m o n t h s , a d m i s s i o n f o r o b s e r v a t i o n a n d e v a l u a t i o n i s recommended.

All children should have blood pressure recorded and a blood glucose should be done (49).

EEG is recommended in all cases and should be done within 4 weeks (43, 50).

Neuro imaging would be needed when there are seizure cluster, focal deficits, altered sensorium, focal EEG background change (47, 50).

In the first seizure, AED should not be recommended, but a detailed d iscussion with the parents is necessary. Exceptions are status epileptic us due to high rate of recurrence (51) or severe parental anxiety. Home management of seizures includes use of rectal diazepam/buccal or nasal midazolam (52) in seizures lasting for more than 5 minutes.

I n t r a n a s a l m i d a z o l a m ( 0 . 2 m g / k g m a x 1 0 m g ) s h o u l d b e considered as an anticonvulsant agent for community, prehospital, and when intravenous access is not available and the rectal route is not desirable (53).Intra nasal lorazepam (0.1 mg/kg, maximum 4 mg) is equally effective as abortive management of seizures (54).

9. Management of Newly Diagnosed Epilepsy Long term AED treatment should be started after second seizure (55). The aim of

treatment is complete seizure control without significant adverse effects. AED is based on the predominant seizure type or syndrome type with possible adverse effects and co-morbidities taken in to account(55, 56)

10

till seizure control is achieved or side effects appear.

Dosage needs to be adjusted to the child's daily activity. Extended release formulations in twice a day do sing are preferable (57).

If no control is obtained with maximum doses of the first drug, then a second first line drugis initiated and the first drug tapered (56). If partia control is achieved (55),then a second AED should be added. All efforts should be made to use only rational poly therapy.

There are no significant differences in the efficacy or tolerability of the four major first line anti convulsants (phenobarbitone, phenytoin, valproate and carbamazepine) and any one can be used first (58), based on side effect profile. Carbamazepine and valproate appear to be better tolerated than phenobarbitone and phenytoin.

A seizure diary should be kept by the parents.

Therapeutic drug monitoring is use ful in only few situations, including break through or refractory seizures, to assess compliance, for diagnosis of clinical toxicity or with use of phenytoin, which has dose dependent pharmacokinetics

(59, 60).

In most epilepsy, AED is with drawn after 2year of seizure freedom. Adolescent onset, remote symptomatic epilepsy, abnormal neurological examination and abnormal EEG after2 years are predictors of relapse (61), warranting drug withdrawal after 4years (62).In children other risk factors of seizure recurrence are multiple seizure types, polytherapy and history of febrile seizures (63)

Drug withdrawal is over 3-6months (64,65) and one drug at a time in cases of polytherapy. A patient discontinuing treatment for seizure freedom should be

followed for at least 2 years (66).

10.Severe Epilepsy Syndromes of Early Childhood / Epileptic E n c e p h a l o p a t h i e s ( C a t a s t ro p h i c E p i l e p s i e s i n I n f a n c y a n d Early Childhood) : The term “ catastrophic childhood epilepsy” was first i n t r o d u c e d b y N o r t h A m e r i c a n g r o u p s o n c h i l d r e n w h o s e seizures begin early in life and were so frequent and intense that their psychomotor development and daily life were significantly impaired.The recent ILAE proposal on terminology has not recommended using the term “

catastrophic” because it sounds hopeless for families (67).

11

All drugs are started in low doses and increased gradually up to a maximum dose

Following age related syndromes are generally included in this group (67): Neonatal period: Early myoclonic encephalopathy (EME) Ohtahara syndrome Infancy: Epilepsy of infancy with migrating focal seizures West syndrome Dravet syndrome Childhood: Epilepsy with myoclonic atonic (previously astatic) seizures (Doose syndrome) Lennox-Gastaut syndrome Epileptic encephalopathy with continuous spike-and-wave during sleep

(CSWS) Landau-Kleffner syndrome (LKS)

West Syndrome, Lennox-Gastaut Syndrome and Dravet Syndrome are most common severe epilepsy syndromes seen in clinical practice. These often require detailed knowledge and expertise in both evaluation and management and are best referred to a specialized centre where pediatric neurologist or epileptologistis available for specialized care. West Syndrome (WS) : West syndrome usually occurs in the first year of life and consists of the triad of infantile spasms, developmental deterioration, and a hypsarrhythmia pattern on EEG. Epileptic spasms are predominant seizure type. Theses are brief, generalized seizures involving extension and/or flexion axially, and of the extremities. An individual spasm lasts for seconds, often longer than myoclonic seizure, though of shorter duration than tonic seizures. The spasms may be subtle and may be isolated at onset, typically clustering later in the course (68).

A detailed history of perinatal events (hypoxic-ischemi cencephal opathy, neonatal hypoglycemia etc), developmental milestones, examination of the skin for stigmata of tuberous sclerosis, head circumference measurement and careful neurologic/developmental examination looking for deficits/delays will help to differentiate unknown vs.structural etiology of spasms.

An EEG should be done to confirm the diagnosis, though the characteristic pattern of hypsarrhythmia is not mandatory for diagnosis (69, 70). Moreover, an experienced electroencephalographer should be available for interpretation. If the history and examination do not reveal an obvious etiology, an MRI preferably with special techniques to look formal formations of cortical development should be undertaken. Metabolic tests are usually unhelpful and should be done only in selected infants (90),where there is a high suspicion for a neurometabolic condition e.g. consanguinity, positive family history, etc.

12

Chromosomal disorders like Downs syndrome and genetic disorders related to ARX, CDKL5, SPTAN1, FOXG1, GRIN2B should be considered as etiology. Steroids are the drugs of first choice in all cases of West syndrome (70, 71), especially so in cryptogenic WS, except in tuberous sclerosis. ACTH is preferred over oral steroids (70, 71).Oral pre dnisol one is given in doses of 2- 4mg/kg(91) or natural ACTH in 30-40 units /day (3-6U/kg) for 2 weeks, with rapid taper over the next 2weeks. Rapid control of the spasms within1month of on set is associated with rapid developmental gains (VPA could be continued after steroids in symptomatic West syndrome).

Viabatr in is preferred in TS as first choice (70, 71) and in steroid failures in the others (taking in to account a availability / afford ability issues).It should be used for a period of 3-6months only, due to the fear of visual field defects. Nitrazepam / high dose VPA / Topiramate can be used as alternatives. Surgery in selected lesional cases and ketogenic diet are other alternatives. Current recommendation : Low-dose ACTH should be considered as first line treatment of infantile spasms. ACTH or VGB may be useful for short-term treatment of infantile spasms, with ACTH considered preferentially over VGB. Hormonal therapy (ACTH or prednisolone) is preferred over VGB in infants with cryptogenic infantile spasms, to possibly improve developmental outcome (72). Lennox Gastaut syndrome : Lennox-Gastaut syndrome (LGS) is a well-known childhood epileptic encephalopathy with atypical absences, tonic seizures, cognitive deterioration, and slow spike wave activity in the EEG. Focal seizures affect <50% patients, but tonic-clonic seizures are rare. Drop attacks are a major complication of this condition. Any toddler, who has epileptic : Drop attacks and is delayed or has arrest in development, should be considered to have LGS (73).

Lennox-Gastaut syndrome usually results from focal, multi focal, or diffuse brain damage. It may follow West syndrome. An MRI is essential in case no obvious cause is identified on history and examination. An EEG should be performed to confirm the diagnosis though the typical slow spike-wave paroxysms are not mandatory for diagnosis (73). It is mandatory for diagnosis of non-convulsive status epilepticus, which often occurs in LGS and manifests as decreased responsiveness, drooling and regression of milestones lasting hours to days (73).

VPA and CLB should be used initially .LTG (74) or TPM (75) should be added in case of continuing seizures. Rufinamide, and Felbamate have been found useful in Lennox Gastaut syndrome. PHT, CBZ and OXZ should be avoided.

The dietary therapies (ketogenic / modified atkins) should be used early, if available. Helmets / head gear should be worn to prevent head injury. It is best to refer such children to a tertiary epilepsy center to manage these complicated patients. Corpus callosotomy and vagus nerve stimulation are other treatment options.

13

Dravet's syndrome (Severe myoclonic epilepsy of infancy) : Dravet syndrome begins in the middle of the first year of life (between 2 and 10 months) usually with febrile convulsions that are either generalized or unilateral (alternately both sides of the body). The tendency of fever as trigger factor, decreases progressively, and convulsions occur without any fever. Episodes of status epilepticus consist either of long-lasting clonic convulsions or of myoclonic status in which the child is drowsy with erratic myoclonus. The former occurs in the first years of the disease, the latter usually after the age of 5 years (68). These may be triggered by fever or illnesses. Myoclonic and absence seizures, often photosensitive usually become prominent after the first year, though they are not mandatory for diagnosis(75).The child progressively develops partial seizures in addition to generalized seizures, myoclonus, and absences.

One should think of this syndrome in normal infants with onset of refractory febrile / a febrile, focal / generalized seizures in the first year of life (76). Over the next 2-3years, delayed language development, autistic features and later, gait difficulties become evident. EEG studies are initially normal, but after 2 years they show generalized spike-wave and polyspike-wave activity with multi focal discharges. Photosensitivity may be seen. Imaging is normal or shows nonspecific findings such as atrophy. SCN1a mutation can be found in > 75% cases though most of them (90%) are de novo mutations (M).VPA,CLBand TPM (77)are drugs most likely to help prevent SE, though a full remission is unlikely to occur. Recent review suggeststiripentol is useful in achieving seizure control in these patients (78). LTG and CBZ regularly worsen these seizures and there fore should be avoided in all febrile seizures in infancy, even those which are clinically focal. Once this condition is considered, it is best to refer to a tertiary care center for further evaluation and management.

11.Refractory Epilepsies in Older Children and Adolescents Mesial Temporal Lobe Epilepsy (MTLE) : Common clinical features of MTLE are

rd well known and described. History of febrile seizures is common (up to 2/3 of patients) , though other causes including head trauma, perinatal injury, congenital brain malformation, central nervous system infection, and brain tumors may be evident. Prolonged, febrile seizures may induce hippocampal edema that progresses to hippocampal sclerosis. The onset of MTLE characteristically occurs at the end of the first or second decade. Focal seizures with and without impaired consciousness are the most common seizure types in MTLE. Status epileptic us and prolonged seizures are infrequently encountered (79).

It presents as complex partial seizures with an aura of fear or epigastric sensation (psychic or viscerosensory aura) followeby unresponsiveness, automatisms and later secondary generalization. Motor manifestations are more common in children

14

before 6 years of age. Sleep deprived EEGs with special electrodes are often needed in these cases and should be also done in specialized centers. High resolution MRIs need to be done to diagnose hippocampalscleros is and where MTLE is suspected, It is better refer the child for an MRI through a specialized center to avoid dual costs. In many children, conventional AEDs like CBZ, PHT and newer AEDs like OXZ and TPM are effective for awhile in controlling seizures. How ever a large number become resistant to AEDs and there is a progressive cognitive, behaviourial and memory impairment, if the epilepsy remains uncontrolled. Early surgery in the form of anterior temporal lobectomy is established treatment for uncontrolled MTLE (80).

Epilepsia Partials Continua : Epilepsia Partialis Continua (EPC) is a rare form of focal status epilepticus. It may have vascular, immune-mediated, neoplastic or metabolic-toxic causes. The origin of EPC has been linked with the motor cortex. This has been solidly supported by sophisticated electro physiological studies (81).

Epilepsia partialis continua should be suspected when focal, fairly constant my colonic / clonic jerks involve one or more parts of the body (face /limb/ tongue) only unilaterally (82). In most children, progressive, presumably immune-mediate den cephalitis, Rasmussen's encephalitis underlies this disorder. Overtime, aprogressive hemiplegia with deterioration in cognition and behavior is usual, as the epilepsy is resistant to all AEDs (82).

Investigations should include a MRI whichis initially often normal but shows progressive hemiatrophy and unilateral signal changes. EEGs are also helpful though they may be deceptively show absence of abnormalities.Only focal background disturbances may be seen. Till a hemiplegia develops immune therapies like steroids, IVIG and others (tacrolimus,rituximab, natalizumab) have been used with variable results.

Treatment is primarily surgical (82) and a hemispheric resection / disconnection are the procedure that seems to benefit a large number. The drawback is that a permanent motor / visual field defect is in variant after a hemispherectomy. Hence, this procedure becomes difficult in children who still have good function of the limbs.

12.Epilepsies and Cognition : Cognitive deterioration, academic under achievement and behavioral problems are common comorbidities in children with chronic epilepsy (83-85).Uncontrolled seizures and worsening of the EEG with increasing epileptic form abnormalities are more likely to be responsible for cognitive deterioration, than any AED (86).

15

Up to three fourth children with epilepsy have some form of behavioural problem and a quarter have intellectual disability (87, 88). Cognitive impairment seen in epileptic children include difficulties in learning, memory, problem solving as well as concept formation. Anxiety, depression and attention deficit hyperkinetic disorders are the most common psychiatric co-morbidities seen.

All children with epilepsy should be screened with a simple child behavior check list (89) consisting of questions directed towards mood, behavior and school performance. Some children merit a more formal neuro psychological examination.

Sensitization of parents and teachers regarding associated co-morbidities and early referral for psycho-educational evaluation and special education is useful.

All attempts to switch to mono therapy should be done to reduce AED induced behavior / cognitive effects.

It is important to recognizes are but important syndromes like the Landau- Kleffner syndrome (LKS) and Continuous Spike-Wave in Slow- Wave Sleep (CSWS) (90, 91). LKS presents as predominant language deterioration In a previously normal child who may or may no thane clinical seizures. Initially the child may stop responding when called and may appear to be deaf ; there may be school performance as well as behavior deterioration. CSWS is a more global disturbance with a frank dementia and autism. Both these syndromes are presumably causally associated with a continuous epileptic discharges in non - REM sleep electrical status in slow wave sleep (ESES). Hence, any child with or without epilepsy, who has cognitive, language and behaviourial deterioration should have an awake and more importantly sleep EEG to establish the diagnosis. Evaluation and management of these complex syndromes need referral to specialized epilepsy centers.

13.Antiepileptic Drugs : Phenobarbitone : Phenobarbitone could be used as a first line AED in neonatal seizures (92), febrile seizures (if treatment is warranted) and established convulsive status epilepticus (SE). It is effective in partial, generalized and Myoclonic seizures but have no role in absence seizures(93). The dosage varies between 3-6mg /kg/day given as a single night- time dose for routine use with low starting dose then gradually building up. In children with status epilepticus the dosage is 20mg / kg followed by 3-6 mg/kg maintenance. Sedation, drowsiness, aggression, paradoxical hyperactivity in children are the common side effects. Since deleterious cognitive and behavioral side effects remain a concern, it should be avoided in school going children.

16

Phenytoin : Phenytoin is effective in control of tonic clonic seizures and partial seizures and is probable the most widely used AED. It is useful in neonatal seizures (refractory to phenobarbitone) and in established status epilepticus. It is contraindicated in absences seizure, myoclonic seizures and in epileptic encephalopathies. Maintenance dosages in older children are between 5-6mg/kg given in one or two divided doses. Cosmetic side effect including gingival hyperplasia and hirsuitism are major concerns among adolescents with chronic use (94). The drug has a narrow therapeutic range and requires frequent monitoring of plasma levels beyond 100-200 mg/day. Fosphenytoin : It is prodrug developed in order to avoid the local tissue complications like thrombophlebitis associated with parenteral phenytoin (95). A vial containing 75 mg/ml of fosphenytoin sodium is equivalent to 50 mg/ml pheytoin sodium after administration. It is useful in status epilepticus in dose of 15-20 mg/kg of phenytoin equivalents. The adverse reaction profile is same as phenytoin and is contraindicated in sinus bradycardia, sino atrial block, second and third degree block. The drug can be used in intramuscular route but peak concentrations are achieved after 30 min. Valproate : Valproate is one of the most effective broad spectrum AED. It is used as the drug of choice for most children with newly diagnosed epilepsy, like idiopathic generalized epilepsy (CAE, JAE, BMEI, and JME), epilepsies with prominent myoclonic seizures or with multiple seizure types, and photosensitive epilepsies (96). It is inferior to oxcarbazepine in treatment of focal seizures. However, it could be used inpartial epilepsies in infants where carbamazepine might precipitate generalized seizures and in refractory status epileptic us. In adolescent girls or obese patients, one may not use it as first line agent due to concerns of weight gain, hair loss and aggravation of polycysticovarian disease (PCOD) (97). It is started in dose of 10 mg/kg/day and in increments of 10 mg/kg/day every 3 days to maintenance dose of 20-30 mg/kg/day in two divided doses. Twice-a-day do singisp referred with extended release preparations except in syrup (3 timesaday).

Parents should be counseled regarding danger symptoms and signs of hepatitis, like nausea, vomiting, drowsiness etc, especially in children below the age of 2years, those on poly therapy and those with associated IEM. However, routine monitoring of LFT is not recommended as transient elevations up to twice normal or borderline elevation of ammonia can bed is regarded when asymptomatic.Valproate associated hepatotoxicity is age dependent with prediction for those under 2 years

17

of age. The drug must be stopped immediately in all symptomatic patients irrespective of enzyme levels. In case the cause of the hepatitis becomes clear e.g. hepatitis A confirmed by serology, then valproate could be restarted after the hepatitis has resolved. In cryptogenic hepatitis it is best avoided. Carnitine supplements are not routinely recommended (98). The other concerns of valproate include acute hemorrhagic pancreatitis, hyperammonaemic encephalopathy, thrombocytopenia, weight gain, hair loss. Carbamazepine : It is the drug of first choice for focal epilepsies with or without secondary generalization (99). The dose varies between 10-30mg/kg in the form of twice a day dosing and preferably given as slow release preparations (100, 101), if syrups are used they should be given three times a day. Carbamazepine may induce or exacerbate generalized seizures like infantile spasms, myoclonic, tonic and absence seizures in the younger child (102). It is contraindicated in idiopathic generalized epilepsies. Important side effects include headache, diploplia, blurred vision, rash, gastrointestinal disturbances, hyponatremia and neutropenia. It may worsen the EEG with deterioration in cognition, behavior and language & can rarely precipitate electrical status in slow wave sleep (ESES) (102). Parents should be informed about the common side effects like appearance of new seizures, deterioration of school performance or appearance of rash (Steven's) Johnson's and Drug Rash Eosinophiliaand Systemic Symptoms- DRESS syndrome shared with phenytoin and phenobarbitone which should be reported immediately. A routine hematological monitoring is not recommended. Oxcarbazepine : Oxcarbazepine is keto derivative of carbamazepine with similar antiepileptic activity. However, it is better tolerated and has fewer interactions with other drugs as it does not undergo metabolism to 10,11-epoxide (103). It has a lower incidence of idiosyncratic reactions but has higher chances of hyponatremia when compared to carbamazepine. It is started in dose of 10 mg/kg/day in two or three divided doses can be increased by 10 mg/kg/day weekly to maximum 30-40 mg/kg/day. Abrupt switch over from CBZ to OXZ can be done in a dose ratio of2:3 (104). No routine monitoring of drug levels, blood counts or sodium is recommended, unless symptomatic (vomiting, drowsiness or increased seizures). Clobazam : It can be used as intermittent therapy (105, 106) or as adjunctive medication in all drug resistant epilepsy in children (107-109); is not recommended as mono therapy for newly diagnosed epilepsy. In the intermittent use, it is used in febrile seizure prophylaxis to prevent acute seizure recurrence (105, 106), in reflex epilepsy e.g. hot water epilepsy (just be fore a hot water bath), in catamenial epilepsy (Straddling themenstrual period) or during seizure clusters. As add-on therapy, it is useful in refractory partial (107)

18

and generalized epilepsies (108, 109). It is also used as add on certain epileptic syndromes like LGS, Myoclonic-astatic epilepsy (Dowse syndrome), Dravet's syndrome, Continuous spike and wave in slow wave sleep (CSWS). The starting dose is 0.1-0.2mg/kg,which is titrated against seizure control every seven day still 0.75mg/kg-1mg/kg is reached .It should be given in two divided doses or as a single nightly dose. Somnolescence is most common adverse effect which can be prevented by giving 1 hour prior to sleep at night. Cognitive and behaviourial side effects like aggressive outburst, hyperactivity is known to occur in children. When indicated for stopping, it should be with drawn very gradually to avoid withdrawal seizures. Tolerance may develop in only one third of the patients (110). Common adverse events to be recognized include behaviour changes (aggression, hyperactivity), sleep disturbances, constipation and weightgain.

Clonazepam : Clonazepam is used as add on drug for all clinical forms of epilepsy in infants and children (111). It is effective in myoclonic, absence and focal seizures. It is particularly effective in reading epilepsy, Juvenile myoclonic epilepsy and epileptic encephalopathy. It is advisable to start the treatment with 0.01-0.02 mg/kg/day and slowly increase to maximum of 0.1 mg/kg/day. It can be divided in two divided doses (smaller dose at day and larger dose at night) or single night time dose. Sedation, drowsiness, hypersalivation, hyperactivity can be major concern with use of clonazepam. Withdrawl symptoms with seizure recurrence and status epilepticus are known to occur after prolonged usage. Lamotrigine : Lamotrigine is an adjunct to refractory focal or generalized epilepsy (112). It is useful in generalized tonic seizures and atypical absence seizures of lennoxgestaut syndrome (113). It is broad spectrum AED effective in all seizure types except Myoclonic seizures of JME and dravet syndrome. Lamotrigine is synergistic with valproate for drug resistant generalized epilepsy. It has minimal sedation, lacks cognitive and behavioural side effects. The dose should initially be 0.5mg/kg(alone), 0.2mg/kg (withVPA), and 0.6mg/kg (with phenobarbitone, phenytoin, carbamazepine); it should be doubled every 2 weeks to a maximum of 15mg/kg (alone) and 5mg/kg/day (withVPA) and higher when used with enzyme inducers. Development of allergic skin rash is most common and most serious adverse effect of LTG. The other rare but serious adverse event reported with use of LTG includes cardiac arrhythmia, and sudden unexpected death (114). It has significant drug interaction with valproate and other enzyme inducing drugs like CBZ, PHT.

19

Levetiracetam : It is a broad spectrum AED effective as an adjunctive treatment in focal seizure in children more than 4years of age, myoclonic seizures in adolescents >12 years of age and primary generalized tonic clonic seizures in children>6 years of age (115-117). It is a good alternative to valproate in adolescents with JME. It has a relatively good safety profile with minimal side effects like dizziness, somnolescence and behaviourial disturbances. Caution in use among children with behaviourial issues. The drug does not require any hematological or drug level monitoring. It is safe in liver disease. The drug is started at dose of 5-10 mg/kg/day, can be titrated to maintenance dose of 20-40 mg/kg/day given in two divided doses. Topiramate : Topiramate is another broad spectrum AED useful asan adjunct in refractory focal seizures. It is effective in all seizure types and is used in epileptic encephalopathies, and generalized epilepsies like Lennox Gastaut syndrome (118). It is particularly useful in certain syndromes like infantile spasms (119, 120) and Dravet's syndrome (121). At present, its use as first line mono therapy in newly diagnosed epilepsy is not recommended be cause of a significant adverse effect profile. It should be started at a dose of 0.5-1mg/kg in bid doses, escalated weekly or biweekly, up to a maximum of 5-10mg/kg (122); Higher doses (10- 30mg/kg) and rapid escalation(every 3days) are considered in special situations (infantile spasms, status epileptic us); however, there could be a higher incidence of adverse events with high doses. Serious adverse effects include abnormal thinking, difficulty in concentration, memory impairment, behavioral and cognitive problems. Other adverse effects include weight loss, metabolic acidosis, nephrolithiasis, oligohydrosis, hyperthermia. Zonisamide : Zonisamide is another broad spectrum AED particularly useful in focal seizures with or without GTCSs. It has been found useful as adjunct in Lennox-Gastaut syndrome and juvenile myoclonic epilepsy (123). It is used in doses of 1-2 mg/kg/day titrated to maintenance dose of 4-8 mg/kg/day. Serious adverse effects include cognitive impairment, word finding difficulty, weight loss, anorexia, nephrolithisasis and oligohidrosis. Lacosamide : Lacosamide is used in children > 16 years of age with refractory focal seizures with or without secondary generalization. IV preparations are useful in adults with refractory focal seizures. Pediatric experience is limited to few retrospective data on a small number of patients with an efficacy rate of 30- 50% (124, 125). Reported side effects include dizziness, headache, diploplia, nausea and vomiting.

20

Rufinamide : Rufinamide has been recently used as an adjunctive drug in the treatment of seizures associated with Lennox–Gastaut syndrome (126). In children < 30 kg: start with 200 mg/day titrated to maximum of 1000 mg/day (400 mg/day when given with valproate). Seizure reduction is almost one third in children with LGS with addition of rufinamide (127). The most commonly observed adverse are headache, dizziness, fatigue, somnolence, and nausea. It is contraindicated in patients with familial short QT syndrome. Stiripentol : Stiripentol is an AED used as an adjunctive drug for generalized tonic-clonic seizures in patients with Dravet syndrome (128). In a RCT, children with Dravet syndrome refractory to valproate and clobazam were randomized to receive stirepentol and placebo. Children who received stiripentol [70%] had a better response as compared to placebo group [10%] (129). There are multiple drug interactions with mnay other AED. Tiagabine : As add-on in refractory partial seizures (130).It is not recommended as mono therapy in children with newly diagnosed epilepsy. NCSE (non convulsive status epileptic us) can occur in about 8% of patients and should be carefully excluded in children whose seizures / mental status deteriorate on treatment (131). It is used in an initial daily dose 0.1mg/kg TID; increased weekly by 0.1mg/kg; maximum daily dose 0.4 and 0.7mg/kg (un induced and induced, respectively). In children over 12years, it can be initiated at 4mg/day; total daily dose increased by 4mg in week2 (divided doses); then increased by 4 to 8mg/day (divided doses) each week until clinical response is achieved or to a maximum daily dose of 32mg/dis reached.

14. Drug resistant Epilepsy : Drug resistant epilepsy has been defined by the International League Against Epilepsy (ILAE) as a failure of adequate trials of two tolerated, appropriately chosen and used antiepileptic drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom (132). When faced with a child with uncontrolled epilepsy, always try and confirm whether the diagnosis is correct. Often non-epileptic conditions may be confused as seizures. Also the type of seizure and if possible, a correct diagnosis of the specific epilepsy syndrome may facilitate correct choice of drug. Errors in management must be looked for as pseudo-intractability often results from an inadequate dose, irrational poly therapy or wrong choice of AED e.g. carbamazepine for absence seizures. Every effort should be made to keep a seizure diary and see if a specific AED is actually helping or in some cases worsening the

21

seizures e.g. carbamazepine / oxcarbazinemay worsen and sometimes even in duce absence/myoclonic seizures. It is best to refer intractable epilepsy early to a tertiary center for appropriate evaluation (including high-end MRI using standardized epilepsy protocols, video EEGetc) as well as to get guidance on management options like newer AEDs, theke to genicdiet and surgery. Uncommon but potentially reversible causes of epilepsy and cognitive decline may be immune-related and high index of suspicion will prevent missing the diagnosis (133, 134)

15. Non pharmacological treatment : KetogenicDiet and Modified Atkins diet in Epilepsy : Ketogenic diet (KD) has been traditionally used in intractable childhood epilepsy (135). It is a medically supervised high fat, low carbohydrate, and restricted protein diet that maintains a chronic state of ketosis while providing proteins and calories for adequate growth. Composition of ketogenic diet is 80% fat, 15% protein, 10% carbohydrate making it a 4:1 diet ratio of fat: non fat (136). Ratio of Fat: protein range from 2.5:1 to 4:1. The traditional ketogenic diet, with 4:1 ratio of fat: carbohydrate + protein has its drawbacks. It restricts calories and fluids, and requires a weighing of foods. Protein is generally restricted to 1 g/kg/day, with the majority of the remaining calories in the form of fat. This may lead to hypoproteinemia and growth problems. Hospitalization is generally advocated for diet initiation in fasting protocol but for non-fasting protocol out patient initiation is possible.Compliance with ketogenic diet is challenging because of acceptability and need for accurate measurement of food preparations. Most of side effects of ketogenic diet are transient and includes constipation, nausea, sleepiness, hypoglycaemia, renal stones, abnormalities of renal and liver functions and hyper cholesterolemia. It can be used with both non- vegetarian and vegetarian diets at any age and for all types of seizures. It should be tried in all children above the age of 1year with drug - resistant epilepsy, especially those who are not a surgical candidates or where surgery cannot be performed due to availability/affordability issues. Referral to centers providing the KD should be considered once adequate trials of two AED shave failed, suggestive of drug resistant epilepsy. The diet should be considered a failure if there is no benefit in 3-6months and it should be discontinued after this time. In responders, it should be continued for 2-3year after which it is gradually tapered. Ketogenic diet is well tolerated and is effective with almost half of patients showing >50% seizure reduction (137).

This diet encourages intake of fat and restriction of carbohydrates but does not restrict protein intake or daily calories or fluid. It allows a meal with 60% fat, 30% protein and

22

10% carbohydrate. It was adapted to the cultural and financial status of families. Modified Atkins diet has been used effectively in children and adults with intractable childhood epilepsy. Modified Atkins diet induces ketosis but without fluid, calorie or protein restriction nor the requirement for fasting, food weighing or hospitalization. It is effective and well tolerated in children with intractable epilepsy (138, 139). It's more palatable and less restrictive when compared to ketogenic diets. Efficacy of MAD in Indian children has been evaluated with 52% of children with refractory epilepsy showing >50% seizure reduction (140). Other dietary treatment includes Low glycemic index treatment (LGIT) diet which is more liberal than KD with carbohydrate content of glycemic index of 50 or lower. Surgical treatment : All infants and children with refractory partial or generalized epilepsy should be referred as early as possible to a comprehensive epilepsy center for possible surgical evaluation. Surgery requires definite demonstration that the seizures originate from a region that can be removed with minimal risk of disabling neurologic or cognitive dysfunction. Patients with lesional epilepsy rather than crytogenic or idiopathic respond better to surgical resection. Patients with discrete lesions such as mesial temporal sclerosis (MTS), low-grade neoplasms, vascular malformations, encephalomalacia from stroke or trauma, and focal cortical dysplasias are common surgical candidates (141). A good surgical outcomes are also possible in patients with normal MRI if the seizures are electrographically well localized to the temporal lobe.This process should be expedited if there is an imaging documented unilateral lesion or if the epilepsy is having significant effects on the child's development. Video-EEG monitoring, positron emission tomography (PET), or ictal single-photon emission computed tomography (SPECT) help in confirming the location of the epileptic focus. Ideal surgically remediable syndromes (142) include 1. Hemispheric epilepsies with pre - existing contra lateral hemiplegias / visual

field defects caused by large unilateral gliotic lesions / atrophy, Rasmussen's encephalitis, hemispheric dys – plasias etc,where hemispherectomy / hemis- pherotomies could offer a possible surgical cure.

2. Discrete lesions without involvement of functional motor, visual and language cortex, where a lesionectomy will often result in complete cure. Common lesions would include developmental tumors, corticaldysplasias, AVMs etc. Some times lesions like large dysplasias / infarcts may need lobectomies / multi- lobar resections.

3. Mesialtemporallobe epilepsy caused often by hippo campalsclerosis is notun common in teenagers and is a men able to an anterior temporallobectomy.

Drop attacks with injuries respond well to corpuscallosotomy and should be offered as a palliative procedure.

23

Status epileptic us : Children with seizure clustersare at increased risk of SE. Use of oral CLB or DZP for 2days may be beneficial in decreasing this risk. A child who is brought to the physician from an extra mural settings till convulsing should be considered to be in SE; the minimum time for this definition of SE is regarded as >5 minutes (143). The definition of refractory status epileptic us (RSE) is variable, but most would agree that patients who fail first- and second-line therapy have RSE (144). Super refractory status epileptic us is defined as the SE that continues or recurs 24 h or more after the onset of anaesthetic therapy or cases where status epilepticus recurs on the reduction or withdrawal of anaesthesia (145). The term "new-onset refractory status epilepticus" (NORSE) syndrome has been used to describe an extremely severe and prolonged SE occurring both in young adult and children with previous good health conditions (referring to an extensive clinic and laboratory work-up, including neuropathology) and a poor prognosis (146). There is an increased risk of irreversible neuronal injury after 30minutes of convulsive status (147). The diagnosis of Febrile infection–related epilepsy syndrome (FIRES) was made in a previously well child with (a) acute onset of a refractory seizure disorder requiring intensive care treatment in the setting of an encephalitis- like illness; (b) no infectious pathogen found on testing of CSF, serum, or other body fluids; and (c) evolution to a chronic intractable epilepsy without an anti convulsant- free latent period if the patient survived the acute phase (148). A management algorithm (149-154) is provided for status epileptic us in figure

24

25

26

Depending on availability, infrastructure, experience and expertise NOTE:ꇚ: If the child is already on these AEDs: For Phenytoin ꇜ6 mg/kg/day, Phenobarbitone ꇜ5 mg/kg/day, Valproate ꇜ30 mg/kg/day, Levetiracetam ꇜ30 mg/kg/day OR If few doses of AED have been missed or child has vomiting/diarrhea: Give half the loading dose of the respective AED. If the child is receiving AEDs at doses higher than mentioned in the sentence above, avoid loading with that AED and move to next step

References : st 1. Pal DK. Epilepsy control in the 21 century: leave no child behind. Epilepsia

2003; 44:273-275. 2. Shiffman RN, Shekelle P, Overhage JM, Slutsky J, Grimshaw J, Deshpande

AM. Standardized Reporting of Clinical Practice Guidelines : A proposal from the Conference on Guidelines Standardization. Ann Intern Med 2003 ; 139:493-498

3. MizrahiEM,Watanabe K. Symptomatic neonatal seizures : In: RogerJ, Bureau M. Epileptic Syndromes in Infancy, Childhood and Adolescence, 4thed. London: John Libbey; 2005.p.16-17.

4. Bauder F, Wohlrab G, Schmitt B. Neonatal seizures:eyes open or closed. Epilepsia 2007; 48:394-396

5. Co JP, Elia M, Engel JJr, Guerrini R, Mizrahi EM Moshé SL.Proposal of anal gorithm for diagnosis and treatment of neonatal seizures in developing countries. Epilepsia2007;48:1158-1164.

6. Sankar MJ, Agarwal R, Aggarwal R, Deorari AK, Paul VK. Seizures in the newborn. Indian J Pediatric 2008;75:149-155.

7. Mc Coy B, Hahn CD. Continuous EEG monitoring in the neonatal intensive care unit. J Clin Neurophysiol 2013;30:106-114.

8. Castro Conde JR, Hernánde Z Borges AA, Doménech Martínez E, González Campo C, Perera Soler R. Midazolamin neonatal seizures with no response to phenobarbital. Neurology 2005;64:876-879.

9. Slaughter LA, Patel AD, Slaughter JL. Pharmacological treatment of neonatal seizures: a systematic review. J Child Neurol 2013;28:351-364

10. Noh GJ, Asher YJT, Graham JM. Clinical review of genetic epileptic encephalopathies. Eur J Med Genet 2012;55:281-298.

11. Guidelines on Neonatal Seizures - World Health Organization. Accessed fromURL: www.who.int/iris/bitstream /10665 /77756 /1 / 9789241548304 _eng.pdf. Accessed on 16 Dec 2013

12. Bergh AT, Carpio A, Forsgren L et al. Recommendations for a definition of acute symptomatic seizure. Epilepsia 2010;51:671-675

13. Beleza P. Acute symptomatic seizures, a clinically oriented review. The Neurologist 2012:18: 109-119

14. Murthy JM, Yangala R. Acute symptomatic seizures-incidence and etiological spectrum : a hospital-baseds tudy from South India. Seizure 1999; 8:162-165.

28

15. Balasubramanian S, Shivbalan S, Kumar PS. Hypocalcemia due to vitaminD deficiency in exclusively breast feed infants. Indian Pediatr 2006;43:247- 251.

16. Agrawal A, Timothy J, Pandit L, Manju M. Post-traumatic epilepsy: an overview. Clin Neurol Neurosurg2006;108:433-439.

17. Capovilla G, Mastrangelo M, Romeo A, Vigevano F. Recommendations for the management of febrile seizures, Adhoc task force of LICE guidelines commission. Epilepsia 2009;50(1):2-6

18. Sadleir LG, Scheffer IE. Febrile seizures. BMJ2007;334:307-311. 19. Grill MF, Ng YT. "Simple febrile seizures plus (SFS+)": more than one febrile

seizure within 24 hours is usually okay. Epilepsy Behav. 2013;27:472-6. 20. Singhi PD, Srinivas M. Febrile seizures. Indian Pediatric 2001;38:733–740.

21. AAP Subcommittee on febrile seizures. Febrile Seizures: Guideline for the Neurodiagnostic Evaluation of the Child With a Simple Febrile Seizure. Pediatrics 2011;127:389-394.

22. Bhattacharyya M,Kalra V,Gulati S. Intra nasal midazolam vs. rectal diazepamin acute childhood seizures. Pediatric Neurol 2006;34:355-359.

23. Khosroshahi N, Faramarzi F, Salamati P, HaghighiSM,Kamrani K. Diazepam versus clobazam for intermittent prophylaxis of febrile seizures. Indian Journal of Pediatrics2011;78(1):38–40.

24. Gulati S, Saini D, Pandey RM, Kalra V. A randomized controlled trial to compare efficacy of oral clobazam with oral diazepam for prophylaxis of febrile seizures. Neuro pediatrics 2006;37:13

25. ILAE Neuroimaging Commission. ILAE Neuroimaging Commission Recommendations for Neuroimaging of Patients with Epilepsy. Epilepsia 1997;38:1-2.

26. Singhi P, Singhi S. Neurocysticercos is in children. J Child Neurol2004;19:482-492

27. DelBrutto OH. Neurocysticercosis: a review. The Scientific World Journal 2012; 1-8

28. Wasay M, Kheleani BA, Moolani MK, Zaheer J, Pui M, Hasan S, etal. Brain CT and MRI findings in 100 consecutive patients within tracranialtu berculoma. J Neuroimaging 2003;13:240-247.

29

29. Pretel lEJ,Martinot CJr, Garcia HH, Alvarado M, Bustos JA, Martinot C. Cysticercosis Working Groupin Peru. Differential diagnosis between cerebraltuberculos is and neurocysticercos is by magnetic resonance spectroscopy. J Comput Assist Tomogr 2005;29:112-114.

30. Garg RK, Sinha MK. Multiple ring enhancing lesions of the brain. J Postgrad Med 2010;56:307-316

31. Del Brutto OH, Roos KL, Coffey CS, Garcia HH. Meta-analysis: Cysticidal drugs for neuro - cysticercosis: albendazole and praziquantel. Annals Int Med 2006;1:43-51.

32. Singhi P, Daya lD, Khandelwal N. One week versus four weeks of albendazole therapy for neuro cysticercos is in children : arandomized, place be-controlled double blind trial. Pediatric Infect Dis J2003;22:268-272.

33. Thussu A, Arora A, Prabhakar S, Lal V, Sawhney IM. Acute symptomatic seizures due to single CT lesions : how long to treat with anti epileptic drugs ? NeurolIndia 2002;50:141-144.

34. Camfield P, Camfield C. Epileptic syndromes in childhood : clinical features, outcomes, and treatment. Epilepsia 2002;43:27-32.

35. Guerrini R, Pellacini S. Benign childhood focal epilepsies. Epilepsia 2012;53 (4) :9-18

36. Panayiotopoulos CP. Early-on set benign childhood occipital seizuresus ceptibility syndrome: a syndrome to recognize. Epilepsia 1999; 40: 621- 630.

37. Prats JM, Garaizar C, García-Nieto ML, Madoz P.Anti epileptic drugs and a typical evolution of idio pathicpartial epilepsy. Pediatric Neurol 1998;18:402- 406.

38. Fran kLM, Enlow T, Holmes GL, Manasco P, Concannon S ,Chen C, etal. Lamictal (lamotrigine) mono therapy for typical absence seizures in children. Epilepsia 1999;40:973-979.

39. CamfieldC, Camfield P. Management guidelines for children with idiopathic generalized epilepsy. Epilepsia 2005;46(9):112-116

40. Reutens DC, Berkovic SE. Idiopathic generalized epilepsy of adolescence : are the syndromes clinically distinct ? Neurology 1995;45:1469-1476

41. Marson AG, Al- Kharusi AM, Alwaidh M, Appleton R, Baker GA, Chadwick DW, et al. SANAD Study group: The SANAD study of effectiveness of valroate, lamotrigine, or top iramate for generalised and unclassifi ableepil epsy: an unblindedr and omised controll edtrialLancet2007;369:1016-1026.

42. Vanessa Delgado Nunesetal, Diagnosis and management of the epilepsies in Adult and children: summary of updated NICE guidance BMJ 2012;344:e28

30

43. American Clinical Neurophysiology Society.Guidelines1, 2:Minimum technical requirements for performing clinicale lectroencephalography. JClin Neurophysiol 2006;23:86-91.

44. Lorie Hamiwka, MD, Neetu Singh, BSc, Silvia Kozlik, REEG, Feasibility and Clinical Utility of Early Electroencephalogram (EEG) in Children With First Seizure. Journal of Child Neurology Volume 23 Number 7 July 2008 762-765.

45. Gretchen M. Brophy Rodney Bell Jan Claassen, Guidelines for the Evaluation and Management of Status Epilepticus Neuro crit Care (2012) 17:3–23

46. Wright NB. Imaging in epilepsy: a paediatric perspective. Br JRadiol2000;74:575-589.

47. William D. Gaillard, Catherine Chiron, J. Helen Cross, Guidelines for imaging infants and children with recent-onset epilepsy. Epilepsia, 50(9):2147–2153, 2009.

48. UldallP, AlvingJ, HansenLK, KibaekM, BuchholtJ. Themis diagnosis of epilepsy in children admitted to atertiary epilepsy centre with paroxy smal events. Arch Dis Child2006; 91:219-221.

49. K Armon, T Stephenson, R MacFaul, An evidence and consensus based guideline for the management of a child after a seizure. Emerg Med J 2003;20:13–20.

50. HirtzD, BergA, BettisD. Practice parameter: treatment of the child with afirst unprovoked seizure:

Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 2003;60:166-175.

51 Stroin kH, Geerts AT, Van Donselaar CA, Peters AC, Brouwer OF, Peeters EA, etal. Status epilepticus in children with epilepsy: Dutch study of epilepsy in childhood. Epilepsia 2007; 48:1708- 1715.

52. Holsti M, Sill BL, Firth SD, Filloux FM, Joyce SM, Furnival RA. Pre hospital intra nasal midazolam for the treatment of pediatric seizures. Pediatric Emerg Care 2007; 23:148-153.

53. Lesley K. Humphries, PharmD, Treatment of Acute Seizures: Is Intranasal Midazolam a Viable Option ? J Pediatric Pharmacol Ther 2013;18(2):79–87

31

54. Arya R, Gulati S, Kabra M. Intranasal versus intravenous lorazepam for control of acute seizures in children: A randomized open-label study. Epilepsia, 52(4):788–793, 2011.

55. Brodie MJ. Medical therapy of epilepsy : when to initiate and combine. J Neurol 2005; 252:125-130.

56. O'Dells. Initiation and discontinuation of AEDs. Neurol Clin 2001;19:289- 311.

57. Bialer M. Extended-release formulations for the treatment of epilepsy. CNS Drugs 2007;21:765-774.

58. De Silva M, Mac Ardle B, Mc Gowan M, Hughes E, Stewart J, Neville BG. Randomised comparative mono therapy trial of phenobarbitone, phenytoin, carbamazepine, or sodium valproate for newly diagnosed childhood epilepsy. Lancet 1996;347 : 709-713.

59. Patsalos PN, Berry DJ, Bourgeois BF, Cloyd JC, Glauser TA, Johannessen SI. Antiepileptic drugs-best practice guidelines for the rapeutic drug monitoring : apposition paper by the sub commission on the rapeutic drug monitoring, ILAE Commissionon Therapeutic Strategies. Epilepsia 2008; 49:1239-1276.

60. Erik K. St. Louis, Monitoring Antiepileptic Drugs: A Level-Headed Approach. Current Neuropharmacology, 2009, 7, 115-119

61. Specchio LM, Beghi E. Should anti epileptic drugs be withdrawn in seizure- free patients ? CNS Drugs 2004 ; 18 : 201-212.

62. Matricardi M, Brinciotti M, Benedetti P. Out come after discontinuation of anti epileptic drug therapy in children with epilepsy. Epilepsia 1989; 30:582- 589.

63. Verrotti, C. D'Egidio, S. Agostinelli, Anti epileptic drug withdrawal in childhood epilepsy: What are the risk factors associated with seizure relapse? European Journal of Paediatric Neurology 16 (2012) 599 e604.

64. Serra JG, Montenegro MA, Guerreiro MM. Anti epileptic drug withdraw a lin childhood: does the duration of tapering off matter for seizure recurrence? J Child Neurol 2005; 20: 624-626.

65. Ranganathan LN, Ramaratnam S. Rapid versus low withdrawal of anti epileptic drugs.Cochrane Database Syst Rev2006; 19:CD 005003.

66. Beghi E, Giussani G, Grosso S. Withdrawal of anti epileptic drugs: Guidelines of the Italian League Against Epilepsy Epilepsia, 54(Suppl. 7):2–12, 2013

67. Anne T. Berg, Samuel F. Berkovic, Martin J. Brodie, Revised terminology and concepts for organization of seizures and epilepsies: Report of the ILAE Commission on Classification and Terminology, 2005–2009 Epilepsia, 51(4):676–685, 2010.

32

68. Nabbout R, Dulac O.Epileptic encephalopathies: a brief overview. J Clin Neurophysiol. 2003 Nov-Dec;20(6):393-7

69. Shields WD. Diagnosis of infantile spasms, Lennox-Gastaut syndrome, and progressive myoclonic epilepsy.Epilepsia2004;45:2-4.

70. Mackay MT, Weiss SK, Adams-WebberT,AshwalS,StephensD, Ballaban- GillK, etal. American Academy of Neurology; Child Neurology Society PracticeParameter: Medical treatment of infantile spasms: report of the American Academy of Neurology and the Child Neurology Society.

Neurology 2004;62:1668-1681. 71. LuxAL, Edwards SW, HancockE, JohnsonAL, KennedyCR, Newton

RW;United Kingdom Infantile Spasms Study. The United Kingdom Infantile Spasms Study (UKISS) comparing hormone treatment with vigabatrin on developmental and epilepsy out come stoage14 months: a multi center and

omizedtrial. Lancet Neuro l2005;4:712-717. 72. C.Y. Go, M.T. Mackay, S.K. Weiss et al, Evidence-based guideline update:

Medical treatment of infantile spasms. Neurology 2012;78;1974-1980.

73. Shields WD. Diagnosis of infantile spasms, Lennox-Gastaut syndrome, and progressive my colonic epilepsy. Epilepsia2004;45:2-4.

74. Eriksson AS, Nergardh A, Hoppu K.The efficacy of lamotrigine in children and adolescents with refractory generalized epilepsy: arandomized, double- blind, cross over study. Epilepsia1998;39:495-501.

75. Sachdeo RC, Glauser TA, Ritter F, Reife R, Lim P, Pledger G.Adouble-blind, rand omized trial of topiramate in Lennox-Gastaut syndrome. Topiramate YL Study Group. Neurology 1999; 52:1882-1887.

76. Korff CM, Nordli DR Jr. Epilepsy syndromes in infancy. Pediatric Neurol2006; 34:253-263.

77. K röll-Seger J, Portilla P,Dulac O,Chiron C. Topiramate in the treatment of highly refractory patients with Dravet syndrome. Neuro pediatrics

2006;37:325-329. 78. Brigo F, Storti M. Anti epileptic drugs for the treatment of severe myoclonic

epilepsy in infancy. Cochrane Database of Systematic Reviews 2013, Issue 11. Art. No.: CD010483. DOI: 10.1002/14651858.

79. William O. Tatum IV, Mesial Temporal Lobe Epilepsy. Clin Neurophysiol 2012;29: 356–365.

33

80. Wiebe S, Blume WT, Girvin JP, Eliasziw M. Effectiveness and efficiency of surgery for temp or all oBE epilepsy study group; Arandomized, controlled trial of surgery for temporal-lobeepilepsy. NEngl JMed 2001;345:311-318.

81. Christian G. Bien, Christian E. Elger, Epilepsia partial is continua: semiology and differential diagnoses. Epileptic Disord 2008; 10 (1): 3-7

82. Freeman JM. Rasmussen's syndrome: progressive auto immune multi-focal encephalopathy. Pediatric Neurol 2005;32:295-299.

83. Aldenkamp AP,WeberB,Overweg-Plandsoen WC, Reijs R,van MilS. Educational under-achievement in children with epilepsy: amodel to predict the effects of epilepsy on educational achievement. J Child Neuro l2005;20:175-180.

84. Sanchez-Carpintero R, Neville BG. Attention ability in children with epilepsy. Epilepsia 2003; 44:1340-1349.

85. Nordli DR Jr. The management of epilepsy in children: cognitive and behavioral side effects. Rev Neurol Dis 2004;1:4-9.

86. Lagae L. Cognitive side effects of anti-epileptic drugs. The relevance in childhood epilepsy. Seizure 2006; 15: 227- 234.

87. Berg AT, Langfitt JT, Testa FM etal. Global cognitive function in children with epilepsy: A community based study. Epilepsia 2008; 49:608-614.,

88. Choudhary A, Gulati S, Sagar R, Kabra M, Sapra S. Behavioral Co Morbidity In Children And Adolescents With Epilepsy: A Cross Sectional Study. Journal of Clinical Neuroscience (in press)

89. Achenbach TM, Ruffle TM. The Child Behavior Check list and related forms for assessing behavioral / emotional problems and competencies. Pediatric Rev 2000; 21:265-271.

90. Van Rijckevorsel K. Cognitive problems related to epilepsy syndromes, especially malignant epilepsies. Seizure 2006; 15: 227-234.

91. Beaumanoir A, Bureau M, Deonna T, Mira L, Tassinari CA. Continuous Spikes and Waves, During Slow Sleep Electrical Status Epilepticus during Slow Sleep. London: John Libbey; 1995.

92. Bartha AI, Shen J, Katz KH, Mischel RE, Yap KR, Ivacko JA. Neonatal seizures: multi center variability in current treatment practices. Pediatric Neurol 2007; 37:85-90.

34

st 93. Kwan P, Brodie MJ. Phenobarbital for the treatment of epilepsy in the 21 century : a critical review. Epilepsia 2004;45:1141-1149.

94. Camfield C, Camfield P. Management guidelines for children with idiopathic generalized epilepsy. Epilepsia 2005;46:112-116.

95. Fischer JH, Patel TV, Fischer PA. Fos phenytoin: clinical pharmacokinetics and comparative advantages in the acute treatment of seizures. Clin Pharmacokinet. 2003;42(1):33-58. Review.

96. Guerrini R.Valproate as a main stay of therapy for pediatric epilepsy. Pediatric Drugs 2006;8:113-129.

97. Verrotti A, Greco R, Latini G, Chiarelli F. Endocrine and metabolic hanges in epileptic patients receiving valproicacid. J Pediatric Endocrinol Metab 2005;18: 423-430.

98. Russell S. Carnit in easanant idote for acute valproate toxicity in children. Curr Op in Pediatric 2007;19:206-210.

99. Wheless JW, Clarke DF, Carpenter D.Treatment of pediatric epilepsy: expert opinion. J Child Neurol 2005;20:S1-56

100. Eeg-Olofsson O, Nilsson HL, Tonnby B, Arvidsson J, Grahn PA, Gylje H,etal. Diurnal variation of carbamazepine and carbamazepine-10,11- epoxidein plasma and saliva in children with epilepsy : a comparison between conventional and slow-release formulations. J Child Neurol 1990;5:159-165.

101. Ryan SW ,Forsythe I, Hartley R, Haworth M, Bowmer CJ. Slow release carbamazepine in treatment of poorly controlled seizures. Arch D is Child 1990;65:930-935.

102. Parmeggiani A, Fraticelli E, Rossi PG. Exacerbation of epileptic seizures by carba-mazepine : report of 10 cases. Seizure 1998; 7: 479- 483.

103. Bang LM, Goa KL. Spotlight on oxcarbazepine in epilepsy. CNS Drugs 2004; 18: 57-61.

104. Albani F, Grassi B, Ferrara R. Immediate (overnight) switching from carbamazepine to oxcarbamazepine mono therapy is equivalent to a progressives witch. Seizure 2004; 13:254-263.

105. Bajaj AS. Intermittent clobazamin febrile seizures: an Indian experience. Pediatric Neurol 2005;3:19-23.

106. Chellam K. Intermittent clobazam therapy in febrile seizures. Indian J Pediatric 2005;72:31-33.

35

107. Himizu H. Use of clobazam for the treatment of refractory complex partial seizures. Seizure 2003;12:282-286.

108. Munn R, Farrell K. Open study of clobazamin refractory epilepsy. Pediatric Neurol1993;9:465-469.

109. Satish Chandra P. Longterm use of clobazamin the management of intractable epilepsy: aprospective study. Neurol Annals1998;46:284-287.

110. Remy C. Clobazam in the treatment of epilepsy: a review of literature. Epilepsia 1994; 35 suppl: 588-591.

111. Camfield P, Camfield C. Benzodiazepine used primarily for chronic treatment (clobazam, clonazepam, clorazepate and nitrazepam). In: Shrovon

rd S, Perruca E, EgelJrr, eds. The treatment of epilepsy. 3 edition. Oxford, Wiley-Blackwell. 2009.p.421-430.

112. Vajda FJ, Dodd S, Horgan D. Lamotrigine in epilepsy, pregnancy and psychiatry--a drug for all seasons?. J Clin Neuro sci. 2013 Jan;20(1):13-6.

doi: 10.1016/j.jocn.2012.05.024. Epub 2012 Oct 1. 113. Hancock EC, Cross JH. Treatment of Lennox-Gastaut syndrome.Cochrane

Database Syst Rev. 2013 Feb 28; 2: CD003277. doi : 10.1002/14651858. CD003277. pub3.

114. Aurlien D, Tauboll E, Gjerstad L. Lamotrigine in idiopathic epilepsy- increased risk of cardiac death. Acta Neuro lSc and 2007; 115: 199-203.

115. GlauserTA, AyalaR, EltermanRD, MitchellWG, VanOrmanCB, GauerLJ, etal; on behalf of the N159 Study Group. Double-blind placebo controlled trial of adjunctive levetiracetam in pediatric partial seizures. Neurology

2006; 66:1654-1660. 116. Grosso S, Franzoni E, Coppola G, Lannetti P, Verrotti A, Cordelli DM, etal.

Efficacy and safety of levetiracetam : An add-on trial in children with refractory epilepsy. Seizure 2005;14:248-253.

117. Crest C, Dupont S, Leguern E, Adam C, Baulac M. Levetiracetam in progressive myoclonic epilepsy : an exploratory study in 9 patients.

Neurology 2004; 62: 640-643. 118. French JA, Kanner AM, Bautista J. Efficacy and to lerability of the new anti

epileptic drugs II. Treatment of refractory epilepsy. Report of the therapeutics and technology assessment sub-committee and quality standards sub committee of the American Academy of Neurology and the American

Epilepsy Society. Neurology 2004;62:1261-1273.

36

119. Glauser TA. Topiramate in the catastrophic epilepsies of childhood. J Child Neurol 2000;15:14-21.

120. Hosain SA. Topiramate for the treatment of infantile spasms. J Child Neurol 2006;21:17-19.

121. Kröll-Seger J, Portilla P, Dulac O,Chiron C. Topiramate in the treatment of highly refractory patients with Dravet syndrome. Neuro pediatrics 2006;37:325-329.

122. Albsoul-Younes AM. Topiramate slow dose titration: improved efficacy and tolerability. Pediatric Neurol2004;31:349-352.

123. Vossler DG, Conry JA, Murphy JV. Zonisamide for the treatment of myoclonic seizures in progressive myoclonic epilepsy: an open-label study. Epileptic Disord 2008;10:31-34.

124. Heyman E, Lahat E, Levin N, Berkovitch M, Gandelman-Marton R. Preliminary efficacy and safety of lacosamide in children with refractory epilepsy. Eur J Paediatr Neurol 2012;16:15-19.

125. Rastogi RG, Ng YT. Lacosamide in refractory mixed pediatric epilepsy: a prospective add-on study. J Child Neurol 2012;27:492-495.

126. Wier HA, Cerna A, So TY. Rufinamide for pediatric patients with Lennox- Gastaut syndrome : a comprehensive overview. Paediatric Drugs 2011;13:97-106.

127. Hsieh DT, Thiele EA. Efficacy and safety of rufinamide in pediatric epilepsy. Ther Adv Neurol Disord 2013; 6: 189-198.

128. Plsker GL. Stiripentol: in severe Myoclonic epilepsy of infancy (dravet syndrome). CNS Drugs 2012; 26: 993-1001.

129. Chiron C, Marchand MC, Tran A, Rey E, d'Athis P, Vincent J, et al. Stiripentol in severe myoclonic epilepsy in infancy: a randomised placebo-controlled syndrome-dedicated trial. STICLO study group. Lancet 2000;356:1638- 1642.

130. Pellock JM. Tiagabine (gabitril) experience in children. Epilepsia 2001; 42:49-51.

131. Balslev T, Uldall P, Buchholt J. Provocation of non-convulsive status epileptic us by tiagabine in three adolescent patients. Eur J Pediatric Neurol 2000;4:169-170.

37

132. Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Allen Hauser W, Mathern G, Moshé SL, Perucca E, Wiebe S, French J. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia. 2010 Jun;51(6):1069-77. doi: 10.1111/j.1528-1167.2009.02397.x. Epub 2009 Nov 3.133. Pandit AK, Ihtisham K, Garg A, Gulati S, Padma MV, Tripathi M. Autoimmune encephalitis: A potentially reversible cause of status

epilepticus, epilepsy, and cognitive decline. Ann Indian Acad Neurol 2013;16:577 84.

134. Chakraborthy B, Tripathi M, Gulati S, Yoganathan S, Pandit AK, Sinha A, Rathi BS. Pediatric Anti-N-Methyl-D-Aspartate (NMDA) Receptor Encephalitis: Experience of a Tertiary Care Teaching Center from North India. J Child Neurol. 2013 Oct 4. [Epub ahead of print].

135. Lefevre F, Aronson N. Ketogenic diet for the treatment of refractory epilepsy in children: A systematic review of efficacy. Pediatrics. 2000 Apr; 105: E46.

136. Vining EP, Freeman JM, Ballaban-Gil K, Camfield CS, Camfield PR, Holmes GL et al. A multi center study of the efficacy of the ketogenic diet.

Arch Neurol. 1998; 55: 1433-7. 137. Sharma S, Gulati S, Kalra V, Agarwala A, Kabra M. Seizure control and

biochemical profile on the ketogenic diet in young children with refractory epilepsy—Indian experience. Seizure 2009; 18: 446-449.

138. Kossoff EH, Krauss GL, Mc Grogan JR, Freeman JM. Efficacy of the Atkins diet as therapy for intractable epilepsy. Neurology. 2003 Dec

23;61(12):1789-91 139. Kossoff EH, McGrogan JR, Bluml RM, Pillas DJ, Rubenstein JE, Vining EP.

A modified Atkins diet is effective for the treatment of intractable pediatric epilepsy. Epilepsia. 2006 Feb;47(2):421-4.

140. Sharma S, Sankhyan N, Gulati S, Agarwala A. Use of the modified Atkins diet for treatment of refractory childhood epilepsy: a randomized controlled trial. Epilepsia. 2013 Mar;54(3):481-6. doi: 10.1111/epi.12069. Epub 2013

Jan 7. 141. Cherian PJ, Radha Krishnan K. Selection of ideal candidates for epilepsy

surgery in developing countries. Neurol India 2002;50:11-16. 142. Miller JW, Hakimian S. Surgical treatment of epilepsy. Continuum (Minneap

Minn). 2013 Jun;19(3 Epilepsy):730-42. doi: 10.1212/01. CON. 0000431398. 69594. 97.

38

143. Low enstein DH, Bleck T, Macdonald RL. It'stimeto revise the definition of status epilepticus. Epilepsia 1999; 40:120-122.

144. Fountain NB, Fugate JE. Refractory status epilepticus: What to put down: The anesthetics or the patient? Neurology. 2013 Dec 6. [Epub ahead of

print]. 145. Shorvon S and Ferlisi M. The treatment of super refractory status

epilepticus: a critical review of available therapies and a clinical treatment protocol. Brain 2011; 134: 2808-2818.

146. Wilder-Smith EP, Lim EC, Teoh HL, Sharma VK, Tan JJ, Chan BP, et al. The NORSE (new-onset refractory status epilepticus) syndrome : defining a

disease entity. Ann Acad Med Singapore 2005;34:417-420. 147. Fountain NB. Status epilepticus: risk factors and complications. Epilepsia

2000;41:23-30. 148. Kramer U, Chi CS, Lin KL, Specchio N, Sahin M, Olson H, Nabbout R,

Kluger G, Lin JJ, van Baalen A. Febrile infection - related epilepsy syndrome (FIRES): pathogenesis, treatment, and outcome: a multi center study on 77 children. Epilepsia. 2011 Nov; 52(11): 1956-65. doi:

10.1111/j.1528-1167.2011.03250.x. Epub 2011 Aug 29. 149. Appleton R, Martland T, Phillips B. Drug management for acute tonic-

clonic convulsions including convulsive status epilepticus in children. Cochrane Data base Syst Rev 2002:4:CD001905.

150. Prasad K, Al- Roomi K, Krishnan PR, Sequeira R. Anti convulsant therapy for status epilepticus. Cochrane Data base SystRev 2005;4: CD003723.

151. Treiman DM, Meyers PD, Walton NY, Collins JF,Colling C, Rowan AJ, etal. A comparison off our treatments for generalized convulsive status epilepticus.Veterans Affairs Status Epilepticus Cooperative Study Group.

NEngl J Med 1998; 339:792-798. 152. Mehta V, Singhi P, Singhi S. Intravenous sodium valproate versus

diazepamin fusion for the control of refractory status epilepticus in children : arandomized controlled trial. J Child Neurol 2007; 22: 1191-

1197. 153. Niermeijer JM, Uiterwaal CS, Van Donselaar CA. Propofolin status

epilepticus: little evidence, many dangers? J Neurol 2003;250:1237-1240. 154. Arya R, Gulati S, Kabra M, Sahu J, Kalra V. Intra nasal versus intravenous

lorazepam for control of acute seizures in children: A randomized open- label study. Epilepsia, 52(4):788–793, 2011.

39

Writing Committee : Vrajesh Udani, Consultant in Pediatric Neurology & Epilepsy, PD Hinduja Hospital & Research Centre, Mumbai. Neeta Naik, Consultant in Pediatric Epilepsy, Epilepsy Research Centre for Children, Mumbai. Chairperson : Nitin Shah, President IAP 2006, Deepak Ugra, Secretary IAP 2006. Conveners : V. Udani, N.Naik. List of Experts : Surekha Rajyadhyaksha, Bharti Vidyapeeth, Medical College & Hospital, Pune ; Veena Kaira, All India Institute of Medical Sciences, New Delhi; Nagabhushana Rao Pothraju, Osmania Medical College & Osmania General Hospital; Pratibha Singh, PGIMR, Chandigarh; K.N. Shah, Wadia Children's Hospital, Lilawati Hospital & Bhatia Hospital, Mumbai; Nandan Yardi, Member, Commission on treatment Strategies, ILAE, Pune; JMK Murthy, Nizam's Institute of Medical Sciences, Hydrabad; Margi Desai, Saifee Hospital, Mumbai; Meher Ursekar, Wellspring Jankharia Imaging, Mumbai; Anaita Hegde , Jaslok Hospital & Research Centre and Wadia Children's Hospital, Mumbai; G. Kumarsenan , Institute of Child Health and Hospital for Children, Chennai; Satinder Aneja, Lady Harding Medical College and Associated Kalawati Saran Children's Hospital, New Delhi; Vrajesh Udani, PD Hinduja Hospital & Research Centre and GMC & JJ Group of Hospitals, Mumbai; Jayanti Mani, Kokilaben Dhirubhai Ambani Hospital, Mumbai; Neeta Naik, Epilepsy Research Centre for Children, Mumbai; Rachna , CHL Apollo Hospital, Indore; GR Passi, Choithram Hospital & Research Centre, Indore; Arijit Chattopadhyay, Institute of Child Health, Kolkata; J. Nathan, Shushrusha Hospital & Research Centre, Mubai; Milind Sankhe, PD Hinduja Hospital & Research Centre, Mumbai; Soono Udani, PD Hinduja National Hospital & Research Centre and Grant Medical College and JJ Group of Hospital

Neuro Pedicon - 2007 (Raipur)

Neuro Pedicon - 2007 (Raipur)

Winter Neuro Pedicon - 2011 (Raipur) Neuro Pedicon - Oct-2011 (Trivendrum)

Neuro Pedicon - 2008 (Trivendram)

Neuro CME in P

edicon-2009

Neuro CME in Pedicon-2011(Jaipur)

Neuropedicon - 2011 (Mumbai)

Neuropedicon - 2013 (Trivendrum)

(Banglore) Neuro CME in Pedicon-2010 (Hydrabad)