Rational Approach to Children with Drug-Resistant Epilepsy

Drug Resistant Childhood Epilepsy

Abstract

Epilepsy is one of the most common neurological disorders to affect children and has its highest incidence in infancy. Approximately one quarter of children have seizures which are drug resistant and place the child at increased risk of cognitive delays, as well as attention, behaviour and psychiatric disorders, injury, sudden unexpected death, and poor quality of life. This article presents a rational approach to the investigation and management of children with drug-resistant epilepsy

Introduction

Epilepsy is one of the most common neuokrological disorders seen in children with an estimated incidence of approximately 44 per 100,000 per year [1,2]. Drug-resistance – which is defined as a failure of adequate trialing of two tolerated, appropriately dosed and chosen antiseizure medications (either in monoor combination therapy) to achieve sustained seizure remission [3] – is not uncommon, and effects approximately 20-25% of all children [4,5]. In addition to ongoing seizures, those with drug-resistant epilepsy are at greater risk for intellectual disability and learning problems, attention and behavioural problems, and emotional difficulties such as anxiety and depression, injury and sudden unexpected death in epilepsy, and poor quality of life.

Predictors of drug resistance have been evaluated in several studies [4,5]. Factors that have been quite consistent include certain syndromes (developmental and epileptic encephalopathies, and lesional focal epilepsy), high initial seizure frequency, neonatal seizures, onset prior to or greater than age 12 years, associated intellectual disability or abnormal neurologic examination, abnormal neuroimaging, and failure to respond to the first antiseizure medication [5]. Additionally, the presence of febrile seizures, status epilepticus, and discharges or focal slowing on EEG have been reported by some, but not most studies, to correlate highly with drug-resistance [4,5].

Although some cases with drug resistance may present after many years, most cases present in the first two to three years after onset of epilepsy [4,5].

Given the significant impact on multiple aspects of well-being, it is essential to have a framework to assess children presenting with drug-resistant epilepsy.

Q1. Does the patient truly have epilepsy?

One of the most common reasons for failure to respond to antiseizure medications is that the diagnosis of epilepsy is incorrect. There are multiple paroxysmal events which occur in children and adolescents which may be mistaken for epilepsy. These are listed in Table 1. Several studies have found that approximately 15% of events captured in a paediatric epilepsy monitoring unit are not epileptic [6,7]. Before age six, psychogenic nonepileptic events are rare, and most nonepileptic conditions are other physiologic disorders. In adolescence, psychogenic nonepileptic events are conversely the most common etiology for nonepileptic events.

Psychogenic nonepileptic seizures have been reported to have two main semiologies in children [6]. The first are typically prolonged periods of unresponsiveness without motor phenomena and the second are motor phenomena with bizarre irregular jerking and thrashing. Importantly however, frontal lobe seizures may also present with bizarre motor phenomena and must be distinguished from psychogenic nonepileptic events. Other characteristic features of psychogenic nonepileptic spells include prolonged duration (often longer than 15 minutes), no incontinence or tongue-biting, an often-minimal postictal phase, events that are frequent and medically intractable from onset, events that occur in situations such as school, events that are elicited by specific triggers, and an underlying psychiatric diagnosis or personality disorder.

It can be very helpful to have the family take a video of the child or adolescent’s event using a cell phone, to be reviewed by the physician. If resources permit, recording of the video EEG during the spell of interest will be helpful to distinguish seizures from nonepileptic events.

Typical age Description
Movement Disorders
Jitteriness Neonates, infants Tremor-like movements in one or morelimbs which attenuate or stop when the infantis wrapped or the affected limb is gentlyflexed.
Hyperekplexia All ages Abnormal excessive startle. In infants, canpresent with abnormal stiffness and apnoeadue to a loud noise or unexpected tactilestimulus.
Shuddering attacks Infants and preschoolers Shiver-like movement typically lastingseconds only, which can be triggered bycertain activities.
Benign paroxysmal tonic upgaze Infancy Sustained upward eye gaze with intactawareness.
Tics Children and adults Brief, frequent movements such as headshakingor shoulder-shrugging, or briefrepetitive noises such as throat-clearing orsniffing.
Stereotypies Children Repetitive movements such as bodyrocking,head-banging or finger movementswhich can be interrupted.
Alternating hemiplegia Infants and children Recurrent attacks of weakness that affectone or the other side of the body, whichcan last minutes to more than half an hour.
Sleep Disorders
Benign neonatal sleep myoclonus Neonates Brief tremor-like movements of one ormore limbs, only in sleep, that stop whenthe baby wakes up.
Sleep-related rhythmic movementdisorders Young children Repetitive body-rocking or head-bangingthat typically occur as the child is fallingasleep.
Hypnic jerks Any age Sudden twitches during sleep which maywake the person.
Parasomnias Children Behaviours such as talking, walking or agitationthat usually arise from deep sleep,often in the first third of the night, lastingseveral minutes. The child may appear agitatedor frightened, but has no recall of theevent.
Narcolepsy-cataplexy Children and adults Excessive daytime sleepiness, cataplexy,hallucinations when waking or on fallingasleep, sleep paralysis.
Table 1.Table 1. Common Seizure Mimics in Children.
Migraine equivalents
Benign paroxysmal torticollis Infants and toddlers Forced turning of the head to one sidewith retained awareness, lasting minutes tohours. Infants may appear distressed andcan vomit during the event.
Benign paroxysmal vertigo Young children Child appears off balance, ataxic and oftenclutches onto an adult. Nystagmus can beseen. Typical duration is minutes.
Cyclical vomiting Children Episodic recurrent vomiting which maylast hours to days, separated by periodswhere the child is well.
Psychological disorders
Daydreaming Children Blank staring, typically during times whenthe child is tired or bored. Child is immediatelyresponsive to tactile stimulation.
Tantrums/rage attacks Children/teens Rage episodes with screaming, swearingor aggression, often with directed violence,typically lasting minutes up to an hour.
Panic attacks Any age Brief episodes of sudden apprehension,feeling of impending doom, and sensationof breathlessness, choking, palpitations orchest pain, lasting minutes. May be situational.
Non-epileptic behavioural spells(psychogenic nonepileptic seizures) Older children, teens, adults Episodic bizarre irregular jerking or prolongedperiods of unresponsiveness, unassociatedwith EEG change.
Other
Tetralogy of Fallot spells Infants and toddlers Cyanosis often after crying, feeding or agitation.Toddlers will often squat duringthese events.
Breath-holding spells Infants and preschoolers Provoked by pain or fright. The child usuallycries, then holds their breath at endexpiration with cyanosis or pallor. Tonicstiffening of the body may be seen, followedby irregular myoclonic jerks.
Sandifer syndrome Infants and young children Arching of back and tilting of head to oneside, often with stiffening of the limbs andcrying. Most commonly seen in childrenwith neurological disability and associatedwith gastro-oesophageal reflux.
Vasovagal syncope All ages Pallor, blurring of vision, ringing in theears, dizziness leading to loss of tone. Oftentriggered by prolonged standing, pain,dehydration.
Long QT or cardiac syncope All ages Lightheadedness, dizziness, palpitations,often triggered by fright, exercise, surpriseor submersion in water.
Table 2.Table 1. Common Seizure Mimics in Children (continued).

Q2. If this is epilepsy, is the seizure type, epilepsy type and epilepsy syndrome correctly diagnosed?

The classification of epilepsy begins with identifying which specific types of seizures a patient has, and utilising that information, deciding if their epilepsy is generalised, focal, both generalised and focal, or unknown [8]. Approximately one quarter to one third of children with epilepsy can be further classified as having a specific electro-clinical syndrome [2]. Choice of antiseizure medication is very much influenced by epilepsy type and syndrome. In some cases, specific antiseizure medications can worsen epilepsy and result in ‘pseudoresistance’. The class of medications that is most likely to result in worsening seizures is the sodium channel agents which include oxcarbazepine, carbamazepine, eslicarbazepine and phenytoin [9-13]. These agents commonly exacerbate generalised epilepsies with absence, myoclonic and atonic seizures. They can also worsen progressive myoclonic epilepsies, electrical status epilepticus in sleep, and Dravet syndrome [13]. Tiagabine and vigabatrin can also exacerbate juvenile myoclonic epilepsy and absence seizures [13,14]. Lamotrigine is contraindicated in young children with Dravet syndrome as it exacerbates this condition [15]. There are also reports of high-dose benzodiazepines exacerbating tonic seizures [13].

If a patient is confirmed to have epilepsy, yet their seizures are drug-resistant, one should exclude inappropriate medication which may exacerbate seizures as a cause of ‘pseudo resistance’.

Q3. Is there a specific etiology -focused treatment?

a. If there is an underlying structural etiology, is the child a surgical candidate?

Structural etiologies are amongst the most common causes of drug-resistant epilepsy in children [16-19]. Common structural etiologies include focal cortical dysplasia, mesial temporal sclerosis, low-grade tumours, vascular abnormalities, and focal encephalomalacia or scarring [19]. Many of these children have an early onset of epilepsy which is drug-resistant [20]. It is important to recognise that some of these children may be candidates for surgical resection, as frequent and ongoing seizures early in life may have a significant negative impact on development and learning. Indeed, surgery is the only curative treatment for structural lesions.

Children with focal structural lesions are generally considered good surgical candidates if they have (1) a single, welldefined epileptogenic zone, and (2) no involvement of eloquent cortex within that zone that would result in postoperative deficits. A single semiology at onset and a single focal lesion on imaging – concordant with the EEG – would suggest a high likelihood of a well-defined epileptogenic zone, although not all children have clear imaging abnormalities. Furthermore, some children who have multifocal or even co-existing generalised interictal EEG discharges have only a single ictal onset [21-23]. Multifocal interictal discharges should therefore not necessarily exclude a child from surgical candidacy.

In young children with severe epilepsy due to a focal or hemispheric lesion, with a poor prognosis for seizure control long term, one must balance the risk of ongoing seizures (mortality, morbidity and the impact on cognition) with the risk of deficit caused by surgery [24-26]. Examples where deficit-incurring surgery is often performed would include children with drug-resistant epilepsy due to SturgeWeber syndrome, Rasmussen encephalitis, or severe focal epilepsy in a young child, leading to a developmental and epileptic encephalopathy. In general, in such challenging cases, earlier surgery is associated with greater recovery if a deficit will be incurred, given greater brain plasticity (Figure 1A and B). In such cases, epilepsy surgery represents the only hope for a true ‘cure’ and may prevent further cognitive regression and ameliorate other comorbidities [24].

b. Is there an underlying metabolic cause with a specific targeted therapy?

Overall, metabolic etiologies are relatively rare causes of epilepsy in children. Many of these entities can also be detected on current epilepsy gene panels (i.e., SLC2A1 pathogenic variants associated with glucose transporter deficiency, CLN2 pathogenic variants associated with late infantile neuronal ceroid lipofuscinosis, and POLG1 pathogenic variants associated with Alper-Huttenlocher syndrome). Metabolic disorders more commonly present early in life with developmental stagnation followed by regression, or with acute metabolic crisis, often associated with intercurrent infection, surgery or fasting. Timely diagnosis and, where possible, initiation of targeted therapy is critical to prevent further developmental regression [27]. Important treatable metabolic causes, along with the typical clinical presentation and recommended therapy are listed in Table 2.

c. Is there an underlying genetic cause with a highly effective antiseizure medication?

Over the last two decades, there has been a rapid expansion in our understanding of the genetic contributions to epilepsy as well as our ability to identify specific pathogenic variants. There are presently relatively few targeted genetic treatments for specific pathogenic variants causing rare epilepsies, but over the next decade, this is likely to grow considerably.

Many of the underlying developmental and epileptic encephalopathies which present early in life are the result of a single gene mutation [28,29]. Some of these mutations may also lead to structural brain changes [30,31]. Thus, an epilepsy gene panel or whole exome-sequencing should be strongly considered in any early onset, drug-resistant epilepsy, where no clear etiology has been found. Even though we presently lack precision genetic therapies for many of the pathogenic variants, understanding the underlying genetic etiology can be enormously helpful

Figure 1.A two-month-old child presented with focal spasms and focal seizures affecting his left arm and leg. His EEG showed right hemispheric periodic sharp wave activity (20 microvolt/mm) (Figure 1(a)). His MRI showed a markedly dysplastic right hemisphere, consistent with right hemimegalencephaly (Figure 2(b)). He was treated with vigabatrin and achieved seizure control until eight months of age, when he relapsed with very frequent focal seizures with left-sided clonic activity. Seizures were resistant to two further antiseizure medications, and he began to show regression of developmental skills. He underwent a functional right hemispherotomy at 12 months of age, and became seizure-free. He showed marked improvement in development. At five years of age, he has borderline intellectual disability, a stable left hemiparesis but is off antiseizure medication.

Disorder Investigation Treatment
Pyridoxine, P5P-dependent, seizures ↑ AASA (CSF, serum and urine), ↓ P5P in CSF Pyridoxine, P5P
GLUT1 transporter deficiency Low CSF glucose and low CSF/plasma glucoseratio Ketogenic diet
Creatine deficiency Urine creatine metabolites, MR spectroscopy Creatine
Serine deficiency CSF and serum amino acids Serine
Biotinidase deficiency Serum biotinidase Biotin
Cerebral folate deficiency CSF methyltetrahydrofolate Folinic acid
Mitochondrial disorders Lactate, pyruvate (CSF, serum), musclebiopsy, mitochondrial genetics cocktail (thiamine, carnitine, CoenzymeQ10, riboflavin).Avoid valproic acid. Consider trial of the ketogenic diet (not inpyruvate carboxylase deficiency)
Late infantile Neuronal CeroidLipofuscinosis (CLN2 disease) Genetic studies, TPP1 Cerliponase alfa
AASA, alpha amino adipic semialdehyde; P5P, Pyridoxal-5-phosphate; TPP1, tripeptidyl peptidase 1.
 Table 3.Table 2. Examples of Treatable Metabolic Conditions Associated with Epilepsy in Children.

in choosing an optimal therapy and avoiding medications which could exacerbate seizures. Table 3 provides some examples of common pathogenic variants seen in early onset epilepsy, the clinical phenotypes associated with these, as well as recommended and contraindicated treatments.

Gene Typical age atonset Clinical phenotype Optimal therapies Contra-indicatedtherapies
SCN1A–severephenotype Infancy Dravet syndrome Valproic acid, clobazam,topiramate,stiripentol,cannabidiol, fenfluramine,ketogenic diet Sodium channel agentsLamotrigine
SCN2A Early infancy Epilepsyininfancywith migrating focalseizures High dose phenytoin orothersodiumchannelagent (in gain of functionvariants)
SCN8A Infancy Early infantile DEEwith severe seizures,intellectualdisabilityand movement disorder High dose phenytoin orothersodiumchannelagent (in gain of functionvariants)
KCNQ2 Neonates Self-limitedneonatalseizuresCarbamazepine or oxcar-bazepineLess commonly earlyinfantile DEE Carbamazepine or oxcar-bazepine
KCNT1 Infancy/earlychildhoodEpilepsyininfancywithmigratingfocalseizures, other Quinidine
PRRT2 Infancy Self-limitedinfantileseizures Low dose carbamazepine
TSC1or 2 Usuallyearlychildhood Infantile spasms, focal,LGS Vigabatrin,everolimus,CBD
Table 4.Table 3. Common pathogenic variants seen in early onset epilepsy, the clinical phenotypes associated and recom-mended, and contraindicated treatments.
Gene Typical age atonset Clinical phenotype Optimal therapies Contra-indicatedtherapies
SLC2A1 Infancy,earlychildhood Early onset absenceseizures,myoclonicatonic or myoclonicabsence seizures, mi-crocephaly, movementdisorders Ketogenic diet Valproic acid
CLN2 Early childhood Myoclonicseizures,other focal and gen-eralisedseizures,followed by develop-mental regression andataxia Cerliponase alfa
ALDH7A1 Neonatesandearly infancy Early-lifedrug-resistant DEE, particu-larly clonic, myoclonicand tonic seizures Pyridoxine
PNPO Neonatesandearly infancy Severe, drug-resistantneonatal seizures, earlyinfantile DEE Pyridoxal-5-phosphate
POLG1 All ages Variable but seizuresare often focal and in-volve the occipital re-gions Elevated transaminasesMitochondrial cocktail(coenzyme Q10, B vi-tamins, carnitine, vita-min C, creatine) Valproic acid
GRIN2A Childhood Epilepsy-aphasia spec-trum disorders memantine
Table 5.Table 3.Common pathogenic variants seen in early onset epilepsy, the clinical phenotypes associated and recom-mended, and contraindicated treatments (continued).

d. Is there an underlying immune etiology which is amenable to immunomodulatory therapy?

Autoimmune etiologies are increasingly recognised in both children and adults with drug-resistant epilepsy [32-35]. In children, most antibodies are directed against antigens on the neuronal surface membrane, have a low likelihood of association with tumours, and are generally responsive to immunotherapy [32,34]. Clinical clues suggesting a possible immune etiology include: a previously healthy child with no history of other factors which could provoke seizures; seizures which are generally severe and drugresistant from onset, often with status epilepticus; multifocal neurological signs and symptoms which include altered mental status, acquired cognitive dysfunction, associated movement disorders, autonomic dysfunction or sleep disturbances; and a personal or family history of autoimmunity [34]. Laboratory clues to diagnosis include: background slowing, often with multifocal discharges on EEG; inflammatory changes on FLAIR or T2 MRI images, and inflammatory changes in the cerebral spinal fluid with negative cultures; positive oligoclonal bands; and elevated CSF neopterin, although the latter may not be highly sensitive [34]. Autoimmune epilepsy panels in the CSF and blood will often show the causal antibody. In addition to symptomatic management of seizures, immunotherapies should also be started as quickly as possible, as the outcome often depends on prompt recognition and treatment [36]. Indeed, there should be a low threshold to refer children with immune-mediated epilepsy to a specialty centre which offers all modalities of immunotherapy. Initial treatments include IV or high dose oral steroids, intravenous gammaglobulin or plasmapheresis, although the latter is used less frequently in children due to a greater risk of adverse events [33,37]py trial with steroids or intravenous gammaglobulin could be given, and the patient followed closely to see if clear improvement has occurred [33,34].

Q4. What if there is no etiology -specific therapy, and seizures are drug-resistant?

Unfortunately, for many children with drug-resistant epilepsy, we are unable to identify a specific etiology with a highly efficacious therapy. In such children, it is important to determine a realistic expectation for seizure control, and to balance that control with antiseizure medication side effects and quality of life. Several studies have shown what clinicians have long recognised, namely that the greater the number of failed antiseizure medications, the lower the likelihood that the next drug will be effective[38-40].

In children with focal epilepsy, a good outcome with another medication was only achieved in 29% after one antiseizure medication failed to achieve seizure control, and only in 11% after the failure of two antiseizure medications [38]. However, etiology plays a significant role in predicting outcome. In one study of children with focal epilepsy, which excluded those with known self-limited focal epilepsy syndromes and after two antiseizure medications had failed for lack of efficacy, only 7.8% of those with a known structural cause versus 23.5% of those with no known cause responded well to a third medication [39].

As many antiseizure medications have side effects including sedation, exacerbation of behavioural problems, and impact on appetite, amongst others, it is imperative to be weaned off a medication that is not working. If a second drug is added, clinicians should consider whether the patient should be weaned off the first medication. When using medications, one should consider combining them with complementary mechanisms of action, and side effects should always be balanced with seizure control.

The ketogenic diet has been utilised for the last 100 years in the treatment of drug-resistant epilepsy in children [41]. This is a high fat, low-carbohydrate, adequate protein diet that has been historically utilised in younger children. More recently, more ‘liberal’ forms of the diet, including a modified Atkins diet and the low glycaemic index diet, have been described which are more palatable and thus easier to adhere to [42,43]. While there is some evidence that the traditional ketogenic diet may be more efficacious in very young children [44], it appears that in older children, adolescents and adults, efficacy of these more liberal forms is similar to the traditional ketogenic diet. A recent international review on the use of the ketogenic diet, including syndromes and etiologies where it has been reported as particularly beneficial, has been published [45,46]. In any child with drugresistant epilepsy, in whom two to three antiseizure medications have failed for lack of efficacy, and who is not a candidate for surgical resection or other etiology-specific therapy, a trial of dietary therapy should be considered, if feasible for the patient and family. In some cases, depending on family preference, dietary therapy could be considered even earlier.

Although the goal of resective surgery is typically curative, in some cases this can also be considered on a palliative basis, particularly if there is one focus that contributes to the majority of the seizures, and in cases where intervention is expected to ameliorate the epileptic encephalopathy and improve cognitive outcome [47,48].

Other palliative surgical options may also markedly improve seizure control, lessen injury risk, and improve quality of life. Corpus callosotomy is an important palliative option for children with drug-resistant drop seizures, including tonic and atonic seizures. Approximately 55% achieve freedom from drop seizures after this procedure [49]. Callosotomy is most considered in children with Lennox-Gastaut syndrome who have significant cognitive disability, and the risk of disconnection complications are rare in this population [50].

Neurostimulation techniques should also be considered in this population. Vagus nerve stimulation is the most used form in children, and results in responder rates of between 40 and 66% [51]. Newer stimulator devices allow for autostimulation with detected heart rate changes at seizure onset, adjustment of settings for specific times in the day, and ability to programme the units remotely. Complications of vagus nerve stimulation are rare but may include bradycardia, infection and bleeding, injury to the vagus nerve with hoarseness, dyspnoea and dysphagia, throat pain and obstructive sleep apnoea.

Other types of brain stimulation have been used predominantly in adults but have also been performed in a limited number of children, although randomised paediatric trials have not been performed. Additionally, availability of these devices is limited in many regions.

The RNS device (Responsive Neurostimulation) can be considered in individuals with no more than two discrete epileptogenic foci. This technique involves placing leads in up to two seizure onset zones. The device monitors brain signals, providing closed-loop stimulation in response to detection of electrocorticographic seizure activity. There is very limited data on efficacy in children; in adults, however, responder rates (patients with a greater than 50% reduction in seizures) were 64.6% in mesial temporal lobe epilepsy and 55% in neocortical epilepsy [52]. Seizure freedom for three, six and 12 months was 45%, 29% and 15% for mesial temporal lobe epilepsy, and 37%, 26% and 14% for neocortical epilepsy [52].

Deep brain stimulation is a therapeutic option that delivers electrical stimulation, most commonly into the thalamic nuclei, to modulate cortical excitability in people with drug-resistant epilepsy who are not good candidates for focal resection. A large trial in adults, the SANTE (Stimulation of Anterior Nucleus of the Thalamus for Epilepsy) trial documented efficacy in adults with responder rates of 43% and 68% at one and five years [53]. However, there are limited reports of this technique in children [54]. The anterior nucleus of the thalamus is the typical target for frontotemporal epilepsy, whereas the centromedian nucleus has been targeted more for generalised epilepsy. Further controlled studies of this technology in children, especially in those with generalised epilepsies are needed.

Conclusion

While many children with epilepsy will achieve seizure control with medication, drug-resistance is problematic for up to one quarter of cases. In addition to ongoing seizures, children with drug-resistant epilepsy are at higher risk of cognitive, behavioural and psychiatric comorbidities, injury, sudden unexpected death in epilepsy and poor quality of life.

A structured approach is needed for those affected. Firstly, the diagnosis of epilepsy should be confirmed, and epilepsy mimics excluded. Secondly, the epilepsy type and seizure syndrome (if present) should be established, and medications reviewed to exclude ‘pseudoresistance’. Thirdly, careful evaluation of the underlying etiology should be undertaken, to determine if there is a ‘best’ treatment, such as possible surgical resection for a single epileptogenic focus. Ideally, all children and adolescents with ongoing seizures despite trialing two or more antiseizure medications, and infants with frequent seizures which are potentially impacting their development – even prior to established drug resistance – should be referred promptly to specialised epilepsy centres, which have greater access to resources and expertise for specialised testing and support of children with intractable epilepsy, and their families. However, specialised epilepsy centres may not be available in resource-limited regions of the world.

In cases where no specific etiology-based treatment is available, realistic and appropriate goals for seizure control should balance the risk of seizures, treatment side effects and quality of life. Excessive polypharmacy should be avoided, and nonmedication options such as palliative surgery, neurostimulation and dietary options should be considered. Comprehensive care should also focus on non-seizure symptoms of epilepsy, including cognitive, behavioural and psychiatric comorbidities to improve the well-being and quality of life of children impacted by drug-resistant epilepsy, and their families.

Competing interests

None.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Cite this article as:

Wirrell, E. C. (2021). Rational Approach to Children with DrugResistant Epilepsy . Journal of the International Child Neurology Association, 21(1). https://doi.org/10.17724/jicna.2021.191

References

  1. Camfield CS, Camfield PR, Gordon K, Wirrell E, DooleyJM. Incidence of Epilepsy in Childhood and Adolescence:A Population-Based Study in Nova Scotia from 1977 to1985. Epilepsia. 1996;37(1):19-23.PubMed
  2. Wirrell E, Camfield C, Camfield P, Dooley J.Prog-nostic Significance of Failure of the Initial Antiepilep-tic Drug in Children with Absence Epilepsy. Epilepsia. 2001;42(6):760-3.PubMed
  3. Wirrell EC, Grossardt BR, Wong-Kisiel LCL, NickelsKC. Incidence and classification of new-onset epilepsyand epilepsy syndromes in children in Olmsted County,Minnesota from 1980 to 2004: A population-based study. Epilepsy Research. 2011;95(1-2):110-8.PubMed
  4. Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, HauserWA, Mathern G, et al. Definition of drug resistant epilepsy:Consensus proposal by the ad hoc Task Force of theILAE Commission on Therapeutic Strategies. Epilepsia. 2009;51(6):1069-77.PubMed
  5. Berg AT. Defining intractable epilepsy. Advances in Neu-rology. 2006;97:5-10.PubMed
  6. Wirrell EC.Predicting pharmacoresistance in pediatricepilepsy. Epilepsia. 2013;54:19-22.PubMed
  7. Kotagal P, Costa M, Wyllie E, Wolgamuth B. ParoxysmalNonepileptic Events in Children and Adolescents. Pedi-atrics. 2002;110(4):e46-6.PubMed
  8. Park EG, Lee J, Lee BL, Lee M, Lee J.Paroxysmalnonepileptic events in pediatric patients. Epilepsy & Be-havior. 2015;48:83-7.PubMed
  9. Scheffer IE, Berkovic S, Capovilla G, Connolly MB,French J, Guilhoto L, et al.ILAE classification ofthe epilepsies: Position paper of the ILAE Commis-sion for Classification and Terminology. Epilepsia. 2017;58(4):512-21.PubMed
  10. Gayatri N, Livingston J. Aggravation of epilepsy by anti-epileptic drugs. Developmental Medicine & Child Neurol-ogy. 2006;48(5):394-8.PubMed
  11. Gelisse P, Genton P, Kuate C, Pesenti A, Baldy-MoulinierM, Crespel A. Worsening of Seizures by Oxcarbazepinein Juvenile Idiopathic Generalized Epilepsies. Epilepsia. 2004;45(10):1282-6.PubMed
  12. Sazgar M, Bourgeois BFD. Aggravation of Epilepsy ByAntiepileptic Drugs. Pediatric Neurology. 2005;33(4):227-34.PubMed
  13. Thomas P, Valton L, Genton P. Absence and myoclonicstatus epilepticus precipitated by antiepileptic drugs in id-iopathic generalized epilepsy. Brain. 2006;129(5):1281-92.PubMed
  14. Perucca E, Gram L, Avanzini G, Dulac O. Antiepilep-tic Drugs as a Cause of Worsening Seizures. Epilepsia.. 1998;39(1):5-17.PubMed
  15. Knake S, Hamer HM, Schomburg U, Oertel WH, RosenowF. Tiagabine-induced absence status in idiopathic general-ized epilepsy. Seizure. 1999;8(5):314-7.PubMed
  16. Guerrini R, Dravet C, Genton P, Belmonte A, KaminskaA, Dulac O. Lamotrigine and Seizure Aggravation in Se-vere Myoclonic Epilepsy. Epilepsia. 1998;39(5):508-12.PubMed
  17. Dhamija R, Moseley BD, Cascino GD, Wirrell EC. Apopulation-based study of long-term outcome of epilepsyin childhood with a focal or hemispheric lesion on neu-roimaging. Epilepsia. 2011;52(8):1522-6.PubMed
  18. Yildiz EP, Gunes D, Bektas G, Uzunhan TA, Tatli B,Caliskan M, et al.Predictive factors of drug-resistantepilepsy in children presenting under 2 years of age: ex-perience of a tertiary center in Turkey. Acta NeurologicaBelgica. 2017;118(1):71-5.PubMed
  19. Wirrell EC, Wong-Kisiel LCL, Mandrekar J, Nickels KC.What predicts enduring intractability in children who ap-pear medically intractable in the first 2 years after diagno-sis? Epilepsia. 2013;54(6):1056-64.PubMed
  20. Moosa ANV, Wyllie E. Focal epileptogenic lesions. In:Handbook of Clinical Neurology. Elsevier; 2013. p. 493-510.PubMed
  21. Wirrell E, Wong-Kisiel L, Mandrekar J, Nickels K. Predic-tors and course of medically intractable epilepsy in youngchildren presenting before 36 months of age: A retrospec-tive, population-based study. Epilepsia. 2012;53(9):1563-9.PubMed
  22. Mohamed A, Wyllie E, Ruggieri P, Kotagal P, Babb T,Hilbig A, et al. Temporal lobe epilepsy due to hippocampalsclerosis in pediatric candidates for epilepsy surgery. Neu-rology. 2001;56(12):1643-9.PubMed
  23. Loddenkemper T, Cosmo G, Kotagal P, Haut J, KlaasP, Gupta A, et al.EPILEPSY SURGERY IN CHIL-DREN WITH ELECTRICAL STATUS EPILEPTICUS INSLEEP. Neurosurgery. 2009;64(2):328-37.PubMed
  24. Hnojciková M, Nickels KC, Wetjen NM, Buchhalter JR,Raffel C, Wirrell EC. EEG and Neuroimaging Studies inYoung Children Having Epilepsy Surgery. Pediatric Neu-rology. 2010;43(5):335-40.PubMed
  25. Saneto RP, Wyllie E. Epilepsy surgery in infancy. Seminarsin Pediatric Neurology. 2000;7(3):187-93.PubMed
  26. Gowda S, Salazar F, Bingaman WE, Kotagal P, LachhwaniDL, Gupta A, et al. Surgery for catastrophic epilepsy ininfants 6 months of age and younger. Journal of Neuro-surgery: Pediatrics. 2010;5(6):603-7.PubMed
  27. Wyllie E. Surgery for Catastrophic Localization-RelatedEpilepsy in Infants.Epilepsia. 1996;37(s1):S22-5.PubMed
  28. Pearl PL. Amenable Treatable Severe Pediatric Epilep-sies. Seminars in Pediatric Neurology. 2016;23(2):158-66.PubMed
  29. Shellhaas RA, Wusthoff CJ, Tsuchida TN, Glass HC, ChuCJ, Massey SL, et al. Profile of neonatal epilepsies. Neu-rology. 2017;89(9):893-9.PubMed
  30. Berg AT, Coryell J, Saneto RP, Grinspan ZM, Alexan-der JJ, Kekis M, et al.Early-Life Epilepsies and theEmerging Role of Genetic Testing.JAMA Pediatrics. 2017;171(9):863.PubMed
  31. Axeen EJT, Olson HE. Neonatal epilepsy genetics. Semi-nars in Fetal and Neonatal Medicine. 2018;23(3):197-203.PubMed
  32. Coryell J, Gaillard WD, Shellhaas RA, Grinspan ZM,Wirrell EC, Knupp KG, et al. Neuroimaging of Early LifeEpilepsy. Pediatrics. 2018;142(3).PubMed
  33. Suleiman J, Brilot F, Lang B, Vincent A, Dale RC. Au-toimmune epilepsy in children: Case series and proposedguidelines for identification. Epilepsia. 2013;54(6):1036-45.PubMed
  34. Suleiman J, Dale RC. The recognition and treatment ofautoimmune epilepsy in children. Developmental Medicine& Child Neurology.. 2014;57(5):431-40.PubMed
  35. Wong-Kisiel LC, McKeon A, Wirrell EC. Autoimmune En-cephalopathies and Epilepsies in Children and Teenagers.Canadian Journal of Neurological Sciences / JournalCanadien des Sciences Neurologiques. 2012;39(2):134-44.PubMed
  36. Korff CM, Dale RC.The Immune System inPediatricSeizuresandEpilepsies.Pediatrics. 2017;140(3):e20163534.PubMed
  37. Toledano M, Britton JW, McKeon A, Shin C, Lennon VA,Quek AML, et al. Utility of an immunotherapy trial in eval-uating patients with presumed autoimmune epilepsy. Neu-rology. 2014;82(18):1578-86.PubMed
  38. Eyre M, Hacohen Y, Lamb K, Absoud M, Agrawal S, Ga-dian J, et al. Utility and safety of plasma exchange in pae-diatric neuroimmune disorders. Developmental Medicine& Child Neurology. 2019;61(5):540-6.PubMed
  39. Aso K, Watanabe K. Limitations in the Medical Treat-ment of Cryptogenic or Symptomatic Localization-RelatedEpilepsies of Childhood Onset. Epilepsia. 2000;41(s9):18-20.PubMed
  40. Wirrell EC, Wong-Kisiel LC, Nickels KC. Seizure outcomeafter AED failure in pediatric focal epilepsy: Impact ofunderlying etiology. Epilepsy & Behavior. 2014;34:20-4.PubMed
  41. Wheless JW. History of the ketogenic diet. Epilepsia. 2008;49:3-5.PubMed
  42. Kossoff EH, Dorward JL.The Modified Atkins Diet.Epilepsia. 2008;49:37-41.PubMed
  43. Pfeifer HH, Thiele EA. Low-glycemic-index treatment:A liberalized ketogenic diet for treatment of intractableepilepsy. Neurology. 2005;65(11):1810-2.PubMed
  44. Kim JA, Yoon JR, Lee EJ, Lee JS, Kim JT, Kim HD,et al. Efficacy of the classic ketogenic and the modifiedAtkins diets in refractory childhood epilepsy. Epilepsia. 2015;57(1):51-8.PubMed
  45. Kossoff EH, Zupec-Kania BA, Amark PE, Ballaban-GilKR, Bergqvist AGC, Blackford R, et al. Optimal clinicalmanagement of children receiving the ketogenic diet: Rec-ommendations of the International Ketogenic Diet StudyGroup. Epilepsia. 2009;50(2):304-17.PubMed
  46. Kossoff EH, Zupec-Kania BA, Auvin S, Ballaban-GilKR, Bergqvist AGC, Blackford R, et al. Optimal clin-ical management of children receiving dietary therapiesfor epilepsy: Updated recommendations of the Interna-tional Ketogenic Diet Study Group.Epilepsia Open. 2018;3(2):175-92.PubMed
  47. Ciliberto MA, Limbrick D, Powers A, Titus JB, Munro R,Smyth MD. Palliative hemispherotomy in children withbilateral seizure onset. Journal of Neurosurgery: Pediatrics. 2012;9(4):381-8.PubMed
  48. Ilyas M, Sivaswamy L, Asano E, Sood S, Zidan M, ChuganiH. Seizure Control Following Palliative Resective Surgeryfor Intractable Epilepsy—A Pilot Study. Pediatric Neurol-ogy. 2014;51(3):330-5.PubMed
  49. Chan AY, Rolston JD, Lee B, Vadera S, Englot DJ. Ratesand predictors of seizure outcome after corpus callosotomyfor drug-resistant epilepsy: a meta-analysis. Journal ofNeurosurgery. 2019;130(4):1193-202.PubMed
  50. Cross JH, Auvin S, Falip M, Striano P, Arzimanoglou A.Expert Opinion on the Management of Lennox–GastautSyndrome: Treatment Algorithms and Practical Consider-ations. Frontiers in Neurology. 2017;8.PubMed
  51. Wheless JW, Gienapp AJ, Ryvlin P. Vagus nerve stim-ulation (VNS) therapy update.Epilepsy & Behavior. 2018;88:2-10.PubMed
  52. Geller EB. Responsive neurostimulation: Review of clini-cal trials and insights into focal epilepsy. Epilepsy & Be-havior. 2018;88:11-20.PubMed
  53. Salanova V, Witt T, Worth R, Henry TR, Gross RE, Naz-zaro JM, et al. Long-term efficacy and safety of thalamicstimulation for drug-resistant partial epilepsy. Neurology. 2015;84(10):1017-25.PubMed
  54. Yan H, Toyota E, Anderson M, Abel TJ, Donner E, KaliaSK, et al. A systematic review of deep brain stimulationfor the treatment of drug-resistant epilepsy in childhood.Journal of Neurosurgery: Pediatrics. 2019;23(3):274-84.PubMed