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.

Table 1

	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 2

	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.

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’.

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

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.