Pharmacological treatment of epilepsy in infants

Epilepsy & Seizures

Updated 06.17.2024
Released 11.19.2021
Expires For CME 06.17.2027

Pharmacological treatment of epilepsy in infants

Authors: K P Vinayan MD DM, Vaishakh Anand MD DM

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Editor: Solomon L Moshé MD

Pharmacological treatment of epilepsy in infants

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Introduction

Overview

Infancy constitutes the period from birth to the acquisition of language. Operationally, this period is considered as the first 1 to 2 years of life, excluding the neonatal period (first 4 weeks after birth in term newborns and 44 weeks of postmenstrual age in preterm babies). Infantile-onset epilepsies include heterogenous conditions with varying prognosis, from benign familial seizures to devastating epileptic encephalopathies. Epidemiological studies have shown that the incidence of epilepsy is highest during the first year of life. A significant proportion is constituted by neonatal-onset epilepsies. Further, many epilepsies with neonatal onset continue in the first year of life. Estimates show that one in 1000 children aged 1 month to 1 year develop epilepsy (28). There are specific seizure types that are mainly seen in the infantile period, such as epileptic spasms and migrating focal seizures. The onset of specific electroclinical and genetic syndromes also occurs during this period. With the advancement of genetic analysis, many more clinical patterns are being identified from the vast pool of complex infantile epilepsies. The term “developmental and epileptic encephalopathies” conceptually recognizes the neurodevelopmental impact of these epilepsies and the need for further targeted therapeutic options, apart from the standard antiseizure drugs, in many of these disorders. The importance of the etiological diagnosis of infantile epilepsies cannot be overstated as many of them will be amenable to precision therapy, such as tuberous sclerosis complex, glucose transporter deficiency, and biotinidase deficiency. Specific high-dose induction regimens are used for sinister syndromes, like infantile spasms, with a significantly adverse developmental potential. The introduction of the newer antiepileptic drugs in this population is usually delayed as most of the drug trials are done in adults and older children. There is an urgent need to have an accelerated pathway for drug development for many of these infantile epilepsies, which are difficult to treat.

Key points

	• Many epileptic seizures and epileptic syndromes start with seizures in the infantile period, ranging from benign infantile epilepsies to very complex developmental and epileptic encephalopathies.
	• Certain seizure types are specific or mostly seen in early infancy, such as epileptic spasms and migrating focal seizures.
	• Infantile-onset complex epileptic syndromes are increasingly found to be monogenic epilepsies with a clearly identifiable phenotype.
	• Infantile-onset complex epilepsies are currently associated with a guarded developmental outcome.
	• Specific therapeutic regimens already exist for syndromes like infantile spasms.
	• Mechanistically driven targeted therapy is useful for infantile-onset epileptic syndromes, such as Glut 1 transporter deficiency disorder, tuberous sclerosis, and certain sodium and potassium channelopathies.
	• There is an urgent need to develop accelerated drug development pathways for many of the complex developmental and epileptic encephalopathies of infancy.

Historical note and terminology

The first specific description of an infantile-onset epilepsy dates back to 1841 when Dr. West described in detail the occurrence of epileptic spasms in his son (92). Dravet syndrome was first described as “severe myoclonic epilepsy in infancy” by Charlotte Dravet in 1978 (26). Claes and colleagues identified the genetic etiology of Dravet syndrome with de novo pathogenic variants in the sodium-channel gene SCN1A in seven studied probands with Dravet syndrome (16). Many other monogenic infantile-onset developmental and epileptic encephalopathies have been subsequently described in the literature, and this list is now growing exponentially following advances in genome sequencing.

Randomized trials in children, especially in infants and neonates, remain a challenge due to ethical and methodological difficulties. To overcome this, extrapolation of efficacy data from the adult population is an imperative strategy. This method has been accepted in focal epilepsies in which disease progression and response to therapy are similar (02). But it may not be applicable to electroclinical syndromes that are specific to infants, such as infantile spasms, in which the etiology, underlying pathophysiology, and therapeutic targets vary considerably.

The known history of the pharmacotherapy of infantile spasms started with Dr. West’s use of mercury chloride, opium, and castor oil in his son, without any benefit. The first report of the effectiveness of adrenocorticotropic hormone in infantile spasms was in 1958 (87). The first double-blind randomized controlled trial for infantile spasms was conducted by Hrachovy and colleagues in 1983 (44). They compared the efficacy of adrenocorticotropic hormone injection with oral prednisone and found no major difference in effectiveness. The first and only randomized controlled trial demonstrating the efficacy of vigabatrin in tuberous sclerosis complex associated with infantile spasms was completed by Chiron and colleagues in 1997 (14). Multiple drugs have subsequently been used in infantile spasms, with variable results; the latest is cannabidiol.

The discovery of SCN1A mutations in patients with Dravet syndrome is one of the major milestones in epileptology and has paved the way for precision medicine. Even before this discovery in 2001, the seizure-aggravating effects of sodium channel blockers in Dravet syndrome were known. Although valproate, topiramate, and clobazam have been used in Dravet syndrome for many decades, the only drug that has been evaluated in randomized controlled trials is stiripentol.

Clinical aspects

Approach

When an infant presents with paroxysmal movements, the first step is an assessment of cardiorespiratory status and stabilization if any alteration is present. Further, the current movements must be classified as seizures or seizure mimics. Various abnormal movements that mimic seizures occur during infancy, and many of them are difficult to differentiate from true seizures in the absence of EEG, even for experienced clinicians. Moreover, many of the developmental and epileptic encephalopathies may also have hyperkinetic movement disorders along with the seizures, and proper characterization of the movements is essential to avoid an unnecessary overload of antiseizure medications.

If the movements are confirmed to be seizures, the next step involves categorizing the types of seizures to focal and multifocal, generalized, or unknown-onset seizures based on the semiology. This is a very important step and helps to further characterize the electroclinical syndrome and, thereby, the possible underlying etiology. Recurrent seizures with consistent focality almost always point towards a structural etiology, such as focal cortical dysplasia, hemimegalencephaly, stroke and stroke sequelae, or vascular malformations. Multifocal or generalized seizures in the presence of a normal MRI or nonspecific MRI changes suggest a genetic, metabolic, infectious, or, rarely, inflammatory etiology. Characteristic clusters of flexion or extension jerks associated with sleep cycles are the diagnostic seizure type in infantile spasm syndrome. Myoclonus-predominant epilepsy, including diaphragmatic myoclonus resembling hiccups, suggests an underlying inborn error of metabolism, such as nonketotic hyperglycinemia. Focal tonic or sequential seizures are mostly associated with genetic epilepsies.

EEG is important in the management of infantile epilepsies. Video-EEG is the gold standard to characterize the event and to further classify the seizure type(s) and epileptic syndrome. Interictal EEG may also show diagnostic patterns. Hypsarrhythmia or modified hypsarrhythmia in EEG is characteristic of infantile spasm syndrome. Focal slowing with interictal discharges may suggest a focal structural etiology, such as focal cortical dysplasia. Multifocal interictal epileptiform discharges with a diffusely slow background, though a nonspecific pattern, point towards an epileptic encephalopathy. Rarely, EEG may show a nonconvulsive status epilepticus or frequent electrographic seizures, which might require urgent intervention. EPISTOP study suggested that early detection of interictal epileptic activity through serial EEGs followed by treatment with vigabatrin may reduce the risk of development of infantile spasms and drug-resistant epilepsies in infants with tuberous sclerosis complex (TSC) (49). However, the subsequent PREVeNT trial failed to demonstrate a significant difference in the neurocognitive outcome or later epilepsy incidence in subjects with tuberous sclerosis complex for whom vigabatrin was started prophylactically at the detection of interictal epileptiform discharges before the onset of seizures (05). Similar to the EPISTOP study, the PREVent trial also reported that preventative vigabatrin was associated with later onset and lower incidence of infantile spasms (46). The utility of the interictal epileptiform activity in surveillance EEGs in predicting the development of later seizures in tuberous sclerosis complex was reinforced in this study with a negative predictive value (NPV) of 0.733 and positive predictive value (PPV) of 0.731. Both studies highlighted the importance of early diagnosis of tuberous sclerosis complex and detection of interictal epileptiform activities in view of the better developmental outcomes in both the cohorts compared to the previous literature. It seems that exposure to vigabatrin early in infancy is the important factor rather than the exact timing of the vigabatrin initiation (46).

Genetic evaluation is mandatory in cases in which the phenotype suggests a specific monogenic epilepsy, such as Dravet syndrome, or if the child has other features of a dysmorphic or neurocutaneous syndrome. Newer patterns are emerging, and it is worthwhile to complete a whole-exome evaluation in complex epilepsies without clear identifiable lesions on MRI. Some of these complex epilepsies have already qualified as candidates for possible precision medicine–based approaches.

Infantile epileptic syndromes with specific therapeutic options

Infantile spasms. Infantile spasms are an age-specific epilepsy disorder occurring mostly in the first year of life, with a peak incidence between 4 and 7 months. The current accepted terminology for this entity is infantile epileptic spasms syndrome (IPSS) (99). Clinically, it is characterized by a brief, synchronous flexor or extensor jerk involving the head, trunk, or limbs, followed by a short period of tonic posturing. These events characteristically occur in clusters after getting up from sleep or just before going to sleep. West syndrome has traditionally been described as the triad of infantile spasms, developmental delay, and EEG showing hypsarrhythmia or its variants. The most common underlying etiology is considered to be acquired-structural and related to perinatal complications followed by genetic-structural causes, such as tuberous sclerosis complex or other cortical malformations (69). Developmental and epileptic encephalopathies, such as STXBP and ARX, are also not uncommon. An exact etiological characterization might be possible in about 60% of cases using proper diagnostic evaluation (69; 96). MRI brain is the recommended imaging of choice and is the most important investigation for etiological evaluation. In the NISC study, clinical examination and MRI brain alone helped to reach an etiological diagnosis in 55% of cases of infantile spasms with proven etiology (96). Genetic investigations include karyotyping and chromosomal microarray in cases with dysmorphic features and exome panels or whole-exome sequencing in cases of suspected developmental and epileptic encephalopathies (84).

The treatment of infantile spasms aims at the complete cessation of spasms along with the normalization of EEG and regaining of milestones. This all-or-none response endpoint has been shown to be associated with the best developmental and cognitive outcomes (73). The initial step in the management of infantile spasms involves dichotomization into tuberous sclerosis complex and nontuberous sclerosis complex–associated infantile spasms (94; 80; 84). For infantile spasms that are not associated with tuberous sclerosis complex, hormonal therapy is the recommended first-line treatment. Hormonal therapy includes adrenocorticotropic hormone injection or oral prednisolone or prednisone.

Corticotropin / adrenocorticotropic hormone. Adrenocorticotropic hormone injection is the most commonly employed first-line therapy. The mechanism of action of adrenocorticotropic hormone is not completely elucidated. The major mechanism proposed is the production of neurosteroids in the periphery, which cross the blood-brain barrier and exert an anticonvulsant action. Negative feedback inhibition of corticotropin-releasing hormone and stimulation of melanocortin receptors are the other plausible mechanisms.

A 2013 Cochrane systematic review reported spasm cessation in 42% to 87% of infants after 2 weeks of adrenocorticotropic hormone therapy (41). The type of adrenocorticotropic hormone used, dose, and duration of adrenocorticotropic hormone vary between countries and regions. Synthetic as well as natural preparations of adrenocorticotropic hormone are available, and there are no head-to-head trials comparing the efficacy of each. However, a systematic review concluded that a natural preparation may be more efficacious (27).

There are high-dose (150 IU/m²/BSA) and low-dose (20 to 30 IU/day) schedules available. Two randomized controlled trials reported comparable efficacies with both regimes, with the low-dose regimen having lower rates of adverse effects (43; 97). Still, most guidelines recommend high-dose, once-daily adrenocorticotropic hormone (42; 84).

The treatment is typically given for 2 weeks, followed by looking for clinical spasm resolution and EEG normalization. With optimal response, adrenocorticotropic hormone is tapered and stopped over the next 2 to 4 weeks. Without optimal response, second-line therapy is considered. Adverse effects include hypertension, hyperglycemia, immunosuppression, irritability, and hirsutism.

Prednisolone. Oral glucocorticoids like prednisone and prednisolone are comparatively less expensive and easier to administer. For this reason, many countries, especially developing countries, prefer oral steroids over adrenocorticotropic hormone for treating infantile spasms (58).

The United Kingdom Infantile Spasm Study (UKISS) found no statistically significant difference in spasm cessation between infants treated with oral prednisolone and adrenocorticotropic hormone injection (70% vs. 76%) (55). The International Collaborative Infantile Spasms Study (ICISS) also reported similar findings (68). However, a comparison between the two forms of hormonal therapy was not the primary objective in either study. Two meta-analyses have also concluded that high-dose oral corticosteroids have a comparable efficacy to adrenocorticotropic hormone (12; 54).

As with adrenocorticotropic hormone, varying doses have been proposed in various studies, from 2 to 8 mg/kg/day. Because lower doses have less efficacy and higher doses have more adverse effects, 4 mg/kg/day is considered an optimal starting dosage (13; 84).

Vigabatrin. Vigabatrin irreversibly inhibits GABA transaminase, thereby increasing the levels of GABA in the CNS. For infantile spasms associated with tuberous sclerosis complex, vigabatrin is the recommended first choice based on a single randomized controlled trial and multiple retrospective studies (14; 50; 17). For infantile spasms associated with nontuberous sclerosis complex etiology, vigabatrin is considered if adrenocorticotropic hormone fails or is not feasible.

The UKISS study included children with infantile spasms with nontuberous sclerosis complex etiology and found a superior efficacy in reaching spasm cessation at day 14 by hormonal therapy compared to the vigabatrin group (73% vs. 54%) (55). But at 14 months and 4 years, spasm cessation rates and developmental scores were similar in both groups (56; 19). In the subgroup of infants with no identified etiologies, hormone therapy led to better development compared to vigabatrin. In the UKISS and ICISS trials, the dose of vigabatrin used was 50 to 150 mg/kg/day.

The most feared adverse effect is vigabatrin-associated visual field loss (VAVFL), which can occur in up to 52% of adults and 34% of children treated with vigabatrin (60). The risk may be comparatively lower in infants and those who receive less cumulative doses (34). To reduce the visual adverse effects, six monthly visual assessments are recommended, and therapy may be limited to 6 months (83; 93). Vigabatrin is also associated with characteristic MRI changes, which may be reversible (72).

Other antiepileptic drugs commonly used in infantile spasms, but without much evidence, are valproate, zonisamide, topiramate, and benzodiazepines. Although a trial of pyridoxine and other vitamins may be considered in infantile spasms of unknown etiology, pyridoxine monotherapy alone is not considered appropriate as the pyridoxine-dependent epilepsy presenting as infantile spasms is exceptional (36).

Dravet syndrome. Dravet syndrome is a severe developmental and epileptic encephalopathy with seizure onset in the first year of life and was previously known as “severe myoclonic epilepsy in infancy.” The majority of cases of Dravet syndrome are caused by a loss-of-function mutation in the SCN1A gene, which encodes the alpha subunit of voltage-gated sodium channels present in the inhibitory interneurons. This, in turn, leads to the decreased activity of inhibitory interneurons, thereby making the nervous system prone to seizures. Other gene mutations that might have a Dravet syndrome–like presentation are SCN2A, SCN1B, SCN8A, PCDH19, GABRA1, GABRG2, KCNA2, and STXBP (89).

The initial presentation is usually an episode of complex febrile seizures in a previously normal infant, typically between 5 and 8 months of age, followed by recurrent and prolonged episodes of febrile seizures that are generalized or focal, with changing laterality between the episodes. Neurologic examination, EEG, and neuroimaging are essentially normal at this stage. Subsequent polymorphic, drug-resistant, febrile and afebrile seizures ensue, along with developmental plateauing and cognitive slowing. A stabilization stage is later reached, with a reduction in seizure frequency; however, there are severe developmental and behavioral issues. The management of Dravet syndrome includes avoidance or modification of triggers, such as fever, hyperthermia, photic stimulation, and certain antiepileptics precipitating seizures in Dravet syndrome.

The loss of function of voltage-gated sodium channels of inhibitory interneurons is the underlying pathophysiology of seizures in Dravet syndrome. Sodium channel blockers like phenytoin, carbamazepine, and lamotrigine further decrease the action of these inhibitory interneurons, leading to a worsening of seizures. Therefore, sodium channel blockers are generally contraindicated in Dravet syndrome. Commonly used first-line antiepileptic drugs in Dravet syndrome are valproate and clobazam, even though they have not been evaluated in randomized trials. For patients who fail this combination, which is a common scenario, the other drugs available are stiripentol, levetiracetam, topiramate, and zonisamide. Cannabinoids and fenfluramine are also approved for this indication. An international consensus was published on the diagnosis and management of Dravet syndrome (95). This consensus recommends sodium valproate as the first antiseizure medication of choice in Dravet syndrome. Second-line therapy includes fenfluramine, stiripentol, or clobazam. Subsequent options include cannabidiol, topiramate, or ketogenic diet. Although the sodium channel blockers are contraindicated, this paper proposes the possibility of utilizing phenytoin in status epilepticus associated with Dravet syndrome.

Stiripentol. Stiripentol is an antiepileptic drug with orphan drug status, and it is approved for adjunctive therapy in Dravet syndrome. It exerts its anticonvulsant action mainly through the positive modulation of GABA(A) receptors, especially the alpha3 subunit, which has the highest expression in the immature brain (31). The STICLO trial showed that add-on stiripentol with valproate and clobazam in Dravet syndrome led to a response in 71% of subjects with Dravet syndrome compared to 5% in the placebo group (15). The dose range is from 50 to 75 mg/kg/day. Because stiripentol is a strong cytochrome p450 inhibitor, the chance of toxicity of concomitant antiepileptic drugs should be considered.

Cannabidiol. Cannabidiol is the component of cannabis with a supposed anticonvulsant property and is the most extensively studied. Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex are the conditions in which cannabidiol has shown efficacy in randomized controlled trials, mainly the GWPCARE trials 1 to 6 (21; 23; 22). A meta-analysis reported the odds ratio for 50% responder rate with cannabidiol with clobazam as 2.51 and without clobazam as 2.40 when compared to placebo (24). The dose range is from 5 to 20 mg/kg/day. Common adverse effects include somnolence, decreased appetite, diarrhea, and alteration of serum transaminase levels.

Fenfluramine. Fenfluramine was previously used as an anti-obesity agent and was withdrawn in 2001 due to concerns regarding its adverse cardiac effects, such as valvular fibrosis. However, the FDA approved fenfluramine in children older than 2 years with Dravet syndrome following two major randomized controlled trials (52; 65). These trials demonstrated significant efficacy in seizure reduction with and without stiripentol and no demonstrable adverse cardiac effects. The dose range is from 0.1 to 0.35 mg/kg/day without stiripentol or 0.2 mg/kg/day with concomitant stiripentol. Common adverse effects include decreased appetite and weight loss, as expected, along with somnolence and diarrhea.

Epilepsy in infancy with migrating focal seizures

Epilepsy in infancy with migrating focal seizures is characterized by multifocal drug-resistant seizures with onset within the first 6 months of age. Development is nearly normal before seizure onset; however, plateauing or regression ensues. The seizure initiates from one focus and migrates to different foci during the same seizure, which is evident clinically as well as electrographically. The prominence of autonomic features is also typical in this epilepsy.

The discovery of potassium channel blocking effects of quinidine in the rodent brain led to its therapeutic use in KCNT1-associated epilepsy (98). Initial case reports showed significant seizure reduction with quinidine (04; 64). However, later studies showed that only about 50% of subjects may have a significant response (63; 59; 71). An observational study of an international cohort of 27 patients with pathogenic KCNT1 mutations also reported similar findings (08).

The starting dose is typically 5 mg/kg/day, with a maintenance dose ranging from 20 to 60 mg/kg/day in various reports. Being a class I antiarrhythmic agent, close monitoring for adverse cardiac effects, particularly QTc prolongation, is warranted. Other drugs tried include cannabidiol and stiripentol, apart from the usual antiepileptic drugs.

Early infantile developmental and epileptic encephalopathy

Developmental and epileptic encephalopathies include the conditions with early-onset, often drug-refractory, seizures and developmental delay. The name implies that the associated neurocognitive morbidity is attributed not only to the underlying etiology but also to the uncontrolled epileptic activity. Early infantile developmental and epileptic encephalopathies include epilepsies with an onset of seizures within the first 3 months of life, with poor developmental and cognitive outcomes. These conditions were previously classified as Ohtahara syndrome or early myoclonic encephalopathy based on clinical and EEG features. However, this classification is becoming obsolete as many cases cannot be classified into either group and many cases overlap. The common associated gene mutations are KCNQ2, CDKL5, SCN2A, SCN8A, STXBP, and UBA5. Channelopathies, such as KCNQ2, SCN2A, and SCN8A mutations, might respond well to sodium channel blockers like carbamazepine.

Benign seizures of infancy

Many self-limited epilepsy syndromes with onset in early infancy are seen in which the seizure predilection is limited to a certain age and then resolves spontaneously. In benign familial neonatal-infantile epilepsy, the seizures start from the neonatal period to late infancy. A gain-of-function mutation in SCN2A is the most common etiology and may readily respond to sodium channel–blocking antiepileptic drugs, such as carbamazepine and phenytoin. Benign familial infantile epilepsy starts at the later age of around 6 months. It is most commonly caused by PRRT2 mutations and responds well to carbamazepine. Both conditions may present sporadically without any family history.

Myoclonic epilepsy of infancy occurs in otherwise normally developing infants. The short duration, occurrence in wakefulness and sleep, and absence of developmental regression clinically differentiate this entity from infantile spasms. The EEG background is also normal interictally, with ictal EEG showing generalized spike-and-waves and polyspikes. The myoclonus usually responds to valproate. Clobazam and clonazepam are also tried in resistant cases.

Precision medicine

Precision medicine is an emerging approach for disease treatment and prevention that takes into account the individual variability in genes, environment, and lifestyle in each person. In the field of epilepsy, it can be loosely described as providing a particular therapy or preventive strategy to individuals with epilepsy based on their underlying causative genetic variation. Even before the widespread availability of gene sequencing techniques, many representative scenarios of precision medicine were known. Providing a ketogenic diet in suspected glucose transporter 1 deficiency and pyridoxine in pyridoxine-dependent seizures has been established for many years. With the discovery of more and more candidate genes, more clinical syndromes that are amenable for precision medicine are slowly being identified.

Epilepsy due to various sodium channelopathies is currently the most common situation in which knowing the genetic basis has a direct therapeutic implication. This is based not only on a particular mutation but also the functional consequence. The SCN1A mutation that causes Dravet syndrome is mostly the loss-of-function type. SCN1A is expressed in GABAergic inhibitory interneurons where their loss of function results in decreased inhibitory drive, leading to increased seizure propensity. In such a scenario, providing sodium channel–blocking drugs, such as carbamazepine, phenytoin, or lamotrigine, results in increased seizures. Therefore, these drugs are contraindicated in SCN1A. On the other hand, other sodium channels, such as SCN1B, SCN2A, and SCN8A, are expressed in glutamatergic pyramidal neurons. Most of the mutations associated with them are gain-of-function type and lead to excessive neuronal excitation, resulting in increased seizure propensity. Here, sodium channels need to be blocked, so sodium channel–blocking antiepileptic drugs, such as carbamazepine and phenytoin, are the drugs of choice. Other examples are given in Table 1.

Everolimus. Everolimus is an oral protein kinase inhibitor of the mTOR pathway. The initial applications of everolimus were in oncology for renal or breast carcinomas and immunology for immunosuppression post-transplantation. The EXIST 1 trial reported a significant reduction in the size of subependymal giant cell astrocytoma in patients with tuberous sclerosis complex (32). The EXIST 2 trial demonstrated efficacy in the volume reduction of renal angiomyolipoma in tuberous sclerosis complex (06). The EXIST 3 trial showed the efficacy of everolimus as an adjunctive therapy in focal seizures associated with tuberous sclerosis complex (33). Based on these trials, the FDA approved everolimus for subependymal giant cell astrocytoma in children 1 year and older as well as for adjunctive therapy in tuberous sclerosis complex–associated focal seizures in children 2 years and older. The dosage range is 4.5 to 5 mg/m² orally once daily to achieve a trough level of 5 to 15 ng/mL.

Sulfonylurea. The gain-of-function mutations in KCNJ11 encoding Kir6.2 subunits of ATP-sensitive potassium channels (KATP) lead to developmental delay, epilepsy, and neonatal diabetes syndrome. These channels are present in pancreatic beta cells, brain, and muscle, thereby explaining the associated neurologic manifestations (86). Sulfonylureas close the opened KATP channels, thereby increasing insulin secretion. Due to the distribution of KATP channels in the brain, it has been suggested that developmental delay and seizures might also respond to these drugs. Further studies are needed for confirmation.

Aspirin. Various small studies support the use of aspirin in children with Sturge-Weber syndrome in addition to antiepileptic drugs for seizure control (53). The leptomeningeal angiomatosis leads to recurrent thrombosis and venous stasis, perpetuating the chronic ischemia of the underlying cortex. Low-dose aspirin prevents this recurrent thrombosis and breaks the cycle. A study reported the possible benefits of presymptomatic aspirin and antiepileptic drugs in infants with Sturge-Weber syndrome (20).

Table 1. Genetic Mutations Causing Epilepsy That Are Amenable to Precision Medicine

Gene	Drug
KCNQ2	Sodium channel blockers
KCNT1	Quinidine
KCNA2	4-amino-pyridine
GRIN2A, GRIN2B	Memantine
PRRT2	Carbamazepine
CAD	Uridine
TSC1, TSC2; DEPDC; NPRL2, NPRL3; mTOR	mTOR inhibitors: everolimus
KCNJ11 (DEND syndrome)	Sulfonylurea
MOCS1 (Molybdenum cofactor deficiency type A)	Fosdenopterin

Other antiepileptic drugs used in infantile-onset epilepsies

Phenobarbital. Phenobarbital was one of the earliest antiepileptics discovered, and it has stood the test of time, even though multiple newer antiepileptic drugs have been discovered. It is still the most widely used antiepileptic drug in the developing world, especially in neonates and infants (51). Phenobarbital exerts its antiepileptic effect through the facilitation of GABAergic neuronal inhibition. It increases the mean duration of channel opening, unlike the benzodiazepines, which increase the frequency of channel opening (81).

The NEOLEV2 trial, a phase 2b study comparing the efficacy of phenobarbital with levetiracetam, demonstrated the superior efficacy of phenobarbital in neonatal seizures (85). Although there are no efficacy trials in infants specifically, the results of the NEOLEV2 trial may be extrapolated to this population. The usual dose range used is 3 to 5 mg/kg/day in one or two divided doses (39).

The most worrisome adverse effects are related to CNS depression-like sedation. However, the concerns of phenobarbital-induced neurotoxicity on the developing brain also need to be considered in neonates and infants. Many animal studies have demonstrated the proapoptotic effects of phenobarbital in the developing rodent brain (07; 47). Many prospective comparative studies have also demonstrated the adverse cognitive effects of phenobarbital in young children (11). A review article analyzing the cognitive effects of antiepileptic drugs in young children concluded that phenobarbital and topiramate are the drugs with the highest potential for cognitive dysfunction in children with epilepsy (09).

Phenytoin. Phenytoin is widely used across the world, even though it has been 82 years since its discovery. It is consistently included in the core item category of the WHO model of the essential list of medicines. It is a sodium channel blocker that stabilizes the neuronal membrane, preventing excessive depolarization. The efficacy of phenytoin in generalized and focal epilepsies, as well as in convulsive status epilepticus, is established in all age groups, including infancy (18; 57).

The nonlinear elimination kinetics of phenytoin is unique among antiepileptic drugs. Infants have the highest relative clearance of phenytoin, which declines gradually and reaches adult value by 10 to 15 years of age (25). As a result, they might need a relatively higher average daily dosage compared to other age groups. In children less than 3 years old, the usual dose is 8 to 10 mg/kg/day as two divided doses (39).

The common adverse effects are ataxia, nystagmus, hirsutism, and gum hypertrophy. Injection-related local complications may be avoided by using fosphenytoin, which is the prodrug of phenytoin. Nevertheless, the cardiac arrhythmic effects seem to be the same with both.

Valproic acid. Valproate is the first and oldest broad spectrum antiepileptic drug still in use. Multiple mechanisms have been proposed for valproate, although the most accepted are GABA modulation at tissue levels and sodium channel blocking. In infancy, valproate is mainly utilized to treat infantile spasms. Other scenarios include developmental and epileptic encephalopathies, such as SCN1A mutation, and neurodegenerative conditions, such as late infantile neuronal ceroid lipofuscinosis, status epilepticus, and acute and remote symptomatic seizures.

Valproate is avoided in suspected inborn errors of metabolism for fear of fatal hepatic failure caused by the inhibition of beta-oxidation of fatty acids and carnitine deficiency. This is particularly true in cases of POLG mutations in which seizures are the presenting complaint. The use of valproate is followed by acute liver failure, which may even act as a diagnostic pointer.

The initiation of valproate in children less than 2 years of age should be done with utmost care. The common adverse effects are gastrointestinal related, like anorexia and vomiting. But most worrisome are serious adverse effects, such as liver failure and acute pancreatitis. Risk factors for valproate-induced liver failure are younger age and polypharmacy.

The dose used in status epilepticus is 20 to 40 mg/kg (10; 37). The usual oral dosage is 15 to 40 mg/kg/day and up to 60 mg/kg/day in the presence of enzyme-inducing antiepileptic drugs, such as phenytoin, phenobarbital, or carbamazepine (39).

Levetiracetam and brivaracetam. Levetiracetam and brivaracetam are analogues of the nootropic agent piracetam. The mechanism of action of levetiracetam is unique in that it is not active in classical animal models of epilepsy and does not seem to decrease hyperexcitability. It has been shown to modulate synaptic vesicle protein 2A (SV2A) and reduce hypersynchronization.

Levetiracetam is one of the most common drugs used in infancy. Many studies have reported its safety and efficacy in the infantile population (03; 01). The Early Life Epilepsy Study, a prospective observational study, found that levetiracetam has superior efficacy in achieving seizure freedom compared to phenobarbital in infants with nonsyndromic epilepsy (38). The usual dosage is from 20 mg/kg/day to 40 to 60 mg/kg/day.

Brivaracetam has similar mechanisms of action, but with better selectivity and adverse effects profiles. It was approved by the FDA for monotherapy or adjunctive therapy in partial-onset seizures in subjects older than 1 month of age. The recommended dosage is 1 to 1.5 mg/kg/day to 4 to 4.5 mg/kg/day.

Carbamazepine, oxcarbazepine, and eslicarbazepine. Carbamazepine is an old-generation sodium channel blocker. There is good evidence for the efficacy of carbamazepine, particularly in focal seizures in the adult population. Oxcarbazepine is a ketoanalogue of carbamazepine and is used in partial-onset seizures. A few studies have demonstrated the safety profile of oxcarbazepine in infants (66). In a randomized controlled trial in infants and young children with partial seizures, high-dose oxcarbazepine was found to be more efficacious than low-dose oxcarbazepine (76). Apart from focal-onset seizures, carbamazepine and oxcarbazepine are particularly effective in channelopathies associated with SCN2A, SCN8A, and KCNQ2 mutations (62; 35).

The usual dosage of carbamazepine is 10 mg/kg/day to 20 to 35 mg/kg/day and of oxcarbazepine is 8 to 10 mg/kg/day to 30 to 60 mg/kg/day. Drug interactions and propensity for drug allergy are the major concerns for carbamazepine; there is less concern with oxcarbazepine. The FDA recommends HLA-B* 1502 screening in subjects of Asian ancestry before the initiation of carbamazepine (91).

The data regarding eslicarbazepine use in infancy are currently limited.

Topiramate. Topiramate is a broad spectrum antiepileptic drug with multiple mechanisms of action. Its long-term safety and tolerability have been demonstrated in the infantile population (79; 61). Studies assessing the efficacy of topiramate as monotherapy or adjunctive therapy in infantile spasms have shown conflicting results. A randomized controlled trial provided class I evidence that topiramate is ineffective as adjunctive therapy in refractory partial-onset seizures in infants (67). The most common adverse effects are somnolence and anorexia. The usual dosage range is from 1 to 3 mg/kg/day to 5 to 9 mg/kg/day.

Zonisamide. Zonisamide acts through the blockade of voltage-gated sodium channels and T-type calcium channels. Like topiramate, the efficacy of zonisamide in infantile spasms is inconsistent. A meta-analysis reported the spasm cessation rate in infantile spasms with zonisamide as 21% (70). Although the efficacy of zonisamide in the treatment of other seizure types, particularly focal seizures, has been evaluated in older children, specific studies in the infantile age group are lacking (40). The usual dosage range is from 1 mg/kg/day to 4 to 8 mg/kg/day, with a maximum dose of 12 mg/kg/day. The common adverse effects are somnolence and anorexia.

Lacosamide. Lacosamide enhances the slow inactivation of voltage-gated sodium channels. Class I evidence for the efficacy of lacosamide in children younger than 4 years of age with focal seizures is available (29). A few case series and retrospective reviews demonstrate the efficacy of lacosamide in the infantile population, particularly in focal seizures and status epilepticus (78; 82; 30). Many reports also demonstrate its efficacy in seizures due to channelopathies like SCN2A and KCNQ2.

The usual dosage range is 7 to 15 mg/kg/day. The most common adverse effects are dizziness, headache, and vomiting. There are concerns about dose-dependent PR interval prolongation with lacosamide, particularly in subjects with conduction defects.

Lamotrigine. Lamotrigine exerts its actions through multiple mechanisms, including voltage-gated sodium and calcium channel inhibition and hyperpolarization-activated cyclic nucleotide-gated channel facilitation. The safety and tolerability of lamotrigine in infants has been reported (75; 45). There is good evidence for the efficacy of lamotrigine in focal-onset seizures, in absence seizures in older children, and in Lennox-Gastaut syndrome. In the only randomized controlled trials of lamotrigine in infants, the proportion of treatment failure was lower (58% vs. 84%), though not statistically significant, and the median time to treatment failure was longer (42 vs. 22 days) for lamotrigine compared to placebo (77).

The dosage range varies with the concomitant medications taken. In monotherapy, the usual dosage range is 4.5 to 7.5 mg/kg/day. Along with valproate, the dosage range is 1 to 5 mg/kg/day, and with enzyme-inducing agents it is 5 to 15 mg/kg/day. Initiation at a low dose and gradual titration is recommended to reduce the most dreaded adverse effects: drug rash, Stevens-Johnson syndrome, and drug rash with eosinophilia and systemic symptoms.

Ganaxolone. Ganaxolone is a neuroactive steroid with positive allosteric modulatory action on GABAA receptors. One Marigold trial assessed the efficacy of ganaxolone in reducing seizures in children with CDKL5 deficiency disorder (CDD) in a randomized double-blinded placebo-controlled manner. Ganaxolone significantly reduced seizure frequency in the treatment group and was well tolerated (48). Following this trial, the FDA approved ganaxolone in children with CDKL5 deficiency disorder older than two years. Multiple studies are ongoing to assess its efficacy in other etiologies like tuberous sclerosis.

Vitamins. Epilepsy associated with a few inborn errors of metabolism respond dramatically to specific vitamin therapies.

Pyridoxine. Pyridoxine-dependent epilepsy is the most well-known vitamin-responsive epilepsy. Pyridoxine-dependent epilepsy is caused by ALDH7A mutations, leading to antiquitin deficiency (90). The seizures usually start in the neonatal period and are associated with unexplained encephalopathy, irritability, and gastrointestinal symptoms. Late-onset forms may present up to 3 years of age.

The seizures, which are usually resistant to traditional antiepileptic drugs, respond within minutes of administration of pyridoxine. Therefore, a trial of intravenous or oral pyridoxine is recommended in all early-onset drug-refractory seizures of unknown cause (74). The intravenous dosage is 100 mg, and the oral dosage is 30 mg/kg/day.

Pyridoxal phosphate. Pyridoxal phosphate–dependent seizures are caused by PNPO gene mutations, leading to enzyme pyridox(am)ine 5’ phosphate oxidase deficiency. Compared to children with pyridoxine-dependent epilepsy, the incidence of fetal distress, prematurity, hypoglycemia, and lactic acidosis is more common. The oral dosage is 30 to 50 mg/kg/day.

Folinic acid. Genetic conditions affecting folate metabolism or folate transport respond to folinic acid therapy. Dihydrofolate reductase deficiency, methyltetrafolate reductase deficiency, hereditary folate malabsorption, and cerebral folate transport deficiency are representative examples. Some cases of antiquitin deficiency also respond to 3 to 5 mg/kg/day of folinic acid.

Biotin. Two clinically indistinguishable conditions respond to oral biotin: biotinidase deficiency and holocarboxylase synthetase deficiency. Seizures are usually early onset, multifocal tonic, tonic-clonic, myoclonic, or spasms. Alopecia and periorificial and facial seborrheic dermatitis-like rash are strong clinical clues. The dosage is 5 to 20 mg/day.

Indications

There are very few drugs that have formal approvals from the U.S. Food and Drug Administration (FDA) for use in this age group. One survey revealed that the use of off-label drugs in infants is common and can lead to more adverse effects (88). Cannabidiol is FDA approved for seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex in subjects over 1 year of age. Levetiracetam is approved for partial-onset seizures in children aged 1 month and older. Oral or intravenous brivaracetam is approved for partial-onset seizures in children aged 1 month and older. Lacosamide is also approved for partial-onset seizures in children aged 1 month and older. Vigabatrin is approved for infantile spasms in children aged 1 month to 2 years. Ganaxolone was approved by the FDA for seizure control in children with CDKL5 deficiency disorder who are more than two years old. Fenfluramine is approved for use in children with Dravet syndrome who are more than two years old.

Contraindications

Apart from drug hypersensitivity, very few contraindications exist specifically in infancy. Mitochondrial disorders, such as POLG mutations, hepatic dysfunction, and urea cycle disorders, are contraindications for valproic acid.

Outcomes

Apart from a few conditions with targeted therapies, such as pyridoxine-dependent epilepsy and biotinidase deficiency, the outcomes of infantile epilepsies are poorer compared to older children and adults. The epileptic and neurocognitive outcomes of early-onset developmental and epileptic encephalopathies are usually guarded. Subjects with cryptogenic West syndrome have better seizure and cognitive outcomes compared to those with symptomatic West syndrome. Earlier treatment initiation and response to initial therapy are associated with better outcomes in infantile spasms. There is an urgent need to develop specific targeted therapeutic regimens for many of the developmental epileptic encephalopathies of infancy.

References

01: Arican P, Gencpinar P, Cavusoglu D, Dundar NO. Levetiracetam monotherapy for the treatment of infants with epilepsy. Seizure 2018;56:73-7. PMID 29453114
02: Arzimanoglou A, D'Cruz O, Nordli D, Shinnar S, Holmes GL; Pediatric Epilepsy Academic Consortium for Extrapolation (PEACE). A review of the new antiepileptic drugs for focal-onset seizures in pediatrics: role of extrapolation. Paediatr Drugs 2018;20(3):249-64. PMID 29616471
03: Arzimanoglou A, Lösch C, Garate P, Bentz J. Safety of levetiracetam among infants younger than 12 months--results from a European multicenter observational study. Eur J Paediatr Neurol 2016;20(3):368-75. PMID 26876768
04: Bearden D, Strong A, Ehnot J, DiGiovine M, Dlugos D, Goldberg EM. Targeted treatment of migrating partial seizures of infancy with quinidine. Ann Neurol 2014;76(3):457-61. PMID 25042079
05: Bebin EM, Peters JM, Porter BE, et al. Early Treatment with vigabatrin does not decrease focal seizures or improve cognition in tuberous sclerosis complex: the PREVeNT Trial. Ann Neurol 2023. [Epub ahead of print] PMID 37638552
06: Bissler JJ, Kingswood JC, Radzikowska E, et al. Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 2013;381(9869):817-24. PMID 23312829
07: Bittigau P, Sifringer M, Genz K, et al. Antiepileptic drugs and apoptotic neurodegeneration in the developing brain. Proc Natl Acad Sci U S A 2002;99(23):15089-94. PMID 12417760
08: Borlot F, Abushama A, Morrison-Levy N, et al. KCNT1-related epilepsy: an international multicenter cohort of 27 pediatric cases. Epilepsia 2020;61(4):679-92. PMID 32167590
09: Bourgeois BF. Determining the effects of antiepileptic drugs on cognitive function in pediatric patients with epilepsy. J Child Neurol 2004;19 Suppl 1:S15-24. PMID 15526967
10: Brophy GM, Bell R, Claassen J, et al. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012;17(1):3-23. PMID 22528274
11: Camfield CS, Chaplin S, Doyle AB, Shapiro SH, Cummings C, Camfield PR. Side effects of phenobarbital in toddlers; behavioral and cognitive aspects. J Pediatr 1979;95(3):361-5. PMID 381616
12: Chang YH, Chen C, Chen SH, Shen YC, Kuo YT. Effectiveness of corticosteroids versus adrenocorticotropic hormone for infantile spasms: a systematic review and meta-analysis. Ann Clin Transl Neurol 2019;6(11):2270-81. PMID 31657133
13: Chellamuthu P, Sharma S, Jain P, Kaushik JS, Seth A, Aneja S. High dose (4 mg/kg/day) versus usual dose (2 mg/kg/day) oral prednisolone for treatment of infantile spasms: an open-label, randomized controlled trial. Epilepsy Res 2014;108(8):1378-84. PMID 25048310
14: Chiron C, Dumas C, Jambaqué I, Mumford J, Dulac O. Randomized trial comparing vigabatrin and hydrocortisone in infantile spasms due to tuberous sclerosis. Epilepsy Res 1997;26(2):389-95. PMID 10642043
15: Chiron C, Marchand MC, Tran A, et al. Stiripentol in severe myoclonic epilepsy in infancy: a randomised placebo-controlled syndrome-dedicated trial. STICLO study group. Lancet 2000;356(9242):1638-42. PMID 11089822
16: Claes L, Del-Favero J, Ceulemans B, Lagae L, Van Broeckhoven C, De Jonghe P. De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. Am J Hum Genet 2001;68(6):1327-32. PMID 11359211
17: Curatolo P, Nabbout R, Lagae L, et al. Management of epilepsy associated with tuberous sclerosis complex: updated clinical recommendations. Eur J Paediatr Neurol 2018;22(5):738-48. PMID 29880258
18: Dalziel SR, Borland ML, Furyk J, et al. Levetiracetam versus phenytoin for second-line treatment of convulsive status epilepticus in children (ConSEPT): an open-label, multicentre, randomised controlled trial. Lancet 2019;393(10186):2135-45. PMID 31005386
19: Darke K, Edwards SW, Hancock E, et al. Developmental and epilepsy outcomes at age 4 years in the UKISS trial comparing hormonal treatments to vigabatrin for infantile spasms: a multi-centre randomised trial. Arch Dis Child 2010;95(5):382-6. PMID 20457702
20: Day AM, Hammill AM, Juhász C, et al. Hypothesis: presymptomatic treatment of Sturge-Weber syndrome with aspirin and antiepileptic drugs may delay seizure onset. Pediatr Neurol 2019;90:8-12. PMID 30482419
21: Devinsky O, Cross JH, Laux L, et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med 2017;376(21):2011-20. PMID 28538134
22: Devinsky O, Nabbout R, Miller I, et al. Long-term cannabidiol treatment in patients with Dravet syndrome: an open-label extension trial. Epilepsia 2019;60(2):294-302. PMID 30582156
23: Devinsky O, Patel AD, Thiele EA, et al. Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome. Neurology 2018;90(14):e1204-11. PMID 29540584
24: Devinsky O, Thiele EA, Wright S, et al. Cannabidiol efficacy independent of clobazam: meta‐analysis of four randomized controlled trials. Acta Neurol Scand 2020;142(6):531-40. PMID 32592183
25: Dodson WE. Nonlinear kinetics of phenytoin in children. Neurology 1982;32(1):42-8. PMID 7198732
26: Dravet C. Dravet syndrome history. Dev Med Child Neurol 2011;53(Suppl 2):1-6. PMID 21504424
27: Duchowny MS, Chopra I, Niewoehner J, Wan GJ, Devine B. A systematic literature review and indirect treatment comparison of efficacy of repository corticotropin injection versus synthetic adrenocorticotropic hormone for infantile spasms. J Health Econ Outcomes Res 2021;8(1):1-9. PMID 33521161
28: England MJ, Liverman CT, Schultz AM, Strawbridge LM. Epilepsy across the spectrum: promoting health and understanding. A summary of the Institute of Medicine report. Epilepsy Behav 2012;25(2):266-76. PMID 23041175
29: Farkas V, Steinborn B, Flamini JR, et al. Efficacy and tolerability of adjunctive lacosamide in pediatric patients with focal seizures. Neurology 2019;93(12):e1212-26. PMID 31462582
30: Ferreira JA, Le Pichon JB, Abdelmoity AT, et al. Safety and tolerability of adjunctive lacosamide in a pediatric population with focal seizures - an open-label trial. Seizure 2019;71:166-73. PMID 31374487
31: Fisher JL. The effects of stiripentol on GABAA receptors. Epilepsia 2011;52 Suppl 2(0 2):76-8. PMID 21463286
32: Franz DN, Belousova E, Sparagana S, et al. Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 2013;381(9861):125-32. PMID 23158522
33: French JA, Lawson JA, Yapici Z, et al. Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study. Lancet 2016;388(10056):2153-63. PMID 27613521
34: Gaily E, Jonsson H, Lappi M. Visual fields at school-age in children treated with vigabatrin in infancy. Epilepsia 2009;50(2):206-16. PMID 19215279
35: Gardella E, Marini C, Trivisano M, et al. The phenotype of SCN8A developmental and epileptic encephalopathy. Neurology 2018;91(12):E1112-24. PMID 30171078
36: Gibaud M, Barth M, Lefranc J, et al. West syndrome is an exceptional presentation of pyridoxine- and pyridoxal phosphate-dependent epilepsy: data from a French cohort and review of the literature. Front Pediatr 2021;9:621200. PMID 33748042
37: Glauser T, Shinnar S, Gloss D, et al. Evidence-based guideline: treatment of convulsive status epilepticus in children and adults: report of the Guideline Committee of the American Epilepsy Society. Epilepsy Curr 2016;16(1):48-61. PMID 26900382
38: Grinspan ZM, Shellhaas RA, Coryell J, et al. Comparative effectiveness of levetiracetam vs phenobarbital for infantile epilepsy. JAMA Pediatr 2018;172(4):352-60. PMID 29435578
39: Guerrini R. Epilepsy in children. Lancet 2006;367(9509):499-524. PMID 16473127
40: Guerrini R, Rosati A, Segieth J, Pellacani S, Bradshaw K, Giorgi L. A randomized phase III trial of adjunctive zonisamide in pediatric patients with partial epilepsy. Epilepsia 2013;54(8):1473-80. PMID 23837461
41: Hancock EC, Osborne JP, Edwards SW. Treatment of infantile spasms. Cochrane Database Syst Rev 2013;(6):CD001770. PMID 23740534
42: Hodgeman RM, Kapur K, Paris A, et al. Effectiveness of once-daily high-dose ACTH for infantile spasms. Epilepsy Behav 2016;59:4-8. PMID 27084976
43: Hrachovy RA, Frost JD Jr, Glaze DG. High-dose, long-duration versus low-dose, short-duration corticotropin therapy for infantile spasms. J Pediatr 1994;124(5 Pt 1):803-6. PMID 8176573
44: Hrachovy RA, Frost JD Jr, Kellaway P, Zion TE. Double-blind study of ACTH vs prednisone therapy in infantile spasms. J Pediatr 1983;103(4):641-5. PMID 6312008
45: Ji L, Chen Y, Mao Z, et al. Efficacy and tolerability of lamotrigine in the treatment of focal epilepsy among children and adolescents: a meta-analysis. Transl Pediatr 2021;10(4):807-18. PMID 34012830
46: Joshi C. Vigabatrin in Epilepsy Related to TSC: Does it PREVeNT and/or (EPI) STOP seizures OR…do we need some more STEPS as VI RAP? Epilepsy Curr 2024;24(2):87-9.
47: Kaushal S, Tamer Z, Opoku F, Forcelli PA. Anticonvulsant drug-induced cell death in the developing white matter of the rodent brain. Epilepsia 2016;57(5):727-34. PMID 27012547
48: Knight EMP, Amin S, Bahi-Buisson N, et al. Safety and efficacy of ganaxolone in patients with CDKL5 deficiency disorder: results from the double-blind phase of a randomised, placebo-controlled, phase 3 trial. Lancet Neurol 2022;21(5):417-27. PMID 35429480
49: Kotulska K, Kwiatkowski DJ, Curatolo P, et al. Prevention of Epilepsy in Infants with Tuberous Sclerosis Complex in the EPISTOP Trial. Ann Neurol 2021;89(2):304-14. PMID 33180985
50: Krueger DA, Northrup H, International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 2013;49(4):255-65. PMID 24053983
51: Kwan P, Brodie MJ. Phenobarbital for the treatment of epilepsy in the 21st century: A critical review. Epilepsia 2004;45(9):1141-9. PMID 15329080
52: Lagae L, Sullivan J, Knupp K, et al. Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial. Lancet 2019;394(10216):2243-54. PMID 31862249
53: Lance EI, Sreenivasan AK, Zabel TA, Kossoff EH, Comi AM. Aspirin use in Sturge-Weber syndrome: side effects and clinical outcomes. J Child Neurol 2013;28(2):213-8. PMID 23112247
54: Li S, Zhong X, Hong S, Li T, Jiang L. Prednisolone/prednisone as adrenocorticotropic hormone alternative for infantile spasms: a meta-analysis of randomized controlled trials. Dev Med Child Neurol 2020;62(5):575-80. PMID 31903560
55: Lux AL, Edwards SW, Hancock E, et al. The United Kingdom Infantile Spasms Study comparing vigabatrin with prednisolone or tetracosactide at 14 days: a multicentre, randomised controlled trial. Lancet 2004;364(9447):1773-8. PMID 15541450
56: Lux AL, Edwards SW, Hancock E, et al. The United Kingdom Infantile Spasms Study (UKISS) comparing hormone treatment with vigabatrin on developmental and epilepsy outcomes to age 14 months: a multicentre randomised trial. Lancet Neurol 2005;4(11):712-7. PMID 16239177
57: Lyttle MD, Rainford NEA, Gamble C, et al. Levetiracetam versus phenytoin for second-line treatment of paediatric convulsive status epilepticus (EcLiPSE): a multicentre, open-label, randomised trial. Lancet 2019;393(10186):2125-34. PMID 31005385
58: Madaan P, Chand P, Linn K, et al. Management practices for West syndrome in South Asia: a survey study and meta-analysis. Epilepsia Open 2020;5(3):461-74. PMID 32913954
59: Madaan P, Jauhari P, Gupta A, Chakrabarty B, Gulati S. A quinidine non responsive novel KCNT1 mutation in an Indian infant with epilepsy of infancy with migrating focal seizures. Brain Dev 2018;40(3):229-32. PMID 29037447
60: Maguire MJ, Hemming K, Wild JM, Hutton JL, Marson AG. Prevalence of visual field loss following exposure to vigabatrin therapy: a systematic review. Epilepsia 2010;51(12):2423-31. PMID 21070215
61: Manitpisitkul P, Shalayda K, Todd M, Wang SS, Ness S, Ford L. Pharmacokinetics and safety of adjunctive topiramate in infants (1-24 months) with refractory partial-onset seizures: a randomized, multicenter, open-label phase 1 study. Epilepsia 2013;54(1):156-64. PMID 23157581
62: Matsufuji H, Ichiyama T, Isumi H, Furukawa S. Low-dose carbamazepine therapy for benign infantile convulsions. Brain Dev 2005;27(8):554-7. PMID 16310589
63: Mikati MA, Jiang YH, Carboni M, et al. Quinidine in the treatment of KCNT1-Positive Epilepsies. Ann Neurol 2015;78(6):995-9. PMID 26369628
64: Milligan CJ, Li M, Gazina EV, et al. KCNT1 gain of function in 2 epilepsy phenotypes is reversed by quinidine. Ann Neurol 2014;75(4):581-90. PMID 24591078
65: Nabbout R, Mistry A, Zuberi S, et al. Fenfluramine for treatment-resistant seizures in patients with Dravet syndrome receiving stiripentol-inclusive regimens: a randomized clinical trial. JAMA Neurol 2020;77(3):300-8. PMID 31790543
66: Northam RS, Hernandez AW, Litzinger MJ, et al. Oxcarbazepine in infants and young children with partial seizures. Pediatr Neurol 2005;33(5):337-44. PMID 16243221
67: Novotny E, Renfroe B, Yardi N, et al. Randomized trial of adjunctive topiramate therapy in infants with refractory partial seizures. Neurology 2010;74(9):714-20. PMID 20089937
68: O'Callaghan FJ, Edwards SW, Alber FD, et al. Safety and effectiveness of hormonal treatment versus hormonal treatment with vigabatrin for infantile spasms (ICISS): a randomised, multicentre, open-label trial. Lancet Neurol 2017;16(1):33-42. PMID 27838190
69: Osborne JP, Lux AL, Edwards SW, et al. The underlying etiology of infantile spasms (West syndrome): information from the United Kingdom Infantile Spasms Study (UKISS) on contemporary causes and their classification. Epilepsia 2010;51(10):2168-74. PMID 20726878
70: Panda PK, Sharawat IK, Panda P, Dawman L. Efficacy, tolerability, and safety of zonisamide in children with epileptic spasms: a systematic review and meta-analysis. Seizure 2021;91:374-83. PMID 34298456
71: Patil AA, Vinayan KP, Roy AG. Two South Indian children with KCNT1-related malignant migrating focal seizures of infancy - clinical characteristics and outcome of targeted treatment with quinidine. Ann Indian Acad Neurol 2019;22(3):311-5. PMID 31359944
72: Pearl PL, Vezina LG, Saneto RP, et al. Cerebral MRI abnormalities associated with vigabatrin therapy. Epilepsia 2009;50(2):184-94. PMID 18783433
73: Pellock JM, Hrachovy R, Shinnar S, et al. Infantile spasms: a U.S. consensus report. Epilepsia 2010;51(10):2175-89. PMID 20608959
74: Pena IA, MacKenzie A, Van Karnebeek CDM. Current knowledge for pyridoxine-dependent epilepsy: a 2016 update. Expert Rev Endocrinol Metab 2017;12(1):5-20. PMID 30058881
75: Pina-Garza JE, Elterman RD, Ayala R, et al. Long-term tolerability and efficacy of lamotrigine in infants 1 to 24 months old. J Child Neurol 2008a;23(8):853-61. PMID 18660469
76: Pina-Garza JE, Espinoza R, Nordli D, et al. Oxcarbazepine adjunctive therapy in infants and young children with partial seizures. Neurology 2005;65(9):1370-5. PMID 16275822
77: Pina-Garza JE, Levisohn P, Gucuyener K, et al. Adjunctive lamotrigine for partial seizures in patients aged 1 to 24 months. Neurology 2008b;70(22 Pt 2):2099-108. PMID 18077797
78: Poddar K, Sharma R, Ng YT. Intravenous lacosamide in pediatric status epilepticus: an open-label efficacy and safety study. Pediatr Neurol 2016;61:83-6. PMID 27241232
79: Puri V, Ness S, Sattaluri SJ, et al. Long-term open-label study of adjunctive topiramate in infants with refractory partial-onset seizures. J Child Neurol 2011;26(10):1271-83. PMID 21673279
80: Raga SV, Wilmshurst JM. Epileptic spasms: evidence for oral corticosteroids and implications for low and middle income countries. Seizure 2018;59:90-8. PMID 29787923
81: Rogawski MA, Porter RJ. Antiepileptic drugs: pharmacological mechanisms and clinical efficacy with consideration of promising developmental stage compounds. Pharmacol Rev 1990;42(3):223-86. PMID 2217531
82: Rosati A, Ilvento L, Rizzi R, et al. Long-term efficacy of add-on lacosamide treatment in children and adolescents with refractory epilepsies: a single-center observational study. Epilepsia 2018;59(5):1004-10. PMID 29663335
83: Sergott RC. Recommendations for visual evaluations of patients treated with vigabatrin. Curr Opin Ophthalmol 2010;21(6):442-6. PMID 20811279
84: Sharma S, Kaushik JS, Srivastava K, et al. Association of Child Neurology (AOCN) - Indian Epilepsy Society (IES) consensus guidelines for the diagnosis and management of West syndrome. Indian Pediatr 2021;58(1):54-66. PMID 33452776
85: Sharpe C, Reiner GE, Davis SL, et al. Levetiracetam versus phenobarbital for neonatal seizures: a randomized controlled trial. Pediatrics 2020;145(6):e20193182. PMID 32385134
86: Shimomura K, Hörster F, de Wet H, et al. A novel mutation causing DEND syndrome: a treatable channelopathy of pancreas and brain. Neurology 2007;69(13):1342-9. PMID 17652641
87: Sorel L, Dusaucy-Bauloye A. Findings in 21 cases of Gibbs' hypsarrhythmia; spectacular effectiveness of ACTH. [Article in French] Acta Neurol Psychiatr Belg 1958;58(2):130-41. PMID 13532578
88: Sourbron J, Auvin S, Arzimanoglou A, et al. Medical treatment in infants and young children with epilepsy: Off-label use of antiseizure medications. Survey Report of ILAE Task Force Medical Therapies in Children. Epilepsia Open 2023;8(1):77-89. PMID 36281833
89: Steel D, Symonds JD, Zuberi SM, Brunklaus A. Dravet syndrome and its mimics: beyond SCN1A. Epilepsia 2017;58(11):1807-16. PMID 28880996
90: Stockler S, Plecko B, Gospe Jr SM, et al. Pyridoxine dependent epilepsy and antiquitin deficiency: clinical and molecular characteristics and recommendations for diagnosis, treatment, and follow-up. Mol Genet Metab 2011;104(1-2):48-60. PMID 21704546
91: Tangamornsuksan W, Chaiyakunapruk N, Somkrua R, Lohitnavy M, Tassaneeyakul W. Relationship between the HLA-B*1502 allele and carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis. JAMA Dermatol 2013;149(9):1025-32. PMID 23884208
92: West WJ. On a peculiar form of infantile convulsions. Lancet 1841;1:724-5.
93: Westall CA, Wright T, Cortese F, Kumarappah A, Snead OC 3rd, Buncic JR. Vigabatrin retinal toxicity in children with infantile spasms: an observational cohort study. Neurology 2014;83(24):2262-8. PMID 25381295
94: Wilmshurst JM, Gaillard WD, Vinayan KP, et al. Summary of recommendations for the management of infantile seizures: Task Force Report for the ILAE Commission of Pediatrics. Epilepsia 2015;56(8):1185-97. PMID 26122601
95: Wirrell EC, Hood V, Knupp KG, et al. International consensus on diagnosis and management of Dravet syndrome. Epilepsia 2022;63(7):1761-77. PMID 35490361
96: Wirrell EC, Shellhaas RA, Joshi C, et al. How should children with West syndrome be efficiently and accurately investigated? Results from the National Infantile Spasms Consortium. Epilepsia 2015;56(4):617-25. PMID 25779538
97: Yanagaki S, Oguni H, Hayashi K, et al. A comparative study of high-dose and low-dose ACTH therapy for West syndrome. Brain Dev 1999;21(7):461-7. PMID 10522523
98: Yang B, Gribkoff VK, Pan J, et al Pharmacological activation and inhibition of Slack (Slo2.2) channels. Neuropharmacology 2006;51(4):896-906. PMID 16876206
99: Zuberi SM, Wirrell E, Yozawitz E, et al. ILAE classification and definition of epilepsy syndromes with onset in neonates and infants: Position statement by the ILAE Task Force on Nosology and Definitions. Epilepsia 2022;63(6):1349-97. PMID 35503712
100: References especially recommended by the author or editor for general reading.

Contributors

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Authors

K P Vinayan MD DM

Dr. Vinayan of the Amrita Institute of Medical Sciences has no relevant financial relationships to disclose.
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Vaishakh Anand MD DM

Dr. Anand of Amrita Institute of Medical Sciences in Kochi, Kerala has no relevant financial relationships to disclose.
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Editor

Solomon L Moshé MD

Dr. Moshé of Albert Einstein College of Medicine has no relevant financial relationships to disclose.
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Pharmacological treatment of epilepsy in infants

Also Relevant

Benign infantile seizures
Developmental and epileptic encephalopathies
Dravet syndrome
Epilepsy in infancy with migrating focal seizures
Neonatal seizures
- West syndrome

Clinical Categories

Epilepsy & Seizures

Pharmacological treatment of epilepsy in infants

Pharmacological treatment of epilepsy in infants

Introduction

Overview

Key points

Historical note and terminology

Clinical aspects

Approach

Infantile epileptic syndromes with specific therapeutic options

Epilepsy in infancy with migrating focal seizures

Early infantile developmental and epileptic encephalopathy

Benign seizures of infancy

Precision medicine

Table 1. Genetic Mutations Causing Epilepsy That Are Amenable to Precision Medicine

Other antiepileptic drugs used in infantile-onset epilepsies

Indications

Contraindications

Outcomes

References

Contributors

Authors

Editor

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Also in This Category

Anti-LGI1 encephalitis

Alcohol withdrawal seizures

Epileptic lesions due to malformation of cortical development

Epileptic spasms

Jacksonian seizures

Transient epileptic amnesia

Generalized onset clonic seizures

Generalized onset tonic-clonic seizures

Pharmacological treatment of epilepsy in infants

Introduction

Overview

Key points

Historical note and terminology

Clinical aspects

Approach

Infantile epileptic syndromes with specific therapeutic options

Epilepsy in infancy with migrating focal seizures

Early infantile developmental and epileptic encephalopathy

Benign seizures of infancy

Precision medicine

Table 1. Genetic Mutations Causing Epilepsy That Are Amenable to Precision Medicine

Other antiepileptic drugs used in infantile-onset epilepsies

Indications

Contraindications

Outcomes

References

Contributors

Authors

Editor

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Anti-LGI1 encephalitis

Alcohol withdrawal seizures

Epileptic lesions due to malformation of cortical development

Epileptic spasms

Jacksonian seizures

Transient epileptic amnesia

Generalized onset clonic seizures

Generalized onset tonic-clonic seizures

This is an article preview.
Start a Free Account
to access the full version.