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  • Updated 03.13.2023
  • Released 11.19.2021
  • Expires For CME 03.13.2026

Pharmacological treatment of epilepsy in infants



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 (27). 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 (90). Dravet syndrome was first described as “severe myoclonic epilepsy in infancy” by Charlotte Dravet in 1978 (25). 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 (15). 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 (85). The first double-blind randomized controlled trial for infantile spasms was conducted by Hrachovy and colleagues in 1983 (43). 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 (13). 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.

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