Myoclonus epilepsy with ragged-red fibers
Nov. 06, 2023
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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.
• 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.
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.
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 established that early detection of epileptic activity through serial EEGs and treatment with vigabatrin can reduce the risk and severity of epilepsy in infants with tuberous sclerosis (47).
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 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) (97). 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 (67). 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 (67; 94). 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 (94). 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 (82).
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 (71). The initial step in the management of infantile spasms involves dichotomization into tuberous sclerosis complex and nontuberous sclerosis complex–associated infantile spasms (92; 78; 82). 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 (40). 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 (26).
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 (42; 95). Still, most guidelines recommend high-dose, once-daily adrenocorticotropic hormone (41; 82).
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 (56).
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%) (53). The International Collaborative Infantile Spasms Study (ICISS) also reported similar findings (66). 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 (11; 52).
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 (12; 82).
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 (13; 48; 16). 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%) (53). But at 14 months and 4 years, spasm cessation rates and developmental scores were similar in both groups (54; 18). 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 (58). The risk may be comparatively lower in infants and those who receive less cumulative doses (33). To reduce the visual adverse effects, six monthly visual assessments are recommended, and therapy may be limited to 6 months (81; 91). Vigabatrin is also associated with characteristic MRI changes, which may be reversible (70).
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 (35).
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 (87).
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 (93). 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 (30). 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 (14). 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 (20; 22; 21). 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 (23). 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 (50; 63). 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 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 (96). Initial case reports showed significant seizure reduction with quinidine (04; 62). However, later studies showed that only about 50% of subjects may have a significant response (61; 57; 69). An observational study of an international cohort of 27 patients with pathogenic KCNT1 mutations also reported similar findings (07).
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.
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.
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 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 (31). The EXIST 2 trial demonstrated efficacy in the volume reduction of renal angiomyolipoma in tuberous sclerosis complex (05). The EXIST 3 trial showed the efficacy of everolimus as an adjunctive therapy in focal seizures associated with tuberous sclerosis complex (32). 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 (84). 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 (51). 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 (19).
Sodium channel blockers
TSC1, TSC2; DEPDC; NPRL2, NPRL3; mTOR
mTOR inhibitors: everolimus
KCNJ11 (DEND syndrome)
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 (49). 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 (79).
The NEOLEV2 trial, a phase 2b study comparing the efficacy of phenobarbital with levetiracetam, demonstrated the superior efficacy of phenobarbital in neonatal seizures (83). 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 (38).
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 (06; 45). Many prospective comparative studies have also demonstrated the adverse cognitive effects of phenobarbital in young children (10). 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 (08).
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 (17; 55).
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 (24). 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 (38).
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 (09; 36). 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 (38).
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 (37). 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 (64). 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 (74). Apart from focal-onset seizures, carbamazepine and oxcarbazepine are particularly effective in channelopathies associated with SCN2A, SCN8A, and KCNQ2 mutations (60; 34).
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 (89).
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 (77; 59). 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 (65). 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% (68). 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 (39). 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 (28). A few case series and retrospective reviews demonstrate the efficacy of lacosamide in the infantile population, particularly in focal seizures and status epilepticus (76; 80; 29). 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 (73; 44). 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 (75).
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 (46). 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 (88). 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 (72). 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.
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 (86). 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.
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.
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.
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Solomon L Moshé MD
Dr. Moshé of Albert Einstein College of Medicine has no relevant financial relationships to disclose.See Profile
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