Clinical manifestations

Presentation and course

Some of the children with epilepsy in infancy with migrating focal seizures may have the seizure onset in utero with postnatal seizures between day 1 and 2 weeks after birth. Seizure onset in the first week of life has been reported in patients with SCN2A, KCNQ2, and BRAT1 mutations. Seizure types at onset range from focal seizures, tonic seizures, and epileptic spasms, with additional seizure types like clonic, myoclonic, tonic-clonic, autonomic, and reflex seizures, over the course of the disease. The seizures may be refractory at onset or become progressively pharmacoresistant. Other major clinical features are developmental slowing at the time of refractory migrating focal seizures or global developmental delay before the onset of seizures. Variable tone abnormalities were noted like isolated limb spasticity, diffuse spastic quadriparesis, global hypotonia, or a combination of axial hypotonia and appendicular hypertonia. Movement disorders including choreoathetosis and dyskinesia were seen rarely. Thermal dysregulation with recurrent episodes of hypo- or hyperthermia, severe gut dysmotility, and other signs of dysautonomia were also rarely found. Acquired microcephaly, scoliosis, and coarse facial features were noted mostly in later childhood (46; 10; 70).

The proposed diagnostic criteria for epilepsy in infancy with migrating focal seizures include: (1) normal or near normal development before the seizure onset, (2) onset of seizures before 6 months, (3) focal motor seizures with a migrating character as the defining seizure type, (4) multifocal seizures becoming intractable, (5) seizures resistant to conventional antiepileptic drugs, (6) no identified structural etiology, and (7) profound psychomotor delay (21; 19; 46).

Three phases have been identified in the natural history of epilepsy in infancy with migrating focal seizures. The initial defining phase is between the first week of life and about 7 months of age during which seizures are sporadic, occurring at weekly to monthly intervals. Seizures are usually focal motor with or without secondary generalization. Autonomic manifestations such as apnea and flushing are frequent; during the second phase or “stormy phase” (between 3 weeks and 10 months), seizures become polymorphic with daily clusters. Almost continuous seizures lasting over days to weeks were also noted. Hypotonia, lethargy, feeding difficulty, and absence of visual response may be noted at this stage along with loss of acquired skills. Minor improvement in developmental status might be noted between seizure clusters. Better control of seizures during this phase might improve the final developmental outcome. Seizures may become less frequent during the third phase (from 1 to 5 years). However, clusters or status epilepticus might be triggered by intercurrent illnesses. The majority of children in this phase will have severe developmental delay and acquired microcephaly. Mortality is increased because of status epilepticus and respiratory failure (44; 11; 18). In the near future, there is a chance that several electroclinical patterns suggestive of specific genetic variations might possibly emerge from this syndrome. These endophenotypes might have better management and prognostic implications.

Prognosis and complications

The long-term seizure and developmental outcomes of epilepsy in infancy with migrating focal seizures depend on the underlying etiology and the response to treatment during the stormy course of the disease. In most of the cases, seizures never come under control with the currently available antiepileptic drugs. However, this might change in the coming years with the advent of targeted therapies. Currently some of the pathogenic mutations in KCNT1 are shown to be responsive to quinidine (05; 47). Acquired microcephaly with permanent psychomotor retardation is very commonly noted. So far, a relatively normal long-term development is reported only in a single patient (44).

Clinical vignette

A baby boy of nonconsanguineous parents with normal birth history had his first episode of seizure at 15 days of life, which was described as clonic jerking of the whole body with blinking of eyes. He was evaluated at a local hospital after one month of age with increased seizure frequency. His magnetic resonance imaging (MRI) and electroencephalography (EEG) were reported to be normal at this point. He was started on oral phenytoin, with which he had transient improvement. The seizures soon recurred when oral levetiracetam was added. Later seizure semiology changed to staring look followed by versive head deviation to left with tonic posturing of left upper and lower limbs, which used to last for 1 to 2 minutes. He used to have 15 to 20 seizures every day. At 4.5 months of age, the baby was brought to our department for further evaluation and management. On examination, he was active and alert. He had attained only partial head control with occasional social smile. Video EEG (VEEG) recorded multifocal interictal epileptiform abnormalities and several electroclinical events suggestive of focal seizures of right temporal origin. In view of the persistent onset of seizures from the right temporal region, a resistant structural focal epilepsy due to a cryptogenic lesion was initially considered at this stage. 3T MRI brain with contrast did not reveal any structural lesion. The following antiepileptic drugs were administered: oxcarbazepine (25.86 mg/kg/day), levetiracetam (43.8 mg/kg/day), clobazam (1.02 mg/kg/day), and phenobarbitone (2.7 mg/kg/day). The frequency of events decreased substantially for the initial few days. However, seizures became very frequent later, and repeat VEEG showed very frequent focal seizures arising independently and sequentially from both posterior head regions with frequent migration from one focus to another suggesting epilepsy in infancy with migrating focal seizures. Cerebrospinal fluid (CSF) study was normal (CSF glucose 67.3 mg/dl, CSF protein 45.1 mg/dl, lactate 1.3 mmol/L, no cells). Plasma ammonia was 56.3 umol/L and lactate1.2 mmol/L. His seizures continued to be refractory with very frequent migrating and nonmigrating focal seizures arising from multiple foci over both the hemispheres.

At 8 months of age, he was initiated on low glycemic index diet according to our institutional protocol and his seizure frequency minimally reduced. Next‑generation sequencing identified a heterozygous missense variation in exon 25 of the KCNT1 gene (chr9:138675877; G> G/A; Depth: ×41) that resulted in the amino acid substitution of glutamine for arginine at codon 950 (p.Arg950GIn; ENST0000037 j757). He continued to have 5 to 10 events per day and was readmitted at 10 months of age for initiation of quinidine. Oral quinidine (quinidine sulfate 200 mg tablet, Sandoz) was initiated at 5 mg/kg/day in three divided doses, with serial ECG monitoring for prolongation of corrected QT interval. Existing antiepileptic drugs were continued. The dose of oral quinidine was hiked up weekly by around 5 mg/kg to a maximum dose of 36 mg/kg/day. His seizures came down to less than 60% of baseline seizure frequency by the time the dosage of quinidine reached 20 mg/kg/day. Corrected QT interval was within acceptable limits even with 30 mg/kg/day. With the reduction of seizures, there was an overall improvement in the developmental status. At the last follow‑up at 13 months of age, his developmental age was around 6 months; he was able to control his head, was saying monosyllables, had eye contact, and was responding to verbal cues. He was on 36 mg/kg/day of quinidine with around 80% reduction in seizure frequency from baseline. Serum antiepileptic drug levels were not done either before or after starting quinidine (55).

Biological basis

Etiology and pathogenesis

No etiology was identified for epilepsy in infancy with migrating focal seizures until 2010, when duplication of 16p11.2 was reported initially (06). Subsequently, mutations in SCN1A, phospholipase C beta 1 (PLCB1), and KCNT1 have been reported by different groups (14; 30; 04; 57; 37). Familial cases (two sisters of unrelated parents) were also reported with compound heterozygous mutations of TBC1D24 gene, which is critical for maturation of neuronal circuits (48). After the advent of next generation sequencing, multiple genes have been implicated in epilepsy in infancy with migrating focal seizures. However, the majority of the currently available reports show pathogenic genetic variants in the KCNT1 gene. In a group of children with genetically confirmed KCNT1 mutation, two thirds presented with epilepsy in infancy with migrating focal seizures (08). In another reported large cohort of 248 patients with KCNT1 mutation, 152 had features suggestive of epilepsy of infancy with migrating focal seizures (07). At the mechanistic level, pathogenic variants of KCNT1 have been found to strongly decrease the firing rate properties of γ-aminobutyric acidergic (GABAergic) interneurons and, to a lesser extent, those of pyramidal cells (42).

Other major genes consistently reported with epilepsy in infancy with migrating focal seizures are AIMP1, ALDH7A1, ALG1, ARV1, ATP1A3, ATP7A, BRAT1, CDKL5, DOCK6, FARS, 2KARS, KCNC1, KCNT2, KCNQ2, GABRA1, GABRB1, GABRB3, GABRG2, HCN1, ITPA, PCDH19, PIGA, PLCB1, PRRT2, QARS, SCN1A, SCN2A, SCN8A, SLC12A5, SLC25A22, SMC1A, TBC1D24, TUBB4A and WWOX (10; 60; 66; 23; 73; 69; 70; 72; 49). Two siblings with epilepsy in infancy with migrating focal seizures were reported to be associated with a variant in SZT2 (26). One patient with ASNS gene mutation causing asparagine synthetase deficiency has been reported; an EEG was performed at 13 months of age, which showed features consistent with epilepsy of infancy with migrating focal seizures (43). There are no cases with mutation of STXBP1, POLG, or pathogenic copy number variations. Three of the children from the original cohort by Coppola were negative for sodium (SCN1A, SCN2A), potassium (KCNQ2, KCNQ3), and chloride (CLCN2) ion channels (22).

There are also reports of other multisystem genetic disorders with migrating focal seizures as one of the initial presenting features like congenital disorders of glycosylation, 47XYY syndrome, Menke syndrome, and Wolf-Hirschhorn syndrome (39; 03; 38; 53).

Malformation of cortical development or acquired brain lesions have not been reported so far, except for in two case reports. One report described a child with temporal lobe atrophy, hippocampal sclerosis, and cortical-subcortical blurring. Coppola and colleagues considered this presentation as a dual pathology (20). The other report described a child with multiple malformations of cortical development, polymicrogyria, and focal cortical dysplasia associated with hippocampal sclerosis on autopsy (28).

Epidemiology

Even though epilepsy in infancy with migrating focal seizures is a very rare syndrome, cases have been reported from all the major geographic regions like Australia, Canada, Europe, Israel, India, Japan, and the United States. A population-based study from Australia reported an estimated incidence of 4.5 out of 100,000 live births per year (34).

Prevention

There is no known method of prevention as most of the cases reported are due to sporadic mutations or of unknown etiologies.

Differential diagnosis

Migrating focal seizures may also be seen rarely in severe neonatal encephalopathies due to acquired etiologies like hypoxic ischemic injury. It may also be seen in severe metabolic encephalopathies in the neonatal period and early infancy. Multifocal and diffuse structural malformations of the brain may also present with very frequent focal seizures arising from multiple foci with a suggestion of migration between these foci.

Early infantile epileptic encephalopathy such as Ohtahara syndrome and early myoclonic encephalopathy may also be considered in the differential diagnoses. Genes known to be associated with Ohtahara syndrome are STXBP1, ARX, SLC25A22, KCNQ2, SCN2A, and GABRA1. Ohtahara syndrome is characterized by intractable seizures within the first few weeks of life. Infants may develop acute generalized or lateralized tonic spasms that can occur either singly or in clusters and are independent of the sleep cycle. The seizure frequency may be very high, ranging from 10 to 300 spasms in 10 to 20 clusters per day. Tonic spasm is the main seizure type in Ohtahara syndrome; other seizure types like focal myoclonic seizures may also be seen. EEG in Ohtahara syndrome is characterized by suppression-burst pattern in sleep and awake. Reports have suggested that suppression-burst patterns may occur in rare patients with epilepsy in infancy with migrating focal seizures (46; 61; 71).

Early myoclonic encephalopathy is an epileptic syndrome associated with inherited metabolic disorders that starts in the early neonatal period or in the first months of life. It is associated with erratic myoclonus, refractory focal seizures, and abnormal neurologic status. In early myoclonic encephalopathy, suppression-burst is typically observed only during sleep (52).

Confusing conditions

Some of the genetic mutations associated with epilepsy in infancy with migrating focal seizures like KCNT1 may present initially with pharmacoresistant focal seizures without showing the classical migration pattern. At this stage, these cases might be confused with a refractory structural focal epilepsy due to a subtle focal cortical dysplasia. KCNQ2 truncations and deletions are usually associated with self-limited neonatal seizures, whereas missense and in frame deletions are associated with severe phenotypes like epilepsy in infancy with migrating focal seizures.

Diagnostic workup

Diagnosis is based on the combination of early-onset focal seizures in a previously normal infant, rapidly progressive course with poor drug response, and psychomotor regression/arrest. Continuous video-EEG is usually required to confirm multifocal independent seizure foci with the classical migratory pattern.

In patients with epilepsy if infancy with migrating focal seizures, initial interictal EEG may be normal. Later, diffuse background slowing and multifocal epileptogenic foci might appear. Other EEG patterns usually noted are multifocal spikes with slow background activity and modified hypsarrhythmia with variable periods of suppression to classical suppression-burst patterns. Later evolution to classical hypsarrhythmia by around 6 months of age were also reported in some cases.

Seizure emergence during early infantile stage may be associated with asymmetrical suppression-burst patterns and emergence during the later infantile period with symmetrical suppression-burst patterns. Immaturity or dysfunction of the corpus callosum plays an important structural or functional role in suppression-burst symmetry. Differences in the synchrony of suppression-burst patterns among patients with epilepsy in infancy with migrating focal seizures may also be explained by the maturity or recovery of normal function of the corpus callosum.

Ictal EEG shows shifting areas of ictal onset (migrating spikes) between hemispheres within the same EEG recording or overlapping seizures with different areas of ictal onset from both the hemispheres. Classical migration of the seizures from one hemispheric focus to another with a completely different ictal rhythm may also been in a majority of cases during the stormy phase of the disease. Focal electro-decremental response during the seizure episode may also be seen in some patients. Significant postictal slowing may be seen in many patients (46; 61; 71).

Magnetic resonance imaging of brain may be normal or may show variable cerebral atrophy, mild to moderate enlargement of both subarachnoid and ventricular spaces, delayed myelination with T2 hyperintensity of the deep white matter, diffuse cerebral atrophy (with an increase in extra axial fluid), forehead dysplasia or widened brain spaces, hippocampal sclerosis, encephalomalacia foci, dysplasia of the corpus callosum, subependymal cyst, pachygyria, or meningeal reinforcement (70).

Genetic screening should be considered early in the course. Targeted sanger sequencing panels may be tried if there are classical signs of a specific genetic mutation. Otherwise, whole exome sequencing might be more cost effective.

Management

Epilepsy in infancy with migrating focal seizures is a developmental/epileptic encephalopathy that is usually very resistant to almost all of the currently used antiepileptic regimens. Partial seizure reduction or brief and unsustained periods of seizure freedom have been reported with antiepileptic drug combination regimens including oxcarbazepine, phenytoin, bromides, topiramate, levetiracetam, and vigabatrin (40; 49). Stiripentol, lacosamide, and rufinamide were also reported as effective (33; 17; 24; 64; 46). Ketogenic diet was reportedly effective in one child with SCN1A mutation (62). Carbamazepine and vigabatrin seem to worsen the condition (25). Variable seizure responses have been reported with adrenocorticotrophic hormone, oral prednisolone, and topiramate in combination with the ketogenic diet (46; 15).

Sustained seizure reduction has been noted with antiepileptic drug regimen combined with cannabinoids. Cannabidiol was used in this case (Epidiolex, GW Pharma UK- oral CBD, 25 mg/ml) with a starting dose of 10 mg/kg/day divided twice daily, increased to a goal of 25 mg/kg/day divided twice daily over 15 days (59). However, subsequent reports did not show such promising responses (58).

Potassium bromide (30 to 80 mg/kg/day) divided in two oral doses with a target therapeutic bromide concentration between 75 and 125 mg/dl have also been tried. Mechanism of action is enhancement of the inhibitory neural pathway by promoting chloride inflow via the gamma-aminobutyric acid (GABA) receptor. Adverse effects like drowsiness, vomiting, and acneiform eruption on face were noted (12; 50).

Seizure reduction has been reported with stiripentol in combination with other conventional antiepileptic drugs. The dose range of stiripentol was 20 to 50 mg/kg/day, given in two to three daily divided doses (maximum dose 3500 mg/day). Titration to this dose was achieved over 2 to 3 weeks. One patient used stiripentol in conjunction with sodium bromide and levetiracetam. Sodium bromide, levetiracetam, and clobazam were used in conjunction with stiripentol in another. In both the patients, reduction in seizure frequency was noted from nearly continuous to fewer than 10 events per day (24; 45; 51).

Acetazolamide (20 mg/kg/day) was noted to be effective for epileptic apnea with severe desaturation in epilepsy in infancy with migrating focal seizures, possibly by reduction of GABA mediated depolarization, and suppression of the excitatory action of NMDA receptors. Acetazolamide was also effective against nonepileptic central apnea by induction of metabolic acidosis that results in stimulation of central chemoreceptors (36).

Patients with ALDH7A1 and PNPO mutations achieved seizure-free status on vitamin B6; oxcarbazepine was found to be effective for patients with SCN2A, ATP7A, WWOX, and PRRT2 mutations; and ACTH was reported to be partly effective for DOCK6 mutations in patients with spasms and hypsarrhythmia (70).

Ketogenic diet is a high-fat, restricted-carbohydrate regimen used for the treatment of drug-resistant epilepsy. Ketogenic diet causes enhancement of inhibitory neural pathway. Ketogenic diet may be tried in patients with epilepsy in infancy with migrating focal seizures resistant to conventional antiepileptic drugs. Significant seizure reduction with improvement in neurocognitive development has been reported with ketogenic diet (13; 50; 02; 01). Initiation and maintenance of ketogenic diet in breastfeeding infants is a therapeutic challenge. A comprehensive dietary plan should be instituted with frequent monitoring of weight gain along with supplementation of trace elements and vitamins.

With the advent of the next-generation sequencing, multiple genetic mutations have been identified in this syndrome. As a result, novel precision medicine approaches are being explored more and more. SCN2A mutations may respond well to sodium channel blockers like carbamazepine, oxcarbazepine, and phenytoin (68). KCNQ2 mutations also might respond to sodium channel blockers (56).

Quinidine has shown to be a partial antagonist of KCNT1 channel in addition to alleviating the effects of KCNT1 activating mutation, namely R428Q (05). Quinidine may reduce seizure frequency in epilepsy in infancy with migrating focal seizures with KCNT1 mutation by reversing the gain of function caused by these mutations. However, despite the initial enthusiasm in this mechanistic therapeutic approach, quinidine has failed to show a consistent response in epilepsy in infancy with migrating focal seizures due to all KCNT1 mutations. Variable seizure responses were seen ranging from minimal or no change in seizure frequency to almost complete seizure remission (05; 47; 16; 55). Synergistic effect with topiramate was also reported in a patient with KCNT1 mutation (41).

The usual dosing range of quinidine is 15 to 60 mg/kg/day in three to four divided doses. However, the exact dosing in early infancy and dosing frequency for use as a KCNT1 inhibitor is yet to be established. In view of its potential cardiac effects, children need careful monitoring with repeated ECG evaluation for prolongation of corrected QT interval and if possible repeated estimation of serum levels (29). Other side effects included gastrointestinal intolerance, hepatic dysfunction, leukopenia, cinchonism, and hemolytic anemia (35).

Nonnarcotic antitussive agents (tipepidine and dextromethorphan) have been found to reduce seizure frequency in a child with epilepsy in infancy with migrating focal seizures with genetically confirmed KCNT1 mutation in one case report (63).

Antisense oligonucleotide therapy for KCNT1 encephalopathy has been tried in a mouse model (09). Antisense oligonucleotide administration at the neonatal age was well tolerated and effective in controlling seizures and extending the life span of treated animals.

Special considerations

Anesthesia

Precautions must be taken regarding seizures.