Myoclonus epilepsy with ragged-red fibers
Jun. 10, 2021
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Epilepsy in infancy with migrating focal seizures (EIMFS) is a devastating developmental and epileptic encephalopathy of early infantile onset characterized by the occurrence of very frequent focal seizures arising from multiple foci in both hemispheres independently and seizure migration between cerebral hemispheres along with profound developmental impairment and often with regression. Seizure onset is in the first 6 months of life with a progressive increase in frequency and change in semiology over the first few months. Between 2011 and 2019 pathogenic variants in more than 24 genes have been implicated in this syndrome. However, most of the currently available reports show pathogenic genetic variants in the KCNT1 gene. Other major genes implicated are SCN2A, KCNQ2, ATP1A3, CDKL5, GABRA1, GABRB1, GABRB3, GABRG2, HCN1, SCN1A, SCN8A, SLC12A5, SLC25A22, and TBC1D24 and this list is expanding. The seizures are mostly refractory to currently available antiepileptic drugs. Novel precision medicine treatment options are being explored. In this article, the authors focus on etiology, clinical features, and advances in the management of epilepsy in infancy with migrating focal seizures.
• Epilepsy in infancy with migrating focal seizures is a rare, intractable, early infantile epileptic encephalopathy with onset in first 6 months of life.
• There are multifocal bilateral independent seizure foci and the seizures migrate from 1 hemisphere to the other.
• It results in severe global developmental delay and regression, along with acquired microcephaly.
• Variants in the KCNT1 gene are most frequently associated with epilepsy in infancy with migrating focal seizures.
A report in 1995 by Coppola and colleagues described 14 infants who developed migrating partial seizures (16). The first seizures had occurred at the mean age of 3 months, and the full pattern was developed between 1 month and 10 months of age. Patients regressed developmentally. Three of them died between 7 months and 8 years of age. Only 2 patients had seizures controlled by medication, and 3 patients resumed psychomotor development. Similar cases were subsequently reported in other countries such as Japan (41), European countries (51; 49; 24), Israel (23), the United States (32), and India (42).
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. Seizure onset in the first week of life has been reported in patients with SCN2A, KCNQ2, and BRAT1 mutations. Seizure type at onset range from focal seizures, tonic seizures, and epileptic spasms, with additional seizure types like clonic, myoclonic, tonic-clonic, 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 (34; 06).
The proposed diagnostic criteria for epilepsy in infancy with migrating focal seizures include: (1) normal or near normal development before 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 (16; 14; 34).
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 and 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 or are almost continuous over days to weeks. 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 (32; 07; 13). In the near future, there is a chance that electroclinical patterns suggestive of specific genetic variations might possibly emerge from this syndrome. These endophenotypes might have better management and prognostic implications.
The long-term outcome of epilepsy in infancy with migrating focal seizures with reference to seizures and psychomotor development depends on underlying etiopathogenesis 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 (04; 35). Acquired microcephaly with permanent psychomotor retardation is very commonly noted. Only a single patient is reported to have had normal development at 7 years of age (32).
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 1 month with increased seizure frequency. His magnetic resonance imaging (MRI) and electroencephalography (EEG) were reported to be normal. He was started on oral phenytoin, with which he had transient improvement. The seizure soon recurred and oral levetiracetam was added and the dosage was hiked up to 27 mg/kg/day. 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 initial few days which was followed later by reemergence. 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/LNo 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 seizure 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 3 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 (42).
No etiology was identified for epilepsy in infancy with migrating focal seizures until 2010, when duplication of 16p11.2 was reported initially (05). Subsequently, mutations in SCN1A, phospholipase C beta 1 (PLCB1), and KCNT1 have been reported by different groups (10; 21; 03; 44; 27). A single familial case (two sisters of unrelated parents) was recently reported in France (36). They had compound heterozygous mutations of TBC1D24 gene, which is critical for maturation of neuronal circuits. 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. Other major genes consistently reported with epilepsy in infancy with migrating focal seizures are AIMP1, ATP1A3, BRAT1, CDKL5, KARS, KCNT1, KCNQ2, GABRA1, GABRB1, GABRB3, GABRG2, HCN1, ITPA, PIGA, PLCB1, QARS, SCN1A, SCN2A, SCN8A, SLC12A5, SLC25A22, SMC1A, TBC1D24, and WWOX (06). There are no cases with mutation of STXBP1, PCDH19, 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 (17).
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 (29; 02; 28; 40).
Malformation of cortical development or acquired brain lesions have not been reported so far, except for in 2 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 (15). The other report described a child with multiple malformations of cortical development, polymicrogyria, and focal cortical dysplasia associated with hippocampal sclerosis on autopsy (20).
The incidence of the syndrome is unknown. There have been around 250 patients reported over 25 years since the original report by Coppola and colleagues in 1995. Cases have been reported from all the major geographic regions like Australia, Canada, Europe, Israel, India, Japan, and the United States.
There is no known method of prevention as most of the cases reported are due to sporadic mutations or of unknown etiologies.
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.
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.
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 (34; 46; 53).
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 (Ohtahara et al 2006).
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 1 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 (34; 46; 53).
Magnetic resonance imaging brain may be normal or may show variable cerebral atrophy, mild to moderate enlargement of both subarachnoid and ventricular spaces, or delayed myelination with T2 hyperintensity of the deep white matter.
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.
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. Stiripentol, lacosamide, and rufinamide were also reported as effective (25; 12; 18; 48; 34). Ketogenic diet was reportedly effective in 1 child with SCN1A mutation (47). Carbamazepine and vigabatrin seem to worsen the condition (19). Variable seizure responses have been reported with adrenocorticotrophic hormone, oral prednisolone, and topiramate in combination with the ketogenic diet (34).
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 (Saade et al 2015).
Potassium bromide (30-80 mg/kg/day) divided in 2 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 (08; 37).
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 2 to 3 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 per day (18; 33; Nickels et al 2017).
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 (26).
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 (09; 37; 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 (52). KCNQ2 mutations also might respond to sodium channel blockers (43).
Quinidine has shown to be a partial antagonist of KCNT1 channel in addition to alleviating the effects of KCNT1 activating mutation, namely R428Q (04). 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, in spite of 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 (04; 35; 11; 42).
The usual dosing range of quinidine is 15 to 60 mg/kg/day in 3 to 4 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. Other side effects included gastrointestinal intolerance, hepatic dysfunction, leukopenia, cinchonism, and hemolytic anemia.
Precautions must be taken regarding seizures.
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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