Infantile epilepsy accompanied by wandering focal seizures: clinical features, etiology, and treatment

Infantile epilepsy of infancy with migrating focal seizures (EIMFS), also known as infantile migratory partial seizures (MPSI) or infantile malignant migratory partial seizures (MMPSI), was first reported by the Italian scholar Coppola in 1995 and named EIMS by the International League Against Epilepsy (ILAE) in 2010

First, the clinical characteristics of EIMFS

The clinical characteristics of EIMFS are: (1) onset within 6 months after birth, and the peak period of onset from 40 days to 3 months of age after birth; (2) Frequent, wandering, multi-type focal seizures; (3) The EEG attack period is manifested as a focal attack of multifocal origin; (4) Backward or retrogressive intellectual and motor development; (5) The efficacy of anti-epilepsy drugs is not good; (6) Usually the prognosis is poor and the mortality rate is high

The natural course of EIMFS is roughly divided into 3 stages: (1) Stage 1: Within 6 months of life, the onset can occur as early as day 1 after birth, and the early onset is infrequent

Clinical studies have found that EIMFS and other epileptic encephalopathies can evolve with each other, which is a type

2.

Most children with EMFS have abnormalities in early monitoring of the EEG, and the background may be diffuse slow waves; Multifocal discharge can be monitored between episodes, and some children can also be monitored for typical or atypical high arrhythmias, with or without spastic seizures, and children with spastic episodes can change to multifocal wandering focal episodes

There are no specific neuroimaging changes in EIMFS, and some children may have abnormal manifestations such as delayed myelination, basal ganglia abnormal signals, callosum dysplasia, diffuse cerebral atrophy, etc.

1.

All have abnormal discharges, which are manifested as wandering and multifocal discharge characteristics; Background activities are slow; Eight cases of inter-attack period were manifested as a large number of multifocal medium and high-amplitude spikes, sharp waves, multi-spike waves, slow spinous waves, multi-spiny slow waves emitted or continuously emitted, mainly in one hemisphere or a certain brain area, and 1 case of inter-attack period was manifested as a large number of multifocal, single,continuous, clustered small spikes on the left and right of the forehead, center, occipital, and temporal regions; Clinical episodes were detected in 9 cases, which were manifested as 9 cases of single or one side limb shaking, 3 cases of eyelid blinking, 2 cases of single or one side limb stiffness, 2 cases of head and eye skew to one side, and 1 case of

Fig.

3.

Eight pathogenic genes associated with EMFS have been identified

KCNT1 gene mutation: The KCNT1 gene encodes a potassium channel activated by sodium ions

2.

3.

4.

5.
PLCB1 gene mutation: PLCB1 gene encodes β1 subgenus (PLCβ1)
of phospholipase C.
Poduri et al.
reported a case of EIMFS with PLCB1 gene deletion, whose parents were related by blood, and the child had a homozygous deletion of about 476 kb of chromosome 20p12.
3, including the promoter region of PLCB1 and exons
1-3.
Mutations in the PLCB1 gene can also cause early-onset epileptic encephalopathy
.
Kurian et al.
reported a child with early-onset epileptic encephalopathy with PLCB1 gene deletion whose parents were related by blood and carried a homozygous deletion of 0.
5 Mb of chromosome 20, which also contained the promoter region of PLCB1 and exons
1-3.
Ngoh et al.
reported a child with refractory epilepsy with heterozygous deletion of the PLCB1 gene, a deletion of 476 kb on chromosome 20p12.
3 and a new heterozygous shear site variant (c.
99+1G>A) of intron No.
1, the former from the mother and the latter from the father
.
Schoonjans et al.
reported a case of early-onset epileptic encephalopathy with partial homozygous deletion of the PLCB1 gene, the parents of the child were related by blood, and the child carried the deletion of 32kb on the chromosome 20p12, including exons
7-9 of the PLCB1 gene.
The above reports support that the inheritance mode of epilepsy caused by mutations in the PLCB1 gene is autosomal recessive inheritance, and most of them are manifested by deletion
of fragments of this gene.

SLC25A22 gene mutation: The SLC25A22 gene encodes mitochondrial glutamate transporters and is highly expressed
in the developing brain.
Poduri et al.
reported 2 cases of EIMFS with SLC25A22 gene mutation in one family, both of whom were c.
G328C/p.
G110R homozygous mutation whose parents are related
by blood.
Molinari et al.
have reported a total of 5 cases of autosomal recessive inheritance of SLC25A22 gene homozygous mutations in 2 families, and in each family, the parents of the children are related by blood, of which 4 cases of 1 family carry SLC25A22 gene homozygous mutation c.
617C > T/p.
Pro206Leu, and 1 family carries the gene homozygous mutation p.
G236W
。 Cohen et al.
[35] reported two sibling children with early-onset myoclonic encephalopathy whose parents were related by blood, and one child was detected carrying the SLC25A22 gene homozygous mutation c.
617C > T/p.
Pro206Leu
.
The above reports support that the SLC25A22 gene mutation causes epilepsy to be inherited in an autosomal recessive manner
.

7.
TBC1D24 gene mutation: The TBC1D24 protein encoded by the TBC1D24 gene is expressed in the central nervous system and plays an important role
in the development of neurons.
A case of TBC1D24 compound heterozygous mutation (c.
619C> T/p.
Gln207X、c.
866C>T / p． Ala289Val) of the infant with EMFS, whose mother was carrying the mutation c.
866C>T, did not obtain peripheral blood DNA
from the father.
The mutation-associated epilepsy phenotype also includes DOORS syndrome, idiopathic infantic myoclonic epilepsy, and early-onset drug-resistant epilepsy with intellectual disability
.

8.
SLC12A5 gene mutation: SLC12A5 gene encodes neuronal K-Cl cotransmitter KCC2, SLC12A5 gene mutation can lead to inhibition
of chloride outflow 。 Stödberg et al.
reported 4 children with SLC12A5 mutations in EMMFS from 2 families; The parents of the children in one family were not related by blood, and the two children carried the compound heterozygous mutations c.
1277T4C/L426P and c.
1652G4A/G551D.
In the other family, the parents of the children were related by blood, and both children carried the homozygous mutation c.
932T4A/L311H
.
Saitsu et al.
[37] reported three cases of confirmed EMFS and one case of SLC12A5 gene mutation with suspected EMFS, of which two children were from the same family and carried mutations p.
Glu50_Gln93del and p.
Ala191Val, and the mutations in the other two children were p.
Ser323Pro, p.
Met415Val, p.
Trp318Ser, and p.
Ser748del (the latter was suspected).

Compound heterozygous mutations in the SLC12A5 gene can lead to EMMFS, which is inherited in an autosomal recessive manner
.
Heterozygous chisense mutations in the SLC12A5 gene are associated
with febrile seizures and idiopathic generalized epilepsy.

9.
Deletion of EIMFS and chromosome fragments: Partial or total deletion of chromosomal fragments (2q24.
3) containing sodium channel genes can lead to complex epileptic phenotypes, including typical or atypical Dravet syndrome and EIMFS, in which children with EMFS can also have developmental malformations, the severity of epilepsy phenotype is associated with missing sodium channel genes, and children with all sodium channel gene fragments are associated with frequent multifocal seizures
。

Testing of known candidate pathogenic genes in children with EIMFS can help to clarify the diagnosis of the etiology and avoid unnecessary duplication of tests; Children with KCNT1 gene mutations may try quinidine therapy; Provide guidance
on genetic counseling and family reproduction.
Although 8 EMFS pathogenic genes have been identified, a clear correlation
between genotype and phenotype has not been found.
The causative genes of some children with EMMFS are still unclear, and whole exome or whole genome sequencing should be further studied
if necessary.

4.
Treatment

There is no specific treatment regimen for EIMFS, and most children have poor
efficacy against epilepsy drugs.
Milligan et al.
found through animal experiments that for KCNT1 functionally acquired mutants, quinidine can significantly inhibit the function acquired by potassium ion channels, thereby controlling seizures
.
Mikati et al.
reported that two children with KCNT1 gene mutations reduced seizures in children with the EIMFS phenotype by about 80% after the application of quinidine, and there was no significant improvement
in seizures in children with ADNFLE phenotype.
Bearden et al.
reported that a child with EMFS with KCNT1 gene mutation had a significant decrease in seizures after using quinidine, and improved intellectual and motor development
.
There is no international consensus on the treatment of EIMFS children with KCNT1 gene mutations with quinidine, and there is no unified treatment dose standard, usually 15-60 mg/(kg·d), taken in 4-5 divided doses, the maximum dose of each time is 600 mg, the maximum daily dose is 3000-4 000 mg, and the literature reports that the minimum age of quinidine treatment of children with EMFS is 3 years old
.
The occurrence of adverse reactions of inquinidine to the heart, such as long QT syndrome, limits the increase
in its dose.
This group reported that 2 children tried quinidine, 1 had a maximum seizure control of 1 week, and another had uncontrolled
seizures.

Clobazam, which is currently considered to be more effective for EMMFS, is also imported
domestically.
This product is suitable for the treatment of refractory epilepsy that is ineffective against other antiepileptic drugs, and can be used alone or as an adjunctive
therapy.
At present, 50 medical institutions in China can use it
.

Caraballo et al.
reported 6 children treated with potassium bromide for EIMFS, of which 4 had seizures controlled or decreased, and 3 had adverse drug reactions, such as vomiting, drowsiness, and acne-like rash, which were relieved
by drug reduction.
Vendrame et al.
used rufiramamide in 5 children with EMFS, and 2 had good efficacy and tolerability, and the seizures were reduced by more than
50%.
Hmaimess et al.
reported a child with EMFS who improved EEG discharge after using levetiracetam
.
Merdariu et al.
reported a child
with EIMFS whose seizure control time was significantly prolonged after the combined use of clonazepam, levetiracetam and sitiglanol.
Irahara et al.
found that 2 children with EIMPS had refractory epileptic apnea and severe hypoxemia, and the seizures could be completely controlled
after increasing the treatment of acetazolamide.
It has been reported that a child with EMFS has used phenobarbital, carbamazepine, clonazepam, levetiracetam, phosphenytoin, topiramate, pyridoxine, stigpentanol and ketogenic diet, and there is no significant improvement in the condition
.

There have been little
reports of the efficacy of the ketogenic diet and vagus nerve stimulation on this disease.
Thammongkol et al.
tried ketogenic diet therapy for children with refractory epilepsy, which showed partial efficacy
.
Ishii et al.
reported 2 children with KCNT1 mutationS with EMMFS, 1 effective for vagus nerve stimulation and 1 effective
for chlorine nitrogen.
Shein et al.
reported a case of EMMFS with SCN1A gene mutation and refractory status epileptics, which was ineffective against midazolam, phenobarbital, phosphenytoin, topiramate, levetiracetam, folinic acid, pyridoxal-5-phosphate, and bumetanil, and was effective
for cryogenic therapy and ketogenic diets.
This research group reported that two children with amphexenoic acid controlled seizures for 2 weeks and 2 months
, respectively.
Because the disease is rare and difficult to treat, large samples need to be accumulated for further study, and if necessary, multi-center collaboration can be used to study its treatment
.

5.
Prognosis

Overall, the long-term prognosis of EIMFS is poor, with some children dying of sudden death and status epilepticus, and some dying from concurrent infections and respiratory failure
.
Age of death in children with EIMFS did not correlate
with their age of onset.
Most children have regressive intellectual and motor development after the onset of the disease, and there is very little progress
in intellectual and motor development after seizure control.

6.
Rare disease information registration

If you are willing to seek constantly updated information, it is recommended that you register the patient's information here, even if you are not fully diagnosed, you can register, click to enter:

Patient Information Registry System for Rare Diseases

Resources:

Chin J Pediatrics, 2016,54(10): 735-739

Chinese Journal of Pediatrics, Vol.
55, No.
5, May 2017

Armeno M et al.
Ketogenic parenteral nutrition in three paediatric patients with epilepsy with migrating focal seizures.
Epileptic Disord.
2019 Oct 16.