Homozygous PLCB1 deletion associated with malignant migrating partial seizures in infancy

Malignant migrating partial seizures in infancy (MMPEI) is an early onset epileptic encephalopathy with few known etiologies. We sought to identify a novel cause of MMPEI in a child with MMPEI whose healthy parents were consanguineous. We used array comparative genomic hybridization (CGH) to identify copy number variants genome-wide and long-range polymerase chain reaction to further delineate the breakpoints of a deletion found by CGH. The proband had an inherited homozygous deletion of chromosome 20p13, disrupting the promoter region and first three coding exons of the gene PLCB1. Additional MMPEI cases were screened for similar deletions or mutations in PLCB1 but did not harbor mutations. Our results suggest that loss of PLCβ1 function is one cause of MMPEI, consistent with prior studies in a Plcb1 knockout mouse model that develops early onset epilepsy. We provide novel insight into the molecular mechanisms underlying MMPEI and further implicate PLCB1 as a candidate gene for severe childhood epilepsies. This work highlights the importance of pursuing genetic etiologies for severe early onset epilepsy syndromes.     

Successful control with bromide of two patients with malignant migrating partial seizures in infancy

A 3-month-old male and a 4-month-old female infant with intractable seizures were diagnosed as having malignant migrating partial seizures in infancy (MMPSI) with developmental arrest on the basis of characteristics of symptoms, clinical courses and EEGs. We treated these two patients with potassium bromide (80 mg/kg) after conventional antiepileptic drugs failed to adequately control the seizures. The potassium bromide therapy resulted in complete control of seizures in one patient, and more than 95% reduction in seizure frequency in the other.     

A case of malignant migrating partial seizures in infancy as a continuum of infantile epileptic encephalopathy

The syndrome of malignant migrating partial seizures in infancy (MMPSI) is characterized by onset before the age of 6 months, nearly continuous electrographic seizures involving multiple independent areas of onset in both hemispheres, and poor developmental outcome. This report presents a case involving a patient with MMPSI, who later developed West syndrome. At the age of 2 months old, he showed multifocal partial seizures, which were refractory to antiepileptic drugs. His electroencephalogram (EEG) revealed characteristic migrating multifocal epileptiform activities and neuroimaging finding was normal. The focal seizures were refractory to antiepileptic drugs and ketogenic diet. When he was 9 months old, epilepic spasms were observed with hypsarrhythmia on EEG. He also showed severe developmental delay. MMPSI may be a continuum of infantile epileptic encephalpathy and could evolve to West syndrome.     

Levetiracetam in a neonate with malignant migrating partial seizures

This report describes the first neonatal case of "malignant migrating partial seizures in infancy" with a positive therapeutic response to levetiracetam. This patient is the youngest reported infant with this rare syndrome, and the report provides the first documentation on levetiracetam treatment in a neonatal patient. Treatment with levetiracetam improved both ictal and interictal status. This observation also highlights the need to consider and include malignant migrating partial seizures in the differential diagnosis of early neonatal seizure disorders, even during the first hours of life.     

Focal resection for malignant partial seizures in infancy

There is little experience with excisional surgery for drug-resistant partial seizures in very young patients. We describe our experience with 5 infants under 1 year of age with malignant partial seizures and deteriorating developmental status. All were experiencing frequent daily seizures that did not respond to 1st-line antiepileptic medications at high therapeutic serum levels and considerable medication toxicity. Three infants had complete resection of epileptic tissue (frontal corticectomy and prefrontal lobectomy) and are seizure-free. Two underwent partial resection (lateral temporal lobectomy, frontal corticectomy with anterior callosotomy) and have experienced a significant reduction in seizure frequency. Surgery did not result in any significant neurologic deficit or lead to compromise of developmental status. From these data, we tentatively conclude that excisional surgery can be performed safely in selected infants with medically uncontrolled malignant partial seizures and may significantly improve long-term seizure status. Referral to a tertiary center specializing in early childhood epilepsy surgical evaluation may be considered in these circumstances.     

Targeted treatment of migrating partial seizures of infancy with quinidine

Migrating partial seizures of infancy is an early onset epileptic encephalopathy syndrome that is typically resistant to treatment. The most common cause is a gain of function mutation in the potassium channel KCNT1. The antiarrhythmic drug quinidine is a partial antagonist of KCNT1 and hence may be a candidate drug for treatment of this condition. We report the case of a child with migrating partial seizures of infancy secondary to an activating mutation in KCNT1 treated with quinidine. Treatment with quinidine was correlated with a marked reduction in seizure frequency and improved psychomotor development. Ann Neurol 2014;76:457–461     

Mutational scanning of potassium, sodium and chloride ion channels in malignant migrating partial seizures in infancy

The mutational analysis of potassium (KCNQ2, KCNQ3), sodium (SCN1A, SCN2A), and chloride (CLCN2) ion channels was performed in three children with typical features of the recently described syndrome of migrating partial seizures in infancy. Mutational analysis was performed by PCR and automatic sequencing. The coding regions, including the exon-intron boundaries, were amplified in the patients using appropriate primers sets. No mutations associated to migrating partial seizures have been found. Mutational screening of CLCN2 gene, revealed a homozygous mutation G2003C (exon 17), leading to a Ser/Thr substitution at the codon 668, in two of the three patients. The same variation has been found in 38 out of 100 control alleles. The identification of the genetic basis of this new epileptic encephalopathy requires further studies that might be enforced by familial cases.     

Characterization of two de novo KCNT1 mutations in children with malignant migrating partial seizures in infancy

The KCNT1 gene encodes for subunits contributing to the Na⁺-activated K⁺ current (K_Na), expressed in many cell types. Mutations in KCNT1 have been found in patients affected with a wide spectrum of early-onset epilepsies, including Malignant Migrating Partial Seizures in Infancy (MMPSI), a severe early-onset epileptic encephalopathy characterized by pharmacoresistant focal seizures migrating from one brain region or hemisphere to another and neurodevelopment arrest or regression, resulting in profound disability. In the present study we report identification by whole exome sequencing (WES) of two de novo, heterozygous KCNT1 mutations (G288S and, not previously reported, M516V) in two unrelated MMPSI probands. Functional studies in a heterologous expression system revealed that channels formed by mutant KCNT1 subunits carried larger currents when compared to wild-type KCNT1 channels, both as homo- and heteromers with these last. Both mutations induced a marked leftward shift in homomeric channel activation gating. Interestingly, the KCNT1 blockers quinidine (3–1000 μM) and bepridil (0.03–10 μM) inhibited both wild-type and mutant KCNT1 currents in a concentration-dependent manner, with mutant channels showing higher sensitivity to blockade. This latter result suggests two genotype-tailored pharmacological strategies to specifically counteract the dysfunction of KCNT1 activating mutations in MMPSI patients.     

Effects of acetazolamide on epileptic apnea in migrating partial seizures in infancy

We report two cases of migrating partial seizures in infancy complicated with intractable epileptic apnea with severe desaturation. Ictal electroencephalography revealed migrating foci of epileptiform discharges, which spread to bilateral temporal areas resulting in the onset of apnea. Magnetoencephalography detected dipole sources at bilateral perisylvian areas. Single photon emission tomography revealed a significant ictal change in perfusion at bilateral anterior temporal lobes in one patient. Addition of acetazolamide to the regimen resulted in complete disappearance of epileptic seizures.     

Malignant migrating partial seizures of infancy controlled by stiripentol and clonazepam

The syndrome of malignant migrating partial seizures of infancy (MMPSI) is characterized by early onset of multiple seizure types and overall poor prognosis. Seizures are markedly drug resistant and few reports have suggested the efficacy of some antiepileptic drugs. We report one case of MMPSI in which prolonged seizure control is obtained with an association of clonazepam, levetiracetam and stiripentol, confirming thus the possibility of complete sustained seizure control in this epileptic syndrome. Of more than 60 cases reported to date, ours is the forth in which sustained complete control of seizures was obtained.     

Malignant migrating partial seizures in infancy: An epilepsy syndrome of unknown etiology

The syndrome of malignant migrating partial seizures in infancy was first reported in 1995, and is now included among the childhood epilepsy syndromes in development in the proposal of the revision of the International League Against Epilepsy (ILAE) classification of the epilepsies and epilepsy syndromes. The main clinical features are seizure onset in the first 6 months of life, occurrence of almost continuous migrating polymorphous focal seizures, combined with multifocal ictal electroencephalography (EEG) discharges, and progressive deterioration of psychomotor development. Etiology is so far unknown. Seizures are markedly drug resistant and outcome is generally severe. Based on age at onset, migrating partial seizures in infancy (MMPEI) may be placed between early epileptic encephalopathies (early myoclonic encephalopathy [EME] and early infantile epileptic encephalopathy [EIEE]) and infantile spasms.     

Temporal lobe epilepsy: analysis of patients with dual pathology

OBJECTIVES: To determine the frequency and types of dual pathology in patients with temporal lobe epilepsy (TLE) and to analyze the clinical manifestations and surgical outcome. MATERIAL AND METHODS: A total of 240 patients with TLE underwent temporal resections following a comprehensive pre-surgical evaluation. Thirty-seven (15.4%) of these had hippocampal sclerosis (HS) or temporal lobe gliosis in association with another lesion (dual pathology). RESULTS: Eighteen of 37 patients with dual pathology had heterotopia of the temporal lobe, nine had cortical dysplasia, four had cavernous angiomas or arteriovenous malformations, one had a dysembryoplastic neuroepithelial tumor, one had a contusion and four patients had cerebral infarctions in childhood. 68.5% had abnormal head magnetic resonance imagings, 91.3% had abnormal positron emission tomography scans, and 96% had abnormal ictal SPECT. The intracarotid amobarbital procedure (IAP) showed impaired memory of the epileptogenic side in 72% of the patients. Twenty patients had left and 17 had right-sided en bloc temporal resections, including the lesion and mesial temporal structures. Twenty-six (70.2%) became seizure-free, eight (21.6%) had rare seizures, two (5.4%) had worthwhile seizure reduction and one (2.7%) had no improvement (range of follow-up 1-16 years, mean = 7.4 years). CONCLUSIONS: 15.4% had dual pathology. The dual pathology was almost exclusively seen in patients whose lesions were congenital, or occurred early in life, suggesting that the hippocampus is more vulnerable and more readily develops HS in early childhood. Resections, including the lateral and mesial temporal structures led to a favorable outcome with no mortality and little morbidity.