Different pharmacoresistance of focal epileptic spasms, generalized epileptic spasms, and generalized epileptic spasms combined with focal seizures.

OBJECTIVE: Among standard treatments for infantile spasms, adrenocorticotropic hormone (ACTH) is reported as the best treatment, but ACTH is ineffective in one-half of the patients. To establish precision medicine, we examined pharmacoresistance of focal epileptic spasms (ES), generalized ES, and generalized ES combined with focal seizures, diagnosed based on the revised seizure classification of ILAE in 2017. METHODS: We conducted a retrospective nationwide study in Japan on the long-term seizure outcome of ES. Long-term seizure outcome was evaluated by seizure-free rate, seizure-free period, and Kaplan-Meier curve. Seizure-free was defined as seizure control for longer than 2 months. RESULTS: From the medical history of 501 patients, 325 patients had generalized ES only (GES group) at the start of the first treatment, 125 patients had generalized ES after focal seizure onset (FS-GES group), seven patients had focal ES after focal seizure onset (FS-FES group), and 24 patients had generalized ES combined with focal seizures after focal seizure onset (FS-GES + FS group). Seizure-free period of ES (generalized ES and focal ES) [mean (95% confidence interval)] was 2.7 (0.0-5.4) months in GES group, 1.1 (0.1-2.2) months in FS-GES group, 1.0 (0.2-1.9) months in FS-GES + FS group, and 0.1 (-0.2-0.5) months in FS-FES group. Seizure-free rate, seizure-free period, and Kaplan-Meier curve of generalized ES were almost the same in GES group and FS-GES group, with characteristics of superior response to ACTH. Mean seizure-free period of generalized ES combined with focal seizures was significantly shorter in FS-GES + FS group than in GES group. Mean seizure-free period of focal ES in FS-FES group was extremely short with exceedingly early relapse. SIGNIFICANCE: Pharmacoresistance was different in generalized ES, focal ES, and generalized ES combined with focal seizures. ES with focal features or with focal seizures may have focal lesions, thus consider surgical options earlier in the course.

[Clinical aspects of epilepsy in children with periventricular leukomalacia].

UNLABELLED: We investigated the frequency and characteristics of epilepsy in 63 children (39 males and 24 females) with cerebral palsy caused by periventricular leukomalacia, who were born preterm at <34 weeks' gestation and followed for more than five years (duration: 5-18 years, mean: 9.6 years). While seven (11%) of the 63 patients had febrile convulsions (FC), 11 (17%) were associated with symptomatic localization-related epilepsy (SLRE) and 8 (13%) with West syndrome (WS). The gestational ages of the WS group were significantly (p<0.05) longer than in FC group. The DQ of the SLRE and WS groups were significantly (p<0.01) lower than in the N-S group. The frequency of spastic quadriplegia was 19%, 29%, 36%, 50% in the N-S, FC, SLRE, WS groups, respectively. Among the 11 SLER patients, 5 had one seizure type, while 3 had two and 3 had three seizure types. The seizure patterns included complex partial seizures (CPS) in 8, secondarily generalized partial epileptic seizures in 8, and simple partial seizures in 4. One patients in the WS group developed CPS, and another patient developed epilepsy undetermined after infancy. Regarding the main localizing symptoms of SLRE, oculogyric seizures were observed in 7 patients and hemi-facial seizures were observed in 8 patients. In all WS patients, the location of the epileptiform discharges was in the parieto-occipital area, while 8 of 11 patients with SLES had it in the central area. IN CONCLUSION: 30% of all patients with PVL were associated with epilepsy. WS developed in 13% during early infancy and SLRE developed in 17% after infancy. The most common epileptic seizure in the patients with PVL was complex partial seizure.

Immediate suppression of seizure clusters by corticosteroids in PCDH19 female epilepsy.

PURPOSE: The pathomechanism and treatment of PCDH19 female epilepsy (PCDH19-FE) remain unclear. Here, we report that corticosteroids are effective for control of the seizure clusters or other acute symptoms of PCDH19-FE and argue for the possible involvement of a compromised blood-brain barrier (BBB) in its pathogenesis. METHODS: The efficacy of corticosteroids was retrospectively reviewed in five Japanese patients with PCDH19-FE. The results of antibody assays against the N-methyl-d-aspartate-type glutamate receptor (abs-NR) in serum/cerebrospinal fluid were also compiled. RESULTS: Corticosteroid treatments significantly improved the acute symptoms, including seizure clusters, in all cases, most often immediately after the initial administration. However, the effect was transient, and some seizures recurred within a few weeks, especially in association with fever. Serum and/or cerebrospinal fluid abs-NR were detected in all patients. Target sequences of the detected antibodies were multiple, and the titers tended to decrease over time. In one patient, immunohistochemical analysis using rat hippocampal slices also revealed serum antibodies targeting an unknown epitope in neuronal cytoplasm. CONCLUSION: Our findings imply an involvement of inflammatory processes in the pathogenesis of PCDH19-FE and therapeutic utility for corticosteroids as an adjunctive option in acute treatment. PCDH19 is well expressed in brain microvascular endothelial cells and thus its impairment may cause BBB vulnerability, which may be ameliorated by corticosteroids. The abs-NR detected in our patients may not indicate an autoimmune pathomechanism, but may rather represent non-specific sensitization to degraded neuronal components entering the general circulation, the latter process facilitated by the BBB vulnerability.

PCDH19-related female-limited epilepsy: further details regarding early clinical features and therapeutic efficacy.

Abnormalities in the protocadherin 19 (PCDH19) gene cause early-onset epilepsy exclusively in females. We aimed to explore the genetic and clinical characteristics of PCDH19-related epilepsy by focusing on its early features and treatment efficacy. PCDH19 was analyzed in 159 Japanese female patients with early-onset epilepsy via direct sequencing and multiplex ligation-dependent probe amplification (MLPA) analysis. We identified 17 patients with PCDH19 abnormalities: point mutations were observed in 14 patients and whole PCDH19 deletions were detected in 3 patients. One affected sister of a proband with a mild phenotype was also analyzed. The frequency of PCDH19 deletion among all probands identified in Japan was 12.5% (3/24, including 7 probands reported previously by us). Clinical features included early onset (mean age at onset, 8.6 months), recurrent clusters of brief seizures (17/18), fever sensitivity (18/18), tonic seizures (13/18, probably including focal tonic seizures), tonic-clonic seizures (8/18), focal seizures often with subsequent generalization (17/18), intellectual disabilities (15/18), and autistic traits (13/18). Three patients exhibited delay in motor milestones before seizure onset. In 16 patients, seizures appeared in clusters from the onset of the disease. Among 6 patients for whom detailed information at onset was available, 2 onset patterns were identified: a biphasic course of short seizure clusters (each within days) in 2 patients and a prolonged course of clusters (from weeks to a month) in 4 patients. In both cases, initial seizures started during fever and transiently disappeared with the decline of fever; however, afebrile clusters recurred. In the former patients, motor development was delayed before onset, and seizures appeared in strong clusters from the onset of the disease. In the latter patients, initial development was normal and initial seizures were mild, but were followed by strong clusters lasting several weeks, even without fever. Treatment using phenytoin, potassium bromide, and clobazam showed high efficacy. Although focal seizures were the main feature in PCDH19-epilepsy, the efficacy of carbamazepine was poor. This study highlighted the significance of PCDH19 deletion, a unique pattern of initial seizure clusters, and the efficacy of antiepileptic drugs. Our data will facilitate early diagnosis and development of a treatment strategy for better clinical management of patients with PCDH19-related epilepsy.