Background: Febrile infection-related epilepsy syndrome is associated with high mortality and morbidity rates. No systematic review of demographics, aetiologies, good treatment options, and causes of deaths has been performed. Thus, we aimed to focus on these factors to provide a structure for patient management and research. Methods: A deep literature search was performed in PubMed and Embase of all years until May 2019. Results: We retrieved 45 aSrticles: 3 multicentre cohort studies, 13 single-centre cohorts, 1 case series, and 28 case reports. We identified 229 cases: most were from Asia; 53% were males; 11.4% had several types of antibodies, and the most common was anti-glutamate receptor epsilon 2; 30% (69 cases) had good treatment outcomes; 12.2% died; and 56% remained with drug-resistant epilepsies. Univariate analysis revealed a statistically significant association between positive outcomes in Japan and China, the use of the ketogenic diet either acutely or chronically, and the use of steroids acutely or chronically. Taiwan showed a statistically significant association with negative outcomes. Multivariate logistic regression revealed the utilisation of the ketogenic diet in the acute phases (P = 0.008, OR = 3.613) and being in Japan (P = 0.003, OR = 3.146) as independent determinants of positive outcomes. Most of the deaths occurred because of the progress of the disease rather than complications of the drugs. Conclusions: Asians are more affected and several cases have antibodies. Positive outcomes are associated with being in Japan and the utilisation of the ketogenic diet in the acute phase.

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Hyperpolarization-activated cyclic nucleotide-gated (HCN) channel plays a critical role in regulating the resting membrane potential and integrating synaptic transmission. Variants of HCN1 have been recognized as causes of epilepsy, and mutant HCN1 channels could act with loss-of-function (LOF), loss- and gain-of-function (LOF and GOF) and gain-of-function (GOF) mechanisms. However, phenotypes and pathogenesis of HCN1-related epilepsy are still poorly understood. This study enrolled five epileptic cases carrying five different HCN1 variants: two pathogenic variants (I380F and S710Rfs*71), two likely pathogenic variants (E240G and A395G), and a paternally inherited variant (V572A). Four variants were novel. Electrophysiological experiments revealed impaired biophysical properties of the identified mutants, including current densities and activation/deactivation kinetics. Moreover, three variants exerted effects on the biophysical properties of wild-type HCN1 channels in heterozygous conditions. Immunofluorescence experiments showed that two variants reduced the protein expression of HCN1channels in neurons. Neurons expressing E240G (GOF) variant showed increased input resistance. However, the variant of I380F (LOF) increased the neuronal firing rate, thus leading to neuronal hyperexcitability. In conclusion, the present study expands the genotypic and phenotypic spectrum of patients with HCN1-related epilepsy and clarifies the underlying mechanisms. We reported five new cases including four unreported likely/pathogenic variants. We provided assessments of biophysical function for each variant, which could help patients to receive individual therapy in the future. We confirmed that HCN1 variants contributed to neuronal hyperexcitability by regulating input resistance and the action potential firing rate, and we have shown that they can affect protein expression in neurons for the first time.

ObjectiveThe limitations of adrenocorticotrophic hormone (ACTH) treatment for infantile spasms (ISs), such as high costs, limited availability, and adverse effects (AEs), make it necessary to explore whether corticosteroids are optimal alternatives. Many other compelling treatments have gone through trials due to the suboptimal effectiveness of hormonal therapy. A systematic review and meta-analysis were performed to evaluate the effectiveness and safety of hormonal therapy for patients with ISs.MethodsEMBASE, Ovid MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), and online registers were searched through April 2021 for randomized controlled trials (RCTs).ResultsA total of 19 RCTs (N = 1,279) were included. There was no significant difference in the effectiveness of oral corticosteroids and ACTH in electro-clinical response (risk ratio [RR] = 0.85, 95% CI 0.41–1.76). Low-dose ACTH had similar effectiveness in electro-clinical response compared to usual-dose group (RR = 0.94, 95% CI 0.60–1.47) but conferred a lower risk of AEs (RR = 1.71, 95% CI 1.08–2.71). ACTH was more beneficial in controlling spasms than vigabatrin (VGB) (RR = 1.31, 95% CI 1.05–1.64) for patients without tuberous sclerosis complex (TSC). All RCTs were connected through network meta-analysis, and we found that ketogenic diet (KD), zonisamide, methylprednisolone, or combined treatment of hormonal therapy with topiramate (TPM) or pyridoxine was not different in electro-clinical response compared to usual-dose ACTH.ConclusionOur analysis showed that oral corticosteroids could be optional alternatives when ACTH is not applicable, and ACTH is more beneficial for patients without TSC. Moreover, low-dose ACTH is recommended due to comparative effectiveness but lower risk of AEs. However, due to the high heterogeneity of included patients and treatment protocols, these results must be interpreted with caution. RCTs with multicentric involvement and larger sample size are needed for solid evaluation of other alternative treatments.

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AbstractGerm cell tumors (GCTs) localized extragonadally are rare, with only 14 reported cases of a yolk sac tumor in the endometrium. Here we report a case of mixed endometrium GCTs in a 65-year-old postmenopausal woman with abnormal vaginal bleeding. An ultrasound examination showed an oval-shaped mass in the patient’s uterine cavity. Biochemical examination revealed elevated serum α-fetoprotein (AFP) at 359 ng/mL, whereas the tumor markers CA-125, CA-199, and CEA were all within normal range. Total hysterectomy and bilateral salpingo-oophorectomy were performed;. a histological examination revealed that the malignant components contained a yolk sac tumor, embryonal carcinoma, and focal immature teratoma. Immunohistochemical staining showed that AFPs were diffusively distributed in both the yolk sac tumor and embryonal carcinoma. The stem cell marker OCT3/4 was positive in the embryonal carcinoma component and that the pan-cytokeratin AE1/AE3 staining was positive in glandular areas. GFAPs (Glial Fibrillary Acidic Proteins) were positive in neuroectodermal tubules; the Ki-67 protein was positive in 90% of the tumor cells, whereas CD117 and placental alkaline phosphatase (PLAP) were negative. The cumulative evidence indicated mixed GCTs of endometrium as the final histopathological diagnosis. The patient received three courses of adjunct chemotherapy that provided good therapeutic efficacy as evidenced by the decreased serum AFP level. Our report on this rare case of mixed GCTs of the endometrium, supported by associated histological patterns and immunophenotypes and successful adjunct chemotherapy after surgery, could provide insight on future treatment of this rare but lethal disease.

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