The roles of RACK1 in the pathogenesis of Alzheimer's disease.

The receptor for activated C kinase 1 (RACK1) is a protein that plays a crucial role in various signaling pathways and is involved in the pathogenesis of Alzheimer's disease (AD), a prevalent neurodegenerative disease. RACK1 is highly expressed in neuronal cells of the central nervous system and regulates the pathogenesis of AD. Specifically, RACK1 is involved in regulation of the amyloid-ß precursor protein processing through α- or ß-secretase by binding to different protein kinase C isoforms. Additionally, RACK1 promotes synaptogenesis and synaptic plasticity by inhibiting N-methyl-D-aspartate receptors and activating gamma-aminobutyric acid A receptors, thereby preventing neuronal excitotoxicity. RACK1 also assembles inflammasomes that are involved in various neuroinflammatory pathways, such as nuclear factor-kappa B, tumor necrosis factor-alpha, and NOD-like receptor family pyrin domain-containing 3 pathways. The potential to design therapeutics that block amyloid-ß accumulation and inflammation or precisely regulate synaptic plasticity represents an attractive therapeutic strategy, in which RACK1 is a potential target. In this review, we summarize the contribution of RACK1 to the pathogenesis of AD and its potential as a therapeutic target.

Tongue Biting Event in Patients with Sleep-Related Facial Mandibular Myoclonus: A Case Series Study.

Background: Sleep-related facial mandibular myoclonus (SRFMM) remains rare in clinical practice. The aim of this study was to provide a comprehensive understanding of the electroclinical manner, therapeutic regimen, and prognosis of SRFMM. Methods: Twenty-three patients who were diagnosed with SRFMM by clinical manifestation, video-electroencephalography (EEG) and electromyography over bilateral masseter and temporalis muscles were enrolled. Clinical and electrophysiological evaluation as well as follow-up information were recorded and analyzed. Results: The cohort involved 4 infants and 19 adults with a mean onset age of 43.5 years for SRFMM, among whom 19 were male. Twenty-one patients complained of tongue injuries and disturbed night-time sleep. SRFMM in 4 patients were ascribed to oral aripiprazole, brainstem ischemia and brain trauma. In 62 SRFMM episodes, 93.5% occurred in NREM sleep and 6.5% in REM sleep, and all events were associated with EEG arousals. In 13 patients with or without clonazepam, the motor events gradually disappeared, and the rest turned to be sporadic. Conclusion: SRFMM is a characteristic parasomnia manifested by tongue biting and accompanying facial mandibular myoclonus, leading to disrupted sleep. Besides adults, infants can also experience SRFMM with spontaneous remission. Most patients respond well to clonazepam, eventually with favorable prognosis.

PCSK6 exacerbates Alzheimer's disease pathogenesis by promoting MT5-MMP maturation.

Proprotein convertase subtilisin/kexin type 6 (PCSK6) is a calcium-dependent serine proteinase that regulates the proteolytic activity of various precursor proteins and facilitates protein maturation. Dysregulation of PCSK6 expression or function has been implicated in several pathological processes including nervous system diseases. However, whether and how PCSK6 is involved in the pathogenesis of Alzheimer's disease (AD) remains unclear. In this study, we reported that the expression of PCSK6 was significantly increased in the brain tissues of postmortem AD patients and APP23/PS45 transgenic AD model mice, as well as N2AAPP cells. Genetic knockdown of PCSK6 reduced amyloidogenic processing of APP in N2AAPP cells by suppressing the activation of membrane-type 5-matrix metalloproteinase (MT5-MMP), referred to as η-secretase. We further found that PCSK6 cleaved and activated MT5-MMP by recognizing the RRRNKR sequence in its N-terminal propeptide domain in N2A cells. The mutation or knockout of this cleavage motif prevented PCSK6 from interacting with MT5-MMP and performing cleavage. Importantly, genetic knockdown of PCSK6 with adeno-associated virus (AAV) reduced Aß production and ameliorated hippocampal long-term potentiation (LTP) and long-term spatial learning and memory in APP23/PS45 transgenic mice. Taken together, these results demonstrate that genetic knockdown of PCSK6 effectively alleviate AD-related pathology and cognitive impairments by inactivating MT5-MMP, highlighting its potential as a novel therapeutic target for AD treatment.

Safety and efficacy of melatonin supplementation as an add-on treatment for infantile epileptic spasms syndrome: A randomized, placebo-controlled, double-blind trial.

This was a prospective, randomized, double-blind, single-center placebo-controlled trial to assess the efficacy and safety of melatonin as an add-on treatment for infantile epileptic spasms syndrome (IESS). Participants aged 3 months to 2 years with a primary diagnosis of IESS were recruited and assigned to two groups in a 1:1 ratio. Both treatment groups received a combination of adrenocorticotrophic hormone (ACTH) and magnesium sulfate (MgSO4 ) for 2 weeks, and the treatment group also received melatonin (3 mg) between 20:00 and 21:00 daily, 0.5-1 h before bedtime. The study's primary endpoint was the average reduction rate in spasm frequency assessed by seizure diaries. Secondary endpoints included assessment of the response rate, EEG hypsarrhythmia (Kramer score), and psychomotor development (Denver Developmental Screening Test, DDST). Sleep quality was assessed by using the Brief Infant Sleep Questionnaire (BISQ), the Infant Sleep Assessment Scale (ISAS), and actigraphy. Safety parameters were also evaluated. Statistical analyses were conducted on intention-to-treat and per-protocol populations. The trial is registered at Clinicaltrials.gov (ChiCTR2000036208). Out of 119 screened patients, 70 were randomized and 66 completed treatments. In the intention-to-treat population, there were no significant differences in the average percentage reduction of spasm frequency (median [interquartile range, IQR: Q3-Q1], 100% [46.7%] vs. 66.7% [55.3%], p = .288), the 3-day response rate (51.4% vs. 37.1%, p = .229), the 28-day response rate (42.9% vs. 28.6%, p = .212), EEG Kramer scores (2 [3.5] vs. 2 [3], p = .853), or DDST comprehensive months (5 [2.5] vs. 6 [6], p = .239) between the melatonin (n = 35) and placebo (n = 35) groups. However, caregivers reported improved sleep quality after melatonin treatment, with 85.7% reporting regular sleep compared to 42.9% with placebo (42.9%, p < .001). The melatonin group had lower ISAS scores in 4-11-month-old patients compared to the placebo (mean ± SD, 29.3 ± 4.4 vs. 35.2 ± 5.9, p < .001). Moreover, the median (IQR) value of sleep-onset latency was shortened by 6.0 (24.5) min after melatonin treatment, while that in the placebo group was extended by 3.0 (22.0) min (p = .030). The serum melatonin (6:00 h) level (pg/mL) of the children in the melatonin group after treatment was significantly higher than in the placebo group (median [IQR], 84.8 [142] vs. 17.5 [37.6], p < .001). No adverse effects related to melatonin were observed in the study, and there were no significant differences in adverse effects between the melatonin and placebo groups. Although not statistically significant, the results of this randomized clinical trial proved that melatonin supplementation, as an add-on treatment, can improve spasm control rate in the treatment of IESS. For IESS children treated with ACTH, the addition of melatonin was found to improve sleep quality, shorten sleep onset latency, and increase blood melatonin levels. Moreover, it was observed to be a safe treatment option.

Abnormalities in Clostridioides and related metabolites before ACTH treatment may be associated with its efficacy in patients with infantile epileptic spasm syndrome.

OBJECTIVE: Adrenocorticotropic hormone (ACTH) is the first-line treatment of infantile epileptic spasm syndrome (IESS). Its reported effectiveness varies, and our current understanding regarding the role of gut microbiota composition in IESS treatment response is limited. This study assessed the microbiome-metabolome association to understand the role and mechanism of gut microbiota composition in IESS treatment outcomes. METHODS: Children with IESS undergoing ACTH treatment were enrolled. Pre-treatment stool and serum samples were collected for 16S rRNA gene sequencing and liquid chromatography-tandem mass spectrometry, respectively. The children were divided into "responsive" and "non-responsive" groups, and gut microbiota and serum metabolome differences were analyzed. RESULTS: Of the 30 patients with IESS, 14 responded to ACTH and 16 did not. The "non-responsive" group had larger maleficent Clostridioides and Peptoclostridium_phage_p630P populations (linear discriminant analysis >2; false discovery rate q < 0.05). Ten metabolites were upregulated (e.g., xanthurenic acid) and 15 were downregulated (e.g., vanillylmandelic acid) (p < 0.05). Association analysis of the gut microbiome and serum metabolome revealed that Clostridioides and Peptoclostridium_phage_p630P2 were positively correlated with linoleic and xanthurenic acids, while Clostridioides was negatively correlated with vanillylmandelic acid (p < 0.05). A classifier using differential gut bacteria and metabolites achieved an area under the receiver operating characteristic curve of 0.906 to distinguish responders from non-responders. CONCLUSION: This study found significant differences in pre-treatment gut microbiota and serum metabolome between children with IESS who responded to ACTH and those who did not. Additional exploration may provide valuable information for treatment selection and potential interventions. Our results suggest that varying ACTH responses in patients with IESS may be associated with increased gut Clostridioides bacteria and kynurenine pathway alteration, but additional experiments are needed to verify this association.

Adrenocorticotropic hormone combined with magnesium sulfate therapy for infantile epileptic spasms syndrome: a real-world study.

BACKGROUND: Infantile epileptic spasms syndrome (IESS) is a serious disease in infants, and it usually evolves to other epilepsy types or syndromes, especially refractory or super-refractory focal epilepsies. Although adrenocorticotropic hormone (ACTH) is one of the first-line and effective treatment plans for IESS, it has serious side effects and is not sufficiently effective. METHODS: A retrospective study of the clinical outcomes of ACTH combined with magnesium sulfate (MgSO4) therapy for IESS in two hospital centers was conducted. The major outcome of the single and combined treatment was evaluated by changes in seizure frequency and improvements in hypsarrhythmia electroencephalography (EEG). To reduce the confounding bias between the two groups, we used SPSS for the propensity score matching (PSM) analysis. RESULTS: We initially recruited 1205 IESS patients from two Chinese hospitals and treated them with ACTH combined with MgSO4 and ACTH alone. Only 1005 patients were enrolled in the treatment (ACTH combined with MgSO4: 744, ACTH: 261), and both treatment plans had a more than 55% response rate. However, compared to patients treated with ACTH alone, those patients treated with ACTH combined with MgSO4 had better performance in terms of the seizure frequency and hypsarrhythmia EEG. After PSM, the two groups also showed significant differences in responder rate [70.8% (95% confidence interval, CI) = 66.7%-74.8%) vs. 53.8% (95% CI = 47.4%-60.2%), P < 0.001], seizure frequency (P < 0.001) and hypsarrhythmia EEG resolution (P < 0.001). Notably, multivariate analysis revealed that the lead time to treatment and the number of antiseizure medications taken before treatment were two factors that may affect the clinical outcome. Patients with less than 3 months of lead time responded to the treatment much better than those with > 3 months (P < 0.05). In addition, the overall incidence of adverse reactions in the ACTH combined with MgSO4 group was much lower than that in the ACTH group (31.4% vs. 63.1%, P < 0.001). During the treatment, only infection (P = 0.045) and hypertension (P = 0.025) were significantly different between the two groups, and no baby died. CONCLUSION: Our findings support that ACTH combined with MgSO4 is a more effective short-term treatment protocol for patients with IESS than ACTH alone, especially for those patients with short lead times to treatment. Video Abstract (MP4 533623 KB).

Case Report: Chronic inflammatory demyelinating polyradiculoneuropathy rather than hemophagocytic lymphohistiocytosis-the initial phenotype of PRF1 gene mutation.

Perforin is essentially involved in the granule-dependent killing activities of cytotoxic T lymphocytes and NK cells. Monoallelic PRF1 mutation increases the risk of autoimmune diseases, and biallelic PRF1 mutation causes familial hemophagocytic lymphohistiocytosis-2. Here, we report a case of a 12-year-old girl with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), followed by a rapidly progressive onset of hemophagocytic lymphohistiocytosis (HLH) 9 months later, alongside manifestations of demyelinating encephalopathy. Genetic sequencing revealed a heterozygous nonsense mutation in the PRF1 gene (c.984G>A; p.W328*) and a heterozygous missense mutation in the PRF1 gene (c.1349C>T; p.T450M). Eventually, she died because of no suitable allogeneic hematopoietic stem cell available in time. Our observations suggest that CIPD might represent the initial phenotype of biallelic PRF1 mutation and could serve as an early sign of subsequent HLH. A comprehensive understanding of this condition is paramount for timely diagnosis, treatment, and ultimately improved patient outcomes.

Hypoxia-sensing VGLL4 promotes LDHA-driven lactate production to ameliorate neuronal dysfunction in a cellular model relevant to Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease where abnormal amyloidogenic processing of amyloid-ß precursor protein (APP) occurs and has been linked to neuronal dysfunction. Hypometabolism of glucose in the brain can lead to synaptic loss and neuronal death, which in turn exacerbates energy deficiency and amyloid-ß peptide (Aß) accumulation. Lactate produced by anaerobic glycolysis serves as an energy substrate supporting neuronal function and facilitating neuronal repair. Vestigial-like family member 4 (VGLL4) has been recognized as a key regulator of the hypoxia-sensing pathway. However, the role of VGLL4 in AD remains unexplored. Here, we reported that the expression of VGLL4 protein was significantly decreased in the brain tissue of AD model mice and AD model cells. We further found that overexpression of VGLL4 reduced APP amyloidogenic processing and ameliorated neuronal synaptic damage. Notably, we identified a compromised hypoxia-sensitive capability of LDHA regulated by VGLL4 in the context of AD. Upregulation of VGLL4 increased the response of LDHA to hypoxia and enhanced the expression levels of LDHA and lactate by inhibiting the ubiquitination and degradation of LDHA. Furthermore, the inhibition of lactate production by using sodium oxamate, an inhibitor of LDHA, suppressed the neuroprotective function of VGLL4 by increasing APP amyloidogenic processing. Taken together, our findings demonstrate that VGLL4 exerts a neuroprotective effect by upregulating LDHA expression and consequently promoting lactate production. Thus, this study suggests that VGLL4 may be a novel player involved in molecular mechanisms relevant for ameliorating neurodegeneration.

Inhibiting NLRP3 inflammasome signaling pathway promotes neurological recovery following hypoxic-ischemic brain damage by increasing p97-mediated surface GluA1-containing AMPA receptors.

BACKGROUND: The nucleotide-binding oligomeric domain (NOD)-like receptor protein 3 (NLRP3) inflammasome is believed to be a key mediator of neuroinflammation and subsequent secondary brain injury induced by ischemic stroke. However, the role and underlying mechanism of the NLRP3 inflammasome in neonates with hypoxic-ischemic encephalopathy (HIE) are still unclear. METHODS: The protein expressions of the NLRP3 inflammasome including NLRP3, cysteinyl aspartate specific proteinase-1 (caspase-1) and interleukin-1ß (IL-1ß), the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionicacid receptor (AMPAR) subunit, and the ATPase valosin-containing protein (VCP/p97), were determined by Western blotting. The interaction between p97 and AMPA glutamate receptor 1 (GluA1) was determined by co-immunoprecipitation. The histopathological level of hypoxic-ischemic brain damage (HIBD) was determined by triphenyltetrazolium chloride (TTC) staining. Polymerase chain reaction (PCR) and Western blotting were used to confirm the genotype of the knockout mice. Motor functions, including myodynamia and coordination, were evaluated by using grasping and rotarod tests. Hippocampus-dependent spatial cognitive function was measured by using the Morris-water maze (MWM). RESULTS: We reported that the NLRP3 inflammasome signaling pathway, such as NLRP3, caspase-1 and IL-1ß, was activated in rats with HIBD and oxygen-glucose deprivation (OGD)-treated cultured primary neurons. Further studies showed that the protein level of the AMPAR GluA1 subunit on the hippocampal postsynaptic membrane was significantly decreased in rats with HIBD, and it could be restored to control levels after treatment with the specific caspase-1 inhibitor AC-YVAD-CMK. Similarly, in vitro studies showed that OGD reduced GluA1 protein levels on the plasma membrane in cultured primary neurons, whereas AC-YVAD-CMK treatment restored this reduction. Importantly, we showed that OGD treatment obviously enhanced the interaction between p97 and GluA1, while AC-YVAD-CMK treatment promoted the dissociation of p97 from the GluA1 complex and consequently facilitated the localization of GluA1 on the plasma membrane of cultured primary neurons. Finally, we reported that the deficits in motor function, learning and memory in animals with HIBD, were ameliorated by pharmacological intervention or genetic ablation of caspase-1. CONCLUSION: Inhibiting the NLRP3 inflammasome signaling pathway promotes neurological recovery in animals with HIBD by increasing p97-mediated surface GluA1 expression, thereby providing new insight into HIE therapy.

Both epilepsy and anti-seizure medications affect bone metabolism in children with self-limited epilepsy with centrotemporal spikes.

OBJECTIVE: Bone metabolism can be influenced by a range of factors. We selected children with self-limited epilepsy with centrotemporal spikes (SeLECTS) and lifestyles similar to those of healthy children to control for the confounding factors that may influence bone metabolism. We aimed to identify the specific effects of epilepsy and/or anti-seizure medications (ASMs) on bone metabolism. METHODS: Patients with SeLECTS were divided into an untreated group and a monotherapy group, and the third group was a healthy control group. We determined the levels of various biochemical markers of bone metabolism, including procollagen type I nitrogenous propeptide (PINP), alkaline phosphatase (ALP), osteocalcin (OC), collagen type I cross-linked C-telopeptide (CTX), calcium, magnesium, phosphorus, parathyroid hormone (PTH), and vitamin D3 (VD3 ). RESULTS: A total of 1487 patients (from 19 centers) were diagnosed with SeLECTS; 1032 were analyzed, including 117 patients who did not receive any ASMs (untreated group), 643 patients who received only one ASM (monotherapy group), and 272 children in the healthy control group. Except for VD3 , other bone metabolism of the three groups were different (p < .001). Bone metabolism was significantly lower in the untreated group than the healthy control group (p < .05). There were significant differences between the monotherapy and healthy control group in the level of many markers. However, when comparing the monotherapy and untreated groups, the results were different; oxcarbazepine, levetiracetam, and topiramate had no significant effect on bone metabolism. Phosphorus and magnesium were significantly lower in the valproic acid group than the untreated group (adjusted p < .05, Cliff's delta .282-.768). CTX was significantly higher in the lamotrigine group than in the untreated group (adjusted p = .012, Cliff's delta = .316). SIGNIFICANCE: Epilepsy can affect many aspects of bone metabolism. After controlling epilepsy and other confounders that affect bone metabolism, we found that the effects of ASMs on bone metabolism differed. Oxcarbazepine, levetiracetam, and topiramate did not affect bone metabolism, and lamotrigine corrected some of the abnormal markers of bone metabolism in patients with epilepsy.

Melatonin supplementation for the treatment of infantile spasms: protocol for a randomised placebo-controlled triple-blind trial.

INTRODUCTION: Infantile spasms (IS) is a type of severe epileptic encephalopathy that occurs in infancy and early childhood. IS is characterised clinically by epileptic spasms, often accompanied by sleep disorder and abnormal circadian rhythm. The endogenous circadian rhythm disorder, in turn, can make spasms worse. Melatonin has also been found to have anticonvulsant and neuroprotective properties by adjusting the circadian rhythm. However, there are lack of relevant studies on controlling IS by using melatonin. This study aims to analyse the therapeutic effect of melatonin supplementation for the treatment of IS. METHODS AND ANALYSIS: This is a triple-blinded (trial participant, outcome assessor and the data analyst), prospective, randomised controlled trial to be conducted in the Department of Paediatrics, The First Medical Center of Chinese PLA General Hospital, Beijing, China from November 2020. Patients (n=70) aged 3 months to 2 years with IS will be recruited in this study after receiving written consent from their parents or guardians. Patients will be randomly divided into two equal groups and treated with a combination of adrenocorticotropic hormone, magnesium sulfate and either melatonin or placebo. Clinical data from the patients in the two groups before and after the treatment will be collected and compared. The primary outcome will be assessed 2 weeks later by seizure diaries and reported as the average reduced rate of spasms frequency. Secondary outcomes include the response rate (the rate of spasms-free), electroencephalogram hypsarrhythmia assessment and the psychomotor development assessment (Denver Developmental Screening Test). Sleep quality and safety will also be assessed. ETHICS AND DISSEMINATION: The protocol for this study was approved by the Ethics Committee of Chinese PLA General Hospital (reference number S2020-337-01) and was reported according to the Standard Protocol Items: Recommendations for Interventional Trials statement. Findings of this research will be disseminated through national and international meetings, conferences and peer-reviewed journals. TRIAL REGISTRATION NUMBER: ChiCTR2000036208.

Integration of multiscale entropy and BASED scale of electroencephalography after adrenocorticotropic hormone therapy predict relapse of infantile spasms.

BACKGROUND: Even though adrenocorticotropic hormone (ACTH) demonstrated powerful efficacy in the initially successful treatment of infantile spasms (IS), nearly half of patients have experienced a relapse. We sought to investigate whether features of electroencephalogram (EEG) predict relapse in those IS patients without structural brain abnormalities. METHODS: We retrospectively reviewed data from children with IS who achieved initial response after ACTH treatment, along with EEG recorded within the last two days of treatment. The recurrence of epileptic spasms following treatment was tracked for 12 months. Subjects were categorized as either non-relapse or relapse groups. General clinical and EEG recordings were collected, burden of amplitudes and epileptiform discharges (BASED) score and multiscale entropy (MSE) were carefully explored for cross-group comparisons. RESULTS: Forty-one patients were enrolled in the study, of which 26 (63.4%) experienced a relapse. The BASED score was significantly higher in the relapse group. MSE in the non-relapse group was significantly lower than the relapse group in the γ band but higher in the lower frequency range (δ, θ, α). Sensitivity and specificity were 85.71% and 92.31%, respectively, when combining MSE in the δ/γ frequency of the occipital region, plus BASED score were used to distinguish relapse from non-relapse groups. CONCLUSIONS: BASED score and MSE of EEG after ACTH treatment could be used to predict relapse for IS patients without brain structural abnormalities. Patients with BASED score ≥ 3, MSE increased in higher frequency, and decreased in lower frequency had a high risk of relapse.

Assessing Risk for Relapse among Children with Infantile Spasms Using the Based Score after ACTH Treatment: A Retrospective Study.

INTRODUCTION: Even though adrenocorticotropic hormone (ACTH) demonstrated powerful efficacy in the initially successful treatment of infantile spasms (IS), nearly one-half of patients whose spasms were once suppressed experienced relapse. There is currently no validated method for the prediction of the risk of relapse. The Burden of Amplitudes and Epileptiform Discharges (BASED) score is an electroencephalogram (EEG) grading scale for children with infantile spasms. We sought to determine whether an association exists between the BASED score after ACTH treatment and relapse after initial response with ACTH. METHODS: Children with IS who achieved initial response after ACTH treatment were selected as the study subjects. Those who experienced relapse within 12 months after ACTH treatment were categorized as the relapse group, and those who did not were categorized as the non-relapse group. Their general clinical data and EEG data (using BASED scoring) after ACTH treatment were collected, and compared between groups. Cox proportional hazards models were fit to determine factors associated with relapse. RESULTS: A total of 64 children with IS were enrolled in the study, of which 37 (57.8%) experienced a relapse, and the median duration after ACTH treatment was 3 (1.5, 6) months. The BASED score was significantly higher in the relapse group than in the non-relapse group. Cox modeling demonstrated that BASED score was independently associated with relapse. The patients with a score greater than or equal to 3 showed a high rate (89.3%) of relapse. The relapse group had stronger, more stable EEG functional networks than the non-relapse group, and there were obvious correlations between BASED score and functional connectivity. CONCLUSION: This study suggests the BASED score after ACTH treatment has potential value as a predictor for relapse after initial response. Children with IS who have a BASED score greater than or equal to 3 after the initial response of ACTH carry a high risk of relapse within 1 year.

Dihydroartemisinin attenuates hypoxic-ischemic brain damage in neonatal rats by inhibiting oxidative stress.

Neonatal hypoxic-ischemic encephalopathy (HIE) induced by perinatal asphyxia is a major cause of neurological disability among infants. Dihydroartemisinin (DHA), derived from artemisinin, well known as an anti-malarial medicine, was proved to be able to inhibit oxidative stress and inflammation. However, whether those functions of DHA play roles in hypoxic-ischemic brain damage (HIBD), an animal model of HIE in patient which also been observed to have oxidative stress and inflammation, is unknown. In this study, we demonstrated that the DHA treatment on newborn rats significantly relieved the neuron loss and motor and cognitive impairment caused by HIBD. One of the underlying mechanisms is that DHA enhanced the anti-oxidant capacity of HIBD rats by up-regulating the total antioxidant capacity (T-AOC), gluathione reductase (GR) and catalase (CAT) while down regulating the pro-oxidative substances including hydrogen peroxide (H2O2), total nitric oxide synthase (T-NOS) and inducible nitric oxide synthase (iNOS). Thus, our study illustrated that DHA could alleviate the damage of brains and improve the cognitive and motor function of HIBD rats by inhibiting oxidative stress, provided an opportunity to interrogate potential therapeutics for affected HIE patients.

Vigabatrin-associated brain abnormalities on MRI in tuberous sclerosis complex patients with infantile spasms: are they preventable?

Background: Vigabatrin (VGB) is currently the most widely prescribed first-line medication for individuals with infantile spasms (IS) and especially for those with tuberous sclerosis complex (TSC), with demonstrated efficacy. Meanwhile, its adverse events, such as vigabatrin-associated brain abnormalities on magnetic resonance imaging (MRI; VABAM), have also been widely reported. Objectives: The objectives of this study were to observe the occurrences of VABAM in patients with IS caused by TSC (IST) and further explore the associated risk factors. Methods: Children with IS receiving VGB were recruited from our institution; clinical, imaging, and medication data were collected. Cerebral MRI was reviewed to determine the occurrence of VABAM. Group comparisons (IS caused by TSC and other etiologies) were performed; subgroup analyses on IST were also performed. Next, a retrospective cohort study of children taking VGB was conducted to explore risk/protective factors associated with VABAM. Results: The study enrolled 172 children with IS who received VGB. VABAM was observed in 38 patients (22.1%) with a peak dosage of 103.5 ± 26.7 mg/kg/day. Subsequent analysis found the incidence of VABAM was significantly lower in the 80 patients with IST than in the 92 patients with IS caused by other etiologies (10% versus 32.6%, p-value < 0.001). In subgroup analyses within the IST cohort, VABAM was significantly lower in children who received concomitant rapamycin therapy. Univariate and multivariate logistic regression analysis of the 172 IS children showed that treatment with rapamycin was the independent factor associated with a lower risk of VABAM; similar results were observed in the survival analysis. Conclusion: The incidence of VABAM was significantly lower in IST patients. Further research is needed to examine the mechanisms that underlie this phenomenon and to determine if treatment with rapamycin may reduce the risk of VABAM.

Risk of vigabatrin-associated brain abnormalities on MRI: A retrospective and controlled study.

OBJECTIVE: Vigabatrin (VGB) is the first-line treatment for infantile spasms (IS). Previous studies have shown that VGB exposure may cause vigabatrin-associated brain abnormalities on magnetic resonance imaging (MRI) (VABAM). Based on previous studies, this study aimed to go further to explore the possible risk factors and the incidence of VABAM. In addition, diffusion-weighted imaging (DWI) and T2-weighted imaging (T2WI) were compared to explore whether DWI should be used as a routine examination sequence when MRI is performed in children receiving VGB. METHODS: Children with IS receiving VGB were selected as the study subjects. Whether VABAM occurred or not was categorized as the VABAM group and the non-VABAM group, respectively. Their general clinical data and medication exposure were collected. The possible risk factors of VABAM and different MRI sequences were compared and statistically analyzed. RESULTS: A total of 77 children with IS were enrolled in the study, of which 25 (32.5%) developed VABAM. Twenty-three of the 25 VABAM cases have a peak dosage of VGB between 50 and 150 mg/kg/day. The earliest observation time of VABAM was 30 days. Regression analysis of relevant risk factors showed that the peak dosage of VGB was the risk factor for VABAM. Comparison between different MRI sequences showed that DWI is more sensitive than T2WI to the evaluation of VABAM. SIGNIFICANCE: In our study, the occurrence of VABAM was 32.5%, indicating a higher incidence than in most previous reports. In addition, we once again verified that the peak dosage of VGB was the risk factor of VABAM. Caution should be exercised that our data also suggest that VABAM may occur even using the conventional dosage of VGB (ie, 50-150 mg/kg/day). Therefore, even when using the conventional dosage of VGB, regular MRI examination should be required. Furthermore, DWI sequence should be used as a routine examination sequence when MRI is performed in children with IS who are receiving VGB.

Safety and efficacy of plasma exchange treatment in children with AQP4-IgG positive neuromyelitis optica spectrum disorder.

Neuromyelitis optica spectrum disorder (NMOSD), a severe demyelinating disease, is rare among children. Plasma exchange (PE) is widely used as a salvage therapy for severe and corticosteroid-unresponsive patients with NMOSD. Presently, there are limited studies on the safety and efficacy of PE in children with NMOSD. Herein, we report the case of six children with NMOSD who received PE along with the outcomes and adverse events. All six children (female, age at onset 4 years 9 months-13 years 2 months) were AQP4-IgG positive and received standard PE using the COM.TEC Cell Separator. The interval between NMOSD onset and PE was 29 days (range 10-98). Only one patient (P3) who received PE 10 days after acute exacerbations exhibited clinical improvement. Her left visual acuity increased from 0.06 to 0.6 (spectacle-corrected visual acuity was 1.0) and her EDSS score decreased from 4 to 3 points. The other five patients had no clinical improvement and no EDSS scores changes after PE. Adverse events included rashes (P1, P3), acute non-occlusive thrombosis of the internal jugular vein (P1), and thrombocytopenia (P2). In conclusion, the timing of PE initiation as a rescue therapy for severe and corticosteroid-unresponsive pediatric AQP4-IgG positive NMOSD may be crucial to treatment efficacy, and early initiation of PE may be associated with a better outcome. Furthermore, PE has the potential risk for clinically significant adverse effects that should be considered before initiating the therapy and should be weighed against potential benefits.

Vagus Nerve Stimulation Therapy for the Treatment of Seizures in Refractory Postencephalitic Epilepsy: A Retrospective Study.

BACKGROUND: Vagus nerve stimulation (VNS) has been demonstrated to be safe and effective for patients with refractory epilepsy, but there are few reports on the use of VNS for postencephalitic epilepsy (PEE). This retrospective study aimed to evaluate the efficacy of VNS for refractory PEE. METHODS: We retrospectively studied 20 patients with refractory PEE who underwent VNS between August 2017 and October 2019 in Chinese PLA General Hospital and Beijing Children's Hospital. VNS efficacy was evaluated based on seizure reduction, effective rate (percentage of cases with seizure reduction ≥ 50%), McHugh classification, modified Early Childhood Epilepsy Severity Scale (E-Chess) score, and Grand Total EEG (GTE) score. The follow-up time points were 3, 6, and 12 months after VNS. Pre- and postoperative data were compared and analyzed. RESULTS: The median [interquartile range (IQR)] seizure reduction rates at 3, 6, and 12 months after VNS were 23.72% (0, 55%), 46.61% (0, 79.04%), and 67.99% (0, 93.78%), respectively. The effective rates were 30% at 3 months, 45% at 6 months, and 70% at 12 months. E-chess scores before the operation and at 3, 6, and 12 months after the operation were 10 (10, 10.75), 9 (9, 10), 9 (9, 9.75), and 9 (8.25, 9) (P < 0.05), respectively. GTE scores before surgery and at 12 months after the operation were 11 (9, 13) and 9 (7, 11) (P < 0.05), respectively. The mean intensity of VNS current was 1.76 ± 0.39 (range: 1.0-2.5) mA. No intraoperative complications or severe post-operative adverse effects were reported. CONCLUSIONS: Our study shows that VNS can reduce the frequency and severity of seizure in patients with refractory PEE. VNS has a good application prospect in patients with refractory PEE.

Investigation of the association between imbalance of the intestinal flora and infantile spasms: a pilot case-control study.

BACKGROUND: The intestinal flora (IF) regulates brain function via the neuroendocrine and neuroimmune systems and influences the development of several neuropsychiatric diseases, including epilepsy. Here, we investigated the specific relationship between the IF and infantile spasms (IS), a specific form of epilepsy. METHODS: Twenty-three children suffering from IS were recruited from the Chinese PLA General Hospital. According to patient response to adrenocorticotropic hormone (ACTH) treatment, the cohort was subdivided into 2 groups: an ACTH-response group and an ACTH-no response (NR) group. A total of 21 healthy children were recruited as a control group (healthy controls: HCs) during the same time period. Fecal samples were collected from infants in the IS and HC groups, and the population of fecal microorganisms was analyzed by 16s ribosomal DNA sequencing. The α and ß diversity of the fecal microflora was determined, and the relative abundance of each species was classified. Tax4Fun2 was used to analyze the metabolic pathways utilized by the microflora, and the Kyoto Encyclopedia of Genes and Genomes database was used to analyze differentially expressed genes and pathways. RESULTS: No significant differences existed in α or ß diversity when compared between the IS and HC groups, nor between the ACTH-response and ACTH-NR groups which were separated before and after ACTH treatment. Although there was no significant difference between the ACTH-response and ACTH-NR groups with respect to α diversity, there was a significant difference in ß diversity. Compared with that of the HCs, the IF of the IS group featured lower proportions of Lactobacillus, Roseburia, and Lachnospira, and a higher proportion of Clostridium. In the IS group, the proportion of Staphylococcus in the IF was higher before treatment than after treatment. Compared with the ACTH-NR group, the ACTH-response group had reduced populations of Odoribacter, Phascolarctobacterium, Anaerotruncus, Mitsuakella, and Robinsoniella. However, an increase was observed in the population of Bifidobacterium. A significant difference was also identified between the IS and HC groups with regard to the expression levels of genes associated with lipoic acid synthesis. CONCLUSIONS: Our analysis demonstrated that imbalance of the IF may be involved in the pathogenesis of IS and is related to response to ACTH. Regulating the composition of the IF may pave the way to developing a potential adjuvant therapy for patients with IS.