Identifying shared genetic factors underlying epilepsy and congenital heart disease in Europeans.

Epilepsy (EP) and congenital heart disease (CHD) are two apparently unrelated diseases that nevertheless display substantial mutual comorbidity. Thus, while congenital heart defects are associated with an elevated risk of developing epilepsy, the incidence of epilepsy in CHD patients correlates with CHD severity. Although genetic determinants have been postulated to underlie the comorbidity of EP and CHD, the precise genetic etiology is unknown. We performed variant and gene association analyses on EP and CHD patients separately, using whole exomes of genetically identified Europeans from the UK Biobank and Mount Sinai BioMe Biobank. We prioritized biologically plausible candidate genes and investigated the enriched pathways and other identified comorbidities by biological proximity calculation, pathway analyses, and gene-level phenome-wide association studies. Our variant- and gene-level results point to the Voltage-Gated Calcium Channels (VGCC) pathway as being a unifying framework for EP and CHD comorbidity. Additionally, pathway-level analyses indicated that the functions of disease-associated genes partially overlap between the two disease entities. Finally, phenome-wide association analyses of prioritized candidate genes revealed that cerebral blood flow and ulcerative colitis constitute the two main traits associated with both EP and CHD.

Seizure control after epilepsy surgery in early childhood: A systematic review and meta-analysis.

OBJECTIVE: This meta-analysis aimed to determine the main factors influencing surgical outcomes in children <3 years old with refractory epilepsy. METHODS: The PubMed and Cochrane database were systematically searched for epilepsy surgery outcomes from December 1, 1991, to March 30, 2021, using the following search terms: "Epilepsy surgery OR Seizure operation" AND "under three years" OR "first three years" OR "early childhood" OR "infancy OR infants." Seizure onset, duration of epilepsy, magnetic resonance imaging findings, age at the time of surgery, surgical methods, resection extent, and pathological findings were considered potential moderators of differences in seizure outcomes. The fixed-effects models, combined effect sizes, and 95% confidence intervals (CI) were used to calculate the influence of potential factors on seizure outcomes. RESULTS: Thirty two studies (559 cases) were included in the meta-analysis. The significant factors that correlated with a lower seizure control rate were frontal lobectomy (odds ratio [OR]: 0.33, 95% CI: 0.12-0.91; p = 0.03) and malformation of cortical development (MCD) (OR, 0.38; 95% CI: 0.24-0.62; p < 0.01). A higher seizure control rate was observed in children with tumors (92.86%) and Sturge-Weber syndrome (SWS, 91.43%). Frontal lobe epilepsy induced by MCD was related to the worst postoperative efficacy (OR, 0.26; 95% CI: 0.13-0.53; p < 0.01). SIGNIFICANCE: The results of our meta-analyses revealed that pathology and surgical location play critical roles in the outcome of epilepsy surgery in children <3 years old. Clarification of the etiology of epilepsy before surgery is critical for better postoperative outcomes.

Therapeutic value of patent foramen ovale closure for drug-resistant epilepsy: A case series report.

OBJECTIVE: Closure surgery of patent foramen ovale (PFO) has been found to effectively control cryptogenic stroke and migraine, but it is uncertain whether PFO closure could also alleviate epileptic seizures. This study aims to observe the therapeutic effect of PFO closure on epileptic seizures. METHODS: Since July 11th, 2017, in the neurology department of West China Hospital, Sichuan University, Chengdu, we have been regularly monitoring patients with epilepsy who have undergone PFO closure. The patient's clinical information, such as frequency, duration, and severity of seizures, before and after surgery was recorded in detail as well as postoperative safety events. RESULTS: Of the 31 epilepsy patients who confirmed PFO observed (27 cases were drug-resistant epilepsy, 87.10%), average age of surgery was 23.74 years, and 12 cases were female (38.71%). After one-year follow-up, 26 patients (83.87%) achieved remission of seizure frequency, and 22 of whom (70.97%) experienced a remission of more than 50%. Additionally, compared to before surgery, 22 cases (70.97%) reported a decrease in the average seizure duration, and 20 cases (64.52%) reported a reduction in seizure severity. In the seizure indicators of frequency, average duration and severity, significant differences were identified between preoperative and postoperative comparisons with all test p values were <0.05. Furthermore, no serious safety events were reported except for one patient who briefly reported chest pain, and all patients expressed effective PFO closure. SIGNIFICANCE: The PFO closure has been shown for the first time to result in a significant reduction in the frequency, duration, and severity of seizures. Patients with drug-resistant epilepsy and PFO with a large shunt are ideal candidates for undergoing PFO closure. PLAIN LANGUAGE SUMMARY: Since PFO closure was found to have a good therapeutic effect on cryptogenic stroke and migraine, it has become a credible complementary therapy for the treatment of neurological diseases, and drug-resistant epilepsy with PFO is expected to become the next target disease that PFO closure could significantly improve.

Association of patent foramen ovale with epilepsy: A hospital-based case-control study.

OBJECTIVE: This study aimed to investigate the proportion of patent foramen ovale (PFO) in people with epilepsy (PWE) compared to controls without epilepsy and to assess whether PWEs with and without PFO exhibit distinctive clinical features. METHODS: This is a case-control study conducted in a hospital. Contrast transthoracic echocardiography with a venous microbubble bolus and provocative maneuvers (Valsalva and coughing) were used to identify PFO and its right-to-left shunt (RLS) among 741 PWEs and 800 controls without epilepsy. The risk of having PFO in PWEs was explored using multiple matching methods and logistic regression with adjusted congenital factors that may affect the occurrence of PFO. RESULTS: The proportion of PFO in PWEs and controls was 39.00% and 24.25%, respectively. After 1:1 propensity score matching, the risk of suffering PFO in PWEs was 1.71 times (OR, 1.71; 95% CI, 1.24-2.36) higher than that in controls. PWEs also had a higher risk of having a high RLS grade (ßepilepsy = 0.390, P < 0.001). Among clinical characteristics of PWEs, migraine, and drug-resistant epilepsy showed significantly different distributions between those without RLS and those with RLS grade I to III. PWEs with PFO had higher risk of suffering from migraine and drug-resistant epilepsy (OR in migraine, 2.54, 95% CI, 1.65-3.95; OR in drug-resistant epilepsy, 1.47, 95% CI, 1.06-2.03). SIGNIFICANCE: The proportion of PFO was found to be higher in PWE than in controls without epilepsy, especially in patients with drug-resistant epilepsy, suggesting potential relationship between the two disorders. Large multicentric study will be needed to confirm this finding.

Relationship between right-to-left shunt, hypoxia, and epilepsy.

OBJECTIVE: A right-to-left shunt (RLS) can mediate the hypoxic state, and hypoxemia is relevant for the development of drug-resistant epilepsy (DRE). The objective of this study was to identify the relationship between RLS and DRE and further investigate the contribution of RLS to the oxygenation state in patients with epilepsy (PWEs). METHODS: We performed a prospective observational clinical study of PWEs who underwent contrast medium transthoracic echocardiography (cTTE) between January 2018 and December 2021 at West China Hospital. The collected data included demographics, clinical features of epilepsy, antiseizure medications (ASMs), RLS identified by cTTE, electroencephalography (EEG), and magnetic resonance imaging (MRI). Arterial blood gas was also assessed in PWEs with or without RLS. The association between DRE and RLS was quantified using multiple logistic regression, and the parameters of oxygen levels were furtherly analyzed in PWEs with or without RLS. RESULTS: A total of 604 PWEs who completed cTTE were included in the analysis, of which 265 were diagnosed with RLS. The proportion of RLS was 47.2% in the group of DRE, and the proportion of RLS was 40.3% in the group of non-DRE. Having RLS was associated with DRE in multivariate logistic regression analysis (adjusted OR = 1.53, P = 0.045). In the analysis of blood gas, the partial oxygen pressure in PWEs with RLS was lower than those without RLS (88.74 mmHg versus 91.84 mmHg, P = 0.044). SIGNIFICANCE: Right-to-left shunt could be an independent risk factor of DRE, and low oxygenation might be a possible reason.

Connection between right-to-left shunt and photosensitivity: a community-based cross-sectional study.

Background: Hypersensitivity to light is a common symptom associated with dysfunction of the occipital region. Earlier studies also suggested that clinically significant right-to-left shunt (RLS) could increase occipital cortical excitability associated with the occurrence of migraine. The aim of this study was to investigate the relationship between RLS and photosensitivity. Methods: This cross-sectional observational study included the residents aged 18-55 years living in the Mianzhu community between November 2021 and October 2022. Photosensitivity was evaluated using the Photosensitivity Assessment Questionnaire along with baseline clinical data through face-to-face interviews. After the interviews, contrast-transthoracic echocardiography (cTTE) was performed to detect RLS. Inverse probability weighting (IPW) was used to reduce selection bias. Photosensitivity score was compared between individuals with and without significant RLS using multivariable linear regression based on IPW. Results: A total of 829 participants containing 759 healthy controls and 70 migraineurs were finally included in the analysis. Multivariable linear regression analysis showed that migraine (ß = 0.422; 95% CI: 0.086-0.759; p = 0.014) and clinically significant RLS (ß = 1.115; 95% CI: 0.760-1.470; p < 0.001) were related to higher photosensitivity score. Subgroup analysis revealed that clinically significant RLS had a positive effect on hypersensitivity to light in the healthy population (ß = 0.763; 95% CI: 0.332-1.195; p < 0.001) or migraineurs (ß = 1.459; 95% CI: 0.271-2.647; p = 0.010). There was also a significant interaction between RLS and migraine for the association with photophobia (pinteraction = 0.009). Conclusion: RLS is associated with photosensitivity independently and might exacerbate photophobia in migraineurs. Future studies with RLS closure are needed to validate the findings. Trial registration: This study was registered at the Chinese Clinical Trial Register, Natural Population Cohort Study of West China Hospital of Sichuan University, ID: ChiCTR1900024623, URL: https://www.chictr.org.cn/showproj.html?proj=40590.

Multisite and multitimepoint proteomics reveal that patent foramen ovale closure improves migraine and epilepsy by reducing right-to-left shunt-induced hypoxia.

Patent foramen ovale (PFO) is a congenital defect in the partition between two atria, which may cause right-to-left shunt (RLS), leading to neurological chronic diseases with episodic manifestations (NCDEMs), such as migraine and epilepsy. However, whether PFO closure was effective in improving NCDEMs and the mechanism were unclear. Twenty-eight patients with migraine or epilepsy who underwent PFO closure were recruited. Notably, approximately half of patients received 50% or more reduction in seizure or headache attacks. Meanwhile, the postoperative blood oxygen partial pressure and oxygen saturation were elevated after PFO closure. Multisite (peripheral, right, and left atrial) and multitimepoint (before and after surgery) plasma proteomics from patients showed that the levels of free hemoglobin and cell adhesion molecules (CAMs) were significantly increased after PFO closure, which may be related to the relief of the hypoxic state. Furtherly, the omics data from multiple brain regions of mice revealed that a large number of proteins were differentially expressed in the occipital region in response to PFO, including redox molecules and CAMs, suggesting PFO-caused hypoxia may have great impacts on occipital region. Collectively, PFO may cause NCDEMs due to RLS-induced hypoxia, and PFO closure could prevent RLS to improve migraine and epilepsy.

The impact of childhood parental loss on risk for depression and anxiety in adulthood: A community-based study in Southwest China.

PURPOSE: Lack of parental raising is an important reason for parental loss in China due to urbanization. We aimed to explore the association between parental loss (including parental death, divorce, alcoholism, crime, drug addiction, bedridden, and lack of parental raising) before 17 years old and mental health disorders in adulthood in Southwest China. METHODS: Childhood parental loss, age, gender, socioeconomic status, smoking, drinking, and medical history were self-reported. Patient Health Questionnaire 9 (PHQ-9) and Generalized Anxiety Disorder 7 (GAD-7) were used for identifying depression and anxiety, respectively. We use logistic regression with inverse probability weighting according to the propensity score to assess the risk of childhood parental loss on mental health disorders in adulthood. RESULTS: A total of 8014 adults were enrolled in this study. Childhood parental loss increased the risk of adulthood depression (OR, 1.60, 95%CI, 1.30-1.98) but not anxiety (p= 0.07) after adjustment of all covariates. Sensitivity analyses including logistic regression with original data, nearest neighbor matching, full matching, and propensity score as the only covariate all yielded similar results. LIMITATIONS: Recall bias could not be fully eliminated due to the retrospective nature of study design. Our study had been conducted in a less-prosperous area in Southwest China and the results may not be representative at nation level. CONCLUSIONS: Childhood parental loss was associated with depression in adulthood in Southwest China, highlighting the need for early intervention in children with parental loss, to prevent long-term negative effects on their mental health.

Association between loneliness, sleep behavior and quality: a propensity-score-matched case-control study.

OBJECTIVE: To explore the influence of loneliness on sleep behavior and sleep quality based on propensity score-matched samples in Southwest China. METHODS: Individual-level data were obtained from a Southwest China cohort study. Participants who felt lonely were matched with those who did not with propensity scores on the basis of age, gender, socioeconomic factors, physical exercise and social connection level. Sleep behavior (onset and offset timing), sleep quality (sleep latency, nocturnal awakenings and subjective sleep quality), and daytime function (daytime sleepiness and fatigue) were assessed with the Pittsburgh Sleep Index Scale (PSQI) and compared between the two groups. The data were collected between May 2019 and December 2019, and data analyses were completed in April 2021. RESULTS: A total of 11,696 participants were included, and 824 out of 839 participants who felt loneliness were statistically matched with 824 participants who did not. Analyses of the matched samples showed that sleep onset and offset timing were similar between those who felt lonely and those who did not (p = 0.110 and p = 0.751, respectively). Sleep latency was longer in those who felt lonely (26.84 [0.9] vs. 35.52 [1.2] min, p < 0.001) than in those who did not. Furthermore, participants who felt lonely tended to have poor subjective sleep, a higher frequency of nocturnal awakenings, daytime sleepiness and fatigue (all p < 0.001). CONCLUSIONS: Loneliness was associated with extended sleep latency, increased nocturnal awakenings, and reduced subjective sleep quality and daytime function but was not associated with sleep behavior, including sleep onset and offset timings.

Behavioral and Brain Structural Changes in Kindled Rats Induced by Coriaria Lactone/Pentylenetetrazol.

Epilepsy is a common chronic neurological disease that is characterized by spontaneous seizures. It is commonly comorbid with behavioral and mood disorders. No studies have yet examined the behavioral or structural brain changes associated with coriaria lactone (CL)-induced and pentylenetetrazol (PTZ)-induced kindlings. This study examined whether the increased seizure susceptibility induced by CL/PTZ is accompanied by behavioral impairments and aimed to identify associated structural brain changes. Kindling models were induced using CL and PTZ, with 10 rats in each group. After successful kindling, rats were subjected to brain structural imaging using T2-weighted imaging and underwent behavioral tests, namely, the open field test, water maze tasks, and contextual fear conditioning. Voxel-based morphometry was then used to identify possible brain structural changes associated with kindling and/or behaviors. Support-vector machine learning was also applied for the integrative analysis of behavioral changes and structural brain imaging. In the open field test, both the CL (P = 0.04) and PTZ groups (P = 0.002) spent more time in the central area than the control group. Only the PTZ group (50.29 ± 29.56 s) showed a freezing time that was significantly less than that of the control group (94.8 ± 41.04 s; P = 0.024, Tukey's HSD-corrected) in contextual fear conditioning, which is suggestive of impaired fear-associated learning ability. Furthermore, brain imaging analysis revealed that the gray matter volume (GMV) of the hippocampus changed in both the CL and PTZ groups when compared to control. The support-vector machine learning model indicated that the retrosplenial dysgranular and primary somatosensory cortices were associated with both of the mentioned kindling models. Furthermore, the support-vector regression model results indicated that kindling-associated GMV changes can be used to predict general exploratory activity in the open field test. In conclusion, this is the first study to report greater general exploratory activity in a CL-induced kindling model. Moreover, the general exploratory activity in the open field test can be predicted by the GMV of brain regions associated with kindling.

Gastric Electrical Dysarrhythmia in Probable Rapid Eye Movement Sleep Behavior Disorder.

Background: Subjective gastrointestinal complaints have been repeatedly reported in patients with REM sleep behavior disorder (RBD), but objective evidence is scarce. We aimed to objectively investigate the gastrointestinal dysfunction in individuals with probable RBD (pRBD) using an electrogastrogram. Methods: Thirty-two participants with pRBD and 60 age- and gender-matched healthy controls were enrolled. pRBD was diagnosed based on questionnaires and further assessed by experienced neurologists. After thorough assessment of participants' subjective gastrointestinal symptoms, preprandial and postprandial gastric activities were measured using an electrogastrogram. Dominant frequency, dominant power ratio, and the ratio of preprandial to postprandial power were analyzed. Results: Among the gastric symptoms, hiccup (34.8 vs. 9.6%, p = 0.017) and postprandial gastric discomfort (43.5 vs. 15.4%, p = 0.017) were more frequent in participants with pRBD than in controls. The dominant frequency on the electrode overlying the gastric pyloric antrum was lower in pRBD than in healthy controls (2.9 [2.6-2.9] vs. 2.9 [2.9-3.2] cpm, p = 0.006). A reduced dominant power ratio from the same electrode was also found in individuals with pRBD (60.7 [58.0-64.5] vs. 64.2 [58.7-69.6] %, p = 0.046). Conclusion: Patients with pRBD have a higher rate of gastric dysfunction, which presented as irregular slow wave rhythmicity on an electrogastrogram.