Identification of neurological complications in childhood influenza: a random forest model.

BACKGROUND: Among the neurological complications of influenza in children, the most severe is acute necrotizing encephalopathy (ANE), with a high mortality rate and neurological sequelae. ANE is characterized by rapid progression to death within 1-2 days from onset. However, the knowledge about the early diagnosis of ANE is limited, which is often misdiagnosed as simple seizures/convulsions or mild acute influenza-associated encephalopathy (IAE). OBJECTIVE: To develop and validate an early prediction model to discriminate the ANE from two common neurological complications, seizures/convulsions and mild IAE in children with influenza. METHODS: This retrospective case-control study included patients with ANE (median age 3.8 (2.3,5.4) years), seizures/convulsions alone (median age 2.6 (1.7,4.3) years), or mild IAE (median age 2.8 (1.5,6.1) years) at a tertiary pediatric medical center in China between November 2012 to January 2020. The random forest algorithm was used to screen the characteristics and construct a prediction model. RESULTS: Of the 433 patients, 278 (64.2%) had seizures/convulsions alone, 106 (24.5%) had mild IAE, and 49 (11.3%) had ANE. The discrimination performance of the model was satisfactory, with an accuracy above 0.80 from both model development (84.2%) and internal validation (88.2%). Seizures/convulsions were less likely to be wrongly classified (3.7%, 2/54), but mild IAE (22.7%, 5/22) was prone to be misdiagnosed as seizures/convulsions, and a small proportion (4.5%, 1/22) of them was prone to be misdiagnosed as ANE. Of the children with ANE, 22.2% (2/9) were misdiagnosed as mild IAE, and none were misdiagnosed as seizures/convulsions. CONCLUSION: This model can distinguish the ANE from seizures/convulsions with high accuracy and from mild IAE close to 80% accuracy, providing valuable information for the early management of children with influenza.

Distinct profiles of cerebral oxygenation in focal vs. secondarily generalized EEG seizures in children undergoing cardiac surgery.

Objectives: Seizures are common in children undergoing cardiopulmonary bypass (CPB). Cerebral oxygen saturation (ScO2) by near-infrared spectroscopy is routinely monitored in many centers, but the relations between the levels and changes of ScO2 and brain injuries remain incompletely understood. We aimed to analyze the postoperative profiles of ScO2 and cerebral blood flow velocity in different types of EEG seizures in relation to brain injuries on MRI. Methods: We monitored continuous EEG and ScO2 in 337 children during the first 48 h after CPB, which were analyzed in 3 h periods. Cerebral blood flow peak systolic velocity (PSV) in the middle cerebral artery was measured daily by transcranial Doppler. Postoperative cerebral MRI was performed before hospital discharge. Results: Based on the occurrence and spreading types of seizures, patients were divided into three groups as patients without seizures (Group N; n = 309), those with focal seizures (Group F; n = 13), or with secondarily generalized seizures (Group G; n = 15). There were no significant differences in the onset time and duration of seizures and incidence of status epilepticus between the two seizures groups (Ps ≥ 0.27). ScO2 increased significantly faster across Group N, Group G, and Group F during the 48 h (p < 0.0001) but its overall levels were not significantly different among the three groups (p = 0.30). PSV was significantly lower (p = 0.003) but increased significantly faster (p = 0.0003) across Group N, Group G, and Group F. Group F had the most severe brain injuries and the highest incidence of white matter injuries on MRI among the three groups (Ps ≤ 0.002). Conclusion: Postoperative cerebral oxygenation showed distinct profiles in secondarily generalized and particularly focal types of EEG seizures in children after CPB. A state of 'overshooting' ScO2 with persistently low PSV was more frequently seen in those with focal seizures and more severe brain injury. Information from this study may have important clinical implications in detecting brain injuries when monitoring cerebral oxygenation in this vulnerable group of children after CPB.

Characteristics of neonatal hypoxic-ischemic encephalopathy at high altitude and early results of therapeutic hypothermia.

BACKGROUND: Altitude hypoxia and limited socioeconomic conditions may result in distinctive features of neonatal hypoxic-ischemic encephalopathy (HIE). Therapeutic hypothermia (TH) has not been used at altitude. We examined characteristics of HIE and early outcomes of TH in 3 centers at two high altitudes, 2 at 2,261 m and 1 at 3,650 m. METHODS: The incidence of HIE at NICUs was noted. TH was conducted when personnel and devices were available in 2019~2020. Standard inclusion criteria were used, with the addition of admission age >6 hours and mild HIE. Demographic and clinical data included gestational age, gender, weight, Apgar score, ethnics, age on admission, age at TH and clinical degree of HIE. EEG was monitored for 96 hours during hypothermia and rewarming. MRI was performed before discharge. RESULTS: There was significant difference in ethnics, HIE degree, age at TH across 3 centers. The overall NICU incidence of HIE was 4.0%. Among 566 HIE patients, 114 (20.1%) received TH. 63 (55.3%) patients had moderate/severe HIE. Age at TH >6 hours occurred in 34 (29.8%) patients. EEG discharges showed seizures in 7~11% of patients, whereas spikes/sharp waves in 94~100%, delta brushes in 50~100%. After TH, MRI showed moderate to severe brain injury in 77% of patients, and correlated with center, demographic and clinical variables (Ps≤0.0003). Mortality was 5% during hospitalization and 11% after discharge until 1 year. CONCLUSIONS: At altitude, the incidence of HIE was high and brain injury was severe. TH was limited and often late >6 hours. EEG showed distinct patterns attributable to altitude hypoxia. TH was relatively safe. TRIAL REGISTRATION: The study was registered on February 23, 2019 in Chinese Clinical Trial Register (ChiCTR1900021481).

Perioperative EEG background and discharge abnormalities in children undergoing cardiac surgery: a prospective single-centre observational study.

BACKGROUND: We analysed the characteristics of abnormal electroencephalogram (EEG) patterns before, during, and 48 h after cardiac surgery in patients with heterogeneous congenital heart disease to assess their relationship to demographic and perioperative variables and to early patient outcomes. METHODS: In 437 patients enrolled in a single centre, EEG was evaluated for background (including sleep-wake cycle) and discharge (seizures, spikes/sharp waves, pathological delta brushes) abnormalities. Clinical data (arterial blood pressure, doses of inotropic drugs, and serum lactate concentrations) were recorded every 3 h. Postoperative brain MRI was performed before discharge. RESULTS: Preoperative, intraoperative, and postoperative EEG was monitored in 139, 215, and 437 patients, respectively. Patients with a degree of preoperative background abnormalities (n=40) had more severe intraoperative and postoperative EEG abnormalities (P<0.0001). Intraoperatively, 106/215 (49.3%) patients progressed into an isoelectric EEG. Longer durations of isoelectric EEG were associated with more severe postoperative EEG abnormalities and brain injury on MRI (Ps≤0.003). Postoperative background abnormalities occurred in 218/437 (49.9%) patients, and 119 (54.6%) of them had not recovered after surgery. Seizures occurred in 36/437 (8.2%) patients, spikes/sharp waves in 359/437 (82.2%), and pathological delta brushes in 9/437 (2.0%). Postoperative EEG abnormalities correlated with degree of brain injury on MRI (Ps≤0.02). Demographic and perioperative variables were significantly correlated with postoperative EEG abnormalities, which in turn correlated with adverse clinical outcomes. CONCLUSIONS: Perioperative EEG abnormalities occurred frequently and correlated with numerous demographic and perioperative variables and adversely correlated with postoperative EEG abnormalities and early outcomes. The relation of EEG background and discharge abnormalities with long-term neurodevelopmental outcomes remains to be explored.

Cerebral Autoregulation Status in Relation to Brain Injury on Electroencephalogram and Magnetic Resonance Imaging in Children Following Cardiac Surgery.

Background Disturbed cerebral autoregulation has been reported in children with congenital heart disease before and during cardiopulmonary bypass surgery, but not after. We sought to characterize the cerebral autoregulation status in the early postoperative period in relation to perioperative variables and brain injuries. Methods and Results A prospective and observational study was conducted in 80 patients in the first 48 hours following cardiac surgery. Cerebral oximetry/pressure index (COPI) was retrospectively calculated as a moving linear correlation coefficient between mean arterial blood pressure and cerebral oxygen saturation. Disturbed autoregulation was defined as COPI >0.3. Correlations of COPI with demographic and perioperative variables as well as brain injuries on electroencephalogram and magnetic resonance imaging and early outcomes were analyzed. Thirty-six (45%) patients had periods of abnormal COPI for 7.81 hours (3.38 hours) either at hypotension (median <45 mm Hg) or hypertension (median >90 mm Hg) or both. Overall, COPI became significantly lower over time, suggesting improved autoregulatory status during the 48 postoperative hours. All of the demographic and perioperative variables were significantly associated with COPI, which in turn was associated with the degree of brain injuries and early outcomes. Conclusions Children with congenital heart disease following cardiac surgery often have disturbed autoregulation. Cerebral autoregulation is at least partly the underlying mechanism of brain injury in those children. Careful clinical management to manipulate the related and modifiable factors, particularly arterial blood pressure, may help to maintain adequate cerebral perfusion and reduce brain injury early after cardiopulmonary bypass surgery. Further studies are warranted to determine the significance of impaired cerebral autoregulation in relation to long-term neurodevelopment outcomes.

Postoperative hypernatremia is associated with worse brain injuries on EEG and MRI following pediatric cardiac surgery.

Objectives: Dysnatremia is a common electrolyte disturbance after cardiopulmonary bypass (CPB) surgery for congenital heart disease (CHD) and a known risk factor for adverse neurological events and clinical outcomes. The objective of this study was to evaluate the association of dysnatremia with worse abnormal EEG patterns, brain injuries detected by magnetic resonance imaging (MRI) and early adverse outcomes. Methods: We monitored continuous EEG in 340 children during the initial 48 h following cardiac surgery. Demographics and clinical characteristics were recorded. Sodium concentrations were measured in the arterial blood gas analysis every 6 h. Hyponatremia and hypernatremia were classified by the average of sodium concentrations over 48 h. Postoperative cerebral MRI was performed before hospital discharge. Results: In our patient cohort, dysnatremia was present in 46 (13.5%) patients. Among them, hyponatremia occurred in 21 (6.2%) and hypernatremia in 25 (7.4%). When compared to patients with normonatremia, hyponatremia was not associated with EEG abnormalities and early adverse outcomes (Ps ≥ .14). In hypernatremia group, the CPB time was significantly longer and more frequent use of DHCA (Ps ≤ .049). After adjusting for time, CPB time and the use of DHCA, hypernatremia was significantly associated with worse EEG abnormalities (including background, seizures and pathological delta brushes), more severe brain injuries on MRI (Ps ≤ .04) and trended to be associated with longer postoperative mechanical ventilation time (P = .06). Conclusion: Hypernatremia and hyponatremia were common in children after cardiac surgery. Hypernatremia, but not hyponatremia, was significantly associated with worse EEG abnormalities and more severe brain injuries on MRI and extended postoperative mechanical ventilation time.

Thyroid Function and Anti-thyroid Antibodies in Pediatric Anti-NMDAR Encephalitis.

Objective: Recent studies found that changes of thyroid antibodies (ATAbs), thyroid hormone, and non-thyroidal illness syndrome (NTIS) characterized by thyroid hormone inactivation with low triiodothyronine and high reverse triiodothyronine followed by suppressed thyroid-stimulating hormone (TSH) in adult anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis were associated with disease severity. This study aimed to explore thyroid function and ATAbs in pediatric anti-NMDAR encephalitis and their clinical association. Methods: We retrospectively analyzed the clinical data of 51 pediatric cases with anti-NMDAR encephalitis hospitalized in Guangzhou Women and Children's Medical Center from August 2016 to 2019. Results: A percentage of 52.9% of patients belonged to the ATAb (+) group, with 26 cases both positive for anti-thyroid peroxidase antibodies (TPOAb) and anti-thyroglobulin antibodies (TGAb), and one patient only positive for TPOAb. A percentage of 62.7% of patients had at least one abnormality in terms of FT3, free thyroxin (FT4), or TSH levels. Meanwhile, 45.1% of patients were diagnosed with NTIS. Among 25 cases retested for thyroid function 2 months after the initial test, the respectively decreased FT3 and FT4 in 13 and 11 cases on admission returned to normal or closer normal than before; TPOAb in eight cases and TGAb in 12 cases were changed from positivity to negativity. Compared with onset, the level of TPOAb and TGAb at relapse remained stable or significantly decreased, respectively. Compared with the ATAb (-) group, the ATAb (+) group had an older onset age, a higher ratio of movement disorders, elevated rate of sleep disorders, increased anti-nuclear antibody positivity rate, and higher ratio of more than one course of intravenous immunoglobulin treatment. There were no significant differences between the NTIS and non-NTIS groups in clinical characteristics. Conclusion: Anti-thyroid antibody positivity, abnormality of FT3, FT4, or TSH levels and NTIS are frequent in pediatric anti-NMDAR encephalitis. Thyroid antibody and thyroid hormone abnormalities could be improved through the course of treatment of anti-NMDAR encephalitis. Cases with ATAbs (+) are at older onset ages and more likely to be treated by intravenous immunoglobulin therapy more than once. Unlike adult anti-NMDAR encephalitis, NTIS might not be associated with the clinical characteristics of anti-NMDAR encephalitis in pediatric patients.

Parameters Indicating Development of Influenza-Associated Acute Necrotizing Encephalopathy: Experiences from a Single Center.

BACKGROUND Influenza-associated acute necrotizing encephalopathy (IANE) can be lethal and disabling and have a sudden onset and deteriorate rapidly but lacks early diagnostic indicators. We aimed to examine the early clinical diagnostic indicators in children with IANE. MATERIAL AND METHODS Acute influenza patients were grouped according to their clinical manifestations: flu alone (FA), flu with febrile seizure (FS), influenza-associated encephalopathy (IAE), and IANE. The clinical features, biomarkers, neuroelectrophysiological results, and neuroimaging examination results were compared. RESULTS A total of 31 patients were included (FA (n=4), FS (n=8), IAE (n=14), and IANE (n=5)). The IANE group, whose mean age was 3.7 years, was more likely to show rapid-onset seizure, acute disturbance of consciousness (ADOC), Babinski's sign, and death/sequela. More patients in the IANE group required tracheal intubation mechanical ventilation and received intravenous immunoglobulins (IVIG) and glucocorticoids. The alanine aminotransferase (ALT), aspartate transaminase (AST), and lactate dehydrogenase (LDH) levels in the IANE group were significantly higher than in the FS and IAE groups. The aquaporin-4 (AQP-4) antibody and malondialdehyde (MDA) levels in the serum and cerebrospinal fluid (CSF) were notably higher in IANE patients in the acute stage compared with FS and IAE patients. All patients in the IANE group had positive neuroimaging findings. CONCLUSIONS Early clinical warning factors for IANE include rapid-onset seizures in patients under 4 years of age, ADOC, and pathological signs. Increased AQP-4 antibodies and MDA levels in CSF might contribute to early diagnosis. Early magnetic resonance venography (MRV) and susceptibility-weighted imaging (SWI) sequences, or thrombelastography to identify deep vein thrombosis, might indicate clinical deterioration.

Assessment of postoperative risk factors for EEG abnormalities in routine clinical management after paediatric cardiopulmonary bypass.

OBJECTIVES: The postoperative risk factors for electroencephalogram(EEG) abnormalities after paediatric cardiopulmonary bypass (CPB) remain to be identified. We investigated the characteristics of EEG abnormalities and risk factors in routine clinical management post-CPB. METHODS: EEG and cerebral oxygen saturation (ScO2) were monitored in 96 patients (aged 3 days, 37 months, median 5 months) for 72 h post-CPB. Clinical measurements included 4-hourly arterial and central venous pressure, arterial blood gases, doses of inotropic and vasoactive drugs, daily C-reactive protein (CRP) and NT-proB-type Natriuretic Peptide (NT-proBNP). Demographics, STAT categories and outcomes (duration of mechanical ventilation,CICU stay) were recorded. Un. RESULTS: Seizures occurred in 20 patients (20.8%) beginning at 0-48 hand lasting 10 min-31 h; background abnormalities occurred in 67 (69.8%) beginning at 0-8 h and lasting 4-48 h. Patients with EEG abnormalities had worse outcomes. In univariable regression, seizures positively correlated with STAT categories, CPB time, temperature, blood pressure, central venous pressure, NT-proBNP, CRP, lactate and epinephrine, negatively with ScO2 and PaCO2 (P < 0.001 for lactate and epinephrine, P < 0.1 for the remaining). The degree of background abnormalities positively correlated with STAT categories, CPB time, operative time, central venous pressure, milrinone, negatively with blood pressure (P = 0.0003-0.087); it negatively correlated with lower dose of epinephrine (P < 0.001) and positively with higher dose (P = 0.03l). In multivariable regression, seizures positively correlated with epinephrine, lactate and temperature; the background abnormality correlations remain significant except for milrinone and operative time (P < 0.001 for epinephrine, P < 0.05 for the remaining). CONCLUSIONS: Numerous perioperative risk factors are associated with EEG abnormalities post-CPB. The most significant and consistent risk factor is epinephrine.

Fully automated simultaneous peripheral arteriovenous exchange transfusion not seen to aggravate brain function and the disorder of the internal environment in neonates with severe hyperbilirubinemia.

BACKGROUND: The acute changes in brain function in newborn infants undergoing ET remain unclear. This study aimed to determine whether fully automated simultaneous peripheral arteriovenous ET would influence the brain function. METHODS: A retrospective analysis was conducted on the clinical data of 39 neonates with hyperbilirubinemia who received ET. Seventeen patients were in the encephalopathy group, and the other 22 patients were in the non-encephalopathy group. Changes in amplitude-integrated electroencephalogram (aEEG) during ETs were analyzed, including background activities, sleep-wake cycling (SWC), and seizures. Before and after the ET, routine blood test parameters, electrolytes, blood glucose, and blood gas parameters were measured. RESULTS: After ETs, there were no significant changes in the levels of pH, PaO2, PaCO2, lactate, and red blood cells, while the levels of total bilirubin, indirect bilirubin, blood potassium, blood sodium, serum calcium, while blood cells, and platelets were significantly lower and the level of blood glucose was significantly higher compared to those before therapy. There was no significant difference in the changes of electroencephalographic activities during ETs, including background activities, SWC, and seizures. However, there were significant differences in suppressions on background activities, while there were no significant statistical differences in SWC or seizures between the 2 groups. CONCLUSION: Fully automated simultaneous peripheral arteriovenous ET is safe and efficient without significant influence on the disorder of the internal environment and electroencephalographic activities after ET in neonates. However, background activities are more significantly depressed in infants of bilirubin encephalopathy than infants of non-encephalopathy during ET.

A follow-up study in children with status epilepticus during sleep: From clinical spectrum to outcome.

PURPOSE: To evaluate the correlation between clinical spectrum and therapeutic outcomes and neuropsychological deficits in children with status epilepticus during sleep (SES). METHODS: The clinical spectrum of patients with SES was defined as follows: status epilepticus of benign childhood epilepsy with centro-temporal spikes (SEBECTs), atypical benign focal epilepsy during childhood (ABFEC), non-idiopathic focal epilepsy (NIFE), and Landau-Kleffner syndrome (LKS). SES cases were divided into 4 groups according to neuropsychological findings before treatment: developmental delay/intellectual disability (DD/ID), cognitive impairment (CI), attention deficit and/or hyperactivity behaviors (AHD), and normal group (NG). The therapeutic outcomes were classified into 3 groups: satisfactory response, recurrence, and seizure control. RESULTS: A total of 39 cases (24 males and 15 females) were recruited, including 3 cases with SEBECTs, 26 with ABFEC, 8 with NIFE [2 with focal cortical dysplasia (FCD)], and 2 with LKS. There were 7 patients in the DD/ID group, 8 in the CI group, 19 in the AHD group, and 5 in the NG group. Neuropsychological outcomes were significantly different among clinical spectrum (P < 0.001), and neuropsychological deficits frequently occurred in the ABFEC group or in the NIFE group. Besides, 18 patients in the satisfactory group had satisfactory response to medicine or surgery (2 out of 18 cases with FCD), whereas recurrence was observed at least one session within one year in 16 cases in the recurrence group, and no improvement in spike-wave index and cognition/behavior was noted in 5 patients in the seizure control group, although seizure could be controlled. There were significant differences in therapeutic outcomes among clinical spectrum (P = 0.041), with the worst outcomes in the NIFE group (only 1 out of 8 with satisfactory good response). CONCLUSIONS: It is important to categorize patients with SES into epilepsy syndromes, including SEBECTs, ABFPEC, NIFE, and LKS; the clinical spectrum may be a significant determinant to influence the outcomes of SES, including neuropsychological deficits and therapeutic outcomes.

Pediatric anti-N-methyl-d-aspartate receptor encephalitis in southern China: Analysis of 111 cases.

OBJECTIVE: To study the clinical features of children diagnosed with anti-NMDAR encephalitis in southern China. METHODS: Clinical data of children diagnosed with anti-NMDAR encephalitis from October 2014 to June 2020 from one national regional medical center were analyzed. Neurological disability was assessed by modified Rankin Scale (mRS) throughout the course of disease. RESULTS: 111 children (M/F = 49/62; mean onset age = 6.8 y) with anti-NMDAR encephalitis were involved. Prodromal events occurred in 34.2% of patients with infectious events being the most common. Seizure was the most common initial symptom, though movement disorder served as the most common event throughout the course of disease. 9.9% of patients had overlapped with other neuronal autoantibodies. Electroencephalogram showed abnormalities with slow wave (100.0%), epileptic discharge (31.5%) and delta brush (8.1%) respectively. 41.4% of patients had abnormal brain MRI, with focal lesions being the most common. None patients had tumor. 80.9% of patients had good response to first line therapy (steroid plus immunoglobulin), while 14 patients accepted second-line therapy (Rituximab) and all had a good response. Boys were significantly more likely to need more course of steroid. 13.8% of patients relapsed. 2 male patients died. mRS score was significantly improved after treatment. 51.4% of patients had a full recovery and 81.7% had mRS score ≤ 2. The median mRS score of boys after treatment was higher than that of girls. Non-infectious prodromal event, past medical history, perivascular lesions in brain MRI, hospital stay, initial mRS score higher than 3, and RTX treatment were independent risk factors associated with poor prognosis, defined as mRS score > 2. CONCLUSION: Of pediatric anti-NMDAR encephalitis in southern China: median onset age around 7 years; girls more common; boys might have poor outcome than girls; seizure or movement disorder respectively being most common onset or course symptom; a few overlapped with other neuronal autoantibodies; rare combined with tumor; most had a good response to immunotherapy and a good prognosis; relapse rate relatively high; fatality rate relatively low; some risk factors associated with poor prognosis.