Pediatric fulminant malignant hyperthermia with severe electroencephalographic abnormality and brain damage: a case report.

BACKGROUND: Malignant hyperthermia is an extremely dangerous condition that can occur with exposure to volatile inhalant anesthetics and depolarizing muscle relaxants, and that requires immediate intervention. Neurological complications have rarely been reported, with no reports of electroencephalographic abnormalities or encephalopathy. Here, we report a case of severe electroencephalographic abnormality in the acute phase of malignant hyperthermia that eventually led to diffuse cerebral cortical damage. CASE PRESENTATION: A 15-month-old Japanese boy underwent a Rastelli procedure to correct a double-outlet right ventricle and pulmonary atresia. Sevoflurane was used for induction and maintenance of anesthesia during surgery. After withdrawal from the heart-lung machine, his body temperature rose at a rate of 0.1 â„ƒ/minute, and when he left the operating room, his core body temperature had reached 42 â„ƒ. After admission to the intensive care unit, tachycardia, high PaCO2, and progressive metabolic acidosis were observed. A clinical grading scale score of 63 indicated malignant hyperthermia, and dantrolene was administered. The pupils were dilated, and the electroencephalogram showed persistent generalized continuous multifocal spikes. Midazolam, levetiracetam, and fosphenytoin were administered without improvement, and thiamylal and ketamine were infused continuously. After the electroencephalogram shifted to burst suppression, the epileptic firing gradually decreased, and the background electroencephalogram became lower in amplitude. Magnetic resonance imaging of the head performed after the patient was hemodynamically stable suggested diffuse cerebral cortical damage. Severe mental retardation, hypertonia, and quadriplegia were observed as neurological complications. CONCLUSIONS: In this case, despite the use of high-dose anticonvulsants, the patient showed severe electroencephalogram abnormality, resulting in diffuse cortical damage. Hyperthermia is known to damage the central nervous system by causing increased brain pressure and cerebral edema, which may have triggered the severe neuronal excitation that we observed in this case. The presence of systemic inflammatory response syndrome and the patient's background, including young age and ethnicity, might also have been factors. Malignant hyperthermia can be complicated by encephalopathy, and continuous electroencephalogram monitoring should be considered.

Dysostosis in mucopolysaccharidosis type 2: A case of longitudinal follow up and literature review.

Mucopolysaccharidosis type 2 is a congenital lysosomal disease characterized by iduronate-2-sulfatase deficiency, which leads to excessive accumulation of glycosaminoglycans in tissue. Dysostosis, which primarily involves decreased bone mineralization with morphological changes in the bone, is a major skeletal condition in mucopolysaccharidosis, but its pathophysiology is not well known. Here, we report a case of mucopolysaccharidosis type 2 diagnosed at the age of 2 years with longitudinal follow-up data for more than 15 years. Although the patient underwent bone marrow transplantation, the developmental quotient did not improve, and cranial hyperostosis progressed prominently with a faintly dilated perivascular space. Other dysostoses and contraction of the joints were observed but did not improve either.

Type IV Collagen 7s Reflects Central Venous Pressure and Right Ventricular End-Diastolic Pressure in Patients with Congenital Heart Disease After Biventricular Repair.

After congenital heart disease repair, right heart dysfunction facilitates venous stasis and elevated central venous pressure; however, methods to evaluate right heart dysfunction are limited. We aimed to evaluate right heart function using liver biomarkers. We investigated 62 patients more than 5 years after congenital heart surgery. The patients underwent cardiac catheterization in our hospital between January 2015 and December 2019. To evaluate liver status, type IV collagen 7s, procollagen type III peptide, and hyaluronic acid levels were measured. The mean age of the 62 patients was 14.0 ± 7.2 years. The mean central venous pressure was 6.8 ± 3.5 mmHg and mean right ventricular end-diastolic pressure was 7.9 ± 3.5 mmHg. The mean levels of serum type IV collagen 7s, procollagen type III peptide, and hyaluronic acid were 5.9 ± 1.6 ng/mL, 24.3 ± 15.5 ng/mL, and 18.5 ± 13.6 ng/mL, respectively. There was a good correlation between central venous pressure, right ventricular end-diastolic pressure and type IV collagen 7s (r = 0.67 and r = 0.64). There was no correlation between central venous pressure and the procollagen type III peptide (r = 0.003), and slight correlation between central venous pressure and hyaluronic acid (r = 0.31). There was no correlation between right ventricular end-diastolic pressure and the procollagen type III peptide (r = 0.003), and slight correlation between right ventricular end-diastolic pressure and hyaluronic acid (r = 0.31). We found that changes in the hemodynamics of the right heart system can be evaluated using liver fibrosis markers. Type IV collagen 7s reflects central venous pressure and right ventricular end-diastolic pressure in postoperative patients with congenital heart disease.

Life-threatening muscle complications of COL4A1-related disorder.

COL4A1-related disorder is recognized as a systemic disease because the alpha 1 chain of type IV collagen, encoded by COL4A1, is essential for basement membrane stability. However, muscular manifestations related to this disorder are rarely reported. We report the case of a 2-year-old boy with porencephaly, who harbored a de novo COL4A1 mutation of c.1853G > A, p. (Gly618Glu) and exhibited recurrent rhabdomyolysis with viral or bacterial infections. Moreover, he developed obstructive hypertrophic cardiomyopathy which required surgical intervention. Skeletal muscle biopsy revealed findings compatible with fiber-type disproportion. Ultrastructural study demonstrated the similar findings previously reported in mice with Col4a1 mutation including collagen disarray and reduction of electron density in the basement membrane of capillary endothelial cells and muscle fibers. Dilated endoplasmic reticulum in the capillary endothelial cells is also noted. This report adds another disease spectrum of COL4A1 mutation which include porencephaly, hypertrophic cardiomyopathy, rhabdomyolysis and fiber-type disproportion.

Assessment of Potential Renal Dysfunction in Patients with Congenital Heart Disease after Biventricular Repair.

BACKGROUND AND OBJECTIVES: There are few reports on renal dysfunction in the remote period after biventricular repair, and biomarkers for early detection of renal dysfunction are not well understood. We examined whether early fluctuation of biomarkers of renal function occurs in the remote period after biventricular repair in patients with congenital heart disease (CHD). METHODS: Fourteen patients with CHD after biventricular repair were included. The examination values obtained by cardiac catheterization test and renal function indices based on blood and urine sampling were compared. RESULTS: The median estimated glomerular filtration rate (eGFR) of creatinine was 113 mL/min/1.73 m², and the median eGFR of cystatin C was 117 mL/min/1.73 m². A urine albumin-to-creatinine ratio (UACR) ≥10 mg/gCr was considered a risk factor for cardiovascular disease in 6 (43%) patients. There was a significant difference in right ventricular ejection fraction and deviation in right ventricular end-diastolic volume from the normal value between the 2 groups divided by UACR. Cyanosis before biventricular repair was noted in 2 (25%) patients with UACR <10 mg/gCr and in 4 (67%) patients with UACR ≥10 mg/gCr. CONCLUSIONS: Increased UACR was noted in 43% of patients. In patients with UACR ≥10 mg/gCr, right heart system abnormality was observed, and several patients had cyanosis before radical treatment. Measurement for UACR may be able to detect renal dysfunction early in the postoperative remote period.

Pulmonary Hemodynamic Changes with Nitric Oxide or Oxygen in a Patient with Asplenia, Single Right Ventricle, and Total Anomalous Pulmonary Venous Connection after Fontan Procedure.

Asplenia syndrome is frequently complicated by a total anomalous pulmonary venous connection. Pulmonary venous obstruction, following total anomalous pulmonary venous connection surgery, is one of the risk factors for morbidity and mortality. In some patients, the pulmonary vasculature is abnormal even in the absence of clinical evidence of pulmonary venous obstruction. We hypothesized that a change in the pulmonary hemodynamics could indicate the abnormality of pulmonary vein in a patient with asplenia, single right ventricle, and total anomalous pulmonary venous connection, following Fontan procedure. Here, we present a case of asplenia, single right ventricle, total anomalous pulmonary venous connection, and right pulmonary venous obstruction in which evidence of a potential left pulmonary venous obstruction was obtained following the administration of inhaled nitric oxide and oxygen.

A Marked Response to Immunosuppressive Intervention for Abruptly Occurring Cardiac Complications in a Case of Juvenile Systemic Sclerosis Overlapped with Dermatomyositis.

Juvenile-onset systemic sclerosis (jSSc) is a rare condition, having unique characteristic features compared to adult-onset SSc. Although cardiac involvement (CI) is known as a leading cause of mortality overall in SSc, the importance of CI in jSSc has not been emphasized. Here we present a 13-year-old female with jSSc overlapped with dermatomyositis (DM) complicated CI. She developed skin thickness and induration, Raynaud's phenomenon, digital pitting scars in fingertips, and skeletal myositis. Oral prednisolone and pulse methotrexate treatment led to the improvement of skin findings; however two weeks after the initiation she suddenly presented with muscle pain and dyspnea within a few days. Cardiac investigations then showed pericardiac effusion and diastolic dysfunction due to significant biventricular hypertrophy causing heart failure. As pericardiac effusion and exacerbation of skeletal myositis were evident, steroid pulse therapy was initiated. Unexpectedly, not only the myositis but also the CI including diastolic dysfunction was improved. She thereafter followed a favorable clinical course without reactivation of the CI or cardiac fibrosis. As a conclusion, close attention to CI must be paid in jSSc patients, especially when skeletal muscle involvement is evident and immunosuppressive therapy may be effective for CI in jSSc in cases where it occurs abruptly.

Non-invasive assessment of liver fibrosis by magnetic resonance elastography in patients with congenital heart disease undergoing the Fontan procedure and intracardiac repair.

BACKGROUND: The incidence of late liver complications such as fibrosis or cirrhosis has increased among patients who have undergone the Fontan procedure. Magnetic resonance elastography (MRE) recently emerged as a technique to clinically evaluate liver fibrosis. However, few reports have described its use in evaluating liver fibrosis in children with congenital heart disease (CHD). METHODS AND RESULTS: Fifty-seven children were examined and divided into four groups: 27 with CHD who underwent intracardiac repair (ICR); 16 with CHD who underwent the Fontan procedure (Fontan); 14 in a control group (control); and two with cirrhosis (cirrhosis). Liver stiffness (LS) was measured using MRE. Other assessments included central venous pressure (CVP) as determined by cardiac catheterization. Circulating biomarker levels were also determined. There were no significant differences in biomarker levels among the groups. However, the LS degree was significantly higher in the Fontan group than in the control group. On stepwise multivariate analysis, only the CVP level was a statistically significant independent predictor of LS. There was also a strong correlation between LS and CVP and between LS and time interval since Fontan surgery. CONCLUSIONS: This study clearly demonstrated that LS was significantly increased after the Fontan procedure and that CVP was a predictor of LS. MRE is a highly sensitive tool that can evaluate liver fibrosis in children who undergo the Fontan procedure and enable earlier detection of LS than biomarkers.

Effectiveness of High-dose Spironolactone Therapy in a Patient with Recurrent Protein-losing Enteropathy after the Fontan Procedure.

Protein-losing enteropathy (PLE) is a rare and life-threatening complication that occurs after the Fontan procedure. We herein report the case of an 11-year-old Japanese boy who developed PLE six times after undergoing the Fontan procedure. High-dose spironolactone therapy has been effective for 2 years. His high level of serum aldosterone decreased to a nearly normal range and spironolactone may have a diuretic and anti-inflammatory potential.

Pharmacokinetics of drugs for pediatric pulmonary hypertension.

BACKGROUND: Over the past few years, several drugs, each with a different mechanism, have been developed for the treatment of pulmonary hypertension (PH) and are now prescribed in the clinical setting. While the optimal doses of these drugs in adults have been determined, the optimal dose in children, however, is unclear. The aim of this study was therefore, to measure blood drug levels and analyze the pharmacokinetics of two such drugs in children. METHODS: From April 2010 to May 2015, we prospectively enrolled 23 children with PH for treatment with bosentan and/or tadalafil. Twenty children were treated with bosentan and 19 received tadalafil. Sixteen children were given both drugs. Blood samples were collected after 2 weeks of treatment, and blood drug levels measured using high-performance liquid chromatography. RESULTS: For both drugs, the peak plasma concentration was lower and the half-life was shorter than the known values in adults. The blood trough level of bosentan significantly correlated with its dose, but no such correlation was seen for tadalafil. For both drugs, no correlation was observed between age and blood drug levels. CONCLUSIONS: Oral dosing with bosentan and tadalafil in children may not achieve therapeutic blood concentration. Thus, the optimal dosing must be established individually while monitoring blood drug level.

Ratio between fms-like tyrosine kinase 1 and placental growth factor in children with congenital heart disease.

Serum levels of soluble fms-like tyrosine kinase 1 (sFlt-1), an antiangiogenic factor, and its binding protein, placental growth factor (PlGF), are altered in women with preeclampsia. Recently, the sFlt-1/PlGF ratio has been shown to predict acute coronary syndrome in adults. However, few reports have described the use of the sFlt-1/PlGF ratio for evaluating an abnormal hemodynamic load in children with congenital heart disease (CHD). The sFlt-1/PlGF ratio was determined in 20 children with atrial septal defects (ASD), 26 children with ventricular septal defects (VSD), 57 children with tetralogy of Fallot (ToF), 35 children who were Fontan candidates (Fontan), and 14 controls. The preoperative sFlt-1/PlGF ratios in the ASD, VSD, and Fontan were significantly higher than those in the controls and were significantly decreased after surgical repair in the ASD and VSD. In the ToF, the sFlt-1/PlGF ratio was highest after first-stage repair and second-highest after final-stage palliation compared with the preoperative levels. The sFlt-1/PlGF ratio was highest after first-stage repair and much lower after final-stage palliation in the Fontan. Furthermore, these ratios correlated with the degree of the ventricular volume overload and hypoxia. Our study clearly demonstrated that the sFlt-1/PlGF ratio increases with volume overload and persistent hypoxia after surgery with CHD. These findings may prove useful in the management of CHD in children.

Assessment of pulmonary arterial pressure by velocity-encoded cine magnetic resonance imaging in children with congenital heart disease.

BACKGROUND: Velocity-encoded cine magnetic resonance imaging (VEC-MRI) has recently been reported as effective for assessing not only pulmonary blood flow (Qp) but also pulmonary arterial pressure (PAP) in adults. However, there have been few reports on the usefulness of VEC-MRI for assessing PAP in children with congenital heart disease (CHD). METHODS AND RESULTS: We evaluated 34 children with CHD. Qp and systemic blood flows (Qs) were determined by cardiac catheterization and VEC-MRI. The right-to-left Qp ratio (R/L) was measured by pulmonary perfusion scintigraphy and VEC-MRI. The pulmonary-to-systemic blood pressure ratio (Pp/Ps) was determined by cardiac catheterization. The acceleration time (AcT), ejection time (ET), peak velocity (PV), acceleration volume (AcV), and maximal change in flow rate during ejection (MCFR) in the pulmonary arteries, which were standardized by body surface area, were determined by VEC-MRI. The children were divided into 2 groups according to Pp/Ps. The Qs, R/L ratio and Qp/Qs obtained by VEC-MRI strongly correlated with those obtained by catheterization and scintigraphy. No significant differences in AcT, ET, AcT/ET, PV, or AcV were observed between the 2 groups. However, a significant difference was observed in MCFR. Furthermore, a significant correlation was observed between the MCFR and Pp/Ps. CONCLUSIONS: This study clearly demonstrated that VEC-MRI is useful for assessing not only blood flow, but also PAP, by referring to MCFR in children.

Volume overload and pressure overload due to left-to-right shunt-induced myocardial injury. - Evaluation using a highly sensitive cardiac Troponin-I assay in children with congenital heart disease-.

BACKGROUND: Cardiac troponin I (cTnI) is currently considered to be the most sensitive and specific biochemical marker of acute coronary syndrome and acute myocardial infarction. However, few reports have described the use of cTnI assays for evaluating abnormal hemodynamic load in children with congenital heart disease (CHD). It was hypothesized that significant hemodynamic overload due to a left-to-right shunt induces myocardial injury. METHODS AND RESULTS: A highly sensitive cTnI assay was used to measure the serum cTnI levels in 30 children with atrial septal defect (ASD), 32 children with ventricular septal defect (VSD), and 350 healthy children. Cardiac catheterization was performed in the children with ASD and VSD to determine the ratio of pulmonary to systemic blood flow, the ratio of pulmonary to systemic arterial pressure (Pp/Ps), the pulmonary vascular resistance index, and the right and left ventricular end-diastolic volume. Serum cTnI levels in both the ASD and VSD children were significantly higher than those in healthy children (P<0.05 and P<0.01, respectively). Furthermore, serum cTnI levels significantly correlated with Pp/Ps (r=0.745, P<0.001) in VSD children. CONCLUSIONS: Significant volume and pressure overload due to a left-to-right shunt induce myocardial injury and might eventually cause irreversible myocardial remodeling in children with CHD. The serum cTnI level is a useful biomarker for evaluating myocardial damage associated with pulmonary hypertension in VSD children.

Molecular analysis and anticonvulsant therapy in two patients with glucose transporter 1 deficiency syndrome: a successful use of zonisamide for controlling the seizures.

Glucose transporter 1 (GLUT1) deficiency syndrome is caused by a deficit in glucose transport to the brain during the pre- and postnatal periods. Here, we report two cases of GLUT1 deficiency syndrome diagnosed on the basis of clinical features, reduced GLUT1 activities, and mutations in the GLUT1 gene. Patient 1 had a novel heterozygous 1bp insertion in exon 7 that resulted in a shift of the reading frame and the introduction of a premature stop codon at amino acid position 380. His clinical phenotype appeared to be more severe than that of Patient 2 who had a missense mutation in exon 8 resulting in an arginine-to-tryptophan substitution at amino acid position 333. Patient 1 had no meaningful words and could not walk unassisted, while Patient 2 could speak and walk unassisted. Both the patients developed seizures of various types that have been successfully treated with zonisamide. Although several antiepileptic drugs, including barbiturates, diazepam, chloralhydrate, and valproic acid, have been shown to inhibit GLUT1 function, the present study demonstrated no inhibitory effect of zonisamide on GLUT1-mediated glucose transport. Our data suggested that zonisamide might be preferable if add-on anticonvulsant therapy is required to control the seizures in patients with this disorder.