Long-Term Effects of Biliverdin Reductase a Deficiency in Ugt1−/− Mice: Impact on Redox Status and Metabolism

Accumulation of neurotoxic bilirubin due to a transient neonatal or persistent inherited deficiency of bilirubin glucuronidation activity can cause irreversible brain damage and death. Strategies to inhibit bilirubin production and prevent neurotoxicity in neonatal and adult settings seem promising. We evaluated the impact of Bvra deficiency in neonatal and aged mice, in a background of unconjugated hyperbilirubinemia, by abolishing bilirubin production. We also investigated the disposal of biliverdin during fetal development. In Ugt1−/− mice, Bvra deficiency appeared sufficient to prevent lethality and to normalize bilirubin level in adults. Although biliverdin accumulated in Bvra-deficient fetuses, both Bvra−/− and Bvra−/−Ugt1−/− pups were healthy and reached adulthood having normal liver, brain, and spleen histology, albeit with increased iron levels in the latter. During aging, both Bvra−/− and Bvra−/−Ugt1−/− mice presented normal levels of relevant hematological and metabolic parameters. Interestingly, the oxidative status in erythrocytes from 9-months-old Bvra−/− and Bvra−/−Ugt1−/− mice was significantly reduced. In addition, triglycerides levels in these 9-months-old Bvra−/− mice were significantly higher than WT controls, while Bvra−/−Ugt1−/− tested normal. The normal parameters observed in Bvra−/−Ugt1−/− mice fed chow diet indicate that Bvra inhibition to treat unconjugated hyperbilirubinemia seems safe and effective.

Clinical application of non-invasive prenatal diagnosis of phenylketonuria based on haplotypes via paired-end molecular tags and weighting algorithm

Background Phenylketonuria (PKU) is a metabolic disease that can cause severe and irreversible brain damage without treatment. Methods Here we developed a non-invasive prenatal diagnosis (NIPD) technique based on haplotypes via paired-end molecular tags and weighting algorithm and applied it to the NIPD of PKU to evaluate its accuracy and feasibility in the early pregnancy. A custom-designed hybridization probes containing regions in phenylalanine hydroxylase (PAH) gene and its 1 Mb flanking region were used for target sequencing on genomic and maternal plasma DNA (7–13 weeks of gestation) to construct the parental haplotypes and the proband’s haplotype. Fetal haplotype was then inferred combined with the parental haplotypes and the proband’s haplotype. The presence of haplotypes linked to both the maternal and paternal mutant alleles indicated affected fetuses. The fetal genotypes were further validated by invasive prenatal diagnosis in a blinded fashion. Results This technique has been successfully applied in twenty-one cases. Six fetuses were diagnosed as patients carrying both of the mutated haplotypes inherited from their parents. Eleven fetuses were carriers of one heterozygous PAH variants, six of which were paternal and five of which were maternal. Four fetuses were absence of pathogenic alleles. All results were consistent with the prenatal diagnosis through amniotic fluid. Conclusions The results showed that our new technique applied to the genotyping of fetuses with high risk for PKU achieves an accurate detection at an early stage of pregnancy with low fetal fraction in cell free DNA.

A Case Report of a Patient with Mild Cognitive Impairment Treated with Gugijihwang-tang

Objective: Alzheimer's disease is characterized by progressive, irreversible brain damage and cognitive decline. Although the diagnosis and treatment of the prodromal symptoms of dementia are important, no treatment for mild cognitive impairment has been currently established. Herein, we report the case of an 80-year-old female patient with memory complaints treated with Gugijihwang-tang, a traditional Korean medicine herbal formula, as an add-on medication.Case Presentation: The patient was diagnosed with mild cognitive impairment based on clinical examinations using the Mini-Mental State Examination (MMSE), the Consortium to Establish a Registry for Alzheimer's Disease (CERAD), Activities of Daily Living (ADL) Scale, Global Deterioration (GDR) Scale, and Clinical Dementia Rating (CDR) Scale. She was treated with Gugijihwang-tang bis in die for 12 months while continuing her original medications, including 5-mg donepezil and 590-mg acetyl-l-carnitine. The MMSE score in the Korean Version of the CERAD Assessment Packet increased from 21 to 27 during the 12-month treatment period, and the CERAD 2 score increased from 33 to 62. The instrumental ADL scale score improved from 11 to 5. Other clinical examination results also showed improvement. The patient was satisfied and experienced no significant adverse events related to the Gugijihwang-tang treatment.Conclusion: This case suggests that Gugijihwang-tang could be considered as a treatment method for patients with mild cognitive impairment.

Seronegative limbic encephalitis manifesting as subacute amnestic syndrome: a case report and review of the literature

Background Limbic encephalitis (LE), a variant of autoimmune encephalitis, is inflammation of the limbic system of the brain. The disorder presents with subacute impairment of short-term memory, psychiatric manifestations, confusion and seizures. “Seronegative LE” is a challenging diagnosis in the absence of well-characterized autoantibodies. Case presentation A 33-year-old Kuwaiti woman with no relevant past history presented with subacute progressive amnesia of 6-month duration. Magnetic resonance imaging (MRI) showed bilateral hyperintensity of the limbic structures. An extensive workup of the blood and cerebrospinal fluid (CSF) failed to identify paraneoplastic or autoimmune antibodies. The diagnosis of seronegative LE was made, and immunotherapy was initiated, with improvement in cognitive function. Conclusion Seronegative LE is a challenging diagnosis. Inability to detect autoantibodies, especially early in the disease course, should not rule out the diagnosis of autoimmune encephalitis. Early diagnosis and treatment with immunotherapy may prevent irreversible brain damage.

Focal congenital hyperinsulinism resulting from biallelic loss of function of KCNJ11 gene

Congenital hyperinsulinism (CHI) characterised by inappropriate secretion of insulin despite low blood glucose can result in irreversible brain damage if not promptly treated. The most common genetic cause of hyperinsulinism is the pathogenic variants in ABCC8 and KCNJ11, causing dysregulated insulin secretion. Rapid testing is crucial for all patients because finding a mutation significantly impacts this condition’s clinical management. We report a rare case of focal CHI after a homozygous KCNJ11 mutation who underwent a selective lesionectomy and required octreotide for euglycaemia.

Possible Role of High-Dose Barbiturates and Early Administration of Parenteral Ketogenic Diet for Reducing Development of Chronic Epilepsy in Febrile Infection-Related Epilepsy Syndrome: A Case Report

We describe the efficacy of high-dose barbiturates and early administration of a parenteral ketogenic diet (KD) as initial treatments for acute status epilepticus (SE) in an 8-year-old girl with febrile infection-related epilepsy syndrome (FIRES). The patient was admitted to our hospital with refractory focal SE. Abundant epileptic discharges over the left frontal region were observed on electroencephalogram (EEG). Treatment with continuous infusion of thiamylal for 4 hours, increased incrementally to 40 mg/kg/h, successfully ended the clinical SE, and induced a burst-suppression coma. The infusion rate was then gradually decreased to 4 mg/kg/h over the next 12 hours. Parenteral KD was administered from days 6 to 21 of illness. Continuous infusion of thiamylal was switched to midazolam on day 10 without causing seizures or EEG exacerbations. The patient has remained seizure free in the 15 months since hospital discharge. The effectiveness of KD for the treatment of FIRES has attracted attention amongst clinicians, but KD treatment may need to last for 2 to 4 days before it can stop SE, a time period that could cause irreversible brain damage. Considering the severity of SE in our patient and the dose of barbiturates needed to treat it, we consider this case to have had a good clinical outcome. The results suggest that rapid termination of seizure using high-dose barbiturates in conjunction with early administration of parenteral KD could reduce the development of chronic epilepsy in patients with FIRES.

White Cerebellum Sign: case series and literature review

Introduction: The white cerebellum sign is a rare radiological finding, seen in severe traumatic brain injury and severe hypoxia. Radiologically, it is characterized by cerebellar hyperdensity, associated with diffuse cerebral hemispheres hypoattenuation. This paper aims to guide the white cerebellum sign diagnosis in traumatic craniocerebral injuries or not in pediatric patients. Patients and Methods: The authors present a series of five cases that showed the white cerebellum sign from the period about 2007 and 2010, associated with a literature review. Results: The white cerebellum sign was present in 5 patients, three of them were male and 2 female. The mean age was 22 months. The causes of which were: traumatic brain injury (3), drowning (1) and metabolic encephalopathy (1). The skull computerized tomography scan was performed in all cases. All patients were submitted to conservative treatment. There were four deaths and one survived with severe neurological sequelae. Conclusion: The white cerebellum sign is associated with irreversible brain damage, and its pathophysiology is controversial. The imaging tests are important to diagnosis. It has a poor prognosis, associated with the development of diffuse cerebral atrophy or cystic encephalomalacia in those who survive.

How should we use imaging in the determination of brainstem death?

Brainstem death is defined as the “irreversible cessation of brainstem function”, either due to primary intracranial events or extracranial factors such as hypoxia. The importance of accurate and timely diagnosis of brainstem death in critical care should not be understated, as it allows the withdrawal of treatment when it is no longer deemed to beneficial. Additionally, it may facilitate the process of organ donation. Overall, the diagnosis of brainstem death has four common principles across the world: (1) neurological criteria based on clinical assessment; (2) evidence of irreversible brain damage from known aetiology; (3) demonstrating an absence of a reversible cause; and (4) the use of ancillary studies. The latter in particular has been a controversial issue, with much debate continuing on how imaging should be used. We discuss three key questions surrounding the role of imaging in the diagnosis of brainstem death as well as important issues the radiology community should consider.