Biallelic variants in ribonuclease inhibitor (RNH1), an inflammasome modulator, are associated with a distinctive subtype of acute, necrotizing encephalopathy.

PURPOSE: Mendelian etiologies for acute encephalopathies in previously healthy children are poorly understood, with the exception of RAN binding protein 2 (RANBP2)-associated acute necrotizing encephalopathy subtype 1 (ANE1). We provide clinical, genetic, and neuroradiological evidence that biallelic variants in ribonuclease inhibitor (RNH1) confer susceptibility to a distinctive ANE subtype. METHODS: This study aimed to evaluate clinical data, neuroradiological studies, genomic sequencing, and protein immunoblotting results in 8 children from 4 families who experienced acute febrile encephalopathy. RESULTS: All 8 healthy children became acutely encephalopathic during a viral/febrile illness and received a variety of immune modulation treatments. Long-term outcomes varied from death to severe neurologic deficits to normal outcomes. The neuroradiological findings overlapped with ANE but had distinguishing features. All affected children had biallelic predicted damaging variants in RNH1: a subset that was studied had undetectable RNH1 protein. Incomplete penetrance of the RNH1 variants was evident in 1 family. CONCLUSION: Biallelic variants in RNH1 confer susceptibility to a subtype of ANE (ANE2) in previously healthy children. Intensive immunological treatments may alter outcomes. Genomic sequencing in children with unexplained acute febrile encephalopathy can detect underlying genetic etiologies, such as RNH1, and improve outcomes in the probands and at-risk siblings.

Identifying Genetic Susceptibility in Neonates With Hypoxic-Ischemic Encephalopathy: A Retrospective Case Series.

Neonatal hypoxic-ischemic encephalopathy is a clinical phenomenon that often results from perinatal asphyxia. To mitigate secondary neurologic injury, prompt initial assessment and diagnosis is needed to identify patients eligible for therapeutic hypothermia. However, occasionally neonates present with a clinical picture of hypoxic-ischemic encephalopathy without significant risk factors for perinatal asphyxia. We hypothesized that in patients with genetic abnormalities, the clinical manifestation of those abnormalities may overlap with hypoxic-ischemic encephalopathy criteria, potentially contributing to a causal misattribution. We reviewed 210 charts of infants meeting local protocol criteria for moderate to severe hypoxic-ischemic encephalopathy in neonatal intensive care units in Calgary, Alberta. All patients that met criteria for therapeutic hypothermia were eligible for the study. Data were collected surrounding pregnancy and birth histories, as well as any available genetic or metabolic testing including microarray, gene panels, whole-exome sequencing, and newborn metabolic screens. Twenty-eight patients had genetic testing such as microarray, whole-exome sequencing, or a gene panel, because of clinical suspicion. Ten of 28 patients had genetic mutations, including CDKL5, pyruvate dehydrogenase, CFTR, CYP21A2, ISY1, KIF1A, KCNQ2, SCN9A, MTFMT, and NPHP1. All patients lacked significant risk factors to support a moderate to severe hypoxic-ischemic encephalopathy diagnosis. Treatment was changed in 2 patients because of confirmed genetic etiology. This study demonstrates the importance of identifying genetic comorbidities as potential contributors to a hypoxic-ischemic encephalopathy phenotype in neonates. Early identification of clinical factors that support an alternate diagnosis should be considered when the patient's clinical picture is not typical of hypoxic-ischemic encephalopathy and could aid in both treatment decisions and outcome prognostication.

Pearls & Oy-sters: Cerebral Abscess Secondary to Pulmonary Arteriovenous Malformation in Hereditary Hemorrhagic Telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant condition that is linked to a myriad of neurologic complications arising from vascular malformations of the brain, spinal cord, and lungs. Our case describes a previously healthy 3-year-old male who presented to hospital with fever of unknown origin and was found to have a brain abscess stemming from a pulmonary arteriovenous malformation (PAVM). This etiology was identified after a period of diagnostic delay; the medical team was suspicious for a proximal embolic source due to the presence of multiple tiny infarcts seen on MRI of the brain, but transthoracic echocardiogram and head and neck angiogram were unremarkable. Fortunately, an enhanced CT of the chest was performed, identifying a moderately sized PAVM. PAVMs are associated with intracranial abscesses due to shunting and loss of the normal filtering effects of the lung capillary bed. Impaired pulmonary filtration can permit paradoxical thromboemboli and septic microemboli to enter systemic circulation, predisposing patients with PAVMs to cerebral abscess and ischemic stroke. Screening for PAVMs with contrast-enhanced echocardiogram or enhanced CT of the chest may be considered in patients with cryptogenic brain abscess or recurrent embolic stroke of unknown origin. PAVMs are often associated with hereditary hemorrhagic telangiectasia (HHT). As many features of HHT have delayed clinical manifestation, genetic testing for HHT should be considered in all people with PAVM, even in the absence of other clinical features. In our case, genetic testing returned positive, confirming a new diagnosis of HHT type 1.

Antenatal diagnosis of fetal intraventricular hemorrhage: systematic review and meta-analysis.

AIM: To determine how the severity of antenatally diagnosed germinal matrix-intraventricular hemorrhage (GMH-IVH) relates to morbidity and mortality, and to explore potential risk factors. METHOD: We conducted a systematic review and individual patient data meta-analysis of antenatally diagnosed fetal GMH-IVH. The primary outcomes were mortality and morbidity. Potential associations with clinical factors during pregnancy were explored. Analysis employed Fisher's exact test and logistic regression. RESULTS: We included 240 cases from 80 studies. Presence of venous infarction was associated with mortality (odds ratio [OR] 4.3, 95% confidence interval [CI] 1.4-13.25), motor impairment (OR 103.2, 95% CI 8.6-1238), epilepsy (OR 6.46, 95% CI 2.64-16.06), and developmental delay (OR 8.55, 95% CI 2.12-48.79). Shunt placement was associated with gestational age at GMH-IVH diagnosis and in utero progression. Many cases had uncomplicated pregnancies but possible co-occurring conditions included twin gestation, small for gestational age, and congenital anomalies. INTERPRETATION: Severity of fetal GMH-IVH, specifically venous infarction, is associated with overall mortality and morbidity. Risk factors for fetal GMH-IVH are poorly understood and controlled studies are required. WHAT THIS PAPER ADDS: Preterm germinal matrix-intraventricular hemorrhage (GMH-IVH) grading can be applied to fetuses. Many fetal germinal matrix hemorrhages occur in otherwise typical pregnancies. Half of fetuses with post-hemorrhagic ventricular dilatation receive a shunt after delivery. Fetuses with grade I or II GMH-IVH have few sequelae. Fetuses with periventricular hemorrhagic infarction have a high burden of motor impairment.

Neuroinflammation and Precision Medicine in Pediatric Neurocritical Care: Multi-Modal Monitoring of Immunometabolic Dysfunction.

The understanding of molecular biology in neurocritical care (NCC) is expanding rapidly and recognizing the important contribution of neuroinflammation, specifically changes in immunometabolism, towards pathological disease processes encountered across all illnesses in the NCC. Additionally, the importance of individualized inflammatory responses has been emphasized, acknowledging that not all individuals have the same mechanisms contributing towards their presentation. By understanding cellular processes that drive disease, we can make better personalized therapy decisions to improve patient outcomes. While the understanding of these cellular processes is evolving, the ability to measure such cellular responses at bedside to make acute care decisions is lacking. In this overview, we review cellular mechanisms involved in pathological neuroinflammation with a focus on immunometabolic dysfunction and review non-invasive bedside tools that have the potential to measure indirect and direct markers of shifts in cellular metabolism related to neuroinflammation. These tools include near-infrared spectroscopy, transcranial doppler, elastography, electroencephalography, magnetic resonance imaging and spectroscopy, and cytokine analysis. Additionally, we review the importance of genetic testing in providing information about unique metabolic profiles to guide individualized interpretation of bedside data. Together in tandem, these modalities have the potential to provide real time information and guide more informed treatment decisions.

Isolated convergence-retraction nystagmus secondary to intralesional haemorrhage of a pineal cyst: an easily missed neurological finding with potentially life-threatening consequences.

This case report describes a patient who presented to the emergency department with intermittent visual disturbance and was found to have convergence-retraction nystagmus. This occurred in the setting of supratherapeutic anticoagulation on warfarin for an aortic dissection graft repair. Urgent imaging demonstrated haemorrhagic transformation of a previously identified incidental pineal cyst. After close monitoring given the risk of secondary hydrocephalus, the patient was discharged in stable condition with symptom resolution and without any further significant complications. This case report highlights the importance of identifying subtle clinical findings and the risk of secondary haemorrhage of pineal cysts when on anticoagulation. While the risk of secondary hydrocephalus is a significant concern, clinically stable patients can be followed without need for neurosurgical intervention.

Recent seizure activity alters motor organization in frontal lobe epilepsy as revealed by task-based fMRI.

PURPOSE: Patients with frontal lobe epilepsy (FLE) commonly demonstrate motor impairments, suggesting that frontal lobe seizures affect motor function. However, the underlying mechanisms of these deficits are not known, nor has any study systematically examined motor organization in these patients. We therefore examined cortical motor organization in a group of adult patients with FLE, using task-based fMRI. METHODS: Eleven right FLE patients, six left FLE patients, and ten control subjects underwent task-based fMRI. Two tasks were performed using the right and left hands separately, and both hands together. The first task was a finger-tapping task and the second task was a more complex coordination task. Functional MR data were compared between patient groups and controls. A laterality index of brain activation was also calculated between the epileptic and healthy hemisphere to determine hemispheric dominance during task performance to explore its relationship with a variety of patient-specific epilepsy factors. RESULTS: Overall, right FLE patients demonstrated decreased BOLD activity in the epileptic hemisphere and increased BOLD activity in the healthy hemisphere compared to controls (p<0.05). The comparison of left FLE patients to controls provided less conclusive differences, possibly due to the low number of left FLE patients studied. Laterality indices of the coordination task were positively correlated to the number of months since the last seizure in both patient groups (right FLE: rs=0.779, left FLE: rs=0.943). Patients that had experienced a recent seizure relied more on the sensorimotor cortex of the healthy hemisphere during task performance, compared to those that were relatively seizure free (p<0.05). SIGNIFICANCE: Patients with FLE exhibited changes in motor BOLD activity that was dependent on the duration of seizure freedom. These results demonstrate the presence of seizure-related alteration of cortical motor organization in FLE, which may underlie the motor deficits seen in these patients.

Frontal lobe epilepsy alters functional connections within the brain's motor network: a resting-state fMRI study.

Patients with frontal lobe epilepsy (FLE) often experience motor deficits, yet little is known of the impact of FLE on the activity of motor networks in the brain. Resting-state functional magnetic resonance imaging (rs-fMRI) has previously demonstrated an association between cognitive deficits in temporal lobe epilepsy patients and disruption of activity within pertinent brain networks. Hence, in the present study, rs-fMRI was used to determine whether FLE is associated with motor network disruption. Seven right-hemisphere FLE patients, six left-hemisphere FLE patients, and nine control subjects underwent rs-fMRI. Functional connectivity was computed between the sensorimotor cortex contralateral to the seizure focus and each voxel in the brain, and then compared voxel-by-voxel between patient groups and controls. A laterality index (LI) of connectivity between contralateral and ipsilateral sensorimotor cortices was calculated to investigate its association with epilepsy duration and seizure frequency. Positive laterality indices indicate reduced connectivity, and zero values indicate strong connectivity. Connectivity between the left and right sensorimotor cortices was significantly reduced in FLE patients compared with controls (p<0.05), and LI was positively correlated with the number of lifetime seizures (left FLE: rs=0.89, right FLE: rs=1.00). Patients with FLE exhibit decreased connectivity within the motor network, in correlation with the number of lifetime seizures, thus demonstrating a potential relationship between seizure activity and changes in motor network organization. These findings suggest that motor network disturbances may in part be responsible for the motor deficits observed in FLE patients.