ABSTRACT
BACKGROUND: Pediatric patients with acute lymphoblastic leukemia (ALL) are at highest risk of venous thromboembolism during the induction therapy (IT). These events are not predictable by conventional coagulation assays. OBJECTIVES: To investigate the utility of global coagulation assays (GCAs) for assessing the hemostatic state in children with ALL during IT. METHODS: We included children with ALL (n = 15) and healthy controls (n = 15). Analyses were performed at different time points during IT of the AIEOP-BFM protocols. In addition to prothrombotic biomarkers, natural anticoagulant proteins, and in vivo thrombin generation (TG) markers, ex vivo TG was measured using the gold standard calibrated automated thrombogram method, automated ST Genesia, and thrombodynamics analyzer (TD). The latter also provided measurement of fibrin clot formation. RESULTS: Different from conventional coagulation assays and in vivo TG markers, ex vivo GCAs detected increasing prothrombotic changes during IT. Particularly, TG measured with TD as expressed by endogenous thrombin potential was already significantly elevated at days 8 to 12 (P < .01) and continued to increase during IT compared with prior to beginning treatment, indicating a very early shift toward a procoagulant state. A similar pattern was observed for the rate of fibrin clot formation (stationary rate of clot growth: P < .01 at days 8-12). Remarkably, in patients developing thrombotic complications (n = 5), both GCAs, ST Genesia and TD, showed a significantly higher endogenous thrombin potential very early (already at days 8-12, P < .05), well before clinical manifestation. CONCLUSION: GCAs capture prothrombotic changes early during IT in ALL pediatric patients. If confirmed, this approach will allow tailoring thromboprophylaxis in children with ALL at highest risk for venous thromboembolism.
Subject(s)
Blood Coagulation , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Thrombin , Venous Thromboembolism , Humans , Child , Precursor Cell Lymphoblastic Leukemia-Lymphoma/blood , Precursor Cell Lymphoblastic Leukemia-Lymphoma/complications , Blood Coagulation Tests , Female , Male , Thrombin/metabolism , Child, Preschool , Case-Control Studies , Adolescent , Venous Thromboembolism/blood , Venous Thromboembolism/etiology , Venous Thromboembolism/diagnosis , Time Factors , Predictive Value of Tests , Risk Factors , Biomarkers/blood , Thrombosis/blood , Thrombosis/etiology , Thrombosis/diagnosisABSTRACT
In response to growing recognition that nonadherence prevents children, adolescents, and young adults from achieving the therapeutic benefits of anticoagulant medication, the International Society on Thrombosis and Haemostasis Scientific and Standardization Committee Subcommittee on Pediatric and Neonatal Thrombosis and Hemostasis convened a working party on medication adherence. The primary aim of this article was to synthesize recommendations from the larger adherence science literature to provide guidance regarding the classification, collection, and interpretation of anticoagulation adherence data. The secondary aim of this article was to evaluate the degree to which trials published from 2013 to 2023 adhered to these guidance recommendations. As less than half of all trials reported on adherence and none included all recommended elements, the proposed International Society on Thrombosis and Haemostasis Scientific and Standardization Committee guidance has the potential to enhance the rigor and reproducibility of pediatric anticoagulant research.
Subject(s)
Anticoagulants , Clinical Trials as Topic , Hemostasis , Medication Adherence , Thrombosis , Humans , Anticoagulants/therapeutic use , Anticoagulants/adverse effects , Child , Thrombosis/prevention & control , Thrombosis/drug therapy , Thrombosis/etiology , Adolescent , Infant, Newborn , Child, Preschool , Hemostasis/drug effects , Infant , Research Design/standards , Age Factors , Guideline AdherenceABSTRACT
The term Hoigné's syndrome denotes a mimicker of anaphylaxis, which occurs immediately after the parenteral administration of a drug and is likely caused by non-thrombotic pulmonary and systemic drug micro-embolization. It has so far been documented uniquely in case reports and small case series. Because this condition has never been systematically evaluated, we performed a structured literature review (pre-registered as CRD42023392962). The search was carried out in Excerpta Medica, National Library of Medicine, and Google Scholar. Cases with features consistent with anaphylaxis, urticaria, angioedema, asthma, syncope, anxiety, or panic attack triggered by needle phobia, and local anesthetic systemic toxicity were excluded. For the final analysis, we retained reports published between 1951 and 2021, which presented 247 patients with Hoigné's syndrome: 37 children and 211 adults with a male: female ratio of 2.1 : 1.0. The patients presented within 1 min after parenteral administration of a drug (intramuscular penicillin in 90 % of the cases) with chest discomfort, shortness of breath, fear of death, psychomotor agitation, and auditory or visual hallucinations and impairment. Recovery occurred within 30 min. The diagnosis of Hoigné's syndrome was also established in five patients 66-91 years of age with pre-existing cardiovascular or pulmonary diseases, who suddenly died after the administration of penicillin despite not exhibiting the aforementioned symptoms. It was therefore speculated that pulmonary drug micro-embolization induced a lethal cardiovascular compromise in these individuals. Histologic investigations supporting this hypothesis were performed in only one case. The diagnosis of Hoigné's pulmonary drug micro-embolization was established also in five patients with pre-existing cardiovascular or pulmonary diseases, who suddenly died after the administration of penicillin despite not exhibiting the afore mentioned symptoms. Histologic investigations supporting this hypothesis were performed in only one case. In conclusion, Hoigné's syndrome is an uncommon non-immune-mediated reaction. This report seeks to promote broader awareness and knowledge regarding this alarming mimicker of anaphylaxis. Diagnosis relies solely on clinical evaluation.
Subject(s)
Anaphylaxis , Humans , Anaphylaxis/diagnosis , Anaphylaxis/etiology , Anaphylaxis/therapy , Diagnosis, Differential , Male , Female , Aged , Adult , Aged, 80 and over , Syndrome , Child , Penicillins/adverse effects , Drug Hypersensitivity/diagnosis , Drug Hypersensitivity/therapyABSTRACT
Finkelstein-Seidlmayer vasculitis, also called acute hemorrhagic edema of young children or infantile immunoglobulin A vasculitis, is habitually a benign skin-limited small vessel leukocytoclastic vasculitis that mainly affects infants 24 months or less of age. Since this disease is commonly triggered by an infection, an immune-mediated origin has been postulated. To better appreciate the possible underlying immune mechanism of this vasculitis, we addressed circulating autoimmune markers and vascular immune deposits in patients contained in the Acute Hemorrhagic Edema BIbliographic Database, which incorporates all original reports on Finkelstein-Seidlmayer vasculitis. A test for at least one circulating autoimmune marker or a vascular immune deposit was performed in 243 cases. Subunits of complement system C4 resulted pathologically reduced in 4.7% and C3 in 1.4%, rheumatoid factor was detected in 6.1%, and antinuclear antibodies in 1.9% of cases. Antineutrophil cytoplasmic antibodies were never demonstrated. Immunofluorescence studies were performed on 125 skin biopsy specimens and resulted positive for complement subunits in 46%, fibrinogen in 45%, immunoglobulin A in 25%, immunoglobulin M in 24%, immunoglobulin G in 13%, and immunoglobulin E in 4.2% of cases. Infants testing positive for vascular immunoglobulin A deposits did not present a higher prevalence of systemic involvement or recurrences, nor a longer disease duration. In conclusion, we detected a very low prevalence of circulating autoimmune marker positivity in Finkelstein-Seidlmayer patients. Available immunofluorescence data support the notion that immune factors play a relevant role in this vasculitis. Furthermore, vascular immunoglobulin A deposits seem not to play a crucial role in this disease.
Subject(s)
Vasculitis, Leukocytoclastic, Cutaneous , Vasculitis , Child , Infant , Humans , Child, Preschool , Vasculitis/diagnosis , Vasculitis, Leukocytoclastic, Cutaneous/diagnosis , Immunoglobulin A , Immunoglobulin G , Hemorrhage , EdemaABSTRACT
Caring for children and adolescents with disorders of hemostasis and thrombosis (HAT) has become more specialized and requires a unique skill set that many providers are not able to obtain in standard pediatric hematology/oncology/bone marrow transplant fellowship training programs. The influx of numerous therapeutic advances and increasing medical complexity has expanded the need for experienced HAT providers and subspecialty collaboration in the inpatient setting due to the nuances in the management of patients with HAT complications and concerns. While there are data highlighting the benefits of an inpatient hemostasis, thrombosis, and anticoagulation management service in adult hospitals, there are limited pediatric data supporting such programs. In this article, we summarize the current practices of various pediatric institutions in the inpatient management of HAT patients and provide a consensus opinion for the development of a pediatric inpatient HAT service at tertiary care referral centers.
Subject(s)
Inpatients , Thrombosis , Adolescent , Adult , Child , Communication , Consensus , Hemostasis , Hospitals, Pediatric , Humans , Infant, Newborn , Referral and Consultation , Thrombosis/diagnosis , Thrombosis/therapyABSTRACT
Clinically unsuspected venous thromboembolism (VTE) in children is defined as a VTE diagnosed via imaging test performed for surveillance (i.e., with an intent to identify clinically silent VTEs) or incidentally found (most often via imaging performed for evaluation of regional pathology unrelated to VTE) in the absence of any VTE-associated signs or symptoms. Our understanding of the clinical significance of these events in children is limited by a paucity of data on the epidemiology and outcomes of this complication. There is an urgent need for further research in this area to inform optimal management. Recognizing this knowledge gap, this Task Force has previously published a systematic review of the literature in this topic. We now provide guidance recommendations for standardization of definitions and identify future research needs on clinically unsuspected VTE in children. These recommendations will serve to enhance the quantity and quality of evidence on the topic and facilitate the design and execution of cooperative observational studies, and interventional trials of risk-stratified management approaches aimed at preventing and optimizing long-term outcomes of clinically unsuspected VTE in children.
Subject(s)
Thrombosis , Venous Thromboembolism , Anticoagulants/therapeutic use , Child , Communication , Hemostasis , Humans , Infant, Newborn , Thrombosis/complications , Venous Thromboembolism/diagnosis , Venous Thromboembolism/epidemiology , Venous Thromboembolism/etiologyABSTRACT
BACKGROUND: The ISTH Scientific and Standardization Committee (SSC) Subcommittee on Pediatric/Neonatal Thrombosis and Hemostasis convened a working group on medication adherence to begin to understand the current state of clinical practice to inform priority areas for efforts to improve adherence for children, and adolescents and young adults (AYA) prescribed anticoagulants. OBJECTIVES: We sought to survey an international group of clinicians involved in anticoagulation management in children and/or AYA about perceptions of medication on health outcomes, clinical practice related to medication adherence, and barriers to assessing and improving medication adherence. METHODS: Clinicians involved in anticoagulation management in children and/or AYA were surveyed via REDCap® . Descriptive statistics were used to summarize demographic and clinical characteristics and responses to multiple choice and Likert-type questions. Free-text answers were coded based on the Behaviour Change Technique Taxonomy and the Expert Recommendations for Implement Change project. RESULTS AND CONCLUSIONS: There were 200 participants, 90% of whom were pediatric hematology/oncology physicians. Based on the results, which demonstrate that clinicians are concerned about impact of poor medication adherence and have limited resources to identify and improve adherence, the working group has identified next steps to further understand impact of medication adherence on anticoagulation-related health outcomes, address the need for validated measures to assess medication adherence for all anticoagulants prescribed to this population, and develop an intervention and implementation research agenda to improve outcomes.
Subject(s)
Hemostasis , Thrombosis , Adolescent , Anticoagulants/adverse effects , Child , Communication , Humans , Infant, Newborn , Medication Adherence , Reference Standards , Thrombosis/drug therapy , Thrombosis/prevention & control , Young AdultABSTRACT
OBJECTIVE: To investigate treatment modalities for children with extremity indwelling catheter (EIC)- or cardiac catheter-related arterial thrombosis. STUDY DESIGN: The treatment of consecutive cases of catheter-related arterial thrombosis (CAT) at our institution between 2002 and 2017 was analyzed retrospectively. RESULTS: A total of 242 CATs developed in 224 children. Of these, 125 (52%) were EIC-related and 117 (48%) were cardiac catheter-related. Treatment included heparin alone in 60 cases (25%), acetylsalicyclic acid (ASA) alone in 6 cases (2%), heparin followed by ASA in 171 cases (71%), heparin followed by vitamin K antagonist (VKA) in 4 cases (1.5%), and VKA alone in 1 case (0.5%). Complete resolution of CAT was observed in 173 cases (71.5%), partial resolution in 13 cases (5.4%), and no resolution in 56 cases (23.1%). No statistical significance in the resolution rate was observed between treatment groups (P = .23). In 66% of cases, complete resolution occurred at a median of 18 days (range, 4-44 days) with heparin alone. A switch from heparin to ASA in children with partial or no resolution of CAT did not increase the resolution rate at follow-up. CONCLUSIONS: Heparin is an efficient treatment modality for CAT in pediatric patients. Long-term, subsequent treatment with ASA does not increase the resolution rate.
Subject(s)
Anticoagulants/therapeutic use , Cardiac Catheterization/adverse effects , Catheters, Indwelling/adverse effects , Femoral Artery , Fibrinolytic Agents/therapeutic use , Iliac Artery , Thrombosis/drug therapy , Adolescent , Aspirin/therapeutic use , Child , Child, Preschool , Drug Administration Schedule , Drug Therapy, Combination , Female , Follow-Up Studies , Heparin/therapeutic use , Humans , Infant , Infant, Newborn , Male , Retrospective Studies , Thrombosis/etiology , Treatment Outcome , Vitamin K/antagonists & inhibitorsABSTRACT
INTRODUCTION: Celiac disease typically presents with symptoms of malabsorption, but extraintestinal manifestations are increasingly reported. Aplastic anemia as the mode of celiac disease presentation is extremely rare in children. CASE PRESENTATION: We report a 2-year-old boy who presented with loose stools, loss of appetite, and bicytopenia with severe aregenerative normocytic anemia. Investigations, including bone marrow aspirate and biopsy, revealed aplastic anemia. Screening for malabsorption showed increased plasma concentrations of anti-transglutaminase and anti-gliadin antibodies. A duodenal biopsy confirmed the histologic features of celiac disease. The child received a packed red cell transfusion and was started on a gluten-free diet, with a very good prognosis and normalization of both his blood and histological parameters. To the best of our knowledge, our report is the sixth pediatric case in the literature. CONCLUSION: Screening for celiac disease should be performed in children with unexplained hematological abnormalities such as aplastic anemia with or without gastrointestinal symptoms.
ABSTRACT
Four individuals from two families presented with a multisystemic condition of suspected genetic origin that was diagnosed only after genome analysis. The main phenotypic features were immune system dysregulation (severe immunodeficiency with autoimmunity) and intellectual disability. The four individuals were found to be homozygous for a 4.4 Kb deletion removing exons 20-23 (NM_003291.4) of the TPP2 gene, predicting a frameshift with premature termination of the protein. The deletion was located on a shared chromosome 13 haplotype indicating a Swiss founder mutation. Tripeptidyl peptidase 2 (TPP2) is a protease involved in HLA/antigen complex processing and amino acid homeostasis. Biallelic variants in TPP2 have been described in 10 individuals with variable features including immune deficiency, autoimmune cytopenias, and intellectual disability or chronic sterile brain inflammation mimicking multiple sclerosis. Our observations further delineate this severe condition not yet included in the OMIM catalog. Timely recognition of TPP2 deficiency is crucial since (1) immune surveillance is needed and hematopoietic stem cell transplantation may be necessary, and (2) for provision of genetic counselling. Additionally, enzyme replacement therapy, as already established for TPP1 deficiency, might be an option in the future.
Subject(s)
Aminopeptidases/genetics , Autoimmune Diseases/genetics , Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/genetics , Frameshift Mutation/genetics , Immunologic Deficiency Syndromes/genetics , Serine Endopeptidases/genetics , Adult , Child , Child, Preschool , Exons/genetics , Female , Humans , Male , Young AdultABSTRACT
Hemophilia A (HA) is a serious inherited bleeding disorder resulting from a deficiency of coagulation factor VIII (FVIII). Replacement therapy with intravenous infusion of FVIII can be associated with treatment failure in approximately one-third of patients secondary to the development of neutralizing alloantibodies (inhibitor). Emicizumab is a recombinant, humanized, bispecific monoclonal antibody that binds factor IXa and factor X and mimics FVIII. It has been licensed in many countries for the treatment of patients with HA with and without inhibitors with a favorable efficacy and safety profile. A 7-year-old child with severe HA and FVIII inhibitors, refractory to immune tolerance therapy, developed hematuria with nephrotic-range proteinuria after the first dose of emicizumab and subsequently also after a second dose 6 weeks later, which was associated with mild and transient leukopenia. Renal biopsy revealed a pattern of a full-house lupus nephritis. The patient fully and spontaneously recovered between 2 weeks after symptoms onset. In this report, we provide insights on a new and so far unreported renal complication associated to emicizumab treatment. Although emicizumab offers significant benefits for patient with HA, clinicians should be aware of this rare and potential serious renal adverse effect.
Subject(s)
Antibodies, Bispecific/adverse effects , Antibodies, Monoclonal, Humanized/adverse effects , Hemophilia A/therapy , Lupus Nephritis/etiology , Child , Factor VIII/immunology , Hemophilia A/blood , Humans , Leukopenia/etiology , Lupus Nephritis/blood , Lupus Nephritis/immunology , Lupus Nephritis/pathology , MaleABSTRACT
Spinal epidural hematoma (SEH) is a rare condition leading to spinal cord compression after trauma, surgery, or other. In 40% of the cases, the cause is unknown or unidentified. Due to the absence of specific symptoms, the diagnosis is often delayed. The mainstay of treatment is urgent evacuation of the hematoma. The choice of the surgical technique is surgeon-dependent and ranges from simple decompression and hematoma evacuation to variable combinations of decompression and reconstruction of the posterior spinal arch. To our knowledge, we describe the youngest case in the literature of a thoracolumbar SEH in a newborn with hemophilia A which was evacuated by spinous process splitting laminoplasty (SPSL). SPSL was chosen to avoid damaging the primary ossification centers, preserve the paravertebral musculature, and evade the sequelae of multilevel laminectomies. In our opinion, this technique should be propagated in the pediatric population for accessing the posterior and posterolateral spinal canal.
Subject(s)
Hematoma, Epidural, Cranial , Hematoma, Epidural, Spinal , Laminoplasty , Child , Decompression, Surgical , Hematoma, Epidural, Spinal/diagnostic imaging , Hematoma, Epidural, Spinal/etiology , Hematoma, Epidural, Spinal/surgery , Humans , Infant, Newborn , LaminectomyABSTRACT
BACKGROUND: Spinal epidural hematoma without significant trauma is a rare condition with potentially severe outcome. This case report and systematic review of the literature illustrates the clinical presentation, risk factors, evaluation, treatment and outcomes of spinal epidural hematoma without significant trauma in children. CASE PRESENTATION: We report one case of a 7-year-old girl who developed a neck pain after minor cervical sprain. MRI showed a right posterior epidural hematoma extending from C2/3 to T1. The hematoma was surgically evacuated, and the histopathology showed an arteriovenous malformation. Postoperative MRI showed complete evacuation of the hematoma and no residual vascular malformation. We report a second ASE with idiopathic spinal epidural hematoma of a 4½-year-old boy presenting with neck pain. MRI showed a right-sided latero-posterior subacute spinal epidural hematoma at C3-C5. Owing to the absence of any neurological deficit, the patient was treated conservatively. MRI at 3 months showed complete resolution of the hematoma. CONCLUSIONS: Spinal epidural hematoma without significant trauma in children is a rare condition. It may present with unspecific symptoms. Screening for bleeding diathesis is warranted and neuroradiologic follow-up is essential to rule out vascular malformation. Whereas most children have a favorable outcome, some do not recover, and neurological follow-up is required.
Subject(s)
Arteriovenous Malformations , Hematoma, Epidural, Spinal , Arteriovenous Malformations/complications , Child , Child, Preschool , Female , Hematoma, Epidural, Spinal/diagnostic imaging , Hematoma, Epidural, Spinal/etiology , Humans , Magnetic Resonance Imaging , Male , Neck Pain/etiologyABSTRACT
Little information on the efficacy and pharmacokinetics of letermovir among immunocompromised children is currently available. We describe here the use of letermovir in a 2-year-old immunocompromised child with ganciclovir-resistant cytomegalovirus disease who required extracorporeal membrane oxygenation. Detailed information on therapeutic-drug-monitoring measures and dosage adjustments for letermovir is provided.
Subject(s)
Acetates/administration & dosage , Antiviral Agents/administration & dosage , Cytomegalovirus Infections/drug therapy , Cytomegalovirus , Drug Monitoring/methods , Immunocompromised Host , Pneumonia, Viral/drug therapy , Quinazolines/administration & dosage , Acetates/pharmacokinetics , Acetates/therapeutic use , Antiviral Agents/pharmacokinetics , Antiviral Agents/therapeutic use , Child, Preschool , Compassionate Use Trials , Cytomegalovirus/genetics , Cytomegalovirus/isolation & purification , Cytomegalovirus Infections/immunology , Cytomegalovirus Infections/virology , DNA, Viral/blood , Dose-Response Relationship, Drug , Extracorporeal Membrane Oxygenation/adverse effects , Fatal Outcome , Female , Ganciclovir/therapeutic use , Hepatitis, Viral, Human/drug therapy , Hepatitis, Viral, Human/immunology , Humans , Opportunistic Infections/drug therapy , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Polymerase Chain Reaction , Quinazolines/pharmacokinetics , Quinazolines/therapeutic use , Treatment Failure , Viral LoadABSTRACT
Children with sickle cell disease (SCD) require specific perioperative care, and clinical practice in this area remains poorly defined. We aimed to conduct a systematic, PRISMA-based review of the literature, available clinical guidelines and practice recommendations. We also aimed to extract any valuable information for the "best of available-evidence"-based prevention of perioperative adverse events in children with SCD, and highlight the most urgent priorities in clinical research. As data sources, US National Library of Medicine, Medline, National Guideline Clearinghouse, International Guideline Network, TRIP databases were searched for any content until January 2019. We also included institutional, consortia and expert group guidelines. Included were reports/guidelines in English, French, German, and Italian. Excluded were reports on obstetrical and fetal management. We identified 202 reports/guidelines fulfilling the criteria outlined above. A majority focused on visceral, cardiovascular and orthopedic surgery procedures, and only five were multicenter randomized controlled trials and two prospective randomized studies. After grading of the quality of the evidence, the extracted data was summarized into clinical recommendations for daily practice. Additionally, we designed a risk-grading algorithm to identify contexts likely to be associated with adverse outcomes. In conclusion, we provide a systematic PRISMA-based review of the existing literature and ancillary practice and delineate a set of clinical recommendations and priorities for research.
Subject(s)
Anemia, Sickle Cell/surgery , Perioperative Care/methods , Practice Guidelines as Topic , Child , Humans , Risk AssessmentABSTRACT
Catheter-related arterial thrombosis (CAT) are increasingly recognized in infants and children. Insufficient data are available on the incidence, risk factors, treatment and outcome of these thrombotic events. This work provides consensus recommendations for future research on catheter-related arterial thrombosis in the paediatric population. In particular, future studies should distinguish between CAT due to indwelling arterial catheters or cardiac catheterization in two different subpopulations (neonates and older children). Further studies should investigate sensitivity and specificity of clinical signs and symptoms for early screening of CAT and the most appropriate imaging modality, focusing on ultrasound due to better feasibility in the very young pediatric population. Adequately powered, well-designed clinical trials should investigate efficacy and safety of different treatment and prevention strategies as well as the risk for and the optimal management of short- and long-term complications.
ABSTRACT
Arterial thrombosis is increasingly recognized in children and is mostly related to the presence of an arterial catheter or an ischemic stroke. Treatment of children with arterial thrombosis varies widely and consists on the administration of the common available anticoagulant und antiplatelet drugs. No evidence-based guidelines are available so far to prefer one treatment approach to another. Data in adults indicate that understanding the pathomechanism and composition of arterial thrombosis is crucial for choosing the most efficient and safe antithrombotic drug. This review will briefly summarize new insights on the pathomechanism and composition of arterial thrombosis in adults and describe available antithrombotic treatment modalities currently used n children.
Subject(s)
Thrombosis/therapy , Adult , Antithrombins/therapeutic use , Child , Fibrinolytic Agents/therapeutic use , Heparin/therapeutic use , Humans , Platelet Aggregation Inhibitors/therapeutic use , Thrombectomy/methods , Thrombosis/drug therapy , Thrombosis/pathology , Thrombosis/surgery , Vitamin K/antagonists & inhibitorsABSTRACT
This paper investigates the ultimate limits of White Rabbit (WR), an high-accuracy time distribution system based on field-programmable gate array (FPGA). The knowledge of such limits is essential for new emerging applications that are evaluating WR. In this paper, we identify and study the key elements in the WR synchronization: the digital dual mixer time difference phase detector and the Gigabit Ethernet transceiver. The benchmarks and experimental analysis of these key elements allow us to determine the WR switch (WRS) performance limits and evaluate their evolution with newer FPGAs. The identified performance limits are achievable by the present-day generation of WRS. The ultimate limits of short-term synchronization performance due to FPGA implementation have been derived through analysis and then demonstrated using the existing WRS enhanced with an additional daughterboard. This combination (WRS and daughterboard) achieves a tenfold improvement in terms of phase noise, jitter, and short-term stability with respect to the current WR performance. Both phase detectors and Gigabit transceivers have a similar phase noise contribution equal to a short-term stability of modified Allan deviation 4E-13 at $\tau = 1$ s (dominated by flicker phase modulation noise).
ABSTRACT
BACKGROUND: Cerebral atrium diverticula are focal enlargements of the ventricular system that may develop in the presence of persistent intracranial hypertension, but they are rarely described in cases of acute intracranial hypertension. Here we present a unique case of obstructive hydrocephalus in a newborn due to the formation of a cerebral atrium diverticulum compressing the ventricular system. CASE DISCUSSION: A preterm 38-week-old boy was born with urgent caesarian section due to severe hydrocephalus. Magnetic resonance imaging showed the presence of a subacute right subdural hematoma with secondary obstructive hydrocephalus. The cystic lesion was characterized as a right ventricular atrium diverticulum. The child underwent urgent burr-hole evacuation of the right subdural hematoma with complete regression of the obstructive hydrocephalus and right atrial diverticulum. CONCLUSION: Cerebral atrium diverticula are rare focal dilatations of the ventricular system, and their radiologic diagnosis may be challenging. Accurate diagnosis of atrial diverticula and understanding of the underlying physiopathology is mandatory to establish the appropriate operative strategy.