Bihemispheric Cerebral Oximetry Monitoring's Functionality in Suspected Cerebral Edema Diabetic Ketoacidosis With Therapeutic 3% Hyperosmolar Therapy in a Pediatric Emergency Department.

BACKGROUND: Suspected cerebral edema diabetic ketoacidosis (SCEDKA) is more common than perceived with symptoms including altered mentation, headache with vomiting, depressed Glasgow coma scale (GCS), abnormal motor or verbal responses, combativeness, and neurological depression. Suspected cerebral edema diabetic ketoacidosis has been associated with initial diabetic ketoacidosis (DKA) presentation and at start of DKA therapy.Cerebral oximetry (bihemispheric regional cerebral oxygen saturation [rcSO2] and cerebral blood volume index [CBVI]) can detect increased intracranial pressure (ICP)-induced altered bihemispheric cerebral physiology (rcSO2) (Crit Care Med 2006;34:2217-2223, J Pediatr 2013;163: 1111-1116, Curr Med Chem 2009;16:94-112, Diabetologia 1985;28:739-742, Pediatr Crit Care Med 2013;14:694-700). In pediatrics, rcSO2 of less than 60% or rcSO2 of greater than 85% reflects increased ICP and cerebral edema (Crit Care Med 2006;34:2217-2223, J Pediatr 2013;163: 1111-1116, Curr Med Chem 2009;16:94-112, Diabetologia 1985;28:739-742, Pediatr Crit Care Med 2013;14:694-700). Cerebral oximetry can detect increased ICP-induced altered bihemispheric cerebral physiology (rcSO2, CBVI) and cerebral physiological changes (rcSO2, CBVI changes) during therapeutic mechanical cerebral spinal fluid removal to decrease increased ICP (Crit Care Med 2006;34:2217-2223, J Pediatr 2013;163: 1111-1116, Curr Med Chem 2009;16:94-112, Diabetologia 1985;28:739-742, Pediatr Crit Care Med 2013;14:694-700).In the pediatric intensive care units, SCEDKA patients with nonbihemispheric cerebral oximetry showed an initial rcSO2 of greater than 90%. Bihemispheric rcSO2 with CBVI in SCEDKA patients has the potential to detect the abnormal cerebral physiology and disruptive autoregulation while detecting 3% hypertonic saline solution (HTS) effects on the SCEDKA altered cerebral physiology (rcSO2). PURPOSE: The purposes of this study were to analyze and compare 3% HTS effect on bihemispheric rcSO2 readings, neurological and biochemical parameters in SCEDKA with 3% HTS infusion to non-SCEDKA patients in pediatric emergency department (PED). METHODS: An observational retrospective comparative analysis study of bihemispheric rcSO2 readings, neurological and biochemical parameters in 2 groups of PED DKA patients were performed: PED DKA patients with SCEDKA +3% HTS infusions versus non-SCEDKA without 3% HTS infusions. RESULTS: From 2008 to 2013, of the 1899 PED DKA patients, 60 SCEDKA patients received 3% HTS (5 mL/kg via peripheral intravenous) infusion (median age of 5 years [range, 3.7-7 years]), with 42 new DKA insulin dependent diabetes mellitus onset. Suspected cerebral edema diabetic ketoacidosis patients had GCS of 11 (range, 11-12), with consistent SCEDKA signs and symptoms (severe headaches with vomiting, confusion, blurred vision, altered speech, lethargy, and combativeness). Suspected cerebral edema diabetic ketoacidosis patients' initial (0-5 minutes) left rcSO2 readings were 91.4% (range, 88.4%-94.1%) and right was 90.3% (range, 88.6%-94.1%) compared with non-SCEDKA patients' left rcSO2 readings of 73.2% (range, 69.7%-77.8%) and right of 73.2% (range, 67.6%-77%) (P < 0.0001). The rcSO2 monitoring time before 3% HTS infusion was 54.9 minutes (range, 48.3-66.8 minutes) with 3% HTS time effect change: pre-3% HTS (54.9 minutes [range, 48.3-66.8 minutes]). Before 3% HTS infusion, the left rcSO2 readings were 90.0% (range, 89%-95%) and right was 91% (range, 86%-95%). The 30 to 45 minutes post-3% HTS showed that left was 64% (range, 62%-69%) and right was 65.4% (range, 63%-70%) (P < 0.0001). rcSO2 Δ change for post-3% HTS (0-20 minutes) to pre-3% HTS was as follows: left, -26.58 (-29.5 to -23.7) (P < 0.0001); right, -25.2 (-27.7 to -22.6) (P < 0.0001). Post-3% HTS GCS (14,15) and biochemistry compared with pre-3% HTS infusions all improved (P < 0.001). CONCLUSIONS: In PED SCEDKA patients, the pre-3% HTS bihemispheric rcSO2 readings were greater than 90% and had lower GCS than non-SCEDKA patients. The post-3% HTS infusion rcSO2 readings showed within minutes a substantial reduction compared with non-SCEDKA patients, with no complications. Changes in rcSO2 readings after 3% HTS correlated with improved SCEDKA indicators (improved mental status, headache, and GCS) without any complications. We showed that cerebral oximetry in PED SCEDKA patients has shown an initial bihemispheric of greater than 90% readings signifying abnormal bihemispheric cerebral physiology. We also showed the cerebral oximetry's functionality in detecting 3% HTS therapeutic effects on SCEDKA's abnormal cerebral physiology and the beneficial therapeutic effects of 3% HTS infusion in SCEDKA patients. Using cerebral oximetry in pediatric DKA patients' initial cerebral assessment could have a significant impact in detecting SCEDKA patients. Further SCEDKA research using cerebral oximetry should be considered.

Assessing the Impact of 3% Hypertonic Saline Hyperosmolar Therapy on Intubated Children With Isolated Traumatic Brain Injury by Cerebral Oximetry in a Pediatric Emergency Setting.

BACKGROUND: Intubated pediatric patients with isolated traumatic brain injury (TBI) are a diagnostic challenge for early detection of altered cerebral physiology instigated by trauma-induced increased intracranial pressure (ICP) while preventing secondary neuronal damage (secondary insult detection) and assessing the effects of increased ICP therapeutic interventions (3% hypertonic saline [HTS]). Invasive brain tissue oxygen monitoring is guiding new intensive care unit TBI management but is not pediatric emergency department (PED) readily accessible. Objective measurements on pediatric isolated TBI-altered bihemispheric cerebral physiology and treatment effects of 3% HTS are currently lacking. Cerebral oximetry can assess increased ICP-induced abnormal bihemispheric cerebral physiology by measuring regional tissue oxygenation (rcSO2) and cerebral blood volume index (CBVI) and the mechanical cerebrospinal fluid removal effects on the increased ICP-induced abnormal bihemispheric cerebral physiology.In the PED intubated patients with isolated TBI, assessing the 3% HTS therapeutic response is solely by vital signs and limited clinical assessment skills. Objective measurements of the 3% HTS hyperosmolar effects on the PED isolated TBI patients' altered bihemispheric cerebral physiology are lacking. We believe that bihemispheric rcSO2 and CBVI could elucidate similar data on 3% HTS impact and influence in the intubated isolated TBI patients. OBJECTIVE: This study aimed to analyze the effects of 3% HTS on bihemispheric rcSO2 and CBVI in intubated patients with isolated TBI. METHODS: An observational, retrospective analysis of bihemispheric rcSO2 and CBVI readings in intubated pediatric patients with isolated TBI receiving 3% HTS infusions, was performed. RESULTS: From 2010 to 2017, 207 intubated patients with isolated TBI received 3% HTS infusions (median age, 2.9 [1.1-6.9 years]; preintubation Glasgow Coma Scale score, 7 [6-8]). The results were as follows: initial pre-3% HTS, 43% (39.5% to 47.5%; left) and 38% (35% to 42%; right) for rcSO2 < 60%, and 8 (-28 to 21; left) and -15 (-34 to 22; right) for CBVI; post-3% HTS, 68.5% (59.3% to 76%, P < 0.0001; left) and 62.5% (56.0% to 74.8%, P < 0.0001; right) for rcSO2 < 60%, and 12 (-7 to 24, P = 0.04; left) and 14 (-21 to 22, P < 0.0001; right) for CBVI; initial pre-3% HTS, 90% (83% to 91%; left) and 87% (82% to 92%; right) for rcSO2 > 80%, and 16.5 (6 to 33, P < 0.0001; left) and 16.8 (-2.5 to 27.5, P = 0.005; right) for CBVI; and post-3% HTS, 69% (62% to 72.5%, P < 0.0001; left) and 63% (59% to 72%, P < 0.0001; right) for rcSO2 > 80%, and 16.5 (6 to 33, P < 0.0001; left) and 16.8 (-2.5 to 27.5, P = 0.005; right) for CBVI. The following results for cerebral pathology pre-3% HTS were as follows: epidural: 85% (58% to 88.5%) for left rcSO2 and -9.25 (-34 to 19) for left CBVI, and 85.5% (57.5% to 89%) for right rcSO2 and -12.5 (-21 to 27) for CBVI; subdural: 45% (38% to 54%) for left rcSO2 and -9.5 (-25 to 19) for left CBVI, and 40% (33% to 49%) for right rcSO2 and -15 (-30.5 to 5) for CBVI. The following results for cerebral pathology post-3% HTS were as follows: epidural: 66% (58% to 69%, P = 0.03) for left rcSO2 and 15 (-1 to 21, P = 0.0004) for left CBVI, and 63% (52% to 72%, P = 0.009) for right rcSO2, and 15.5 (-22 to 24, P = 0.02) for CBVI; subdural: 63% (56% to 72%, P < 0.0001) for left rcSO2 and 9 (-20 to 22, P < 0.0001) for left CBVI, and 62.5% (48% to 73%, P < 0.0001) for right rcSO2, and 3 (-26 to 22, P < 0.0001) for CBVI. Overall, heart rate showed no significant change. Three percent HTS effect on interhemispheric rcSO2 difference >10 showed rcSO2 < 60%, and subdural hematomas had the greatest reduction (P < 0.001). The greatest positive changes occurred in bihemispheric or one-hemispheric rcSO2 < 60% with an interhemispheric discordance rcSO2 > 10 and required the greatest number of 3% HTS infusions. For 3% HTS 15% rcSO2 change time effect, all patients achieved positive change with subdural hematomas and hemispheric rcSO2 readings <60% with the shortest achievement time of 1.2 minutes (0.59-1.75; P < 0.001). CONCLUSIONS: In intubated pediatric patients with isolated TBI who received 3% HTS infusions, bihemispheric rcSO2 and CBVI readings immediately detected and trended the 3% HTS effects on the trauma-induced cerebral pathophysiology. The 3% HTS infusion produced a significant improvement in rcSO2 and CBVI readings and a reduction in interhemispheric rcSO2 discordance differences. In patients with bihemispheric or one-hemispheric rcSO2 readings <60% with or without an interhemispheric discordance, rcSO2 > 10 demonstrated the greatest significant positive delta change and required the greatest numbers of 3% HTS infusions. Overall, 3% HTS produced a significant positive 15% change within 2.1 minutes of infusion, whereas heart rate showed no significant change. During trauma neuroresuscitation, especially in intubated isolated TBI patients requiring 3% HTS, cerebral oximetry has shown its functionality as a rapid adjunct neurological, therapeutic assessment tool and should be considered in the initial emergency department pediatric trauma neurological assessment and neuroresuscitation regimen.

Admission Characteristics Identify Risk of Pediatric Acute-on-Chronic Liver Failure.

OBJECTIVES: Acute-on-chronic liver failure (ACLF) is well-studied in adults and characterized by decompensated cirrhosis, multi-organ failure, and early mortality. Studies of ACLF in children are limited. We sought to characterize the prevalence and clinical factors associated with pediatric ACLF (PACLF). METHODS: A retrospective review of children 3 months to 18 years listed for liver transplantation and hospitalized for decompensated cirrhosis between January 2007 and December 2017 at a single pediatric hospital. Primary outcome was the development of PACLF, characterized as failure of at least 1 extrahepatic organ (mechanical ventilation, renal replacement therapy, vasoactive medications, grade III/IV hepatic encephalopathy). Characteristics were recorded for each hospitalization. RESULTS: Sixty-six patients had 186 hospitalizations with mean age at admission 4.0 ±â€Š5.6 years and diagnosis of biliary atresia (BA) in 65%. PACLF developed in 20 patients during 23 hospitalizations (12%) and respiratory failure was most common (17/23, 74%). Duration of intensive care unit stay, 13.1 ±â€Š1.2 days versus 0.6 ±â€Š0.6 days (P < 0.001) and length of stay, 24.3 ±â€Š5.0 days versus 7.9 ±â€Š1.9 days (P = 0.003) were longer in PACLF compared with non-PACLF. Mortality during PACLF hospitalizations was 22%. Clinical factors associated with PACLF were reported from a generalized linear mixed model and included increased admission creatinine (P < 0.0001), increased aspartate aminotransferase (AST) (P = 0.014), increased international normalized ration (INR) (P = 0.0015), and a positive blood culture (P = 0.007). CONCLUSION: In this pediatric series, PACLF developed in 12% of hospitalizations and mortality was high. Admission creatinine, AST, INR, and presence of a positive blood culture were associated with PACLF development.

Pediatric Acute Stroke Protocol Activation in a Children's Hospital Emergency Department.

BACKGROUND AND PURPOSE: Pediatric acute stroke teams are a new phenomenon. We sought to characterize the final diagnoses of children with brain attacks in the emergency department where the pediatric acute stroke protocol was activated and to describe the time to neurological evaluation and neuroimaging. METHODS: Clinical and demographic information was obtained from a quality improvement database and medical records for consecutive patients (age, ≤20 years) presenting to a single institution's pediatric emergency department where the acute stroke protocol was activated between April 2011 and October 2014. Stroke protocol activation means that a neurology resident evaluates the child within 15 minutes, and urgent magnetic resonance imaging is available. RESULTS: There were 124 stroke alerts (age, 11.2±5.2 years; 63 boys/61 girls); 30 were confirmed strokes and 2 children had a transient ischemic attack. Forty-six of 124 (37%) cases were healthy children without any significant medical history. Nonstroke neurological emergencies were found in 17 children (14%); the majority were meningitis/encephalitis (n=5) or intracranial neoplasm (n=4). Other common final diagnoses were complex migraine (17%) and seizure (15%). All children except 1 had urgent neuroimaging. Magnetic resonance imaging was the first study in 76%. The median time from emergency department arrival to magnetic resonance imaging was 94 minutes (interquartile range, 49-151 minutes); the median time to computed tomography was 59 minutes (interquartile range, 40-112 minutes). CONCLUSIONS: Of pediatric brain attacks, 24% were stroke, 2% were transient ischemic attack, and 14% were other neurological emergencies. Together, 40% had a stroke or other neurological emergency, underscoring the need for prompt evaluation and management of children with brain attacks.

A Comparative Analysis of Equations to Estimate Patient Energy Requirements Following Cardiopulmonary Bypass for Correction of Congenital Heart Disease.

BACKGROUND: No consensus exists on the optimal method to estimate resting energy expenditure (REE) in critically ill children following cardiopulmonary bypass (CPB). This study assesses the accuracy of REE estimation equations in children with congenital heart disease following CPB and tests the feasibility of using allometric scaling as an alternative energy prediction equation. METHODS: A retrospective analysis of a pediatric cohort following CPB (n = 107; median age 5.2 months, median weight 5.65 kg) who underwent serial measures (median 5 measurements) of REE using indirect calorimetry for 72 hours following CPB. We estimated REE using common estimation methods (Dietary Reference Intake, Harris Benedict, Schofield, World Health Organization [WHO]) as well as novel allometric equations. We compared estimated with measured REE to determine accuracy of each equation using overall discrepancy, calculated as a time-weighted average of the absolute deviation. RESULTS: All equations incorrectly estimated REE at all time points following CPB, with overestimation error predominating. WHO had the lowest discrepancy at 10.7 ± 8.4 kcal/kg/d. The allometric equation was inferior, with an overall discrepancy of 16.9 ± 10.4. There is a strong nonlinear relationship between body surface area and measured REE in this cohort, which is a key source of estimation error using linear equations. CONCLUSION: In a cohort of pediatric patients with congenital heart disease following CPB, no currently utilized clinical estimation equation reliably estimated REE. Allometric scaling proved inferior in estimating REE in children following CPB. Indirect calorimetry remains the ideal method of determining REE after CPB until nonlinear methods can be derived due to overestimation using linear equations.

Critical care resources utilized in high-risk adenotonsillectomy patients.

OBJECTIVE: Children at high risk for respiratory complication after adenotonsillectomy are often admitted to a pediatric intensive care unit (PICU) postoperatively. Although many patients receive care in such units, it is unknown how many utilize critical care resources. METHODS: A review was conducted to audit intensive care needs of postadenotonsillectomy patients admitted to the PICU at a tertiary, academic, pediatric hospital between July 2013, and March 2017. Demographic information, ICU indication, polysomnogram results, and comorbidities were collected. Patients were defined as needing ICU resources based on supplemental oxygen requirements greater than 2 L between 2 to 24 hours postoperatively, more than two desaturation events in a 2-hour period, or more than hourly nursing intervention. Factors associated with utilization of ICU resources were assessed. RESULTS: One hundred and ten patients were admitted to the PICU after adenotonsillectomy. Median age was 4.2 years, median body mass index was 90.8 percentile, and median apnea hypopnea index (AHI) was 34.3. Twenty patients (18.2%) utilized ICU resources by criteria defined. Of these patients, 14 were known to need such resources by 2 hours postoperatively (70%, negative predictive value 93.8%). Neither AHI nor obesity status was correlated with need for resources; however, resource need was associated with young age, gastrostomy tube status, and neuromuscular disorders (P = 0.048, P = 0.002 and 0.013, respectively). CONCLUSION: Most high-risk adenotonsillectomy patients do not utilize critical care resources despite their increased perioperative risk. Patients with respiratory complications are frequently identifiable within the first 2 hours of surgery. LEVEL OF EVIDENCE: 4 Laryngoscope, 129:1229-1234, 2019.

Reductions in heel bone quality across gestation are attenuated in pregnant adolescents with higher prepregnancy weight and greater increases in PTH across gestation.

Few studies have examined the effect of maternal calcium intake and vitamin D status on bone health across gestation in pregnant adolescents. This study aimed to characterize maternal bone quality and determinants of bone-quality change across gestation in pregnant adolescents. Healthy pregnant adolescents (n = 156; aged 13 to 18 years) with singleton pregnancies and at 12 to 30 weeks gestation at enrollment were recruited from two urban maternity clinics in Baltimore, MD, and Rochester, NY, for this prospective longitudinal study. Maternal serum was collected at midgestation and at delivery for assessment of bone biomarkers and calcitropic hormones. Maternal bone quality (assessed by heel ultrasound) and sonographic fetal biometry were measured up to three times across pregnancy. Racially diverse teens (64.7% African American, 35.3% white) were followed from 21.0 (interquartile range [IQR] 17.3, 27.0) weeks of gestation until delivery at 40.0 (IQR 39.0, 40.7) weeks. Significant decreases in calcaneal speed of sound (SOS), broadband ultrasound attenuation (BUA), and quantitative ultrasound index (QUI) (-9.2 ± 16.1 m/s, -3.2 (-8.0, 2.1) dB/MHz and -5.3 ± 8.8, respectively) were evident across pregnancy. Multivariate analysis controlling for baseline measures and measurement intervals was used to identify independent predictors of normalized (per week) calcaneal bone loss. Weekly decreases in bone quality were not significantly associated with maternal calcium intake or 25(OH)D concentration. Greater weekly reductions in calcaneal bone quality were evident in teens with lower prepregnancy weight (BUA, p = 0.006 and QUI, p = 0.012) and among those with lower weekly increase in PTH (SOS, p = 0.046). Overall, significant decreases in calcaneal bone quality occurred across pregnancy in adolescents, but the magnitude of this loss was attenuated in those with greater prepregnancy weight and weekly increases in PTH. Further studies are needed to understand the role of elevated PTH and greater prepregnancy weight in preserving adolescent bone during pregnancy.

Employment of a needs assessment survey to shape a novel web-based pediatric rheumatology curriculum for primary care providers.

BACKGROUND: Pediatric rheumatology faces many challenges due to the shortage of board certified physicians in the field and the imbalance in their geographic distribution. This shortage has required primary care physicians and adult rheumatologists to assume the care of children with rheumatologic diseases, though these physicians report significant discomfort doing so. We are addressing this issue through the development of a novel web-based curriculum aimed at primary care physicians. METHODS: We pursued a needs assessment survey of Vanderbilt pediatric residency graduates (1981-2010) working in primary care. Our goals were to understand their perceptions of what the needs are and what educational interventions would be most effective. RESULTS: Of 152 surveys sent successfully via Survey Monkey, we received 28 responses (18.4%). Responses suggest there to be a discrepancy between physicians' general assessment of their training and their self-reported ability to recognize specific diseases. Nearly 80% of respondents felt that additional education in pediatric rheumatology would improve their ability to co-manage children with the rheumatologist. Action plans for common rheumatologic complaints and potential emergencies were thought to be of potential benefit by a majority of respondents. CONCLUSIONS: We will utilize our survey results to develop a learner centered curriculum to have the highest positive impact in assisting primary care providers in caring for children with rheumatologic diseases.

Ceruloplasmin is a NO oxidase and nitrite synthase that determines endocrine NO homeostasis.

Nitrite represents a bioactive reservoir of nitric oxide (NO) that may modulate vasodilation, respiration and cytoprotection after ischemia-reperfusion injury. Although nitrite formation is thought to occur via reaction of NO with oxygen, this third-order reaction cannot compete kinetically with the reaction of NO with hemoglobin to form nitrate. Indeed, the formation of nitrite from NO in the blood is limited when plasma is substituted with physiological buffers, which suggests that plasma contains metal-based enzymatic pathways for nitrite synthesis. We therefore hypothesized that the multicopper oxidase, ceruloplasmin, could oxidize NO to NO+, with subsequent hydration to nitrite. Accordingly, plasma NO oxidase activity was decreased after ceruloplasmin immunodepletion, in ceruloplasmin knockout mice and in people with congenital aceruloplasminemia. Compared to controls, plasma nitrite concentrations were substantially reduced in ceruloplasmin knockout mice, which were more susceptible to liver infarction after ischemia and reperfusion. The extent of hepatocellular infarction normalized after nitrite repletion. These data suggest new functions for the multicopper oxidases in endocrine NO homeostasis and nitrite synthesis, and they support the hypothesis that physiological concentrations of nitrite contribute to hypoxic signaling and cytoprotection.

Ceruloplasmin in neurodegenerative diseases.

For decades, abnormalities in ceruloplasmin (Cp) synthesis have been associated with neurodegenerative disease. From the early observation that low circulating serum ceruloplasmin levels served as a marker for Wilson's disease to the recent characterization of a neurodegenerative disorder associated with a complete lack of serum ceruloplasmin, the link between Cp and neuropathology has strengthened. The mechanisms associated with these different central nervous system abnormalities are very distinct. In Wilson's disease, a defect in the P-type ATPase results in abnormal hepatic copper accumulation that eventually leaks into the circulation and is abnormally deposited in the brain. In this case, copper deposition results in the neurodegenerative phenotype observed. Patients with autosomal recessive condition, aceruloplasminemia, lack the ferroxidase activity inherent to the multi-copper oxidase ceruloplasmin and develop abnormal iron accumulation within the central nervous system. In the following review ceruloplasmin gene expression, structure and function will be presented and the role of ceruloplasmin in iron metabolism will be discussed. The molecular events underlying the different forms of neurodegeneration observed will be presented. Understanding the role of ceruloplasmin within the central nervous system is fundamental to further our understanding of the pathology observed. Is the ferroxidase function more essential than the antioxidant role? Does Cp help maintain nitrosothiol stores or does it oxidize critical brain substrates? The answers to these questions hold the promise for the treatment of devastating neurodegenerative conditions such as Alzheimer's and Parkinson's diseases. It is essential to further elucidate the mechanism of the neuronal injury associated with these disorders.

Disruption of ceruloplasmin and hephaestin in mice causes retinal iron overload and retinal degeneration with features of age-related macular degeneration.

Mechanisms of brain and retinal iron homeostasis have become subjects of increased interest after the discovery of elevated iron levels in brains of patients with Alzheimer's disease and retinas of patients with age-related macular degeneration. To determine whether the ferroxidase ceruloplasmin (Cp) and its homolog hephaestin (Heph) are important for retinal iron homeostasis, we studied retinas from mice deficient in Cp and/or Heph. In normal mice, Cp and Heph localize to Müller glia and retinal pigment epithelium, a blood-brain barrier. Mice deficient in both Cp and Heph, but not each individually, had a striking, age-dependent increase in retinal pigment epithelium and retinal iron. The iron storage protein ferritin was also increased in Cp-/-Heph-/Y retinas. After retinal iron levels had increased, Cp-/-Heph-/Y mice had age-dependent retinal pigment epithelium hypertrophy, hyperplasia and death, photoreceptor degeneration, and subretinal neovascularization, providing a model of some features of the human retinal diseases aceruloplasminemia and age-related macular degeneration. This pathology indicates that Cp and Heph are critical for CNS iron homeostasis and that loss of Cp and Heph in the mouse leads to age-dependent retinal neurodegeneration, providing a model that can be used to test the therapeutic efficacy of iron chelators and antiangiogenic agents.