OBJECTIVES:Sensorineural hearing loss (SNHL) and vestibular symptoms in sickle cell disease (SCD) may result from hypoxic damage of inner ear structures, including the stria vascularis (SV), spiral ganglion cells (SGC), and vestibular ganglion neurons (VGN). SV cross-sectional area, SGC counts, and VGN counts were compared between SCD and control groups and correlated with temporal bone histopathology and clinical data. STUDY DESIGN:Hematoxylin and eosin-stained slides from 36 temporal bones were analyzed, including both ears from 6 SCD cases and 12 controls matched for age, sex, and race. A deep learning model was developed to measure SV area, total ear SGC counts, and VGN counts. Single and multivariable analyses were performed to compare histopathologic correlates between groups and available clinical data. RESULTS:The mean age was 19 ± 7.8 years for the SCD group [male: n = 3 (50%); black/African American: n = 6 (100%)] and 19 ± 6.7 years for controls [male: n = 6 (50%); black/African American: n = 10 (83%)]. Mean pure tone averages were normal for both groups (SCD = 12.2 ± 10.4; control = 11.1 ± 7.8, P = 0.84). SV area was similar in the SCD group compared with controls at the basal turn, middle turn, and apex; however, qualitative analysis of individual cases revealed signs of atrophy in a higher proportion of SCD cases. No significant difference was found in SGC (SCD = 25,721 ± 3283; control = 24,585 ± 5016, P = 0.43) or VGN counts (SCD = 20,673 ± 2294; control = 21,275 ± 4948, P = 0.68) between groups. The remainder of cochlear structures were preserved. CONCLUSIONS:SV area, SGC, and VGN populations are preserved in primarily young individuals with SCD and normal hearing. Otopathologic correlates of SNHL in SCD may manifest following the onset of hearing loss.

Introduction: Near universal survival of children with sickle cell disease (SCD) into adulthood makes transition from pediatric to adult care a necessary step. Got Transition guidelines define core elements of healthcare transition but offer little on supporting young people after arrival in adult care. In 2025, the National Alliance of Sickle Cell Centers (NASCC) published consensus definitions of successful transfer and integration into adult SCD care. The purpose of this study was to apply these definitions to our previously described cohort of young adults with SCD at a single Center and identify factors associated with transfer and integration into adult care. Methods – This retrospective cohort study was approved by the Johns Hopkins Institutional Review Board. In May 2025, we collected young adult clinic visits for patients aged 18-24 years who transitioned to our adult Center. All patients attended an initial hematologist visit between March 2019 and May 2024. Patient demographics, disease characteristics, and Montreal Cognitive Assessment (MoCA) screening were collected by chart review. At their first visit, a subset of patients completed the American Society of Hematology's Sickle Cell Disease Transition Readiness Assessment, Transition Intervention Program - Readiness for Transition, and the Adult Sickle Cell Quality of Life Measurement (ASCQ-Me). A NASCC consensus statement defines successful transfer of care as attending two visits with a comprehensive sickle cell program in the first year in adult care. We operationalized this definition as routine visits with the hematologist or advanced practice providers in our Center. The NASCC definition of successful integration into care is completion of at least 50% of annual comprehensive visits in the first 5 years of adult care. We considered one hematologist appointment per calendar year an annual comprehensive visit. Applying these definitions to our cohort, we categorized patients to determine rates of successful transfer and integration. Subsequent analyses determined patient characteristics and survey results associated with these outcomes. Patient characteristics were compared using chi-square tests for independence. Differences in mean ages, scores on cognitive screening assessments, and surveys were compared using t-tests. Results: One hundred and forty-five patients met inclusion criteria, mean age of 22.7 (SD 1.4) years, 57% female, 97% Black, 74% HbSS/HbSβ0 genotypes, and 54% publicly insured. Following the initial young adult clinic hematologist visit, 83% attended a second Center visit within a year, meeting successful transfer of care standards. Failure to transfer was associated with lower cognitive screening scores (mean MoCA score 25.2 vs 23.2, p=0.01). Successful transfer was associated with completion of the ASCQ-Me (51% vs 28% completion, p=0.04). No other associations between characteristics or surveys were identified. Fifty-one patients had 5 years of data from their initial visit until May 2025. Thirty-four (67%) attended at least half of their annual hematologist visits over that period and met criteria for successful integration into adult care. Among the remaining patients, 5 (10%) left the Center, with all but one transferring SCD care elsewhere. Four (8%) remained in the Center, seeing advanced practice providers. Three (6%) moved out of state for work or family, 2 (4%) died, 2 (4%) had successful bone marrow transplant, and 1 (2%) was seen only in consultation. Better cognitive screening scores were also associated with successful integration (mean score 25.7 vs 23.8, p<0.05). There were no patient characteristics or survey results associated with integration. Discussion: Most patients successfully transferred and integrated into a dedicated young adult clinic embedded in a comprehensive adult SCD Center. To our knowledge, this is the first application of NASCC consensus definitions of transfer and integration. Better cognitive screening scores were associated with successful transfer and integration. Participation in specific survey assessments was associated with successful transfer. Of the patients falling below the threshold for integration, nearly half moved or changed care centers, and only one patient became unaffiliated with SCD care entirely. Our findings highlight the challenge of collecting and interpreting appointment attendance data during the dynamic period of young adulthood.

Background: Sickle cell disease (SCD) is a complex hematologic disorder marked by chronic pain and neurocognitive impairments. While these complications are well-documented, the biological mechanisms driving them remain elusive. Platelets, known for their role in inflammation and vascular regulation, may serve as a window into systemic dysfunction in SCD. This study explored the platelet proteome in individuals with SCD to expose molecular correlates of pain and indicators of neurological risk. Methods: Peripheral blood samples were obtained from 16 adult volunteers living with sickle cell disease (SCD), all of whom reported experiencing moderate to severe pain (rated >3 on a 0–10 scale) related to SCD within the past 12 months. None of the participants had known degenerative conditions. Informed consent was obtained, and the study was approved by the institutional ethics board. To isolate ultra-pure platelets, a density gradient purification step was employed using OptiPrep™ (iodixanol-based medium). A discontinuous gradient was prepared by layering 6%, 10%, and 14% iodixanol solutions in sterile ultracentrifuge tubes. Platelet proteomes were analyzed using high-resolution mass spectrometry, identifying 4,197 proteins. Of these, 1,047 met statistical significance (FDR < 0.05) and were subjected to unsupervised clustering, pathway enrichment, and protein-protein interaction (PPI) network analyses. Pain phenotypes were assessed using SLANSS scores and pain word descriptors. Results: Unsupervised clustering stratified participants into high and low pain groups. Contrary to our hypothesis, pain-related pathways were not significantly enriched. Instead, 242 pathways showed significant alterations (FDR < 0.05), with robust enrichment in neurodegeneration, cognitive dysfunction, mitochondrial metabolism, ATP regulation, mitophagy, and tRNA aminoacylation. Volcano plot analysis prioritized proteins with FDR < 0.05 and log₂ fold change > 0.56 for downstream analysis. Distinct proteomic profiles emerged between pain groups. High-pain individuals exhibited elevated levels of UBQLN2, AP4B1, and WASHC5—proteins implicated in neurodegeneration and proteostasis. Low-pain individuals showed higher expression of GBA2, ATL1, and SOD1, associated with mitochondrial function and neuroprotection. PPI network analysis revealed tightly connected clusters within neurodegenerative and central nervous system (CNS)-related pathways. Particularly, tRNA aminoacylation proteins formed a distinct cluster, including ERLIN1, REEP2, SPG21, and AP4B1, while mitochondrial and proteostasis proteins such as UBQLN2, VCP, and AFG3L2 formed another. Disease association analysis ranked neurodegenerative and mitochondrial pathways as most strongly associated, surpassing traditional hematologic and pain-related mechanisms. Heatmap analyses confirmed consistent clustering of high-pain individuals with neurodegeneration-associated proteins (e.g., WARS, UBQLN2, COASY), while low-pain individuals aligned with neuroprotective markers (e.g., DNAJC5, SOD1, SCARB2). Conclusions: This study reveals unexpected platelet proteomic signatures in SCD, implicating neurodegenerative and mitochondrial pathways in pain phenotypes. These findings suggest that platelets may serve as accessible biomarkers for peripheral and/or CNS vulnerability and cognitive risk in SCD. The enrichment of tRNA aminoacylation and mitochondrial regulation pathways underscores the metabolic complexity of SCD and opens avenues for biomarker development and targeted intervention. Further longitudinal and functional studies are warranted to validate these findings and explore their clinical utility.

Introduction: Sickle cell disease (SCD) is an inherited hematological disorder with high rates of neurological complications, including ischemic stroke and silent cerebral infarction. Even without brain injury, individuals with SCD may experience progressive neurocognitive impairment. Executive dysfunction and processing speed deficits are particularly common in patients with SCD, negatively impacting medical adherence, educational and occupational outcomes, and the transition from pediatric to adult care. The latest guidelines recommend neurocognitive surveillance and screening in adult patients with SCD, with referral for formal evaluation as needed. However, no cognitive screening measures have been validated in SCD. The Montreal Cognitive Assessment (MoCA) and the Rowland Universal Dementia Assessment Scale (RUDAS) were previously studied in adults with SCD with promising results. An easily accessible, clinically validated cognitive screening tool is urgently needed for the adult SCD population. This pilot study aimed to assess the performance of the MoCA and RUDAS while evaluating the feasibility of virtual neurocognitive screening in an adult SCD population. Methods: Participants were recruited at a SCD clinical center. Individuals over 18 years of age with all types of SCD and any past medical history, including stroke, were included in the pilot study. After obtaining informed consent, the MoCA and RUDAS were administered to patients by a research coordinator. The participants then completed a virtual or in-person neuropsychological battery administered by a neuropsychological associate supervised by a licensed neuropsychologist. MRIs were obtained in participants if they did not have prior imaging within the last 6 months. Self-reported measures of mood, fatigue and pain were also collected. Statistical analyses included summary data and Spearman correlations given our small sample size. Results: A total of 33 participants, ages 22 to 64 years (mean 39.97 years), were consented for the study. Thirty-one completed the MoCA and RUDAS testing and twenty-three completed the neuropsychology testing. The study sample was primarily female (61%) with SCD genotypes SS (76%), S-beta null thalassemia (3%), SC (18%), and S-beta plus thalassemia (3%) included. The median hemoglobin level was 9.5 g/dL (range 6 to 13.5). The majority of the participants (78.2%) completed the formal neuropsychological testing virtually. All but two of the remaining participants completed in-person testing with another in-person component of the study (e.g. MRIs). Participants' median scores were all in the reference average range, except for the Oral Symbol Digits Modalities Test, a measure of processing speed, which was in the low average range. Certain participants' scores on measures of vocabulary (WASI Vocabulary), working memory (WAIS Digit Span) and executive functioning (DKEFS) were in the low average and borderline ranges. The MoCA and RUDAS scores had a strong significant correlation with each other (rho=0.5, p=0.005). The MoCA had strong significant correlations with the WASI Vocabulary scores (rho=0.5, p=0.02) and the WASI Full Scale IQ (rho=0.51, p=0.02). The RUDAS also had strong significant correlations with the WASI Vocabulary scores (rho=0.47, p=0.03) and the WASI Full Scale IQ (rho=0.52, p=0.01). There was a very strong significant correlation between RUDAS scores and hemoglobin (rho 0.74, p=0.004). Relationships were not seen between MoCA and RUDAS scores and age, sex, and SCD type. A limited number of study MRIs (12) were completed and not included in analyses at this time. Discussion/Conclusions: Pilot results are promising regarding feasibility of virtual neuropsychological testing and relationships between cognitive screening tests and gold-standard neuropsychological testing. Despite overlap between the measures, they may have different relationships with various SCD characteristics, such as anemia. Future study is needed with expanded populations for generalizability and validation.

Introduction: Sickle cell disease (SCD) is a genetic blood disorder affecting multiple organ systems, particularly the brain (Pinto, V.M. et al 2019). Neurocognitive deficits can occur in the presence or absence of overt brain injury, such as stroke or silent cerebral infarction (SCI). Using diffusion tensor imaging (DTI) metrics, multiple studies have identified widespread white matter alterations in individuals with SCD. DTI abnormalities, such as decreased fractional anisotropy (FA) and increased mean diffusivity (MD), have been associated with decreased processing speed in this population (Stotesbury et al. 2018). The goals of this study are to 1) define developmental differences in diffuse (brain-wide) white matter microstructure between SCD and control pediatric participants and 2) determine medical and neurocognitive characteristics of pediatric participants with SCD and abnormal DTI metrics. Methods: Thirty-eight participants between 8 to 12 years of age with no prior known history of stroke, SCI, or seizures were recruited for a prospective longitudinal study. Study groups consisted of 28 participants with SCD and 10 sibling or unrelated control participants. This study was a cross-sectional analysis of participants who completed DTI scans and neuropsychological testing at study entry (n=35). DTI was obtained on a 3T Philips research scanner 2.2mm nominal isotropic resolution; 32 diffusion directions obtained at b=700 s/mm 2. Preprocessing, tensor estimation, and calculation of FA and MD maps were performed using DTI Studio/MRICloud and its pediatric DTI atlas. Neurocognitive evaluation was performed and interpreted by a trained psychology associate with supervision from a board-certified neuropsychologist and included intelligence testing (Weschler Intelligence Scale for Children, WISC-5). Statistical analyses were performed using STATA 18 and MATLAB 2022a. We examined cohort-level demographics using chi-square tests, T-tests, and Wilcoxon rank sum tests (Table 1). To examine diffuse differences in white matter microstructure development, we used 19 bilateral white matter regions of interest [ROIs] shown in prior research to be important in patients with SCD with and without SCI. We examined MD and FA values within ANOVA models (each in terms of Group*Age + ROI) to assess group-level differences (SCD vs. control) and group x age interactions. We used ANOVA loadings to compute global MD and FA scores and computed 95% prediction intervals by age based on control participants. We identified participants with SCD with global scores suggestive of white matter microstructural differences (high MD and/or low FA) and compared their overall neurocognitive profiles. Results: The SCD and control participants were similar with regards to age, sex, and full-scale IQ. SCD participants had significantly lower median hemoglobin levels than control participants. There was one control participant who met criteria for SCI. SCD vs. control group status, age, and group x age interactions all significantly impacted our MD model (explaining 0.8%, 1.1%, and 0.8% of total variance, respectively; all p<0.001). MD decreased with age in the combined cohort (β=-9.3±1.6e-7/month) with significant flattening of this trend in children with SCD (group x age interaction: β=+7.9±2.0e-7/month). In contrast, only age significantly impacted our FA model (p<0.001, explaining 1.1% of variance); group status and group x age interactions each explained <0.2% of variance in FA. Four children with SCD had global DTI metrics suggestive of white matter injury (one with high MD and low FA; two with high MD only; one with low FA only). All 4 participants with abnormal DTI metrics had abnormal MRIs, three of whom had SCI and one of whom had lesions that did not meet the size criteria for SCI. Three participants had full scale IQs 1 standard deviation below the expected mean of 100 (<85). Conclusion: We identified differences in global white matter microstructural indices between SCD and control participants with an apparent blunting of expected decreases in mean diffusivity with age. Our continuing longitudinal study will explicitly assess DTI trajectories and implications for neurocognitive functioning in children with SCD.

Introduction: Sickle cell disease (SCD) is a genetic disorder that impacts the shape and functional capacity of red blood cells. Beyond altered cerebral perfusion, individuals with SCD have higher rates of neurodevelopmental disorders (NDDs), including attention deficit hyperactivity disorder (ADHD), intellectual disability, and specific learning disabilities. Past research has shown that in adolescent populations with either SCD or NDDs, pica, the act of eating non-food items, and enuresis, or involuntary urination, commonly occur. Both pica and enuresis are associated with biopsychosocial issues in typically developing children. However, the etiology of both of these disorders, as well as the confluence of NDDs and SCD on their occurrence, remains unclear. Hypothesis: The objective of this study was to determine the rates of pica and enuresis in a local pediatric SCD clinic and determine if these conditions present differently and/or have different associations in SCD than in the general population. We hypothesized that NDDs would serve as risk factors for both pica and enuresis with both conditions being associated with increased sickle cell severity. Methods: To test these hypotheses, we performed a retrospective chart review on 275 SCD patients. Using Epic, patients who at point visited either Kennedy Krieger Institute or John Hopkins Medical Center for SCD and were in an existing database were queried. Patients in the database ranged from 1 to 17 years old and were predominantly Black, non-Hispanic individuals. Primary keywords searched included: “enuresis, pica, bedwetting, diurnal, nocturnal, eating, non-food, peeing, urination, incontinence.” Results: Pica was reported in 9% (Table 1), while enuresis was reported in 27% of patient charts reviewed (Table 2). Both enuresis (Chi-squared test, p = 0.0050) and pica (Chi-squared test, p = 0.0190) were significantly linked to NDD occurrence, with pica being nearly three times as likely to occur alongside NDDs and/or enuresis. Notably, SCD patients with pica most commonly ate paper or wood, different from the general population with pica primarily eating rocks or dirt. Through the Wilcoxon rank sum test, we also noted no associations between pica and median hemoglobin (p=0.9572), ferritin (p=0.6209), iron serum (p=0.9500), total iron-binding capacity (p=0.1598), iron saturation (p=0.6292), or transferrin (p=0.1765) levels. Beyond this, our data also validate prior results demonstrating that enuresis is associated with both SCD type and hydroxyurea usage. There were no significant differences in rates of enuresis between males and females, unlike what is seen in the general population. Sleep apnea was associated with enuresis, at a higher rate than in the general population (Chi-squared post-hoc residual test, p = 0.0004). Patients with SCD and enuresis had higher mean reticulocyte counts and lower mean hemoglobin levels than patients with SCD without enuresis, consistent with increased hemolysis and worsening SCD severity. Conclusion: These results suggest etiologies for pica and enuresis in SCD patients may differ from the general population. As pica and enuresis commonly occur together with NDDs, there is a clear need for increased standardized screening for these conditions in clinics. Understanding why the risk factors for these conditions in SCD differ from the general population requires further investigation into their respective mechanisms of disease.

BackgroundThe COVID-19 pandemic uniquely affects patients with neurologic and developmental disabilities at the Kennedy Krieger Institute. These patients are at increased risk of co-morbidities, increasing their risk of contracting COVID-19. Disruptions in their home and school routines, and restrictions accessing crucial healthcare services has had a significant impact.MethodsA Pandemic Intake questionnaire regarding COVID-19 related medical concerns of guardians of patients was distributed using Qualtrics. Data from May-December 2020 were merged with demographic information of patients from 10 clinics (Center for Autism and Related Disorders (CARD), Neurology, Epigenetics, Neurogenetics, Center for Development and Learning (CDL) Sickle Cell, Spinal Cord, Sturge-Weber syndrome (SWS), Tourette's, and Metabolism). A provider feedback survey was distributed to program directors to assess the effectiveness of this intervention.ResultsAnalysis included responses from 1643 guardians of pediatric patients (mean age 9.5 years, range 0–21.6 years). Guardians of patients in more medically complicated clinics reported perceived increased risk of COVID-19 (p < 0.001) and inability to obtain therapies (p < 0.001) and surgeries (p < 0.001). Guardian responses from CARD had increased reports of worsening behavior (p = 0.01). Providers increased availability of in-person and virtual therapies and visits and made referrals for additional care to address this. In a survey of medical providers, five out of six program directors who received the responses to this survey found this questionnaire helpful in caring for their patients.ConclusionThis quality improvement project successfully implemented a pre-visit questionnaire to quickly assess areas of impact of COVID-19 on patients with neurodevelopmental disorders. During the pandemic, results identified several major areas of impact, including patient populations at increased risk for behavioral changes, sleep and/or disruptions of medical care. Most program directors reported improved patient care as a result.

Sickle cell disease (SCD) is an inherited hemoglobinopathy with an increased risk of neurological complications. Due to anemia and other factors related to the underlying hemoglobinopathy, cerebral blood flow (CBF) increases as compensation; however, the nature of alterations in oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2) in SCD remains controversial, largely attributed to the different calibration models. In addition, limited studies have been done to investigate oxygen metabolism in pediatric patients. Thus, this study used a non-invasive T2-based MR oximetry, T2-Relaxation-Under-Spin-Tagging (TRUST) MRI, to measure oxygen homeostasis in pediatric patients with SCD using four different calibration models and examined its relationship to hematological measures. It was found that, compared with controls, SCD patients showed an increased CBF, unchanged total oxygen delivery and increased venous blood T2. The results of OEF and CMRO2 were dependent on the calibration models used. When using sickle-specific, hemoglobin S (HbS) level-dependent calibration, there was a decreased OEF and CMRO2, while the bovine model showed an opposite result. OEF and CMRO2 were also associated with hemoglobin and HbS level; the direction of the relationship was again dependent on the model. Future studies with in vivo calibration are needed to provide more accurate information on the T2-Yv relationship.

Children exposed to maternal sickle cell disease (SCD) have many theoretical risks for developmental disorders, but little is known about long-term outcomes for these children. We used the Boston Birth Cohort to compare developmental outcomes between children exposed to maternal SCD and matched, unexposed controls. Children with exposure to maternal SCD had increased risk of attention deficit hyperactivity disorder (OR 5.12, 95% CI 1.36-19.19, p = 0.02) and obesity (OR 2.74, 95% CI 1.10-6.87, p = 0.03). In utero and/or environmental exposures may help explain these findings. Further studies of outcomes of children born to women with SCD are needed.

Adults with sickle cell disease (SCD) are at risk for cognitive impairment, which causes significant morbidity. Guidelines support routine cognitive screening, but no screening test is validated in this population. We explored the Montreal Cognitive Assessment (MoCA) as a possible screening test in SCD. We administered the MoCA; a literacy test, the Wide Range Achievement Test, fourth edition (WRAT-4); and a health literacy test, the Shortened Test of Functional Health Literacy in Adults (S-TOFHLA) to adults with SCD and gathered clinical variables through chart review. Spearman's rho, Mann-Whitney, and Kruskal-Wallis tests and quantile regression models were used. Among our sample of 49 adults with SCD, the median MoCA score was 25.0 [interquartile range (IQR) 22.0-28.0]. Higher educational attainment was associated with MoCA scores (p = 0.001). In multivariable models, MoCA scores were associated with S-TOFHLA (p = 0.001) and WRAT-4 Reading (p = 0.002) scores, and overt stroke (p = 0.03) at the median. This pilot study adds to the limited literature of cognitive screening tests in adults with SCD and demonstrates a relationship between MoCA scores and measures of literacy and health literacy. The MoCA is a promising option for briefly screening for cognitive impairment in adults with SCD, though further study is needed to confirm its validity.

Purpose:The COVID-19 pandemic created novel challenges for school systems and students, particularly students with disabilities. In the shift to remote/distance learning, this report explores the degree to which children with disabilities did not receive the special education and related services defined in their individualized education program (IEP). Methods:Patients attending an outpatient tertiary care center for neurodevelopmental disabilities in Maryland were surveyed on the impact of the pandemic on educational services provision. Results:Nearly half (46%) of respondents qualified for special education and related services through an IEP before the start of the COVID-19 pandemic. Among those with IEPs, 48% attested to reduced frequency and/or duration of special education and/or related services during the pandemic. The reduction was greatest in occupational therapy services (47%), followed physical therapy services (46%), and special education services (34%). Conclusion:This survey of children with disabilities observes a substantial reduction in IEP services reported in their completed surveys. To address the observed reduction in IEP services, we sought additional education for clinicians on the rights of students with disabilities in anticipation of students' re-entry to the classroom. A special education law attorney provided an instructional session on compensatory education and recovery services to prepare clinicians to properly inform parents about their rights and advocate for patients with unmet IEP services during the pandemic.

Despite recent developmental screening guidelines, rates of neurodevelopmental disorders (NDDs) remain lower than expected in children with sickle cell disease (SCD). A retrospective chart review identified 276 eligible patients; 214 charts were available for developmental screening and 207 charts for autism-specific screening. Developmental surveillance/screening was conducted in 70% of charts and autism-specific screening in 19% of charts. Validated tools were used in 32% of developmental screenings and 92% of autism-specific screenings. Many children (57%) were screened outside recommended ages. In conclusion, children with SCD are not regularly receiving appropriate developmental screening and surveillance by their healthcare providers.

Sickle cell disease (SCD), a group of inherited hemoglobinopathies, is associated with high rates of neurological complications, particularly ischemic stroke and silent cerebral infarction.1 Silent cerebral infarction is now considered the most common neurological complication of SCD, affecting 39% of children with HbSS or HbSβ0 thalassemia by 18 years of age, and up to 50% of adults with HbSS or HbSβ0 thalassemia by 30 years of age.2-4 However, silent cerebral infarction is not, in fact, silent. It is associated with several symptoms, including deficits in cognition as well as an increased risk of future stroke and silent cerebral infarction.5 In the latest American Society of Hematology SCD Clinical Practice Guidelines on Sickle Cell Disease for cerebrovascular disease,6 the authors “placed a higher value on maintaining cognitive function than on being alive with significantly less than baseline cognitive function.” Neurocognitive evaluation is recommended after positive developmental surveillance by a hematologist or clinician, followed by positive formal developmental screening by a primary care provider or psychologist or after stroke or silent cerebral infarction have been diagnosed. While we agree with the guidelines in general, we question whether preservation of cognitive function is achievable if we are only making provisions for neurocognitive evaluation after neurocognitive dysfunction or structural brain injury has already occurred. Serial neurocognitive evaluation at regular intervals may detect impairment prior to the development of observable structural brain injury, allowing earlier introduction of disease-modifying and neuroprotective therapies as well as consideration of curative treatments, therapeutic services, and cognitive rehabilitation. We feel the guideline recommendation for neurocognitive testing after brain injury is not sufficient. As neurocognitive impairment has been found in patients with SCD with and without structural evidence of brain injury,7, 8 prevalence of these deficits is likely greater than the prevalence of silent cerebral infarcts. In addition, evidence from several studies and review articles indicates that progressive and subtle neurocognitive dysfunction is present in SCD, from as early as 1 year of age into adulthood.9-15 In the Cooperative Study of Sickle Disease, school-age children with SS-type SCD were shown to have decreasing scores in verbal IQ and math achievement.16 Data from the BABY HUG study showed worsening behavior and adaptive functioning with increasing age in toddlers with SCD.17 Adults with SCD and no prior history of neurological diagnoses, normal neurological examinations, and normal neuroimaging were found to have deficits in performance IQ, full-scale IQ, working memory, and processing speed in comparison to community controls.8 The guidelines state that children with SCD should be surveilled for neurocognitive difficulties by their hematologists and, if positive, should be referred to a primary care provider or a psychologist capable of performing formal screening. We take issue with this “gatekeepers” approach. Given that children with SCD are already known to be at increased risk for neurocognitive impairment, we propose that baseline testing and periodic re-evaluation should be the standard of care, as is done with other high-risk pediatric populations (e.g., premature and low birth-weight infants, children with congenital heart disease, pediatric oncology patients, children with epilepsy, etc.).18 Per the neurodevelopmental guidelines developed for high-risk congenital heart disease patients, direct referral for formal developmental/medical evaluation and services with periodic re-evaluation at 12–24 months, 3–5 years, and 11–12 years of age is indicated.19 In children with diagnosed neurodevelopmental disabilities, comprehensive re-evaluation is indicated at the times of educational transition, specifically the start/end of elementary, middle, and high school. Another study recommended cognitive evaluations prior to school entry and during transition to adult medical care for children with SCD.11 These modifications would enable providers to better document longitudinal change and institute appropriate interventions. Surveillance and screening for neurodevelopmental concerns are fundamental parts of well-child visits; however, for patients with SCD, these components may not be performed because of the need to address competing medical and psychosocial issues during clinic visits. There is still significant likelihood that children with SCD and developmental concerns will be missed by the screening/surveillance approach or that patients will not be referred for appropriate evaluation and treatment. In addition, the outcome of screening is “risk.” Children with SCD are already at higher neurocognitive risk. Consequently, the appropriate course of action is evaluation. Children with SCD should be assessed by providers who are aware of the impact of SCD on neurocognitive outcome, and who are capable of determining what level of evaluation is necessary. We acknowledge the perception that neuropsychological testing is difficult to assess, but we would respond that these challenges are not insurmountable, as demonstrated by the services provided to other high-risk pediatric populations mentioned above. We should expand our scope and provide adequate care to this often underserved population. Universal baseline neurodevelopmental evaluation for all children with SCD is achievable through early referral by either hematologists or pediatricians to a specific neurodevelopmental provider experienced with SCD, embedded neuropsychological or neurodevelopmental services in pediatric hematology clinics, or formal psycho-educational assessment through local schools. Importantly, under the Individuals with Disabilities Education Act (IDEA), children with SCD are eligible for a multidisciplinary team evaluation, because of their elevated disease-associated neurocognitive risk; thus, some form of neurocognitive assessment should be available to all children with SCD from birth to high school graduation or age 21 years. The new guidelines provide comprehensive recommendations for cognitive surveillance and screening, and call for research to improve the implementation and neurocognitive evaluation and specific cognitive rehabilitation. However, without including a recommendation for a standard baseline comprehensive neurocognitive evaluation for every person with SCD, we feel the stated goal of protecting neurocognitive functioning will not be achieved. We must identify and refer children with neurocognitive difficulties for early evaluation with an experienced neurodevelopmental provider familiar with sequelae from vascular brain injury and the specific evolving subtle deficits these patients have across the lifespan; as the authors of the guidelines note, “both stroke and silent cerebral infarcts are associated with significant cognitive impairments that may significantly alter educational attainment, employment status, and quality of life.” Early identification and intervention are often the key to modifying the developmental trajectory. We, as providers, should endeavor to start that process as early as possible. None. Eboni I. Lance served on an advisory board for Novartis. James F. Casella holds a patent for aptamers that are potential treatments for sickle cell disease. Under a license agreement between Immunarray, Ltd. and the Johns Hopkins University, James F. Casella is entitled to royalties on a license for a brain biomarker panel. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. Neither the aptamers nor any of the analytes involved in this panel were studied in the current paper. For the remaining authors, no additional disclosures were declared.

Children with sickle cell disease (SCD) commonly experience headaches, both acutely and chronically. Although migraine and tension headache are common causes, headaches may also be related to their underlying SCD and associated with acute central nervous system events. The purpose of this study was to determine the frequency, severity, and associated characteristics of headaches in children with SCD. This retrospective study was approved by the Johns Hopkins Institutional Review Board. Subjects were children < 18 years old with SCD identified using Hopkins' clinic rosters and medical records. Patient medical records were searched to determine reports of headaches in inpatient or outpatient encounters. Data were extracted from subjects' charts including, SCD history, headache history, stroke and silent cerebral infarction (SCI) history with additional review of imaging by neurologist (EIL) and radiologist if needed to confirm diagnosis, medications, laboratory values, neurology referrals, and neuroimaging results. Based on patient-reported headache details in the medical record, we determined headache type using the International Classification of Headache Disorders criteria. Headaches were further characterized by frequency and severity. We used descriptive statistics to describe the SCD population with and without headaches. We then compared demographic and clinical characteristics of patients with headaches to those without headaches using parametric and nonparametric statistical tests when appropriate. We included 276 subjects in our data analysis. Fifty three percent of patients had a history of headache. Characteristics of subjects with (N=147) and without (N=129) headache are in Table 1. Sixty-six of the headache subjects were seen by a neurologist/neurodevelopmental physician. The primary reason for referral for 10 subjects was headache, SCI for seven subjects, ADHD for 11 subjects, learning difficulties for 25 subjects, and other for 19 subjects. Compared to those without headaches, subjects with headaches were significantly older at time of chart review (10.52 vs. 6.67, p < 0.0001), had more severe disease (62.2% sickle cell anemia vs. 37.4% compound heterozygous, p<0.001), had more neurological complications (7% stroke & 12% SCI - headache group vs. 3% stroke and 1% SCI - no headache group, p <0.003), had higher median reticulocyte count (8.0% vs. 4.3%, p < 0.003), and lower median hemoglobin F (7.95% vs. 11.7%, p <0.003). In terms of headache characteristics, nine patients reported headaches less than one day per month on average; 13 subjects reported one to 14 days of headache per month on average for more than three months; and four subjects reported greater than 15 days of headache per month on average for more than three months. Five subjects also reported avoidance of their routine due to headaches. Twelve subjects were hospitalized for headache and 30 reported an emergency department visit for headache. Only 10 subjects had enough details about their headache features to determine their headache type (Table 2). Nine of the subjects' headache types were consistent with criteria for migraine headaches and one subject had tension type headache. Headaches are common in children with SCD. Our findings suggest that children with SCD and history of headache are more likely to have SCD-related and neurological complications. Additionally, children with SCD and headache are more likely to have a higher median reticulocyte count which is associated with more severe disease. More studies are needed to classify and understand headaches in children with SCD, which may help guide management and treatment in this patient population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

BACKGROUND:Blood-brain barrier (BBB) disruption may lead to endothelium dysfunction and inflammation in sickle cell disease (SCD). However, abnormalities of BBB in SCD, especially in pediatric patients for whom contrast agent administration less than optimal, have not been fully characterized. PURPOSE:To examine BBB permeability to water in a group of pediatric SCD participants using a non-invasive magnetic resonance imaging technique. We hypothesized that SCD participants will have increased BBB permeability. STUDY TYPE:Prospective cross-sectional. POPULATION:Twenty-six pediatric participants (10 ± 1 years, 15F/11M) were enrolled, including 21 SCD participants and 5 sickle cell trait (SCT) participants, who were siblings of SCD patients. FIELD STRENGTH/SEQUENCE:3 T. Water extraction with phase-contrast arterial spin tagging with echo-planer imaging, phase-contrast and T1 -weighted magnetization-prepared rapid acquisition of gradient echo. ASSESSMENT:Water extraction fraction (E), BBB permeability-surface area product (PS), cerebral blood flow, hematological measures (hemoglobin, hematocrit, hemoglobin S), neuropsychological scores (including domains of intellectual ability, attention and executive function, academic achievement and adaptive function, and a composite score). Regions of interest were drawn by Z.L. (6 years of experience). STATISTICAL TESTS:Wilcoxon rank sum test and chi-square test for group comparison of demographics. Multiple linear regression analysis of PS with diagnostic category (SCD or SCT), hematological measures, and neuropsychological scores. A two-tailed P value of 0.05 or less was considered statistically significant. RESULTS:Compared with SCT participants, SCD participants had a significantly higher BBB permeability to water (SCD: 207.0 ± 33.3 mL/100 g/minute, SCT: 171.2 ± 27.2 mL/100 g/minute). SCD participants with typically more severe phenotypes also had a significantly leakier BBB than those with typically milder phenotypes (severe: 217.3 ± 31.7 mL/100 g/minute, mild: 193.3 ± 31.8 mL/100 g/minute). Furthermore, more severe BBB disruption was associated with worse hematological symptoms, including lower hemoglobin concentrations (β = -8.84, 95% confidence interval [CI] [-14.69, -3.00]), lower hematocrits (β = -2.96, 95% CI [-4.84, -1.08]), and higher hemoglobin S fraction (β = 0.77, 95% CI [0.014, 1.53]). DATA CONCLUSION:These findings support a potential role for BBB dysfunction in SCD pathogenesis of ischemic injury. LEVEL OF EVIDENCE:2 TECHNICAL EFFICACY: Stage 2.

Purpose: To determine the relationship between macular microvascular abnormalities on optical coherence tomography angiography and silent cerebral infarctions (SCIs) on cerebral magnetic resonance imaging in sickle cell disease. Methods: Patients (age <18 years old) from our previous pediatric sickle cell disease study cohort who had prior optical coherence tomography angiography and brain magnetic resonance imaging were identified. Brain magnetic resonance imaging images were compared with macular optical coherence tomography angiography scans to identify macular vascular density differences between patients with SCI and without SCI. Results: Sixty-eight eyes from 34 patients who underwent optical coherence tomography angiography were evaluated, of whom 28 eyes from 14 patients met the inclusion criteria for this study. Eight patients (57%) with SCI and 6 patients (43%) without SCI were identified. The mean age (17 years in SCI and 16.3 years in non-SCI) was comparable between groups. There was no statistically significant difference in systemic complications. Deep capillary plexus vessel density was lower in the temporal quadrant in patients with SCI (49.3% vs. 53.7%, P = 0.014). Conclusion: Patients with SCI were found to have lower vessel density in the deep capillary plexus compared with those without SCI. This finding suggests that deep capillary plexus vessel density may have utility as an imaging biomarker to predict the presence of SCI.

Sickle cell disease (SCD) is an inherited hemoglobinopathy that frequently causes neurological complications, such as stroke, silent cerebral infarct (SCI) and other forms of brain injury, including loss of cognition. SCI is defined as any ischemic lesion visible on T2-weighted magnetic resonance imaging (MRI) that is not associated with a focal neurologic deficit in the same vascular distribution, and is the most commonly recognized form of brain injury in SCD. SCI is associated with decreased neurocognitive function and increased risk for new or enlarging SCI/stroke. The purpose of this study was to use mass spectrometry (MS) based proteomics to discover and validate plasma brain proteins associated with brain injury in children with SCD. The plasma samples used for the proteomics discovery analyses were from two groups: screening samples of participants in the Silent Cerebral Infarct Multi-Center Clinical Trial (SIT Trial) (n=15), and 6 age-matched, healthy non-SCD controls, three of whom had sickle cell trait. Samples from children with SCD were divided into two groups: those with SCI (n=7) and those without SCI (n=8) matched for age, hemoglobin (Hb) and white blood cell counts. To identify circulating markers of SCI, plasma proteomes were analyzed using a sequential separation approach of Hb and top abundant plasma protein depletion, followed by reverse phase separation of intact proteins, trypsin digestion and tandem MS. Neurogranin (NRGN), a small calmodulin-binding synaptic protein (PMID 9886843), was the most abundant brain-enriched protein found in the plasma of children with SCD. We developed a NRGN sandwich immunoassay for verification of MS analysis results in an independent cohort from the SIT Trial longitudinal samples. For this verification study, plasma samples from the SIT Trial and 25 normal controls were tested for NRGN levels at study entry and exit by immunoassay. The majority of the SCD samples were obtained from an ancillary study to collect longitudinal samples that started after the SIT Trial had begun. There was no overlap between the discovery and the verification group samples. The normal control samples were from 25 healthy, age and gender comparable non-SCD pediatric controls unrelated to the SIT Trial, without evidence of acute/chronic illness. From the discovery SCD group, 1172 unambiguous proteins were identified; 639 proteins were identified from normal controls, as shown in Figure 1. Twenty-five percent (289/1172) of these proteins were found solely in the SCI group. Our MS protein identification data were filtered against this list of expressed brain proteins to produce a composite list of brain proteins found in plasma from children with SCD, but not found in plasma from age, gender and race-matched healthy control children. Twenty-five plasma proteins known to be expressed in one or more cell type enriched in the human brain based on bioinformatics searches were more abundant in the SCD vs control groups, as shown in Table 1. Median NRGN levels were higher at study entry in children with SCD (0.44 ng/mL, N=98), in comparison to a healthy, non-SCD control group (0.12 ng/mL, N=25, p < 0.0001), as shown in Figure 2. Using the longitudinal samples from the SIT Trial, there were no differences in NRGN levels between the observation group and the treatment group (p=0.35) over time. There was no significant difference in median NRGN levels between the observation group and the treatment group at the initial visit (0.36 vs 0.19, p=0.069) or final visit (0.39 vs 0.52, p=0.52). Using the initial visit samples from the SIT Trial, there was no significant difference in median NRGN levels between the non-SCI (n=35) and SCI groups (n=61) (p=0.073). There was no significant correlation between NRGN levels and neuropsychological measures of executive function (rho=0.089, p=0.58) and IQ (rho=-0.081, p=0.62). Our non-biased proteomic discovery studies demonstrate that NRGN levels are increased in children with SCD, when compared to normal children. Additional studies will be necessary to determine whether NRGN levels correlate with specific forms of neurologic injury. Further validation studies of larger cohorts with a multi-analyte ELISA of these brain proteins identified in plasma (Table 1) are warranted, and could help establish possible links between brain-specific proteins and neurocognitive outcomes. Disclosures Lance: NIH: Research Funding; KKI: Research Funding. Faulcon:FDA: Employment, Other: Although the author is a FDA/CTP employee, this work was not done as part his/her official duties. This publication reflects the views of the author and should not be construed to reflect the FDA/CTP's views or policies.. Fu:GSK: Employment. Yang:ImmunArray: Patents & Royalties: ImmunArray. Strouse:Global Blood Therapeutics: Consultancy. Barron-Casella:Mast Pharmaceudicals - spouse: Consultancy; ImmunArray - spouse: Patents & Royalties. Van Eck:ImmunArray: Consultancy, Patents & Royalties. Casella:NIH: Research Funding; Mast Pharmaceuticals: Consultancy; Immunoarray Ltd.: Patents & Royalties. Everett:ImmunArray: Consultancy, Patents & Royalties.

ABSTRACT: Objective: The objective of this study is to retrospectively determine the co-occurrence, associated characteristics, and risk factors for neurodevelopmental disorders (NDD) in a pediatric sickle cell disease (SCD) clinic population. Method: We investigated the co-occurrence and features of NDD in pediatric SCD through a retrospective cohort study conducted between July 2017 and January 2019. The participants were patients with SCD younger than 18 years of age identified from our institutions' clinic rosters and medical records databases. Results: A total of 276 participants were eligible for study inclusion, and 65 participants were found to have various NDD. Children with SCD and NDD were more likely to have a history of multiple SCD-related complications in comparison to children with SCD without NDD. Children with SCD and NDD were more likely to use disease-modifying therapies in comparison to children with SCD without NDD (χ 2 27.2, p < 0.001). Conclusion: Children with SCD and NDD have higher odds of having certain disease-related complications and higher use of disease-modifying treatments than children with SCD who do not have NDD. Screening and diagnoses of NDD may be relevant to clinical management of pediatric SCD.

Children with sickle cell disease (SCD) have a high risk of developing cerebrovascular complications, such as stroke and silent cerebral infarction (SCI). SCI is associated with increased risk of future infarction as well as neurocognitive deficits related to brain injury location and size; however, neurocognitive impairment may occur in the absence of neuroimaging abnormalities. Resting state functional magnetic resonance imaging (RS-fMRI) measures blood oxygen level dependent (BOLD) signal during rest to evaluate functional connectivity between brain regions. Functional connectivity is the temporal correlation between the BOLD signal in spatially distant brain regions, which reflects synchronous activity. For this study, we hypothesized that participants with SCI would have lower functional connectivity than participants without SCI and that specific resting state networks would be associated with specific cognitive tests in SCD and control participants.