Pro-inflammatory cerebrospinal fluid profile of neonates with intraventricular hemorrhage: clinical relevance and contrast with CNS infection.

BACKGROUND: Interpretation of cerebrospinal fluid (CSF) studies can be challenging in preterm infants. We hypothesized that intraventricular hemorrhage (IVH), post-hemorrhagic hydrocephalus (PHH), and infection (meningitis) promote pro-inflammatory CSF conditions reflected in CSF parameters. METHODS: Biochemical and cytological profiles of lumbar CSF and peripheral blood samples were analyzed for 81 control, 29 IVH grade 1/2 (IVH1/2), 13 IVH grade 3/4 (IVH3/4), 15 PHH, 20 culture-confirmed bacterial meningitis (BM), and 27 viral meningitis (VM) infants at 36.5 ± 4 weeks estimated gestational age. RESULTS: PHH infants had higher (p < 0.02) CSF total cell and red blood cell (RBC) counts compared to control, IVH1/2, BM, and VM infants. No differences in white blood cell (WBC) count were found between IVH3/4, PHH, BM, and VM infants. CSF neutrophil counts increased (p ≤ 0.03) for all groups compared to controls except IVH1/2. CSF protein levels were higher (p ≤ 0.02) and CSF glucose levels were lower (p ≤ 0.003) for PHH infants compared to all other groups. In peripheral blood, PHH infants had higher (p ≤ 0.001) WBC counts and lower (p ≤ 0.03) hemoglobin and hematocrit than all groups except for IVH3/4. CONCLUSIONS: Similarities in CSF parameters may reflect common pathological processes in the inflammatory response and show the complexity associated with interpreting CSF profiles, especially in PHH and meningitis/ventriculitis.

Dry Eye Symptoms and Signs in US Veterans With Gulf War Illness.

PURPOSE: To examine dry eye (DE) symptoms and signs in individuals with vs without Gulf War illness (GWI). DESIGN: Prospective cross-sectional study. METHODS: We performed a prospective, cross-sectional study of South Florida veterans who were active duty during the Gulf War era (GWE; 1990-1991) and seen at an eye clinic between October 1, 2020, and March 13, 2021. Veterans were split into 2 groups: those who met Kansas criteria for GWI (cases, n = 30) and those who did not (controls, n = 41). DE symptoms were assessed via standardized questionnaires whereas DE signs were assessed using a series of ocular surface parameters. Differences between groups were assessed via Mann-Whitney U test. Linear regression analyses were used to examine which GWI symptoms most closely aligned with DE symptoms. RESULTS: Veterans with GWI had higher DE symptoms scores compared to controls (Ocular Surface Disease Index [OSDI] scores: mean 41.20±22.92 vs 27.99±24.03, P = .01). In addition, veterans with GWI had higher eye pain scores compared with controls (average eye pain over past week: 2.63±2.72 vs 1.22±1.50, P = .03), including on neuropathic ocular pain questionnaires (Neuropathic Pain Symptom Inventory modified for the Eye [NPSI-E]: 17.33±17.20 vs 9.63±12.64, P = .03). DE signs were mostly similar between the groups. GWI symptoms "nausea or upset stomach" (ß=14.58, SE = 3.02, P < .001) and "headache" (ß=7.90, SE = 2.91, P = .011) correlated with higher OSDI scores. CONCLUSION: Individuals with GWI have more severe DE symptoms and ocular pain scores but similar tear and ocular surface parameters compared to controls without GWI. This finding suggests that mechanisms beyond tear dysfunction drive eye symptoms in GWI.

Ocular Pain Symptoms in Individuals With and Without a History of Refractive Surgery: Results From a Cross-Sectional Survey.

PURPOSE: This study characterized ocular pain symptoms in individuals with and without a history of refractive surgery (RS) using a cross-sectional survey of individuals with ocular pain. METHODS: A link to an anonymous survey was posted on a corneal neuralgia Facebook group that included individuals with ocular pain from any etiology and sent to individuals seen in our clinic with ocular pain. The survey asked about medical history, ocular pain symptoms (using standardized questionnaires), and treatment responses. Respondents were split into 2 groups based on a history of RS. RESULTS: One hundred one individuals responded to the survey. The mean age for all respondents was 41.6 ± 15.6 years, and 50% reported a history of RS. A total of 46% of individuals with a history of RS reported that their ocular pain started within 1 month of surgery, with median pain duration of 36 (interquartile range 22-84) months. The median Dry Eye Questionnaire-5 (range 0-22) scores were 16 and 15 for the RS and no-RS groups, respectively. Most individuals in both groups characterized their pain as burning (score ≥1: RS, 86%; no-RS, 80%) and reported evoked pain to wind, light, or temperature (score ≥1: RS, 97%; no-RS, 85%). Fifty-nine of 101 individuals responded to treatment questions. Individuals in both groups reported >30% improvement in pain symptoms with some topical and systemic approaches. CONCLUSIONS: Individuals with a history of RS developed ocular pain soon after surgery, which persisted for years. Symptom profiles were similar between those with and without RS. Topical and systemic approaches can treat pain in both groups.

Exploring the Link Between Dry Eye and Migraine: From Eye to Brain.

Dry eye and migraine are common diseases with large societal and economic burdens that have recently been associated in the literature. This review outlines the link between dry eye and migraine, which may have implications for reducing their respective burdens. We highlight possible shared pathophysiology, including peripheral and central sensitization, as the potential link between dry eye and migraine. Finally, therapies targeting similar pathophysiological mechanisms between dry eye and migraine are discussed.

Ocular manifestations and biomarkers of Gulf War Illness in US veterans.

Gulf War Illness (GWI) is a multisystem disease with variable presentations, making diagnosis difficult. Non-invasive biomarkers would aid in disease diagnosis. We hypothesized that the eye could serve as a biomarker for GWI. We performed a retrospective case-control study using a sample of 1246 patients seen during a 5-month period in an optometry clinic. We identified veterans who were active duty during the Gulf War Era and either had a questionnaire-based diagnosis of GWI (cases) or did not (controls). Medical records were reviewed for eye and medical co-morbidities, medication use, and retinal macular and nerve fiber layer (NFL) thicknesses based on optical coherence tomography (OCT) images. Compared to controls (n = 85), individuals with GWI (n = 60) had a higher frequency of dry eye symptoms (50% vs 32.9%, p = 0.039). Multivariable analysis revealed average retinal NFL thickness (odds ratio; OR = 0.95), cup-to-disc ratio (OR = 0.005), age (OR = 0.82), and PTSD (OR = 20.5) were predictors of a GWI diagnosis. We conclude that GWI is associated with dry eye symptoms and RNFL thinning may serve as a biomarker for disease.

Effect of non-invasive intranasal neurostimulation on tear volume, dryness and ocular pain.

PURPOSE: To evaluate the effect of one TrueTear session on change in tear volume and symptoms of dryness and ocular pain. METHODS: Retrospective interventional case series of patients seen in a dry eye clinic. Seventy-five individuals underwent an ocular surface examination and one session of neurostimulation. Outcome measures included objective change in tear volume measured via phenol red test, and subjective change in sensations of dryness and ocular pain measured on a 0-10 Numerical Rating Scale. RESULTS: The mean age of the 75 individuals was 59±13 years, and the majority were male (73%). Intranasal neurostimulation increased tear volume (mean 13.40±8.00 mm, p<0.0005) and reduced intensities of dryness (mean -2.85±2.79, p<0.0005) and ocular pain (mean -1.48±2.41, p<0.0005 for both). However, these effects were independent of one another as change in symptom report did not correlate with change in tear volume (r=-0.13, p=0.25 for dryness; r=0.07, p=0.56 for pain). In a multivariable model, the strongest predictors for increased tear volume were lower baseline tear volume (standardised beta (ß)=-0.50, p<0.0005) and absence of an autoimmune disease (ß=-0.36, p=0.001) (R2=0.30). The strongest predictors for reduced dryness and pain scores were lower baseline dryness and ocular pain scores. No complications related to neurostimulation were noted. CONCLUSION: Intranasal neurostimulation increased tear volume and reduced intensities of dryness and ocular pain, independently of one another.

Widely Metastatic Choroid Plexus Carcinoma Associated with Novel TP53 Somatic Mutation.

BACKGROUND: Choroid plexus carcinoma (CPC) is a rare, malignant tumor occurring more commonly in children than adults. This case report describes the clinical course of a 3-year-old boy with a rare case of metastatic CPC with a novel TP53 mutation. CASE DESCRIPTION: A 3-year-old boy presented with postconcussive symptoms after a fall. Computed tomography and magnetic resonance imaging revealed lesions in the suprasellar cistern, left lateral ventricle, and cauda equina. The tumor was diagnosed as choroid plexus carcinoma with a novel TP53 V216M somatic mutation. The patient underwent resection of the left lateral ventricle lesion. CONCLUSION: We describe a case of CPC with highly metastatic characteristics and a novel TP53 mutation. Our report implicates TP53 in the pathogenesis of pediatric CPC, and we emphasize that CPC in children should prompt careful consideration of TP53 status to inform prognosis and clinical treatment.

Predictors of mortality for preterm infants with intraventricular hemorrhage: a population-based study.

PURPOSE: The goal of this longitudinal, population-level study was to examine factors affecting mortality in preterm infants with intraventricular hemorrhage (IVH). METHODS: The study examined patients who were born at 36 weeks estimated gestational age (EGA) or less with a diagnosis of IVH between the years 2005 and 2014 using data from the New York and Nebraska State Inpatient Databases. Potential predictors for mortality were investigated with multivariable survival analysis. RESULTS: The cohort included 7437 preterm infants with IVH. All-cause inpatient mortality occurred in 746 (10.0%). The majority of deaths were in infants born at less than 25 weeks EGA (378 or 50.7%) and with birthweight less than 750 g (459 or 61.5%). Mortality was highest for children with grade IV IVH (306/848 or 36.1%), followed by grades III (203/955 or 21.3%), II (103/1328 or 7.8%), and I (134/4306 or 3.1%). Hydrocephalus was diagnosed within 6 months in 627 (8.4%) patients, with cerebrospinal fluid shunts required in 237 (3.2%). Shunts were eventually revised in 122 (51.5% of shunts), and 43 (18.1%) had infections. Multivariable Cox survival analyses found male sex (HR 1.3 [95% CI 1.1-1.5]), Asian race (HR 1.5 [1.1-2.2]), lower EGA (HR 9.9 [6.3-15.5] for < 25 weeks), higher IVH grade (HR 6.1 [4.9-7.6] for grade IV), gastrostomy (HR 4.0 [2.0-7.7]), tracheostomy (HR 3.5 [1.7-7.1]), and shunt infection (HR 3.2 [1.0-9.9]) to be independently associated with increased mortality risk. CONCLUSIONS: This database is the first of its kind assembled for population-based investigations of long-term neurosurgical outcomes in preterm infants with IVH.

Chemokine and cytokine levels in the lumbar cerebrospinal fluid of preterm infants with post-hemorrhagic hydrocephalus.

BACKGROUND: Neuroinflammation has been implicated in the pathophysiology of post-hemorrhagic hydrocephalus (PHH) of prematurity, but no comprehensive analysis of signaling molecules has been performed using human cerebrospinal fluid (CSF). METHODS: Lumbar CSF levels of key cytokines (IL-1α, IL-1ß, IL-4, IL-6, IL-8, IL-10, IL-12, TNF-α, TGF-ß1, IFN-γ) and chemokines (XCL-1, CCL-2, CCL-3, CCL-19, CXCL-10, CXCL-11, CXCL-12) were measured using conventional and multiplexed Enzyme-linked Immunosorbent Assays and compared between preterm infants with PHH and those with no known neurological injury. The relationships between individual biomarker levels and specific CSF cell counts were examined. RESULTS: Total protein (TP) CSF levels were elevated in the PHH subjects compared to controls. CSF levels of IL-1α, IL-4, IL-6, IL-12, TNF-α, CCL-3, CCL-19, and CXCL-10 were significantly increased in PHH whereas XCL-1 was significantly decreased in PHH. When normalizing by TP, IL-1α, IL-1ß, IL-10, IL-12, CCL-3, and CCL-19 levels were significantly elevated compared to controls, while XCL-1 levels remained significantly decreased. Among those with significantly different levels in both absolute and normalized levels, only absolute CCL-19 levels showed a significant correlation with CSF nucleated cells, neutrophils, and lymphocytes. IL-1ß and CXCL-10 also were correlated with total cell count, nucleated cells, red blood cells, and neutrophils. CONCLUSIONS: Neuroinflammation is likely to be an important process in the pathophysiology of PHH. To our knowledge, this is the first study to investigate CSF levels of chemokines in PHH as well as the only one to show XCL-1 selectively decreased in a diseased state. Additionally, CCL-19 was the only analyte studied that showed significant differences between groups and had significant correlation with cell count analysis. The selectivity of CCL-19 and XCL-1 should be further investigated. Future studies will further delineate the role of these cytokines and chemokines in PHH.

Time-to-event analysis of surgically treated posthemorrhagic hydrocephalus in preterm infants: a single-institution retrospective study.

PURPOSE: The purpose of this study is to report time points relevant to the neurosurgical management of posthemorrhagic hydrocephalus (PHH). METHODS: Data were collected retrospectively on 104 preterm infants with intraventricular hemorrhage (IVH) who received neurosurgical intervention for PHH at St. Louis Children's Hospital from 1994 to 2016. Kaplan-Meier curves were constructed for various endpoints. RESULTS: IVH grade on head ultrasound obtained through routine clinical care was II, III, and IV in 5 (4.8%), 33 (31.7%), and 66 (63.5%) of the patients, respectively. Neither IVH size nor location appeared to affect development of PHH. Days from birth to IVH, ventriculomegaly, temporizing neurosurgical procedure (TNP), and permanent neurosurgical intervention were 2.0 (95% CI 1.7-2.3), 3.0 (2.5-3.5), 24.0 (22.2-25.8), and 101.0 (90.4-111.6), respectively. Grades III and IV IVH did not differ in age at IVH diagnosis (Χ 2 (1 d.f.) = 1.32, p = 0.25), ventriculomegaly (Χ 2 = 0.73, p = 0.40), TNP (Χ 2 = 0.61, p = 0.43), or permanent intervention (Χ 2 = 2.48, p = 0.17). Ventricular reservoirs and ventriculosubgaleal shunts were used in 71 (68.3%) and 30 (28.8%), respectively. Eighty (76.9%) of the patients ultimately received a VPS. Five (4.8%) underwent a primary endoscopic third ventriculostomy (ETV), and two (1.9%) had ETV for a revision procedure. Four of the seven ETVs had choroid plexus cauterization. CONCLUSIONS: Although most infants who develop IVH and ventriculomegaly will do so within a few days of birth, at-risk infants should be observed for at least 4 weeks with serial head ultrasounds to monitor for PHH requiring surgery.

Cerebrospinal fluid biomarkers of infantile congenital hydrocephalus.

INTRODUCTION: Hydrocephalus is a complex neurological disorder with a pervasive impact on the central nervous system. Previous work has demonstrated derangements in the biochemical profile of cerebrospinal fluid (CSF) in hydrocephalus, particularly in infants and children, in whom neurodevelopment is progressing in parallel with concomitant neurological injury. The objective of this study was to examine the CSF of children with congenital hydrocephalus (CHC) to gain insight into the pathophysiology of hydrocephalus and identify candidate biomarkers of CHC with potential diagnostic and therapeutic value. METHODS: CSF levels of amyloid precursor protein (APP) and derivative isoforms (sAPPα, sAPPß, Aß42), tau, phosphorylated tau (pTau), L1CAM, NCAM-1, aquaporin 4 (AQP4), and total protein (TP) were measured by ELISA in 20 children with CHC. Two comparative groups were included: age-matched controls and children with other neurological diseases. Demographic parameters, ventricular frontal-occipital horn ratio, associated brain malformations, genetic alterations, and surgical treatments were recorded. Logistic regression analysis and receiver operating characteristic curves were used to examine the association of each CSF protein with CHC. RESULTS: CSF levels of APP, sAPPα, sAPPß, Aß42, tau, pTau, L1CAM, and NCAM-1 but not AQP4 or TP were increased in untreated CHC. CSF TP and normalized L1CAM levels were associated with FOR in CHC subjects, while normalized CSF tau levels were associated with FOR in control subjects. Predictive ability for CHC was strongest for sAPPα, especially in subjects ≤12 months of age (p<0.0001 and AUC = 0.99), followed by normalized sAPPß (p = 0.0001, AUC = 0.95), tau, APP, and L1CAM. Among subjects ≤12 months, a normalized CSF sAPPα cut-point of 0.41 provided the best prediction of CHC (odds ratio = 528, sensitivity = 0.94, specificity = 0.97); these infants were 32 times more likely to have CHC. CONCLUSIONS: CSF proteins such as sAPPα and related proteins hold promise as biomarkers of CHC in infants and young children, and provide insight into the pathophysiology of CHC during this critical period in neurodevelopment.