Robert A. Avery

Reference Range for Cerebrospinal Fluid Opening Pressure in Children

To the Editor: A reference range for cerebrospinal fluid (CSF) opening pressure in children undergoing diagnostic lumbar puncture has not been established.1 The influence of age, body-mass index (B...

Retinal Nerve Fiber Layer Thickness in Children With Optic Pathway Gliomas

PURPOSE To determine the relationship of high-contrast visual acuity (VA) and low-contrast letter acuity with retinal nerve fiber layer (RNFL) thickness in children with optic pathway gliomas. DESIGN Cross-sectional convenience sample, with prospective data collection, from a tertiary care childrens hospital of patients with optic pathway gliomas associated with neurofibromatosis type 1, sporadic optic pathway gliomas, and neurofibromatosis type 1 without optic pathway gliomas. METHODS Patients underwent best-corrected VA testing using surrounded H, O, T, V optotypes and low-contrast letter acuity (5%, 2.5%, and 1.25% low-contrast Sloan letter charts). Mean RNFL thickness (micrometers) was measured by a Stratus optical coherence tomography device (Carl Zeiss Meditec) using the fast RNFL thickness protocol. Eyes were classified as having abnormal vision if they had high-contrast VA of more than 0.1 logarithm of the minimal angle of resolution units or visual field loss. The association of subject age, glioma location, and RNFL thickness with both VA and low-contrast letter acuity scores was evaluated by 1-way analysis of variance and linear regression, using the generalized estimating equation approach to account for within-patient intereye correlations. RESULTS Eighty-nine eyes of patients with optic pathway gliomas were included, and 41 were classified as having abnormal VA or visual field loss. Reduced RNFL thickness was associated significantly with higher logarithm of the minimal angle of resolution scores for both VA (P < .001) and all low-contrast letter acuity charts (P < .001) when accounting for age and glioma location. CONCLUSIONS Eyes of most children with optic pathway gliomas and decreased RNFL thickness had abnormal VA or visual field loss.

Functional outcome measures for NF1-associated optic pathway glioma clinical trials.

Objective: The goal of the Response Evaluation in Neurofibromatosis and Schwannomatosis Visual Outcomes Committee is to define the best functional outcome measures for future neurofibromatosis type 1 (NF1)-associated optic pathway glioma (OPG) clinical trials. Methods: The committee considered the components of vision, other ophthalmologic parameters affected by OPG, potential biomarkers of visual function, and quality of life measures to arrive at consensus-based, evidence-driven recommendations for objective and measurable functional endpoints for OPG trials. Results: Visual acuity (VA) assessments using consistent quantitative testing methods are recommended as the main functional outcome measure for NF1-OPG clinical trials. Teller acuity cards are recommended for use as the primary VA endpoint, and HOTV as a secondary endpoint once subjects are old enough to complete it. The optic disc should be assessed for pallor, as this appears to be a contributory variable that may affect the interpretation of VA change over time. Given the importance of capturing patient-reported outcomes in clinical trials, evaluating visual quality of life using the Childrens Visual Function Questionnaire as a secondary endpoint is also proposed. Conclusions: The use of these key functional endpoints will be essential for evaluating the efficacy of future OPG clinical trials.

Prediction of Lyme Meningitis in Children From a Lyme Disease–Endemic Region: A Logistic-Regression Model Using History, Physical, and Laboratory Findings

BACKGROUND. Differentiating Lyme meningitis (LM) from other forms of aseptic meningitis (AM) in children is a common diagnostic dilemma in Lyme disease–endemic regions. Prior studies have compared clinical characteristics of patients with LM versus patients with documented enteroviral infections. No large studies have compared patients with LM to all patients presenting with AM and attempted to define a clinical prediction model. OBJECTIVE. To create a statistical model to predict LM versus AM in children based on history, physical, and laboratory findings during the initial presentation of meningitis. METHODS. Children older than 2 years presenting to the Alfred I. duPont Hospital for Children between October 1999 and September 2004 were identified if both Lyme serology and cerebrospinal fluid (CSF) were collected during the same hospital encounter. Patients were considered to have Lyme disease only if they met Centers for Disease Control and Prevention criteria (documented erythema migrans and/or positive Lyme serology). Patients were eligible for study inclusion if they had documented meningitis (CSF white blood cell count: >8 per mm3). Retrospective chart review abstracted duration of headache and cranial neuritis (papilledema or cranial nerve palsy) on physical examination and percent CSF mononuclear cells. Using logistic-regression analysis, the type of meningitis (LM versus AM) was simultaneously regressed on these 3 variables. The Hosmer-Lemeshow test was performed and the area under the receiver operating characteristic curve was calculated. RESULTS. A total of 175 children with meningitis were included in the final statistical model. Logistic-regression analysis included 27 patients with LM and 148 patients classified as having AM. Duration of headache, cranial neuritis, and percent CSF mononuclear cells independently predicted LM. The Hosmer-Lemeshow test revealed a good fit for the model, and the Nagelkerke R2 effect size demonstrated good predictive efficacy. Odds ratios based on the logistic-regression results were calculated for these variables. The final model was transformed into a clinical prediction model that allows practitioners to calculate the probability of a child having LM. CONCLUSIONS. Longer duration of headache, presence of cranial neuritis, and predominance of CSF mononuclear cells are predictive of LM in children presenting with meningitis in a Lyme disease–endemic region. The clinical prediction model can help guide the clinician about the need for parenteral antibiotics while awaiting serology results.

Visual acuity in children with low grade gliomas of the visual pathway: implications for patient care and clinical research

Low grade gliomas affecting the visual pathway, commonly referred to as optic pathway gliomas (OPGs), have a relatively high survival rate but can cause significant vision loss. While previous treatment outcomes for tumors of the central nervous system have focused primarily on changes in tumor size or patient survival, more recently preservation of vision has also become a primary objective when treating these tumors. Visual acuity (VA) is the most testable and reliable visual parameter in young children with OPGs. Unfortunately, standardized VA assessments have neither been employed to make treatment decisions nor used as primary outcomes in clinical trials. The lack of a standardized VA assessment has also hindered the ability to interpret and compare results between studies. It is essential that all members of the multidisciplinary care team (i.e., pediatric neuro-oncologist, neurologist, neurosurgeon, and ophthalmologist) can accurately interpret VA results and properly use them to guide management decisions. Specifically, determining what constitutes a significant change in VA and the factors that may influence these results should be incorporated into collective team recommendations. This review describes the VA assessment in children with OPGs and proposes a standardized VA testing protocol for future pediatric OPG clinical treatment trials.

Marked Recovery of Vision in Children With Optic Pathway Gliomas Treated With Bevacizumab

IMPORTANCE Children with optic pathway gliomas (OPGs) frequently experience vision loss from their tumors. Standard front-line treatment using carboplatin-based chemotherapy typically produces only a modest benefit (eg, stabilization or 0.2 logMAR improvement) in visual acuity (VA). Bevacizumab is a monoclonal antibody that targets vascular endothelial growth factor and acts primarily as an anti-angiogenic agent. Recent reports suggest a qualitative improvement in vision after bevacizumab-based treatment in children with OPGs. OBSERVATIONS We report 4 cases of pediatric OPGs (2 neurofibromatosis type 1-related and 2 sporadic cases) that received treatment with bevacizumab due to progressive VA or visual field (VF) loss despite prior treatment with chemotherapy or proton-beam radiation. All 4 subjects demonstrated a marked improvement in their VA, VF, or both while receiving bevacizumab-based therapy. Three patients had complete resolution of their VA or VF loss in at least 1 eye-2 of whom had previously received bevacizumab therapy. CONCLUSIONS AND RELEVANCE Given that most patients with OPG-related visual impairment will show modest or no visual improvement with standard treatment, the incorporation of bevacizumab in these cases may greatly improve visual outcomes and should be considered in appropriate clinical situations.

CSF opening pressure in children with optic nerve head edema.

Background: We previously reported that an abnormal CSF opening pressure (OP) in children was greater than 28 cm H2O. Since elevated intracranial pressure can cause optic nerve head edema (ONHE), we would expect that most patients with ONHE would have an OP greater than 28 cm H2O. This study describes the range of OP for children with ONHE and compared them to age-matched controls without ONHE. Methods: Case subjects were children (1–18 years of age) enrolled in a prospective study of CSF OP that demonstrated ONHE at time of lumbar puncture and that the ONHE later resolved. Patients with ONHE secondary to infectious, inflammatory, or ischemic conditions were excluded. Control subjects from the same study, but without ONHE, were matched to cases. Results: Of the 472 subjects enrolled in the study, 41 OP measurements were obtained from 33 patients with ONHE who did not have any exclusionary criteria and matched to 41 control subjects without ONHE. Case subjects had a significantly higher OP (mean, 41.4 cm H20; range, 22–56) than control subjects (mean, 18.9 cm H2O; range, 9–29; p < 0.01). Forty of 41 (97.6%) case subjects and 2 of 41 (4.8%) control subjects had OP measures >28 cm H2O. Conclusions: Children with ONHE not related to infectious, inflammatory, or ischemic causes typically have an OP >28 cm H2O, significantly higher than age-matched controls without ONHE. This study provides further support to our previously published findings that suggests an abnormal OP in children is typically above 28 cm H2O.

Ganglion Cell Layer–Inner Plexiform Layer Thickness and Vision Loss in Young Children With Optic Pathway Gliomas

PURPOSE To determine if measures of macular ganglion cell layer-inner plexiform layer (GCL-IPL) thickness can discriminate between children with and without vision loss (visual acuity or field) from their optic pathway glioma (OPG) using spectral-domain optical coherence tomography (SD-OCT). METHODS Children with OPGs (sporadic or secondary to neurofibromatosis type 1) enrolled in a prospective study of SD-OCT were included if they were cooperative for vision testing and macular SD-OCT images were acquired. Manual segmentation of the macular GCL-IPL and macular retinal nerve fiber layer (RNFL) was performed using elliptical annuli with diameters of 1.5, 3.0, and 4.5 mm. Logistic regression assessed the ability of GCL-IPL and RNFL thickness measures (micrometers) to differentiate between the normal and abnormal vision groups. RESULTS Forty-seven study eyes (normal vision = 31, abnormal vision = 16) from 26 children with OPGs were included. Median age was 5.3 years (range, 2.5-12.8). Thickness of all GCL-IPL and RNFL quadrants differed between the normal and abnormal vision groups (P < 0.01). All GCL-IPL measures demonstrated excellent discrimination between groups (area under the curve [AUC] > 0.90 for all diameters). Using the lower fifth percentile threshold, the number of abnormal GCL-IPL inner macula (3.0 mm) quadrants achieved the highest AUC (0.989) and was greater than the macula RNFL AUCs (P < 0.05). CONCLUSIONS Decreased GCL-IPL thickness (<fifth percentile) can discriminate between children with and without vision loss from their OPG. Ganglion cell layer-inner plexiform layer thickness could be used as a surrogate marker of vision in children with OPGs.

Handheld optical coherence tomography during sedation in young children with optic pathway gliomas

IMPORTANCE Monitoring young children with optic pathway gliomas (OPGs) for visual deterioration can be difficult owing to age-related noncompliance. Optical coherence tomography (OCT) measures of retinal nerve fiber layer (RNFL) thickness have been proposed as a surrogate marker of vision but this technique is also limited by patient cooperation. OBJECTIVE To determine whether measures of circumpapillary RNFL thickness, acquired with handheld OCT (HH-OCT) during sedation, can differentiate between young children with and without vision loss from OPGs. DESIGN, SETTING, AND PARTICIPANTS This cross-sectional analysis of a prospective observational study was conducted at a tertiary-care childrens hospital. Children with an OPG (sporadic or secondary to neurofibromatosis type 1) who were cooperative for visual acuity testing, but required sedation to complete magnetic resonance imaging, underwent HH-OCT imaging of the circumpapillary RNFL while sedated. MAIN OUTCOMES AND MEASURES Area under the curve of the receiver operating characteristic, sensitivity, specificity, positive predictive value, and negative predictive value of the average and quadrant-specific RNFL thicknesses. RESULTS Thirty-three children (64 eyes) met inclusion criteria (median age, 4.8 years; range, 1.8-12.6 years). In children with vision loss (abnormal visual acuity and/or visual field), RNFL thickness was decreased in all quadrants compared with the normal-vision group (P < .001 for all comparisons). Using abnormal criteria of less than 5% and less than 1%, the area under the curve was highest for the average RNFL thickness (0.96 and 0.97, respectively) compared with specific anatomic quadrants. The highest discrimination and predictive values were demonstrated for participants with 2 or more quadrants meeting less than 5% (sensitivity = 93.3; specificity = 97.9; positive predictive value = 93.3; and negative predictive value = 97.9) and less than 1% (sensitivity = 93.3; specificity = 100; positive predictive value = 100; and negative predictive value = 98.0) criteria. CONCLUSIONS AND RELEVANCE Measures of RNFL thickness acquired with HH-OCT during sedation can differentiate between young children with and without vision loss from OPGs. For young children who do not cooperate with vision testing, HH-OCT measures may be a surrogate marker of vision. Longitudinal studies are needed to delineate the temporal relationship between RNFL decline and vision loss.

Feasibility and comparison of visual acuity testing methods in children with neurofibromatosis type 1 and/or optic pathway gliomas.

PURPOSE Longitudinal ophthalmologic clinical trials in young children require multiple visual acuity (VA) testing methods-especially when the subjects have cognitive and developmental delay. This study evaluated the success rate and comparability of two different VA testing methods in children with neurofibromatosis type 1 (NF1) and/or optic pathway gliomas (OPGs). METHODS Two institutions prospectively enrolled children 10 years or younger with NF1 and/or an OPG. Both Teller grating acuity (TAC) and recognition acuity using the computerized version of the Amblyopia Treatment Study VA testing protocol that limits responses to four letters (H, O, T, or V) were attempted in all subjects. The association of age and diagnosis of NF1 on success rate was analyzed. Differences in grating and recognition acuity were compared. RESULTS One hundred twenty-seven children met inclusion criteria (median age = 5.58 years). Of 127 subjects, 11 (8.7%) could not complete monocular TAC testing in either eye; 39 (30.7%) could not complete HOTV testing and were younger than those able to complete HOTV testing (mean = 2.9 vs. 7.0 years, respectively; Z = -8.3, P < 0.01). Older age was associated with successful HOTV testing and remained significant in all regression analyses (P < 0.01). The within-subject logMAR values for TAC and HOTV testing results were significantly correlated (r = 0.69, P < 0.01). CONCLUSIONS Young children with NF1 and/or OPGs were frequently unable to complete recognition acuity testing. These factors are important to consider when designing a clinical trial for children with NF1 and/or OPGs.