The BONSAI (Brain and Optic Nerve Study with Artificial Intelligence) deep learning system can accurately identify pediatric papilledema on standard ocular fundus photographs.

BACKGROUND: Pediatric papilledema often reflects an underlying severe neurologic disorder and may be difficult to appreciate, especially in young children. Ocular fundus photographs are easy to obtain even in young children and in nonophthalmology settings. The aim of our study was to ascertain whether an improved deep-learning system (DLS), previously validated in adults, can accurately identify papilledema and other optic disk abnormalities in children. METHODS: The DLS was tested on mydriatic fundus photographs obtained in a multiethnic pediatric population (<17 years) from three centers (Atlanta-USA; Bucharest-Romania; Singapore). The DLS's multiclass classification accuracy (ie, normal optic disk, papilledema, disks with other abnormality) was calculated, and the DLS's performance to specifically detect papilledema and normal disks was evaluated in a one-vs-rest strategy using the AUC, sensitivity and specificity, with reference to expert neuro-ophthalmologists. RESULTS: External testing was performed on 898 fundus photographs: 447 patients; mean age, 10.33 (231 patients ≤10 years of age; 216, 11-16 years); 558 normal disks, 254 papilledema, 86 other disk abnormalities. Overall multiclass accuracy of the DLS was 89.6% (range, 87.8%-91.6%). The DLS successfully distinguished "normal" from "abnormal" optic disks (AUC 0.99 [0.98-0.99]; sensitivity, 87.3% [84.9%-89.8%]; specificity, 98.5% [97.6%-99.6%]), and "papilledema" from "normal and other" (AUC 0.99 [0.98-1.0]; sensitivity, 98.0% [96.8%-99.4%]; specificity, 94.1% (92.4%-95.9%)]. CONCLUSIONS: Our DLS reliably distinguished papilledema from normal optic disks and other disk abnormalities in children, suggesting it could be utilized as a diagnostic aid for the assessment of optic nerve head appearance in the pediatric age group.

Visual Morbidity and Outcomes of Scleritis Associated with Intraocular Inflammation Compared to Isolated Scleritis.

PURPOSE: To compare visual outcomes, ocular complications and therapies for patients with scleritis-associated intraocular inflammation (SAI) and patients with isolated scleritis (IS). RESULTS: A total of 52 patients (36 with SAI and 16 with IS) were reviewed. Mean age (standard deviation) at presentation was 48.4 years old (± 15.4) in the SAI group and 53 years old (± 17.1) in the IS group (p = .37). Visual acuity was worse at presentation and last visit for patients with SAI compared to IS (p = .04). Patients in the SAI group developed greater posterior segment complications than in the IS group (p = .002). CONCLUSIONS: Scleritis with intraocular inflammation was associated with a higher rate of visual morbidity compared to isolated scleritis. More aggressive management strategies may be needed for patients who present with scleritis associated with inflammation.

Deep Learning System Outperforms Clinicians in Identifying Optic Disc Abnormalities.

BACKGROUND: The examination of the optic nerve head (optic disc) is mandatory in patients with headache, hypertension, or any neurological symptoms, yet it is rarely or poorly performed in general clinics. We recently developed a brain and optic nerve study with artificial intelligence-deep learning system (BONSAI-DLS) capable of accurately detecting optic disc abnormalities including papilledema (swelling due to elevated intracranial pressure) on digital fundus photographs with a comparable classification performance to expert neuro-ophthalmologists, but its performance compared to first-line clinicians remains unknown. METHODS: In this international, cross-sectional multicenter study, the DLS, trained on 14,341 fundus photographs, was tested on a retrospectively collected convenience sample of 800 photographs (400 normal optic discs, 201 papilledema and 199 other abnormalities) from 454 patients with a robust ground truth diagnosis provided by the referring expert neuro-ophthalmologists. The areas under the receiver-operating-characteristic curves were calculated for the BONSAI-DLS. Error rates, accuracy, sensitivity, and specificity of the algorithm were compared with those of 30 clinicians with or without ophthalmic training (6 general ophthalmologists, 6 optometrists, 6 neurologists, 6 internists, 6 emergency department [ED] physicians) who graded the same testing set of images. RESULTS: With an error rate of 15.3%, the DLS outperformed all clinicians (average error rates 24.4%, 24.8%, 38.2%, 44.8%, 47.9% for general ophthalmologists, optometrists, neurologists, internists and ED physicians, respectively) in the overall classification of optic disc appearance. The DLS displayed significantly higher accuracies than 100%, 86.7% and 93.3% of clinicians (n = 30) for the classification of papilledema, normal, and other disc abnormalities, respectively. CONCLUSIONS: The performance of the BONSAI-DLS to classify optic discs on fundus photographs was superior to that of clinicians with or without ophthalmic training. A trained DLS may offer valuable diagnostic aid to clinicians from various clinical settings for the screening of optic disc abnormalities harboring potentially sight- or life-threatening neurological conditions.

Artificial Intelligence Meets Neuro-Ophthalmology.

ABSTRACT: Recent advances in artificial intelligence have provided ophthalmologists with fast, accurate, and automated means for diagnosing and treating ocular conditions, paving the way to a modern and scalable eye care system. Compared to other ophthalmic disciplines, neuro-ophthalmology has, until recently, not benefitted from significant advances in the area of artificial intelligence. In this narrative review, we summarize and discuss recent advancements utilizing artificial intelligence for the detection of structural and functional optic nerve head abnormalities, and ocular movement disorders in neuro-ophthalmology.

Machine learning to determine relative contribution of modifiable and non-modifiable risk factors of major eye diseases.

AIMS: To use machine learning (ML) to determine the relative contributions of modifiable and non-modifiable clinical, metabolic, genetic, lifestyle and socioeconomic factors on the risk of major eye diseases. METHODS: We conducted analyses in a cross-sectional multi-ethnic population-based study (n=10 033 participants) and determined a range of modifiable and non-modifiable risk factors of common eye diseases, including diabetic retinopathy (DR), non-diabetic-related retinopathy (NDR); early and late age-related macular degeneration (AMD); nuclear, cortical and posterior subcapsular (PSC) cataract; and primary open-angle (POAG) and primary angle-closure glaucoma (PACG). Risk factors included individual characteristics, metabolic profiles, genetic background, lifestyle patterns and socioeconomic status (n~100 risk factors). We used gradient boosting machine to estimate the relative influence (RI) of each risk factor. RESULTS: Among the range of risk factors studied, the highest contributions were duration of diabetes for DR (RI=22.1%), and alcohol consumption for NDR (RI=6.4%). For early and late AMD, genetic background (RI~20%) and age (RI~15%) contributed the most. Axial length was the main risk factor of PSC (RI=30.8%). For PACG, socioeconomic factor (mainly educational level) had the highest influence (20%). POAG was the disease with the highest contribution of modifiable risk factors (cumulative RI~35%), followed by PACG (cumulative RI ~30%), retinopathy (cumulative RI between 20% and 30%) and late AMD (cumulative RI ~20%). CONCLUSION: This study illustrates the utility of ML in identifying factors with the highest contributions. Risk factors possibly amenable to interventions were intraocular pressure (IOP) and Body Mass Index (BMI) for glaucoma, alcohol consumption for NDR and levels of HbA1c for DR.

Vision-related quality-of-life in pediatric primary brain tumor patients.

PURPOSE: Brain tumors are the leading cause of death from childhood cancer. Although overall survival has improved due to earlier detection, better therapies, and improved surveillance, visual dysfunction and impaired vision-related quality-of-life (VR-QOL) are often unrecognized in children. This project investigated VR-QOL in pediatric brain tumor patients. METHODS: We evaluated visual impairment and quality-of-life (QOL) in a quality improvement project at one tertiary care center. Patients ≤ 18, greater than 6 months from diagnosis of brain tumor, excluding intrinsic anterior visual pathway tumors, underwent standardized neuro-ophthalmologic examination. Health-related QOL (HR-QOL) (PedsQL Brain Tumor Module) and VR-QOL questionnaires [CVFQ (Children's Visual Function Questionnaire) in children < 8, and EYE-Q in children 8-18] were obtained from patients and parents. RESULTS: Among 77 patients, craniopharyngiomas (n = 16, 21%) and astrocytomas (n = 15, 20%) were the most common tumors. Among 44/77 (57%) visually impaired children, 7 (16%) were legally blind. Eye-Q median score was 3.40 (interquartile range 3.00-3.75), worse than average scores for normal children. Eye-Q score decreased 0.12 with every 0.1 increase in logMAR visual acuity (p < 0.001). Patients who were legally blind had a significantly lower Eye-Q score than those who were not [0.70 vs. 3.44 (p < 0.001)]. Cognitive HR-QOL scores decreased 1.3 for every 0.1 increase in logMAR visual acuity (p = 0.02). CONCLUSIONS: Pediatric brain tumor patients' vision, HR-QOL, and VR-QOL were often severely affected even when tumors were considered cured. Visual acuity and legal blindness correlated with VR-QOL. Systematic neuro-ophthalmologic examinations in pediatric primary brain tumor patients are necessary to facilitate early preventative and corrective ophthalmologic interventions.

Accuracy of a Deep Learning System for Classification of Papilledema Severity on Ocular Fundus Photographs.

OBJECTIVE: To evaluate the performance of a deep learning system (DLS) in classifying the severity of papilledema associated with increased intracranial pressure on standard retinal fundus photographs. METHODS: A DLS was trained to automatically classify papilledema severity in 965 patients (2,103 mydriatic fundus photographs), representing a multiethnic cohort of patients with confirmed elevated intracranial pressure. Training was performed on 1,052 photographs with mild/moderate papilledema (MP) and 1,051 photographs with severe papilledema (SP) classified by a panel of experts. The performance of the DLS and that of 3 independent neuro-ophthalmologists were tested in 111 patients (214 photographs, 92 with MP and 122 with SP) by calculating the area under the receiver operating characteristics curve (AUC), accuracy, sensitivity, and specificity. Kappa agreement scores between the DLS and each of the 3 graders and among the 3 graders were calculated. RESULTS: The DLS successfully discriminated between photographs of MP and SP, with an AUC of 0.93 (95% confidence interval [CI] 0.89-0.96) and an accuracy, sensitivity, and specificity of 87.9%, 91.8%, and 86.2%, respectively. This performance was comparable with that of the 3 neuro-ophthalmologists (84.1%, 91.8%, and 73.9%, p = 0.19, p = 1, p = 0.09, respectively). Misclassification by the DLS was mainly observed for moderate papilledema (Frisén grade 3). Agreement scores between the DLS and the neuro-ophthalmologists' evaluation was 0.62 (95% CI 0.57-0.68), whereas the intergrader agreement among the 3 neuro-ophthalmologists was 0.54 (95% CI 0.47-0.62). CONCLUSIONS: Our DLS accurately classified the severity of papilledema on an independent set of mydriatic fundus photographs, achieving a comparable performance with that of independent neuro-ophthalmologists. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that a DLS using mydriatic retinal fundus photographs accurately classified the severity of papilledema associated in patients with a diagnosis of increased intracranial pressure.

Prospective study of serum and aqueous humour anti-Hsp70.1 IgG antibody levels in ocular toxoplasmosis.

AIMS: We evaluate whether the serum and aqueous humour (AH) level of IgG anti-Hsp70.1 antibodies improved the biological diagnosis of ocular toxoplasmosis. METHODS AND RESULTS: In this prospective cross-sectional and multicentre study, serum and AH were collected at the time of active uveitis. Anti-Hsp70.1-antibody levels were determined by ELISA. Patients with confirmed (Group A1, n = 21) or suspected ocular toxoplasmosis (group A2, n = 30) were enrolled, as well as a control group of patients with cataract (group B, n = 42). Serum IgG anti-Hsp70.1 antibody levels were not significantly different within the group of uveitis patients (A1, n = 21 vs A2, n = 30, P = .8) and were significantly associated with the affected retinal zone (P = .006) and with the size of the retinal lesion (P = .03). Serum anti-Hsp70.1 antibody level was positive in 10 out of the 18 patients of group A2. Significant anti-Hsp-70.1 antibody level in AH was reported in only three patients (3 eyes) with confirmed ocular toxoplasmosis. CONCLUSION: While the level of IgG anti-Hsp-70.1 antibody in AH did not improve the laboratory diagnosis of ocular toxoplasmosis, its level in serum was of major significance for retinal damage diagnosis.

Optic Disc Classification by Deep Learning versus Expert Neuro-Ophthalmologists.

OBJECTIVE: To compare the diagnostic performance of an artificial intelligence deep learning system with that of expert neuro-ophthalmologists in classifying optic disc appearance. METHODS: The deep learning system was previously trained and validated on 14,341 ocular fundus photographs from 19 international centers. The performance of the system was evaluated on 800 new fundus photographs (400 normal optic discs, 201 papilledema [disc edema from elevated intracranial pressure], 199 other optic disc abnormalities) and compared with that of 2 expert neuro-ophthalmologists who independently reviewed the same randomly presented images without clinical information. Area under the receiver operating characteristic curve, accuracy, sensitivity, and specificity were calculated. RESULTS: The system correctly classified 678 of 800 (84.7%) photographs, compared with 675 of 800 (84.4%) for Expert 1 and 641 of 800 (80.1%) for Expert 2. The system yielded areas under the receiver operating characteristic curve of 0.97 (95% confidence interval [CI] = 0.96-0.98), 0.96 (95% CI = 0.94-0.97), and 0.89 (95% CI = 0.87-0.92) for the detection of normal discs, papilledema, and other disc abnormalities, respectively. The accuracy, sensitivity, and specificity of the system's classification of optic discs were similar to or better than the 2 experts. Intergrader agreement at the eye level was 0.71 (95% CI = 0.67-0.76) between Expert 1 and Expert 2, 0.72 (95% CI = 0.68-0.76) between the system and Expert 1, and 0.65 (95% CI = 0.61-0.70) between the system and Expert 2. INTERPRETATION: The performance of this deep learning system at classifying optic disc abnormalities was at least as good as 2 expert neuro-ophthalmologists. Future prospective studies are needed to validate this system as a diagnostic aid in relevant clinical settings. ANN NEUROL 2020;88:785-795.

Influence of Optic Nerve Appearance on Visual Outcome in Pediatric Idiopathic Intracranial Hypertension.

OBJECTIVES: To determine whether optic disc hemorrhages (ODH) and cotton wool spots (CWS) at presentation are associated with worse visual outcomes in pediatric patients with idiopathic intracranial hypertension (IIH). METHODS: Retrospective institutional review of 100 eyes of 50 consecutive pediatric IIH patients (aged 16 years or less) who had baseline optic disc photographs before or within 30 days of their diagnostic lumbar puncture and initiation of medical treatment. Optic disc photographs were independently graded by three ophthalmologists in a standardized manner. Visual function was assessed using visual acuity (VA) and visual field grade (VFG). RESULTS: At least one ODH was found in 41% of eyes, at least one CWS was found in 27% of eyes, and 20% of eyes had both ODH and CWS. At presentation, Frisén grade was associated with the presence of CWS (p = 0.013) and showed no association with ODH (p = 0.060). When controlling for Frisén grade, ODH and CWS were not associated with worse VA or VFG at final follow-up. Severe ODH were associated with worse VA and VFG at presentation (p < 0.03), but not at final follow-up. Severe CWS at presentation was strongly associated with a worse Humphrey mean deviation of 5.0 dB (95% confidence interval 1.6-8.3) at final follow-up (p = 0.002). CONCLUSION: When controlling for the severity of papilledema, ODH do not provide any additional prognostic value in pediatric IIH patients. Frisén grade and severe CWS at presentation were independently associated with worse visual outcomes at the final follow-up.

Artificial Intelligence to Detect Papilledema from Ocular Fundus Photographs.

BACKGROUND: Nonophthalmologist physicians do not confidently perform direct ophthalmoscopy. The use of artificial intelligence to detect papilledema and other optic-disk abnormalities from fundus photographs has not been well studied. METHODS: We trained, validated, and externally tested a deep-learning system to classify optic disks as being normal or having papilledema or other abnormalities from 15,846 retrospectively collected ocular fundus photographs that had been obtained with pharmacologic pupillary dilation and various digital cameras in persons from multiple ethnic populations. Of these photographs, 14,341 from 19 sites in 11 countries were used for training and validation, and 1505 photographs from 5 other sites were used for external testing. Performance at classifying the optic-disk appearance was evaluated by calculating the area under the receiver-operating-characteristic curve (AUC), sensitivity, and specificity, as compared with a reference standard of clinical diagnoses by neuro-ophthalmologists. RESULTS: The training and validation data sets from 6779 patients included 14,341 photographs: 9156 of normal disks, 2148 of disks with papilledema, and 3037 of disks with other abnormalities. The percentage classified as being normal ranged across sites from 9.8 to 100%; the percentage classified as having papilledema ranged across sites from zero to 59.5%. In the validation set, the system discriminated disks with papilledema from normal disks and disks with nonpapilledema abnormalities with an AUC of 0.99 (95% confidence interval [CI], 0.98 to 0.99) and normal from abnormal disks with an AUC of 0.99 (95% CI, 0.99 to 0.99). In the external-testing data set of 1505 photographs, the system had an AUC for the detection of papilledema of 0.96 (95% CI, 0.95 to 0.97), a sensitivity of 96.4% (95% CI, 93.9 to 98.3), and a specificity of 84.7% (95% CI, 82.3 to 87.1). CONCLUSIONS: A deep-learning system using fundus photographs with pharmacologically dilated pupils differentiated among optic disks with papilledema, normal disks, and disks with nonpapilledema abnormalities. (Funded by the Singapore National Medical Research Council and the SingHealth Duke-NUS Ophthalmology and Visual Sciences Academic Clinical Program.).

Optic nerve appearance as a predictor of visual outcome in patients with idiopathic intracranial hypertension.

BACKGROUND/AIMS: It remains unclear whether the presence of optic disc haemorrhages (ODH) or cotton wool spots (CWS) at presentation in patients with papilloedema from idiopathic intracranial hypertension (IIH) has prognostic value. The aim of this study was to determine if optic disc appearance at presentation predicts visual outcome in patients with IIH. METHODS: Retrospective study of 708 eyes of 360 consecutive patients with IIH who had baseline optic disc photographs before or within 30 days of their diagnostic lumbar puncture and initiation of medical treatment. Optic disc photographs were independently graded by three ophthalmologists in a standardised manner. Visual function was assessed using Snellen converted to logMAR visual acuity, Humphrey mean deviation and visual field grade. RESULTS: At least one ODH was found in 201 (28.4%) eyes, at least one CWS was found in 101 (14.3%) eyes and 88 eyes had both ODH and CWS (12.4%). At presentation, Frisén grade was associated with the presence and severity of ODH and CWS (p<0.001). ODH were associated with a worse visual acuity and CWS were associated with a worse visual field grade and mean deviation at presentation (p<0.05). Frisén grade was associated with worse visual function at presentation and final follow-up (p<0.001). Neither ODH nor CWS at presentation were associated with visual function at final follow-up when controlling for the Frisén grade. CONCLUSIONS AND RELEVANCE: ODH and CWS at baseline are not independent predictors of final visual function in IIH when controlling for the severity of papilloedema.

Nonmydriatic Fundus Photography in Patients with Acute Vision Loss.

Background:Acute visual loss is a common chief complaint in emergency department (ED) patients, but the scarcity of ophthalmologists in most EDs limits its evaluation.Introduction:Our objective was to evaluate whether nonmydriatic fundus photography (NMFP) in the ED helps triage patients with acute visual loss.Materials and Methods:We included 213 patients with acute visual loss evaluated in the ED with NMFP as part of the Fundus Photography versus Ophthalmoscopy Trial Outcomes in the ED studies. Demographics, referral patterns, results of NMFP, and final diagnoses were recorded.Results:A final ophthalmological diagnosis was made in 109/213 (51%) patients. NMFP allowed a definite diagnosis in 51/109 (47%) patients: 14 nonglaucomatous optic neuropathies, 10 papilledema, 13 acute retinal ischemia, 2 retinal detachments, 2 choroidal metastases, 4 maculopathies, and 6 glaucoma. In 58/109 (53%) patients, NMFP was not diagnostic even when interpreted remotely by ophthalmologists due to disorders undiagnosable with NMFP. Ophthalmology consultation was requested in 109/213 (51%) patients, 41/54 (76%) patients with abnormal NMFP versus 68/159 (43%) patients with normal NMPF (p < 0.001).Discussion:Although NMFP allowed rapid diagnosis in 51/213 (24%) patients presenting to the ED with acute visual loss, NMFP alone was not sufficient to detect all ocular diseases; ophthalmology consultation was more often requested when NMFP was abnormal.Conclusions:Our study emphasizes the limitations of teleophthalmology with NMFP in remotely detecting ocular diseases related to acute visual loss in the ED. NMFP helped triage and referral decisions and can be used to complement ophthalmology consultations in the ED.

Lack of Relationship between Central Corneal Thickness and Papilloedema in Idiopathic Intracranial Hypertension.

Translaminar pressure gradient abnormalities have been implicated in the pathogenesis and progression of glaucoma. A "reversed" translaminar pressure gradient may be related to papilloedema severity in idiopathic intracranial hypertension. Central corneal thickness is related to intraocular pressure measurements and, by extension, to translaminar pressure gradients. We evaluated if central corneal thickness could be a marker of worse papilloedema due to altered translaminar pressure gradients in patients with idiopathic intracranial hypertension. We found that central corneal thickness was not related to the severity of papilloedema in idiopathic intracranial hypertension.

Fundus Photography vs. Ophthalmoscopy Outcomes in the Emergency Department (FOTO-ED) Phase III: Web-based, In-service Training of Emergency Providers.

We evaluated a web-based training aimed at improving the review of fundus photography by emergency providers. 587 patients were included, 12.6% with relevant abnormalities. Emergency providers spent 31 minutes (median) training and evaluated 359 patients. Median post-test score improvement was 6 percentage points (IQR: 2-14; p = 0.06). Pre- vs. post-training, the emergency providers reviewed 45% vs. 43% of photographs; correctly identified abnormals in 67% vs. 57% of cases; and correctly identified normals in 80% vs. 84%. The Fundus photography vs. Ophthalmoscopy Trial Outcomes in the Emergency Department studies have demonstrated that emergency providers perform substantially better with fundus photography than direct ophthalmoscopy, but our web-based, in-service training did not result in further improvements at our institution.

Optic nerve head edema among patients presenting to the emergency department.

OBJECTIVE: To determine the frequency of and predictive factors for optic nerve head edema (ONHE) among patients with headache, neurologic deficit, visual loss, or elevated blood pressure in the emergency department (ED). METHODS: Cross-sectional analysis was done of patients with ONHE in the prospective Fundus Photography vs Ophthalmoscopy Trial Outcomes in the Emergency Department (FOTO-ED) study. Demographics, neuroimaging results, management, and patient disposition were collected. Patients in the ONHE and non-ONHE groups were compared with bivariate and logistic regression analyses. RESULTS: Of 1,408 patients included, 37 (2.6%, 95% confidence interval 1.9-3.6) had ONHE (median age 31 [interquartile range 26-40] years, women 27 [73%], black 28 [76%]). ONHE was bilateral in 27 of 37 (73%). Presenting complaints were headache (18 of 37), visual loss (10 of 37), acute neurologic deficit (4 of 37), elevated blood pressure (2 of 37), and multiple (3 of 37). The most common final diagnoses were idiopathic intracranial hypertension (19 of 37), CSF shunt malfunction/infection (3 of 37), and optic neuritis (3 of 37). Multivariable logistic regression found that body mass index ≥35 kg/m2 (odds ratio [OR] 1.9, p = 0.0002), younger age (OR 0.5 per 10-year increase, p < 0.0001), and visual loss (OR 5, p = 0.0002) were associated with ONHE. Patients with ONHE were more likely to be admitted (62% vs 19%), to be referred to other specialists (100% vs 54%), and to receive neuroimaging (89% vs 63%) than patients without ONHE (p < 0.001). Fundus photographs in the ED allowed initial diagnosis of ONHE for 21 of 37 (57%) patients. Detection of ONHE on ED fundus photography changed the final diagnosis for 10 patients. CONCLUSIONS: One in 38 patients (2.6%) presenting to the ED with a chief complaint of headache, neurologic deficit, visual loss, or elevated blood pressure had ONHE. Identification of ONHE altered patient disposition and contributed to the final diagnosis, confirming the importance of funduscopic examination in the ED.

Cerebrospinal fluid total protein in idiopathic intracranial hypertension.

OBJECTIVE: To evaluate the relationship between CSF total protein concentration (CSF protein) and CSF opening pressure in idiopathic intracranial hypertension (IIH), and to explore the association of age, gender, race, BMI, and Humphrey visual field mean deviation (HVF MD) with CSF total protein. METHODS: The medical records of all IIH patients seen between 1989 and 2016 at one institution were systematically reviewed for demographics, CSF opening pressure, CSF contents, and HVF MD (at initial evaluation and most recent follow-up). Linear regression of CSF protein on CSF opening pressure was performed also considering BMI, age, gender, race, HVF MD, and year of lumbar puncture. RESULTS: We included 266 IIH patients (13 pre-pubertal children, 35 post-pubertal children, 218 adults). There was a negative linear association between CSF opening pressure and CSF protein: CSF protein decreased by 0.18mg/dL for each 1cm H2O increase in CSF opening pressure (p<0.001). After controlling for CSF opening pressure, mean CSF protein was 4.1mg/dL higher in white patients than in black patients (p<0.001). Multivariable analysis found that CSF opening pressure (p=0.007), white race (p<0.001), and HVF MD (most recent follow-up, worst eye, p=0.05) remained independently associated with CSF protein controlling for year of lumbar puncture and age. CONCLUSIONS: There was a negative association between CSF protein and CSF opening pressure. After controlling for CSF opening pressure, CSF protein was higher in white patients and unaffected by age, gender, or BMI. Our findings help clarify inconsistent results of prior studies, but do not really help clarify IIH pathophysiology.

A keratitis rat model for evaluation of anti-Acanthamoeba polyphaga agents.

PURPOSE: To develop a rat model of chronic Acanthamoeba polyphaga keratitis suitable for pharmacologic assessment of therapeutic agents. METHODS: An A. polyphaga isolate (ATCC #50495) was grown in peptone-yeast extract-glucose medium. Five-weeks-old, Sprague-Dawley male rats were injected with 10(3) or 10(4) trophozoites in the left cornea stromal layer. A subconjunctival injection of 0.14, 0.28, or 0.57 mg long-acting betamethasone was performed weekly. At the end of experiments, rats were killed; the superficial corneal epithelium gently scraped and cultured; and globes histologically examined. Topical polyhexamethylene biguanide (PHMB), hexamidine diisethionate, and miltefosine (hexadecylphosphocholine) were administered topically as eye drops 3 times a day at concentrations of 0.02%, 0.1%, and 0.01% respectively. In vitro minimal inhibitory concentration (MIC) and fractional inhibitory concentration values were measured in A. polyphaga cultures. RESULTS: In infected eyes, lesions consisted of the sequential appearance within 2 weeks of edema, infiltrates, and/or abscesses. On day 35 postinfection, a combination of 10(4) parasites with a regimen of 0.28 mg/week betamethasone resulted in the highest ratio of rats with abscesses. Presence of A. polyphaga was confirmed histologically and inconsistently in cultures. In rats optimally prepared as said earlier, agents were administered on day 6 postinfection. A combination of PHMB and hexamidine diisethionate exerted a synergistic effect and was more effective than PHMB, hexamidine diisethionate, or miltefosine alone. In vitro, PHMB (MIC = 14.6 microM) and hexamidine diisethionate (MIC = 555 microM) exerted a synergistic effect (fractional inhibitory concentration = 0.06), and miltefosine exhibited antiamoebal activity (MIC = 27.4 microM). CONCLUSIONS: In this study, a rat model of chronic A. polyphaga keratitis was obtained and found suitable for assessment of pharmacologic agents. It provides an in vivo approach of drug resistance, pathogenicity, and physiopathologic mechanisms of chronic amoebic keratitis.