Secondary Intracranial Hypertension in Pediatric Patients With Cryopyrin-Associated Periodic Syndrome.

BACKGROUND: Cryopyrin-associated periodic syndrome is characterized by periodic fever, rash, and joint pain. Papilledema rarely occurs. We present our series of patients with cryopyrin-associated periodic syndrome who clinically met the diagnostic criteria for Muckle-Wells syndrome and our experience with secondary intracranial hypertension. METHODS: Retrospective review of all patients with cryopyrin-associated periodic syndrome at Nationwide Children's Hospital from October 2015 to September 2017. RESULTS: Eighteen children met inclusion criteria: 15 females and three males, aged 1.5 to 16.2 years. Fifteen had periodic fever genetic testing; three had a known genetic defect identified, eight had a defect identified not currently known to be associated with cryopyrin-associated periodic syndrome, and four had no defect identified. Six patients (30%) developed headaches and were diagnosed with secondary intracranial hypertension. Lumbar puncture opening pressures ranged from 28 to 45 cm H2O. Only one patient had papilledema. Initial treatment was medical in all cases, by increasing interleukin-1 inhibitor dose and/or acetazolamide. One patient required a ventriculoperitoneal shunt for headache management. No visual acuity loss was detected. All six patients with secondary intracranial hypertension had a known genetic mutation or genetic variant of unknown significance; five involved the NLRP3 gene. CONCLUSIONS: In our series of 18 patients with cryopyrin-associated periodic syndrome, secondary intracranial hypertension occurred at a higher than expected rate. We suspect that genetic defects involving the NLRP3 gene may be a risk factor. Papilledema was present in only one patient. Physicians treating cryopyrin-associated periodic syndrome should be aware of this vision-threatening association and potential therapeutic approach.

Surgical intervention in pediatric intracranial hypertension: incidence, risk factors, and visual outcomes.

PURPOSE: To evaluate the incidence of surgical intervention in pediatric intracranial hypertension (IH), evaluate the visual outcomes of surgically managed patients, and identify potential predictors for surgical intervention. METHODS: The medical records of patients with primary and secondary IH at Nationwide Children's Hospital from 2010 to 2017 were reviewed retrospectively. Presenting characteristics of medically and surgically managed patients were compared, and the clinical courses of surgically managed patients were reviewed. RESULTS: A total of 129 medically and 14 surgically managed patients were included. The surgical incidence was 9.8%. Final visual acuity in 27 of 28 surgically managed eyes was 20/25 or better. In combined primary and secondary IH patients, elevations in body mass index (BMI; OR = 1.06; 95% CI, 1.01-1.11; P = 0.022) and lumbar puncture opening pressures ≥52 cm H2O (OR = 6.17; 95% CI, 1.93-19.67; P = 0.002) were significantly associated with the likelihood of surgical intervention when assessed by univariate logistic regression; grade of papilledema >2 was of marginal significance. After controlling for BMI, a lumbar puncture opening pressure of ≥52 cm H2O was more likely to result in surgery (adjusted OR = 4.69; 95% CI = 1.39-15.98; P = 0.013). CONCLUSIONS: Most pediatric IH can be treated medically. Patients with lumbar puncture opening pressures ≥52 cm H2O at the time of diagnosis are at a higher risk of surgical intervention and should be monitored closely. Elevations in presenting BMI and grade of papilledema may also increase the odds of surgery.

Diagnostic criteria in pediatric intracranial hypertension.

BACKGROUND: The modified Dandy criteria and the newer diagnostic criteria for pseudotumor cerebri syndrome (PTCS) are both used to diagnose intracranial hypertension (IH). In comparison to the modified Dandy criteria, the PTCS criteria stratify the IH diagnosis into definite, probable, and suggested categories, exclude clinical symptoms, and use radiologic evidence for diagnosis. There is a lack of consensus on which criteria should be used in the pediatric population. The purpose of this study was to compare the diagnostic criteria for PTCS to the modified Dandy criteria and to identify limitations within both sets of criteria. METHODS: The PTCS criteria were retrospectively applied to 50 patients originally diagnosed with IH under the modified Dandy criteria. RESULTS: Of the 50 patients, 31 (62%) met diagnostic criteria for definite PTCS, 10 (20%) met criteria for probable PTCS, and 9 patients (18%) failed to meet sufficient PTCS criteria for diagnosis. CONCLUSIONS: Although the PTCS criteria use objective data to make the IH diagnosis, we found subjective symptoms to be useful indicators of disease in this group of patients. Additionally, distinguishing probable from definite IH may not have clinical relevance, because both groups were treated similarly. The absence of radiographic evidence of IH should not preclude a diagnosis of the condition, as it was present in a minority of patients included in this study. Further research is needed to clarify the disease process in patients who present with signs and symptoms of elevated intracranial pressure but lack ocular pathology.

Incidence and Demographics of Pediatric Intracranial Hypertension.

OBJECTIVE: We analyzed the incidence and demographic features of pediatric intracranial hypertension. METHODS: Inpatient and outpatient encounters of children aged 18 years or younger who were diagnosed with primary (idiopathic) or secondary intracranial hypertension between January 2010 and December 2013 were identified. Data were collected from a subspecialty clinic devoted to intracranial hypertension and the sole children's hospital in a large Midwestern city of the United States. Estimated incidence rates were calculated based on the number of newly diagnosed patients in our hospital's primary service area, which includes seven central Ohio counties. Sex, race, body mass index, socioeconomic status, and geographic distribution were also noted. RESULTS: A total of 74 pediatric patients were diagnosed with intracranial hypertension (49 primary/idiopathic and 25 secondary) between January 2010 and December 2013. Using census data, we determined the pediatric population in our service area during the four-year period. The Ohio Hospital Association's database indicated that 92.3% of patients aged 0 to 17 years residing in the region sought care at our institution. By combining these data, we calculated an annual incidence of primary and secondary intracranial hypertension of 0.63 and 0.32 per 100,000 children, respectively. CONCLUSIONS: The estimated annual incidence of pediatric primary intracranial hypertension in our seven county service area in central Ohio is similar to previous pediatric reports from other countries and is 67% of that reported in the US adult population.

Pediatric Intracranial Hypertension.

Primary (idiopathic) intracranial hypertension has been considered to be a rare entity, but with no precise estimates of the pediatric incidence in the United States. There have been attempts to revise the criteria over the years and adapt the adult criteria for use in pediatrics. The clinical presentation varies with age, and symptoms tending to be less obvious in younger individuals. In the prepubertal population, incidentally discovered optic disc edema is relatively common. By far the most consistent symptom is headache; other symptoms include nausea, vomiting tinnitus, and diplopia. Treatment mainstays include weight loss when appropriate and acetazolamide. Furosemide may exhibit a synergistic benefit when used in conjunction with acetazolamide. Surgical interventions are required relatively infrequently, but include optic nerve sheath fenestration and cerebrospinal fluid shunting. Pain and permanent vision loss are the two major complications of this disorder and these manifestations justify aggressive treatment. Once intracranial hypertension has resolved, up to two thirds of patients develop a new or chronic headache type that is different from their initial presenting headache.

Sixth Nerve Palsy in Paediatric Intracranial Hypertension.

The purpose of this study was to report the incidence and describe the characteristics of sixth cranial nerve (CN VI) palsy in paediatric patients with intracranial hypertension (IH). A retrospective chart review of central Ohio children diagnosed with IH over the 3-year period from 2010 to 2013 was conducted. IH without identifiable cause was defined as idiopathic intracranial hypertension (IIH), whereas IH with identifiable pathologic aetiology was deemed secondary intracranial hypertension (SIH). A subset of patients with CN VI palsy was identified. Data collected included patient age, gender, past medical history, aetiology of SIH, ophthalmic examination, lumbar puncture results, neuroimaging results, and response to treatment. Seventy-eight children with intracranial hypertension were included in the study. Nine (11.5%) children (four males, five females; median age 14, range: 3-18) were found to have a unilateral (n = 2) or bilateral (n = 7) CN VI palsy. Five children had IIH; the remaining four had SIH from cerebral venous sinus thrombosis (n = 2) and infection (n = 2). The mean lumbar puncture opening pressure for the nine patients with CN VI palsy was 40 cm H2O (range: 21-65 cm H2O). Papilloedema was present in 8/9 (89%) patients. One patient required a lumboperitoneal shunt, and two others required optic nerve sheath fenestrations in addition to medical management. All cases of CN VI palsy resolved with treatment. In our primary service area, the incidence of CN VI palsy is approximately 12% among paediatric IH patients. The majority of cases with CN VI palsy presented with papilloedema and all cases resolved with treatment of intracranial hypertension.

Long-term visual acuity outcomes in patients with uveal melanoma treated with 125I episcleral OSU-Nag plaque brachytherapy.

PURPOSE: To report our experience in long-term follow-up of ocular melanoma patients treated with custom OSU-Nag eye plaques using (125)I sources. METHODS: A retrospective chart review was conducted for 113 consecutive ocular melanoma patients with follow-up visual acuity data who were treated with OSU-Nag plaque episcleral brachytherapy at The Ohio State University Medical Center from 1994 to 2009. Visual acuity, complication data, and recurrence rates were recorded up to 120 months after brachytherapy. RESULTS: Median age at presentation was 63.0 years (range, 22-93). Median follow-up was 65.5 months (range, 2-180). Median radiation dose at the prescription point was 85.8 Gy (range, 51.8-103.7). Preservation of useful visual acuity, defined as better than 20/200, was noted in 43 of 74 (58%) of patients in the present study at 36 months compared with 50.1% of Collaborative Ocular Melanoma Study participants. By 120 months, 17 of 30 (57%; 95% confidence interval, 45-69%) progressed to visual acuity worse than 20/200, whereas 9 of 30 (30%) retained visual acuity of 20/40 or better, and 4 of 30 (13%) were 20/50-20/200. The rate of retinopathy after radiation was approximately 40% of all those observed by 60 months. Baseline visual acuity, apical tumor height, American Joint Committee on Cancer tumor category, and distance between the tumor and the fovea were all significantly associated with loss of visual acuity. The local tumor control rate by 60 months of follow-up was 93% (95% confidence interval, 85-97%). CONCLUSIONS: The OSU-Nag custom (125)I plaque is an effective treatment for uveal melanoma, with preservation of useful visual acuity in 58% of eyes 3 years after treatment and 43% of eyes 10 years after treatment.

Periocular hemangiomas and lymphangiomas.

Infantile hemangiomas are the most common benign tumor of childhood. Lymphangiomas are benign hamartomatous vascular tumors. Both lesions can be problematic when located in the periocular region. Pediatricians must be familiar with the characteristics of each which would necessitate referral to an ophthalmologist or other subspecialist for evaluation, including obstruction of the visual axis which can lead to amblyopia of the affected eye. Additional potential complications include proptosis, ocular motility limitation, optic nerve injury, and poor eyelid closure with or without corneal surface disease. All children with periocular hemangiomas or lymphangiomas should be referred to an ophthalmologist for further evaluation.

Screening and characterization of Staphylococcus aureus from ophthalmology clinic surfaces: a proposed surveillance tool.

PURPOSE: To screen environmental surfaces of an outpatient ophthalmic clinic for methicillin-susceptible and methicillin-resistant Staphylococcus aureus (MSSA and MRSA); to identify the most commonly contaminated surfaces and to phenotype and genotype all collected isolates. DESIGN: A single institution, 1-year prospective environmental study. METHODS: Commonly touched surfaces in examination rooms and common areas were targeted and sampled on a quarterly basis for 1 year. Samples were collected using electrostatic cloths and swabs. S. aureus was isolated using nonselective and selective media. Morphologic characteristics and standard biologic testing were used to confirm staphylococcal species. S. aureus isolates were phenotypically (Kirby-Bauer method) and genotypically characterized (mecA confirmation, SCCmec typing and pulsed-field gel electrophoresis). Dendrogram analysis was used to establish genetic relatedness between the isolates. RESULTS: Of 112 total samples, 27 (24%) and 5 (4%) were MSSA- and MRSA-positive, respectively. Both community-associated (SCCmec IV, USA300) and hospital-associated (SCCmec II, USA100) MRSA isolates were found. No single surface remained consistently positive with the same isolate over time, and molecular analysis demonstrated high levels of diversity among isolates. Doorknobs, slit-lamp headrests and chinrests, and computer keyboards were commonly found to be contaminated. CONCLUSIONS: The proposed surveillance protocol successfully allowed the detection of both MSSA and MRSA contaminating important high-touch surfaces in a representative ophthalmology clinic. Frequently contaminated surfaces must be targeted for routine cleaning and disinfection because there is a constant introduction of clones over time. Hence, other clinics may consider implementing and adapting surveillance tools, like the one described here, to help them control these important nosocomial pathogens.

Abnormal vascularization in mouse retina with dysregulated retinal cholesterol homeostasis.

Several lines of evidence suggest a link between age-related macular degeneration and retinal cholesterol maintenance. Cytochrome P450 27A1 (CYP27A1) is a ubiquitously expressed mitochondrial sterol 27-hydroxylase that plays an important role in the metabolism of cholesterol and cholesterol-related compounds. We conducted a comprehensive ophthalmic evaluation of mice lacking CYP27A1. We found that the loss of CYP27A1 led to dysregulation of retinal cholesterol homeostasis, including unexpected upregulation of retinal cholesterol biosynthesis. Cyp27a1-/- mice developed retinal lesions characterized by cholesterol deposition beneath the retinal pigment epithelium. Further, Cyp27a1-null mice showed pathological neovascularization, which likely arose from both the retina and the choroid, that led to the formation of retinal-choroidal anastomosis. Blood flow alterations and blood vessel leakage were noted in the areas of pathology. The Cyp27a1-/- retina was hypoxic and had activated Müller cells. We suggest a mechanism whereby abolished sterol 27-hydroxylase activity leads to vascular changes and identify Cyp27a1-/- mice as a model for one of the variants of type 3 retinal neovascularization occurring in some patients with age-related macular degeneration.

Spatial distribution of the pathways of cholesterol homeostasis in human retina.

BACKGROUND: The retina is a light-sensitive tissue lining the inner surface of the eye and one of the few human organs whose cholesterol maintenance is still poorly understood. Challenges in studies of the retina include its complex multicellular and multilayered structure; unique cell types and functions; and specific physico-chemical environment. METHODOLOGY/PRINCIPAL FINDINGS: We isolated specimens of the neural retina (NR) and underlying retinal pigment epithelium (RPE)/choroid from six deceased human donors and evaluated them for expression of genes and proteins representing the major pathways of cholesterol input, output and regulation. Eighty-four genes were studied by PCR array, 16 genes were assessed by quantitative real time PCR, and 13 proteins were characterized by immunohistochemistry. Cholesterol distribution among different retinal layers was analyzed as well by histochemical staining with filipin. Our major findings pertain to two adjacent retinal layers: the photoreceptor outer segments of NR and the RPE. We demonstrate that in the photoreceptor outer segments, cholesterol biosynthesis, catabolism and regulation via LXR and SREBP are weak or absent and cholesterol content is the lowest of all retinal layers. Cholesterol maintenance in the RPE is different, yet the gene expression also does not appear to be regulated by the SREBPs and varies significantly among different individuals. CONCLUSIONS/SIGNIFICANCE: This comprehensive investigation provides important insights into the relationship and spatial distribution of different pathways of cholesterol input, output and regulation in the NR-RPE region. The data obtained are important for deciphering the putative link between cholesterol and age-related macular degeneration, a major cause of irreversible vision loss in the elderly.

A unique case of autoimmune retinopathy associated with anti-alpha-enolase antibodies.

Background. We report a case of autoimmune retinopathy associated with anti-alpha-enolase antibodies with unique manifestations. Methods. A case report. Results. A 30-year-old male experienced recurrent, primarily peripheral visual field disturbances and minimal photopsia, with interval symptom resolution. Fundus changes subsequently developed in areas corresponding to the previous visual field symptoms. Electroretinogram showed bilaterally symmetric abnormalities of light-adapted responses and suggested loss of photoreceptor function. Only anti-alpha-enolase antibodies were detected on Western blot. Our patient noted cutaneous symptoms at the time of both episodes of visual symptoms, but not in the interim. Biomicroscopy revealed subtle small reddish spots in areas of the peripheral retina corresponding to the areas of the patient's visual field where he noted symptoms. To our knowledge these reddish spots have not been reported in autoimmune retinopathy and may clinically support in vitro and in vivo evidence that anti-alpha-enolase antibodies may target photoreceptors. Conclusions. Our patient demonstrates some unique features adding to the known characteristics of autoimmune retinopathy associated with anti-alpha-enolase antibodies. As more cases are reported, further understanding of the features and pathophysiology of this rare condition will hopefully be elucidated.

Quantification of cholesterol-metabolizing P450s CYP27A1 and CYP46A1 in neural tissues reveals a lack of enzyme-product correlations in human retina but not human brain.

Cytochrome P450 enzymes (CYP or P450) 46A1 and 27A1 play important roles in cholesterol elimination from the brain and retina, respectively, yet they have not been quantified in human organs because of their low abundance and association with membrane. On the basis of our previous development of a multiple reaction monitoring (MRM) workflow for measurements of low-abundance membrane proteins, we quantified CYP46A1 and CYP27A1 in human brain and retina samples from four donors. These enzymes were quantified in the total membrane pellet, a fraction of the whole tissue homogenate, using ¹5N-labled recombinant P450s as internal standards. The average P450 concentrations/mg of total tissue protein were 345 fmol of CYP46A1 and 110 fmol of CYP27A1 in the temporal lobe, and 60 fmol of CYP46A1 and 490 fmol of CYP27A1 in the retina. The corresponding P450 metabolites were then measured in the same tissue samples and compared to the P450 enzyme concentrations. Investigation of the enzyme-product relationships and analysis of the P450 measurements based on different signature peptides revealed a possibility of retina-specific post-translational modification of CYP27A1. The data obtained provide important insights into the mechanisms of cholesterol elimination from different neural tissues.

Contrast sensitivity of cats and humans in scotopic and mesopic conditions.

Human contrast sensitivity in low scotopic conditions is regulated according to the deVries-Rose law. Previous cat behavioral data, as well as cat and mice electrophysiological data, have not confirmed this relationship. To resolve this discrepancy at the behavioral level, we compared sensitivity in dim light for cats and humans in parallel experiments using the same visual stimuli and similar behavioral paradigms. Both species had to detect Gabor functions (SD = 1.5 degrees, spatial frequencies from 0 to 4 cpd, temporal frequency 4 Hz) presented 8 degrees to the right or left of a central fixation point over an 8 log-unit range of adaptation levels spanning scotopic vision and extending well into the mesopic range. Cats had 0.74 log unit greater absolute sensitivity than that of humans for spatial frequencies