Ann U. Stout

Etanercept therapy in children with treatment-resistant uveitis

OBJECTIVE To evaluate the safety and efficacy of the tumor necrosis factor fusion protein etanercept in children with treatment-resistant uveitis. METHODS Ten children with chronic active uveitis (7 girls and 3 boys, mean age 7.5 years [range 3-12 years]) were enrolled in this prospective study. In 7 children, uveitis was associated with pauciarticular juvenile rheumatoid arthritis. Five children were antinuclear antibody positive. All patients had failed previous therapy with topical steroids and methotrexate and/or cyclosporine. All were treated with etanercept at a dosage of 0.4 mg/kg twice weekly for the first 3 months, and then, if eyes did not improve, with 25 mg twice weekly (mean 1.1 mg/kg) for at least 3 additional months. RESULTS At the beginning of the trial, uveitis affected 18 eyes in the 10 children. Within 3 months, 10 of 16 affected eyes (63%; P = 0.017) showed a rapid decrease in anterior chamber cell density, including remission of uveitis in 4 eyes. In children with visual acuity of less than 20/25, 4 of 10 eyes (40%) improved. An exacerbation of uveitis during etanercept therapy occurred in only 1 child (1 of 14 eyes [7%]). Other ocular outcome parameters, such as intraocular pressure, synechia formation, and lens clarity, remained unchanged. Following a dosage increase to an average of 1.1 mg/kg after 3 months in 7 children, no further improvement was noted. CONCLUSION Our data suggest that etanercept injected subcutaneously twice a week has a beneficial effect on treatment-resistant chronic uveitis in children. Further controlled studies with etanercept in systemic or topical form are necessary to confirm its efficacy and optimal mode of administration.

The Infant Aphakia Treatment Study: Design and Clinical Measures at Enrollment

OBJECTIVE To compare the use of contact lenses and intraocular lenses (IOLs) for the optical correction of unilateral aphakia during infancy. METHODS In a randomized, multicenter (12 sites) clinical trial, 114 infants with unilateral congenital cataracts were assigned to undergo cataract surgery with or without IOL implantation. Children randomized to IOL treatment had their residual refractive error corrected with spectacles. Children randomized to no IOL treatment had their aphakia treated with a contact lens. MAIN OUTCOME MEASURES Grating acuity at 12 months of age and HOTV visual acuity at 4 1/2 years of age. APPLICATION TO CLINICAL PRACTICE This study should determine whether either treatment for an infant with a visually significant unilateral congenital cataract results in a better visual outcome. RESULTS Enrollment began December 23, 2004, and was completed January 16, 2009. The median age at the time of cataract surgery was 1.8 months. Fifty patients were 4 to 6 weeks of age at the time of enrollment; 32, 7 weeks to 3 months of age; and the remaining 32, more than 3 to less than 7 months of age. Fifty-seven children were randomized to each treatment group. Eyes with cataracts had shorter axial lengths and steeper corneas on average than the fellow eyes. CONCLUSIONS The optimal optical treatment of aphakia in infants is unknown. However, the Infant Aphakia Treatment Study was designed to provide empirical evidence of whether optical treatment with an IOL or a contact lens after unilateral cataract surgery during infancy is associated with a better visual outcome.

Stereopsis Results at 4.5 Years of Age in the Infant Aphakia Treatment Study

PURPOSE To determine whether stereopsis of infants treated for monocular cataracts varies with the type of optical correction used. DESIGN Randomized prospective clinical trial. METHODS The Infant Aphakia Treatment Study randomized 114 patients with unilateral cataracts at age 1-7 months to either primary intraocular lens (IOL) or contact lens correction. At 4.5 years of age a masked examiner assessed stereopsis on these patients using 3 different tests: (1) Frisby; (2) Randot Preschool; and (3) Titmus Fly. RESULTS Twenty-eight patients (25%) had a positive response to at least 1 of the stereopsis tests. There was no statistically significant difference in stereopsis between the 2 treatment groups: Frisby (contact lens, 6 [11%]; IOL, 7 [13%]; P = .99), Randot (contact lens, 3 [6%]; IOL, 1 [2%]; P = .62), or Titmus (contact lens, 8 [15%]; IOL, 13 [23%]; P = .34). The median age at surgery for patients with stereopsis was younger than for those without stereopsis (1.2 vs 2.4 months; P = .002). The median visual acuity for patients with stereopsis was better than for those without stereopsis (20/40 vs 20/252; P = .0003). CONCLUSION The type of optical correction did not influence stereopsis outcomes. However, 2 other factors did: age at surgery and visual acuity in the treated eye at age 4.5 years. Early surgery for unilateral congenital cataract and the presence of visual acuity better than or equal to 20/40 appear to be more important than the type of initial optical correction used for the development of stereopsis.

Cerebrotendinous xanthomatosis: a treatable disease with juvenile cataracts as a presenting sign.

Cerebrotendinous Xanthomatosis (CTX) is an autosomal recessive disorder of bile acid synthesis1. At least 50 different causative mutations have been identified in the CYP27A1 gene encoding for a sterol 27-hydroxylase important in bile acid synthesis2. Sterol 27-hydroxylase deficiency leads to 5α-cholestanol accumulation in the blood and tissues of affected patients1, including brain, often leading to severe neurological dysfunction that can incapacitate patients by the 4th–5th decade of life1. CTX generally presents clinically in the 2nd–3rd decade; childhood signs and symptoms can include chronic diarrhea, juvenile cataracts, school failure1,3, and potentially xanthomas1. Eighty-five percent of CTX patients develop cataracts of multiple types2, reported to occur as young as age 5–6 years1, with cataracts and chronic diarrhea commonly presenting before neurologic disease3. For this reason, and since diarrhea is non-specific, the clinician may not consider a diagnosis of CTX when cataracts are identified. Treatment for CTX is available in the form of chenodeoxycholic acid (CDCA)1,4. The FDA recently reapproved CDCA (Manchester Pharmaceuticals, Inc). As treatment of CTX from the preclinical stage prevents the onset of disease complications4, the value of early diagnosis for this disorder cannot be overstated. We describe two cases of CTX affected children enrolled in an IRB approved study at OHSU with bilateral cataracts as presenting signs of disease. Case 1 A 9 year old female was referred to an ophthalmologist for decreased vision over several months. Past ocular history was unremarkable; full ocular exam 2 years prior was normal. Family history was unremarkable. Past medical history was significant for diarrhea and nonverbal learning disorder. On examination uncorrected distance visual acuity was 20/80 and uncorrected near acuity was 20/50 in each eye. Manifest refraction was 0.75+0.50X90 in each eye, with corrected distance acuity of 20/60 in the right and 20/80 in the left. Complete dilated exam was remarkable for the presence of cataract in each eye and described as a diffuse nuclear haze on slit lamp examination, with mild posterior capsular opacification (figure 1). Retroillumination highlighted posterior capsular findings (figure 2). Sequential bilateral cataract surgery with intraocular lens placement resulted in a corrected visual acuity of 20/20 in each eye. A metabolic workup indicated plasma 5α-cholestanol was markedly elevated at 3.7 mg/dl (normal < 0.2 mg/dl1), suggestive of CTX. Urine testing confirmed CTX with elevated bile alcohol glucuronides present (30.1 μg/ml). CDCA treatment was initiated and diarrhea resolved within one month, with accompanying weight gain. Plasma cholestanol dropped to 0.5 mg/dl within 7 months and after 6 years of treatment is currently stable at <0.2 mg/dl. No further clinical symptoms of CTX have developed. Figure 1 Diffuse nuclear haze and posterior sub capsular capsule opacification in right (A) and left (B) eye. Figure 2 Posterior sub capsular opacification in right (A) and left (B) eye. Case 2 An 11 year old male was referred to an ophthalmologist for cataract evaluation. High myopia was noted by a previous ophthalmologist at age 4. Family history was significant for high myopia and detached retina in mother and grandmother. Medical history included diarrhea from infancy, delayed language, autism, and seizures. Examination was limited by cooperation; however uncorrected distance visual acuity was at least 20/400 with both eyes open. Dilated examination revealed a refraction of −9.00 +1.00X090 in the right eye, and −9.50+1.25X090 in the left and was remarkable for bilateral cataracts. The lens opacities appeared visually significant with cortical flecks and distorted retinoscopic reflexes. Sequential bilateral cataract surgery was conducted with intraocular lens placement. The corrected visual acuity was 20/30+1 in the right and 20/40 in the left eye. Approximately 5 years later the patient was screened for a cholesterol disorder. Plasma 5α-cholestanol was elevated at 3.1–4.2 mg/dl, consistent with CTX. Elevated bile alcohol glucuronides in urine confirmed CTX. Diarrhea resolved within one month of initiating treatment. Plasma 5α-cholestanol dropped to 0.6 mg/dl within 6–8 months. After 8 months of treatment, the patient remains intellectually impaired, and continues to require an augmentative communication device. Although he still types single words to express wishes and needs, his spoken vocabulary has expanded modestly. His behavioral difficulties (making loud noises/head banging) also appear to be subsiding.

Associated systemic and ocular disorders in patients with congenital unilateral cataracts: the Infant Aphakia Treatment Study experience.

PurposeFive-year prospective data on children enrolled in the Infant Aphakia Treatment Study (IATS) provided an opportunity to explore ocular and systemic associations in patients with a unilateral congenital cataract.MethodsInfants <7 months of age with a unilateral cataract were eligible for IATS screening. We reviewed data pertaining to the exclusion of patients as well as data collected on standardized study forms used at any time for documentation of ocular or systemic disorders.ResultsOverall, 227 infants were referred for possible enrollment. Of these, 10 had insignificant cataracts and 32 refused to participate. Of those excluded, 3 were premature, 27 had significant ocular disease (usually persistent fetal vasculature (PFV) or corneal diameter <9 mm), and 4 had systemic disorders. An additional 26 were excluded at the time of the first EUA, most often because of PFV or variants thereof. On follow-up, in the 114 enrolled patients, the following disorders were diagnosed: Stickler syndrome (1), mitochondrial disease (1), autism (1), and presumed congenital rubella syndrome (1). No patient developed a cataract in the fellow eye.DiscussionSome conditions that can feature unilateral cataracts are diagnosed at birth or very early in life, but others may be diagnosed at varying periods thereafter. PFV and its variants are the most common associated ocular findings in about a quarter of cases of unilateral congenital cataracts.ConclusionAlthough patients with a unilateral cataract may have significant associated abnormalities in the affected eye, most commonly PFV and its variants, the prevalence of associated significant systemic disease is quite low.