Intraretinal cystoid spaces in a patient with retinitis pigmentosa due to mutation in the MAK gene

Background: Cystoid macular edema (CME) and non-leaking intraretinal cystoid spaces (ICS) have different pathophysiologic mechanisms.

Materials and methods: We report a patient with retinitis pigmentosa (RP) with ICS due to a mutation in the male germ cell-associated kinase (MAK) gene.

Results: A 41-year-old Ashkenazi Jewish male was referred for abnormal visual field revealed by regular optometric examination. His visual acuity was 20/20 in each eye. Dilated examination revealed typical finding of RP. Optical coherence tomography showed cystoid changes in each fovea. Photoreceptors were also degenerated. Intravenous fluorescein angiography showed no leakage. Genetic testing identified a homozygous mutation in the MAK gene: a 353-bp Alu insertion (K429insAlu).

Conclusions: Mak regulates microtubule stability via phosphorylating RP1. Abnormal Mak may impact retinal photoreceptor ciliary length and subcompartmentalization. Mak is required for the survival of photoreceptors in mice. ICS has been reported in other ciliopathies. We report the first case of ICS due to mutation in MAK.     

Utility of Leflunomide in the Treatment of Drug Resistant Cytomegalovirus Retinitis

Purpose: To describe leflunomide use in the treatment of drug resistant cytomegalovirus retinitis. Leflunomide has been shown to be effective in the treatment of systemic CMV viremia.

Methods: Retrospective chart review of patients with CMV retinitis treated with leflunomide.

Results: Two HIV-negative organ transplant recipients with UL 97 mutation resistant-genotype CMV were identified. Patient 1 developed CMV viremia post-kidney transplant and subsequently bilateral CMV retinitis. Retinitis progressed, despite intravitreal injection of ganciclovir and foscarnet, and IV foscarnet and oral valganciclovir. Retinitis control was achieved with the addition of oral leflunomide. Disease remained inactive for 22 months. Patient 2 developed CMV retinitis after lung transplant. Disease progressed despite intravitreal foscarnet injections and oral valganciclovir. Control of retinitis was achieved with addition of oral leflunomide, allowing cessation of intravitreal therapy. Disease remained inactive until his death.

Conclusions: Leflunomide may be considered as a treatment option for resistant CMV retinitis.     

A novel C8orf37 splice mutation and genotype-phenotype correlation for cone-rod dystrophy

Background: To identify the disease-causing mutation in a consanguineous family of Morrocan origin with syndromic autosomal recessive (ar) cone-rod dystrophy (CRD) in two patients and describe genotype-phenotype correlations.

Materials and Methods: Genome-wide homozygosity mapping and direct sequencing of C8orf37, located in a homozygous interval, was performed in the family. mRNA analysis revealed the effect of the newly identified splice-site mutation. For a comparative analysis phenotypic and genetic data of C8orf37 mutations were extracted from published cases.

Results: The new splice-site mutation c.155+2T>C identified in the family results in a skipping of 82 bp. The CRD phenotypes of our patients were consistent with previous reports. Non-ocular findings in our patients and two previously described patients were postaxial polydactyly present at birth. Both families with additional postaxial polydactyly had splice site mutations affecting intron 1 of C8orf37, one at the slice donor and one at the splice acceptor site.

Conclusions: This report extends the genotypic spectrum of C8orf37-associated retinal dystrophies and demonstrates for the first time a genotype-phenotype correlation between an arCRD-polydactyly-association and truncating germline mutations affecting the N-terminal region of the protein. Furthermore, our findings underline the ciliary function of C8orf37 protein.     

Roth Spots in Ocular Toxoplasmosis

Purpose: To report a case with unilateral preexisting ocular toxoplasmosis (OT) and newly occurred active retinochoroidal inflammation associated with white-centered retinal hemorrhages (Roth spots) in the healthy eye.

Design: Case report.

Methods: A 20 year-old man presented with a decrease of visual acuity in his right eye associated with 2+ cells in the anterior chamber. Ophthalmoscopy revealed an active retinochoroidal lesion on the upper nasal border of the optic disc associated with local hemorrhage and vitritis. The posterior pole presented white-centered flame-shaped retinal hemorrhages.

Results: Toxoplasmosis serology showed an IgG titer >300IU/ml and a negative IgM titer. A complete blood count revealed no abnormalities; other serologies were negative. After 2 weeks of treatment with sulfadiazine, pyrimethamine, folinic acid and prednisone, although the peripapillary lesion was still active, the Roth spots disappeared.

Conclusion: OT may be one differential diagnosis of patients suffering Roth spots in association with retinochoroidal inflammation.     

Impact of Superior Oblique Transposition on Primary Position Deviation,a Pattern and Intorsion in Third Nerve Palsy

Purpose: To evaluate the role of superior oblique transposition on primary position alignment, A pattern, and intorsion in third nerve palsy.

Methods: Ten patients with isolated, unilateral third nerve palsy were included in this prospective study. The patients were treated by conventional surgery on horizontal recti together with superior oblique transposition by Scott’s procedure in the paretic eye.

Results: Pre-operative primary horizontal deviation was 60-80 PD (mean 70.00±7.45 PD). Pre-operative primary hypotropia was 15-22 PD (mean 18.80±2.48 PD). Mean A-pattern was 17.80±2.65 PD. All patients included in the study had some degree of objective torsion as measured by Guyton’s method. One patient had grade I objective intorsion, 2 had grade II, 6 had grade III, and 1 had grade IV objective intorsion.

Primary position horizontal alignment (up to ±8 PD) was achieved in 9 patients. Primary position vertical alignment (up to ±8 PD) was achieved in all 10 patients.

Only 2 of 10 patients had A-pattern of 10 PD, in the remaining 8 patients it was eliminated (P<0.05). Postoperatively, 5 patients had no objective intorsion and 5 had grade I intorsion, and none of the patients had hypertropia or paradoxical eye movements.

Conclusion: Superior oblique transposition by Scott’s procedure along with conventional surgery on horizontal recti in third nerve palsy results in better horizontal and vertical alignment, and improves A-pattern and intorsion, thus leading to better binocular interaction.     

Multimodal Imaging in Sympathetic Ophthalmia

Purpose: To show the current status of multimodal imaging and its role in supporting an early diagnosis of sympathetic ophthalmia.

Methods: The diagnosis is mainly clinical supported with ancillary investigations; mainly fluorescein angiography and others, including indocyanine angiography optical coherence tomography (OCT), OCT enhanced depth imaging, autofluorescence imaging, and ultrasonography.

Results: Various imaging modalities such as OCT, autofluorescence imaging and angiography are critical in the diagnosis and management of sympathetic ophthalmia. The clinician must make adequate use of such ancillary investigations in the management of the patients.

Conclusions: Sympathetic ophthalmia is a rare, bilateral inflammation of the uveal tract following penetrating trauma or surgery in one eye. The intraocular inflammation requires a prompt diagnosis so that the treatment can be initiated as early as possible.     

Repeat Conjunctival Biopsy after Immunomodulatory Therapy for Ocular Mucous Membrane Pemphigoid

Purpose: To evaluate whether conjunctival biopsy findings in patients with ocular mucous membrane pemphigoid (MMP) persist as positive or revert to negative following treatment with immunomodulatory therapy (IMT).

Methods: Patients with biopsy-proven MMP were treated with IMT for at least 2 years before undergoing repeat conjunctival biopsy for immunofluorescence microscopy. Their records were reviewed and findings evaluated to ascertain which patients’ biopsies showed antibody deposition on the conjunctival basement membrane.

Results: Following 2 years of IMT, conjunctival biopsies showed persistent antibody deposition in two patients, and were negative in four patients.

Conclusions: Conjunctival biopsies in patients with ocular MMP may show reversion to inactive disease following IMT. Post-treatment biopsy might be clinically useful as a means of evaluating the efficacy of therapy in this chronic disease.     

Ferritin light chain gene mutation in a large Australian family with hereditary hyperferritinemia-cataract syndrome

Background: Hereditary hyperferritinemia-cataract syndrome (HHCS) is an autosomal dominant Mendelian disorder characterized by early onset cataracts and elevated levels of serum ferritin in the absence of iron overload. Numerous mutations associated with the development of HHCS have been reported in the 5′ non-coding region of the ferritin light chain (FTL) gene in family studies. We present an FTL mutation in an Australian family with 10 HHCS-affected members spanning three generations.

Materials and methods: Blood and saliva samples were collected from affected and unaffected family members and DNA was extracted using commercially available kits (Qiagen). The complete sequencing of the iron-responsive element (IRE) of the FTL gene was analyzed using bi-directional genomic sequencing.

Results: A heterozygous single nucleotide substitution (c.-167 C>T) was identified in the proband and five affected family members (logarithm of the odds score [Z] = 3.61, recombination distance [θ = 0]). All affected individuals had previously been found to have high ferritin levels and early onset cataracts.

Conclusion: This is the first Australian report of the c.-167 C>T mutation in a large family with multiple affected individuals. This finding raises the possibility that identification of HHCS mutations may be an effective means of disease detection and may aid in facilitating appropriate genetic counseling.     

Recessive Mutations in LEPREL1 Underlie a Recognizable Lens Subluxation Phenotype

Purpose: To uncover the homozygous recessive gene mutation underlying familial lens subluxation and/or juvenile lens opacities in four sisters from a consanguineous family.

Methods: Prospective family study (clinical phenotyping; homozygosity-analysis-guided candidate gene testing).

Results: The proband was a 14-year-old girl with long-standing poor vision, bilateral temporal lens subluxation, lens opacities, and axial high myopia. There were no syndromic findings, and fibrillin-1 sequencing was normal. Three sisters, also non-syndromic, had undergone bilateral juvenile lens surgery (two for juvenile cataract, 1 for lens subluxation) within the first two decades of life. Both sisters who had cataract surgery developed bilateral post-operative retinal detachments and one had documented lens instability during cataract surgery. Genetic analysis revealed the phenotype to segregate with a novel homozygous recessive mutation in LEPREL1 (c.292delC; p.Gly100Alafs*104). Recessive mutations in this gene were recently highlighted as a cause for axial myopia and early-onset cataract in two families for whom some affected members also had ectopia lentis and/or post-operative retinal detachments.

Conclusions: Recessive LEPREL1 mutations should be recognized as part of the differential diagnosis of lens subluxation. The associated phenotype is non-syndromic and distinguishable from other causes of ectopia lentis in the context of its additional features: juvenile lens opacities, axial myopia, and a predisposition to retinal tears/detachment following intraocular surgery.     

A family harboring homozygous FZD4 deletion supports the existence of recessive FZD4-related familial exudative vitreoretinopathy

Purpose: To document recessive FZD4-related familial exudative vitreoretinopathy.

Methods: Retrospective case series.

Results: Two brothers, the only two males among five siblings, had bilateral infantile retinal detachments and were referred for genetic counseling. Next-generation sequencing uncovered a homozygous FZD4 frameshift deletion in both affected brothers (c.40_49delCCCGGGGGCG; p.Pro14Serfs*44). None of the other immediate family members had clinical evidence for retinal disease, including the three family members who underwent confirmatory genetic testing and were found to be heterozygous for the mutation (both parents and one sister).

Conclusions: The findings in this family support the concept that some mutated FZD4 alleles can be associated with recessive rather than dominant disease.     

In Vivo Confocal Microscopic Characteristics of Crystalline Keratopathy in Patients with Sclerokeratitis

Purpose: To report in vivo confocal features in a clinical case series of patients with sclerokeratitis presenting as crystalline keratopathy.

Methods: Five cases of crystalline keratopathy following sclerokeratitis are described. Confocal microscopic images of the cornea were captured in all cases to confirm the diagnosis by evaluating the morphology of the crystals.

Results: Unilateral and non-progressive peripheral crystalline keratopathy manifested after previous episodes of sclerokeratitis in the involved eye. Confocal microscopy revealed numerous, discrete, hyperreflective, needle-like, shiny crystals in the anterior and posterior stromal layers of the cornea. These deposits were oriented randomly and showed occasional confluence. An extensive ophthalmic and systemic evaluation did not reveal any other contributory factors.

Conclusion: Crystalline keratopathy, probably resulting from an immune-mediated response, is a possible manifestation of sclerokeratitis. This should be considered during long-term follow-up of such patients and differentiated from infectious crystalline keratopathy.     

Atypical VZV Retinitis in a Patient with Good Syndrome

Purpose: To describe atypical varicella zoster virus (VZV) retinitis in a patient with Good syndrome.

Methods: A 63-year-old patient with Good syndrome presented with bilateral necrotizing retinitis starting from the posterior pole. He had a history of thymoma status post thymectomy 4 years previously, left-sided sinusitis, and recent pulmonary aspergillosis. Qualitative PCR was performed on aqueous fluid.

Results: Immunological investigations revealed reduced levels of CD4⁺ T cells and immunoglobulins. Qualitative PCR was positive for VZV and negative for cytomegalovirus, herpes simplex virus (HSV)-1, and HSV-2. The patient was treated with oral valacyclovir and three courses of immunoglobulin supplementation. The atypical retinitis showed improvement after therapy.

Conclusion: Good syndrome should be considered in a patient with opportunistic infections and history of thymoma in the absence of human immunodeficiency virus. Atypical retinitis can occur in patients with Good syndrome and quantitative PCR is important for accurate diagnosis.     

Osseous Metaplasia (Cataracta Ossea) of Lens Remnants in Chronic Uveitis—A Clinicopathologic Report

Purpose: To describe clinically and pathologically the rare occurrence of calcification and osseous metaplasia in lens remnants in both eyes of a patient with pseudophakic chronic uveitis.

Methods: We performed 25-gauge pars plana vitrectomy, removal of dislocated intraocular lens (IOL), and secondary IOL fixation in the left eye. A similar procedure was performed in the right eye with 27-gauge pars plana vitrectomy.

Results: The postoperative visual acuities were 20/30 OD and 20/125 OS. Hematoxylin and eosin staining demonstrated an abundance of calcified tissue and rare osteoclasts in lacunae, compatible with osseous metaplasia (cataracta ossea).

Conclusion: To our knowledge this is the first clinicopathologic report demonstrating cellular metaplasia that resulted in osseous transformation of the cortical lens remnants into bone in both eyes of a psuedophakic patient with chronic granulomatous pan uveitis of unknown etiology. The surgical technique described in the supplemental videos demonstrates an effective way of managing this complication.     

Localization of Human Copper Transporter 1 in the Eye and its Role in Eales Disease

Purpose: Copper (Cu) is an essential trace element; however excess is toxic due to the pro-oxidant activity. Increased intracellular Cu levels in vitreous and monocyte were reported in Eales disease (ED) previously. Copper transporter1 (CTR1) maintains copper homeostasis and hence, we studied the presence of CTR1 in ocular tissues and its role in ED.

Methods: Real-time PCR, ELISA and Western blot experiments were performed in donor eyeballs tissues and PBMCs isolated from controls and ED. Immunostaining were performed for CTR1 from donor eyeballs and one ED case.

Results: CTR1 protein was expressed in all ocular tissues. PBMCs showed a three-fold increase in CTR1 protein in ED when compared with controls. Retinal sections from ED patients also revealed increased CTR1 protein expression in retinal tissues, compared with control.

Conclusions: CTR1 was significantly increased in ED when compared with controls, indicating its considerable role in the ED pathology.     

Diagnosed cataracts in patients with cystic fibrosis in a United States administrative database

Background: We estimated the incidence and prevalence of diagnosed cataracts among patients with cystic fibrosis (CF) versus the general population (GP).

Methods: Using a large US health insurance claims database, we identified a CF cohort and a GP cohort matched with respect to age, gender, and calendar year. The prevalence and incidence of diagnosed cataract (primary outcome) for both cohorts were calculated, as well as the incidence rate ratios (IRRs).

Results: The prevalence of diagnosed cataracts among patients with CF alive and enrolled in the health plan on August 31, 2012 was 4.8% versus 2.8% in the GP. The incidence in the CF cohort was higher than in the GP and increased with age in both cohorts. The adjusted IRR comparing the CF and GP cohorts was 1.5 (95% CI: 1.2–1.8).

Conclusions: The study suggests that the risk of developing cataract was higher among patients with CF than among the GP.     

Clinical Features of Systemic Metastatic Retinal Lymphoma in Japanese Patients

Purpose: Systemic metastatic retinal lymphoma (SMRL) originates in systemic organs. It has been reported to exhibit clinical features similar to those of primary vitreoretinal lymphoma (PVRL). We report six cases of SMRL in a single-center survey in Japan.

Methods: The clinical and pathologic features in SMRL at the Kyushu University Hospital were retrospectively studied.

Results: The mean patient age at the onset of ocular involvement was 75.3 years. Four patients had brain involvement. The primary sites were: breast (2); chest (1); testis (1); intestinal tract (1); and nasal sinus (1). In all patients, the cytology of vitreous samples indicated diffuse large B-cell lymphoma (DLBCL).

Conclusions: DLBCL is the most common subtype in our study. The prevalence of CNS involvement in patients with SMRL is similar to that with PVRL. The testis and breast may be common sites of origin for SMRL.     

The Prevalence of Dry Eye and Sjögren Syndrome in Patients with Migraine

Purpose: To evaluate the presence of dry eye and primary Sjögren syndrome (SS) in patients with migraine.

Methods: In total, 46 eyes of 46 patients with migraine (group 1) and 50 eyes of 50 healthy subjects (group 2) were included in this study. Detailed ophthalmologic, neurologic and rheumatologic examination were performed on all participants. Ocular surface disease index questionnaire, tear function tests, visual analog scale for pain, serologic analysis were also performed.

Results: Dry eye symptoms and findings were significantly higher and more severe in group 1 when compared with group 2. Primary SS was not found in any of the participants. The migraine lifetime duration was negatively correlated with the tear function tests while it was positively correlated with the ocular surface disease index scores.

Conclusions: Dry eye symptoms and findings are higher in migraine patients when compared with the healthy subjects without the presence of Sjögren syndrome.     

Infliximab after Boston Keratoprosthesis in Stevens–Johnson Syndrome: An Update

Purpose: To report our experience using intravenous infliximab for the treatment of tissue melt after Boston keratoprosthesis (B-KPro) types I and II in patients with autoimmune disease.

Methods: Case series.

Results: We identified four patients who were treated with intravenous infliximab in the context of tissue melt after B-KPro. Stevens–Johnson syndrome-associated corneal blindness was the primary surgical indication for B-KPro implantation in all patients. Two patients received a B-KPro type I and two patients received a B-KPro type II. The patients received intravenous infliximab for skin retraction around B-KPro type II, melting of the carrier graft or leak. Treatment resulted in a dramatic decrease in inflammation and, in some cases, arrest of the melting process. Cost and patient adherence were limiting factors to pursuing infliximab therapy. In addition, one patient developed infusion reactions.

Conclusions: Intravenous infliximab may be considered as globe- and sight-saving therapy for tissue melt after B-KPro.     

The Usage of a Conjunctival Flap to Improve Retention of Boston Type 1 Keratoprosthesis in Severe Ocular Surface Disease

Purpose: The Boston keratoprostheses type 1 devices (KPro) are utilized in cases unfavorable to penetrating keratoplasty. The prognosis remains guarded in cases of ocular surface disease due to risk of tissue necrosis. We describe a novel surgical approach using a conjunctival flap with a delayed opening to improve retention.

Methods: In three patients with advanced cicatrizing conjunctivitis, a Type 1 keratoprosthesis was stabilized using a full tarsal conjunctival flap. Three months postoperatively, an opening was created in the flap overlying the optical portion of the device.

Results: All patients had no device related complications over a mean follow-up period of 17.7 months (range 15-21 months) and vision remained excellent at better than 20/200 for all patients.

Conclusions: Utilization of a tarsal flap either primarily as part of a two stage modified technique or secondarily in cases of tissue necrosis and impending device extrusion might maximize retention of the type 1 KPro.     

Intravitreal Adalimumab in Active Noninfectious Uveitis: A Pilot Study

Purpose: To evaluate the short-term efficacy of intravitreal adalimumab (IVA) for the treatment of eyes with active noninfectious uveitis.

Methods: Consecutive eyes with active noninfectious uveitis were injected with IVA at 0, 2, then every 4 weeks for total of 26 weeks.

Results: Six out of 7 patients (12 of 13 eyes) completed 26 weeks of treatment. One patient (1 eye) failed treatment. Seven out of 12 eyes had improvement of ≥2 ETDRS lines. Three out of three eyes had resolution of anterior chamber cells. And 9 of 10 eyes with vitreous haze had zero haze at 26 weeks. Five out of 8 eyes with macular edema had complete resolution. Median fluorescein angiography score improved from 14 to 4 on last follow-up.

Conclusions: IVA was effective in controlling the inflammation, decreasing the macular edema, and improving the best corrected visual acuity in the majority of eyes in this series.