Optic neuritis and rapidly progressive necrotizing retinitis as the initial signs of subacute sclerosing panencephalitis: a case report with clinical and histopathologic findings.

We report a case of subacute sclerosing panencephalitis (SSPE) presenting first with optic neuritis and rapidly progressive necrotizing retinitis at the posterior pole. We reviewed the clinical, laboratory, photographic, angiographic, and histopathologic records of a patient with SSPE. A 15-year-old girl was referred after rapid loss of vision due to optic neuritis and macular necrosis in the right eye. She had a history of cardiac valve surgery, but had no systemic symptoms and extensive work-up was unrewarding. Contralateral involvement with rapidly progressive optic neuritis and macular necrotizing retinitis prompted retinochoroidal biopsy of the right eye, which revealed necrosis of inner retinal layers and perivascular lymphoplasmocytic infiltration with intact choroid and outer retina without any findings of inclusion bodies, microorganisms, or atypical cells. The diagnosis was based on histopathologic findings consistent with SSPE, and detection of elevated measles antibody titers in cerebrospinal fluid and serum. It was further confirmed by development of typical electroencephalography pattern at 6 months and neurological symptoms at 4-year follow-up. Clinicians need to be aware that optic neuritis and necrotizing retinitis at the posterior pole may be the presenting features of SSPE.

Bilateral intraocular calcification in necrotizing cytomegalovirus retinitis.

We report a unique case of bilateral intraocular calcification due to necrotizing cytomegalovirus (CMV) retinitis associated with congenital CMV infection. A 7-month-old boy with a history of congenital CMV infection showed bilateral intraocular calcific plaques on computed tomography (CT) and ultrasonography. We reviewed the patient's medical files for the purpose of this report. The patient had a prior medical history of hospitalization for fever and swelling in the neck at 3 months of age. Systemic findings (anemia, neutropenia, hepatosplenomegaly, and reactive lymphadenomegaly) in association with a low CD4 count, high blood CMV viral load, and positivity for urine CMV DNA by polymerase chain reaction led to the diagnosis of bone marrow suppression and congenital CMV infection. At 7 months, he developed horizontal nystagmus and bilateral leukocoria over 20 days. Cranial CT and ultrasonography revealed bilateral intraocular calcific plaques and the patient was referred to rule out retinoblastoma. Fundoscopy was consistent with bilateral hemorrhagic, necrotizing CMV retinitis. Significant resolution of the retinal infiltrations occurred 2 weeks after initiation of systemic treatment with ganciclovir. Intraocular calcification may be a sign of active CMV retinitis. To our knowledge this is the first report of bilateral intraocular calcification serving as the presenting clinical manifestation of necrotizing CMV retinitis.

Investigation of the methylation changes in the promoter region of RB1 gene in retinoblastoma: Unraveling the epigenetic puzzle in retinoblastoma.

Retinoblastoma is an infrequent neoplasm that arises during childhood from retinal nerve cells and is attributed to the biallelic inactivation of the RB1 gene. In conjunction with anatomical anomalies, it is widely acknowledged that epigenetic modifications play a significant role in the pathogenesis of cancer. The association between methylation of the RB1 gene promoter and tumor formation has been established; however, there is currently no scholarly evidence to substantiate the claim that it is responsible for the inheritance of retinoblastoma. The initial hypothesis posited for this work was that familial retinoblastoma disease would be similarly observed in cases with RB1 promotor gene methylation, akin to RB1 mutations. The RB1 gene promoter region was subjected to methylation screening using real-time PCR in individuals diagnosed with familial retinoblastoma but lacking RB1 mutations. The study involved a comparison of the germline methylation status of the RB1 gene in the peripheral blood samples of 50 retinoblastoma patients and 52 healthy individuals. The healthy individuals were carefully selected to match the retinoblastoma patients in terms of age, sex, and ethnicity. The data obtained from both groups were subjected to statistical analysis. The study revealed that the methylation level in a cohort of 50 individuals diagnosed with retinoblastoma and 52 healthy control participants was determined to be 36.1% and 33.9%, respectively. As a result, there was no statistically significant disparity observed in RB1 promoter methylation between the patient and control groups (p = 0.126). The methylation of the promoter region of the RB1 gene in familial retinoblastoma does not exert any influence on the hereditary transmission of the disease.

Diagnosis and management of tumor-induced osteomalacia: a single center experience.

PURPOSE: The aim of this study is to review the clinical and laboratory characteristics, diagnostic and treatment modalities of tumor-induced osteomalacia (TIO) cases managed in a single center. MATERIAL METHODS: Demographic and clinical features, biochemical findings, diagnostic procedures, treatment modalities, and outcomes of nine patients who had the diagnosis of TIO were reviewed retrospectively. RESULTS: Mean age of the study group (F/M: 4/5) was 45.8 ± 10.8 years, and mean time from the onset of symptoms to diagnosis was 4.7 ± 2.8 years. The clinical manifestations were muscle weakness and difficulty in walking (8/9), hip pain (3/9), multiple fractures (2/9), stress fracture (2/9). Mean plasma phosphorus concentration was 1.28 ± 0.4 mg/dl at presentation. We performed radionuclide imaging modalities (18F-FDG PET/CT, Ga68-DOTATATE PET/CT, octreotide scintigraphy) in seven of nine patients, and tumor was detected in all. Lower extremity (n = 6; %67), head region (n = 2; %22) and thorax (n = 1; %11) were the tumor locations of our cases. Eight patients underwent surgery and remission was achieved postoperatively in all of the operated patients and plasma phosphorus level normalized in 4 ± 2 days. Pathological examination revealed mesenchymal tumors with different subtypes. Recurrence occurred in three patients at 13 ± 10.5 months after the first surgery. Two patients were reoperated and radiotherapy was also performed in one of them. CONCLUSION: Hypophosphatemia necessitates careful evaluation for the etiology. TIO is one of the important causes of adult-onset hypophosphatemic osteomalacia. Diagnosis of TIO is essential because the laboratory and clinical findings resolve after appropriate treatment.

RB1 gene mutations and genetic spectrum in retinoblastoma cases.

The aim of the study was to investigate the frequency and types of mutations on the retinoblastoma gene (RB1 gene) in Turkish population. RB1 gene mutation analysis was performed in a total of 219 individuals (122 probands with retinoblastoma, 14 family members with retinoblastoma and 83 clinically healthy family members). All 27 exons and close intronic regions of the RB1 gene were sequenced for small deletions and insertions using both the Sanger sequencing or NGS methods, and the large deletions and duplications were investigated using the MLPA analysis and CNV algorithm. The bilateral/trilateral retinoblastoma rate was 66% in the study population. The general frequency of RB1 gene mutation in the germline of the patients with retinoblastoma was 41.9%. Approximately 51.5% of the patients were diagnosed earlier than 12 months old, and de novo mutation was found in 32.4% of the patients. Germline small genetic rearrangement mutations were detected in 78.9% of patients and LGRs were detected in 21.1% of patients. An association was detected between the eye color of the RB patients and RB1 mutations. 8 of the mutations detected in the RB1 gene were novel in the study.

Multimodal Imaging Characteristics of Circumscribed Choroidal Hemangioma Accompanying with Central Serous Chorioretinopathy: A Case Report.

A 42-year-old man presented with a temporal visual field defect in his right eye. His history revealed systemic steroid use before onset of his complaints. Multimodal imaging techniques including ultrasonography, fluorescein angiography, indocyanine green angiography, and optical coherence tomography angiography (OCTA) suggested the presence of circumscribed choroidal hemangioma (CCH) accompanying with central serous chorioretinopathy (CSCR) in the right eye, which might have worsened with systemic steroid treatment. CCH may rarely present with accompanying CSCR. Besides, OCTA is a non-invasive reliable method for the diagnosis of CCH in terms of visualizing vascular features of tumor.

Surgical Repair of Orbital Blow-Out Fractures: Outcomes and Complications.

Objectives: The purpose of this study is to evaluate the demographics of patients with orbital blow-out fractures, as well as the success and complications of surgical repair with porous polyethylene membrane sheet implants through transconjunctival technique and to compare the results to previously published studies. Methods: This retrospective study included 57 patients diagnosed with orbital blow-out fractures referred to our clinic between 2018 and 2022. Seventeen patients (29.8%) underwent orbital fracture repair through a transconjunctival technique employing porous polyethylene membrane sheets. The indications for surgery were enophthalmos >2 mm and persistent ocular motility restriction, diplopia, and strabismus. The success criteria were <2 mm of enophthalmos and complete correction of eye motility, diplopia, and strabismus. Results: The study group consisted of ten females and 47 males with a mean age of 31.12 years. The most common cause of injury was assaults (50.9%), followed by falls (38.6%), traffic accidents (5.3%), and accidental impacts (5.3%). The inferior wall (61.4%) was the most common fracture site, followed by the medial wall (21.1%) and a combination of the inferior and medial walls (21.1%). The surgically treated group showed a significant improvement in ocular motility restriction (88.2-23.5%, p=0.002), diplopia (70.6-23.5%, p=0.008), and enophthalmos (1.41 mm to 0.82 mm, p=0.012) after surgery. The surgery was successful in ten of 17 cases (58.8%), and the success rate was higher in patients who were treated early (77.8% vs. 37.5%), but the difference was not statistically significant (p=0.092). Conclusion: Orbital blow-out fracture repair using porous polyethylene membrane sheets through a transconjunctival approach is a safe and effective surgical technique for orbital blow-out fracture repair. Although patients who had early surgery had a higher success rate in our study group, larger study groups are needed to assess the effect of surgical timing on success.

Digital Quantification of Intratumoral CD8+ T-Cells Predicts Relapse and Unfavorable Outcome in Uveal Melanoma.

Although it is a disease that occurs mainly in the Caucasian population, uveal melanoma (UM) is the most common primary intraocular tumor in adults. Here, we used digital pathology and image analysis for the diagnosis of UM and the prediction of the prognosis. Our retrospective study included a total of 404 histopathological slides from 101 patients. A digital image acquisition and quantitative analysis of tissue immune biomarkers (CD4, CD8, CD68, CD163) were performed. A negative impact of the intratumoral CD8 positive cell density higher than 13.3 cells/mm2 was detected for both RFS (HR 2.08, 95% Cl 1.09 to 3.99, p = 0.027) and OS (HR 3.30, 95% CI 1.58 to 6.88, p = 0.001). Moreover, we confirmed that older age and stage III were independent negative prognostic factors for both RFS and OS. Our results suggest that a specific distribution profile of CD8 in UM might predict the risk of relapse and death, with potential implications for determining which subgroups of UMs are amenable to specific pharmacological treatment regimens.

Optic disc and choroidal metastasis from sporadic medullary thyroid carcinoma: case report and review of the literature.

BACKGROUND: Choroidal metastasis is a very rare clinical manifestation of thyroid cancer. Herein, we report on a patient with non-familial medullary thyroid carcinoma (MTC), who presented with choroidal metastasis. CASE REPORT: A 63-year-old male patient with MTC presented with sudden loss of vision in his right eye for 1 month. The patient had a history of complete thyroidectomy and chemotherapy for disseminated MTC. Ophthalmological examination showed optic disc and choroidal metastases in the right eye and a small choroidal metastasis in the left eye. The patient was scheduled for external irradiation therapy for the ocular area but died 2 months after choroidal metastasis was diagnosed. CONCLUSIONS: Choroidal metastasis must be considered in MTC patients who develop loss of vision. This is a very rare clinical situation that generally occurs in the late advanced stages of the disease and carries a poor prognosis for these patients.

Tumor-related lipid exudation after plaque radiotherapy of choroidal melanoma: the role of Bruch's membrane rupture.

PURPOSE: To identify the risk factors predictive of development of tumor-related lipid exudation (TRLE) after plaque radiotherapy of posterior uveal melanoma. DESIGN: Case-control study. PARTICIPANTS: Cases included 294 patients with posterior uveal melanoma who had developed TRLE after plaque radiotherapy. Controls included 294 patients with posterior uveal melanoma who had not developed TRLE after plaque radiotherapy. Controls were matched with cases for age, gender, and initial tumor thickness. METHODS: Data were extracted from medical charts containing demographic, clinical, and treatment information. Detailed fundus drawings and color fundus photographs were reviewed for each patient. MAIN OUTCOME MEASURES: Tumor and ocular features of eyes with posterior uveal melanoma treated with plaque radiotherapy. RESULTS: Multivariate analysis identified Bruch's membrane rupture (P<0.001), serous retinal detachment (RD) before radiation (P< or =0.019), closer proximity to the optic disc and foveola (P = 0.004 and 0.013, respectively), greater tumor base (P = 0.035), failure to receive transpupillary thermotherapy (TTT) after radiation (P<0.001), and initial increase of serous RD after radiation (P<0.001) as significant risk factors predictive of development of TRLE after plaque radiotherapy of posterior uveal melanoma. Radiation dose at the tumor base correlated with maximum extent of TRLE (P = 0.003). The mean interval between plaque radiotherapy and onset of TRLE was 14 months (median, 11 months; range, 2-97 months), with 88% of cases developing TRLE within 2 years of radiation. The interval between the onset of TRLE and the first evidence of its regression was a mean of 33 months (median, 38 months; range, 2-194 months). CONCLUSIONS: Our study identified Bruch's membrane rupture as an important factor predisposing to development of TRLE after plaque radiotherapy of posterior uveal melanoma. Other predictive factors included serous RD before radiation, large tumor basal diameter, posterior tumor location, lack of adjunctive TTT, and early increase of serous RD after plaque radiotherapy.

Clinical Features and Long-Term Follow-Up of Patients with Retinoblastoma in Turkish Children Older Than 5 Years of Age.

PURPOSE: The diagnosis and management of retinoblastoma can be difficult in older children. This study reports the clinical features and long-term outcomes of such patients in a Turkish patient population. METHODS: Medical records of 18 patients, between January 1992 and December 2017, were reviewed retrospectively. RESULTS: Of 298 consecutive patients with retinoblastoma, 18 (6%) were at the age of 5 years and older. The median age at diagnosis was 9 years (range, 5-18 years). Misdiagnosis was noted in 8 patients (44.4%). Treatment options included enucleation in 16 patients (88.8%), adjuvant systemic chemotherapy in 3 (16.6%), intra-arterial chemotherapy in one (5.5%), and additional orbital irradiation in one (5.5%). After a median follow-up of 97 months (range, 6-252 months), all patients survived without any recurrence. CONCLUSIONS: Our series showed that 6% of patients with retinoblastoma were 5 years of age and older. Over a 15-year period, ocular salvage rate of 11.2% and survival rate of 100% were attained.

FGFR4 c.1162G > A (p.Gly388Arg) Polymorphism Analysis in Turkish Patients with Retinoblastoma.

PURPOSE: Various molecular variations are known to result in different gene variants in the FGFR4 gene, known for its oncogenic transformation activity. The goal of this study was to investigate the FGFR4 p.Gly388Arg variant that plays role in the progression of cancer and retinal growth and may be an effective candidate variant in the Turkish population in retinoblastoma patients with no RB1 gene mutation. METHODS: Using the Sanger sequencing methods, the FGFR4 p.Gly388Arg variant was bidirectionally sequenced in 49 patients with non-RB1 gene mutation in retinoblastoma patients and 13 healthy first-degree relatives and 146 individuals matched by sex and age in the control group. RESULTS: In Turkish population-specific study, the FGFR4 p.Gly388Arg variant was found in 27 (55.1 percent) of 49 patients; mutation was found in 7 (53.8 percent) of these patients' 13 healthy relatives screened. When FGFR4 p.Gly388Arg mutation status is evaluated in terms of 146 healthy controls, in 70 (47.9 percent) individuals, mutation was observed. Our analysis showed that the FGFR4 p.Gly388Arg allele frequency, which according to different databases is seen as 30 percent in the general population, is 50 percent common in the Turkish population. CONCLUSIONS: In patients with advanced retinoblastoma who were diagnosed with retinoblastoma prior to 24 months, the FGFR4 p.Gly388Arg allele was found to be significantly higher. As a result, these results indicate that the polymorphism of FGFR4 p.Gly388Arg may play a role in both the development of tumors and the progression of aggressive tumors.

Primary orbital leiomyosarcoma.

A 79-year-old woman was presented with a 6-month history of painless proptosis in the left eye. On examination, there was a palpable superotemporal mass displacing the left eye inferomedially. Orbital CT revealed a heterogeneous, lobulated mass occupying the left orbital space with no bone erosion or destruction. MRI showed an extraconal, heterogenous, lobulated orbital mass in the lacrimal gland region of the left eye. The lesion was excised, and the diagnosis of leiomyosarcoma was made by histopathologic examination and immunohistochemistry. Systemic examinations were negative for a primary or a metastatic tumor. There was no evidence of tumor recurrence after 12 months of follow-up. Primary orbital leiomyosarcoma is a rare tumor that mainly occurs in older women and presents with painless proptosis. It should be considered in the differential diagnosis of superotemporal extraconal lesions.

Multiple anterior and posterior chamber pseudocysts in a 12-year-old boy with diffuse infiltrating retinoblastoma.

Diffuse infiltrating retinoblastoma is a rare subtype, occurring in 1% of all patients with retinoblastoma. It usually presents with pseudoinflammatory response in the anterior chamber and the vitreous, masquerading as endophthalmitis or uveitis. This report describes a 12-year-old boy with multiple free-floating intraocular pseudocysts as a unique finding in diffuse infiltrating retinoblastoma. These pseudocysts represent necrotic seeds without epithelial lining. Invasive surgical procedures should be avoided in children presenting with atypical, chronic, unilateral intraocular inflammation of unknown cause until retinoblastoma is excluded.

Neuroblastoma of the Iris in Children.

Neuroblastoma of the iris is an extremely rare clinical entity. An otherwise healthy 2-month-old male infant presented to the oncology clinic with a nodular whitish iris lesion in his right eye. The excisional tumor biopsy was consistent with a pathological diagnosis of neuroblastoma with differentiation and negative MYCN gene mutation. Further systemic evaluation revealed a right adrenal mass with no metastatic lesion. The biopsy of the adrenal lesion was also consistent with neuroblastoma. After four courses of chemotherapy, the adrenal mass was completely resected. The patient underwent two additional courses of postoperative chemotherapy and continued retinoic acid treatment. The patient is under regular follow-up with no evidence of recurrence 36 months after the initial diagnosis. This is the first case report to present a histopathological verification of neuroblastoma of the iris. The authors suggest that neonates and infants who are diagnosed as having neuroblastoma undergo an ophthalmologic examination after the initial diagnosis to investigate the true incidence of small iris lesions in neuroblastoma that may have been unrecognized. Neuroblastoma should be included in the differential diagnosis of amelanotic iris lesions in infants and young children. [J Pediatr Ophthalmol Strabismus. 2019;56:e12-e16.].

Investigation of new candidate genes in retinoblastoma using the TruSight One "clinical exome" gene panel.

BACKGROUND: Retinoblastoma (Rb) is the most prevalent intraocular pediatric malignancy of the retina. Significant genetic factors are known to have a role in the development of Rb. METHODS: Here, we report the mutation status of 4813 clinically significant genes in six patients with noncarrier of RB1 gene mutation and having normal RB1 promoter methylation from three families having higher risk for developing Rb in the study. RESULTS: A total of 27 variants were detected in the study. Heterozygous missense variants c.1162G > A (p.Gly388Arg) in the FGFR4 gene; c.559C > T (p.Pro187Ser) in the NQO1 gene were identified. The family based evaluation of the variants showed that the variant, c.714T > G (p.Tyr238Ter), in the CLEC7A gene in first family; the variant, c.55C > T (p.Arg19Ter), in the APOC3 gene and the variant, c.1171C > T (p.Gln391Ter), in the MUTYH gene in second family; and the variant, c.211G > A (p.Gly71Arg), in the UGT1A1 gene in the third family, were found statistically significant (p < 0.05). CONCLUSION: This study might be an important report on emphazing the mutational status of other genes in patients without RB1 gene mutations and having high risk for developing Rb. The study also indicates the interaction between the retinoic acid pathway and Rb oncogenesis for the first time.

Clinical spectrum of diffuse infiltrating retinoblastoma in 34 consecutive eyes.

PURPOSE: To evaluate the clinical features and management of diffuse infiltrating retinoblastoma. DESIGN: Retrospective case series. PARTICIPANTS: Thirty-four eyes in 32 patients. METHODS: The patients' records were reviewed for patient and tumor features, ocular management, histopathologic findings, and patient survival. MAIN OUTCOME MEASURES: Clinical features, tumor management, and patient survival. RESULTS: Of 1507 patients with retinoblastoma, only 32 (2%) were classified with diffuse infiltrating retinoblastoma. The mean age at diagnosis was 4 years (range 1.5-16 years). The referring diagnoses included retinoblastoma (26 eyes, 76%), uveitis (3, 9%), Coats disease (1, 3%), trauma (1, 3%), and unspecified retinal problem (3, 9%). The anterior segment displayed tumor seeds on the corneal endothelium (8, 24%), cornea stromal edema (3, 9%), pseudohypopyon (11, 32%), hyphema (3, 9%), iris neovascularization (17, 50%), and iris tumor nodules (6, 18%). The posterior segment revealed extensive ill-defined retinoblastoma infiltrating the retina for a mean basal diameter of 20 mm and overall flat growth, sometimes with undulating retinal thickening. Overlying extensive vitreous tumor seeds (31, 91%) and vitreous hemorrhage (8, 24%) were noted. Calcification was present on ultrasonography (27/34, 79%) and computed tomography (8/9, 89%). Enucleation was performed for all 34 eyes, and there were no cases of metastases at 47 months follow-up. CONCLUSIONS: Diffuse infiltrating retinoblastoma can masquerade as uveitis or unexplained hyphema or keratic precipitates. Suspicion for retinoblastoma is important. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article.

A novel mutation in the NF1 gene in two siblings with neurofibromatosis type 1 and bilateral optic pathway glioma.

We present the clinical and ophthalmological findings, genetic analysis, and therapy of two siblings with NF1 and bilateral OPG. In genetic analysis, a heteroduplex profile was detected in exon 4b of the NF1 gene for the affected patients and mother. Sequencing of the DNA samples identified a C > T nucleotide change in exon 4b (c484CAG > TAG). This nonsense mutation resulted in a change of glutamine to a stop codon (Q162X) and is a novel NF1 gene alteration.

Uveal prolapse following cataract extraction simulating melanoma.

Prolapsed uveal tissue through a cataract incision can simulate any pigmented epibulbar mass, including conjunctival melanoma, extraocular extension ofa ciliary body or choroidal melanoma, and pigmented squamous cell carcinoma of the conjunctiva. The authors describe an 88-year-old woman who presented with an enlarging pigmented epibulbar mass on the left eye. Although the lesion closely simulated a conjunctival melanoma or extraocular extension of a uveal melanoma, closer evaluation revealed thin uveal tissue extending through partial wound dehiscence from cataract surgery that was performed 3 years earlier. The lesion was consistent with prolapsed uveal tissue through a cataract wound masquerading as a melanoma. Therefore, uveal prolapse should be considered in the differential diagnosis of conjunctival melanoma or extraocular extension of uveal melanoma.

Surgical Outcomes in Radiation-induced Cataracts After External-beam Radiotherapy in Retinoblastoma.

OBJECTIVES: To investigate visual outcomes, surgical complications and tumor recurrence among children with retinoblastoma undergoing phacoemulsification and posterior chamber intraocular lens (PCIOL) implantation for radiation-induced cataract secondary to external beam radiotherapy. MATERIALS AND METHODS: The medical records of all patients treated by phacoemulsification and PCIOL implantation for radiation-induced cataract after external beam radiotherapy for retinoblastoma at a single institution between 1980 and 2014 were reviewed retrospectively. The study included 6 eyes of 6 children (4 girls, 2 boys). RESULTS: Four patients had bilateral and two patients had unilateral retinoblastoma. The median age at diagnosis of retinoblastoma was 28.3 months (range, 12-96 months). All patients received chemoreduction (OPEC protocol) and external beam radiotherapy with or without local ophthalmic therapies and developed radiation-induced cataracts. The median interval from retinoblastoma diagnosis to cataract surgery was 96.3 months (range, 73-122 months). Time interval between surgery and last retinoblastoma treatment was 67.2 months. Postoperative complications included iridocyclitis in 2 eyes and posterior capsule opacification in all eyes. The mean follow-up after surgery was 105.8 months (range, 59-120 months). Final visual acuity was better in all eyes than preoperative visual acuities. CONCLUSION: Phacoemulsification and PCIOL implantation is an effective method of managing radiation-induced cataracts in eyes with previously treated retinoblastoma. However, visual acuity was limited by the presence of primary macular tumor.