Isolated Primary Central Nervous System Lymphoma of the Optic Nerve: A Case Report and Review of the Literature.

INTRODUCTION: Optic nerve involvement in primary central nervous system lymphoma (PCNSL) has been reported only a few times in the literature, with generally dismal outcomes. We focused on an extremely rare presentation of PCNSL in an immunocompetent patient with isolated manifestations of the optic nerve. CASE REPORT: A 72-year-old man presented with subacute vision loss in his left eye and optic disc swelling. Initial magnetic resonance imaging (MRI) of the orbits revealed a T2 hyperintense signal with enhancement of the left prechiasmatic optic nerve, suggestive of optic neuritis. He experienced visual improvement after 6 weeks of prednisone. However, 2 months after steroid tapering, he presented with worsening left-eye vision loss and new right-eye vision loss with imaging showing a peripherally enhancing chiasm lesion. A biopsy of the left optic nerve confirmed diffuse large B-cell lymphoma and negative systemic imaging was consistent with PCNSL. He was treated with high-dose methotrexate, rituximab, procarbazine vincristine (R-MVP), and cytarabine (AraC) with some visual improvement in the right eye and resolution of previously seen enhancement on MRI. The patient is in remission with no further deterioration of his vision. CONCLUSION: This is the first reported case of isolated optic nerve involvement with a durable response to chemotherapy. This case emphasizes the importance of considering malignancy and maintaining a low threshold for optic nerve biopsy in patients with atypical cases of severe steroid-refractory vision loss with enhancement or enlargement of the optic nerve on MRI. Standard chemotherapy regimens for PCNSL can potentially achieve a curative response in these patients.

Optic Nerve Infiltration in Systemic Metastatic Retinal Lymphoma (SMRL): Multimodal Imaging and Challenges in Diagnosis.

A 45-year-old man was diagnosed with diffuse large B-cell lymphoma stage IV which was confirmed by celiac lymph node biopsy. He subsequently completed six cycles of R-CHOP chemotherapy. Six months later, he presented with panuveitis OU with positive relative afferent pupillary defect OD. OCT revealed hyper-reflective lesions and irregularity of the retinal pigment epithelium OU. Fundus fluorescein angiogram shows hyper-auto fluorescence and granular changes on the retina. A month later, he developed swollen optic disc OD and hemorrhagic retinitis OU and treated as presumed CMV retinitis. Anti-TB was started after a positive Mantoux test. He finally consented for a vitreous biopsy which showed atypical lymphoid cells highly suggestive for vitreoretinal lymphoma and subsequently received intravitreal methotrexate OU.Conclusion: Optic nerve infiltration in systemic metastatic retinal lymphoma may have initial occult signs but with profound visual loss. Ocular infections like CMV retinitis and tuberculosis may mask and delay the diagnosis in immunocompromised patients.

Transient Hepatotoxicity Induced by Vinblastine in a Young Girl with Chiasmatic Low Grade Glioma.

BACKGROUND: Vinblastine (VBL) is a cytostatic drug frequently applied in children with lymphoma and progressive low-grade glioma (LGG), with hematotoxicity as the main side effect. CASE REPORT: Here, the case of a 7-month-old girl with tumor progression of an LGG during standard chemotherapy with carboplatin and vincristine, is presented. Switching to VBL led to a 20-30- fold increase of transaminases (grade IV CTCAE 5.0), spontaneously resolving after the end of treatment. The toxicity is possibly age-related since it did not re-occur at the restart of VBL at 4 years old. This finding might have consequences for toxicity screening in future protocols, especially when including infants.

Antitumor effects of Farnesol in optic nerve sheath meningioma cell line and its effects on cell cycle progression, autophagy, cell migration and invasion.

PURPOSE: Farnesol has been shown to exhibit important anticancer potential. However, its antiproliferative effects have not been examined against the optic nerve sheath meningioma cells. In this study the potential of Farnesol in the treatment of optic nerve meningioma was evaluated by examining its antiproliferative effects against the HBL-52 cells. METHODS: The MTT assay was used to determine cell viability of HBL-52 cells. Autophagy was detected by transfection assay. The cell migration and invasion of HBL-52 cells was determined by transwell assay. Protein expression was checked by western blot assay. RESULTS: The results showed that Farnesol decreased significantly the viability of HBL-52 cells and showed an IC50 of 25 µM. The antiproliferative effects were due to the activation of the autophagy in the HBL-52 cells. The autophagy was also accompanied by upsurge of LC3 II and Beclin 1 expression. Farnesol also triggered the cell cycle arrest of the HBL-52 at the G2/M phase of the cell cycle which was accompanied by suppression of cyclin B1. The cell migration and invasion of the HBL-52 cells was also suppressed by Farnesol via inhibition of MMP-2 and 9 expressions. CONCLUSIONS: To sum up, Farnesol may prove beneficial in the treatment of optic nerve sheath meningioma as it has shown significant antiproliferative effects against this rare form of tumor.

Antitumor Effects of Chrysophanol in Malignant Optic Nerve Meningioma Cell Lines are Mediated via Caspase Activation, Induction of Mitochondrial Mediated Apoptosis, Mitochondrial Membrane Depolarization and Targeting the Mitogen-Activated Protein Kinase Signaling Pathway.

BACKGROUND: Anthroquinones are considered remarkable anticancer agents. Chrysophanol is an important anthroquinone and it has shown to have the potential to inhibit the growth of the range of cancers. However, there are no studies regarding the anticancer effects of chrysophanol against the malignant meningioma of optic nerve. In this review, the potential of chrysophanol in the treatment of malignant -meningioma of optic nerve was explored by evaluating its anticancer activity against the malignant meningioma CH157-MN cells. MATERIALS AND METHODS: The 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide assay was used for cell viability determination. The 4',6-diamidino-2-phenylindole (DAPI), acridine orange and ethidium bromide (AO/EB) and annexin V/PI assays were used to determine the induction of apoptosis. The potential of reactive oxygen species and the mitochondrial membrane was estimated by flow cytometry. Western blot analysis was performed to determine the protein expression. RESULTS: The results showed that chrysophanol caused significant decline in the viability of the CH157-MN cells and exhibited an IC50 of 30 µmol/L. Anticancer effects were found to be due to the induction of apoptosis as evident form the DAPI and AO/EB staining. The annexin V/PI staining revealed that the apoptotic cells increased from 1.77% in control to 37.21% at 60 µmol/L concentration of chrysophanol. The Bcl-2/Bax expression ratio was decreased and the caspases-3 and 9 were activated upon chrysophanol treatment of the CH157-MN cells. Chrysophanol also triggered the formation of reactive oxygen species and reduction of the mitochondrial membrane potential in the CH157-MN cells and also blocked the Mitogen-activated protein kinase signaling pathway. CONCLUSION: The findings of the present study suggest that chrysophanol may prove beneficial in the treatment of malignant meningioma of optic nerve. Key Message: The study revealed the anticancer potential of chrysophanol against the malignant optic nerve meningioma.

Monitoring optic chiasmatic-hypothalamic glioma volumetric changes by MRI in children under clinical surveillance or chemotherapy.

PURPOSE: Optic pathway gliomas represent 5% of pediatric brain tumors and are typically low-grade lesions. Because of their unpredictable clinical course, adequate treatment approaches have been controversial, involving surveillance, surgery, chemotherapy, and radiotherapy. In this study, we use volumetric imaging to compare evolution of optic chiasmatic-hypothalamic gliomas (OCHG) treated with and without chemotherapy, analyzing tumor volume variation during the overall period. METHODS: A total of 45 brain MRI were retrospectively analyzed for 14 patients with OCHG. Volumetric assessment of the lesions was performed by a neuroradiologist, using software DISPLAY. OCHG patients were allocated into two groups: group 1 (n = 8) who underwent chemotherapy and group 2 (n = 6) who did not receive chemotherapy. Outcome analysis was performed comparing tumor volume evolution of these two groups. RESULTS: The results showed a reduction of 4.4% of the volume of the lesions for group 1 after the end of chemotherapy, with an increase of 5.3% in volume in the late follow-up examination. For group 2, we found a slight reduction (5%) of the overall volume of the lesions, both with no statistical significance (p > 0.05). CONCLUSIONS: From the limited series analyzed in this study, no significant differences were observed in relation to the volume change of lesions treated or not treated with chemotherapy. Larger prospective clinical trials are needed to better evaluate the effect of chemotherapy and radiological response of OCHG.

Optic disk melanocytoma associated with polypoidal choroidal vasculopathy lesions, after combination treatment of photodynamic therapy and intavitreal aflibercept (Eylea), a case report.

BACKGROUND: We report a rare case of a woman with optic disk melanocytoma (ODMC) in conjunction with polypoidal choroidal vasculopathy (PCV). We also present, for the first time in literature, the clinical and morphological outcomes of the applied treatment, consisting of a session of photodynamic therapy (PDT) and three monthly intravitreal aflibercept injections. CASE PRESENTATION: An 83-year-old Greek woman, complaining for visual decline at her left eye, referred to our department and was diagnosed with ODMC associated with PCV. At presentation, best corrected visual acuity (BCVA) was 2/10, fundus examination revealed a pigmented lesion covering partially the optic nerve head and extending into the peripapillary choroid and retina, while hard exudates were observed temporal to it. Blocked hypofluorescence in the area covered by the lesion and diffuse hyperfluorescence at its temporal rim were shown by fluorescein angiography (FA). Indocyanine green angiography (ICGA) identified 3 hyperfluorescent polypoidal lesions arising from the choroidal vasculature. Optical coherence tomography (OCT) revealed subretinal fluid and retinal pigment epithelium detachment (RPE) at the region corresponding to polyps. The treatment included a PDT session combined with 3 monthly intravitreal aflibercept injections. Three months since the treatment initiation, new BCVA was 5/10, ICGA demonstrated total polyps occlusion, while OCT detected RPE detachment without subretinal fluid. Ten months later, ODMC was stable, BCVA rose to 7/10, no polyps were present, and total resolution of RPE detachment was achieved. CONCLUSIONS: This is the first case report of PCV coexisting with ODMC, presenting both ICGA and OCT findings, and the applied treatment and its outcomes. Furthermore, we demonstrated that PDT combined with intravitreal aflibercept injections seems to be a promising treatment for PCV.

Magnetic resonance imaging for tumor restaging after chemotherapy in retinoblastoma with optic nerve invasion.

PURPOSE: Extraocular retinoblastoma with optic nerve invasion is treated by a multimodal protocol consisting of neoadjuvant chemotherapy, enucleation, and adjuvant therapy. This study was conducted to evaluate the performance of magnetic resonance imaging (MRI) used for tumor restaging in these children after systemic chemotherapy administration. METHODS: Contrast-enhanced MRI scan of orbits and brain was performed at diagnosis and patients were treated with neoadjuvant chemotherapy. After chemotherapy, MRI scan was repeated for tumor restaging and residual post-laminar thickening and/or enhancement of the affected optic nerve, if any, was recorded. MRI findings were correlated with histopathology in enucleated specimens. The main outcome measures were specificity, sensitivity, and accuracy of MRI in predicting post-laminar invasion after neoadjuvant chemotherapy. RESULTS: A total of 46 eyes (46 patients) were studied. Optic nerve thickening on MRI had a sensitivity, specificity, and accuracy of 100% (95% Confidence Interval (CI): 64.6-100%), 76.9% (95% CI: 61.7-87.4%), and 80.4% (95% CI: 66.8-89.4%), respectively. Optic nerve enhancement had a sensitivity, specificity, and accuracy of 85.7% (95% CI: 48.7-97.4%), 79.5 % (95% CI: 64.5-89.2%), and 80.4% (95% CI: 66.8-89.4%), respectively. Combined thickening and enhancement of the optic nerve had a sensitivity, specificity, and accuracy of 100% (95% CI: 60.9-100%), 82.4% (95% CI: 66.5-91.7%), and 85% (95% CI: 70.9-92.9%), respectively. CONCLUSION: MRI is a valuable tool for restaging of retinoblastoma and predicting residual optic nerve disease after neoadjuvant chemotherapy. Combined thickening and enhancement on MRI appeared to be a more reliable indicator of post-laminar invasion as compared to thickening or enhancement alone.

Visual outcomes after chemotherapy for optic pathway glioma in children with and without neurofibromatosis type 1: results of the International Society of Paediatric Oncology (SIOP) Low-Grade Glioma 2004 trial UK cohort.

AIMS: To report visual acuity (VA) outcomes following chemotherapy for optic pathway glioma (OPG) in children with or without neurofibromatosis type-1 (NF1) and to analyse associated risk factors. METHODS: A prospective, multicentre, cohort study involving 155 children treated between September 2004 and December 2012. Initial and final VA was used for per-eye and per-subject analysis. Correlation tests were performed to determine whether initial VA predicted final VA. Logistic regression was used to determine whether age and tumour location were associated risk factors. RESULTS: 90 children had complete ophthalmological data. At initiation of chemotherapy, 26% and 49% of eyes with NF1-OPG and sporadic OPG, respectively, had VA of ≥0.7 log of the minimum angle of resolution (logMAR). At final visit, per eye, 49% had ≤0.2, 23% had 0.30-0.60 and 28% had VA≥0.70 logMAR in the NF1-OPG group. In the sporadic OPG group, per eye, 32% had ≤0.2, 11% had VA 0.30-0.60 and 57% had ≥0.70 logMAR. Children with sporadic OPG, per eye, were significantly less likely to have VA outcomes ≤0.60 logMAR compared with children with NF1-OPG (OR=0.30; 95% CI 0.16 to 0.56; P<0.0001). Per subject, VA improved in 24%, remained stable in 35% and worsened in 41% of children with NF1-OPG and improved in 18%, remained stable in 43% and worsened in 39% of children with sporadic OPG. CONCLUSIONS: Children with and without NF1 demonstrated the same rate of VA improvement, stabilisation or worsening; however, children with sporadic OPG had a poorer VA outcome. Better initial VA, older age, absence of postchiasm tumour and presence of NF1 were associated with improved or stable VA outcomes.

INTRAVITREAL METHOTREXATE FOR MANTLE CELL LYMPHOMA INFILTRATION OF THE OPTIC NERVES: A CASE REPORT.

PURPOSE: To report the successful treatment of a 78-year-old woman with bilateral mantle cell lymphoma involving the optic nerves. Chemotherapy initially was administered in the form of intravitreal methotrexate (MTX) monotherapy and was subsequently combined with systemic ibrutinib. METHODS: Retrospective case report. The diagnosis of CD5-negative mantle cell lymphoma was confirmed via immunohistopathological analysis of an axillary lymph node. Serial ophthalmologic examinations in conjunction with fluorescein angiography, fundus photography, and spectral domain optical coherence tomography were used to assess the treatment response. RESULTS: Prompt improvement in optic nerve infiltration, no significant side effects, and excellent tolerability were noted after two weekly injections of unilateral intravitreal MTX monotherapy. Combined systemic treatment with ibrutinib and bilateral weekly MTX intravitreal injections then resulted in continued regression of optic nerve infiltration bilaterally as confirmed by serial fundus photography and optical coherence tomography. After eight additional bilateral weekly injections, a mild MTX-associated keratopathy developed, which resolved promptly with cessation of injections and administration of topical lubrication. Six weeks after MTX cessation, but with continued ibrutinib treatment, the optic nerves revealed near-complete resolution of the lymphomatous infiltration and the visual acuity improved. CONCLUSION: Intravitreal MTX injections and systemic ibrutinib may represent effective treatment options for patients diagnosed with intraocular mantle cell lymphoma.

Therapeutic surprise! Photodynamic therapy for cavernous haemangioma of the disc.

PURPOSE: To report the response of cavernous haemangioma of the disc to PDT. METHODS AND PATIENTS: A 32 years old lady presented to us with complaints of sudden onset of blurry vision in her right eye. What seemed initially as polypoidal choroidal vasculopathy turned out as cavernous haemangioma of the disc after pneumatic displacement of the sub-retinal haeme. She was treated with PDT as she was prone to recurrent haemorrhage from the lesion due to her low platelet count. RESULTS: Complete regression of the cavernous haemangioma was noted as early as the second week itself and remained regressed for 4 months. CONCLUSION: PDT can be safe option for patients presenting with symptomatic cavernous haemangioma of the disc or retina.

Endocrine Long-Term Follow-Up of Children with Neurofibromatosis Type 1 and Optic Pathway Glioma
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BACKGROUND/AIMS: Children with optic pathway glioma (OPG) face sequelae related to tumour location and treatment modalities. We aimed to assess the prevalence of hypothalamic-pituitary dysfunctions in children with neurofibromatosis type 1 (NF1) and OPG who did not receive radiotherapy or surgical resection. The causative role of tumour location on endocrinopathy development is investigated. METHODS: A retrospective follow-up study of 40 children with NF1 and OPG evaluated between August 1996 and May 2015 was undertaken. Patients who underwent radiotherapy or surgical resection were excluded and 36 patients were studied. Tumour location was classified according to the Dodge criteria: stage I, optic nerve alone; stage II, optic chiasm with or without optic nerve involvement; and stage III, involvement of the hypothalamus or other adjacent structures. RESULTS: Endocrinopathies were diagnosed in 20/36 (55.6%) children during a mean follow-up of 9.1 (0.2-13.6) years: 0/4 OPGs were Dodge stage I, 12/21 (57.1%) stage II, and 8/11 (72.7%) stage III. The first endocrinopathy was found at a mean age of 7.4 (5.0-13.2) years, 2.4 (0-6.7) years after tumour diagnosis. We found growth hormone deficiency (GHD; 36.1%), central precocious puberty (33.3%), obesity with insulin resistance/impaired glucose tolerance (11.1%), early puberty (5.5%), GH excess (5.5%), ACTH deficiency (5.5%), hypogonadotropic hypogonadism (2.7%), and thyrotropin deficiency (2.7%). GHD was transient in all of those who were retested. CONCLUSION: This population is at high risk of endocrinopathies due to tumour location. Lifelong endocrine follow-up is recommended.
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Report of effective trametinib therapy in 2 children with progressive hypothalamic optic pathway pilocytic astrocytoma: documentation of volumetric response.

Brain tumors are the most common solid tumor in childhood, and astrocytomas account for the largest proportion of these tumors. Increasing sophistication in genetic testing has allowed for the detection of specific mutations within tumor subtypes that may represent targets for individualized tumor treatment. The mitogen-activating protein kinase (MAPK) pathway and, more specifically, BRAF mutations have been shown to be prevalent in pediatric pilocytic astrocytomas and may represent one such area to target. Herein, the authors describe 2 cases of inoperable, chemotherapy-resistant pediatric pilocytic astrocytomas with a documented response to trametinib, an MAPK pathway inhibitor. While these cases were not treated in the setting of a clinical trial, their data support further ongoing clinical trial investigation to evaluate the safety and efficacy of this agent in pediatric low-grade gliomas.

Separation of outer retinal layers secondary to selumetinib.

New therapeutic agents targeting the mitogen-activated protein (MAP) kinase pathway, including MEK inhibitors, are currently being evaluated in phase 1 and 2 clinical trials for pediatric brain tumors. Ophthalmologic side effects from MEK inhibitors have previously only been reported in adults and included retinal vein occlusion, central retinal artery occlusion, and separation of the neurosensory retina. We report 2 patients with optic pathway gliomas who developed outer retinal layer separation visualized by optical coherence tomography while taking the MEK inhibitor selumetinib. After discontinuation of selumetinib, the outer retinal layer separation resolved without visual sequelae. One patient has been retreated with selumetinib and experienced recurrence of these findings.

Chronic Myelogenous Leukemia Relapse Presenting With Central Nervous System Blast Crisis and Bilateral Optic Nerve Infiltration.

Bilateral, simultaneous optic nerve sheath infiltration as a manifestation of leukemia relapse is very rare. A 45-year-old woman with chronic myelogenous leukemia was successfully treated to cytogenetic bone marrow remission 1 year previously and maintained on imatinib. She developed total bilateral blindness with marked, bilateral optic disc edema and evidence of bilateral optic nerve infiltration on magnetic resonance imaging. Cerebrospinal fluid cytology confirmed central nervous system (CNS) blast crisis. She recovered visual acuity of 20/20 in the right eye, and 20/25 in the left eye with salvage systemic and intrathecal chemotherapy before radiation therapy. Our report underscores the importance of timely and aggressive intervention of blast crisis of the CNS and the need for CNS penetrating induction and maintenance therapy.

Primary atypical teratoid/rhabdoid tumor of the optic nerve: a rare entity in an exceptional location.

Atypical teratoid/rhabdoid tumors are rare and highly malignant central nervous system tumors. They have no specific radiological features and often present several histological components that make a problem in differential diagnosis with medulloblastoma and primitive neuroectodermal tumors. We present the case of a newborn girl complained of a gradual proptosis of the left eye secondary to an expansive lesional process of the optic nerve. The location at the optic nerve, reported only twice in the literature, and an exclusive rhabdoid appearance on biopsy added additional differential diagnosis problems. The proptosis worsened and the infant died few days after two cycles of chemotherapy. VIRTUAL SLIDES: The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2037718783145212 .