Surgical Management of Full-Thickness Macular Holes in Macular Telangiectasia Type 2: A Global Multicenter Study.

PURPOSE: To report on macular hole repair in macular telangiectasia type 2 (MacTel2). DESIGN: Global, multicenter, retrospective case series. PARTICIPANTS: Patients undergoing surgery for MacTel2-associated full-thickness macular hole (MTMH). METHODS: Standardized data collection sheet distributed to all surgeons. MAIN OUTCOME MEASURES: Anatomic closure and visual outcomes of MTMH. RESULTS: Sixty-three surgeries in 47 patients with MTMH were included from 30 surgeons. Mean age was 68.1 years, with 62% female, 72% White, 21% East or South Asian, 2% African American, and 2% Hispanic or Latino. Procedures included 34 internal limiting membrane (ILM) peeling alone, 22 ILM flaps, 5 autologous retinal transplantations (ARTs), 1 retinotomy, and 1 subretinal bleb. For ILM peeling, preoperative visual acuity (VA) was 0.667 ± 0.423 logarithm of the minimum angle of resolution (logMAR). Minimum hole diameter (MHD) was 305.5 ± 159.4 µm (range, 34-573 µm). Sixteen of 34 ILM peels (47%) resulted in MTMH closure. At postoperative month 6, VA was stable at 0.602 ± 0.516 logMAR (P = 0.65). VA improved by at least 2 lines in 43% and at least 4 lines in 24%. For ILM flaps, preoperative VA was 0.878 ± 0.552 logMAR. MHD was 440.8 ± 175.5 µm (range, 97-697 µm), which was significantly larger than for ILM peels (P < 0.01). Twenty of 22 ILM flaps (90%) resulted in MTMH closure, which was significantly higher than for ILM peels (P < 0.01). At postoperative month 6, VA improved to 0.555 ± 0.405 logMAR (P < 0.05). VA improved by at least 2 lines in 56% and at least 4 lines in 28%. For ARTs, preoperative VA was 1.460 ± 0.391 logMAR. MHD was 390.2 ± 203.7 µm (range, 132-687 µm). All 5 ARTs (100%) resulted in MTMH closure. At postoperative month 6, VA was stable at 1.000 ± 0.246 logMAR (P = 0.08). Visual acuity improved at least 2 lines in 25%. CONCLUSIONS: Surgical closure of macular holes improved VA in 57% of MTMHs. Internal limiting membrane flaps achieved better anatomic and functional outcomes than ILM peeling alone. Autologous retinal transplantation may be an option for refractory MTMHs. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

LONG-TERM USE OF ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION.

PURPOSE: Although pivotal trials have demonstrated efficacy of anti-vascular endothelial growth factor therapy in neovascular age-related macular degeneration, there is a paucity of clinical data about the long-term (>5 years) treatment. METHODS: Retrospective analysis of all patients with neovascular age-related macular degeneration who were actively treated, had received >40 anti-vascular endothelial growth factor injections, and were followed for ≥5 years. Snellen-corrected visual acuity, initial drug choice, and times elapsed between treatments were collected. Rates of endophthalmitis and outcomes of submacular hemorrhage were also evaluated. RESULTS: A total of 88 patients (162 eyes) met the inclusion criteria: the average patient age was 86.3 years with an average follow-up period of 7.6 years. The average total number of injections per eye was 69 (18.0 SD); a total of 11,208 injections were given throughout the study period, and 6 cases (0.05%) of endophthalmitis were observed. Overall, there was a clinical and statistical difference in average Snellen-corrected visual acuity at Injections #2,#3, #4, #5, #6, #10, and #20, as compared with baseline ( P = 0.03, P < 0.01, P = 0.02, P < 0.01, P = 0.01, P = 0.01, P < 0.01, respectively). Patients in the Snellen-corrected visual acuity subgroup 20/20 to 20/40 maintained vision until injection #30. Seven eyes experienced a visually significant submacular hemorrhage. CONCLUSION: This neovascular age-related macular degeneration cohort received on average eight anti-vascular endothelial growth factor injections per year for approximately 8 years; eyes with good (≥20/40) initial baseline vision maintained their visual acuity, whereas those with worse Snellen-corrected visual acuity (≤20/50) had a robust initial improvement that diminished with time. Most patients were maintained on the same initial drug of choice and the rate of endophthalmitis was low.

REPRODUCTIVE OPHTHALMOLOGY: The Intersection of Inherited Eye Diseases and Reproductive Technologies.

PURPOSE: To propose a working framework for patients with inherited eye diseases presenting to ophthalmologists who are interested in assisted reproductive technology and preimplantation genetic testing. METHODS: Retrospective chart review and case series of three families with inherited eye diseases who successfully underwent preimplantation genetic testing, in vitro fertilization, and birth of unaffected children. RESULTS: Preimplantation genetic testing was performed for three families with different inherited eye diseases, which included autosomal dominant retinitis pigmentosa, autosomal recessive achromatopsia, and X-linked Goltz syndrome. Preimplantation genetic testing led to the identification of unaffected embryos, which were then selected for in vitro fertilization and resulted in the birth of unaffected children. CONCLUSION: A close collaboration between patients, families, ophthalmologists, reproductive genetic counselors, and reproductive endocrinology and infertility specialists is the ideal model for taking care of patients interested in preimplantation genetic testing for preventing the transmission of inherited eye diseases.

Loss of MAFB Function in Humans and Mice Causes Duane Syndrome, Aberrant Extraocular Muscle Innervation, and Inner-Ear Defects.

Duane retraction syndrome (DRS) is a congenital eye-movement disorder defined by limited outward gaze and retraction of the eye on attempted inward gaze. Here, we report on three heterozygous loss-of-function MAFB mutations causing DRS and a dominant-negative MAFB mutation causing DRS and deafness. Using genotype-phenotype correlations in humans and Mafb-knockout mice, we propose a threshold model for variable loss of MAFB function. Postmortem studies of DRS have reported abducens nerve hypoplasia and aberrant innervation of the lateral rectus muscle by the oculomotor nerve. Our studies in mice now confirm this human DRS pathology. Moreover, we demonstrate that selectively disrupting abducens nerve development is sufficient to cause secondary innervation of the lateral rectus muscle by aberrant oculomotor nerve branches, which form at developmental decision regions close to target extraocular muscles. Thus, we present evidence that the primary cause of DRS is failure of the abducens nerve to fully innervate the lateral rectus muscle in early development.

Eccrine Chromhidrosis in an Adolescent with Sickle Cell Disease.

Eccrine chromhidrosis can occur secondary to hyperbilirubinemia. We report an adolescent with sickle cell disease who presented with eccrine chromhidrosis on his palmar and plantar surfaces. He had extremely high levels of conjugated bilirubin but no fever. This is the youngest known reported patient with eccrine chromhidrosis and the first in a patient with sickle cell disease.

INFUSION-ASSISTED EVACUATION OF SUBMACULAR HEMORRHAGE.

PURPOSE: To report a novel surgical technique for evacuating submacular hemorrhage using the infusion stream of a 25-gauge vitrectomy system. METHODS: Surgical case and video. RESULTS: A 54-year-old man was taken to the operating room for a total hyphema, nonclearing vitreous hemorrhage, and elevated intraocular pressure after multiple tractional retinal detachment repairs by an outside surgeon. Intraoperatively, the hyphema and vitreous hemorrhage were cleared, and the source of bleeding was discovered to be an avulsed vessel through a pre-existing retinal break just superior to the optic nerve. A large submacular hemorrhage was also present that was unable to be drained through the break by aspiration alone. With the vitreous cavity under fluid, the infusion cannula was manipulated to guide the infusion stream onto the macula. The stream was directed in a distal to proximal manner toward the retinal break, and the submacular blood was successfully expressed out through the break. Postoperatively, the retina remained attached with almost complete resolution of the submacular hemorrhage. CONCLUSION: Using the mechanical pressure of the infusion stream can be an effective method for evacuating large subretinal hemorrhages.

Distinct Patterns of Choroidal Lesions in Punctate Inner Choroidopathy and Multifocal Choroiditis Determined by Heatmap Analysis.

PURPOSE: A heatmap analysis of choroidal lesions in patients with punctate inner choroidopathy (PIC) or multifocal choroiditis (MFC) with or without uveitis was performed to determine if there were any distinguishing features among these uveitic entities. METHODS: Retrospective review of medical records was conducted at the Byers Eye Institute, Stanford. Fundus photographs were masked and placed on a standardized template. Lesions were identified and heatmaps were generated in a standardized fashion. RESULTS: 30 eyes were identified with PIC or MFC. Heatmap analysis revealed three distinct patterns of fundus lesions: posterior, peripheral, and combined. All patients with PIC had the posterior pattern. Patients with MFC had the peripheral or combined pattern, and all patients with MFC with uveitis had the combined pattern. CONCLUSION: Three patterns of fundus lesions were identified in patients with PIC and MFC. PIC and MFC may represent two separate disease entities with distinct phenotypes of choroidal lesions.

Intravitreal methotrexate and fluocinolone acetonide implantation for Vogt-Koyanagi-Harada uveitis.

PURPOSE: To report a case of intravitreal methotrexate treatment and fluocinolone acetonide (Retisert®) implantation in a patient with Vogt-Koyanagi-Harada syndrome (VKH). OBSERVATIONS: A 34-year-old male was referred for worsening vision and bilateral panuveitis consistent with VKH. He was treated with prednisone, mycophenolate mofetil, prednisolone acetate eye drops, and injections of triamcinolone and adalimumab. He failed to improve with these therapies and developed multiple adverse effects, including hepatotoxicity, severe eye pain, cataracts, and cystoid macular edema. We treated him with intravitreal methotrexate injections in both eyes, which rapidly improved his eye pain, inflammation, and vision. He subsequently underwent fluocinolone acetonide (Retisert®) implantation, cataract extraction with intraocular lens insertion, and Ahmed tube placement for long-term intraocular pressure control. His vision improved from hand motions to 20/30, intraocular pressure remained stable at 17, there was complete resolution of his panuveitis and uveitic macular edema, and his systemic medications were able to be discontinued. CONCLUSIONS: /Importance: This case demonstrates intravitreal methotrexate may successfully treat intraocular inflammation, pain, and macular edema in VKH. Excellent long-term vision and reduction of adverse effects of systemic medications were also achieved with subsequent fluocinolone acetonide implantation. Combining these two targeted therapies may be an effective strategy in treating VKH in patients who have severe pain and cannot tolerate systemic therapy.

Ocular Motor Nerve Development in the Presence and Absence of Extraocular Muscle.

Purpose: To spatially and temporally define ocular motor nerve development in the presence and absence of extraocular muscles (EOMs). Methods: Myf5cre mice, which in the homozygous state lack EOMs, were crossed to an IslMN:GFP reporter line to fluorescently label motor neuron cell bodies and axons. Embryonic day (E) 11.5 to E15.5 wild-type and Myf5cre/cre:IslMN:GFP whole mount embryos and dissected orbits were imaged by confocal microscopy to visualize the developing oculomotor, trochlear, and abducens nerves in the presence and absence of EOMs. E11.5 and E18.5 brainstems were serially sectioned and stained for Islet1 to determine the fate of ocular motor neurons. Results: At E11.5, all three ocular motor nerves in mutant embryos approached the orbit with a trajectory similar to that of wild-type. Subsequently, while wild-type nerves send terminal branches that contact target EOMs in a stereotypical pattern, the Myf5cre/cre ocular motor nerves failed to form terminal branches, regressed, and by E18.5 two-thirds of their corresponding motor neurons died. Comparisons between mutant and wild-type embryos revealed novel aspects of trochlear and oculomotor nerve development. Conclusions: We delineated mouse ocular motor nerve spatial and temporal development in unprecedented detail. Moreover, we found that EOMs are not necessary for initial outgrowth and guidance of ocular motor axons from the brainstem to the orbit but are required for their terminal branching and survival. These data suggest that intermediate targets in the mesenchyme provide cues necessary for appropriate targeting of ocular motor axons to the orbit, while EOM cues are responsible for terminal branching and motor neuron survival.

Mutant α2-chimaerin signals via bidirectional ephrin pathways in Duane retraction syndrome.

Duane retraction syndrome (DRS) is the most common form of congenital paralytic strabismus in humans and can result from α2-chimaerin (CHN1) missense mutations. We report a knockin α2-chimaerin mouse (Chn1KI/KI) that models DRS. Whole embryo imaging of Chn1KI/KI mice revealed stalled abducens nerve growth and selective trochlear and first cervical spinal nerve guidance abnormalities. Stalled abducens nerve bundles did not reach the orbit, resulting in secondary aberrant misinnervation of the lateral rectus muscle by the oculomotor nerve. By contrast, Chn1KO/KO mice did not have DRS, and embryos displayed abducens nerve wandering distinct from the Chn1KI/KI phenotype. Murine embryos lacking EPH receptor A4 (Epha4KO/KO), which is upstream of α2-chimaerin in corticospinal neurons, exhibited similar abducens wandering that paralleled previously reported gait alterations in Chn1KO/KO and Epha4KO/KO adult mice. Findings from Chn1KI/KI Epha4KO/KO mice demonstrated that mutant α2-chimaerin and EphA4 have different genetic interactions in distinct motor neuron pools: abducens neurons use bidirectional ephrin signaling via mutant α2-chimaerin to direct growth, while cervical spinal neurons use only ephrin forward signaling, and trochlear neurons do not use ephrin signaling. These findings reveal a role for ephrin bidirectional signaling upstream of mutant α2-chimaerin in DRS, which may contribute to the selective vulnerability of abducens motor neurons in this disorder.

Refinements in nasolabial fold reconstruction for facial paralysis.

OBJECTIVES/HYPOTHESIS: The objective of this study was to describe a methodology for creation of a nasolabial fold in patients with facial paralysis and to report patient-reported outcome measures following this procedure. STUDY DESIGN: Retrospective case series. METHODS: All patients who underwent nasolabial fold modification at our institution since July 2010 were included in our analysis. Patient demographics and characteristics of their facial paralysis were noted. Preoperative Facial Clinimetric Evaluation scores were compared with postoperative scores to quantify outcomes. Pre- and postoperative photos were then presented to an observer for ratings of overall midfacial appearance. RESULTS: Thirty-one patients were included in the review. Most of the patients were male. The average onset of paralysis was 50 years, and the average age at time of surgery was 61 years. The majority of patients had flaccid paralysis, with 10% of patients having synkinesis. Most patients presented with complaints of oral incompetence or drooling and generalized facial asymmetry. Facial Clinimetric Evaluation scores (P < .004) and overall midfacial appearance (P < .05) improved significantly following surgery. CONCLUSIONS: The nasolabial fold is an important aesthetic component of the face commonly affected in patients with facial paralysis. We demonstrate quantitative improvement in quality of life scores and aesthetic appearance following nasolabial fold refinement and describe the procedure in depth. LEVEL OF EVIDENCE: 4.

Low-grade astrocytomas: the prognostic value of fibrillary, gemistocytic, and protoplasmic tumor histology.

OBJECT: Low-grade astrocytomas are slow-growing, infiltrative gliomas that over time may progress into more malignant tumors. Various factors have been shown to affect the time to progression and overall survival including age, performance status, tumor size, and the extent of resection. However, more recently it has been suggested that histological subtypes (fibrillary, protoplasmic, and gemistocytic) may impact patient outcome. In this study the authors have performed a large comparative population-based analysis to examine the characteristics and survival of patients with the various subtypes of WHO Grade II astrocytomas. METHODS: Patients diagnosed with fibrillary, protoplasmic, and gemistocytic astrocytomas were identified through the Surveillance, Epidemiology, and End Results (SEER) database. The chi-square test and Student t-test were used to evaluate differences in patient and treatment characteristics between astrocytoma subtypes. Kaplan-Meier analysis was used to assess overall survival, and the log-rank test was used to evaluate the differences between survival curves. Univariate and multivariate analyses were also performed to determine the effect of various patient, tumor, and treatment variables on overall survival. RESULTS: A total of 500 cases were included in the analysis, consisting of 326 fibrillary (65.2%), 29 protoplasmic (5.8%), and 145 gemistocytic (29%) variants. Gemistocytic astrocytomas presented at a significantly older age than the fibrillary variant (46.8 vs 37.7 years, p < 0.0001), with protoplasmic and fibrillary subtypes having a similar age. Although protoplasmic and fibrillary variants underwent radiotherapy at similar rates, gemistocytic tumors more frequently received radiotherapy (p = 0.0001). Univariate analysis revealed older age, larger tumor size, and the use of radiotherapy to be poor prognostic factors, with resection being associated with improved survival. The gemistocytic subtype (hazard ratio [HR] 1.62 [95% CI 1.27-2.07], p = 0.0001) also resulted in significantly worse survival than fibrillary tumors. Bivariate analyses demonstrated that older age, the use of radiotherapy, and resection significantly influenced median survival. Tumor subtype also affected median survival; patients who harbored gemistocytic tumors experienced less than half the median survival of fibrillary and protoplasmic tumors (38 vs 82 months, p = 0.0003). Multivariate analysis revealed increasing age (HR 1.05 [95% CI 1.04-1.05], p < 0.0001), larger tumor size (HR 1.02 [95% CI 1.01-1.03], p = 0.0002), and the use of resection (HR 0.70 [95% CI 0.52-0.94], p = 0.018) to be independent predictors of survival. Examination of tumor subtype revealed that the gemistocytic variant (HR 1.30 [95% CI 0.98-1.74], p = 0.074) was associated with worse patient survival than fibrillary tumors, although this only approached significance. The protoplasmic subtype did not affect overall survival (p = 0.33). CONCLUSIONS: Gemistocytic tumor histology was associated with worse survival than fibrillary and protoplasmic astrocytomas. As protoplasmic astrocytomas have a survival similar to fibrillary tumors, there may be limited utility to the identification of this rare variant. However, increased attention should be paid to the presence of gemistocytes in low-grade gliomas as this is associated with shorter time to progression, increased malignant transformation, and reduced overall survival.

Intraaxial dermoid cyst of the medulla.

Intracranial dermoid cysts are rare congenital lesions that typically occur in the cisternal spaces. However, exceptionally rare cases of intraaxial involvement have been reported, with only 8 cases having been described in the literature. The authors report the first case of an intraaxial dermoid cyst located in the medulla and the first occurrence in an elderly patient. They also review the literature of the existing intraparenchymal cases and provide treatment guidelines. A 66-year-old man presented with slowly progressive dysphagia, left lower-extremity numbness, nausea, and hyperhidrosis. Neurological examination revealed decreased pinprick sensation of the left side of his face and body, and decreased vibratory sensation in his left lower extremity. Additionally, he had an unusual extraocular movement in which abduction of the eye resulted in closure of the contralateral eye. Magnetic resonance imaging revealed a nonenhancing cystic lesion centered in the medulla. The patient underwent a suboccipital craniotomy with laminectomy of C1-2 for excision of the cyst, with subtotal resection due to adherence of the cyst wall to the brainstem. At follow-up 7.5 years after surgery, the patient's neurological examination was stable. Magnetic resonance imaging did not reveal any progression or recurrence of the cyst. As the cyst wall is typically adherent to surrounding structures, resection is usually subtotal due to the risk of neurological deficits. As there have been no cases of progression after subtotal resection, gross-total resection is not warranted for the treatment of these lesions.

Comparison of superior-level facet joint violations during open and percutaneous pedicle screw placement.

BACKGROUND: Superior-level facet joint violation by pedicle screws may result in increased stress to the level above the instrumentation and may contribute to adjacent segment disease. Previous studies have evaluated facet joint violations in open or percutaneous screw cases, but there are no reports describing a direct institutional comparison. OBJECTIVE: To compare the incidence of superior-level facet violation for open vs percutaneous pedicle screws and to evaluate patient and surgical factors that affect this outcome. METHODS: We reviewed 279 consecutive patients who underwent an index instrumented lumbar fusion from 2007 to 2011 for degenerative spine disease with stenosis with or without spondylolisthesis. We used a computed tomography grading system that represents progressively increasing grades of facet joint violation. Patient and surgical factors were evaluated to determine their impact on facet violation. RESULTS: Our cohort consisted of 126 open and 153 percutaneous cases. Percutaneous procedures had a higher overall violation grade (P = .02) and a greater incidence of high-grade violations (P = .006) compared with open procedures. Bivariate analysis showed significantly greater violations in percutaneous cases for age < 65 years, obesity, pedicle screws at L4, and 1- and 2-level surgeries. Multivariate analysis showed the percutaneous approach and depth of the spine to be independent risk factors for high-grade violations. CONCLUSION: This study demonstrates greater facet violations for percutaneously placed pedicle screws compared with open screws.