Histologic correlates of "Choroidal abnormalities" in Neurofibromatosis type 1 (NF1).

Neurofibromatosis type 1 (NF1) is a rare autosomal dominant disorder characterized by proliferation of cells from neural crest origin. The most common manifestations are cutaneous, neurologic, skeletal and ocular. The distinction of NF1 from other syndromes with multiple café-au-lait macules may be difficult in the pediatric age group, and ocular findings, especially Lisch nodules (i.e., melanocytic hamartomas on the irides), are a useful, early diagnostic tool. In recent years, novel ocular manifestations descriptively referred to as "choroidal abnormalities", choroidal "hyperpigmented spots" and "retinal vascular abnormalities" have been recognized in NF1. Choroidal abnormalities (CA) appear as bright patchy nodules that can be best detected with near-infrared ocular coherence tomography imaging (NIR-OCT). Because of their high specificity and sensitivity for NF1, CA have been added as an ocular diagnostic criterion of NF1 as an alternative to Lisch nodules. Although CA are important ocular diagnostic criteria for NF1, the histologic correlates are controversial. We present the postmortem ocular pathology findings of an NF1 patient for whom clinical notes and ocular imaging were available. Findings in this patient included choroidal hyperpigmented spots on funduscopy and retinal vascular abnormalities, both of which have been reported to be closely associated with CA. Histologic examination of the eyes showed multiple clusters of melanocytes of varying sizes in the choroid. Pathologic review of 12 additional postmortem eyes from 6 NF1 patients showed multiple, bilateral choroidal melanocytic aggregates in all eyes. These findings suggest that the CA seen on NIR-OCT and the hyperpigmented spots seen clinically in NF1 patients are manifestations of multifocal choroidal melanocytic clusters, consistent with choroidal melanocytic hamartomas. Lisch nodules, often multiple, were present in all eyes with morphology that differed from the choroidal hamartomas. As such, although CA and Lisch nodules are melanocytic hamartomas, there are clear phenotypical differences in their morphologies.

Site of Origin of the Ophthalmic Artery Influences the Risk for Retinal Versus Cerebral Embolic Events.

BACKGROUND: Embolic events leading to retinal ischemia or cerebral ischemia share common risk factors; however, it has been well documented that the rate of concurrent cerebral infarction is higher in patients with a history of transient ischemic attack (TIA) than in those with monocular vision loss (MVL) due to retinal ischemia. Despite the fact that emboli to the ophthalmic artery (OA) and middle cerebral artery share the internal carotid artery (ICA) as a common origin or transit for emboli, the asymmetry in their final destination has not been fully explained. We hypothesize that the anatomic location of the OA takeoff from the ICA may contribute to the differential flow of small emboli to the retinal circulation vs the cerebral circulation. METHODS: We report a retrospective, comparative, case-control study on 28 patients with retinal ischemia and 26 patients with TIA or cerebral infarction caused by embolic events. All subjects underwent either computed tomography angiography or MRA. The location of the ipsilateral OA origin off the ICA was then graded in a blinded fashion and compared between cohorts. Vascular risk factors were collected for all patients, including age, sex, hypertension, hyperlipidemia, arrhythmia, diabetes, coronary artery disease, and smoking. RESULTS: We find that in patients with retinal ischemia of embolic etiology, the ipsilateral OA takeoff from the ICA is more proximal than in patients with cerebral infarcts or TIA (P = 0.0002). We found no statistically significant differences in demographic, vascular, or systemic risk factors. CONCLUSIONS: We find that the mean anatomical location of the OA takeoff from the ICA is significantly more proximal in patients with MVL due to retinal ischemia compared with patients with TIA or cerebral ischemia. This finding contributes significantly to our understanding of a long observed but poorly understood phenomenon that patients with MVL are less likely to have concurrent cerebral ischemia than are patients with TIA.

Harmonization of Outcomes and Vision Endpoints in Vision Restoration Trials: Recommendations from the International HOVER Taskforce.

Translational research in vision prosthetics, gene therapy, optogenetics, stem cell and other forms of transplantation, and sensory substitution is creating new therapeutic options for patients with neural forms of blindness. The technical challenges faced by each of these disciplines differ considerably, but they all face the same challenge of how to assess vision in patients with ultra-low vision (ULV), who will be the earliest subjects to receive new therapies. Historically, there were few tests to assess vision in ULV patients. In the 1990s, the field of visual prosthetics expanded rapidly, and this activity led to a heightened need to develop better tests to quantify end points for clinical studies. Each group tended to develop novel tests, which made it difficult to compare outcomes across groups. The common lack of validation of the tests and the variable use of controls added to the challenge of interpreting the outcomes of these clinical studies. In 2014, at the bi-annual International "Eye and the Chip" meeting of experts in the field of visual prosthetics, a group of interested leaders agreed to work cooperatively to develop the International Harmonization of Outcomes and Vision Endpoints in Vision Restoration Trials (HOVER) Taskforce. Under this banner, more than 80 specialists across seven topic areas joined an effort to formulate guidelines for performing and reporting psychophysical tests in humans who participate in clinical trials for visual restoration. This document provides the complete version of the consensus opinions from the HOVER taskforce, which, together with its rules of governance, will be posted on the website of the Henry Ford Department of Ophthalmology (www.artificialvision.org). Research groups or companies that choose to follow these guidelines are encouraged to include a specific statement to that effect in their communications to the public. The Executive Committee of the HOVER Taskforce will maintain a list of all human psychophysical research in the relevant fields of research on the same website to provide an overview of methods and outcomes of all clinical work being performed in an attempt to restore vision to the blind. This website will also specify which scientific publications contain the statement of certification. The website will be updated every 2 years and continue to exist as a living document of worldwide efforts to restore vision to the blind. The HOVER consensus document has been written by over 80 of the world's experts in vision restoration and low vision and provides recommendations on the measurement and reporting of patient outcomes in vision restoration trials.

Implantation and Extraction of Penetrating Electrode Arrays in Minipig Retinas.

Purpose: This work was motivated by the goals of demonstrating methods to fabricate and implant large numbers of penetrating arrays into the retina and the feasibility of extraction. Methods: Arrays of inactive, three-dimensional (3D) SU-8 structures were microfabricated onto 13-µm polyimide substrates. Standard vitreoretinal surgical techniques were used with an ab externo approach for subretinal implantation of arrays in 12 mini-pigs. In the first three surgeries, different post-geometries were explored, while a preferred design (128-µm tall, 30-µm diameter, 200-µm spacing) was used for the remaining nine implantations. Two arrays were extracted. Funduscopy, optical coherence tomography (OCT) and immunohistochemistry of the retinae were performed. The unoperated eyes and tissue far from implantation served as controls. A thirteenth pig was implanted with a planar array. Results: Ten implant surgeries had no significant complication, and two arrays were successfully extracted. One retinal tear occurred after implantation due to too long posts in an early surgery. In "successful" cases, OCT showed close apposition of the arrays to the retina and integration of the posts, the tops of which were positioned at the junction of the inner plexiform and ganglion cells, without significant gliosis. Conclusions: These results provide a proof-of-concept that relatively large numbers of 3D posts can be implanted into, and extracted from, the retina of mini-pigs. Our surgical numbers were relatively small, especially for the extractions, and our conclusions must be viewed with that limitation. Our methods are applicable for human surgeries. Translational Relevance: This study provides results of implantation and extraction of relatively large numbers of 3D posts from the retina of minipig eyes. If similar technology were used in humans, a 3D array of this type should lower perceptual thresholds, provide safer long-term stimulation, and perhaps provide better perceptual outcomes.

Mitochondrial Encephalopathy and Optic Neuropathy Due to m.10158 MT-ND3 Complex I Mutation Presenting in an Adult Patient: Case Report and Review of the Literature.

INTRODUCTION: Establishing a diagnosis of mitochondrial disease in adults remains a clinician's challenge. We report a case of syndrome reminiscent of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) in an adult patient who carries m.10158T>C mutation in complex I respiratory chain gene MT-ND3 (mitochondrially encoded NADH dehydrogenase 3). CASE REPORT: This 26-year-old man from Thailand presented with new-onset headaches, seizures, stroke-like episodes, and poor vision due to optic neuropathy and cortical blindness. Instead of expected mutations in the mitochondrial tRNA gene that are frequently associated with MELAS, the mutation in MT-ND3 with variable tissue heteroplasmy (blood 5.3%, muscle 89.5%) was demonstrated. The patient's clinical features, blood biomarkers, neuroimaging findings, muscle biopsy with histochemical and functional in vitro analysis, and genetic studies were analyzed and compared with all previously reported ND3 disease cases. CONCLUSIONS: ND3 disease due to m.10158T>C mutation was previously described only in patients with Leigh or Leigh-like syndrome. Our findings thus indicate that ND3 disease can manifest with atypical phenotype in adults. The diagnosis of mitochondrial disease caused by other than typical MELAS-associated mutations in adults with stroke-like episodes, headaches, and seizures should be considered. An analysis of tissue other than blood, which is more likely to harbor a tissue-specific mitochondrial DNA mutation at a measurable level, may be necessary for diagnosis.

An Atypical Case of Lymphocytic Panhypophysitis in a Pregnant Woman.

We describe a case of lymphocytic panhypophysitis (LPH) in a 30-year-old woman presenting with throbbing headaches and vision changes during her third trimester. LPH is the rarest subclassification of lymphocytic hypophysitis; it is typically found in males and has not previously been associated with pregnancy. Anterior and posterior pituitary deficits together with headaches should raise a high degree of suspicion regarding the possibility of LPH. The atypical magnetic resonance imaging finding of a heterogeneous pituitary mass additionally raised concern about pituitary apoplexy. Tissue from a transsphenoidal biopsy permitted diagnosis of lymphocytic hypophysitis. There was infiltration of the pituitary gland by small B and T lymphocytes. Resolution of the visual symptoms occurred after the biopsy and treatment with intravenous steroids.

Correlation of clinical profile and specific histopathological features of temporal artery biopsies.

BACKGROUND: This study sought to correlate the clinical features of patients with giant cell arteritis (GCA) who present with ophthalmic symptoms and signs, with 2 specific histopathological findings-the presence of giant cells and arterial wall neoangiogenesis. The goal was to assess if these pathological features might be useful in guiding the approach to patient management. METHODS: Medical charts were retrospectively reviewed from 58 patients who underwent a temporal artery biopsy at a single institution. Detailed information was collected about the clinical presentation and course, with an emphasis on visual function. Histopathological and immunohistochemical techniques were used to examine temporal artery biopsies for evidence of inflammation. Correlations were made between the clinical data and the presence of giant cells and neoangiogenesis. RESULTS: Twenty-one (34%) biopsies were positive for inflammation consistent with GCA. Although the percentage of positive biopsies with giant cells was high, neither the presence of giant cells nor neoangiogenesis was predictive of a patient's presenting visual symptoms, severity and bilaterality of vision loss, other ophthalmic manifestations of GCA, presence of headache or jaw claudication, or erythrocyte sedimentation rate. Giant cells were more common in patients with recent weight loss. Immunohistochemistry confirmed diagnoses but did not alter the clinical course or treatment plan. CONCLUSIONS: There was no correlation between the clinical, specifically visual, features of GCA and the presence or absence of giant cells or neoangiogenesis in temporal artery biopsy specimens. Although the presence of neoangiogenesis may be important in the pathogenesis of GCA, our study showed no correlation between this finding and the clinical course.

Subtleties in the histopathology of giant cell arteritis.

A temporal artery biopsy is typically obtained in cases of suspected giant cell arteritis (GCA). The differentiation between a "positive" versus a "negative" biopsy is sometimes not simple. Degrees of inflammation can vary from obvious, florid accumulations of giant cells to subtle pockets of non-granulomatous inflammation. Areas of normal pathology, or "skip lesions," may be interspersed within inflamed sections of the artery, resulting in a false negative diagnosis. Other features of the biopsy, such as the state of the internal elastic lamina and inflammation of the adjacent, smaller vessels, must also be evaluated and considered as possible signs of disease. Finally, some biopsies have an intermediate histopathologic appearance with mild inflammation and scarring, which may indicate prior treatment with corticosteroids, or "healed" arteritis. Careful examination and clinical correlation is therefore essential to evaluate for these subtleties, which can affect the final diagnosis.

Update on retinal prosthetic research: the Boston Retinal Implant Project.

The field of retinal prosthetic research, now more than 20 years old, has produced many high-quality technical options that have the potential to restore vision to patients with acquired disease of the outer retina. Five companies have performed Phase I clinical trials demonstrating that blind patients can reliably report basic elements of visual percepts induced by electrical stimulation. However, at present patients and observers generally do not consider the results to be useful enough in the performance of tasks of daily living to justify the risks of surgery and chronic implantation or the costs. Having developed a wireless device implanted in the subretinal space, the Boston Retinal Implant Project has focused its efforts on developing scalable technologies to create a hermetic device that can deliver individually controlled pulses of electrical stimulation to each of hundreds of electrodes. An advanced device with such attributes will be needed to justify the risks of implantation. An assessment of long-term biocompatibility for all devices remains to be done.

The use of onabotulinum toxin A in the treatment of see-saw nystagmus.

See-saw nystagmus (SSN) is an uncommon disorder that consists of cycles in which one eye rises and intorts while the other depresses and extorts, followed by reversal of the pattern. It typically causes debilitating symptoms including oscillopsia that interfere with activities of daily living. There are myriad etiologies, including stroke, tumors, trauma, and multiple sclerosis. Treatment options are limited and are often unsatisfactory. The authors report a case in which targeted injections of onabotulinum toxin A were used to decrease the torsional component of SSN and thus significantly improve the subjective symptoms of oscillopsia in a patient with acquired SSN.

Use of optical coherence tomography to evaluate papilledema and pseudopapilledema.

Idiopathic intracranial hypertension (IIH), or pseudotumor cerebri, describes a condition of elevated intracranial pressure (ICP) that typically presents in obese women of childbearing age with symptoms and signs of posture-dependent headaches, pulsatile tinnitus, visual changes, and papilledema. Optical coherence tomography (OCT) has begun to be utilized as an adjunctive, quantitative tool in the evaluation of patients with IIH to help distinguish between true optic nerve head edema and pseudopapilledema, and to contribute to our understanding of the consequences of prolonged optic nerve edema. Although few longitudinal studies of patients with IIH have been published to date, it appears that there may be a correlation between retinal nerve fiber layer (RNFL) thickness and visual function. With the new spectral domain OCT, additional parameters of the optic nerve imaging, including volume and height measurements, might provide greater sensitivity of the response to treatment and the long-term visual outcome in patients with IIH.

Subjectively quantified Maddox rod testing improves diagnostic yield over alternate cover testing alone in patients with diplopia.

We aimed to assess the added diagnostic value of subjectively-quantified red Maddox rod testing in patients with diplopia or suspected strabismus. Over 9 months we compared measures of ocular alignment (inspection; alternate cover; Maddox rod) with final anatomic and etiologic diagnoses using clinical records in a cross-sectional study in an academic neuro-ophthalmology unit. Seventy-seven consecutive patients (98 visits) met study criteria. Mean age was 54 years (range 11-100 years). Most visits (73%) were for symptomatic diplopia and all three measures of alignment were generally available (92%). Maddox findings prompted additional diagnostic tests for 13 patients, leading to an important new diagnosis (systemic vasculitis; posterior fossa arachnoid cyst with mass effect; cavernous sinus mass) in three patients (4%). Maddox rod testing may add clinically relevant diagnostic information to that obtained by alternate cover testing alone. Its use might help prevent missed diagnoses in the evaluation of patients with diplopia or suspected strabismus.

Extraction of a chronically implanted, microfabricated, subretinal electrode array.

PURPOSE: To assess the feasibility of extraction of a chronically implanted subretinal electrode array. METHODS: Inactive, polyimide strips (10 mm x 1.5 mm x 15 microm) were surgically implanted into the subretinal space of 8 rabbits using a mostly ab externo approach. Pre- and postoperative clinical examinations, electroretinography and in some cases optical coherence tomography were performed to follow the course of the eyes. Two months after implantation, the polyimide strips were extracted from 5 eyes; 2 animals kept the implants and served as controls. All animals were then sacrificed and eyes enucleated for histological examination. RESULTS: All 8 surgeries yielded successful placement of the arrays into the subretinal space. All 5 extraction surgeries were performed without obvious complications. Clinical examinations and electroretinography did not reveal any significant abnormalities. The histological examinations showed alterations from normal anatomy in all animals; the anatomical changes in the explanted animals were relatively mild and confined to the area of the surgery. CONCLUSIONS: Successful extraction of electrode arrays from the subretinal space of rabbits can be reliably performed 2 months after implantation, which is beyond the time period when postoperative scarring would be most intense.

Development and implantation of a minimally invasive wireless subretinal neurostimulator.

A wirelessly operated, minimally invasive retinal prosthesis was developed for preclinical chronic implantation studies in Yucatan minipig models. The implant conforms to the outer wall of the eye and drives a microfabricated polyimide stimulating electrode array with sputtered iridium oxide electrodes. This array is implanted in the subretinal space using a specially designed ab externo surgical technique that fixes the bulk of the prosthesis to the outer surface of the sclera. The implanted device is fabricated on a host polyimide flexible circuit. It consists of a 15-channel stimulator chip, secondary power and data receiving coils, and discrete power supply components. The completed device is encapsulated in poly(dimethylsiloxane) except for the reference/counter electrode and the thin electrode array. In vitro testing was performed to verify the performance of the system in biological saline using a custom RF transmitter circuit and primary coils. Stimulation patterns as well as pulse strength, duration, and frequency were programmed wirelessly using custom software and a graphical user interface. Wireless operation of the retinal implant has been verified both in vitro and in vivo in three pigs for more than seven months, the latter by measuring stimulus artifacts on the eye surface using contact lens electrodes.

Visual outcome and tumor control after conformal radiotherapy for patients with optic nerve sheath meningioma.

PURPOSE: Optic nerve sheath meningioma (ONSM) is a rare tumor that almost uniformly leads to visual dysfunction and even blindness without intervention. Because surgical extirpation carries a high risk of postoperative blindness, vision-sparing treatment strategies are desirable. METHODS AND MATERIALS: We retrospectively reviewed the outcomes of 25 patients (25 optic nerves) with ONSM, treated at a single institution with conformal fractionated radiotherapy by either stereotactic photon or proton radiation. Primary endpoints were local control and visual acuity. RESULTS: The patients presented with symptoms of visual loss (21) or orbital pain (3) or were incidentally diagnosed by imaging (3). The mean age was 44 years, and 64% were female patients. The indication for treatment was the development or progression of symptoms. Of the patients, 13 were treated with photons, 9 were treated with protons, and 3 received a combination of photons and protons. The median dose delivered was 50.4 gray equivalents (range, 45-59.4 gray equivalents). Median follow-up after radiotherapy was 30 months (range, 3-168 months), with 3 patients lost to follow-up. At most recent follow-up, 21 of 22 patients (95%) had improved (14) or stable (7) visual acuity. One patient had worsened visual acuity after initial postirradiation improvement. Of the 22 patients, 20 (95%) had no radiographic progression. Three patients had evidence of asymptomatic, limited retinopathy on ophthalmologic examination, and one had recurrent ONSM 11 years after treatment. CONCLUSIONS: Highly conformal, fractionated radiation therapy for symptomatic primary ONSM provides tumor control and improvement in visual function in most cases, with minimal treatment-induced morbidity. Longer follow-up is needed to assess the durability of tumor control and treatment-related late effects.