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.

The Role of Epigenetics in Accelerated Aging: A Reconsideration of Later-Life Visual Loss After Early Optic Neuropathy.

BACKGROUND: In 2005, we reported 3 patients with bilateral optic nerve damage early in life. These patients had stable vision for decades but then experienced significant bilateral vision loss with no obvious cause. Our hypothesis, novel at that time, was that the late decline of vision was due to age-related attrition of retinal ganglion cells superimposed on a reduced neuronal population due to the earlier injury. EVIDENCE ACQUISITION: The field of epigenetics provides a new paradigm with which to consider the normal aging process and the impact of neuronal injury, which has been shown to accelerate aging. Late-in-life decline in function after early neuronal injury occurs in multiple sclerosis due to dysregulated inflammation and postpolio syndrome. Recent studies by our group in mice have also demonstrated the possibility of partial reversal of cellular aging and the potential to mitigate anatomical damage after injury and even improve visual function. RESULTS: The results in mice and nonhuman primates published elsewhere have shown enhanced neuronal survival and visual function after partial epigenetic reprogramming. CONCLUSIONS: Injury promotes epigenetic aging , and this finding can be observed in several clinically relevant scenarios. An understanding of the epigenetic mechanisms at play opens the opportunity to restore function in the nervous system and elsewhere with cellular rejuvenation therapies. Our earlier cases exemplify how reconsideration of previously established concepts can motivate inquiry of new paradigms.

Orbital Vasculopathy With Unexpected Finding of Calcium Oxalosis in the Context of a Clinical Diagnosis of Optic Neuropathy.

BACKGROUND: There are few reports of histopathology of any form of optic neuropathy. This article provides histopathologic findings of an adult-onset, nonprogressive optic neuropathy that was diagnosed clinically as nonacute, nonarteritic anterior ischemic optic neuropathy (NAION) but which was found by a pathological study to be associated with diffuse calcium oxalosis that was confined in the involved orbit. METHODS: This is a case report that includes results of a neuro-ophthalmologic examination and histopathology of a complete autopsy, including en bloc removal of both orbits and the brain. The unaffected orbit/optic nerve served as a control. The affected orbit was serially sectioned into 2,550 increments each separated by 10 µm; the uninvolved orbit was sectioned into 150 equally spaced sections. The main outcome measures were derived from the autopsy, especially from the thin-section histopathologic study of both orbits that focused on blood vessels and the site of neural damage within the optic nerve. RESULTS: The neuro-ophthalmologic examination revealed a unilateral optic neuropathy with pallor of the left optic nerve head that had been documented just before death. The general autopsy showed acute bacterial endocarditis and a recent cerebral hematoma that caused death. Histopathology revealed sectoral loss of optic nerve axons in the left eye. Numerous arterial walls in the left orbit, including short posterior ciliary arteries and the central retinal artery, contained hundreds of crystals with anisotropic, colorful birefringence consistent with calcium oxalosis. Crystals were not found in the right, control orbit or elsewhere in the body. CONCLUSIONS: The patient developed an optic neuropathy late in life that was diagnosed by an experienced neuro-ophthalmologist as being most consistent with nonacute, nonarteritic anterior ischemic optic neuropathy. The autopsy identified sectoral loss of optic nerve fibers consistent with that diagnosis. However, the unexpected discovery of calcium oxalate crystals in blood vessels of the involved orbit, which curiously were not present elsewhere in the body, raises a question of their etiological role in this particular optic neuropathy. Whether the crystals were causal, epiphenomenal, or purely incidental to the optic neuropathy cannot be answered by our study.

Lamina cribrosa vessel and collagen beam networks are distinct.

Our goal was to analyze the spatial interrelation between vascular and collagen networks in the lamina cribrosa (LC). Specifically, we quantified the percentages of collagen beams with/without vessels and of vessels inside/outside of collagen beams. To do this, the vasculature of six normal monkey eyes was labeled by perfusion post-mortem. After enucleation, coronal cryosections through the LC were imaged using fluorescence and polarized light microscopy to visualize the blood vessels and collagen beams, respectively. The images were registered to form 3D volumes. Beams and vessels were segmented, and their spatial interrelationship was quantified in 3D. We found that 22% of the beams contained a vessel (range 14%-32%), and 21% of vessels were outside beams (13%-36%). Stated differently, 78% of beams did not contain a vessel (68%-86%), and 79% of vessels were inside a beam (64%-87%). Individual monkeys differed significantly in the fraction of vessels outside beams (p < 0.01 by linear mixed effect analysis), but not in the fraction of beams with vessels (p > 0.05). There were no significant differences between contralateral eyes in the percent of beams with vessels and of vessels outside beams (p > 0.05). Our results show that the vascular and collagenous networks of the LC in monkey are clearly distinct, and the historical notions that each LC beam contains a vessel and all vessels are within beams are inaccurate. We postulate that vessels outside beams may be relatively more vulnerable to mechanical compression by elevated IOP than are vessels shielded inside of beams.

Sectoral Sparing Associated With a Cilioretinal Artery in Arteritic Anterior Ischemic Optic Neuropathy.

ABSTRACT: Giant cell arteritis (GCA) is a life-threatening vasculitis occurring in older adults that can cause blindness by ischemia of the choroid, retina, and optic nerve. We report a case of a patient who presented with "occult" GCA with severe anterior ischemic optic neuropathy affecting both optic nerves, delayed choroidal filling, and a concomitant cilioretinal artery occlusion in the left eye. The retinal territory supplied by the affected cilioretinal artery was hypoperfused, yet this retinal territory at least partially corresponded to the only preserved visual field in that eye. The sector of the optic disc corresponding to the emergence of the cilioretinal artery was the only sector spared by pallid edema. This pattern of sectoral sparing associated with a cilioretinal artery has been observed in other patients with GCA and in animal models of posterior ciliary artery occlusion. This case serves as a clear example of an incompletely understood phenomenon in posterior pole circulation in vascular occlusive disease that deserves further study.

Elevated Intracranial Pressure Associated With Exogenous Hormonal Therapy Used for Gender Affirmation.

BACKGROUND: Addison disease, corticosteroid withdrawal, and taking synthetic growth hormone have been linked with development of intracranial hypertension, but there is still debate on whether administration of other exogenous hormones plays a role in precipitating elevated pressure. The growing use of hormonal therapy for gender affirmation provides an opportunity to explore this possibility. METHODS: All transgender patients taking exogenous hormones for female-to-male (FTM) and male-to-female (MTF) transitions who were diagnosed with intracranial hypertension at Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital and Beth Israel Deaconess Medical Center between August 2014 and November 2018 were included in a retrospective review. Visual acuity, type, and dose of exogenous hormone, visual field testing, clinical exam, results of neuroimaging and lumbar puncture, and treatment modalities were catalogued and analyzed. RESULTS: Six transgender individuals were identified. Five were FTM, with an average hormone treatment time of 18.4 months, and one was MTF who had been treated with hormones for 4 years. The average age of all patients was 23.5 years. The average time between onset of symptoms and presentation was 5 months. Fifty percent of the patients reported pulse-synchronous tinnitus, 83% reported positional headache, 33% reported transient visual obscurations, and 16% reported diplopia. Lumbar punctures performed on 4 of the patients revealed elevated opening pressures and normal cerebrospinal fluid constituents. MRI findings consistent with elevated intracranial pressure (ICP) were present in the other 2 patients in whom lumbar puncture was unsuccessful. Four patients were treated with acetazolamide and one was treated with topiramate, with an average follow-up time of 15.7 months. All patients demonstrated bilateral optic disc swelling, and all maintained normal acuity and color vision. Performance on visual field testing was not significantly affected in any patient. CONCLUSIONS: This is the largest reported series to date of gender-transitioning patients with intracranial hypertension, including one novel MTF conversion. These observations warrant further investigation into the possible link of exogenous hormonal therapy and elevated ICP and any mechanisms or confounders underlying this potential association.

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.

Case report: Orbital myositis triggering oxygen-responsive cluster headache.

BACKGROUND: Orbital myositis is an idiopathic, non-infectious condition, typically seen in young females and usually affecting one extraocular muscle. Orbital myositis mimicking cluster headache is a rare clinical entity, and this is the first description of a case of a secondary trigeminal autonomic cephalalgia from orbital myositis responsive to high-flow oxygen. CASE: A young woman presented with new-onset, oxygen-responsive headache, periorbital pain and autonomic features. She had associated vertical diplopia on downgaze and subtle ocular misalignment. An initial diagnosis of cluster headache was made. Initial brain MRI was unrevealing, but dedicated MRI of the orbits showed enhancement of orbital muscles. The diplopia and the imaging findings were consistent with orbital myositis. CONCLUSION: Orbital myositis mimicking cluster headache is rare, and not previously reported as an oxygen-responsive headache.

Unraveling the Enigma of Nonarteritic Anterior Ischemic Optic Neuropathy.

Non-arteritic anterior ischemic optic neuropathy (NAON) is the second most common optic neuropathy in adults. Despite extensive study, the etiology of NAION is not definitively known. The best evidence suggests that NAION is caused by an infarction in the region of the optic nerve head (ONH), which is perfused by paraoptic short posterior ciliary arteries (sPCAs) and their branches. To examine the gaps in knowledge that defies our understanding of NAION, a historical review was performed both of anatomical investigations of the ONH and its relevant blood vessels and the evolution of clinical understanding of NAION. Notably, almost all of the in vitro vascular research was performed prior our current understanding of NAION, which has largely precluded a hypothesis-based laboratory approach to study the etiological conundrum of NAION. More recent investigative techniques, like fluorescein angiography, have provided valuable insight into vascular physiology, but such light-based techniques have not been able to image blood vessels located within or behind the dense connective tissue of the sclera and laminar cribrosa, sites that are likely culpable in NAION. The lingering gaps in knowledge clarify investigative paths that might be taken to uncover the pathogenesis of NAION and possibly glaucoma, the most common optic neuropathy for which evidence of a vascular pathology also exists.

Ophthalmic manifestations of giant cell arteritis.

GCA, the most common systemic arteritis, affects medium-sized and larger extradural arteries that have the internal elastic lamina. Involvement of the ophthalmic artery and its branches results in visual loss, which is often complete but is usually painless. Visual loss may be monocular or binocular developing simultaneously or sequentially. Rarely, it stems from occipital lobe infarct that result in homonymous hemianopia, a visual field defect involving the two identical halves (right or left) of the visual fields of both eyes. Visual hallucinations and diplopia are less common. All visual symptoms, including those that are transient, require urgent ophthalmological evaluation and treatment with high-dose glucocorticoids to avoid permanent visual loss.

Rehabilitation of Visual Loss: Where We Are and Where We Need to Be.

BACKGROUND: Spontaneous recovery of visual loss resulting from injury to the brain is variable. A variety of traditional rehabilitative strategies, including the use of prisms or compensatory saccadic eye movements, have been used successfully to improve visual function and quality-of-life for patients with homonymous hemianopia. More recently, repetitive visual stimulation of the blind area has been reported to be of benefit in expanding the field of vision. EVIDENCE ACQUISITION: We performed a literature review with main focus on clinical studies spanning from 1963 to 2016, including 52 peer-reviewed articles, relevant cross-referenced citations, editorials, and reviews. RESULTS: Repetitive visual stimulation is reported to expand the visual field, although the interpretation of results is confounded by a variety of methodological factors and conflicting outcomes from different research groups. Many studies used subjective assessments of vision and did not include a sufficient number of subjects or controls. CONCLUSIONS: The available clinical evidence does not strongly support claims of visual restoration using repetitive visual stimulation beyond the time that spontaneous visual recovery might occur. This lack of firm supportive evidence does not preclude the potential of real benefit demonstrated in laboratories. Additional well-designed clinical studies with adequate controls and methods to record ocular fixation are needed.

Diagnostic genetic testing for patients with bilateral optic neuropathy and comparison of clinical features according to OPA1 mutation status.

PURPOSE: Inherited optic neuropathy is genetically heterogeneous, and genetic testing has an important role in risk assessment and counseling. The purpose of this study is to determine the prevalence and spectrum of mutations in a group of patients referred for genetic testing to a tertiary center in the United States. In addition, we compared the clinical features of patients with and without mutations in OPA1, the gene most commonly involved in dominantly inherited optic atrophy. METHODS: Clinical data and genetic testing results were reviewed for 74 unrelated, consecutive patients referred with a history of insidious, relatively symmetric, bilateral visual loss secondary to an optic neuropathy. Patients were evaluated for disease-causing variants in OPA1, OPA3, WFS1, and the entire mitochondrial genome with DNA sequencing and copy number variation (CNV) testing. RESULTS: Pathogenic DNA variants were found in 25 cases, with the majority (24 patients) located in OPA1. Demographics, clinical history, and clinical features for the group of patients with mutations in OPA1 were compared to those without disease-causing variants. Compared to the patients without mutations, cases with mutations in OPA1 were more likely to have a family history of optic nerve disease (p = 0.027); however, 30.4% of patients without a family history of disease also had mutations in OPA1. OPA1 mutation carriers had less severe mean deviation and pattern standard deviation on automated visual field testing than patients with optic atrophy without mutations in OPA1 (p<0.005). Other demographic and ocular features were not statistically significantly different between the two groups, including the fraction of patients with central scotomas (42.9% of OPA1 mutation positive and 66.0% of OPA1 mutation negative). CONCLUSIONS: Genetic testing identified disease-causing mutations in 34% of referred cases, with the majority of these in OPA1. Patients with mutations in OPA1 were more likely to have a family history of disease; however, 30.4% of patients without a family history were also found to have an OPA1 mutation. This observation, as well as similar frequencies of central scotomas in the groups with and without mutations in OPA1, underscores the need for genetic testing to establish an OPA1 genetic diagnosis.

Focal Capillary Dropout Associated With Optic Disc Drusen Using Optical Coherence Tomographic Angiography.

Optic disc drusen may be a cause of visual field defects and visual loss. The mechanism by which this occurs is unclear. We report a patient who developed decreased vision in the right eye and was found to have a heavy burden of superficial optic disc drusen. Optical coherence tomography (OCT) confirmed focal retinal nerve fiber layer thinning that corresponded with the distribution of drusen. OCT angiography, with superficial laminar segmentation, showed focal capillary attenuation overlying the most prominent drusen. These findings demonstrate alterations in the superficial retinal capillary network associated with optic disc drusen.

Transient Monocular Vision Loss on Awakening: A Benign Amaurotic Phenomenon.

BACKGROUND: Transient monocular vision loss (TMVL) is an alarming symptom owing to potentially serious etiologies such as thromboembolism or giant cell arteritis. Our objective is to describe the phenomenon of TMVL present on awakening, which may represent a distinct and benign entity. METHODS: We performed a retrospective observational case series of 29 patients who experienced TMVL on awakening. Patients who described monocular dimming or blackout of vision were included, and those with blurred vision, concurrent eye pain, and binocular vision loss were excluded. Descriptive statistics were used to summarize the study population. RESULTS: Of the 29 patients we studied, 90% (n = 26) were female and 48% had crowded discs (cup-to-disc ratio ≤0.2). The mean age was 45.4 years, although women were significantly younger than men (mean ages 43.4 and 62.7 years, respectively, P = 0.017). Brain magnetic resonance imaging and vascular imaging (magnetic resonance angiography, computed tomographic angiography, or carotid Doppler) were performed in 69% and 55% of cases, respectively, and were uniformly negative. In 14 patients for whom clear follow-up data could be obtained, no medically or visually significant sequelae of this syndrome were found, and 50% experienced resolution of symptoms. CONCLUSIONS: Evaluation was uniformly negative when patients described waking with isolated vision loss in 1 eye with subsequent resolution, usually in less than 15 minutes. The natural history seems benign with symptoms frequently remitting spontaneously. This visual phenomenon may represent an autoregulatory failure resulting in a supply/demand mismatch during low-light conditions.

Demographic, Systemic, and Ocular Factors Associated with Nonarteritic Anterior Ischemic Optic Neuropathy.

OBJECTIVE: Nonarteritic anterior ischemic optic neuropathy (NAION) is a devastating ocular condition causing permanent vision loss. Little is known about risk factors for developing this disease. We assessed demographic, systemic, and ocular factors associated with NAION. DESIGN: Retrospective longitudinal cohort study. PARTICIPANTS: Beneficiaries between 40 and 75 years old without NAION at baseline enrolled in a large U.S. managed care network. METHODS: Enrollees were monitored continuously for ≥2 years between 2001 and 2014 to identify those newly diagnosed with NAION (International Classification of Diseases, 9th Revision, Clinical Modification [ICD-9-CM] code 377.41). All persons were under ophthalmic surveillance and all cases had ≥1 confirmatory ICD-9-CM code for NAION during follow-up. MAIN OUTCOME MEASURES: Multivariable Cox regression modeling was used to generate hazard ratios (HRs) with 95% confidence intervals (CIs) to describe the statistical relationship between selected demographic characteristics, systemic and ocular conditions, and the hazard of developing NAION. RESULTS: Of 1 381 477 eligible enrollees, 977 (0.1%) developed NAION during a mean ± standard deviation (SD) follow-up of 7.8±3.1 years. The mean ± SD age for NAION cases at the index date was 64.0±9.2 years vs. 58.4±9.4 years for the remainder of the beneficiaries. After adjustment for confounding factors, each additional year older was associated with a 2% increased hazard of NAION (HR = 1.02; 95% CI: 1.01-1.03). Female subjects had a 36% decreased hazard of developing NAION (HR = 0.64; 95% CI: 0.55-0.74) compared with male subjects. Compared with whites, Latinos had a 46% decreased hazard of developing NAION (HR = 0.54; 95% CI: 0.36-0.82), whereas African ancestry was not significantly associated with NAION (HR = 0.91; 95% CI: 0.72-1.15). Systemic diseases associated with NAION included hypertension (HR = 1.62; 95% CI: 1.26-2.07) and hypercoagulable states (HR = 2.46; 95% CI: 1.51-4.00). Although diabetes mellitus (DM) was not significantly associated with NAION compared with those without DM (P = 0.45), patients with end-organ involvement from DM had a 27% increased hazard of NAION relative to those with uncomplicated DM (HR = 1.27; 95% CI: 1.01-1.59). Ocular diseases associated with NAION were age-related macular degeneration (HR = 1.29; 95% CI: 1.08-1.54) and retinal vein occlusion (HR = 3.94; 95% CI: 3.11-4.99). CONCLUSIONS: Our study identified several modifiable risk factors that may be associated with NAION. Should future studies confirm these findings, they may offer opportunities to prevent or treat this debilitating condition.

Dominant optic atrophy: updates on the pathophysiology and clinical manifestations of the optic atrophy 1 mutation.

PURPOSE OF REVIEW: Review recent advances in clinical and experimental studies of dominant optic atrophy (DOA) to better understand the complexities of pathophysiology caused by the optic atrophy 1 (OPA1) mutation. RECENT FINDINGS: DOA is the most commonly diagnosed inherited optic atrophy, causing progressive bilateral visual loss that begins early in life. During the past 25 years, there has been substantial progress in the understanding of the clinical, genetic, and pathophysiological basis of this disease. The histopathological hallmark of DOA is the primary degeneration of retinal ganglion cells, preferentially in the papillomacular bundle, which results temporal optic disc pallor and cecocentral scotomata in patients with DOA. Loss of OPA1 protein function by OPA1 gene mutations causes mitochondrial dysfunction because of the loss of mitochondrial fusion, impaired mitochondrial oxidative phosphorylation, increases in reactive oxygen species, and altered calcium homeostasis. These factors lead to apoptosis of retinal ganglion cells by a haploinsufficiency mechanism. SUMMARY: Improved understanding of the pathophysiology of DOA provides insights that can be used to develop therapeutic approaches to the DOA.