Neuro-ophthalmology

Neuro-ophthalmology publications

Labowsky MT, Rizzo JF. The Controversy of Chronotherapy: Emerging Evidence regarding Bedtime Dosing of Antihypertensive Medications in Non-Arteritic Anterior Ischemic Optic Neuropathy. Semin Ophthalmol 2023;38(1):99-104.Abstract
"Blindness upon awakening" occurs in a significant proportion of patients with non-arteritic anterior ischemic optic neuropathy (NAION). This observation has led to a notion that nocturnal hypotension is a significant contributor and, perhaps, the final insult in a multifactorial process leading to the development of NAION, as has been proposed in other ischemic events like strokes, myocardial infarction, and ischemic rest pain. An extension of this concept has led to the recommendation that patients who have experienced NAION avoid taking blood pressure medications at bedtime. However, mounting evidence in the cardiology literature suggests that nocturnal hypertension is associated with increased risk of cardiovascular morbidity. In two prospective blood pressure monitoring studies in 1994 and 1999, Hayreh observed an extreme dipping pattern in nocturnal systolic blood pressure in NAION patients compared to reported normal values. Yet, two subsequent ambulatory blood pressure studies found either normal or non-dipping patterns in NAION patients. The majority of clinical trials published since 1976 that have studied nocturnal administration of antihypertensives have reported enhanced blood pressure control and reduced cardiovascular risk. Most notably, the large, prospective 2020 Hygia Chronotherapy Trial reported a statistically-significant beneficial effect of nocturnal antihypertensive dosing on cardiovascular outcomes and mortality. The controversy regarding nocturnal hypotension and NAION is of increasing relevance as there is new evidence to suggest a beneficial effect of nocturnal antihypertensive dosing in cardiovascular risk. This new information should prompt a re-evaluation of the relevant risk-to-benefit of reducing the risk of NAION on one hand, and the potential increase of cardiovascular risk on the other. Definitive resolution of this question would require a prospective, randomized control study with input from both cardiology and ophthalmology.
Guadix SW, Marianayagam NJ, Weidman EK, Yuan M, Liechty B, Greenfield JP, Souweidane MM. Defining Occult High-Risk Cysts of the Pineal Region: A Case Series. Oper Neurosurg (Hagerstown) 2023;Abstract
BACKGROUND: Absence of hydrocephalus on neuroimaging may impart a false sense of security for patients with pineal cysts. In this case series, we characterize a subset of patients with pineal cysts having an occult presentation. Unifying features of worsening paroxysmal headaches suggesting intermittent obstructive hydrocephalus and radiographic evidence of third ventricular invagination characterize these patients as high risk. OBJECTIVE: To define features of occult, high-risk pineal cysts and outcomes of endoscopic cyst fenestration. METHODS: Charts were retrospectively reviewed for patients with pineal cysts evaluated at our institution between 2018 and 2021 who underwent endoscopic cyst fenestration. To capture cysts presenting as occult, patients were excluded if hydrocephalus was noted at presentation. Relevant clinical history, imaging, operative data, and clinical outcomes were reviewed. RESULTS: Of 50 pineal cyst patients, 4 satisfied inclusion criteria. All patients presented with worsening paroxysmal headaches. In addition, 75% (3/4) also experienced intermittent syncope. Patients exhibited no hydrocephalus (n = 3) or fluctuating ventricular size on longitudinal imaging (n = 1). In all cases, high-resolution sagittal 3-dimensional T2 magnetic resonance imaging demonstrated invagination of the cyst anteriorly into the posterior third ventricle. All patients underwent endoscopic cyst fenestration with complete symptom resolution (mean follow-up of 20.6 months; range 3.5-37.4 months). CONCLUSION: The clinical history for occult, high-risk pineal cysts is notable for worsening paroxysmal headaches and episodic alterations of consciousness suggesting intermittent obstructive hydrocephalus. Because ventricular size can appear normal on standard imaging protocols, clinical suspicion should trigger workup with high-resolution magnetic resonance imaging designed to detect these cysts. Endoscopic cyst fenestration is a safe and efficacious management strategy.
Feng Y, Lin CC, Hamedani AG, De Lott LB. A Validated Method to Identify Neuro-Ophthalmologists in a Large Administrative Claims Database. J Neuroophthalmol 2023;Abstract
BACKGROUND: Validated methods to identify neuro-ophthalmologists in administrative data do not exist. The development of such method will facilitate research on the quality of neuro-ophthalmic care and health care utilization for patients with neuro-ophthalmic conditions in the United States. METHODS: Using nationally representative, 20% sample from Medicare carrier files from 2018, we identified all neurologists and ophthalmologists billing at least 1 office-based evaluation and management (E/M) outpatient visit claim in 2018. To isolate neuro-ophthalmologists, the National Provider Identifier numbers of neuro-ophthalmologists in the North American Neuro-Ophthalmology Society (NANOS) directory were collected and linked to Medicare files. The proportion of E/M visits with International Classification of Diseases-10 diagnosis codes that best distinguished neuro-ophthalmic care ("neuro-ophthalmology-specific codes" or NSC) was calculated for each physician. Multiple logistic regression models assessed predictors of neuro-ophthalmology specialty designation after accounting for proportion of ophthalmology, neurology, and NSC claims and primary specialty designation. Sensitivity, specificity, and positive predictive value (PPV) for varying proportions of E/M visits with NSC were calculated. RESULTS: We identified 32,293 neurologists and ophthalmologists who billed at least 1 outpatient E/M visit claim in 2018 in Medicare. Of the 472 NANOS members with a valid individual National Provider Identifier, 399 (84.5%) had a Medicare outpatient E/M visit in 2018. The model containing only the proportion of E/M visits with NSC best predicted neuro-ophthalmology specialty designation (odds ratio 1.05 [95% confidence interval 1.04, 1.05]; P < 0.001; area under the receiver operating characteristic [AUROC] = 0.91). Model predictiveness for neuro-ophthalmology designation was maximized when 6% of all billed claims were for NSC (AUROC = 0.89; sensitivity: 84.0%; specificity: 93.9%), but PPV was low (14.9%). The threshold was unchanged when limited only to neurologists billing ≥1% ophthalmology claims or ophthalmologists billing ≥1% neurology claims, but PPV increased (33.3%). CONCLUSIONS: Our study provides a validated method to identify neuro-ophthalmologists who can be further adapted for use in other administrative databases to facilitate future research of neuro-ophthalmic care delivery in the United States.
Kennedy B, Bex P, Hunter DG, Nasr S. Two fine-scale channels for encoding motion and stereopsis within the human magnocellular stream. Prog Neurobiol 2023;220:102374.Abstract
In humans and non-human primates (NHPs), motion and stereopsis are processed within fine-scale cortical sites, including V2 thick stripes and their extensions into areas V3 and V3A that are believed to be under the influence of magnocellular stream. However, in both species, the relative functional organization (overlapping vs. none overlapping) of these sites remains unclear. Using high-resolution functional MRI (fMRI), we found evidence for two minimally-overlapping channels within human extrastriate areas that contribute to processing motion and stereopsis. Across multiple experiments that included different stimuli (random dots, gratings, and natural scenes), the functional selectivity of these channels for motion vs. stereopsis remained consistent. Furthermore, an analysis of resting-state functional connectivity revealed stronger functional connectivity within the two channels rather than between them. This finding provides a new perspective toward the mesoscale organization of the magnocellular stream within the human extrastriate visual cortex, beyond our previous understanding based on animal models.
Mazumder AG, Julé AM, Cullen PF, Sun D. Astrocyte heterogeneity within white matter tracts and a unique subpopulation of optic nerve head astrocytes. iScience 2022;25(12):105568.Abstract
Much of what we know about astrocyte form and function is derived from the study of gray matter protoplasmic astrocytes, whereas white matter fibrous astrocytes remain relatively unexplored. Here, we used the ribotag approach to isolate ribosome-associated mRNA and investigated the transcriptome of uninjured fibrous astrocytes from three regions: unmyelinated optic nerve head, myelinated optic nerve proper, and corpus callosum. Astrocytes from each region were transcriptionally distinct and we identified region-specific astrocyte genes and pathways. Energy metabolism, particularly oxidative phosphorylation and mitochondrial protein translation emerged as key differentiators of astrocyte populations. Optic nerve astrocytes expressed higher levels of neuroinflammatory pathways than corpus callosum astrocytes and we further identified CARTPT as a new marker of optic nerve head astrocytes. These previously uncharacterized transcriptional profiles of white matter astrocyte types reveal their functional diversity and a greater heterogeneity than previously appreciated.
Newman NJ, Yu-Wai-Man P, Subramanian PS, Moster ML, Wang A-G, Donahue SP, Leroy BP, Carelli V, Biousse V, Vignal-Clermont C, Sergott RC, Sadun AA, Fernández GR, Chwalisz BK, Banik R, Bazin F, Roux M, Cox ED, Taiel M, Sahel J-A, Sahel J-A. Randomized trial of bilateral gene therapy injection for m.11778G > A MT-ND4 Leber optic neuropathy. Brain 2022;Abstract
Leber hereditary optic neuropathy (LHON) is an important example of mitochondrial blindness with the m.11778G > A mutation in the MT-ND4 gene being the most common disease-causing mitochondrial DNA (mtDNA) variant worldwide. The REFLECT phase 3 pivotal study is a randomized, double-masked, placebo-controlled trial investigating the efficacy and safety of bilateral intravitreal injection of lenadogene nolparvovec in patients with a confirmed m.11778G > A mutation, using a recombinant adeno-associated virus vector 2, serotype 2 (rAAV2/2-ND4). The first-affected eye received gene therapy; the fellow (affected/not-yet-affected) eye was randomly injected with gene therapy or placebo. The primary endpoint was the difference in change from baseline of best-corrected visual acuity (BCVA) in second-affected/not-yet-affected eyes treated with lenadogene nolparvovec versus placebo at 1.5 years post-treatment, expressed in logarithm of the minimal angle of resolution (LogMAR). Forty-eight patients were treated bilaterally and 50 unilaterally. At 1.5 years, the change from baseline in BCVA was not statistically different between second-affected/not-yet-affected eyes receiving lenadogene nolparvovec and placebo (primary endpoint). A statistically significant improvement in BCVA was reported from baseline to 1.5 years in lenadogene nolparvovec-treated eyes: -0.23 LogMAR for the first-affected eyes of bilaterally treated patients (p < 0.01); and -0.15 LogMAR for second-affected/not-yet-affected eyes of bilaterally treated patients and the first-affected eyes of unilaterally treated patients (p < 0.05). The mean improvement in BCVA from nadir to 1.5 years was -0.38 (0.052) LogMAR and -0.33 (0.052) LogMAR in first-affected and second-affected/not-yet-affected eyes treated with lenadogene nolparvovec, respectively (bilateral treatment group). A mean improvement of -0.33 (0.051) LogMAR and -0.26 (0.051) LogMAR was observed in first-affected lenadogene nolparvovec-treated eyes and second-affected/not-yet-affected placebo-treated eyes, respectively (unilateral treatment group). The proportion of patients with one or both eyes on-chart at 1.5 years was 85.4% and 72.0% for bilaterally and unilaterally treated patients, respectively. The gene therapy was well tolerated, with no systemic issues. Intraocular inflammation, which was mostly mild and well controlled with topical corticosteroids, occurred in 70.7% of lenadogene nolparvovec-treated eyes versus 10.2% of placebo-treated eyes. Among eyes treated with lenadogene nolparvovec, there was no difference in the incidence of intraocular inflammation between bilaterally and unilaterally treated patients. Overall, the REFLECT trial demonstrated an improvement of BCVA in LHON eyes carrying the m.11778G > A mtDNA mutation treated with lenadogene nolparvovec or placebo to a degree not reported in natural history studies and supports an improved benefit/risk profile for bilateral injections of lenadogene nolparvovec relative to unilateral injections.
Solli E, Doshi H, Elze T, Pasquale LR, Branco J, Wall M, Kupersmith M. Archetypal analysis of visual fields in optic neuritis reveals functional biomarkers associated with outcome and treatment response. Mult Scler Relat Disord 2022;67:104074.Abstract
BACKGROUND AND OBJECTIVES: Archetypal analysis (AA), a form of unsupervised machine learning, can identify quantifiable visual field (VF) patterns seen in optic neuritis (ON), known as archetypes (ATs). We hypothesized that AT weight changes over time would reflect the course of recovery and the effects of therapy in ON. We explored whether baseline AT weights would be associated with VF status at the clinical trial outcome and if ATs would indicate residual VF defects in eyes with mean deviation (MD) ≥ -2.00 at six months. METHODS: We used a published 16-AT model derived from 3892 Optic Neuritis Treatment Trial VFs (456 eyes) for all analyses. We measured AT weight changes over the six-month study period and used asymptotic regression to analyze the rate of change. We compared AT weights at six months between treatment groups. We evaluated associations between baseline AT weight thresholds and VF outcome or treatment effect. We calculated residual AT weights in eyes with MD ≥ -2.00 dB at six months. RESULTS: Over six months, AT1 (a normal VF pattern) demonstrated the greatest median weight change, increasing from 0.00% (IQR 0.00-0.00%) at baseline to 60.0% (IQR 38.3-70.8%) at six months (p < 0.001). At outcome, the intravenous methylprednisolone (IVMP) group had the highest median AT1 weight (IVMP: 63.3%, IQR 51.3-72.8%; placebo: 56.2%, IQR 35.1-71.6%; prednisone 58.3%, IQR 35.1-71.6%; p = 0.019). Eyes with AT1 weight ≥ 19% at baseline had superior median MD values (-0.91 vs. -2.07 dB, p < 0.001) and AT1 weights (70.8% vs. 57.8% p < 0.001) at six months. Only eyes with AT1 weight < 19% at baseline showed a treatment benefit for IVMP, with a higher six-month median AT1 weight compared to placebo (p = 0.015) and prednisone (p = 0.016), and a higher median MD compared to placebo (p = 0.027). At six months, 182 (80.2%) VFs with MD ≥ -2.00 had at least one abnormal AT. DISCUSSION: Changes in quantifiable, archetypal patterns of VF loss reflect recovery in ON. Machine learning analysis of the VFs in optic neuritis reveals associations with response to therapy and VF outcome, and uncovers residual deficits, not readily seen with standard evaluations.
Saitakis G, Chwalisz BK. Optic perineuritis. Curr Opin Ophthalmol 2022;33(6):519-524.Abstract
PURPOSE OF REVIEW: This review paper aims at discussing pathogenesis, etiology, clinical features, management, and prognosis of OPN. RECENT FINDINGS: Optic perineuritis (OPN) is an inflammatory process primarily involving the optic nerve sheath. Clinically, OPN usually presents with unilateral, gradual decline of visual function, eye pain, and/or pain on eye movements, disc edema and various features of optic nerve dysfunction, including visual field defects. It can mimic typical optic neuritis. In most cases of OPN, the disease is isolated with no specific etiology being identified, however, it can also occur secondary to a wide range of underlying systemic diseases. OPN is clinically diagnosed and radiologically confirmed based on the finding of circumferential perineural enhancement of the optic nerve sheath on magnetic resonance imaging (MRI). SUMMARY: Unlike optic nerve, OPN is not typically self-limited without treatment. High-dose oral corticosteroids are the mainstay of treatment in OPN. The initiation of therapy usually causes rapid and dramatic improvement in signs and symptoms. In general, OPN usually has a relatively good visual prognosis, which is influenced by delays between the onset of visual loss and the initiation of steroid therapy as well as the presence of underlying systemic diseases.
Galli J, Loi E, Strobio C, Micheletti S, Martelli P, Merabet LB, Pasini N, Semeraro F, Fazzi E, Fazzi E. Neurovisual profile in children affected by Angelman syndrome. Brain Dev 2022;Abstract
BACKGROUND: Angelman syndrome (AS) is a rare neurogenetic disorder caused by altered expression of the maternal copy of the UBE3A gene. Together with motor, cognitive, and speech impairment, ophthalmological findings including strabismus, and ocular fundus hypopigmentation characterize the clinical phenotype. The aim of this study was to detail the neurovisual profile of children affected by AS and to explore any possible genotype-phenotype correlations. METHODS: Thirty-seven children (23 females, mean age 102.8 ± 54.4 months, age range 22 to 251 months) with molecular confirmed diagnosis of AS were enrolled in the study. All underwent a comprehensive video-recorded neurovisual evaluation including the assessment of ophthalmological aspects, oculomotor functions, and basic visual abilities. RESULTS: All children had visual impairments mainly characterized by refractive errors, ocular fundus changes, strabismus, discontinuous/jerky smooth pursuit and altered saccadic movements, and/or reduced visual acuity. Comparing the neurovisual profiles between the deletion and non-deletion genetic subgroups, we found a significant statistical correlation between genotype and ocular fundus hypopigmentation (p = 0.03), discontinuous smooth pursuit (p < 0.05), and contrast sensitivity abnormalities (p < 0.01) being more frequent in the deletion subgroup. CONCLUSIONS: Subjects affected by AS present a wide spectrum of neurovisual impairments that lead to a clinical profile consistent with cerebral visual impairment (CVI). Moreover, subjects with a chromosome deletion show a more severe visual phenotype with respect to ocular fundus changes, smooth pursuit movements, and contrast sensitivity. Early detection of these impaired visual functions may help promote the introduction of neurovisual habilitative programs which can improve children's visual, neuromotor, and cognitive outcomes.
Henao-Restrepo J, López-Murillo C, Valderrama-Carmona P, Orozco-Santa N, Gomez J, Gutiérrez-Vargas J, Moraga R, Toledo J, Littau JL, Härtel S, Arboleda-Velásquez JF, Sepulveda-Falla D, Lopera F, Cardona-Gómez GP, Villegas A, Posada-Duque R. Gliovascular alterations in sporadic and familial Alzheimer's disease: APOE3 Christchurch homozygote glioprotection. Brain Pathol 2022;:e13119.Abstract
In response to brain insults, astrocytes become reactive, promoting protection and tissue repair. However, astroglial reactivity is typical of brain pathologies, including Alzheimer's disease (AD). Considering the heterogeneity of the reactive response, the role of astrocytes in the course of different forms of AD has been underestimated. Colombia has the largest human group known to have familial AD (FAD). This group carries the autosomal dominant and fully penetrant mutation E280A in PSEN1, which causes early-onset AD. Recently, our group identified an E280A carrier who did not develop FAD. The individual was homozygous for the Christchurch mutation R136S in APOE3 (APOEch). Remarkably, APOE is the main genetic risk factor for developing sporadic AD (SAD) and most of cerebral ApoE is produced by astroglia. Here, we characterized astrocyte properties related to reactivity, glutamate homeostasis, and structural integrity of the gliovascular unit (GVU), as factors that could underlie the pathogenesis or protection of AD. Specifically, through histological and 3D microscopy analyses of postmortem samples, we briefly describe the histopathology and cytoarchitecture of the frontal cortex of SAD, FAD, and APOEch, and demonstrate that, while astrodegeneration and vascular deterioration are prominent in SAD, FAD is characterized by hyperreactive-like glia, and APOEch displays the mildest astrocytic and vascular alterations despite having the highest burden of Aβ. Notably, astroglial, gliovascular, and vascular disturbances, as well as brain cell death, correlate with the specific astrocytic phenotypes identified in each condition. This study provides new insights into the potential relevance of the gliovasculature in the development and protection of AD. To our knowledge, this is the first study assessing the components of the GVU in human samples of SAD, FAD, and APOEch.
Chwalisz BK, Levy M. The Treatment of Myelin Oligodendrocyte Glycoprotein Antibody Disease: A State-of-the-Art Review. J Neuroophthalmol 2022;42(3):292-296.Abstract
BACKGROUND: Myelin oligodendrocyte glycoprotein antibody disease (MOGAD) is an important etiology of neurologic morbidity and specifically, atypical, and relapsing optic neuritis. This review summarizes acute treatment and long-term prevention approaches in MOGAD. EVIDENCE ACQUISITION: PubMed and Google Scholar databases were manually searched and reviewed. RESULTS: We review the evidence base for acute treatment of MOGAD with corticosteroids and adjunct therapies, such as intravenous immunoglobulin (IVIg) and plasma exchange. We discuss the utility of prolonged corticosteroid tapering after the acute attack. We then summarize the commonly used disease-modifying treatments for relapsing MOGAD, including chronic low-dose corticosteroids, classic antirheumatic immune suppressants, biologic agents, and IVIg. CONCLUSIONS: While acute MOGAD attacks are usually treated with high-dose IV corticosteroids, longer oral corticosteroid tapers may prevent rapid relapse. Multiple long-term treatment strategies are being employed in recurrent MOGAD, with IVIg is emerging as probably the most effective therapy.

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