Neuro-ophthalmology

Winter A, Chwalisz B. MRI Characteristics of NMO, MOG and MS Related Optic Neuritis. Semin Ophthalmol 2021;:1-10.Abstract
Acute isolated optic neuritis can be the initial presentation of demyelinating inflammatory central nervous system disease related to multiple sclerosis (MS), neuromyelitis optica (NMO) or myelin oligodendrocyte glycoprotein antibody disease (MOG-AD). In addition to the well-characterized brain and spinal cord imaging features, important and characteristic differences in the radiologic appearance of the optic nerves in these disorders are being described, and magnetic resonance imaging (MRI) of the optic nerves is becoming an essential tool in the differential diagnosis of optic neuritis. Whereas typical demyelinating optic neuritis is a relatively mild and self-limited disease, atypical optic neuritis in NMO and MOG-AD is potentially much more vision-threatening and merits a different treatment approach. Thus, differentiation based on MRI features may be particularly important during the first attack of optic neuritis, when antibody status is not yet known. This review discusses the optic nerve imaging in the major demyelinating disorders with an emphasis on clinically relevant differences that can help clinicians assess and manage these important neuro-ophthalmic disorders. It also reviews the utility of optic nerve MRI as a prognostic indicator in acute optic neuritis.
Gu P, Fan T, Wong SSC, Pan Z, Tai WL, Chung SK, Cheung CW. Central Endothelin-1 Confers Analgesia by Triggering Spinal Neuronal Histone Deacetylase 5 (HDAC5) Nuclear Exclusion in Peripheral Neuropathic Pain in Mice. J Pain 2021;22(4):454-471.Abstract
The rationale of spinal administration of endothelin-1(ET-1) mediated anti-nociceptive effect has not been elucidated. ET-1 is reported to promote nuclear effluxion of histone deacetylase 5 (HDAC5) in myocytes, and spinal HDAC5 is implicated in modulation of pain processing. In this study, we aimed to investigate whether central ET-1 plays an anti-nociceptive role by facilitating spinal HDAC5 nuclear shuttling under neuropathic pain. Here, we demonstrate that upregulating spinal ET-1 attenuated the nociception induced by partial sciatic nerve ligation surgery and this analgesic effect mediated by ET-1 was attenuated by intrathecal injection of endothelin A receptor selective inhibitor (BQ123) or by blocking the exportation of nuclear HDAC5 by adeno-associated viruses targeting neuronal HDAC5 (AVV-HDAC5 S259/498A Mutant). Notably, ET-1 administration increased spinal glutamate acid decarboxylases (GAD65/67) expression via initiating HDAC5 nuclear exportation and increased the acetylation of histone 3 at lysine 9 (Acetyl-H3K9) in the promotor regions of spinal Gad1 and Gad2 genes. This was reversed by blocking endothelin A receptor function or by inhibiting the spinal neuronal nuclear exportation of HDAC5. Therefore, inducing spinal GABAergic neuronal HDAC5 nuclear exportation may be a novel therapeutic approach for managing neuropathic pain. PERSPECTIVE: Neuropathic pain is intractable in a clinical setting, and epigenetic regulation is considered to contribute to this processing. Characterizing the anti-nociceptive effect of ET-1 and investigating the associated epigenetic mechanisms in animal models may lead to the development of new therapeutic strategies and targets for treating neuropathic pain.
Lehky T, Joseph R, Toro C, Wu T, Van Ryzin C, Gropman A, Facio FM, Webb BD, Jabs EW, Barry BS, Engle EC, Collins FS, Manoli I, Manoli I. Differentiating Moebius syndrome and other congenital facial weakness disorders with electrodiagnostic studies. Muscle Nerve 2021;63(4):516-524.Abstract
INTRODUCTION: Congenital facial weakness (CFW) can result from facial nerve paresis with or without other cranial nerve and systemic involvement, or generalized neuropathic and myopathic disorders. Moebius syndrome is one type of CFW. In this study we explored the utility of electrodiagnostic studies (EDx) in the evaluation of individuals with CFW. METHODS: Forty-three subjects enrolled prospectively into a dedicated clinical protocol and had EDx evaluations, including blink reflex and facial and peripheral nerve conduction studies, with optional needle electromyography. RESULTS: MBS and hereditary congenital facial paresis (HCFP) subjects had low-amplitude cranial nerve 7 responses without other neuropathic or myopathic findings. Carriers of specific pathogenic variants in TUBB3 had, in addition, a generalized sensorimotor axonal polyneuropathy with demyelinating features. Myopathic findings were detected in individuals with Carey-Fineman-Ziter syndrome, myotonic dystrophy, other undefined myopathies, or CFW with arthrogryposis, ophthalmoplegia, and other system involvement. DISCUSSION: EDx in CFW subjects can assist in characterizing the underlying pathogenesis, as well as guide diagnosis and genetic counseling.
Sharif F, Tayebi B, Buzsáki G, Royer S, Fernandez-Ruiz A. Subcircuits of Deep and Superficial CA1 Place Cells Support Efficient Spatial Coding across Heterogeneous Environments. Neuron 2021;109(2):363-376.e6.Abstract
The hippocampus is thought to guide navigation by forming a cognitive map of space. Different environments differ in geometry and the availability of cues that can be used for navigation. Although several spatial coding mechanisms are known to coexist in the hippocampus, how they are influenced by various environmental features is not well understood. To address this issue, we examined the spatial coding characteristics of hippocampal neurons in mice and rats navigating in different environments. We found that CA1 place cells located in the superficial sublayer were more active in cue-poor environments and preferentially used a firing rate code driven by intra-hippocampal inputs. In contrast, place cells located in the deep sublayer were more active in cue-rich environments and used a phase code driven by entorhinal inputs. Switching between these two spatial coding modes was supported by the interaction between excitatory gamma inputs and local inhibition.
Wladis EJ, Aakalu VK, Sobel RK, McCulley TJ, Foster JA, Tao JP, Freitag SK, Yen MT. Interventions for Indirect Traumatic Optic Neuropathy: A Report by the American Academy of Ophthalmology. Ophthalmology 2021;128(6):928-937.Abstract
PURPOSE: To review the literature on the efficacy and safety of medical and surgical interventions for indirect traumatic optic neuropathy (TON), defined as injury to the nerve that occurs distal to the optic nerve head. METHODS: A literature search was conducted on October 22, 2019, and updated on April 8, 2020, in the PubMed database for English language original research that assessed the effect of various interventions for indirect TON. One hundred seventy-two articles were identified; 41 met the inclusion criteria outlined for assessment and were selected for full-text review and abstraction. On full-text review, a total of 32 studies met all of the study criteria and were included in the analysis. RESULTS: No study met criteria for level I evidence. Seven studies (1 level II study and 6 level III studies) explored corticosteroid therapy that did not have uniformly better outcomes than observation. Twenty studies (3 level II studies and 17 level III studies) assessed optic canal decompression and the use of corticosteroids. Although visual improvement was noted after decompression, studies that directly compared surgery with medical therapy did not report uniformly improved outcomes after decompression. Four studies (1 level II study and 3 level III studies) evaluated the use of erythropoietin. Although initial studies demonstrated benefit, a direct comparison of its use with observation and corticosteroids failed to confirm the usefulness of this medication. One study (level II) documented visual improvement with levodopa plus carbidopa. Complication rates were variable with all of these interventions. Pharmacologic interventions generally were associated with few complications, whereas optical canal decompression carried risks of serious side effects, including hemorrhages and cerebrospinal fluid leakage. CONCLUSIONS: Despite reports of visual improvement with corticosteroids, optic canal decompression, and medical therapy for indirect TON, the weight of published evidence does not demonstrate a consistent benefit for any of these interventions. In summary, no consensus exists from studies published to date on a preferred treatment for TON. Treatment strategies should be customized for each individual patient. More definitive treatment trials will be needed to identify optimal treatment strategies for indirect TON.
Waldman AT, Benson L, Sollee JR, Lavery AM, Liu GW, Green AJ, Waubant E, Heidary G, Conger D, Graves J, Greenberg B. Interocular Difference in Retinal Nerve Fiber Layer Thickness Predicts Optic Neuritis in Pediatric-Onset Multiple Sclerosis. J Neuroophthalmol 2021;41(4):469-475.Abstract
BACKGROUND: Optical coherence tomography (OCT) is capable of quantifying retinal damage. Defining the extent of anterior visual pathway injury is important in multiple sclerosis (MS) as a way to document evidence of prior disease, including subclinical injury, and setting a baseline for patients early in the course of disease. Retinal nerve fiber layer (RNFL) thickness is typically classified as low if values fall outside of a predefined range for a healthy population. In adults, an interocular difference (IOD) in RNFL thickness greater than 5 μm identified a history of unilateral optic neuritis (ON). Through our PERCEPTION (PEdiatric Research Collaboration ExPloring Tests in Ocular Neuroimmunology) study, we explored whether RNFL IOD informs on remote ON in a multicenter pediatric-onset MS (POMS) cohort. METHODS: POMS (defined using consensus criteria and first attack <18 years) patients were recruited from 4 academic centers. A clinical history of ON (>6 months prior to an OCT scan) was confirmed by medical record review. RNFL thickness was measured on Spectralis machines (Heidelberg, Germany). Using a cohort of healthy controls from our centers tested on the same machines, RNFL thickness <86 μm (<2 SDs below the mean) was defined as abnormal. Based on previously published findings in adults, an RNFL IOD >5 μm was defined as abnormal. The proportions of POMS participants with RNFL thinning (<86 μm) and abnormal IOD (>5 μm) were calculated. Logistic regression was used to determine whether IOD was associated with remote ON. RESULTS: A total of 157 participants with POMS (mean age 15.2 years, SD 3.2; 67 [43%] with remote ON) were enrolled. RNFL thinning occurred in 45 of 90 (50%) ON eyes and 24 of 224 (11%) non-ON eyes. An IOD >5 μm was associated with a history of remote ON (P < 0.001). An IOD >5 μm occurred in 62 participants, 40 (65%) with remote ON. Among 33 participants with remote ON but normal RNFL values (≥86 μm in both eyes), 14 (42%) were confirmed to have ON by IOD criteria (>5 μm). CONCLUSIONS: In POMS, the diagnostic yield of OCT in confirming remote ON is enhanced by considering RNFL IOD, especially for those patients with RNFL thickness for each eye in the normal range. An IOD >5 μm in patients with previous visual symptoms suggests a history of remote ON.
Caton MT, Zamani AA, Du R, Prasad S. Optic Neuropathy Due to Compression by an Ectatic Internal Carotid Artery Within the Orbital Apex. J Neuroophthalmol 2021;41(1):e103-e104.Abstract
ABSTRACT: Neurovascular compression is a rare but potentially treatable cause of optic neuropathy. Although incidental contact of the cisternal optic nerve and internal carotid artery (ICA) is common, compressive optic neuropathy occurring within the orbital apex has not been comprehensively described. We report a case of intra-orbital and intracanalicular optic nerve compression due to an ectatic ICA in a patient with congenital absence of the contralateral ICA. This report describes the complementary roles of advanced neuroimaging and neuro-ophthalmologic examination in rendering the diagnosis.
Rossin EJ, Gilbert AL, Koen N, Leslie-Mazwi TM, Cunnane ME, Rizzo JF. Site of Origin of the Ophthalmic Artery Influences the Risk for Retinal Versus Cerebral Embolic Events. J Neuroophthalmol 2021;41(1):24-28.Abstract
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.
Webb LM, Chen JJ, Aksamit AJ, Bhattacharyya S, Chwalisz BK, Balaban D, Manzano GS, Ali AS, Lord J, Clardy SL, Samudralwar RD, Mao-Draayer Y, Garrity JA, Bhatti TM, Turner LE, Flanagan EP. A multi-center case series of sarcoid optic neuropathy. J Neurol Sci 2020;:117282.Abstract
OBJECTIVE: The diagnosis of sarcoid optic neuropathy is time-sensitive, as delayed treatment risks irreversible vision loss. We sought to analyze its characteristics and outcomes. METHODS: We performed a multi-center retrospective study of sarcoid optic neuropathy among 5 USA medical centers. Inclusion criteria were: 1) clinical optic neuropathy; 2) optic nerve/sheath enhancement on neuroimaging; 3) pathological confirmation of systemic or nervous system sarcoidosis. RESULTS: Fifty-one patients were included. The median onset age of sarcoid optic neuropathy was 50 years (range, 17-70 years) and 71% were female. The median visual acuity at nadir in the most affected eye was 20/80 (range, 20/20 to no-light-perception). Thirty-four of 50 (68%) patients had radiologic evidence of other nervous system involvement and 20 (39%) patients had symptoms/signs of other cranial nerve dysfunction. Cerebrospinal fluid analysis revealed an elevated white blood cell count in 22 of 31 (71%) patients (median: 14/μL; range: 1-643/μL). Pathologic confirmation of sarcoidosis was by biopsy of systemic/pulmonary site, 34 (67%); optic nerve/sheath, 9 (18%); or other nervous system region, 8 (16%). Forty patients improved with treatment (78%), 98% receiving corticosteroids and 65% receiving steroid-sparing immunosuppressants, yet 11/46 patients (24%) had a visual acuity of 20/200 or worse at last follow-up. CONCLUSIONS: Sarcoid optic neuropathy frequently occurs with other clinical and radiologic abnormalities caused by neurosarcoidosis and diagnostic confirmation occasionally requires optic nerve/sheath biopsy. Improvement with treatment is common but most patients have some residual visual disability. Improved recognition and a more expeditious diagnosis and treatment may spare patients from permanent vision loss.
Tisdale AK, Chwalisz BK. Neuro-ophthalmic manifestations of coronavirus disease 19. Curr Opin Ophthalmol 2020;31(6):489-494.Abstract
PURPOSE OF REVIEW: To provide a summary of the neuro-ophthalmic manifestations of coronavirus disease 19 (COVID-19), documented in the literature thus far. RECENT FINDINGS: A small but growing literature documents cases of new onset neuro-ophthalmic disease, in the setting of COVID-19 infection. Patients with COVID-19 have experienced acute onset vision loss, optic neuritis, cranial neuropathies, and Miller Fisher syndrome. In addition, COVID-19 increases the risk of cerebrovascular diseases that can impact the visual system. SUMMARY: The literature on COVID-19 continues to evolve. Although COVID-19 primarily impacts the respiratory system, there are several reports of new onset neuro-ophthalmic conditions in COVID-infected patients. When patients present with new onset neuro-ophthalmic issues, COVID-19 should be kept on the differential. Testing for COVID-19 should be considered, especially when fever or respiratory symptoms are also present. When screening general patients for COVID-19-associated symptoms, frontline physicians can consider including questions about diplopia, eye pain, pain with extraocular movements, decreased vision, gait issues, and other neurologic symptoms. The presence of these symptoms may increase the overall probability of viral infection, especially when fever or respiratory symptoms are present. More research is needed to establish a causal relationship between COVID-19 and neuro-ophthalmic disease, and better understand pathogenesis.
Douglas VP, Douglas KA, Cestari DM. Optic nerve sheath meningioma. Curr Opin Ophthalmol 2020;31(6):455-461.Abstract
PURPOSE OF REVIEW: Optic nerve sheath meningiomas (ONSMs) are rare benign tumors of the anterior visual pathway which present with slowly progressive and painless vision loss and account for approximately 2% of all orbital tumors. This article provides an overview as well as an update on the ONSMs with regards to cause, epidemiology, clinical presentation, diagnosis, and management in adults and pediatric population. RECENT FINDINGS: The clinical presentation and prognosis of ONSMs can vary and largely depend on the location of tumor as well as the histologic type. Overall, the diagnosis is based on clinical presentation, examination, and neuroimaging findings. Nevertheless, delays in diagnosis or misdiagnosis are not uncommon and can result in higher morbidity rates. Recent advances in diagnostic as well as more effective and less-invasive treatment options are discussed in this review. SUMMARY: ONSMs are a rare cause of slowly progressive and inexorable visual loss. Although ONSM diagnosis depends on the characteristic clinical and radiologic findings, prompt diagnosis, and appropriate management is critical for favorable visual outcomes. Thus, current focus is optimizing diagnostic as well-treatment methods for patients with ONSMs.
Truong-Le M, Chwalisz B. Antibody Testing in Atypical Optic Neuritis. Semin Ophthalmol 2020;:1-9.Abstract
Optic neuritis (ON) is a common manifestation of central nervous system demyelinating disorders such as multiple sclerosis (MS). The last two decades have seen increasing recognition of atypical optic neuritis syndromes, driven in large part by characterization of demyelinating diseases associated with antibodies to aquaporin 4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG). Given their increased importance in the workup of ON, familiarity with serological tests for ON has become essential for ophthalmologists. This review will discuss technological aspects, performance, and clinical implications of serological tests for atypical ON.
Redler Y, Levy M. Rodent Models of Optic Neuritis. Front Neurol 2020;11:580951.Abstract
Optic neuritis (ON) is an inflammatory attack of the optic nerve that leads to visual disability. It is the most common optic neuropathy affecting healthy young adults, most commonly women aged 20-45 years. It can be idiopathic and monophasic or as part of a neurologic disease such as multiple sclerosis with recurrence and cumulative damage. Currently, there is no therapy to repair the damage from optic neuritis. Animal models are an essential tool for the understanding of the pathogenesis of optic neuritis and for the development of potential treatment strategies. Experimental autoimmune encephalomyelitis (EAE) is the most commonly used experimental rodent model for human autoimmune inflammatory demyelinating diseases of the central nervous system (CNS). In this review, we discuss the latest rodent models regarding optic neuritis, focusing on EAE model, and on its recent achievements and developments.

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