Secondary Logo

Journal Logo


The Eye Is a Window to Systemic and Neuro-Ophthalmic Diseases

Mortensen, Peter W. MD; Wong, Tien Y. MD, PhD†,‡; Milea, Dan MD, PhD†,§; Lee, Andrew G. MD∗,¶,||,∗∗,††,‡‡

Author Information
Asia-Pacific Journal of Ophthalmology: March-April 2022 - Volume 11 - Issue 2 - p 91-93
doi: 10.1097/APO.0000000000000531
  • Open

Ocular involvement is a common and well-known presenting or defining manifestation of many important systemic and neuro-ophthalmic diseases, including multiple vascular, rheumatologic, neoplastic, degenerative, inflammatory, and infectious diseases. Thus, ophthalmologists should be aware of the close relationship between various systemic diseases and their ophthalmic and neuro-ophthalmic manifestations.

This special issue of the journal will highlight and review some of the new and interesting ophthalmic and neuro-ophthalmic presentations of vascular disease. Systemic diseases are typically associated with multiple risk factors, including age, smoking, diet, exercise, and chronic inflammation. One of the most common diseases of the eye, age-related macular degeneration (AMD), is associated with many of these same risk factors,1 consistent with an underlying “common soil” hypothesis. New and emerging information have implicated an increased incidence of cardiovascular complications (eg, myocardial infarction and stroke) in patients with AMD.2 Hence, management of underlying modifiable risk factors (eg, smoking, diet) could presumably slow the incidence or progression of both AMD and cardiovascular diseases. In this issue, Mauschitz et al3 discuss the many studies that support this “common soil” hypothesis. Other pigmentary maculopathies can mimic AMD, and Mukhopadhyay et al4 discuss the relationship between the interstitial cystitis medication pentosan polysulfate and its association with pigmentary maculopathy.

In addition, advancements in artificial intelligence (AI), machine learning, and deep learning (DL) have allowed for the use of AI to detect systemic diseases across many fields of medicine. Ophthalmology is uniquely positioned to utilize the data from multiple diagnostic tests, including automated perimetry, optical coherence tomography, and fundus photography, for further development of AI algorithms that would help identify various ocular pathologies. Specifically, major studies have already demonstrated that AI possesses the capability of detecting multiple ophthalmologic diseases, including glaucoma,5 AMD,6 and diabetic retinopathy (DR).7 More recently, DL methods have been successfully applied to neuro-ophthalmology for detection of both afferent and efferent pathways dysfunction, as described in the article by Leong et al8 in this current issue.

In the coming years, AI will likely play not only a larger role in detecting these diseases but perhaps will even help provide information on the likelihood of common systemic diseases, such as hypertension, stroke, dementia, and heart disease. Multiple studies have shown exciting associations. Chen et al9 demonstrated the utility of AI and optical coherence tomography in screening for anemia. Tian et al10 showed that retinal images can help distinguish patients with Alzheimer disease from healthy controls. Lee et al11 noted that DL helped identify a strong association between neurofibrillary tangles and development of dementia in patients with significant amyloid plaques from neuropathology specimens. Additional systemic disease associations are discussed further by Peng et al12 in this special issue. It may be that AI will help elucidate similar findings from the ophthalmologic examination that might predict which patients are at future risk of cognitive impairment from Alzheimer disease. As noted by Yuan and Lee13 in this issue, retinal biomarkers may eventually be able to even screen for and monitor the progression of Alzheimer disease. Likewise, Tan et al14 discuss, in this issue, how DL may help prognosticate systemic complications of hypertension via noninvasive retinal imaging modalities such as optical coherence tomography angiography and adaptive optics.

Diabetes mellitus has multiple systemic and ophthalmic complications, which are frequently subdivided into macrovascular and microvascular manifestations. DR is the most frequent complication of diabetes and is considered one of the many microvascular complications of diabetes mellitus. However, further advances in our understanding of the disease have demonstrated the role of neurodegeneration in the pathogenesis of DR. In this issue, Simo et al15 discuss the neurodegenerative processes associated with DR and the implications for future therapies.

Transient visual loss (TVL) is often a harbinger of underlying ischemic risk factors and impending cerebral infarction.16 The workup for TVL can be quite variable across different providers and geographic locations, and in this issue, Mbonde et al17 will discuss current guidelines in the management of patients with amaurosis fugax and transient ischemic attacks. TVL may also occur in the setting of giant cell arteritis, Takayasu arteritis, and other vasculitides. The diagnosis of giant cell arteritis can often be challenging, even after a temporal artery biopsy. Thus, many new laboratory and imaging tests are being used for the diagnosis of this disease, and a thorough understanding of the new diagnostic tools for giant cell arteritis can allow for more accurate diagnosis of this disease. Likewise, Takayasu arteritis also presents similar challenges during the diagnostic workup. These 2 large vessel vasculitides have a significant degree of overlap, and one diagnostic dilemma is distinguishing between these similar disease processes. In this issue, Lee et al18 discuss the overlap and the distinguishing epidemiologic, pathologic, and histologic features and differences in management for these large vessels vasculitides.

Vision loss of greater duration, and permanent vision loss, is observed in optic neuritis secondary to both neuromyelitis optic spectrum diseases (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). In optic neuritis associated with multiple sclerosis, steroids do not significantly impact final visual acuity or visual field loss according to the Optic Neuritis Treatment Trial.19 However, optic neuritis related to NMOSD and MOGAD has a poorer visual prognosis if steroids are not administered during a flare. Furthermore, these diseases are associated with high risk of relapse, including roughly 80% of NMOSD patients in 2 to 3 years, which can then manifest with transverse myelitis, paraplegia, bladder dysfunction, and multiple neurologic sequelae.20 NMOSD is frequently associated with hypothalamic-pituitary axis dysfunction, intractable vomiting, hiccups, and altered level of consciousness. Although MS-related optic neuritis, MOGAD, and NMOSD share significant overlap in their disease presentations, the treatment for these diseases can significantly differ. In this issue, Foo et al21 present the results of their investigation related to the current approaches to optic neuritis in NMOSD and MOGAD in Singapore, a part of the world where these conditions are not uncommon.21 Interestingly, serologic testing for NMOSD and MOGAD has recently become in Singapore a routine procedure, adopted by 100% of neuro-ophthalmologists, irrespective of the clinical or radiological features of the disease. Similarly, new therapeutic patterns based on immunosuppression seem to emerge in these conditions, both at the acute and chronic stages, requiring however further international consensus, in the future underlying systemic disease process and commencement of appropriate therapies.

Severe acute respiratory syndrome coronavirus 2 is associated with multiple systemic complications. This disease itself and severe acute respiratory syndrome coronavirus 2 vaccinations have been associated with a number of ophthalmic pathologies, including infarction, cerebral venous sinus thrombosis, demyelinating disorders, optic neuropathies, and ocular motor cranial neuropathies.22 These many ophthalmic associations are reviewed further in this special issue.

Overall, ocular involvement is a hallmark of many systemic and neuro-ophthalmic diseases and is frequently indicative of disease progression. Advances in technology from AI and DL will increase our knowledge of these disease processes and may result in greater utilization of the ophthalmologic examination in the diagnosis and management not only of eye diseases but eventually systemic diseases. Lastly, vision changes—and particularly vision loss—can be a final common pathway of many systemic diseases. Ophthalmologists and vision scientists must be aware that the eye is really just one of the organs of the human body.


1. Armstrong RA, Mousavi M. Overview of risk factors for age-related macular degeneration (AMD). J Stem Cells 2015; 10:171–191.
2. McGuinness MB, Karahalios A, Finger RP, et al. Age-related macular degeneration and mortality: a systematic review and meta-analysis. Ophthalmic Epidemiol 2017; 24:141–152.
3. Mauschitz MM, Finger RP. Age-related macular degeneration and cardiovascular diseases: revisiting the common soil theory. Asia Pac J Ophthalmol (Phila) 2022; 11:
4. Mukhopadhyay C, Boyce TM, Gehrs KM, et al. Age-related macular degeneration masquerade: a review of pentosan polysulfate maculopathy and implications for clinic practice. Asia Pac J Ophthalmol (Phila) 2022; 11:
5. Mariottoni EB, Datta S, Dov D, et al. Artificial intelligence mapping of structure to function in glaucoma. Transl Vis Sci Technol 2020; 9:19.
6. Yan Q, Weeks DE, Xin H, et al. Deep-learning-based prediction of late age-related macular degeneration progression. Nat Mach Intell 2020; 2:141–150.
7. Bellemo V, Lim G, Rim TH, et al. Artificial intelligence screening for diabetic retinopathy: the real-world emerging application. Curr Diab Rep 2019; 19:72.
8. Leong YY, Vasseneix C, Finkelstein MT, et al. Artificial intelligence meets neuro-ophthalmology. Asia Pac J Ophthalmol (Phila) 2022; 11:
9. Chen Z, Mo Y, Ouyang P, et al. Retinal vessel optical coherence tomography images for anemia screening. Med Biol Eng Comput 2019; 57:953–966.
10. Tian J, Smith G, Guo H, et al. Modular machine learning for Alzheimer's disease classification from retinal vasculature. Sci Rep 2021; 11:238.
11. Lee CS, Latimer CS, Henriksen JC, et al. Application of deep learning to understand resilience to Alzheimer's disease pathology. Brain Pathol 2021; 31:e12974.
12. Peng Q, Tseng RMWW, Tham YC, et al. Detection of systemic diseases from ocular images using artificial intelligence: a systemic review. Asia Pac J Ophthalmol (Phila) 2022; 11:
13. Yuan A, Lee CS. Retinal biomarkers for Alzheimer disease: the facts and the future. Asia Pac J Ophthalmol (Phila) 2022; 11:
14. Tan W, Yao X, Le TT, et al. The new era of retinal imaging in hypertensive patients. Asia Pac J Ophthalmol (Phila) 2022; 11:
15. Simo R, Simo-Servat O, Bogdanov P, et al. Diabetic retinopathy: role of neurodegeneration and therapeutic perspectives. Asia Pac J Ophthalmol (Phila) 2022; 11:
16. Kvickstrom P, Lindblom B, Bergstrom G, et al. Amaurosis fugax: risk factors and prevalence of significant carotid stenosis. Clin Ophthalmol Auckl N Z 2016; 10:2165–2170.
17. Mbonde AA, O’Carroll CB, Dulamea OA, et al. Current guidelines on management of amaurosis fugax and transient ischemic attacks. Asia Pac J Ophthalmol (Phila) 2022; 11:
18. Dhanani U, Zhao MY, Charoenkijkajorn C, et al. Large vessel vasculitis in ophthalmology: giant cell arteritis and Takayasu arteritis. Asia Pac J Ophthalmol (Phila) 2022; 11:
19. Beck RW, Cleary PA, Anderson MM Jr, et al. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. N Engl J Med 1992; 326:581–588.
20. Jiwon Oh, Michael Levy. Neuromyelitis optica: an antibody-mediated disorder of the central nervous system. Neurol Res Int 2012; 2012:460825.
21. Foo R, Yau C, Singhal S, et al. Optic neuritis in the era of NMOSD and MOGAD: a survey of practice patterns in Singapore. Asia Pac J Ophthalmol (Phila) 2022; 11:
22. Petzold A. Neuro-ophthalmic implications of SARS-CoV-2 related infection and vaccination. Asia Pac J Ophthalmol (Phila) 2022; 11:
Copyright © 2022 Asia-Pacific Academy of Ophthalmology. Published by Wolters Kluwer Health, Inc. on behalf of the Asia-Pacific Academy of Ophthalmology.