Ophthalmologists in ideal position to recognize signs of systemic disease
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Systemic diseases often first reveal themselves as ocular symptoms, so the ability of an ophthalmologist to recognize when a symptom is a sign of something more serious is an important skill to acquire.
The eye is comprised of many different tissues, which makes it susceptible to a variety of systemic diseases. A significant number of systemic diseases are known to present with ocular symptoms, such as diabetes, rheumatic diseases, vascular diseases or diseases involving the nervous system, according to a study published in the Journal of Ophthalmology.
Ophthalmologists are often the first to diagnose these systemic diseases, as ocular manifestations of the disease can be the presenting symptoms, according to OSN Cornea/External Disease Board Member Preeya K. Gupta, MD.
Ophthalmologists who contribute to an early diagnosis can be instrumental in implementing early treatment that can inhibit progression if a patient’s medical history and symptoms are properly taken into consideration, she said.
Source: Preeya K. Gupta, MD
Recognizing the signs of systemic disease during the ophthalmic exam can save a patient’s life.
“I had a patient who came in with severe dry eye, and we completed Sjögren’s testing, which she did have. But when I examined her, she had swelling of her parotid glands, which turned out to be an undiagnosed lymphoma,” Gupta said.
The cancer was subsequently diagnosed, and treatment was expedited.
“She came in for her dry eye assessment, and that ended up becoming a lifesaving visit,” Gupta said.
Complete a full evaluation
When a patient presents with complaints of dry eye or meibomian gland dysfunction, it is important to inquire about systemic symptoms during the ophthalmic examination. It can be surprising how often patients have systemic disease that contributes to their ocular symptoms, Gupta said.
Despite the associations between systemic diseases and ocular manifestations, patients are not always fully evaluated. Nancy S. Harrison, MD, presented a study at the 2019 North American Young Rheumatology Investigator Forum that found only 17% of 1,095 patients with uveitis underwent evaluation for systemic disease or were diagnosed with a systemic autoimmune disease when they received ophthalmic care. Yet, according to a study published in American Family Physician, uveitis is caused by systemic disease in 30% to 45% of cases.
Warning signs
Ophthalmologists should be aware of the warning signs of systemic disease, OSN Cornea/External Disease Section Editor Elizabeth Yeu, MD, said.
“First and foremost, anytime you see pathology in the ocular surface, including the cornea, sclera and/or episclera, we as clinicians should be looking for a systemic disease that could be the underlying etiology, especially if there is an apparent inflammatory component,” Yeu said.
Autoimmune disorders commonly result in ocular manifestations such as keratitis, scleritis, keratoconjunctivitis sicca, episcleritis, uveitis and optic neuritis, she said.
“Corneal inflammation could fall into the ‘bucket’ of autoimmune diseases such as lupus, rheumatoid arthritis, sarcoidosis or tuberculosis,” she said.
It is important for ophthalmologists to be able to identify symptomatic outliers, Yeu said. For instance, a premenopausal patient in her 40s with significant meibomian gland dropout and significant staining disproportionate to her age group who has failed multiple therapies and should not have an androgenic source for her dry eye is a patient “who should absolutely be considered for a systemic disease,” she said.
“Anyone who is younger than 55 who has significant disease with significant staining and is matched with symptomatology, I’m definitely checking them for an inflammatory condition and Sjögren’s syndrome,” Yeu said.
Diabetes is far reaching
Diabetes is an often underrecognized source of ocular surface disease, Gupta said. Patients with diabetes are prone to dry eye and breakdown of their corneal surface, and over time, depending on the diabetes severity, corneas can become neurotrophic and have abnormal manifestations.
Patients with diabetes are known to exhibit abnormalities of the corneal epithelium that can lead to corneal erosion, persistent epithelial defects or corneal ulcers. In one study, corneal abnormalities were detected in up to 73.5% of patients with diabetes.
Diabetes is also the most common disease associated with cataracts, Nick Mamalis, MD, professor of ophthalmology and director of ocular pathology at the Moran Eye Center of the University of Utah, said.
Several major epidemiologic studies have found strong evidence linking diabetes with cataracts. The Blue Mountains Eye Study and the Beaver Dam Eye Study are the two most prominent to make the connection, he said.
A 5-year follow-up examination of the Beaver Dam Eye Study found diabetes was associated with incidence of cortical and posterior subcapsular cataracts. Additionally, diabetes was associated with the progression of more minor cortical and posterior subcapsular lens opacities.
According to a study in the Journal of Ophthalmic and Vision Research, patients with diabetes are two to five times more likely to develop cataracts compared with nondiabetic patients. Development of cataracts in patients with diabetes involved three molecular mechanisms: Non-enzymatic glycation of lens proteins, oxidative stress and activated polyol pathway.
The crystalline lens is not well equipped to metabolize high blood sugar, Mamalis said. When glucose sits in the lens, the eye can experience an osmotic shift, which may lead to the development of cataracts, he said.
A patient with diabetes has a higher chance of early cataract development, in their early 40s or 50s, Mamalis said.
Diabetes is the most common systemic disease that may lead to cataracts, but collagen vascular diseases, such as arthritis or juvenile idiopathic arthritis, can lead to the formation of cataracts at a younger age as well, he said.
Retinal manifestations
Diabetes and hypertension are systemic diseases observed by specialists almost daily in clinic, said OSN Retina/Vitreous Section Editor Andrew A. Moshfeghi, MD, MBA.
Retina specialists can begin to suspect diabetes if “a solitary intraretinal hemorrhage or a microaneurysm in the macula” is observed, he said.
“If we observe arteriovenous nicking and an occasional flame-shaped intraretinal hemorrhage, then we start to consider hypertensive retinopathy and hyperlipidemia, especially if we observe silver wiring of arterioles indicating arteriosclerosis,” he said.
Hypertension and diabetes are common systemic diseases with specific symptoms that can affect the retina, but initial ocular manifestations of other systemic diseases may be less specific.
For instance, the ocular manifestations of syphilis can initially be nonspecific, but an ophthalmologist can narrow down the possibilities by ordering specialized blood tests and imaging tests to rule out causes such as tuberculosis, Moshfeghi said.
Syphilis is a common “great masquerader” in ophthalmology and can present in many ways. “Therefore, it is good to familiarize oneself with the various patterns of presentation,” Moshfeghi said.
Patients with diabetes are also at a higher risk for developing diabetic retinopathy. Researchers found in a 2016 study published in the International Journal of Retina and Vitreous that patients with diabetes who had poor glycemic control and nephropathy after 10 years with the disease were twice as likely to develop diabetic retinopathy and approximately three times more likely when the exposure was more than 20 years. Patients with HbA1c greater than 7% were more likely to develop diabetic retinopathy, placing a greater importance on glycemic control in both type 1 and type 2 diabetes.
Systemic diseases and glaucoma
Hypertension can affect the development of primary open-angle glaucoma, but other risk factors, such as family history and myopia, have more of an effect than any specific systemic disease, according to OSN Glaucoma Board Member Douglas J. Rhee, MD.
“Aging is the No. 1 risk factor for glaucoma. When you look at trabecular meshwork biology in patients with open-angle glaucoma, it looks like hyper-accelerated senescence. It’s possible systemic diseases might be accelerating the aging process,” Rhee said.
However, low-tension glaucoma can be affected by certain autoimmune vasculopathic systemic conditions, such as Raynaud’s disease or lupus.
There is not much evidence to support the theory that systemic diseases can hasten the progression of either primary open-angle glaucoma or low-tension glaucoma, Rhee said.
“Once you have glaucoma, in my opinion, there is no strong literature that shows any association with more rapid progression with systemic disease. Do people with diabetes progress worse, or faster, than people who are not diabetic? There’s not a lot of convincing evidence to say that’s the case,” he said.
Treatments may worsen symptoms
In some cases, the treatment of a systemic disease itself can negatively affect the eye. Patients with obstructive sleep apnea who use a continuous positive airway pressure (CPAP) machine and mask at night may often experience ocular manifestations, such as dry eye, and could experience worse symptoms if their CPAP use is coupled with a diagnosis of floppy eyelid syndrome.
If a CPAP mask does not have a perfect seal on a patient’s face, the forced air from the machine is driven up toward the eye. More forced air will contact the ocular surface if the patient has also been diagnosed with floppy eyelid syndrome, Yeu said.
Even with a perfect seal through the nostrils, air can still contact the eye through the nasolacrimal duct system, she said.
“It’s not just the underlying systemic disease, but the treatment of the systemic disease that can affect the ocular surface,” Yeu said.
Any patient with obstructive sleep apnea has a two to three times higher risk for developing diabetic retinopathy, proliferative diabetic retinopathy or diabetic macular edema when compared with patients without signs of obstructive sleep apnea, Albert Y. Wu, MD, PhD, FACS, told Ocular Surgery News in a 2017 interview.
Wu and colleagues conducted an analysis of 317 patients with or without obstructive sleep apnea to determine their risk for developing diabetic retinopathy or diabetic macular edema. The cohort consisted of 172 patients with severe obstructive sleep apnea, 71 with moderate obstructive sleep apnea, 53 with mild obstructive sleep apnea and 21 with no obstructive sleep apnea. Severe obstructive sleep apnea was more prevalent in patients with proliferative diabetic retinopathy when compared with patients with mild nonproliferative diabetic retinopathy or patients without diabetic retinopathy (P = .005).
However, Wu said several studies have found that obstructive sleep apnea treatments with CPAP can also lower inflammatory marker levels and possibly reduce the microvascular damage seen in patients with diabetic retinopathy with obstructive sleep apnea.
Balancing treatments
Balancing the treatment of a systemic disease requires coordinated care between ophthalmologists and primary care providers. Moshfeghi said he will treat ocular symptoms in a targeted fashion while waiting for further results of systemic disease testing. Then, if appropriate, he will integrate anti-VEGF therapy intravitreally for patients with diabetic macular edema or diabetic retinopathy.
Often, treatment of the eye is still necessary even after giving the patient the definitive treatment for the systemic disease. Continual communication with health care providers can ensure the proper handling of the disease, he said.
“Our uveitis colleagues, perhaps, have the most experience with this insofar as they are constantly seeing complex patients with multiple ocular and systemic comorbidities daily and increasingly using complex systemic treatments that require specialized blood testing to rule out systemic toxicity of these drugs,” Moshfeghi said.
Identify the whole picture
Ophthalmologists may recognize symptoms of only eye disease, which can result in missed opportunities to diagnose systemic conditions. But by recognizing the warning signs and symptoms of systemic disease, better and quicker care can be provided, Gupta said.
“There is so much opportunity for collaborative care, whether with either primary care specialists or rheumatologists, and that collaboration is really necessary to get the best out of your patients,” she said.
Understanding when certain symptoms do not “fit” a patient’s profile can lead to better diagnoses and improved care, Moshfeghi said.
“There is a big difference between some of the ocular manifestations of common diseases, such as diabetes or hypertension, and rare birds like tuberculosis and sarcoidosis. The key is to keep an open mind when seeing something that doesn’t quite fit into the patient profile,” he said. – by Robert Linnehan
Editor’s note: Read more about ocular manifestations of systemic disease treatments in OSN’s January 25, 2020, issue.
- References:
- Chang AC, et al. Retina. 2017;doi:10.1097/IAE.0000000000001848.
- Cikamatana L, et al. Eye (Lond). 2007;doi:10.1038/sj.eye.6702771.
- Harman LE, et al. Am Fam Physician. 2014;90(10):711-716.
- Javadi MA, et al. J Ophthalmic Vis Res. 2008;3(1):52-65.
- Jeganathan VSE, et al. Diabetes Care. 2008;doi:10.2337/dc08-0342.
- Klein BEK, et al. Arch Ophthalmol. 1998;doi:10.1001/archopht.116.2.219.
- Laday J. Only 17% of patients with uveitis receive systemic disease evaluation, diagnoses. www.healio.com/rheumatology/spondyloarthropathies/news/online/%7Bc1db1843-eb3c-4a0d-a1a0-f7d34cd16fe6%7D/only-17-of-patients-with-uveitis-receive-systemic-disease-evaluation-diagnoses. Published May 1, 2019. Accessed Nov. 4, 2019.
- Lima VC, et al. Int J Retina Vitreous. 2016;doi:10.1186/s40942-016-0047-6.
- Linnehan R. Patients with obstructive sleep apnea at higher risk for diabetic retinopathy. www.healio.com/ophthalmology/retina-vitreous/news/print/ocular-surgery-news/%7Bb67b0fa9-8b45-459e-93c5-cda353a5cfe7%7D/patients-with-obstructive-sleep-apnea-at-higher-risk-for-diabetic-retinopathy. Published Nov. 25, 2017. Accessed Nov. 4, 2019.
- Nowinska AK, et al. J Ophthalmol. 2018;doi:10.1155/2018/7851691.
- For more information:
- Preeya K. Gupta, MD, can be reached at Duke University, Department of Ophthalmology, Box 3802, Durham, NC 27710; email: preeya.gupta@duke.edu.
- Nick Mamalis, MD, can be reached at John Moran Eye Center, University of Utah, 65 Mario Capecchi Drive, Salt Lake City, UT 84132; email: nick.mamalis@hsc.utah.edu.
- Andrew A. Moshfeghi, MD, MBA, can be reached at USC Roski Eye Institute, Keck School of Medicine, University of Southern California, 1450 San Pablo St., 4th Floor, Los Angeles, CA 90033; email: moshfega@med.usc.edu.
- Douglas J. Rhee, MD, can be reached at Department of Ophthalmology and Visual Sciences, Case Western Reserve University School of Medicine, Euclid Ave., Mail Stop WRN5068, UHI Institute, Cleveland, OH 44106; email: dougrhee@aol.com.
- Elizabeth Yeu, MD, can be reached at Virginia Eye Consultants, 241 Corporate Blvd., Suite 210, Norfolk, VA 23502; email: eyeulin@gmail.com.
Disclosures: Gupta reports no relevant financial disclosures. Mamalis reports no relevant financial disclosures. Moshfeghi reports he is a consultant and has research grants with Novartis, Genentech and Regeneron. Rhee reports he receives research funding form Allergan, Glaukos and Ivantis; is a consultant with Aerie Pharmaceuticals, Allergan, Alcon, Ivantis, Bausch + Lomb and pH Pharma; is on the scientific advisory board for Ocular Therapeutix; and is on the speakers bureau for Bausch + Lomb, Ivantis and Aerie Pharmaceuticals. Yeu reports no relevant financial disclosures.
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