48
QUESTION
I SAW SOME RETINAL NEOVASCULARIZATION BUT MY PATIENT DOES NOT HAVE DIABETES, SO WHAT ELSE CAN IT BE?
Brian E. Goldhagen, MD
While diabetes is certainly the most common cause of retinal neovascularization, it is also important to consider other causes when evaluating a patient, particularly when the clinical picture does not fit. Retinal neovascularization occurs when new abnormal blood vessels proliferate from preexisting retinal vessels due to a pro-angiogenic stimulus, the source of which is often ischemia. The detection and accurate diagnosis of this retinal finding is imperative. Untreated retinal neovascularization has the potential to lead to devastating ocular complications, including tractional retinal detachment and neovascular glaucoma due to associated anterior segment neovascularization, which can result in irreversible vision loss. Understanding the underlying cause for the neovascularization is not only important in attempting to prevent these ocular complications, but also in the management or possibly even the diagnosis of an underlying systemic condition and thus the protection of the fellow eye. Perhaps the patient actually does have diabetes and it simply is not diagnosed yet.
There is a rather large differential diagnosis for retinal neovascularization, which may seem overwhelming at first (Table 48-1).1 When I see retinal neovascularization, I begin by attempting to further assess and describe what it is that I am seeing on exam. What does the neovascularization look like and where is it located? Is it located peripherally or closer to the posterior pole, perhaps even involving the optic nerve? I also find it helpful to remember that neovascularization is almost never an isolated ocular exam finding; therefore, I pay particular attention to any other abnormal findings that may be present including their distribution. I also take note of any inflammation or vasculitis that may be present. Finally, I make sure to pay attention to the actual patient presenting before me including the presenting symptoms, age, gender, and any pertinent past medical or family history.
Table 48-1
Causes of Retinal Neovascularization
| Neovascularization of the Posterior Pole/Mid-Periphery | Neovascularization of the Retinal Periphery |
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I generally try to think of the diseases that cause retinal neovascularization as belonging to 1 of 2 basic groups: those with the neovascularization found at the posterior pole and mid-periphery and those with more peripheral neovascularization. This second group I further subdivide into those with evidence of inflammation or vasculitis and those without.
Retinal Neovascularization at the Posterior Pole and Mid-Periphery
When I see neovascularization and findings closer to the posterior pole, I typically begin thinking of cardiovascular-related ocular diseases including proliferative diabetic retinopathy, CRVO, BRVO, and in some cases, OIS. Although retinal artery occlusion is also related to cardiovascular disease, it rarely manifests with retinal neovascularization, but rather, more commonly with anterior segment neovascularization.
Funduscopic examination in diabetes, vein occlusion, and OIS often include microaneurysms, dot-blot hemorrhages, cotton-wool spots, vascular attenuation, and/or macular edema. Lipid exudates are more commonly seen in diabetic retinopathy, whereas flame hemorrhages are more common in vein occlusions. The laterality of retinal findings is helpful in differentiating these diseases, with diabetic retinopathy typically having bilateral findings as compared to both vein occlusion and OIS, which are usually unilateral.
In distinguishing vein occlusions from OIS, OIS typically presents with hemorrhages located in the mid-periphery and periphery and veins that are described as dilated but not tortuous.2 Carotid imaging should be ordered in any patient where OIS is suspected. CRVO typically presents with unilateral vision loss in patients over 60 years of age with a known history of hypertension. Atypical presentations should prompt further investigation with particular attention to hypercoagulable states and risk factors for thrombosis, including a review of the patient’s medical history, family history, and medications, as well as laboratory studies.
Radiation retinopathy also manifests with posterior findings and may have retinal neovascularization. Ophthalmoscopically, it looks very similar to diabetic retinopathy except that microaneurysms are rarely seen. On further questioning, these patients will typically endorse having a recent history, usually within the past few years, of radiation treatment.
Peripheral Retinal Neovascularization
When the retinal neovascularization and other retinal findings are more peripheral in location, I pay particular attention to evidence of vasculitis or inflammation. If these are not present, I begin thinking about hemoglobinopathies, ROP, familial exudative vitreoretinopathy (FEVR), and hyperviscosity syndromes. Conditions resulting from exogenous embolization, such as talc retinopathy, may also be considered when multiple small emboli are present. Such findings should prompt further questioning about intravenous drug abuse.
The hemoglobinopathies include sickle cell trait (AS), sickle cell disease (SS), sickle cell hemoglobin C disease (SC), hemoglobin C trait (AC), and sickle beta thalassemia (Sβthal), of which SC and Sβthal are the most likely to have retinal disease.3 Often, patients are unaware that they are carriers when they do not have systemic manifestations, and as such, a discussion about lab work to confirm the diagnosis as well as possible genetic counseling may be indicated. Like other peripheral causes of retinal neovascularization, dot-blot hemorrhages are an uncommon finding. Instead, oval salmon patch hemorrhages, glistening iridescent spots, and hyperpigmented black sunbursts are typically seen. The neovascularization has a sea fan appearance and is typically seen at the border of perfused and nonperfused retina.
While ROP and FEVR look rather distinct from the other retinal diseases, and typically initially present in younger patients, they look quite similar to one another.4 Funduscopic features include bilateral peripheral nonperfusion with adjacent arteriovenous shunts, microaneurysms, and temporal macular dragging. The fundamental difference between these 2 entities lies in the history; patients with FEVR often have a family history of similar retinal findings and are typically born full-term without a history of supplemental oxygen. Although incontinentia pigmenti is also on the differential for retinal neovascularization in younger individuals, it is typically easily distinguishable based on its accompanying characteristic skin and nervous system abnormalities.
Hyperviscosity syndromes may also manifest with retinal neovascularization, the most common of which is Waldenstrom macroglobulinemia. Funduscopically, this looks similar to bilateral CRVO; however, the presence of serous retinal detachments without significant intraretinal fluid should raise suspicion for this as the causative etiology. That being said, patients with Waldenstrom macroglobulinemia rarely initially present with ocular manifestations, and a thorough review of the patient’s medical history and review of systems are useful clues to establishing the diagnosis. Chronic myeloid leukemia is another hyperviscosity syndrome that may lead to peripheral retinal neovascularization.
Retinal Neovascularization With Inflammation/Vasculitis
When I see neovascularization present in a patient with ocular inflammation or vasculitis, other types of eye conditions come to mind. Intermediate uveitis is typically on the top of my differential, particularly pars planitis and sarcoidosis-related uveitis. Pars planitis is an idiopathic type of intermediate uveitis characterized by snowballs and snowbanks; however, these findings may be present in sarcoidosis as well. It is along the inferior snowbanks that retinal neovascularization, with the potential to lead to vitreous hemorrhage or retinal detachment, is most commonly seen. Both pars planitis and sarcoidosis typically have bilateral findings and may also demonstrate macular edema and periphlebitis. The periphlebitis classically appears like candle wax drippings in sarcoidosis. Sarcoidosis may also present as a panuveitis with chorioretinal lesions and/or keratic precipitates. Obtaining a chest X-ray or blood test for angiotensin-converting enzyme may aid in the diagnosis. Chronic retinal vasculitis of any etiology may also lead to retinal neovascularization.
When periphlebitis is present with peripheral neovascularization, but without evidence of intermediate uveitis, I would start considering other conditions, including Eales’ disease. This idiopathic occlusive perivasculitis most commonly affects otherwise healthy young men and features peripheral inflammatory BRVOs and venous sheathing.5 Patients with Eales’ disease classically present with an acute onset of unilateral blurred vision and floaters secondary to vitreous hemorrhage from peripheral neovascularization. Eales’ disease is a diagnosis of exclusion, and other causes of vasocclusive disease should first be considered. These include those diseases with peripheral neovascularization that also have systemic findings, including lupus, Takayasu arteritis (aortic arch syndrome), Susac syndrome, and syphilis.
What If You Are Still Unsure About What Is Causing the Retinal Neovascularization?
If I am still uncertain as to the cause of the retinal neovascularization after careful history taking and a complete ocular examination, I usually will attempt to better understand the retinal vasculature through fluorescein angiography. Additional clues may be elucidated through a full physical exam as well as lab work directed by pertinent findings. Involving the patient’s internist may also be useful, especially because understanding the reason for the neovascularization may be important in the management or possibly even the diagnosis of an underlying systemic condition.
References
1. Jampol LM, Ebroon DA, Goldbaum MH. Peripheral proliferative retinopathies: an update on angiogenesis, etiologies and management. Surv Ophthalmol. 1994;38(6):519-540.
2. Brown GC, Magargal LE. The ocular ischemic syndrome. Clinical, fluorescein angiographic and carotid angiographic features. Int Ophthalmol. 1988;11(4):239-251.
3. Goldberg MF. Natural history of untreated proliferative sickle retinopathy. Arch Ophthalmol. 1971;85(4):428-437.
4. Canny CL, Oliver GL. Fluorescein angiographic findings in familial exudative vitreoretinopathy. Arch Ophthalmol. 1976;94(7):1114-1120.
5. Biswas J, Sharma T, Gopal L, Madhavan HN, Sulochana KN, Ramakrishnan S. Eales disease—an update. Surv Ophthalmol. 2002;47(3):197-214.
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