Management of Cotton-wool Spots in Retina

A review of the etiology, diagnosis, and treatment of a sometimes puzzling pathology.

Management of Cotton-wool Spots in Retina

A review of the etiology, diagnosis, and treatment of a sometimes puzzling pathology.


James Zimmerman, MD, is chief resident and Bryan D. Propes, MD, is assistant professor and vice chairman of the Department of Ophthalmology at the Naval Medical Center San Diego, CA. He reports no financial interests in any products mentioned in this article. Dr. Propes’ e-mail is The views expressed are solely the authors’ and do not represent official Department of Defense policy.

Cotton-wool spots (CWS) (Figure) are acute signs of vascular insufficiency to an area of retina. They have been described in many conditions, but only occasionally cause symptoms in patients. The most common symptoms associated with retinal CWS can include scotoma, arcuate defects, blurred vision, and amaurosis fugax.

Although they tend not to have any visual significance to the patient, CWS are typically harbingers of significant systemic disease. They also typically appear with other retinal findings and systemic diseases that cause significant symptoms and have long-term implications.


In the middle of last century, CWS were described as “soft masses of irregular shape, grayish-white appearance with fluffy margins” with a “preference for the central regions, particularly near the disk.”1

Other terms for CWS include “soft exudates” and “cottonwool patches.” Soft exudates are a misnomer; the appearance of these lesions does not occur due to fluid exudation.

Exudation of fluid can occur on fluorescein angiography, but the characteristic retinal whitening is not due to this exudation. The current preferred terminology is cotton-wool spot.

A Developing Description

Dollery2 described CWS as “a milky-white area of retina between 0.1 and 1 mm in diameter, which is usually found at the posterior pole of the fundus along the line of the main vessel groups.” He wrote that the CWS of hypertension start as gray discolorations, which become shiny white within one or two days after appearance.


Figure. Fundus photograph of the right optic disc of a patient demonstrates multiple cotton-wool spots, retinal edema, a few intraretinal hemorrhages, and lipid exudates temporal to the disc. This patient suffered from radiation retinopathy.


The Early Treatment of Diabetic Retinopathy Study Report 103 describes “soft exudates” as “localized superficial swellings in the nerve fiber layer. They are round or oval in shape, white, pale yellow-white, or grayish-white in color, and have ill-defined (feathery) edges, frequently with striations parallel to the nerve fibers.” This report created a grading system of CWS based on size.


Studies have theorized the pathophysiology of CWS by histologic section,4 microdissection,5-7 FA,8 and electron microscopy.9 The histology of CWS includes nerve fiber layer edema and corpuscles termed “cytoid bodies.”

Wolter4 used post mortem evaluation of an eye with a large visible CWS stained with silver to confirm that cytoid bodies were in fact bulb-like terminal swellings of damaged nerve fiber stumps.

Cajal previously described these terminal swellings in other parts of the nervous system. He also described the general swelling found in the nerve fiber layer of the retina surrounding cytoid bodies. He theorized the section of nerve distal to the injury quickly degenerated, while the proximal portion developed a bulb-like swelling.

Nerve and Circulatory Signs

These bulb-like swellings are the first phase of nerve regeneration in the peripheral nervous system. In the retina, the proximal nerve survives for a time but finally degenerates as well. Some of the cytoid bodies will remain and hyalinize.

Some authors have noted cytoid bodies in the periphery of lesions, and these lesions may have distinct pseudonuclei or may have none on pathology. Other authors have found with sclerotic arterioles, with loss of endothelial cells, thickened basal lamina, and atrophied smooth muscle.6

Ashton7 showed that when the retina is perfused with colloidal carbon, the capillaries within the area of the CWS fail to fill or partially fill. We can see these same capillaries in digest preparations, which make it seem that these capillaries are closed.

The capillaries surrounding the area of lost perfusion are usually dilated and can show microaneurysms. Lipohyaline material was building up in the vessel walls and occluding them.

A Model of Ischemia

Shakib and Ashton9 reported on an experimental model of ischemia using microsphere embolization of small retinal arterioles. Using electron microscopy, they showed nerve fiber swelling within 1 hour of embolization.

Histology revealed three distinct zones in each lesion. Swelling of the nerve fiber layer, related to retardation of axoplasmic flow, flanked the central area of necrosis on either side. Over time, backup of organelles and vesicles continued, and structural elements began to proliferate.

The authors believed these changes to be an attempt at regeneration. Fluid exudation only occurred at the area where the vessel wall was damaged directly from the glass microsphere in this model.

Table 1. Conditions Associated With Cotton-wool Spots

Common causes

Diabetes mellitus

Arterial hypertension

Central and branch retinal vein and artery occlusions

Ischemic optic neuropathies

Carotid artery occlusion


Human immunodeficiency virus (HIV) infection/

acquired immune deficiency syndrome (AIDS)



Rocky Mountain spotted fever

Cytomegalovirus retinitis



Immune and collagen vascular diseases

Systemic lupus erythematosus


Rheumatoid arthritis

Polyarteritis nodosa


Wegeners granulomatosis

Giant cell arteritis

Waldenstroms macroglobulinemia

Embolic phenomena

IV drug abuse


Carotid artery plaques

Cardiac valvular disease

Purtscher and Purtscher-like retinopathy

Trauma (long bone fractures, blunt chest trauma)


Hypercoagulability or hyperviscosity syndromes


Protein C or S deficiency

Anti-thrombin III deficiency

Sickle cell disease



Metastatic carcinoma





Transient hypoperfusion

Anemia (severe)

High altitude retinopathy

Radiation retinopathy

Epiretinal membrane


The initial theory of the pathophysiology of the development of CWS is an occlusion of precapillary arterioles, which causes a focal area of ischemia. The classic retinal whitening develops due to a halt of axoplasmic flow, both in the orthograde and retrograde directions.

Experimental models have clearly established this disruption of axoplasmic flow.10 This retarded flow allows for accumulation of organelles, mitochondria, secretory and enzymatic vesicles, and other axoplasmic constituents.

These accumulations represent the cytoid bodies found on pathology. Leakage seen on FA is due to localized vascular damage and increased permeability.

The Role of Mechanical Force

Studies have also implicated mechanical force in the formation of certain CWS in rare situations. The theory in these cases is that axonal flow disruption can be due to distortion of the nerve fiber layer and kinking of the axons.

One study specifically associated epiretinal membrane contraction with formation of CWS.11 These spots resolved soon after removal of the membranes, seemingly giving weight to the argument that mechanical force, and not ischemia, was the cause of the CWS in this series.


Cotton-wool spots have an ocular differential diagnosis and a systemic differential diagnosis. The ocular differential diagnosis includes the numerous entities that could appear like CWS. The systemic differential diagnosis refers to the underlying conditions that can cause CWS.

The ocular differential diagnosis of CWS includes any retinal lesion that appears white or yellow-white. In cases of retinal whitening, the physician should consider acute retinal necrosis, progressive outer retinal necrosis, cytomegalovirus retinitis, toxoplasmosis, and other posterior uveitic conditions. Diagnosis can sometimes mistake myelinated nerve fiber layer, retinal astrocytic hamartoma, and regressed retinoblastoma for a CWS.

A Host of Systemic Conditions

More extensive than the ocular differential diagnosis of CWS is the systemic differential diagnosis of conditions associated with CWS. CWS are not specific to any disease process. A myriad of common and rare conditions are associated with these lesions.

Essentially, any entity that can cause terminal arteriolar occlusion or localized hypoperfusion should appear in the systemic differential diagnosis. Table 1 (page 65) provides a list of diseases associated with CWS.

We cannot overemphasize the importance of systemic diseases with a vascular component. In a case series,12 23 of 24 patients with a new finding of CWS had an underlying disorder on systemic evaluation.

Tab1e 2. Basic Diagnostic Eva1uation

Complete dilated examination (if not already performed)

Blood pressure measurement

Fasting glucose

Glucose tolerance test

HIV antibodies screen

Basic chemistry

Complete blood count

Diabetes and Hypertension

It is important to note that the study authors excluded known diabetics from this case series. Previously undiagnosed diabetes, hypertension, and collagen vascular diseases were the most common diagnoses in this series.

It is also important to evaluate for diabetes completely when finding a CWS, because fasting glucose can be normal in these situations. In the above series,12 the majority of the patients had normal fasting glucose, and the diagnosis of diabetes arose from glucose tolerance testing.

Arterial hypertension associated with CWS is typically of the acute and significantly elevated nature, so a single blood pressure measurement will usually clinch the diagnosis in the majority of these cases.


Due to the extensive nature of the associated conditions related to CWS, the doctor should undertake a staged approach to evaluation, based on the patient’s symptoms and history and the extent of the retinal findings.

In addition to this historical information, some authors have tried to glean other information from the appearance of the CWS themselves. Several articles have attempted to classify the differences in appearance of CWS.

A 1988 retrospective review of color photos of CWS attempted to determine differences in the spots related to the etiology.13 The studied etiologies were HIV retinopathy, diabetic retinopathy, hypertensive retinopathy, and central RVO.

HIV-related CWS were smaller in size than CWS of other diagnoses. The total number of CWS was significantly greater in CRVO. Both of these findings were statistically significant. The authors also noted that CWS in CRVO assumed a ring configuration around the optic disc.

Another retrospective review of images of CWS attempted to use specific measurement criteria to determine differences between HIV-related CWS and diabetic CWS.14 The main difference in the appearance of the CWS of patients with diabetes and those with HIV retinopathy was related to eccentricity, ie, the ratio of the long axis to the short axis. HIV-retinopathy lesions had greater eccentricity than diabetic lesions.


Diabetic Retinopathy

The ETDRS research group published guidelines for grading diabetic retinopathy, including soft exudates or CWS. Their grading paradigm addressing CWS was based on comparison with standard photographs 8A and 5 from the ETDRS. The scale used was 0 to 5, with grade 0 indicating none, grade 4 indicating CWS larger than standard photo 5, and grade 5 being unable to grade.

Hypertensive Retinopathy Grading

For systemic hypertension, a grading system has been in place since 1939, as presented by Keith, Wagener, and Barker.15 Grade 1 and 2 retinopathy includes arteriolar narrowing and arteriovenous nicking. These grades typically appear with chronic hypertension.

Grade 3 findings include CWS, hemorrhages, and intraretinal lipid exudates. Grade 4 findings include the previous findings, with either blurring of the optic disc margins or exudates in a macular star pattern. Grade 3 and 4 typically appear with acute or severe chronic hypertension including malignant hypertension.

The first step should be to revisit the medical and ocular history and medications and to discuss any symptoms of the most common disorders.

Grade 3 and 4 hypertensive retinopathy can accompany hypertensive choroidopathy, such as Elschnig spots and Segrist streaks. Elschnig spots are pigment spots with a surrounding yellow or whitish halo. They represent small choroidal infarctions with subsequent overlying retinal pigment epithelial changes. Segrist streaks are hyperpigmented streaks that follow the choroidal vascular pattern.

Hypertensive choroidopathy is highly indicative of acute hypertensive injury from extremely high arterial pressures, whereas retinal findings typically predominate if the hypertension is chronic.

Table 3. Guided Work-up

Erythrocyte sedimentation rate (ESR) C-reactive protein (CRP)

Prothrombin time (PT)

Activated partial thromboplastin time (APTT) Lipid profile

Anti-nuclear antibody test (ANA)

Anti-phospholipid antibodies

Rheumatoid factor

Carotid duplex ultrasound

Anti-nuclear cytoplasmic antibodies (ANCA)

CD4 count


Toxoplasmosis levels

Homocystine level

Protein C and S levels and function

Diagnostic imaging

A More Recent System

Wong and Mitchell,16 in a recent review of hypertensive retinopathy, elucidated another grading system. This newer system consists of mild, moderate, and malignant retinopathy. The authors associated these categories with specific systemic associations based on their review.

Mild retinopathy consists of arteriovenous nicking, arteriolar narrowing, or copper wiring. Moderate retinopathy consists of retinal hemorrhages, microaneurysms, CWS, or hard exudates. Malignant retinopathy includes moderate retinopathy with optic disc swelling.

In addition, mild retinopathy has modest associations with stroke,17,18 coronary artery disease,19,20 and death,21 while moderate and malignant retinopathy both have strong association with the same conditions,17,18,21 as well as with cognitive decline.22

Regardless of the grading system used, seeing even one cotton wool spot in a hypertensive patient should cause significant concern for the evaluating physician, as this finding directly correlates with acute hypertension and end-stage organ damage, as well as having strong associations with increased risk of stroke, myocardial infarction, and death.


If a CWS is found on examination, the first step should be to revisit the patient’s medical and ocular history and medications, compliance, and to discuss any symptoms of the most common disorders

Concerning symptoms include polyuria, polydipsia, weight change, headache, altered mental status, fevers and chills, joint or muscle pains, rashes, fatigue, lymph node swelling or tenderness, and recent illness.

Ophthalmic symptoms to which the doctor should pay particular attention include dry eye, a history of uveitis, vision changes, and significant recent refractive changes.

The workup for CWS will depend significantly on other ocular findings and on the patient’s history. Refer to Table 1 for the diseases associated with CWS. If the medical or ocular history reveals a specific diagnosis associated with CWS, then a workup may not be warranted.

The Basic Evaluation

A recommended basic evaluation for a patient with a new CWS finding and without a known cause of CWS appears in Table 2 (page 66).

The eye-care provider can initiate this workup, but it should involve correspondence with the patient’s primary care physician to coordinate care of the underlying issue if found or to continue the work-up as needed in conjunction with the eye-care provider. It is imperative that the ophthalmologist stress the significance of CWS in systemic disease to the PCP.

The doctor should order some or all of the more extensive work-up in Table 3 (page 67) if the symptoms or findings point to one of the less common underlying etiologies or if the initial workup does not elucidate a cause.


Fluorescein angiography has been used for decades to image CWS. More recently, many case studies have reported findings of newer technologies in ophthalmic imaging. Reports of OCT23,24 and scanning laser polarimetry25 have also appeared.


Studies have documented well the FA findings of CWS. Most CWS fluoresce brightly in the first few minutes after fluorescein injection. Often the fluorescence is much larger than the spot visible on examination.

One early study of fluorescein angiography8 noted that not only did visible CWS fluoresce, but also a fluorescent area could precede a visible spot and remain after clearance of any visible spot on standard fundus photos.

These authors also noted in this study that, at times, a ring of microaneurysms could surround a visible CWS, giving the entire lesion an annular appearance.

OCT and Scanning Laser Polarimetry

It should not be surprising that OCT shows thickening confined to the retinal nerve fiber layer in the area of CWS.23,24 At nine weeks24 and one year23 after presentation, the edema had completely resolved. In addition, in both examples, definitive retinal thinning occurred in the area of the resolved lesion.

Zhang23 was able to show that retinal thinning corresponded to a loss of thickness in the nerve fiber layer, as well as a nerve fiber layer defect on fundus photography.

At least one case study reported using scanning laser polarimetry to identify a retinal nerve fiber layer defect following a peripapillary CWS.25 The patient in this report had an arcuate visual field defect following the finding of the CWS.

As the patient did not have the typical optic nerve findings consistent with glaucomatous damage, the doctor believed the CWS and subsequent nerve fiber layer defect caused the patient’s visual field changes.


In addition to differences in morphology and pathophysiology, depending on the underlying cause, CWS may demonstrate a differential time course for the resolution of the ocular findings and prognoses for diseases.

It is important to understand the time to resolution of CWS because the physician should expect resolution in an appropriate time frame of all CWS once the underlying condition has been appropriately treated.

It has been shown that the size of cotton wool spots in HIV/AIDS are significantly smaller than those in diabetes, hypertension, and CRVO.13 In addition to these differences, the half-life of CWS in HIV/AIDS is significantly shorter. One study reported the half-life of CWS in AIDS at four to 13 weeks, with a mean of 6.9 weeks.26 Another study observed a similar time to resolution in hypertensive CWS, which typically resolve in six to 12 weeks.27

Both of these disease processes contrast with the findings in diabetes, which had mean half-life of 8.1 months in patients younger than 40 and a mean half-life of 17.2 months in those older than 40.27

The difference in the time to resolution of CWS in diabetics, compared to hypertensives and HIV/AIDS patients, likely stems from the difference in scope of the vessel damage between the disease processes.

Typically, diffuse capillary damage occurs in patients with advanced diabetic retinopathy, while both HIV/AIDS and hypertensive retinopathy tend to be much more local phenomena of arteriolar and capillary damage.


CWS, in and of themselves, do not typically cause a significant decline in visual function. However, the most common systemic causes of CWS, including hypertension, diabetes, inflammatory conditions, and HIV, can cause significant ocular and visual problems. We recommend that CWS should be primarily thought of as harbingers of significant pathologies that cause organ damage systemically.

McLeod’s28 suggestion of renaming these lesions “cotton-wool sentinels” may be helpful in this aspect. His call for new nomenclature and thinking about these lesions may also bring attention to CWS as sentinels of significant systemic pathology to ophthalmologists and primary care physicians alike.

Ophthalmologists should engage primary-care colleagues regarding the significance of ocular findings to the general health of the patient. Ophthalmologists have the unique opportunity to view end-stage organ damage

and to assist in altering the trajectory of a disease. CWS are a superb example of an ocular finding with significant systemic relevance that can be the catalyst of that change in trajectory. RP


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