Cotton-wool spots

Key Points at a Glance

Key Points of This Disease

• Cotton-wool spots (soft exudates) reflect swelling of the nerve fiber layer due to microinfarction of retinal arterioles and are not observed in healthy eyes.
• Hypertension and diabetes are the most common causes, and even in patients without a history, 50% have a diastolic blood pressure of 90 mmHg or higher.
• Causes include ischemic, immune-inflammatory, infectious, embolic, and drug-induced factors, among others.
• The lesions themselves usually resolve spontaneously within 6 to 12 weeks, but identifying and treating the underlying disease is essential.
• If giant cell arteritis (GCA) is suspected, urgent steroid therapy is necessary, and up to 20% of patients may experience vision loss.
• OCT shows hyperreflective thickening of the nerve fiber layer, and FA reveals adjacent capillary nonperfusion.

1. What are cotton wool spots?

Cotton wool spots are small, yellowish-white (grayish-white), slightly elevated lesions that appear on the superficial retina. They are also called “soft exudates.”

It is not normal to observe cotton wool spots in a healthy patient. Even a single spot in one eye is highly likely to be the earliest fundus finding of diabetic retinopathy or hypertensive retinopathy. Among patients with cotton wool spots and no relevant history, 50% have elevated diastolic blood pressure of 90 mmHg or higher, and 20% have elevated blood glucose levels.

Lesions commonly occur around the optic disc and along the superior and inferior temporal arcade vessels. They are observed as ill-defined white to yellowish patchy lesions.

The lesions resolve over time. They usually disappear within 6 to 12 weeks, but may persist longer in patients with diabetic retinopathy.

Appearance

Color tone: White to yellowish-white. Indistinct borders with a fluffy, cotton-wool-like texture.

Size: Usually less than 1/3 of the optic disc area

Common Sites

Peripapillary area: May occur multiple times around the optic disc

Along the arcades: Appears along the superior and inferior temporal arcades

Course

Spontaneous resolution: Usually disappears within 6–12 weeks

Persistent cases: May persist longer in diabetic retinopathy

Clinical Significance

Not normal: An abnormal finding not seen in healthy eyes

Sign of systemic disease: An ocular sign of systemic conditions such as hypertension and diabetes

2. Main Symptoms and Clinical Findings

Cotton Wool Spots image

Kuryati Kipli; Mohammed Enamul Hoque; Lik Thai Lim; Muhammad Hamdi Mahmood; Siti Kudnie Sahari; Rohana Sapawi; Nordiana Rajaee; Annie Joseph. A Review on the Extraction of Quantitative Retinal Microvascular Image Feature. Comput Math Methods Med. 2018 Jul 2; 2018:4019538. Figure 4. PMCID: PMC6051289. License: CC BY.

Cotton wool spot in retinal fundus image (in black circle) [32].

Subjective Symptoms

Generally, cotton wool spots themselves do not cause visual symptoms. If the fovea is involved, decreased visual acuity may occur. Systemic symptoms due to the underlying disease may also be present.

Examples of symptoms associated with each causative disease are shown below.

• GCA case: 2 weeks of dull temporal headache, jaw claudication during chewing, bilateral vision loss (right: counting fingers, left: 6/36) ³⁾
• COVID-19 case: Blurring in both eyes after discharge. Initial visual acuity: right 20/50, left 20/60 ²⁾
• Chemotherapy case: No subjective ocular symptoms. Corrected visual acuity: right 20/30+1, left 20/25-2 ¹⁾

Clinical Findings

On dilated fundus examination, it appears as a slightly elevated, white lesion with indistinct borders on the superficial retina of the posterior pole. The lesion has a tufted margin and is characterized by a soft, cotton-wool-like texture. It is often mistaken for myelinated nerve fibers, but differs in both shape and texture.

The following table shows the differential diagnosis of major white lesions.

Lesion Name	Color/Texture	Layer Involved
Soft exudates (cotton-wool spots)	White, soft, indistinct borders	Nerve fiber layer
Hard exudates	Yellow, hard, distinct borders	Outer plexiform layer
Drusen	Yellow-white, granular	Sub-retinal pigment epithelium

Findings from representative cases are shown below.

• GCA case: Multiple cotton-wool spots around the optic disc in both eyes (right eye predominant) ³⁾
• COVID-19 case: Bilateral cotton-wool spots in the posterior pole. History of hypertension but no arteriolar narrowing or AV crossing abnormalities ²⁾
• Chemotherapy cases: scattered peripapillary cotton-wool spots, scattered dot/blot hemorrhages. FA shows 360-degree microaneurysms, drusen staining, and peripheral capillary dropout ¹⁾

Q If cotton wool spots are found, is treatment always necessary?

A

There is no direct treatment for cotton wool spots themselves. The lesions usually resolve spontaneously within 6 to 12 weeks. The highest priority is to identify and treat the underlying disease; in suspected GCA, emergency intervention is necessary to prevent vision loss. For details, see the section on “Standard Treatment.”

3. Causes and Risk Factors

Cotton-wool spots are not a specific disease but a fundus sign of various systemic and local diseases. The causes are broadly classified into four categories.

Ischemic

Hypertension: The most common cause. Also appears in renal hypertension.

Diabetes: An early finding of diabetic retinopathy.

Others: Retinal vein occlusion, ocular ischemic syndrome, anemia (red blood cell count less than 50% of normal), hyperviscosity syndrome, hypercoagulable state, radiation exposure, acute blood loss.

Immune/Inflammatory

GCA (Giant cell arteritis): 15-25 per 100,000 people over age 50. May present as bilateral cotton-wool spots³⁾.

Collagen diseases: SLE (soft exudates prominent), dermatomyositis, scleroderma, polyarteritis nodosa.

Infectious

HIV retinopathy: various findings such as soft exudates, hemorrhages, Roth spots

Others: cat scratch disease, Rocky Mountain spotted fever, leptospirosis, bacteremia, fungemia

Other

Embolic: Purtscher-like retinopathy (carotid embolism, cardiogenic embolism, drug-induced)

Neoplastic: leukemia (venous dilation, tortuosity, hemorrhage, cotton-wool spots, Roth spots), lymphoma, metastasis

COVID-19: Cotton-wool spots were observed in 6 of 27 (22%) patients recovering from pneumonia ²⁾

Drug-induced: Purtscher-like retinopathy

Chemotherapeutic agents (gemcitabine, cisplatin) can cause cotton-wool spots as Purtscher-like retinopathy. Diabetes and hypertension increase the risk of gemcitabine-induced Purtscher-like retinopathy. ¹⁾

In COVID-19, hypercoagulability and vasculitis due to direct viral infection of vascular endothelium are considered mechanisms. ²⁾

Retinal vein occlusion (RVO) may present with cotton-wool spots as an early clinical finding. ⁴⁾

Prevention and daily care

• If you have high blood pressure or diabetes, please regularly manage your blood pressure and blood sugar levels.
• If cotton wool spots are found during a fundus examination, do not self-diagnose; follow your doctor’s instructions and undergo a systemic evaluation.
• If you are receiving chemotherapy and notice changes in vision or eye abnormalities, promptly consider seeing an ophthalmologist.

Q What is the most common cause of cotton wool spots?

A

Hypertension and diabetes are the most common causes. Even in patients without a history, 50% of those with cotton wool spots have elevated diastolic blood pressure of 90 mmHg or higher, and 20% have elevated blood sugar levels.

4. Diagnosis and Testing Methods

Diagnosis is usually made by dilated fundus examination. After confirming the lesion, it is essential to investigate the underlying disease.

Imaging Tests

The following are the main imaging tests and their findings.

Test	Main Findings
Fundus Examination	White, poorly demarcated elevated lesion (at the level of the nerve fiber layer)
OCT	Focal thickening with hyperreflectivity of the nerve fiber layer (acute phase) → inner layer thinning (resolution phase)
FA	Adjacent capillary non-perfusion area

Detailed findings of each examination are shown below.

• FA: Reveals capillary non-perfusion areas adjacent to cotton-wool spots. In chemotherapy cases, 360-degree microaneurysms, capillary non-perfusion at cotton-wool spot sites, and a course from hypofluorescence to late hyperfluorescence were recorded. ¹⁾ In COVID-19 cases, no abnormalities other than mild blockage were noted. ²⁾
• OCT: In the acute phase, localized or segmental thickening with hyperreflectivity of the nerve fiber layer is observed. The outer layers are preserved. In the resolution phase, it progresses to thinning and atrophy of the inner layers. In COVID-19 cases, no macular edema was present, and thickening and hyperreflectivity of the nerve fiber layer were confirmed at the cotton wool spot sites. ²⁾
• OCT-A: In COVID-19 cases, flow voids were observed at the superficial capillary plexus level. ²⁾

Evaluation of cotton wool spots is also required in the differential diagnosis of retinal artery occlusion. ⁵⁾

Workup for underlying diseases

The following initial tests are performed:

• Vital signs (blood pressure): To rule out hypertensive retinopathy
• HbA1c: To rule out diabetic retinopathy
• CBC (complete blood count): To rule out anemia or leukemia
• HIV test: To rule out HIV retinopathy

Additional tests that may be performed as needed are as follows:

• Echocardiography and carotid ultrasound: To search for embolic sources
• ESR and CRP: To evaluate inflammatory diseases (especially GCA)
• PT/PTT: Evaluation of coagulation abnormalities
• Suspected GCA: ESR/CRP (in GCA cases, ESR 120 mm/h, CRP 79 mg/L), temporal artery ultrasound (halo sign)³⁾

Importance of ultrasound in GCA diagnosis

The halo sign on temporal artery ultrasound is useful for diagnosing GCA. The sensitivity of unilateral halo sign is 68% and specificity 91%, while the specificity of bilateral halo sign reaches 100%.³⁾

Differential diagnosis

It is important to differentiate from myelinated nerve fibers, hard exudates, retinal infiltration, retinitis, drusen, and chorioretinal atrophy.

Q If cotton wool spots are found on fundus examination, what systemic tests should be performed?

A

Initial tests include blood pressure measurement, HbA1c, CBC, and HIV testing. If necessary, echocardiography, carotid ultrasound, ESR, CRP, and coagulation tests may be added. In suspected GCA, temporal artery ultrasound is useful for differential diagnosis and may require urgent management.

5. Standard Treatment

There is no direct treatment for cotton wool spots themselves. Identifying and treating the underlying disease is essential. The lesions usually resolve spontaneously within 6 to 12 weeks.

In HIV-infected patients with CD4 count below 200, new cotton wool spots may be an early sign of viral retinitis and require attention.

Treatment by Underlying Disease

• GCA: IV methylprednisolone 1 g × 3 days, followed by oral prednisolone 60 mg/day with tapering. Visual improvement has been reported after 3 days of treatment. Complete resolution of cotton wool spots was confirmed at 12 months. In case of recurrence, adding methotrexate 10 mg/week or tocilizumab are options. ³⁾
• Hypertension: Retinal findings disappear within months with antihypertensive therapy (same for renal hypertension).
• Anemia: Fundus findings improve with correction of anemia.
• COVID-19 related: No specific ophthalmic treatment. Spontaneous visual improvement has been reported after 2 months (right 20/50→20/20, left 20/60→20/25). ²⁾
• Chemotherapy-related: Ocular side effects from gemcitabine are reversible. Damage from cisplatin may be irreversible. ¹⁾
• Retinal vein occlusion: Cotton wool spots resolve as the acute process subsides. ⁴⁾

The following summarizes treatment and outcomes by underlying disease.

Underlying disease	Treatment	Outcome
GCA	High-dose steroid therapy	Resolves within months3)
Hypertension	Antihypertensive therapy	Resolves within months
Anemia	Treat underlying cause	Resolves with blood improvement

Points to note in treatment

• If left untreated, GCA causes permanent vision loss in up to 20% of patients. If suspected, emergency consultation is required. ³⁾
• 34–62% of GCA patients relapse. Long-term follow-up and prompt response to recurrence are necessary. ³⁾
• Cisplatin-induced retinal damage can be irreversible, making regular ophthalmologic monitoring during chemotherapy important. ¹⁾

Q Does vision remain affected after cotton-wool spots disappear?

A

In many cases, they resolve without sequelae. However, if the fovea is involved or optic neuropathy due to GCA occurs, visual impairment may persist. In GCA, up to 20% of patients experience permanent vision loss. ³⁾

6. Pathophysiology and Detailed Mechanism

Cotton-wool spots occur following ischemia due to occlusion of retinal arterioles. They are associated with local accumulation of axoplasmic transport debris and are a sign of retinal ischemia. ³⁾

Mechanism

The process follows: microinfarction of retinal arterioles → occlusion of precapillary arterioles → infarction of the nerve fiber layer.

Local ischemia blocks axoplasmic flow. Mitochondria and intracellular materials accumulate within the blocked axons, causing swelling of nerve fibers. This swollen tissue appears as white to yellowish-white lesions on the fundus.

Histologically, cytoid bodies are characteristic findings. Cytoid bodies are eosinophilic fragments of swollen ganglion cell axons, filled with accumulated mitochondria and intracellular materials.

Mechanism of Purtscher-like retinopathy

Cotton-wool spots due to specific causes follow the mechanism of Purtscher-like retinopathy.

• Microemboli: Air, fat, leukocyte aggregates, platelets, and fibrin reach the retinal capillaries and cause occlusion. ²⁾
• COVID-19: Hypercoagulable state or vasculitis due to viral infection of the vascular endothelium damages retinal vessels. ²⁾
• Cisplatin: Causes retinal ischemia through a vascular occlusion process. ¹⁾
• Gemcitabine: Can cause Purtscher-like retinopathy, renal ischemia, and myocardial ischemia due to vascular toxicity. ¹⁾

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7. Latest Research and Future Prospects

For Patients: Please Read

The following content is currently at the research stage or under clinical trials and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

COVID-19 and Retinal Microvascular Disorders

Reports of retinal microvascular disorders in COVID-19 patients are increasing. Cotton-wool spots were observed in 6 out of 27 (22%) recovered COVID-19 pneumonia patients, drawing attention to the effects of SARS-CoV-2 on vascular endothelium. ²⁾ Visualization of flow voids by OCT-A is contributing to disease assessment.

Advances in GCA Treatment

Tocilizumab has been shown to be effective in preventing relapse in GCA treatment. It is expected to prolong time to relapse and reduce cumulative steroid dose. ³⁾ Temporal artery ultrasound is becoming widespread as a non-invasive diagnostic method for GCA. Reports of 100% specificity for bilateral halo sign contribute to improved diagnostic accuracy. ³⁾

Monitoring Retinal Toxicity from Chemotherapy

Awareness of retinal toxicity from chemotherapeutic agents such as gemcitabine is increasing. The risk is particularly high in patients with diabetes or hypertension, and the importance of regular ophthalmic monitoring during chemotherapy is emphasized. ¹⁾

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8. References

1. Brummer SR, Joffe JA, Liggett PE. Chemotherapy-induced retinopathy in a diabetic and hypertensive patient with stage 4 metastatic pancreatic adenocarcinoma. J Vitreoret Dis. 2023;7(3):242-244.

2. Bottini AR, Steinmetz S, Blinder KJ, Shah GK. Purtscher-like retinopathy in a patient with COVID-19. Case Rep Ophthalmol Med. 2021;2021:6661541.

3. Fu L, O’Sullivan EP. Giant cell arteritis presenting as bilateral cotton wool spots. Cureus. 2022;14(10):e29804.

4. Retinal Vein Occlusions Preferred Practice Pattern. American Academy of Ophthalmology. 2024.

5. Retinal and Ophthalmic Artery Occlusions Preferred Practice Pattern. American Academy of Ophthalmology. 2024.