Leo P. Semes, OD, FAAO

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A 55-year old patient with a 20-year history of insulin-dependent diabetes presented for periodic ophthalmic evaluation. He was new to our area and did not recall the timing of his previous examination.

Related: Case study: Vascular abnormality diagnosed as arteriovenous malformations of the iris

He reported no visual symptoms. In addition to his history of diabetes, he had also been treated for systemic hypertension (medications unreported) for 20 years. Significant in his history was the admission of blood sugar levels in the 140 to 200 range. He was unaware of his HbA1c levels.

At examination, best-corrected visual acuity was 20/25 in each eye. The appearance of the right and left fundi is depicted in Figure 1. Note the vascular abnormalities in each eye consistent with diabetic retinopathy, including hemorrhages and microaneurysms, cotton-wool spots, intraretinal microvascular abnormalities, and a specific cluster of exudates affecting the left eye within 500 μm of the macula. In the fundus photo of the right eye, note particularly the vascular irregularity associated with cotton-wool spot superior temporal to the optic disc.

Related: Masquerading maculopathy: The importance of correct diagnosis

The patient was diagnosed with moderate to severe diabetic retinopathy, and optical coherence tomography (OCT) was ordered. Normal foveal contour with mild thickening as well as absence of intra- and sub-retinal fluid are noted in the cross-sectional presentation of each eye. See Figure 2.

Topographical analysis revealed mild thickening within the posterior pole of each eye. See Figure 3. The retinal nerve fiber layer (RNFL) profile captured a portion of the cotton-wool spot superior temporal to the optic disc of the right eye. See Figure 4.

The patient refused consultation with a retinologist and was subsequently advised to follow up in 3 months. At this visit, his visual acuity was unchanged, but there were some changes to the fundus appearance in each eye. See Figure 5 for changes to the right eye.

Most significantly, the prominent cotton-wool spot in the right eye had resolved but left in its wake a distinct RNFL defect. Refer to Figure 5.

The OCT at this visit revealed intra-retinal and sub-retinal fluid perilously close to the center of the fovea of the right eye. See Figure 6.

This was considered potentially treatable although not center-involving, and the patient was referred to a retinologist. Treatment was recommended, and the patient refused.

Related: Retinal detachment seals itself

It is well known that cotton-wool spots are consistent with underlying ischemia, perhaps of a single retinal arteriole.1 They have been reported to correspond with arcuate visual-field defects.2

The specific pathophysiology for the manifestation of CWS appears to begin with retinal arteriolar obstruction. As such, CWS can be regarded as sentinels for neovascularization.

Related: New-onset, atypical retinopathy in a patient with diabetes

A previous report of CWS resolution with subsequent RNFL defect was published.3 The case involved a patient with severe arterial hypertension whose CWS appeared inferior to the optic disc. Upon CWS resolution, the patient exhibited a distinct wedge-shaped RNFL defect. The report also included OCT analysis showing characteristic inner retinal tissue loss.

On further follow-up, the current patient eventually developed center-involving macular edema in the right eye and high-risk vitreous hemorrhage (nasal to the optic disc) in the left eye.

He received a single treatment to the left eye but was lost to subsequent follow-up.

More by Dr. Semes: OCT in DR follow-up highlights importance of retina-vitreous attachment

 McLeod D. Why cotton wool spots should not be regarded as retinal nerve fibre layer infarcts. 

 Chui TY, Thibos LN, Bradley A, Burns SA. The mechanisms of vision loss associated with a cotton wool spot. 

 Zhang L, Xu L, Zhang JS, Zhang YQ, Yang H, Jonas J. Cotton-wool spot and optical coherence tomography of a retinal nerve fiber layer defect. 

Articles

Imaging reveals diabetic retinopathy, cotton wool spot, and resulting RNFL defect.

Resolved cotton-wool spot leaves RNFL defect in its wake

This case example highlights how continued attachment between retina and vitreous among patients with diabetic retinopathy may be an ominous sign. Conversely, documentation of complete vitreous detachment offers a more benign prognosis regarding the vascular complications of diabetic retinopathy.

A 74-year old black female with diabetes was evaluated as part of her follow-up for non-proliferative diabetic retinopathy. While she did not admit to new visual complaints, visual acuity was correctable to 20/60 in her right eye and 20/25 in her left, which was stable from the previous visit (Figures 1 A and B).

Note the distinct differences in the color-fundus photography which is due to artifacts interfering with image capture. Optical coherence tomography (OCT) was ordered and revealed significant disturbances of the retinal layers in each eye but to a greater extent in the right eye. (Figures 3 and 4). 

Of note is that there appeared to be a corrugated contour to the retinal surface of each eye on the volumetric scan of the OCT. This corresponds with the projected undulations of the vitreous. However, the cross-sectional views do not support this nor did the clinical observation.

Analysis of the cross-sectional images of the right eye reveals thickened hyaloid membrane as well as irregularity of the separated vitreous gel. In addition, there is the presence of at least one cystic space (horizonal sample) in this eye.

The topographic representation of the retina suggests overall thickening that may not be apparent in the cross-sectional scan samples. The volumetric representations in each eye are revealing in that there is evidence of vitreo-macular traction (not adhesion

), which  probably contributes to the reduced visual acuity. 

Clinically, it is difficult to assess the relationship between the vitreous and macula, especially in the right eye of this patient. It is important to know the vitreo-macular interface status because continued attachment between retina and vitreous among patients with diabetic retinopathy may be an ominous sign. Conversely, documentation of complete vitreous detachment offers a more benign prognosis regarding the vascular complications of diabetic retinopathy.

Cotton-wool spots lead to tissue loss and RNFL defect

1. Duker JS, Kaiser PK, Binder SP, et al. The International Vitreomacular Traction Study Group classification of vitreomacular adhesion, traction, and macular hole. Ophthalmology. 2013 Dec;120(12):2611-2619.
	2. Jackson TL, Nicod E, Angelis A, et al. Vitreous attachment in age-related macular degeneration, diabetic macular edema, and retinal vein occlusion:  A systematic review and metaanalysis. Retina. 2013 Jun;33(6):1099-1108.
	3. Akiba J, Arzabe CW, Trempe CL. Posterior vitreous detachment and neovascularization in diabetic retinopathy. Ophthalmology. 1990 Jul;97(7):889-91.

Relationship between these two clinical structures difficult to assess without imaging.

OCT in DR follow-up highlights importance of retina-vitreous attachment

57-year-old male patient with a 20+- year history of systemic hypertension and diabetes presented to the clinic for refractive care.

He was an insulin dependent diabetic, but he was unsure of his hypertension medication. He reported that his blood sugar levels were between 140 and 200 but that his A1C was unknown.

Related: Look at more than the optic nerve head in glaucoma patients

Best-corrected visual acuity was 20/25 in each eye. He had normal extraocular muscle movements as well as full confrontation fields. The anterior segment examination was unremarkable and applanation tensions were 16 mm Hg in each eye.

The color fundus photograph (CFP) of the right eye is shown in Figure 1. There are a few notable features that include hemorrhages and microaneurysms, cotton-wool spots  CWS) as well as a distinct vascular irregularity superior temporal to the optic disc.

Assessment of the diabetic retinopathy was moderate to severe for this patient’s right eye. Alternatively, this would correspond to approximately Level 35 on the Diabetic Retinopathy Severity Scale algorithm.

Cross-sectional optical coherence tomography (OCT) of the right eye demonstrates normal central macular thickness and contour (Figure 2). Topographic OCT demonstrated thickening of the macula and corroborated clinical evidence of the CWS within the RNFL profile (Figure 3).

The left eye had similar but more extensive diabetic retinopathy manifestations; however, that is not included in this report.

Related: Macular diseases: Emerging best practices for diagnosis, management and follow-up protocols

The patient was observed closely over the next four months, at which point he developed center-involving macular edema of the left eye. 

He was referred to a retina specialist who recommended treatment with anti-vascular endothelial growth factor (VEGF) injections that the patient refused. 

He was followed up in a further three months. The CFP of the right eye from that visit appears in Figure 4. Note that the area where the cotton-wool spot had been now has a retinal nerve fiber layer (RNFL) defect. 

Related: Toxoplasmosis retinochoroiditis pictorial review

Ischemia is the pathophysiology behind cotton- wool spots. It is not unreasonable to expect that a sequela may be tissue loss and consequent RNFL defect. This has been documented subsequently from a case as part of the Beijing Eye Study.

The appearance of a RNFL defect has been associated classically with glaucomatous optic neuropathy as well as secondary to optic disc drusen. These well-known progenitors of RNFL defects may have a similar ischemic etiology to the RNFL defect, in this case. Clinicians should be aware of this possible sequela from cotton-wool spots and investigate every incidence.

More by Dr. Semes: Toxoplasmosis shows varied diagnosis

1. Slakter, JS, Schneebaum JW, Shah SA. Digital Algorithmic Diabetic Retinopathy Severity Scoring System (An American Ophthalmological Society Thesis). Trans Am Ophthalmol Soc. 2015 Sep; 113: T9.
	2. Zhang L, Xu L, Zhang JS, Zhang YQ, Yang H, Jonas J. Cotton-wool spot and optical coherence tomography of a retinal nerve fiber layer defect. Arch Ophthalmol. 2012 Jul 1;130(7):913.

RNFL defects are associated with glaucomatous optic neuropathy and secondary to optic disc drusen.

Controversy surrounding treatment guidelines plays role in patient case

A 39-year-old male attended the clinic seeking a second opinion for a right-eye problem for which he had been treated elsewhere. The 

complaint that brought him initially was blurry vision centrally in the right eye. He reported being treated with oral clindamycin (150 mg, three times a day 

). 
	
	This treatment had been initiated along with an oral steroid approximately six weeks prior, but he had self-discontinued the steroid after three weeks because he claimed that he disliked the side effects. 
	
	He denied taking any prescription medications as well as systemic problems. On clinical examination, best-corrected visual acuity (BCVA) was 20/200 (OD) and 20/20(OS).
	
	Remarkably, slit-lamp examination showed the absence of an anterior-chamber reaction in either eye, along with mild vitritis involving the right eye only. The fundus appearance (OD) is shown in Figure 1. 
	
	

Vision loss diagnosis presents potential complications 


	A working diagnosis of ocular toxoplasmosis was made. Because the clindamycin appeared to be ineffective and the patient denied sulfa allergy, Bactrim DS (trimethoprim/sulfmethoxazole; Roche; 160/800 mg) was prescribed empirically, twice a day (bid), dosing orally. The patient was asked to return in two weeks. 
	
	The two-week fundus appearance is shown in Figure 2.
	
	While there appears to be little improvement, the emergence of subtle pigmentary changes can be seen with careful comparison with baseline. The patient was monitored biweekly for the next month.
	
	Following this course of the trimethoprim/sulfmethoxazole combination, the fundus appearance is shown in Figure 3.
	
	Of note is that the central lesion, ascribed to ocular toxoplasmosis, showed an increased pigmentation-indicating further retinal pigment epithelium (RPE) remodeling secondary to the inflammatory process as well as communication of a retinal blood vessel with the choroid as another component of remodeling. 
	
	

How inflammation may play a role in retinal disease


	There has been considerable controversy over the decades concerning the treatment of ocular toxoplasmosis.
	
	What has emerged is a general guideline for recommending treatment, broadly if the infectious nidus involves the posterior pole; that is, if the macular is involved or the optic nerve is threatened.


	
	While a significant proportion of literature regarding treatment is from outside the U.S., current consensus recommendations for treatment underscore this template by suggesting trimethoprim/sulfamethoxazole in combination orally alone in the absence of vitritis and the addition of an oral steroid (prednisone, 40 to 80 mg/day) in the presence of vitritis with biweekly follow-up.


	
	The clinical presentation of ocular toxoplasmosis is varied. This is likely due to the latency after the initial infection and inflammatory process begins, and if the patient becomes symptomatic or presents for ophthalmic evaluation.


	
	This spectrum extends from the central lesion presenting initially as a primary retinitis with extension posteriorly (choroiditis) and anteriorly (vitritis). A variety of features consistent with a primary retinitis have also been reported from optical coherence tomography evaluations.


	
	While the diagnosis is typically made from clinical findings, laboratory investigations for systemic involvement can be undertaken.
	
	

Case: New protocol for macular hole treatment 


	A number of vectors have been identified for the transmission of this obligate intracellular parasite (

). Those at risk include meatpacking workers, those consuming raw mollusks (oysters, clams, mussels) or locally cured meat, those who may be immunocompromised, or owning three-plus kittens.


	
	This list is derived from the national toxoplasmosis clearinghouse laboratory at Stanford University. Its purpose it to alert clinicians of potential risks for susceptible patients.
	
	Recurrences of ocular toxoplasmosis are possible. While this risk appears to decrease with age, increasing age makes continued surveillance for recurring vision-threatening recurrences a necessity.


	
	Finally, the consideration of prophylaxis against future infection must be addressed.  One template has suggested that a discussion of a one-year antibiotic regimen should be proposed to any patient with an active lesion.
	
	With frequent recurrences (<2 year), a one- to two-year antibiotic prophylaxis course should be recommended.

Acknowledgement: The patient was also attended by K. Prezgay, OD.

1. Stanford MR, Gilbert RE. Treating ocular toxoplasmosis: current evidence. 

2. Lima GS, Saraiva PG, Saraiva FP. Current therapy of acquired ocular toxoplasmosis: a review. 

3. Commodaro AG, Belfort RN, Rizzo LV, Muccioli C, Silveira C, Burnier MN Jr, Belfort R Jr. Ocular toxoplasmosis: an update and review of the literature. 

5.  Chen KC, Jung JJ, Engelbert M. Single acquisition of the vitreous, retina, and choroid with swept-source optical coherence tomography in acute toxoplasmosis. 

6. Vezzola D, Allegrini D, Borgia A, fl. Swept-source optical coherence tomography and optical coherence tomography angiography in acquired toxoplasmic chorioretinitis: a case report. 

7. Jones JL, Dargelas V, Robets J, Press C, Remington JS. Montoya JG. Risk factors for Toxoplasma gondii infection in the United States. 

8. Holland GN, Crespi CM, ten-Dam Loon N, Charonis AC, Yu F, Bosch-Driessen LH, Rothova A. Analysis of recurrence patterns associated with toxoplasmic retinochoroiditis. 

9. Reich M, Mackensen F. Ocular toxoplasmosis: background and evidence for antibiotic prophylaxis. 

Author | Leo P. Semes, OD, FAAO

Articles

Resolved cotton-wool spot leaves RNFL defect in its wake

OCT in DR follow-up highlights importance of retina-vitreous attachment

Cotton-wool spots lead to tissue loss and RNFL defect

Toxoplasmosis shows varied diagnosis