PURTSCHER-LIKE RETINOPATHY ASSOCIATED WITH ATYPICAL HEMOLYTIC UREMIC SYNDROME: CASE REPORT AND REVIEW OF OUTCOMES

Abstract

Purpose:

The purpose of this study was to report the case of a patient presenting with newly diagnosed atypical hemolytic uremic syndrome (aHUS) and Purtscher-like retinopathy.

Methods:

This is an observational case report and review of literature. A 38-year-old woman presented with 3 months of rashes, fevers, arthralgias, and abdominal pain. Initial workup was suggestive of hypereosinophilic syndrome or adult-onset Still disease. The patient developed acute renal failure and progressively blurry vision bilaterally over the course of 5 days. Funduscopic examination was notable for numerous Purtscher flecken and cotton–wool spots, with rare intraretinal hemorrhages at the posterior pole. The con-stellation of renal failure, hemolytic anemia, and thrombocytopenia prompted a workup for thrombotic microangiopathy that was remarkable for a mutation in the gene coding for complement protein C9.

Results:

The patient was diagnosed with aHUS. The patient was treated with intravenous pulse dose steroids for 3 days and an extended course of eculizumab. The patient’s renal failure resolved, and her visual acuity improved, although she had residual visual field constriction and developed bilateral optic atrophy. Outcomes of other cases of Purtscher-like retinopathy related to aHUS are reviewed.

Conclusion:

Purtscher-like retinopathy is a rare but severe ophthalmic complication of aHUS. Eculizumab is an effective treatment for the systemic illness caused by aHUS, and anatomical resolution of Purtscher-like retinopathy may follow, although visual prognosis remains guarded. Recovery of visual acuity may lag behind resolution of macular edema in these patients.

A typical hemolytic uremic syndrome (aHUS) is a rare, genetic, life-threatening condition, characterized by chronic, uncontrolled activation of the complement system.¹ Platelet activation, hemolytic anemia, and thrombotic microangiopathy lead to renal failure and other end-organ damage.² Laboratory findings are notable for thrombocytopenia, anemia with numerous schistocytes, elevated lactate dehydrogenase, low haptoglobin, elevated blood urea nitrogen, and declining kidney function.² A negative Shiga toxin test differentiates aHUS from typical HUS, which is caused by infection with Shiga toxin–producing pathogens.²

Purtscher retinopathy is an occlusive retinal micro-vasculopathy associated with cranial trauma or thoracic compression.³ Purtscher-like retinopathy is the term used to describe cases not associated with trauma.⁴ Although numerous etiologies for Purtscher-like retinopathy have been reported, common etiologies include pancreatitis, renal failure, and autoimmune disease.⁴ Purtscher and Purtscher-like retinopathy are characterized by Purtscher flecken, cotton–wool spots (CWS), and few retinal hemorrhages, focused at the posterior pole.⁴ Purtscher flecken are polygonal, well-defined areas of retinal whitening because of occlusion of the precapillary arterioles in the intermediate and deep capillary plexuses.³ The mechanism of Purtscher-like retinopathy is debated, with the leading theory being leukoemboli-zation, caused by leukocyte aggregation and complement activation, leading to retinal ischemia.⁴

Very few cases of Purtscher-like retinopathy associated with aHUS exist in the literature.^5–7 We present the case of a patient newly diagnosed with aHUS and presenting with severe Purtscher-like retinopathy. We review the clinical course of our patient along with those published in the literature.

Case Report

A 38-year-old woman presented with 3 months of fluctuating symptoms, including rashes, fevers, arthralgias, abdominal pain, and diarrhea, with multiple hospital admissions. Workup was notable for eosinophilia, hyperferritinemia, and a simple liver cyst on abdominal imaging. A parasitic workup was negative, and bone marrow biopsy revealed 40% eosinophils, yielding a working diagnosis of hypereosinophilic syndrome or adult-onset Still disease. The patient was treated with 1 mg/kg oral prednisone on discharge.

Five days later, the patient presented with encephalopathy and progressive blurry vision bilaterally. Initial workup was notable for microangiopathic hemolytic anemia (hemoglobin 6.1 g/dL, lactate dehydrogenase 2479 U/L, haptoglobin, <10 mg/dL, and numerous schistocytes), thrombocytopenia (platelets 23,000/μL), and acute renal failure (creatinine 7.36 mg/dL, glomerular filtration rate 6 mL/minute/1.73 m²) with uremia (blood urea nitrogen 130 mg/dL). The patient was admitted to the intensive care unit for urgent hemodialysis.

Ophthalmology was consulted on admission to the intensive care unit. Visual acuity was 4/200 bilaterally. Pupils, intraocular pressure, and anterior segment examination were normal. Confron-tational visual field testing demonstrated severe bilateral constriction. Funduscopic examination was notable for numerous Purtscher flecken and CWS, with few retinal hemorrhages at the posterior pole bilaterally (Figure 1, A and B). Fluorescein angiography demonstrated arteriolar nonperfusion, vascular leakage, peripapillary staining, and blockage corresponding to areas of CWS, Purtscher flecken, and retinal hemorrhages (Figure 1, C and D). Optical coherence tomography (OCT) demonstrated retinal thickening with intraretinal and subretinal fluid bilaterally, right worse than left (Figure 1, E and F). These findings of Purtscher-like retinopathy were highly suggestive of a systemic microembolic process.

Fig. 1.

Fundus photographs of the right (A) and left (B) eyes demonstrating multifocal CWS (asterisks), Purtscher flecken (black arrowheads), with few retinal hemorrhages, focused at the posterior pole. Fluorescein angiography (C and D) demonstrates arteriolar nonperfusion (white arrows), peripapillary staining, mild vascular leakage, and blockage in areas of CWS and retinal hemorrhage. Optical coherence tomography (E and F) shows retinal thickening with cystoid macular edema and subretinal fluid in the right more than the left eye.

Based on the above findings from the ophthalmic examination, further workup of a systemic thrombotic microangiopathy was pursued. Given the history of diarrhea, typical HUS was strongly considered, but Shiga toxin testing was negative. Additionally, disseminated intravascular coagulation was ruled out based on normal aPTT and fibrinogen levels, and thrombotic thrombocytopenic purpura was ruled out based on normal ADAMTS13 activity. An extensive rheumatologic workup was otherwise normal. Therefore, the patient was diagnosed with aHUS, with genetic testing later confirming a mutation in the gene coding for complement factor C9. The patient was started on IV methylpred-nisolone 1 g daily for 3 days, along with eculizumab 900 mg weekly for 2 weeks, 1,200 mg weekly for 4 weeks, then maintained on 1,200 mg every other week. After initiation of steroids and eculizumab, the patient’s anemia, thrombocytopenia, renal function, and vision gradually improved, and the patient was discharged 3 weeks later. Optical coherence tomography at discharge also demonstrated improved macular edema with just mild residual intraretinal fluid cysts.

At 2-month follow-up, the patient’s vision had improved to 20/60–2 in the right eye and 20/40 in the left eye. The Purtscher flecken and CWS had faded, with interval development of disc pallor (Figure 2, A and B). Optical coherence tomography imaging demonstrated complete resolution of macular edema, with interval development of diffuse inner retinal atrophy and scattered ellipsoid zone loss (Figure 2, C and D).

Fig. 2.

At 2-month follow-up examination, improvement in CWS and Purtscher flecken is noted (A and B). Macular edema has resolved, with evidence of retinal thinning and scattered ellipsoid zone loss (C and D). At 6-month follow-up examination, there is complete resolution of CWS and Purtscher flecken, and notable disc pallor bilaterally (E and F). Optical coherence tomography remains stable with inner than outer retinal thinning (G and H).

The patient was maintained on eculizumab infusions every other week, and at 6 months of follow-up, vision remained stable at 20/70 in the right eye and 20/40 in the left eye. On funduscopic examination, there was complete resolution of Purtscher flecken and CWS, with optic atrophy bilaterally (Figure 2, E and F). Optical coherence tomography remained stable with inner than outer retinal atrophy bilaterally (Figure 2, G and H). Optical coherence tomography retinal nerve fiber layer confirmed severe thinning bilaterally, and visual fields demonstrated diffuse depression in the right eye worse than the left eye (Figure 3). The patient was referred to the Braille Institute for low vision services given the severity of her visual field loss.

Fig. 3.

At 6-month follow-up, OCT retinal nerve fiber layer demonstrates marked thinning bilaterally (A). Humphrey visual fields 24–2 (B and C) show diffuse depression bilaterally worse in the right eye.

Discussion

Hemolytic uremic syndrome comprises a heteroge-neous group of disorders presenting with the triad of thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury.² There are three subtypes of HUS: typical, atypical, and secondary.² Typical HUS is because of an infection from Shiga toxin–producing Escherichia coli, which causes damage to endothelial cells and activation of the clotting cascade by increasing tissue factor expression.² Atypical HUS refers to HUS occurring because of dysregulation of the complement alternative pathway.² Although most patients will have a mutation in the genes controlling the complement alternative pathway, up to 30% of patients have an unknown mechanism for aHUS.² Finally, secondary HUS is because of an underlying disease or condition, such as infection with Streptococcus pneumoniae or the influenza virus, or a history of transplantation, autoimmune disease, cancer, pregnancy, or use of cytotoxic medications.² These conditions are all thought to cause direct cell damage, leading to activation of the complement system, which leads to HUS.²

Atypical HUS is an exceedingly rare condition with evolving treatment strategies. Until 2013, the primary treatment for aHUS was plasma exchange, which transiently improved platelet counts and lactate dehydrogenase in some patients but failed to address the underlying complement dysregulation seen in aHUS.¹ End-stage renal disease or death occurred in 33%–40% of patients during the first presentation with aHUS, whereas 65% suffered permanent renal damage, developed end-stage renal disease, or died within 1 year of diagnosis.¹ This changed after introduction of a terminal complement inhibitor, eculizumab (Soliris; Alexion Pharmaceuticals, Boston, MA). Eculizumab is a humanized monoclonal antibody that binds C5 and prevents generation of C5a and C5b-C9, halting the complement alternative pathway.¹ Eculizumab has been shown to improve hematologic, renal, and survival outcomes in aHUS, although is quite expensive at roughly $500,000 per year.¹

Although ocular manifestations of aHUS are rare, central retinal artery occlusion, central retinal vein occlusion, associated hypertensive retinopathy, multifocal serous retinal detachments, choroidal and vitreous hemorrhage, and paralytic strabismus have all been reported.^8–10 To date, three cases of Purtscher-like retinopathy associated with aHUS have been reported in the literature (Table 1).^5–7

Table 1.

Visual Outcomes, OCT Findings, and Treatments of All Reported Cases of Purtscher-Like Retinopathy Associated With Atypical Hemolytic Uremic Syndrome

Case	Initial VA	IRF	SRF	Treatment	Time to Resolution of CI-CME	Time to Final VA	Final VA
Ramos de Carvalho et al	20/15 OD	N	N	Eculizumab	5 days	15 days	20/15 OD
	20/200-2 OS	Y	N				20/15-2 OS
Ustaoğlu et al	20/60 OD	Y	Y	Plasmapheresis and eculizumab	3 months	3 months	20/20 OD
	20/60 OS	Y	Y				20/20 OS
Álvarez et al	20/50 OD	N	Y	Plasmapheresis, IV steroids, eculizumab	4 months	4 months	20/25 OD
	20/40 OS	N	Y				20/20 OS
Present case	4/200 OD	Y	Y	IV steroids and eculizumab	3 weeks	2 months	20/70 OD
	4/200 OS	Y	Y				20/40 OS

Time to final visual acuity calculated based on time from initiation of treatment to the first time each patient was reported to reach his/her best-recorded visual acuity.

CI-CME, center-involving cystoid macular edema; IRF, intraretinal fluid on initial OCT; SRF, subretinal fluid on initial OCT.

Ramos de Carvalho et al first reported this association in a 20-year-old woman with a history of familial aHUS because of a complement factor H mutation, who developed Purtscher-like retinopathy. The patient had renal failure from an early age because of aHUS and had a history of bilateral renal transplants. Her aHUS was treated with chronic maintenance plasmapheresis that was discontinued before the onset of her vision changes. She presented with two days of blurry vision in the left eye, with visual acuity of 20/15 in the right eye and 20/200–2 in the left eye, with CWS in the macula bilaterally. Fluorescein angiography showed evidence of capillary nonperfusion bilaterally, with cystoid macular edema noted on OCT of the left eye. The patient’s aHUS was treated with eculizumab, and the patient experienced significant visual improvement to 20/15–2 in her left eye two weeks after the onset of treatment.

Ustaoğlu, et al then reported the case of a 25-year-old woman who presented with headaches, blurry vision, and acute renal failure. Numerous peripapillary CWS and macular edema were noted. Workup revealed a microangiopathic hemolytic anemia, and the patient was treated with plasmapheresis. After diagnosis with aHUS, eculizumab was started for treatment of her systemic disease. Visual acuity improved from 20/60 in both eyes to 20/20 in both eyes 3 months later, with resolution of macular edema and CWS.⁷

Lastly, Álvarez, et al reported the case of a 22-year-old man who presented with 1 week of headaches, dizziness, and blurry vision. Visual acuity was 20/50 in the right eye and 20/40 in the left eye, with CWS at the posterior pole, and multifocal serous retinal detachments in the macula bilaterally. Optical coherence tomography angiography (OCTA) demonstrated perifoveal ischemia in the superficial and deep capillary plexuses with an enlarged foveal avascular zone. Laboratory work revealed renal failure, thrombocytopenia, and microangiopathic hemolytic anemia, and the patient was hospitalized. The patient was initially treated with corticosteroids, plasmapheresis, and hemodialysis; then eculizumab was added after conclusive diagnosis with aHUS. At 4-month follow-up, visual acuity had improved to 20/25 in the right eye and 20/20 in the left eye, with OCTA demonstrating revascularization of the previously ischemic perifoveal capillaries and slight decrease in the size of the foveal avascular zone.

Previous cases of Purtscher-like retinopathy associated with aHUS have had good outcomes, with return to baseline visual acuity after treatment of aHUS with eculizumab ± plasmapheresis and steroids. Although eculizumab is the treatment of choice for aHUS, as demonstrated in these cases, patients with aHUS are often critically ill, with a significant workup required before arriving at the diagnosis of aHUS. Our patient also improved after steroids and eculizumab, although her visual outcomes were worse than previous published cases, with significant optic atrophy and depressed visual fields bilaterally after resolution of clinical stigmata of Purtscher-like retinopathy and macular edema. Reviewing these other published cases, our patient had significantly more severe Purtscher-like retinopathy at presentation, with worse starting visual acuity and larger areas of retinal whitening. Additionally, our patient had a prolonged prodrome before reaching a diagnosis of aHUS and starting treatment with eculizumab. Although eculizumab was started after just 5 days of visual symptoms, it is possible she may have had undetected retinal vascular changes and ischemia for a longer period, which may have negatively affected her outcome.

Given the rarity of Purtscher and Purtscher-like retinopathy, it is difficult to draw conclusion on the effects of treatment on visual recovery. In patients not receiving treatment, Agrawal, et al demonstrated spontaneous improvement in visual acuity by >2 lines in 50% of eyes and improvement by >4 lines in 23% of patients with Purtscher and Purtscher-like retinopathy.¹¹ Xia et al performed a systematic review of outcomes for 139 eyes with Purtscher and Purtscher-like retinopathy.¹² The most common treatment was corticosteroids, with 63% of patients receiving this treatment. A minority of patients were treated with traditional Chinese medicine therapies, hyperbaric oxygen, or some combination of steroids, traditional Chinese medicine, and hyperbaric oxygen. They found no statistical difference in visual acuity at any time point between those treated with steroids and those without treatment. Similarly, pooling all treatments, there was no difference between those with and without treatment.

Of the four patients with Purtscher-like retinopathy associated with aHUS, all received eculizumab, two received steroids, and two received plasmapheresis. Excluding the eye with an initial visual acuity of 20/15, all 7 eyes improved by >2 lines, with 71.4% of eyes improving by >4 lines. Time to resolution of center-involving cystoid macular edema (CI-CME) may have a prognostic role in these patients. For four of seven eyes, short-term follow-up was not reported, and final OCT and visual acuity were reported 3 to 4 months after the onset of Purtscher-like retinopathy, limiting our ability to draw conclusion about the temporal relation between OCT findings and visual acuity in these patients. However, for the remaining three eyes with initial CME, CI-CME resolved 10 days to 5 weeks before the best-recorded visual acuity. Given the revascularization seen on serial OCTA in the case of Alvarez, et al,⁵ and the delay from time of resolution of CI-CME to final visual acuity in these eyes, this may suggest that improvement in vision is not only related to resolution of CI-CME but also to vascular remodeling after treatment.

In summary, Purtscher-like retinopathy is a rare but vision-threatening complication of aHUS. Eculizumab is an effective treatment for the systemic illness caused by aHUS. The outcomes for the patients in this small case series would suggest eculizumab, and control of the systemic compliment-mediated disease may be effective for Purtscher-like retinopathy associated with aHUS. Although limited conclusions can be drawn from such a small series, early initiation of treatment with eculizumab may lead to better visual outcomes. Therefore, a prompt inpatient ophthalmology consult should be pursued in all patients with evidence of thrombotic microangiopathy and acute changes in vision.