Hemolytic uremic syndrome (HUS) is a common cause of acute renal failure in children, classically characterized by the triad of microangiopathic hemolytic anemia, consumptive thrombocytopenia, and renal insufficiency. There are two types of HUS: a post-infectious, post-diarrheal (D+HUS) form and a nondiarrheal form, which is less common (approximately 10%) and associated with mutations in the alternative complement pathway (ie, atypical HUS).1 Atypical HUS often presents with a relapsing course, extrarenal complications, and a poor prognosis. Ocular involvement is reported in only 4% of pediatric HUS cases2 and is even rarer in atypical HUS cases. We report the case of a child diagnosed as having atypical HUS with recurrent ocular involvement.
An 11-year-old girl was admitted for 6 days for hematuria, headaches, epistaxis, and diffuse petechiae. Her laboratory results were significant for an increased leukocyte count (12,500/mm3), a decreased hemoglobin (4.8 g/dL) with schizocytes, a decreased platelet count (36,000/mm3), a decreased C3 level (0.45 g/L), and elevated levels of serum creatinine (567.8 µmol/L), urea (54.99 µmol/L), and lactate dehydrogenase (2,773 U/L). Urinalysis revealed red cell casts and the patient was mildly hypertensive for her age (120/80 mm Hg). Coagulation laboratory results were normal and Coombs’, antistreptolysin O, antinuclear antibody, anti-neutrophil cytoplasmic antibody, platelet-rich plasma, and hepatitis B surface antigen tests were all negative. Renal ultrasonography revealed enlarged kidneys with a blurred cortico-medullary boundary.
Given this constellation of laboratory and physical examination findings, the patient was diagnosed as having atypical HUS and received infusions of red blood cells and fresh frozen plasma and heparin anti-coagulation. Three days later, persistent renal failure necessitated 3 days of hemodialysis. Following these interventions, the patient’s hematological parameters and renal function normalized.
However, 8 days after hemodialysis was stopped, the patient reported a sudden decrease in visual acuity. Her laboratory and hematologic parameters showed early evidence of a relapse of atypical HUS. On ocular examination, visual acuity was 20/100 in the right eye and 20/200 in the left eye. Fundus examination revealed bilateral flame-shaped intraretinal hemorrhages, venous tortuosity, and mild optic disc edema consistent with central retinal vein occlusion/venous stasis retinopathy. Given these findings, the patient underwent aggressive infusions of fresh frozen plasma and washed red blood cells transfusions.
Ten days after the onset of visual symptoms, the flame-shaped retinal hemorrhages had improved, but subhyaloid, premacular hemorrhages were noted (Figures 1A–1B). Fluorescein angiography revealed no evidence of retinal nonperfusion, neovascularization, or arteriovenous transit delay. After 3 weeks of treatment, partial improvement of premacular hemorrhage was noted and the patient was discharged. Three months after discharge, visual acuity was 20/20 bilaterally with complete resolution of fundus findings and normal systemic laboratory tests.
Day 10: bilateral subhyaloid, premacular hemorrhages. (A) Central retinal vein occlusion partly absorbed in the right eye. (B) Intraretinal hemorrhage along the inferior temporal branch in the left eye. (C, D) Day 1 during the relapsing episode: bilateral optic disc edema. (E, F) Remarkable resolution of disc edema at the 3-month follow-up visit. (G, H) Hess screen test indicated inferior rectus palsy in the right eye.
One year later, the patient was readmitted with malaise, petechiae, and dark urine. Laboratory studies confirmed a relapse of atypical HUS and the patient underwent treatment. Three days later, the patient was febrile with worsening acute renal failure, requiring 3 days of hemodialysis. The patient continued to improve; however, 2 weeks after hospitalization, she developed sudden onset diplopia.
Computed tomography was unremarkable at this time. Visual acuity was 20/20 in both eyes. The pupils were normal. Dilated fundus examination revealed bilateral optic disc edema (Figures 1C–1D). The Hess screen test for assessing extraocular muscle function revealed inferior rectus paralysis in the right eye (Figures 1G–1H). The patient was treated with intravenous dexamethasone followed by an oral course of prednisolone. Three weeks later, diplopia and optic disc edema resolved (Figures 1E–1F). Repeat ocular examination was normal at the 9-month follow-up visit.
The pathophysiology of atypical HUS is characterized by a cascade of microvascular thrombi formation that obstructs vascular lumina throughout the body, especially in the kidneys.3 Extrarenal complications in atypical HUS have been reported in the brain, heart, lungs, gastrointestinal system, and extremities, often with multi-organ involvement.3 Interestingly, ocular involvement is uncommon in HUS, but it can manifest as periorbital edema, vitreous hemorrhage, retinal hemorrhage, retinal arterial/vein occlusion, ischemic retinopathy, neovascularization, retinal detachment, subretinal fibrosis, choroidal hemorrhage, and/or optic atrophy (Table 1).3–5
Details of Reported Ocular Involvement in Patients With HUS
An extensive literature review (ie, a PubMed search for “hemolytic uremic syndrome,” “ocular,” “eye,” “ophthalmic,” and combinations as of September 2, 2013, limited to English and Chinese) revealed only one recent report of pediatric atypical HUS, with ocular findings describing a 12-year-old boy with ocular pain, vitreous bleeding, elevated ocular pressure, choroidal hemorrhage, and retinal ischemia.6 In contrast, our case demonstrated a different disease course regarding the onset and nature of ocular symptoms. To the best of our knowledge, this is the first report of recurrent ocular involvement with premacular subhyaloid hemorrhage in pediatric atypical HUS.
Preretinal hemorrhage has been reported in cases of D+HUS and thrombotic thrombocytopenic purpura (ie, the other subtype of thrombotic microangiopathy disease)7; however, macular involvement has not been reported. In our case, preretinal hemorrhage and central retinal vein occlusion were most likely due to microcirculation occlusion found in atypical HUS. The premacular hemorrhages were likely preceded by injury to the perifoveal capillary endothelium induced by complement dysregulation and aggravated by increased venous pressure transmitted from the central retinal vein. Despite the severity of ocular involvement, fluorescein angiography revealed preserved retinal perfusion and visual recovery was complete.
Although optic disc edema and diplopia have been reported as signs of neurological involvement in HUS,8 the absence of other neurological dysfunction and normal computed tomography in our patient make neurological involvement (namely, cerebral thrombotic microangiopathy and hypertensive encephalopathy) unlikely. Ideally, a complete evaluation would include lumbar puncture with cerebro-spinal fluid analysis and a measurement of opening pressure, but this was not obtained due to parental reluctance. Anemia and hypoproteinemia were also unlikely to cause optic disc swelling because there was no evidence of edema elsewhere. As such, optic nerve edema and diplopia were most likely due to ocular thrombotic microangiopathy, which affected both the optic nerve head as papillitis and the inferior rectus muscle as ophthalmoplegia.
This is the first case report of a pediatric patient diagnosed as having atypical HUS who developed diverse ocular manifestations during two distinct episodes. Clinical remission or hemodialysis did not appear to prevent ocular thrombotic microangiopathy. Premacular hemorrhage and ophthalmoplegia have not been reported previously in HUS. Review of the literature revealed that ocular involvement was most commonly observed in the acute phase (Table 1). Our case represents the first report of ocular involvement during the convalescence phase after improvement of acute atypical HUS. For patients younger than 3 years, ocular abnormalities were usually discovered by ophthalmologists, which suggests a role for ophthalmic evaluation in children who are pre-verbal. Although visual impairment can be severe, full recovery is possible, as demonstrated by our patient.
- Zimmerhackl LB, Besbas N, Jungraithmayr T, et al. Epidemiology and pathophysiology of atypical and recurrent hemolytic uremic syndrome. Sem Throm Hem. 2006;32:113–120.
- Sturm V, Menke MN, Landau K, Laube GF, Neuhaus TJ. Ocular involvement in paediatric haemolytic uraemic syndrome. Acta Ophthalmol. 2010;88:804–807.
- Dragon-Durey MA, Sethi SK, Bagga A, et al. Clinical features of anti-factor H autoantibody-associated hemolytic uremic syndrome. J Am Soc Nephrol. 2010;21:2180–2187.
- Krott R, Querfeld U, Bartz-Schmidt KU, Hammers H, Hammers W, Heimann K. Progressive subretinal fibrosis in a child following hemolytic uremic syndrome. Retina. 1999;19:77–79.
- Lauer AK, Klein ML, Kovarik WD, Palmer EA. Hemolytic uremic syndrome associated with Purtscher-like retinopathy. Arch Ophthalmol. 1998;116:1119–1120.
- Larakeb A, Leroy S, Frémeaux-Bacchi V, et al. Ocular involvement in hemolytic uremic syndrome from factor H deficiency. Pediatr Nephrol. 2007;22:1967–1970.
- Bobbio-Pallavicini E, Porta C, Brocchieri A, Saporiti A, Tacconi F. Ocular involvement in acute thrombotic thrombocytopenic purpura. Haematologica. 1995;80:194–195.
- Sheth KJ, Swick HM. Neurological involvement in hemolytic-uremic syndrome. Ann Neurol. 1986;19:90–93.
- Caton B, Diaz de Otazu R, Aldamiz-Echebarria M, Viguri A. Haemolytic-uraemic syndrome with thrombotic microangiopathy of the retina following cytomegalovirus infection: postmortem findings. Postgrad Med J. 1993;69:653–655.
- Benzimra RE, Antao AJ, Donovan KL, Williams AJ. The association between retinal ischaemia and end-stage renal damage in thrombotic microangiopathy. QJM. 1998;91:417–422.
- Patel MR, Bains AK, O’Hara JP, Kallab AM, Marcus DM. Purtscher retinopathy as the initial sign of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome. Arch Ophthalmol. 2001;119:1388–1389.
- David R, Hochberg-Klein S, Amer R. Resolution of ocular involvement with systemic eculizumab therapy in atypical hemolytic-uremic syndrome. Eye. 2013;27:997–998.
- Eberhard OK, Labjuhn SO, Olbricht CJ. Ocular involvement in haemolytic uraemic syndrome: case report and review of the literature. Nephrol Dial Transplant. 1995;10:266–269.
- Siegler RL, Brewer ED, Swartz M. Ocular involvement in hemolytic-uremic syndrome. J Pediatr. 1988;112:594–597.
Details of Reported Ocular Involvement in Patients With HUS
|Caton et al., 19939||D–||33||Acute||DV||OU: chorioretinitis, periorbital edema, peripapillary retinal edema||HD, PE||Blindness, deceased|
|Benzimra et al., 199810,b||D–||19 to 46||Acute||DV (2)||OU: retinal ischemia, cotton-wool spots, flame hemorrhages||FFP, HD (2); PE, HD (4)||End stage renal failure (6), visual improvement (2)|
|Patel et al., 200111||D–||52||Before acute phase||OU: DV||OU: Purtscher retinopathy (retinal edema, cotton-wool spots, retinal hemorrhages)||Steroids||Deceased|
|Larakeb et al., 20076||D–||7 mo||Chronic||OS: DV, pain||OS: vitreous hemorrhage, elevated ocular pressure, choroidal hemorrhage, retinal ischemia||PE, HD||OS: recovered|
|David et al., 201312||D–||23||Acute||OU: DV||OU: serous retinal detachment, cotton-wool spots, retinal hemorrhages||Plasmapheresis, HD, steroids, anti-hypertension, eculizumab||DV (OD: 20/50, OS: 20/27), retinal detachment resolved|
|Eberhard et al., 199513||D+||33||Acute||OD: DV, center scotoma||OD: retinal vessel occlusion (macular edema, retinal hemorrhages, optic disc edema)||PE, steroids, pentoxifylline||Near-blind|
|Lauer et al., 19985||D+||2.6||Acute||N/A||OU: retinal ischemia, intraretinal hemorrhages; OS: preretinal and peripapillary nerve fiber layer hemorrhage||Plasmapheresis, HD||Deceased|
|Krott et al., 19994||D+||1||Chronic||N/A||OD: esotropia, subretinal fibrotic tissue involving papilla and macula; OS: normal||HD||DV (OD: 20/1000, OS: 20/400)|
|Chronic||OS: DV||OD: not changed; OS: progressive subretinal fibrosis|
|Sturm et al., 20092||D+||1.1||Acute||N/A||OU: retinal hemorrhages, disc hemorrhages, cotton-wool spots, tortuous vessels, venous engorgement||Dialysis||OS: DV (OU: 20/50), optic atrophy, vessel tortuosity; OD: recovered|
|D+||1||Acute||N/A||OU: Purtscher-like retinopathy (flame-shaped intraretinal hemorrhages, peripapillary retinal ischemia, cotton-wool spots)||Dialysis, panretinal laser photocoagulation||OU: DV (OD: 20/60, OS: 20/100), neovascularizations, optic atrophy|
|D+||3.3||Acute||N/A||OU: intraretinal hemorrhages; OD: flame-shaped hemorrhages||Dialysis||OU: recovered|
|Siegler et al., 198814||D+||1.3||Acute||N/A||OU: optic atrophy, cotton-wool spots, BRAO, retinal ischemia, neovascularization||PD, red blood cell transfusion, anti-hypertension||Blindness|