Incidentally detected bilateral sub-internal limiting membrane hemorrhages in typical hemolytic uremic syndrome: a case report

Han Jo Kwon; Ji Yeon Song

doi:10.3339/ckd.25.003

Abstract

We present an incidentally detected case of bilateral sub-internal limiting membrane (ILM) hemorrhage secondary to typical hemolytic uremic syndrome (HUS) along with a literature review. A 4-year-old girl presented to our emergency department with bloody diarrhea, abdominal pain, fever, and oliguria. HUS was suspected based on clinical symptoms and laboratory findings suggestive of hemolytic anemia, thrombocytopenia, and acute kidney injury. Supportive management, including intermittent dialysis, was provided during admission. However, the patient exhibited central nervous system involvement and presented with a seizure. Despite the absence of visual symptoms, a fundus examination revealed unexpected bilateral sub-ILM hemorrhages and a cotton wool spot in the right eye. Blood dyscrasia improved with repeated hemodialysis and red blood cell transfusions. The sub-ILM hemorrhage gradually resolved, as observed on consecutive fundus photographs. Multimodal retinal imaging revealed healthy capillary structures without evidence of macular ischemia or fibrosis. Typical HUS can be accompanied by a sub-ILM hemorrhage without preceding symptoms. The absence of visual symptoms, despite significant retinal abnormalities, emphasizes the importance of immediate and routine fundus examinations in patients with typical HUS. This proactive approach improves early detection of ocular involvement, enabling prompt intervention to manage potential visual complications, and ultimately improving patient outcomes.

Key words: Case reports; Hemolytic-uremic syndrome; Pediatrics; Retinal hemorrhage

Introduction

Hemolytic uremic syndrome (HUS) is a common cause of acute kidney injury in children, and it is characterized by the clinical triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury [1,2]. Typical HUS is induced by Shiga toxin-producing bacteria that often affect the kidneys, resulting in conditions ranging from mild hematuria to severe acute kidney injury with renal cortical necrosis [3]. Extrarenal manifestations contribute significantly to morbidity and mortality, potentially affecting various organ systems, such as the central nervous, gastrointestinal, endocrine, and cardiovascular systems [4]. Ocular involvement in HUS, especially in typical HUS, is very rare, and it presents as cortical blindness, paresis of the ocular muscles, or thrombotic microangiopathy of the retinal vasculature, which pose potential acute or chronic visual complications [5]. Herein, we present a case of bilateral sub-internal limiting membrane (ILM) hemorrhage secondary to typical HUS in a child, along with a detailed literature review.

Case report

Systemic evaluation and treatment of typical HUS

A 4-year-old girl presented to our clinic with a 5-day history of bloody stools accompanied by abdominal pain for 4 days and fever for 3 days. Physical examination revealed periorbital edema, abdominal distension, decreased skin turgor, and grade 3 pitting edema in the pretibial area. The patient had no history of drug allergies or trauma. Initial examination revealed a heart rate of 117 beats/min with a blood pressure 105/56 mmHg, respiratory rate of 28 breaths/min, oxygen saturation of 99%, and a body temperature of 37.3 ℃. Initial laboratory test results were as follows: white blood cell count, 24.4×10³/μL (normal range: 4.9–13.2×10³/μL); hemoglobin, 10.6 g/dL (10.2–12.7 g/dL); neutrophil percentage, 77.7% (22.4%–69.0%); platelet count, 57.0×10³/μL (189–394×10³/μL); reticulocyte, 1.70% (0.82%–1.45%); positive schistocytes on the peripheral blood smear; blood urea nitrogen, 25.8 mg/dL (6.60–23.6 mg/dL); creatinine, 1.44 mg/dL (0.26–0.77 mg/dL); and high-sensitivity C-reactive protein, 3.80 mg/dL (0.00–0.50 mg/dL). The estimated glomerular filtration rate calculated from cystatin c was 22 mL/min/1.73 m². Urinalysis revealed a red blood cell count >30 per high power field and a protein/creatinine ratio >3.0. Stool polymerase chain reaction detected verotoxin-producing Escherichia coli. Finally, typical HUS was suspected based on the clinical presentation and laboratory findings. The patient did not respond to hydration and diuretic therapy, leading to the initiation of intermittent hemodialysis on hospital day 3 because of worsening renal function and fluid overload. On hospital day 5, the patient experienced a generalized tonic-type seizure, although computed tomography and electroencephalography showed no remarkable abnormalities. Urine output gradually increased from anuria to oliguria by hospital day 8, prompting the discontinuation of intermittent hemodialysis on day 9. On hospital day 15, the patient complained of mild swelling and yellowish pus in the right conjunctiva without visual problems. During the examination, an ophthalmologist identified an internal hordeolum in the right eye and incidentally discovered a bilateral retinal hemorrhage.

Fundus examination and multimodal retinal imaging

On slit-lamp examination, the conjunctival swelling resulted from a chalazion, and the patient was administered an antibiotic eye solution. Fundus photography revealed hourglass patterns of bilateral preretinal hemorrhages with horizontal fluid level and a right cotton wool spot near the fovea (Fig. 1A, B). The patient’s best-corrected visual acuity decreased to 20/50 in the right eye and 20/25 in the left eye without subjective visual symptoms. Intraocular pressure and pupillary responses were normal. Optical coherence tomography (OCT) revealed bilateral sub-ILM hemorrhages in the right superior and left inferior macula (Fig. 1C-F). No retinal vasculitis, retinitis, or neovascularization was observed in either macula. The patient underwent regular fundus examinations every 2 weeks. The pediatrician performed brain magnetic resonance imaging and angiography to rule out Terson syndrome, and no abnormal findings were noted. The sub-ILM hemorrhage in the right eye gradually disappeared as it moved upward toward the fovea (Fig. 2A-C). In the left eye, it spread to the perifovea and was steadily absorbed (Fig. 2D-F). Seven weeks after the initial ophthalmic examination, right fluorescein angiography showed no leakage from the vascular wall and no retinal or disc neovascularization (Fig. 2G). Three weeks later, right OCT angiography (OCTA) and OCT showed a normal superficial capillary plexus on the macula and complete absorption of the sub-ILM hemorrhage (Fig. 2H-J). Left fluorescein angiography and OCTA revealed healthy macular capillaries; however, a focal wedge-shaped remnant of the sub-ILM hemorrhage was present in the left OCT (Fig. 2K-N). Finally, best-corrected visual acuity improved to 20/16 in both eyes. The patient’s clinical condition and laboratory test results markedly improved. She was discharged from the hospital on day 14 with scheduled follow-up on an outpatient basis. Currently, her kidney function is normal, and neurological symptoms are stable.

Discussion

This report is the first to present the progressive resolution of bilateral sub-ILM hemorrhages using multimodal retinal imaging, presenting the amelioration of systemic conditions during typical HUS.

Ocular involvement in pediatric patients with HUS has rarely been reported, although the retinal microvasculature can easily be observed by fundoscopy [5]. Ocular findings from previous studies revealed retinal, choroidal, and vitreous hemorrhages, along with ischemic signs such as cotton wool spots, retinal whitening, and nonperfusion areas, which may cause retinal neovascularization and optic atrophy [5]. These ocular manifestations can occur secondary to thrombotic microangiopathy with increased platelet consumption following an initial injury to the vascular endothelial cells in HUS [5].

Siegler [6] reported an approximate frequency of ocular involvement of <1%, including cortical blindness, paresis of the ocular muscles, and, rarely, thrombotic microangiopathy of the retinal vasculature. Sturm et al. [5] reported that three of 67 patients with HUS (4%) had ocular involvement, and ophthalmic findings showed intraretinal hemorrhages to Purtscher-like retinopathy with retinal ischemia. Rooney et al. [7] described retinal hemorrhages in one of their 25 patients, and in a group of 44 children reported by Sheth et al. [8], two children had vitreous hemorrhages and one had a retinal infarct. Spizzirri et al. [9] reported fundoscopic abnormalities in 13.1% of typical HUS cases, and showed a higher incidence of ocular involvement compared to previous reports. Signs of retinal abnormalities with typical HUS have only been reported in approximately 20% of studies, and determining the frequency and severity of ocular abnormalities is difficult in pediatric patients with HUS, possibly causing the underestimation of the frequency of retinal abnormalities. Therefore, early detection of ocular manifestations through fundoscopy examination is recommended for typical HUS patients.

Table 1 summarizes previous cases of retinal abnormalities associated with typical HUS in children, including the present case [5,10-14]. Eight cases were reported by six literatures. The mean age was 25.7±13.7 months, and E. coli was detected in stool culture in only one other case in addition to the present case. Only two patients (cases 4 and 7) had decreased vision, while the others had no suspicion of visual loss before the inspection. In 88.9% of cases, retinal abnormalities were observed in both eyes. Retinal hemorrhage (77.8%) was the most frequent retinal lesion, followed by cotton wool spots (66.7%), increased vascular tortuosity (66.7%), optic disc involvement (atrophy or hemorrhage, 66.7%), neovascularization (44.4%), and macular fibrosis (33.3%). Pan-retinal photocoagulation was performed in two cases; however, their final visual acuity was below 20/60. In all cases, the final vision median was 20/100. The leading causes of visual loss were irreversible macular fibrosis and optic disc atrophy associated with severe retinal ischemia [10,12-14].

Sub-ILM hemorrhages can be caused by Valsalva maneuver, Terson syndrome, blunt facial trauma, or blood dyscrasia [15]. Along with anemia and thrombocytopenia, vascular injury to the endothelial cells of the superficial capillaries between the ILM and the nerve fiber layer is likely to cause sub-ILM hemorrhage. Seizures may accelerate sudden capillary damage. ILM puncture using pulsed neodymium-doped yttrium–aluminum–garnet laser and ILM peeling with vitrectomy are the primary treatment methods for long-standing or vision-threatening sub-ILM hemorrhages. Ophthalmologists should regularly monitor, rather than actively treat, resorptive sub-ILM hemorrhages in such cases, owing to retinal damage from laser treatment and the various complications of vitrectomy, including cataract formation. Even after HUS treatment, macular fibrosis accompanied by severe retinal ischemia results in decreased vision in both eyes, which could decrease the quality of life. In cases of severely ischemic retinas, an ophthalmologist should consider pan-retinal photocoagulation, injection of anti-vascular endothelial growth factor, and initiation of vitrectomy as treatment options, along with frequent follow-up to prevent irreversible visual loss. When retinal abnormalities are observed in typical HUS, noninvasive OCT and OCTA may be efficient in revealing vascular abnormalities and deciding the treatment.

This report has several limitations, including its nature as a single-case report and its short follow-up period. Further investigation into the prevalence and characteristics of ocular manifestations in patients with typical HUS could provide deeper insights into the pathophysiology and clinical course of the disease. Longitudinal studies are warranted to assess the natural history and prognosis of sub-ILM hemorrhage in HUS patients, including the resolution of retinal abnormalities and long-term visual outcomes. Sub-ILM hemorrhages of the macula impede the acquisition of satisfactory fluorescein angiography and OCTA images. Nevertheless, this report demonstrated the successive resorption of a sub-ILM hemorrhage in a patient with typical HUS.

In conclusion, the identification of a bilateral sub-ILM hemorrhage in a patient with typical HUS highlights the importance of comprehensive ophthalmological assessments in such cases. Moreover, the absence of preceding visual symptoms despite significant retinal abnormalities emphasizes the need for immediate and routine fundus examinations in patients presenting with typical HUS, even in the absence of visual complaints. Early detection of ocular involvement through regular fundus examinations enables timely intervention to manage potential visual complications, improving patient outcomes and reducing the risk of permanent vision loss.

Notes

Ethical statements

This report was approved by the Institutional Review Board of Pusan National University Yangsan Hospital (IRB No. 05-2021-108). The ethics committee waived the requirement for written informed consent for this case report.

Conflicts of interest

No potential conflict of interest relevant to this article was reported.

Funding

This study was supported by a 2023 research grant from Pusan National University Yangsan Hospital.

Author contributions

Conceptualization: JYS, HJK

Data curation: HJK

Investigation: JYS, HJK

Methodology: HJK

Visualization: HJK

Writing-original draft: HJK

Writing–review & editing: JYS

All authors read and approved the final manuscript.

References

1. Salvadori M, Bertoni E. Update on hemolytic uremic syndrome: diagnostic and therapeutic recommendations. World J Nephrol 2013;2:56-76.

2. Manrique-Caballero CL, Peerapornratana S, Formeck C, Del Rio-Pertuz G, Gomez Danies H, Kellum JA. Typical and atypical hemolytic uremic syndrome in the critically ill. Crit Care Clin 2020;36:333-56.

3. Petruzziello-Pellegrini TN, Moslemi-Naeini M, Marsden PA. New insights into Shiga toxin-mediated endothelial dysfunction in hemolytic uremic syndrome. Virulence 2013;4:556-63.

4. Khalid M, Andreoli S. Extrarenal manifestations of the hemolytic uremic syndrome associated with Shiga toxin-producing Escherichia coli (STEC HUS). Pediatr Nephrol 2019;34:2495-507.

5. Sturm V, Menke MN, Landau K, Laube GF, Neuhaus TJ. Ocular involvement in paediatric haemolytic uraemic syndrome. Acta Ophthalmol 2010;88:804-7.

6. Siegler RL. Spectrum of extrarenal involvement in postdiarrheal hemolytic-uremic syndrome. J Pediatr 1994;125:511-8.

7. Rooney JC, Anderson RM, Hopkins IJ. Clinical and pathological aspects of central nervous system involvement in the haemolytic uraemic syndrome. Aust Paediatr J 1971;7:28-33.

8. Sheth KJ, Swick HM, Haworth N. Neurological involvement in hemolytic-uremic syndrome. Ann Neurol 1986;19:90-3.

9. Spizzirri AP, Cobenas CJ, Alconcher LF, Murray N, Zarate C, Curutchet L, et al. Ocular involvement in STEC-associated hemolytic uremic syndrome. Pediatr Nephrol 2022;37:2699-703.

10. Siegler RL, Brewer ED, Swartz M. Ocular involvement in hemolytic-uremic syndrome. J Pediatr 1988;112:594-7.

11. Lauer AK, Klein ML, Kovarik WD, Palmer EA. Hemolytic uremic syndrome associated with Purtscher-like retinopathy. Arch Ophthalmol 1998;116:1119-20.

12. 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;19:77-9.

13. Geraissate JC, Yamamoto RE, Isaac DL, Avila MP. Hemorrhagic retinopathy in an infant with hemolytic-uremic syndrome. Arq Bras Oftalmol 2014;77:397-9.

14. Sedarous F, Makar I. Progressive retinal findings in hemolytic uremic syndrome. J Pediatr Ophthalmol Strabismus 2018;55:e49-51.

15. De Maeyer K, Van Ginderdeuren R, Postelmans L, Stalmans P, Van Calster J. Sub-inner limiting membrane haemorrhage: causes and treatment with vitrectomy. Br J Ophthalmol 2007;91:869-72.

Fig. 1.

Bilateral sub-internal limiting membrane (ILM) hemorrhages in typical hemolytic uremic syndrome at the initial ophthalmic examination. (A, B) Fundus photography. (C, D) Cross-sectional horizontal and (E, F) vertical optical coherence tomography (OCT) B-scan images at the initial ophthalmic examination. In both eyes, hourglass-patterned preretinal hemorrhages surround the fovea with distinct and horizontal fluid-clot levels. A small cotton wool spot is on the right macula at the superonasal side of the fovea. In the OCT images, these preretinal hemorrhages corresponding to hyper-signal intensity beneath the detached ILM were diagnosed as sub-ILM hemorrhages. The right visual acuity is 20/50, and the left is 20/25.

Fig. 2.

Progressive resolution of sub-internal limiting membrane (ILM) hemorrhages and multimodal retinal imaging of typical hemolytic uremic syndrome. At 2, 6, and 10 weeks after the initial ophthalmic examination: (A-C) right fundus photographs and (D-F) left fundus photographs. Sub-ILM hemorrhages were gradually absorbed. (G) At week 7, fluorescein angiography reveals absence of nonperfusion or neovascularization in the right eye. The focal hypofluorescence region is a blockade of background fluorescence because of the less-absorbed sub-ILM hemorrhage. At week 10, (H) normal superficial capillary plexus on optical coherence tomography (OCT) angiography and (I, J) normal macular structures on OCT are observed. The patient’s vision improved to 20/16. (K, L) The left eye has no complications, such as nonperfusion, neovascularization, or capillary dropout. (M, N) Focal sub-ILM hemorrhage remnants and mild foveal elevation are observed in the left macula; however, the left visual acuity was restored to 20/16.

Table 1.

Summary of the literature review on retinal abnormalities associated with typical hemolytic uremic syndrome in children

Author	Case No.	Age (mo)	Detected pathogen	Initial ophthalmic signs before fundus examination	Laterality	Retinal hemorrhages	Cotton wool spots	Increased vascular tortuosity	Optic disc involvement	Retinal and disc neovascularization	Macular fibrosis	Treatments for retinal lesion	Final vision (Snellen)
Sturm et al. [5]	1	13	None	Routine examination, no clinical signs	OU	O	O	O	O	X	X	None	OD 20/20
	1	13			OU	O	O	O	O	X	X	None	OS 20/50
	2	12			OU	O	O	O	O	O	X	PRP	OD 20/60
	2	12			OU	O	O	O	O	O	X	PRP	OS 20/100
	3	40			OU	O	X	X	X	X	X	None	OD 20/20
	3	40			OU	O	X	X	X	X	X	None	OS 20/20
Siegler [10]	4	16	None	Decreased vision	OU	O	O	O	O	O	X	None	OD NLP
Siegler [10]	4	16	None	Decreased vision	OU	O	O	O	O	O	X	None	OS NLP
Lauer et al. [11]	5	31	Stool culture:	Abnormal pupil response, conjunctival chemosis	OU	O	O	X	X	X	X	None	Decease
Lauer et al. [11]	5	31	E. coli (O157:H7)	Abnormal pupil response, conjunctival chemosis	OU	O	O	X	X	X	X	None	Decease
Krott et al. [12]	6	12	None	Esotropic convergence	OU	X	X	O	O	X	O	None	OD 20/1000
Krott et al. [12]	6	12	None	Esotropic convergence	OU	X	X	O	O	X	O	None	OS 20/400
Geraissate et al. [13]	7	23	None	Decreased vision	OU	O	O	O	O	O	O	PRP	OD 20/540
Geraissate et al. [13]	7	23	None	Decreased vision	OU	O	O	O	O	O	O	PRP	OS 20/270
Sedarous et al. [14]	8	35	None	Strabismus	OS	X	X	O	O	X	O	None	OS 20/2000
Our case	9	49	Multiplex PCR:	Right conjunctival swelling	OU	O	O	X	X	X	X	None	OD 20/16
Our case	9	49	verotoxin-producing E. coli	Right conjunctival swelling	OU	O	O	X	X	X	X	None	OS 20/16

OU, oculi uterque (both eyes); OD, oculus dexter (right eye); OS, oculus sinister (left eye); PRP, pan-retinal photocoagulation; NLP, no light perception; E. coli, Escherichia coli; PCR, polymerase chain reaction.