Bilateral Ischemic Retinopathy Associated With Upshaw-Schulman Syndrome: A Case Report

Abstract

Purpose:

This is the first report to our knowledge of ischemic retinopathy in a pediatric patient with Upshaw-Schulman syndrome (USS).

Methods:

A 6-year-old girl previously diagnosed with USS was referred to our clinic with exodeviation of the left eye and a 2-month-long decrease in vision of both eyes. A dilated fundus examination showed a total vitreous hemorrhage in both eyes. The first course of action was conservative treatment, with the patient experiencing visual-acuity improvement in her right eye.

Results:

An ischemic retina and optic nerve atrophy was found once the left eye was cleared of the hemorrhage.

Conclusions:

We present a case of a vitreous hemorrhage, possibly secondary to an episode of severe thrombocytopenia. Following USS diagnosis, providers should perform dilated ophthalmologic examinations as part of initial and follow-up general evaluations. This case exemplifies that, in understudied and underdescribed pediatric retinal diseases, extreme therapeutic decisions—such as surgery—should not be rushed.

Introduction

Upshaw-Schulman syndrome (USS) is a congenital type of thrombotic thrombocytopenic purpura (TTP) typically beginning during childhood. USS is an autosomal recessive disease associated with an ADAMTS13 deficiency, encoded by a gene on the long arm of chromosome 9 (locus 9q34). ^1,2

ADAMTS13 is a plasma metalloprotease that cleaves a specific peptide bond in the von Willebrand factor subunit. An ADAMTS13 deficiency decreases the size of von Willebrand factor multimers in circulation, causing thrombi in the microvasculature. ³ USS differs from the acquired form of TTP—found commonly in adolescents and adults—in which autoantibodies are responsible for neutralizing the ADAMTS13 metalloprotease. ² While the incidence of USS has not been established exactly, it is known to be fewer than 1 case per million individuals per year. More than 130 mutations have been reported as homozygous or heterozygous in ADAMTS13, resulting in severe deficiencies of this metalloprotease. ⁴

USS’s characteristic pentad includes thrombocytopenia, microangiopathic hemolytic anemia with schistocytes in the peripheral blood smear, renal failure, central nervous system dysfunction, and fever. Renal and central nervous system conditions appear during the course of the disease, although rarely at initial presentation. ⁴ Typical USS presentation involves relapsing episodes of microangiopathic hemolytic anemia, often triggered by physiological stressors such as infection, pregnancy, birth, or child delivery. ¹² USS is a rare cause of neonatal jaundice, and it should be considered in the differential diagnosis of intractable TTP. ⁵ In at least 30% of patients, USS crises are associated with cerebral ischemic vascular events. Acute renal failure and progressive renal deterioration are frequent because of hemoglobinuria and/or thrombotic microangiopathy during hemolytic crisis, occurring in approximately 50% of cases. ²

Treatment consists of administering fresh-frozen plasma because it contains physiological amounts of the ADAMTS13 enzyme or intermediated purity factor VIII concentrate, which in turn contains measurable ADAMTS13. ⁴ Fresh-frozen plasma has also been administered prophylactically. ⁵ In children, severe hyperbilirubinemia is typically found as a consequence of hemolytic anemia, and exchange transfusion is performed to prevent kernicterus. ⁶ It is necessary to monitor the platelet count of patients throughout this treatment. ⁴

We report—for the first time to our knowledge—the initial presentation and follow-up of a 6-year-old girl presenting to our clinic with bilateral vision loss and multimodal imaging of an ischemic retinopathy associated with USS.

Methods

Case Report

A 6-year-old girl was referred to our clinic with exodeviation of the left eye and a 2-month decrease in visual acuity (VA) in both eyes. Her gestational age was 40 weeks, and she was hospitalized for 3 days after birth with phototherapy for neonatal hyperbilirubinemia. Her first hospitalization was at age 1.5 years with fever, anemia with hemoglobin level at 5.6 g/dL, and thrombocytopenia with a platelet count of 8 × 10³/µL. ADAMTS13 count was found to be at 0%. With those findings, she was diagnosed with USS. A cranial computed tomography scan was also performed, with no alterations found.

The patient was referred to our clinic because of a bilateral vitreous hemorrhage previously diagnosed by an ophthalmologist. At that time, she received a transfusion of 2 units of erythrocyte concentrate, 5 of platelet apheresis, and 2 of fresh-frozen plasma. Her last fresh-frozen plasma transfusion occurred 5 days before being admitted to our clinic, and her last platelet count was 246 × 10³/µL. She also had systemic arterial hypertension in treatment with enalapril and hydralazine.

On examination in our clinic, the patient detected hand movement in the right eye but no light perception in the left eye. An exodeviation of the right eye was evident. Except for subtle, pigmented keratic precipitates in the right eye, the rest of the anterior segment was normal in both eyes. Intraocular pressure was normal in both eyes. A dilated fundus examination showed a total vitreous hemorrhage in both eyes. The retina was totally obscured in the right eye, whereas the peripheral upper retina of the left eye was visible without many details. Conservative treatment with a semi-Fowler position was selected because of the unstable systemic clinical course. The B scan showed only vitreous hemorrhage in both eyes. Pars plana vitrectomy was offered when systemic status allowed it.

We referred the patient back to the National Pediatrics Institute, where she had suspended treatment. There, continuous transfusions of fresh-frozen plasma and platelet concentrate were initiated on a weekly or biweekly basis for severe thrombocytopenia. The patient was lost to follow-up for 4 months (with us); she returned with a spontaneous improvement of her best-corrected VA (BCVA) in both eyes. Her surgery was consequently put on hold for 1 month. BCVA was 20/400 OD with vitreous hemorrhage that allowed poor visualization of the optic nerve head and far periphery. The left eye had no light perception with vitreous hemorrhage that allowed for the visualization of a white optic nerve head and exudates in the macular area.

One month later, at examination, the patient’s right-eye BCVA was 20/80. Her surgery was therefore deferred again, and she continued with observation only. The left eye remained without changes. Her BCVA improved to 20/40 OD after 1 year of observation, and the fundus examination displayed dehemoglobinized blood that allowed poor visualization of the optic nerve head and far periphery. The left eye did not reverse its no-light-perception vision, and there still were bloodless vasculature throughout the retina, a white optic nerve head, and exudates in the macular area (Figure 1). She was unable to suspend transfusions. At the last visit, when the retina was able to be better assessed, we performed an oral fluorescein angiogram (FA) (Figure 2). We have been unable to obtain an optical coherence tomography because of opaque media and limited patient cooperation.

Figure 1.

Ultra-widefield fundus photography (A) of the right eye with central dehemoglobinized vitreous hemorrhage that allowed poor visualization of the posterior pole. The periphery is visible with a temporal atrophic area with overlying fibrous tissue. (B) Left-eye bloodless vasculature throughout the retina, generalized atrophic retina and retinal pigment epithelium, white optic nerve head, and hard exudates in the macular area.

Figure 2.

(A) Right eye fluorescein angiography. Central hemorrhage blocks the underlying retina. A peripheral hypofluorescent area surrounded by hyperfluorescence corresponds to a chorioretinal atrophic scar. Within this atrophic area there is a gradual hyperfluorescence due to staining from preretinal fibrosis. (B) Left eye fluorescein angiography. In the posterior pole area, there is a generalized window defect hyperfluorescence with mottled hyperfluorescence and hypofluorescence that corresponds to generalized atrophic changes of the retina and retinal pigment epithelium.

Results

We present a case of a vitreous hemorrhage, possibly secondary to an episode of severe thrombocytopenia and arterial occlusive events. Hematologic conditions can present with intraocular manifestations due to vaso-occlusive or hemolytic disturbances. Our patient’s ocular manifestations coincided with an untreated low platelet count that spontaneously corrected after initiating systemic treatment and subsequent improved systemic condition. However, there were ischemic changes observed in both eyes. We could not rule out that the vitreous hemorrhage could have been due to retina neovascularization secondary to an ischemic event. However, the improved retinal condition and the absence of neovascularization on the FA prevented us from suspecting that the vitreous hemorrhage was secondary to diseased neovascularization, unless they had regressed over time.

Our patient showed no evidence of an ischemic cerebral event throughout the entire follow-up, although there was evidence of optic nerve atrophy. We could not establish whether the left eye’s optic nerve damage was a primary neuropathy with secondary ischemic retinopathy (or vice versa), because the hemorrhage obscured the fundus view. When the hemorrhage cleared, the retinal findings were as mentioned and remained stable in both eyes.

Conclusions

Several USS cases have been reported with typical presentations, such as microangiopathic hemolytic anemia, strokes, reversible cerebral vasoconstriction syndrome, and other signs/symptoms. ^2,3,7 However, few reports have specifically addressed ophthalmologic manifestations in USS.

Richa and Alpana Kondeker ⁷ reported a case of a 3-and-a-half-year-old boy with USS; the patient was readmitted only once for acute onset of bilateral vision loss and anemia (hemoglobin level, 6.8 mg/dL). Because an ophthalmologic examination and visual evoked potential test had normal findings, the vision loss was attributed to a cerebral infarction. Yagi and colleagues ⁸ reported 17 cases of patients with USS and mentioned only “visual disturbance” without further information. Veyradier et al ⁹ reported 6 cases of USS, but only 1 case, without accompanying images or detailed descriptions, was mentioned to have transient amaurosis and retinal ischemia. Williams and colleagues ¹⁰ reported a case of serous retinal detachment in a patient with acquired TTP. Thus, to our knowledge, the case presented here is the first reported in detail and with color pictures and FA.

While a single case will not suffice for us to generate treatment and/or diagnosis guidelines, we do recommend that a dilated ophthalmologic examination be performed as part of the initial and follow-up general evaluation following a USS diagnosis. However, as in other ischemic retinopathies, we recommend an eye examination with pharmacological dilation of the pupil and follow-up visits with clinical photographs every 6 to 12 months in patients with no manifestations and every 1 to 2 months in patients with any extraocular or ocular symptoms. ¹¹ FA should be considered on a case-by-case basis.

We have examined our patient every 3 to 4 months and have engaged her mother in committing to regular follow-ups. The patient has a neutral refraction that does not need correction to date, but she must be carefully monitored for any visual change. We hypothesize that our patient will have a lifelong risk of retinal neovascularization, tractional retinal detachment due to ischemia, or new vitreous hemorrhage due to either ischemia and/or a new thrombocytopenic episode.

Given the restrictions posed by infants being unable to verbally report their symptoms, regular ophthalmologic examinations must take place even in the absence of explicit manifestations (eg, decreased VA, strabismus, or abnormal red reflex).

Our case exemplifies that observation is frequently a good therapeutic approach for pediatric retinal abnormalities, particularly in patients whose fragile systemic status might make general anesthesia undesirable. Therefore, in understudied and underdescribed pediatric retinal diseases, we recommend not rushing to extreme therapeutic decisions such as surgery. It is important to consider the risk of amblyopia when deciding on interventions, have a multidisciplinary team for decision-making, and have treatment available for possible complications, given the risk of potentially fatal outcomes.

In summary, we report an ischemic retinopathy that manifested as bilateral vitreous hemorrhage in a patient with USS. Routine dilated fundus ophthalmoscopy is suggested in all infants with USS.