Look into my eyes: An unusual first presentation of sickle cell disease
Authors: Rupali Sood, Kim Jiramongkolchai, Michael Streiff, Christopher Gonzalez, Satish Shanbhag, Sophie Lanzkron, J. Fernando Arevalo, Rakhi Naik
Journal: American Journal of Hematology (2017)

A 46-year-old African American woman presented to an outside hospital for severe 10/10 back pain. One day after admission, she developed acute-onset fever, tachypnea, and tachycardia prompting transfer to the ICU. Her husband also noted mental status change characterized by confusion, blank stares, and urinary incontinence. Within <12 hours, she became unresponsive, requiring intubation for airway protection. MRI was negative for intracranial abnormality and EEG did not show epileptiform activity. Lumbar puncture revealed a cerebrospinal fluid (CSF) white blood count of 1, red blood cell count of 1, total protein of 56 mg/dL (normal 15–45mg/dL), glucose of 103 mg/dL (normal 40–75 mg/dL). Urine toxicology was positive only for opiates, which had been administered on admission. After 3 days of intubation, the patient was transferred to our tertiary care institution for further care. On exam, she was intubated, obtunded, and aroused only to painful stimuli. Temperature, heart rate, blood pressure, and room air oxygen saturation were 38.2°C, 114 beats per minute, 135/75 mm Hg, and 100% on 40% FiO2. Cardiac exam revealed a regular rate and rhythm with a 2/6 systolic murmur over the left sternal border. There was no hepatosplenomegaly. Her extremities were well perfused with normal capillary refill. The acuity of this patient's presentation was concerning for an acute encephalopathy with a differential including infectious meningitis, toxic/metabolic encephalopathy, stroke or seizure. In this case, the initial negative MRI and EEG findings pointed against seizure and stroke as an underlying etiology, and normal CSF findings pointed against an infectious meningitis. However, given her fever, underlying systemic infection remained high on the differential. Other considerations included metabolic disturbance such as central pontine myelinolysis, hepatic encephalopathy or myxedema or other systemic condition such as CNS vasculitis or thrombotic thrombocytopenic purpura (TTP). Review of outside records revealed admission labs with hemoglobin values of 11.5 g/dL (ref: 12–15 g/dL) and platelet count of 209 K/cu mm (ref: 150–350 K/cu mm). Laboratory studies at our institution revealed a white blood cell count of 10.16 K/cu mm (ref: 4.50–11.0 K/cu mm) with a differential of 78% neutrophils (ref: 40–70%), and 11.1% lymphocytes (ref: 24–44%), hemoglobin of 7.7 g/dL (ref: 12–15 g/dL), hematocrit of 23.1% (ref: 36- 46%), MCV of 68.5 fL (ref: 80–100 fL), and platelet count of 112 K/cu mm (ref: 150–350 K/cu mm). Reticulocyte count was 2.3% (ref: 0.5–1.8%) with an absolute reticulocyte count of 67.6 K/cu mm (ref: 24.1- 87.7 K/cu mm). Creatinine was 1.1 mg/dL (ref: 0.6–1.3 mg/dL), increased from her 0.74 mg/dL baseline. Lactate dehydrogenase and bilirubin were elevated to 720 U/L (ref: 100–190 U/L) and 1.8 mg/dL (ref: 0.2–1.2 mg/dL), respectively. Ferritin was elevated at 1030 ng/mL (ref: 13–150 ng/mL). Additional labs revealed an ammonia of 37 umol/L (normal 0–32 umol/L) and thyroid stimulating hormone (TSH) of 1.91 (normal 0.45–4.50). Peripheral smear (Figure 1) demonstrated anisocytosis and poikilocytosis with occasional target cells and rare fragments (0–1/high power field). Platelets appeared adequate. Peripheral smear shows mild anisopoikocytosis with occasional target cells and rare fragments [Color figure can be viewed at wileyonlinelibrary.com] Laboratory work-up did not reveal evidence of metabolic disturbance. Although TTP was initially considered as a possible unifying diagnosis given the patient's fever, hemolytic anemia, thrombocytopenia, and increased creatinine, the severity of her neurologic presentation in the setting of a relatively mild degree of thrombocytopenia and lack of a preponderance of schistocytes on peripheral smear pointed against this diagnosis. However, closer review of her complete blood count (CBC) did reveal an unexpected finding. In particular, her anemia was microcytic in the setting of a high ferritin. In general, this pattern is due either to anemia of chronic disease in the setting of severe inflammation, sideroblastic anemia, or thalassemia. Given the targets on her smear, more directed questions were asked to determine a personal and family history of hemoglobinopathy. Upon questioning family members, they noted that the patient's history was notable for sickle cell trait and iron deficiency. She had been on iron supplementation for several years. Over the past year, she reported a history of diffuse body aches and pain which usually remitted with oral analgesics. One month prior to admission, she developed a single episode of bilateral shoulder pain requiring emergency room visit and iv analgesics. She had no family history of sickle cell disease. The patient's history of sickle cell trait coupled with her microcytosis and normal iron stores raised the concern for sickle-β+ thalassemia, a generally phenotypically mild form of sickle cell disease. In addition, her recent history of painful episodes suggested possible vaso-occlusive episodes. Given that her current presentation had also started with an acute pain episode, the possibility of fat embolism syndrome was considered. This syndrome can be associated with laboratory findings that mimic TTP, and is associated with end-organ damage, often multi-organ failure, in individuals with sickle cell disease. Diagnosis requires a high suspicion as imaging findings can be negative or nonspecific, as was the case with this patient's MRI. While awaiting hemoglobin electrophoresis results to confirm sickle-β+ thalassemia, urgent ophthalmologic evaluation was undertaken to evaluate for evidence of ocular fat embolism or sickle cell retinopathy that would help solidify the diagnosis. Ophthalmologic exam revealed multifocal infarcts with cotton wool spots, flame-shaped hemorrhages, and retinal edema. Peripheral areas of the retina showed nonperfusion. (Figures 2 and 3; Normal images for comparison in Figure 4) Ultra-wide field fundus photograph of the right (A) and left eye (B). In the right eye, there is slight temporal pallor of the optic nerve, with blunted foveal light reflex, inferotemporal cotton wool spots (white arrow), superonasal superficial hemorrhage and Roth spot (black arrows) and peripheral arteriovenous anastomosis (*). In the left eye, there is slight temporal pallor of the optic nerve, blunted foveal light reflex, mild attenuation of the retinal vessels, superotemporal superficial hemorrhage and roth spot (black arrows), and peripheral arteriovenous anastamosis (*) [Color figure can be viewed at wileyonlinelibrary.com] Ultrawide field fluorescein angiography of the early (top row) and late frames (bottom row). In the early frames (top row), there is enlarged foveal avascular zone with macular hairpin loops (arrow) and peripheral areas of arteriovenous anastamosis and nonperfusion (*) but no neovascularization. In the late frames (bottom row), there are more extensive areas of macular capillary drop out (arrow) and peripheral nonperfusion (*) Normal ultra-wide field fundus photograph (left) and normal ultra-wide field fluorescein angiography (right) of the right eye [Color figure can be viewed at wileyonlinelibrary.com] Sickle cell disease can cause proliferative retinopathy due to chronic local hypoperfusion, but the acute nature of the infarcts in this case was consistent with an embolic phenomenon, namely fat emboli syndrome. Subsequent hemoglobin studies revealed a hemoglobin S% of 55.2% (ref: 30–43%), hemoglobin A% of 28% and hemoglobin F% of 6.9% (sent after 1 unit packed red blood cell transfusion). The findings of a hemoglobin S fraction greater than the hemoglobin A confirmed the suspected diagnosis of sickle-β+ thalassemia. The patient underwent emergent exchange transfusion with gradual improvement in her mental status. Echocardiographic evaluation was negative for intracardiac or intrapulmonary shunt. After 1 month of rehabilitation, she had regained full motor and language function, and by 2 months, had recovered her full memory. She is currently maintained on hydroxyurea for long-term management and continues to do well. This case highlights several important points. First, it demonstrates an unusual presentation of sickle- β+ thalassemia in a patient with previously undiagnosed sickle cell disease. Given the patient's age, she had not undergone screening for sickle cell disease through the United States Newborn Screening Program, which was adopted by a majority of States by 1990 and in all 50 states by 2006.1 Sickle variant syndromes such as sickle- β+ thalassemia and SC disease can have a wide phenotypic variation in symptoms, with some individuals presenting with severe symptoms in childhood and others who remain asymptomatic into adulthood. For those without significant symptoms or with mild symptoms such as intermittent pain, these syndromes are often missed by providers owing to the mild anemia, lack of robust hemolysis, and nonspecific smear, as noted in this case. Microcytosis in the presence of normal iron stores, is frequently the only abnormality suggestive of a hemoglobinopathy in these instances. This case also highlights the difficulty of diagnosing fat embolism syndrome. The textbook symptoms of fat embolism often requires a triad of respiratory distress, rash, and neurologic compromise, the latter of which was the only presenting symptom in our patient.2 Furthermore, the characteristic “starfield” pattern on brain MRI is absent in nearly 40% of recognized cases.3 While not a widely-recognized method of diagnosing fat embolism, ophthalmologic evaluation can provide additional objective findings that can confirm the presence of an embolic process such as fat embolism. Purtscher-like retinopathy is the constellation of retinal findings which include cotton-wool spots, retinal hemorrhages, optic disc edema, and Purtscher flecken (areas of inner retinal whitening), an entity that has been described in multiple clinical entities including acute pancreatitis, connective tissue disorder, fat embolism syndrome, lymphoproliferative disorders, and cryoglobulinemia. The mechanism of Purtscher-like retinopathy is under active research and debate. The most widely accepted theory focuses on microembolization of the retinal vasculature resulting in microvascular infarcts of the retinal nerve fiber layer (cotton wool spots) and precapillary arteriolar occlusion (retinal nonperfusion and retinal hemorrhages).4, 5 In this patient, there were no embolic plaques visible on fundoscopic examination. However, the combination of cotton-wool spots and/or hemorrhage without Purtscher flecken have been noted in 4% of patients with long bone fracture.4 Given her clinical picture, it is likely that the Purtscher-like retinopathy was caused by fat emboli occluding multiple retinal vessels. Among patients with sickle hemoglobinopathies, compound heterozygotes are the most common genotypes associated with fat emboli syndrome, possibly related to high blood viscosity. Although numerous case reports and case series of this syndrome in SC and sickle- β+ thalassemia exist, they are often associated with multi-organ failure such as acute chest syndrome, renal dysfunction, or hepatic failure.6-9 Isolated cerebral symptoms are rare and require a high index of suspicion. Although the pathophysiology is not clear, organ failure in this syndrome is thought to be due to widespread infarcts from systemic embolization of fat from infarcted long bones. The origin of fat emboli from right to left-sided circulation has also been a subject of much debate. Paradoxical embolism through an intra-cardiac or intra-pulmonary shunt has been suggested, as has microembolism of tiny fat globules through pulmonary capillaries.10 In the case of paradoxical embolization, echocardiography with agitated saline can be performed to assess for shunt, although the utility of closure as prevention for future events has not been studied.11 Regardless of etiology, prompt treatment with exchange transfusion can result in complete resolution of symptoms as was seen in our patient. Long-term preventive management of recurrent episodes have not been established, but may include exchange transfusion therapy and hydroxyurea.