Cerebral fat embolism in sickle cell disease
Authors: Segolene Gendreau, Margaux Scholer, Jérôme Cecchini, Anoosha Habibi, Keyvan Razazi, Nicolas De Prost, Guillaume Carteaux, Pablo Bartolucci, Thierry Gendre, Pierre Brugieres, Jérôme Hodel, Armand Mekontso Dessap
Journal: American Journal of Hematology (2019)

Fat embolism is mostly commonly seen as a complication of long bones fractures. In sickle-cell disease (SCD), pulmonary fat embolism has been reported as a causative agent of acute chest syndrome (ACS),1 but its neurological complications have not been studied systematically. Brain magnetic resonance imaging with susceptibility-weighted imaging sequences (SWI-MRI) is a sensitive and specific tool to diagnose cerebral fat embolism (CFE).2 In this study, we describe the presentations and outcomes of CFE in patients with SCD admitted to intensive care unit (ICU). We retrospectively searched our ICU database for patients with SCD admitted between 2010 and 2018, who underwent brain MRI for an acute non-focal neurological sign (defined as altered consciousness or a neurologic sign without vascular distribution or specific location). Patients with a focal sign suggestive of ischemic or hemorrhagic stroke were excluded. Brain MRI included SWI sequences to improve detection of CFE. Images were primarily analyzed by the senior radiologist on duty, and reviewed by a second senior radiologist to confirm CFE. We identified two groups of patients based on brain MRI results: CFE group (showed scattered embolic ischemia, sometimes with petechial hemorrhage),2 and non-CFE group (patients with another diagnosis or normal MRI). We collected demographic data, baseline laboratory data, chronic complications, long-term treatments of SCD, medical history, clinical evaluation at ICU admission, laboratory findings (including bone marrow examination, parvovirus B19 polymerase chain reaction, and cerebrospinal fluid analysis whenever available), and imaging results (chest X-ray, echocardiography and brain CT-scan whenever available). Patient condition severity and organ failure were assessed using Simplified Acute Physiology Score II and Sequential Organ Failure Assessment score, respectively. A traumatology-derived fat embolism score was calculated using Gurd's criteria3 and Schonfeld4 score, but modified for SCD to take into account the difficulty of assessing jaundice on black skin and the common use of oxygen therapy during arterial blood gas assessment (see supplementary methods). Vaso-occlusive crisis was defined as pain or tenderness affecting at least one part of the body, requiring opioids, and not explained by other causes. Acute chest syndrome was defined as an acute illness with fever and/or respiratory symptoms, accompanied by new pulmonary infiltrate on chest X-ray. Cor pulmonale was assessed with bedside echocardiography and defined as the combination of right ventricular dilatation and a paradoxical motion of the interventricular septum. Supportive treatment and transfusion strategy were administered in compliance with the French guidelines. Neurological evolution was assessed by the modified Rankin scale at ICU and hospital discharge. This retrospective study was approved by the French Intensive Care Society ethical committee as a component of standard care. The data were analyzed using SPSS Base 19.0 statistical software package (IBM Corp., Armonk, NY). Continuous data were expressed as median [25th-75th percentiles] and compared using Mann-Whitney test. Categorical variables, expressed as percentages, were evaluated using Chi square test. All tests were two-tailed, and p values of <.05 were considered statistically significant. Twenty-five patients with SCD had cerebral SWI-MRI for acute non-focal neurological manifestations. Initial causes of admission to intensive care were hyperalgesic vaso-occlusive crisis (n = 2), acute chest syndrome (n = 9), neurological manifestation (n = 12), and other organs failure (n = 2). The median interval between neurological manifestation onset and SWI-MRI was 2 [1-4] days. SWI-MRI detected CFE in ten (40%) patients whereas the other 15 did not have CFE (of whom seven patients had normal MRI, and eight had other lesions, including two with ischemic stroke, three with intracranial hemorrhage, one with tumor, one with abscess, and one with posterior reversible encephalopathy syndrome). Study results are summarized in Table 1. Baseline characteristics of the two groups were similar. On first day of neurological manifestations, fever was more frequent and heart and respiratory rates were higher in the CFE group as compared with the non-CFE group. Lung radiological infiltrates were found in all CFE patients, but in only seven (47%) of non-CFE group. Fat embolism diagnosis according to Gurd's criteria and Schonfeld score had higher prevalence in the CFE group. Echocardiography was performed in all CFE patients and eight of non-CFE (total 18) and detected acute cor pulmonale in seven CFE patients, but none in the eight non-CFE patients. Patients with CFE had more consciousness alteration with a lower Glasgow coma scale level, however none had seizures. Electroencephalography was performed in 16 patients, and showed moderate to severe encephalopathy in all of the eight tested CFE patients. Cerebral CT-scan was performed in 20 patients and was normal in all of the eight tested CFE patients. Biological data showed a lower platelet count and a higher lactate dehydrogenase level in CFE patients as compared with non-CFE. Bone marrow examination was performed in 11 patients (all CFE and one non-CFE) and exhibited bone necrosis in seven CFE patients. Parvovirus B19 polymerase chain reaction was performed in eight patients (seven CFE and one non-CFE) and was positive in four CFE patients. Cardiopulmonary complications (acute respiratory distress syndrome and shock) were more common in patients with CFE during their stay at ICU. Modified Rankin score at ICU discharge and hospital discharge was higher in patients with CFE as compared with non-CFE. One patient died in each group, from cardiac arrest and septic shock, respectively. In the ICU and at hospital discharge, there were more sequelae in patients with CFE as compared with their counterparts. Overall, sequelae at hospital discharge included sensory and motor impairment (in four patients), language and memory loss (in four patients), and sustained confusion status (in six patients). All patients with neurological sequelae required prolonged rehabilitation. A literature review5 on SCD patients reported, between 1941 and 2013, 58 cases of fat embolism, with 83% of neurological impairment, possibly related to CFE. In our study, conducted between 2010 and 2018, we identified CFE in ten of the 25 patients with SCD who underwent brain MRI for acute non-focal neurological manifestations. The neurological manifestations of CFE in our study are consistent with previous studies, and highlight the massive brain injury induced by diffuse fat embolism (Figure 1). Computed tomography is easily accessible in critically-ill patients and is often the first imaging performed in acute neurological manifestation. However, it is mostly unremarkable in the acute phase of CFE. MRI with specific sequences (ie, SWI-MRI) is therefore recommended for patients with clinically suspected CFE. We identified several features that may help distinguish patients with CFE. SCD patients presenting CFE in our study had more fever and severe cardiorespiratory involvement as compared with their counterparts. Clinical and biological data also suggested bone marrow necrosis in most of CFE patients, with lower platelet count and higher lactate dehydrogenase level. Revised Gurd3 and Schonfeld4 scores were positive for all patients in the CFE group, suggesting their potential clinical usefulness in this setting. Our findings shed light on the high incidence of ACS secondary to fat embolism occurring in lungs capillaries, as previously suggested.1 Vichinsky et al6 found that ACS might be more severe in the presence of pulmonary fat embolism. A patient diagnosed with CFE (Figure 1) was found to have a pulmonary fistula and very severe disseminated cerebral embolism. Patent foramen ovale could also potentiate direct cerebral fat embolism. Treatment of CFE is mainly supportive, leaning on shock resuscitation, gas exchange support, and organ replacement therapy if needed, associated with transfusion therapy. In our study, CFE was associated with poorer neurological outcome at ICU discharge. Further studies are needed to evaluate long term outcome of CFE in patients with SCD. To our knowledge and despite its limited size, this is the largest cohort describing CFE in SCD patients. Limitations of our study lie in its retrospective design and the fact that the MRI protocol was not fully standardized. In addition, brain MRI is not a routine exam and the less severe patients (with fast recovery), as well as the most critically ill (too unstable to complete MRI examination), could have been missed. Bedside funduscopic examination could be of interest in this setting, but needs further evaluation. In conclusion, CFE is common in patients with SCD presenting non-focal neurological manifestations. In most cases, it seems associated with bone marrow necrosis. Simple clinical and biological findings may help identify patients that should benefit from brain SWI-MRI examination. Long-term outcome deserves more investigations since many patients presented persisting neurological signs at ICU discharge. 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