Discussion
This case presented an interesting diagnostic challenge regarding the patient’s rapid decline in mental status, with a differential diagnosis including diffuse axonal injury (DAI), anoxic brain injury, posttraumatic seizure, other intracranial pathology, such as stroke or hemorrhage, and FES. FES was diagnosed, when other possibilities were ruled out, given the characteristic findings on brain MRI described above in the context of multiple fractures.
Pathophysiology
Despite its recognition in 1873, there is no consensus on the pathophysiological mechanism that causes the clinical symptoms of FES. In the setting of trauma, there are 2 predominant theories. The mechanical theory postulates that fat globules enter the circulation through disrupted venules after the fracture of marrow-containing bones, passing to the arterial circulation through pulmonary vasculature, or paradoxically, by way of a right-to-left shunt, such as a PFO.1,3 The presence of fat in the heart, visualized as echogenic material in the right and left atria on transesophageal echocardiography, has been confirmed in multiple studies during orthopedic procedures, including total knee arthroplasty and femoral reaming.8,9 These fat particles can lodge as microembolisms in target organs such as the skin and brain. However, autopsy studies have shown a lack of correlation of the severity of symptoms and the quantity of intravascular fat.1 In addition, the typical 24- to 72-hour delay in the onset of symptoms after initial trauma would argue against a solely mechanical explanation.10
Alternatively or concomitantly, the biochemical theory proposes that embolized fat may be degraded to toxic intermediaries, such as free fatty acids and C-reactive protein, which cause end-organ damage.3 This has been shown in an animal model, in which intravascular injection of free fatty acids was associated with endothelial damage and increased capillary permeability in the lung, leading to acute respiratory distress syndrome (ARDS).11 The same mechanism could explain injury to other end organs and is consistent with the delay in onset of symptoms after acute injury. In our patient’s case, the absence of pulmonary involvement, lack of a right-to-left vascular shunt such as a PFO, and presence of a systemic inflammatory response on admission may implicate the production of toxic intermediaries from the metabolism of embolized fat as the source of this patient’s FES.
Clinical Presentation
The initial presentation of FES usually manifests as respiratory distress and hypoxia.10 Chest radiographs are often normal, as in our patient, but can show bilateral diffuse interstitial or alveolar infiltrates.2,6 CT more often has findings, including bilateral ground-glass opacities with interlobar septal thickening.12 A petechial rash can be found on the head, neck, anterior thorax, axillae, subconjunctiva, and oral mucous membranes, although it occurs in only 20% to 50% of cases.1,2,13 Neurologic sequelae are present in up to 80% of patients,7 with onset typically following pulmonary symptoms.1,10 These sequelae can range from headache, confusion, and agitation to stupor, focal neurologic signs, and, less commonly, coma.7 Onset of symptoms generally occurs between 24 and 48 hours after trauma,1 although they have been reported as early as 12 hours.10 This case is an example of an atypical course, with the initial presentation of neurologic symptoms at approximately 14 hours after trauma with rapid progression to coma without classic pulmonary symptoms.
Diagnosis
Owing to the nonspecific clinical features of FES, a variety of clinical, laboratory, and imaging criteria has been described. Of these criteria, the most frequently referenced is by Gurd in 1970,4,5 who divided the features into major and minor, with 1 major and 4 minor features required to make the diagnosis (Table). In applying these criteria to our patient, we found that he exhibited the major criteria of cerebral involvement and minor criteria of tachycardia, fever, and thrombocytopenia. Respiratory insufficiency and petechial rash, as well as jaundice, renal changes, and anemia were negative features. Retinal changes, elevated erythrocyte sedimentation rate, and fat macroglobulinemia were not tested or examined. Although in our case the clinical and laboratory criteria for the diagnosis of FES as defined by Gurd were not met, the sensitivity of Gurd’s and other criteria is debated.10
Laboratory tests specific for the disease have not been developed. Although elevated serum levels of lipase, increased blood lipid levels, and fat globules in the urine, sputum, and blood have all been proposed, they are found in trauma patients with and without FES.2,5,6
The nonspecific nature of the signs and symptoms of FES and the lack of reliable laboratory tests for diagnosis of the syndrome highlight the importance of radiographic evaluation in patients with neurologic symptoms. Brain CT scans are usually negative,14 although, in some cases, they may show diffuse edema with scattered low attenuating areas and hemorrhage.15 MRI is more sensitive, and T2-weighted images typically reveal multiple small, nonconfluent hyperintense lesions, usually in the periventricular, subcortical, and deep white matter, sometimes referred to as the “starfield” pattern.14,16 The differential diagnosis for these findings is broad and, in addition to FES, includes DAI, vasogenic edema with microinfarcts, and demyelinating disease.14 Sensitivity and specificity may be increased with the addition of diffusion-weighted MRI, which shows scattered bright spots on a dark background in a similar “starfield” pattern as on T2-weighted images.15 Susceptibility-weighted MRI has recently been introduced as having utility in the diagnosis of FES, with areas of low-signal intensity indicating diffuse microhemorrhages.17 DAI can show a similar pattern; however, the autopsy-confirmed locations of the abnormalities are distinct, with those of FES being found in cerebral and cerebellar white matter and splenium of the corpus callosum and radiographic abnormalities of DAI being found in the gray-white matter junction, dorsolateral brainstem, and splenium of corpus callosum.17