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BACKGROUND AND PURPOSE: Patients infected with the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) can develop a spectrum of neurological disorders, including a leukoencephalopathy of variable severity. Our aim was to characterize imaging, lab, and clinical correlates of severe coronavirus disease 2019 (COVID-19) leukoencephalopathy, which may provide insight into the SARS-CoV-2 pathophysiology.MATERIALS AND METHODS: Twenty-seven consecutive patients positive for SARS-CoV-2 who had brain MR imaging following intensive care unit admission were included. Seven (7/27, 26%) developed an unusual pattern of "leukoencephalopathy with reduced diffusivity" on diffusion-weighted MR imaging. The remaining patients did not exhibit this pattern. Clinical and laboratory indices, as well as neuroimaging findings, were compared between groups. RESULTS:The reduced-diffusivity group had a significantly higher body mass index (36 versus 28 kg/m 2 , P , .01). Patients with reduced diffusivity trended toward more frequent acute renal failure (7/7, 100% versus 9/20, 45%; P ¼ .06) and lower estimated glomerular filtration rate values (49 versus 85 mL/min; P ¼ .06) at the time of MRI. Patients with reduced diffusivity also showed lesser mean values of the lowest hemoglobin levels (8.1 versus 10.2 g/dL, P , .05) and higher serum sodium levels (147 versus 139 mmol/L, P ¼ .04) within 24 hours before MR imaging. The reduced-diffusivity group showed a striking and highly reproducible distribution of confluent, predominantly symmetric, supratentorial, and middle cerebellar peduncular white matter lesions (P , .001). CONCLUSIONS:Our findings highlight notable correlations between severe COVID-19 leukoencephalopathy with reduced diffusivity and obesity, acute renal failure, mild hypernatremia, anemia, and an unusual brain MR imaging white matter lesion distribution pattern. Together, these observations may shed light on possible SARS-CoV-2 pathophysiologic mechanisms associated with leukoencephalopathy, including borderzone ischemic changes, electrolyte transport disturbances, and silent hypoxia in the setting of the known cytokine storm syndrome that accompanies severe COVID-19.ABBREVIATIONS: BMI ¼ body mass index; COVID-19 ¼ coronavirus disease 2019; ICU ¼ intensive care unit; RT-PCR ¼ reverse transcription polymerase chain reaction; SARS-CoV-2 ¼ Severe Acute Respiratory Syndrome coronavirus 2; SOFA ¼ Sequential Organ Failure Assessment A mong the neurologic disorders associated with Severe Acute Respiratory Syndrome coronavirus-2 (SARS-CoV-2) 1-3 infection, there have been several reports of diffuse white matter abnormalities, including a "leukoencephalopathy with reduced diffusivity" on diffusion-weighted MR imaging. 4 This pattern of severe, bilateral white matter involvement appears to develop late in the course of coronavirus disease 2019 in critically ill patients and may be related to the prolonged hypoxemia that these patients experience, often even while asymptomatic. 5 Indeed, although leukoencephalopathy can result fr...