Clinical, Imaging, and Lab Correlates of Severe COVID-19 Leukoencephalopathy

DISCUSSION

Our results show that in a consecutive cohort of adult patients positive for SARS-CoV-2 in the ICU requiring post-admission brain MR imaging, severe COVID-19 leukoencephalopathy with reduced diffusivity was associated with obesity, acute renal failure, mild hypernatremia, anemia, and an unusual, striking, and abnormal brain white matter lesion distribution pattern on MR imaging, featuring diffuse, confluent, predominantly symmetric supratentorial and middle cerebellar peduncular lesions. Although there were no significant differences in age, gender, race, or ethnicity between the reduced diffusivity and control groups, in both groups, older age (mean 63 years) and male sex (71–75%) were predominant.

Several articles to date have reported the occurrence of white matter signal abnormalities in patients with severe COVID-19.^4,17⇓-19 Kandemirli et al¹⁷ observed 3 (of 12) critically ill patients with subcortical or deep white matter lesions but without reduced diffusivity. More recently, Radmanesh et al⁴ described a series of patients with leukoencephalopathy, reduced diffusivity, and microhemorrhages. A systematic analysis of the risk factors and laboratory and clinical variables associated with this unusual leukoencephalopathy, however, has not previously been emphasized in the literature.³

We saw no significant differences between groups regarding the duration of subjective dyspnea before ICU admission, the lowest reported pulse oximetry before admission, PaO₂/FiO₂ ratios on admission, the need for extracorporeal membrane oxygenation, or worst arterial partial pressure of oxygen (PO₂) and lowest oxygen saturation during the first 24 hours in the ICU (Online Supplemental Data). These similarities in baseline oxygenation parameters were surprising, given that hypoxia has been hypothesized to be a major culprit in the pathophysiology of these white matter changes. Indeed, oxygenation indices (worst arterial PO₂ and lowest O₂ saturation oxygenation) on the day of MR imaging were lower in the control group, likely reflecting that 45% of those patients had been extubated by that time (versus 14% extubated in the reduced-diffusivity group, Online Supplemental Data).

Except for body mass index (BMI), our reduced-diffusivity and control groups were well-matched (Online Supplemental Data). The reduced-diffusivity group had a significantly higher mean BMI of 36 versus 28 in the control group (corresponding to “moderately obese” versus “overweight,” respectively). Although there is no established direct link between obesity and leukoencephalopathy, obesity is a known risk factor for insulin resistance, lacunar infarcts, and chronic small-vessel disease.^20⇓-22 The effect of obesity on arteriosclerosis might be a contributing factor to the increasingly recognized thrombotic microangiopathy and endotheliitis associated with SARS-CoV-2 infection.²³ Lampe et al²⁴ described visceral obesity being associated with a predominance of deep white matter (rather than periventricular) MR imaging abnormalities and suggested a potential role for interleukin 6 and other proinflammatory cytokines in the development of white matter pathology. The microangiopathic effect of obesity (with potential superimposed effects mediated by cytokines) might further compromise borderzone regions located in the deep cerebral white matter and middle cerebellar peduncles.²⁵

Several clinical variables were different between our 2 cohorts, including a lower mean value for the lowest hemoglobin level within 24 hours before MR imaging (8.1 versus 10.2, P < .05), mildly higher mean values of the most elevated serum sodium at the same time point (147 versus 139, P < .04), and a trend toward more acute renal dysfunction (glomerular filtration rate = 49 versus 85 mL/min; P < .06) in the reduced-diffusivity group. Other organ system damage was not significantly different between groups, including cardiac events, acute liver failure, overt Disseminated Intravascular Coagulation, ischemic bowel, and mean number of systems affected (Online Supplemental Data).

Although these differences may simply reflect an epiphenomenon, it is intriguing to speculate whether cytokine effects, which could also be related to obesity, might contribute to some of these abnormal lab indices. For example, interleukin 6 and other proinflammatory cytokines (eg, interleukin 1 and tumor necrosis factor-α) are known to have a central role in the anemia seen during systemic inflammatory processes, impacting iron homeostasis and the reticuloendothelial system as well as impairing regulatory feedback of iron absorption in the gastrointestinal tract.^26,27 Interleukin 6 has been shown to mediate low iron levels during inflammatory states via the production of hepcidin.²⁸ These cytokines might also modulate the transcription of the erythropoietin (EPO) gene and inhibit erythroid progenitor cells in the bone marrow.²⁶

The modest hypernatremia at the time of MR imaging is more challenging to explain. Both groups had similar critical illness severity (reflected by SOFA scores of 9.3 and 7, respectively; P = .09) and had no reported differences in water intake or extrarenal water losses (gastrointestinal- or skin-mediated). Although this finding might reflect hypothalamic involvement with impaired water homeostasis, renal dysfunction in COVID-19 has more often been reported to result in hyponatremia.^29,30

The pattern of MR imaging signal abnormalities we observed is striking. This pattern of diffuse, confluent, predominantly symmetric supra- and infratentorial involvment with middle cerebellar peduncle lesions (seen in 6/7 cases, 86%) is unusual and noteworthy. The neuroanatomic distribution of these abnormalities appears more selective than those reported in cases of delayed posthypoxic leukoencephalopathy at our institution and in the literature. Delayed posthypoxic encephalopathy is often more extensive, with subcortical white matter involvement and less frequent infratentorial involvement.^7,31 None of the patients in our reduced-diffusivity group had a history of recent cardiac arrest, though 1 patient in the control group had an episode of cardiac arrest without developing these findings.

There have been multiple reports of white matter abnormalities associated with sepsis and critical illness. Sharshar et al¹² described white matter lesions in 5/9 (55%) patients with septic shock and clinical brain dysfunction (mean SOFA, 8). Polito et al¹¹ published a similar study of 71 patients with septic shock and noted 15 patients (21%) with leukoencephalopathy (median highest SOFA score, 9). These authors suggested that the leukoencephalopathy seen with septic shock may be related to an altered blood-brain barrier, allowing passage of proinflammatory molecules and neurotoxins.¹¹

Another possibility in the imaging-based differential diagnosis of the unusual pattern of leukoencephalopathy in these patients is a metabolic or toxic etiology.^32,33 There were no differences between the reduced-diffusivity and control groups regarding sedatives, the use of opioid medications, nitric oxide, or extracorporeal membrane oxygenation treatment. The possibility of a metabolic etiology is intriguing because the anatomic distribution of white matter lesions in our patients overlaps the pattern seen with a genetic chloride channelopathy (chloride voltage-gated channel 2 [CLCN2]–related leukoencephalopathy).^34,35 It has been established, however, that the angiotensin-converting enzyme 2 receptor used by the SARS-CoV-2 virus has a chloride-binding site and is regulated by this electrolyte.³⁶ There is also some degree of overlap between the angiotensin II and chloride channel pathways physiologically, with angiotensin II producing activation of chloride currents in cerebral vessels.^37,38 A direct connection between COVID-19 and specific ion-transport abnormalities, however, has not been reported to date.

One of our patients showed cavitary, necrotic-appearing lesions in regions with reduced diffusivity, suggestive of the MR imaging findings that accompany multifocal necrotizing leukoencephalopathy (Fig 3).³⁹ The anatomic distribution of these lesions resembled that of our other patients with leukoencephalopathy with reduced diffusivity; hence, this appearance may reflect a more advanced stage of white matter cellular injury, as was described in some early case reports of COVID-19–associated acute necrotizing encephalopathy.^39,40

This observational study has several limitations, including a small sample size, which could be affecting the potential effect of some clinical variables. The patients included in the study may reflect a proportion of those with severe COVID-19 in the ICU who were stable enough to have a brain MR imaging, potentially biasing this analysis. The development of cavitary changes in only one of the patients in the group with restricted diffusion could be related to a more advanced stage of white matter injury, but this is difficult to confirm with the small number of cases included in the study. Nevertheless, we observed several significant correlations among the imaging, clinical, and laboratory findings, providing a basis for future hypothesis testing in larger cohorts. Different field strengths and susceptibility sequences in different MR imaging scanners limit comparison of the prevalence of microhemorrhages between cohorts. Lack of prior imaging in several patients limits assessment of pre-existing or other pathologies. Finally, the retrospective design also limits the availability of oxygenation data during ICU admission, which may have provided a more precise measure of the cumulative burden of hypoxia experienced by each patient.