Covid-19–associated diffuse posthypoxic leukoencephalopathy and microhemorrhages – A case report

Background Delayed post-hypoxic leukoencephalopathy (DPHL) with associated microbleeds is a clinical entity presenting with cognitive impairment days or weeks after an episode of acute hypoxic brain injury. Case report We describe a 68-year-old male with SARS-CoV2 infection who had cardiac arrest, required sedation and mechanical ventilation for 17 days, and after sedation was discontinued, he became unresponsive. Brain MRI showed diffuse confluent hyperintense signals in the subcortical white matter and multiple subcortical white matter microhemorrhages. EEG revealed diffuse attenuation of brain electrical activity with isolated polymorphic delta waves in the frontal region without epileptiform activity. Conclusions Clinicians need to be aware that patients with Covid-19 can develop delayed post-hypoxic leukoencephalopathy.


Background
Delayed post-hypoxic leukoencephalopathy (DPHL) with associated microbleeds is a clinical entity presenting with cognitive impairment days or weeks after an episode of acute hypoxic brain injury. Besides hypoxia, there are many possible mechanisms of brain injury within critically ill patients, which also could contribute to it. In this report, we describe a patient with DPHL which developed in a Covid-19 patient diagnosed based on characteristic imaging findings.

Case report
A 68-years-old right-handed man with a history of obesity, conserve neurocognitive function but no other comorbidities. He was diagnosed with SARS-CoV2 infection after developing cough and shortness of breath. A SARS-CoV2 antigen test was positive. Eight days after onset of symptoms (cough, shortness of breath) the patient was admitted to a tertiary hospital and transferred to the intensive care unit (ICU) due to acute respiratory distress syndrome and cardiac arrest, requiring sedation and mechanical ventilation. During hospitalization, he developed rhabdomyolysis (creatine kinase enzyme, 1049.80U/L) and acute kidney injury. He was treated with antibiotics for urinary tract infection with a good response. On the 14th day, he underwent a tracheostomy and subsequent sedation weaning. Three days after sedation was discon- * Corresponding author.
tinued, he became unresponsive. However, after the abrupt decline of mental status changes he had spontaneous eye-opening, followed simple verbal commands, and exhibited conjugated gaze with isochoric pupils, reactive to light. His exam showed flaccid muscle tone, hyporeflexia, bilateral foot drop, and bilateral extensor plantar responses. There were no abnormal movements or meningeal signs. The initial brain CT on the 17th day showed diffuse symmetric leukoencephalopathy involving the entirety the white matter of both hemispheres. His EEG revealed diffuse attenuation of brain electrical activity with isolated polymorphic delta waves in the frontal region without epileptiform activity. Cerebrospinal Fluid (CSF) on the 18th day was showed mild pleocytosis and increased protein ( Table 1 ); however all microbiological studies including culture, common microbial stains, and PCR multiplex assay for bacteria (Escherichia coli, Haemophilus influenzae, Listeria monocytogenes, Neisseria meningitidis, Streptococcus agalactiae, Streptococcus pneumoniea), virus (Cytomegalovirus, Enterovirus, Herpes simplex virus 1 and 2, Human herpesvirus 3 and 6, and Parechorivus) and fungi (Cryptococcus neoformans/gattii) were all negative.
A brain MRI showed diffuse confluent hyperintense signals in the subcortical white matter on the T2/FLAIR sequences and multiple subcortical white matter microhemorrhages ( < 4 mm) on SWI images.  Over the 30th day, the patient's mental status slowly improved to the point of being awake and alert. He followed simple commands and mouthed a few words. He was discharged to a rehabilitation unit.

Discussion
DPHL typically occurs after prolonged lower blood oxygen saturation known as hypoxia ( Katyal N et al., 2018 ). DPHL clinical manifestations are alteration of consciousness, encephalopathy and delayed cognitive decline ( Katyal N et al., 2018 ;Manjunath V et al., 2021 ). In our case, neurologic symptoms were initially detected 17-23 days after the lowest PaO2 was recorded, which is consistent with DPHL. DPHL could be poorly recognized in Covid-19 patients, probably due to their sedation status, making it difficult to perform an appropriate neurological examination. This case adds to the existing literature on DPHL associated with Covid-19 ( Manjunath V et al., 2021 ).
Neuroimaging findings in DPHL follow two patterns: First, related to diffuse leukoencephalopathy, with confluent and symmetrical white matter hyperintensities in T2 sequences and restriction of diffusion with relative preservation of juxtacortical and infratentorial white matter; second, associated with microhemorrhages at the juxtacortical white matter and corpus callosum ( Freeman et al., 2021 ), as those present in the present case. Because imaging in Covid-19 patients is limited due to isolation precautions and the severity of respiratory compromise, a high grade of suspicion in situations of persistent encephalopathy and diffuse neurological involvement after sedation weaning should raise concerns for DPHL.
The COVID-related encephalopathy is non-specific but, in our case, the most plausible explanation was DPHL. After ruled out differential diagnoses such as neuroinfectious causes (supported by negative CSF), posterior reversible leukoencephalopathy syndrome (lacked risk factors such as hypertension or drugs), toxic-metabolic causes due to patient system illness and acute toxic leukoencephalopathy due to absence of heroin, morphine or methadone abuse ( Virhammar et al., 2020 ;Manjunath V et al., 2021 ;Ozutemiz C et atl 2019 ) In our case, CSF analysis demonstrated mixed elevated CSF protein which likely reflect brain injury secondary to microhemorrhages and brain-blood barrier disruption and a marker of acute widespread demyelination from the hypoxic region as it has been described ( Shprecher D et al., 2010 ).
Treatment of DPHL is mainly supportive, and outcomes are variable, with permanent disabling sequelae frequently observed ( Shprecher et al., 2008 ). Our patient, despite a severe degree of dependence (Barthel < 20) at discharge, showed remarkable recovery at one-month follow-up, and still under a successful rehabilitation process.
In conclusion, Covid-19 can cause DPHL. This entity should be considered in patients with prolonged encephalopathy in ICUs.

Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Ethics
Informed consent was obtained.