Significance of Persistent Systemic Support in the Clinical Course of Delayed Post-hypoxic Leukoencephalopathy Following Severe Coronavirus Disease 2019

Abstract

A 45-year-old woman was hospitalized with severe coronavirus disease 2019 pneumonia. Following cytokine storm-induced multiorgan failure and lethal arrhythmia, the patient developed a sustained coma with flaccid quadriplegia. A cerebrospinal fluid examination excluded infectious and immunogenic encephalopathies, and diffusion-weighted magnetic resonance imaging demonstrated high-intensity areas in the white matter with a cortex-sparing distribution, suggesting delayed post-hypoxic leukoencephalopathy. As a result of intensive cardiopulmonary support for a month, the neurological function gradually recovered. Based on the reversible clinical course noted in this patient, accurate diagnosis and persistent medical approaches are important for the management of coronavirus disease 2019-related delayed post-hypoxic leukoencephalopathy.

Introduction

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (1). Ongoing infections have resulted in the loss of over 6 million lives worldwide. Furthermore, COVID-19 remains a challenge due to the following: i) ceaseless genome mutations of the spike protein leading to immune escape, ii) unavailability of effective treatments, and iii) induction of various systemic complications by the host immune response. Neurological disorders are common and serious complications of COVID-19, and are observed in 45.5% of patients with severe COVID-19 pneumonia (2). Apart from impairment of taste and smell, various serious symptoms (e.g. stroke, ataxia, seizure, impaired consciousness, and encephalopathy) have also been reported (3). The underlying mechanisms of encephalopathy are diverse and include direct viral invasion, coagulation abnormalities, immune response, toxic metabolic factors, and neurologic injury due to systemic dysfunction (e.g. hypoxia).

Delayed post-hypoxic leukoencephalopathy (DPHL) is a demyelinating disease caused by cerebral hypoxic events (4). Thus far, several cases of COVID-19-associated DPHL have been reported (5-8), and in addition to the typical hypoxic episode, cerebral hypoperfusion during the clinical course of severe COVID-19 is considered a risk factor for DPHL (8). The major difference between well-studied hypoxic encephalopathy and DPHL is the localization of the damaged area and reversibility of symptoms. However, knowledge regarding the clinical characteristics of DPHL in COVID-19 patients, such as the process from onset to recovery, is limited.

We herein report a case of successful recovery of DPHL following severe COVID-19. We describe the entire clinical course, from the detection of neurological symptoms to the final convalescent phase. Based on these findings, fulminant systemic inflammation due to COVID-19-associated cytokine storms is considered a risk factor for the development of DPHL.

Case Report

A 45-year-old woman visited a rural hospital because of progressive dyspnea. The patient had developed a fever and cough 7 days earlier. A nasal swab test using polymerase chain reaction yielded positive results for the SARS-CoV-2 delta variant, and chest computed tomography showed bilateral lung ground-glass attenuation, consistent with COVID-19 pneumonia. Oxygenation rapidly deteriorated, and the patient was transferred to our hospital 8 days after the onset of COVID-19 symptoms.

On admission, a physical examination revealed the following: height, 158 cm; weight, 86 kg (body mass index: 34.4); clear consciousness; body temperature, 37.6°C; respiratory rate, 32 breaths/min; pulse, 68 beats/min; blood pressure, 139/85 mmHg; and SpO₂, 96% under high-flow oxygen therapy with a fraction of inspired oxygen (F_IO₂) of 0.8. Laboratory examinations revealed the following: white blood cell count, 5,400 /μL (neutrophils, 81.7%; lymphocytes, 14.2%); hemoglobin, 12.9 g/dL; platelet count, 27×10⁴/μL; blood urea nitrogen, 11 mg/dL; creatinine, 0.36 mg/dL; total bilirubin, 0.5 mg/dL; aspartate aminotransferase, 192 U/L; alanine aminotransferase, 172 U/L; lactate dehydrogenase, 671 U/L; C-reactive protein, 3.06 mg/dL; Krebs von den Lungen-6 (KL-6), 544 U/mL; and ferritin, 678 ng/mL. An arterial blood gas analysis (F_IO₂: 1.0, on mechanical ventilation) revealed the following: partial pressure of oxygen (PaO₂), 75 Torr; partial pressure of carbon dioxide (PaCO₂), 41.5 Torr; and bicarbonate (HCO₃^-), 25.9 mmol/L. Chest radiography (after intubation) showed bilateral hazy lung opacities and consolidation, predominantly in the right lung (Fig. 1A). Chest computed tomography showed bilateral lung ground-glass attenuation and peribronchovascular consolidation, predominantly in the right lung (Fig. 1B). Fig. 2 illustrates the clinical course of the patient. Mechanical ventilation was immediately introduced in the intensive care unit. Prone positioning was repeated five times because of poor oxygenation caused by a ventilation/perfusion (V/Q) mismatch. The patient received a regular dose of dexamethasone (6 mg/day) for 7 days (9). However, 6 days after admission, the patient developed critical hyperthermia (41°C) and multiple organ failure with hypotensive shock. Septic shock was suspected; however, an analysis of blood and airway specimens did not identify specific pathogens, and the administration of broad-spectrum antibiotics was ineffective. The use of vasopressors and antipyretics, as well as the re-administration of glucocorticoids at maximum doses, also exerted limited effects. On day 10, the patient developed pulseless ventricular tachycardia. Unfortunately, we could not immediately prepare for cardioversion because of the prone position and isolation precautions, which were sustained for 5 min. Serum levels of procalcitonin were maintained at low levels, whereas those of ferritin constantly increased to 2,886 ng/mL. These findings suggest that the COVID-19-induced cytokine storm contributes to refractory hyperthermia and hypotensive shock. On day 11, intensive care physicians introduced an intravascular cooling system (Thermogard XP™; ZOLL Medical, Chelmsford, USA) through the femoral vein. Then, the body temperature gradually normalized, and the hemodynamics and functions of multiple organs gradually stabilized. Subsequently, sedation was discontinued, and extubation was attempted on day 19. Nevertheless, the patient remained in a coma after cessation of sedatives. On day 22, electroencephalography revealed diffuse, slow waves. A cerebrospinal fluid (CSF) examination did not reveal an increase in cell count or protein levels or a decrease in glucose levels. Furthermore, bacterial and fungal cultures, as well as various viral polymerase chain reaction tests (including SARS-CoV-2) in the CSF, yielded negative findings. In addition, oligoclonal bands were negative, and the immunoglobulin G index and myelin basic protein levels were normal.

Figure 1.

Chest imaging findings on admission. (A) Chest radiograph showing bilateral lung hazy opacities and consolidation predominantly in the right lung. (B) Chest computed tomography showing bilateral lung ground-glass attenuation and peribronchovascular consolidation predominantly in the right lung.

Figure 2.

Clinical course of the patient. Sequential changes in serum ferritin levels, body temperature, main clinical events, and medications. CFPM: cefepime, CHDF: continuous hemodiafiltration, EEG: electroencephalogram, HD: hemodialysis, MNZ: metronidazole, PIPC/TAZ: piperacillin/tazobactam, VCM: vancomycin, VT: ventricular tachycardia

Although the patient remained on mechanical ventilation, we decided to perform brain magnetic resonance imaging (MRI) on day 22 to determine the etiology. The cerebral cortex was unaffected; however, diffusion-weighted imaging (DWI) and T2/fluid-attenuated inversion recovery (FLAIR) MRI revealed symmetric, wide, high-intensity areas in the deep white matter of both cerebral hemispheres and middle cerebellar peduncles. The distinctive MRI findings were consistent with those of DPHL (Fig. 3). Neurological dysfunction persisted for one month, and the prognosis was expected to be poor. However, a previous report noted that the clinical course and recovery time of DPHL significantly differed among individuals (10), so we carried out systemic support in collaboration with a multidisciplinary medical team consisting of intensive care physicians, pulmonologists, neurologists, radiologists, and rehabilitation staff. Eventually, the patient opened her eyes on day 34, and consciousness and motor dysfunction gradually recovered after one month. However, systemic muscle hypotonia persisted, so the patient was transferred from our hospital to a rural hospital on day 67 to continue rehabilitation. Two months later, the patient was discharged on foot and successfully returned home. Brain MRI performed at a rural hospital revealed that the extensive leukoencephalopathy had diminished (Fig. 4).

Figure 3.

Diffusion-weighted magnetic resonance imaging of the brain (B1000). Symmetric restricted diffusion on day 22 after transfer to our hospital. (A) Deep white matter of both cerebral hemispheres; (B) deep white matter at the basal ganglia level; and (C) middle cerebellar peduncles.

Figure 4.

Diffusion-weighted magnetic resonance imaging of the brain (B1000). Time-dependent changes in the imaging of the deep white matter of both cerebral hemispheres. On (A) day 22, (B) day 52, and (C) day 118.

In the present case, a series of neurological dysfunctions was caused by DPHL as a result of cerebral hypoxia and hypoperfusion during the clinical course of severe COVID-19. Based on the reversible clinical course noted in this patient, persistent medical approaches are important for the management of COVID-19-related DPHL.

Discussion

In this article, we present a case of DPHL following severe COVID-19 infection. Previous studies have reported that neurological complications are frequent in patients with severe COVID-19 requiring treatment in the intensive care unit, and brain MRI revealed substantial findings in 11 of 58 patients with COVID-19-associated acute respiratory distress syndrome (3,11). Although SARS-CoV-2 itself has a neurotropic nature (12), most COVID-19-associated encephalopathies are caused by noninfectious mechanisms. Through an experimental model, it was established that SARS-CoV-2 could result in neuroinflammation and affect the reactivity of white matter microglial cells by the prominent elevation of cytokines and chemokines (13). Acute necrotizing encephalopathy and acute disseminated encephalomyelitis are representative immunogenic encephalopathies induced by the activation of the immune system in the central nervous system (14-17). In contrast, hypoxic encephalopathy, posterior reversible leukoencephalopathy syndrome, and DPHL have been recognized as non-immunogenic pathologies (5-8,18). In the present case, the normal results obtained from the CSF examination helped rule out direct SARS-CoV-2-infection and immunogenic inflammatory mechanism as the cause of encephalopathy.

DPHL is a demyelinating disease caused by oligodendroglial cell death that occurs one to four weeks after mild to moderate brain hypoxic episodes (4). Cardiopulmonary arrest, hemorrhagic shock, carbon monoxide poisoning, and anesthetic overdose are notable triggers of DPHL (10). This condition is characterized by bilateral symmetrical diffuse white matter signal abnormalities on brain MRI (8). The major difference between well-studied hypoxic encephalopathy and DPHL is the localization of the damaged area and reversibility of symptoms. Hypoxic encephalopathy results in irreversible neuronal damage to the whole brain, including the cerebral cortex, which is a crucial area for higher cognitive functions. In contrast, injury caused by DPHL is limited to the cerebral white matter, with the cerebral cortex left unaffected. In this case, brain MRI demonstrated bilateral symmetric high-intensity areas in the deep white matter with a cortex-sparing distribution, and the neurological symptoms were eventually reversible, which was consistent with the clinical profile of DPHL.

In COVID-19-related DPHL, some cases are caused by severe hypoxemia due to COVID-19 pneumonia (5-7). However, cerebral hypoperfusion during circulatory failure is also considered a risk factor for DPHL (8). Large studies have reported that the overall prevalence of arrhythmia in COVID-19 ranges from 10-20%, and even higher arrhythmia rates have been observed in COVID-19 patients treated in the intensive care unit (19,20). In COVID-19-induced cytokine storm, many inflammatory cytokines, such as interleukin-1 (IL-1), IL-6, and tumor necrosis factor, are elevated approximately 2- to 100-fold above normative values (21). These inflammatory cytokines increase myocardial electric instability by direct cell injury (21). In a study of arrhythmia prevalence in critically ill patients with severe COVID-19, increased IL-6 levels and a high fever were associated with QT prolongation and high rates of ventricular tachyarrhythmias (22). In the present case, although we were unable to evaluate the titer of inflammatory cytokines, it was expected that the cytokine storm in severe COVID-19 would be associated with the occurrence of pulseless ventricular tachycardia, leading to cerebral hypoperfusion.

Although DPHL is typically accompanied by biphasic deterioration of consciousness (23), the initial symptoms were unclear because of sedation in this case. Vines et al. reported a similar case in which biphasic deterioration could not be established during intensive care, and coma was evident after sedation was weaned (8). Therefore, it should be noted that neurological complications in patients with severe COVID-19 are occasionally masked by sedatives, leading to a delay in the diagnosis and treatment. In addition, aggressive therapies have been discontinued in some cases of COVID-19-associated encephalopathy, considering their poor outcomes (24). However, a proportion of patients with DPHL completely recover, although the recovery time differs among individuals (from 3 to 17 months in previous reports) (6,10). Therefore, we emphasize the importance of i) accurate diagnosis of DPHL by MRI and a CSF analysis to exclude other encephalopathies and ii) aggressive approaches cooperating with a multidisciplinary medical team consisting of intensive care physicians, pulmonologists, neurologists, radiologists, and rehabilitation staff in the management of DPHL in severe COVID-19.

The present COVID-19 case was caused by SARS-CoV-2 lineage B.1.617.2 (delta variant), which is a representative variant showing high transmissibility and pathogenicity in humans. In contrast, the recent predominant variant of concern is B.1.1.529 (omicron variant), which shows less pathogenicity than the prior delta variant (25). However, SARS-CoV-2 has been continuously evolving because of ceaseless genome mutations, and critically ill patients are constantly present. We endeavored to discuss the universal management of COVID-19-related DPHL in this article, regardless of the type of variant.

In conclusion, the present case suggests that tenacious medical approaches may lead to favorable outcomes for DPHL following severe COVID-19.

The present report conforms to the tenets of the Declaration of Helsinki, and the patient provided her written consent for the publication of this case report.

The authors state that they have no Conflict of Interest (COI).