Case presentation

A 64-year-old woman was admitted to our hospital with a 10-day history of fever and dyspnea treated at home with ceftriaxone.

Her medical history included hypertension, gastroesophageal reflux disease, hyperuricemia, dyslipidemia, obstructive sleep apnea and paroxysmal atrial fibrillation. Her medications were: irbesartan/hydrochlorothiazide, acetylsalicylic acid, pantoprazole, rosuvastatin, allopurinol and bisoprolol.

She was febrile (39 °C) with marked dyspnea. Neurological examination was unremarkable. Laboratory tests were significant for lymphocytopenia with increased transaminases and LDH. Oxygen saturation was low, thereby oxygen therapy was administered (Table 1). Chest X-ray showed reduction of the parenchymal transparency in basal region of right lung.

Table 1 Laboratory and neurophysiologic assessment

A continuous positive airway pressure had to be started. A nasopharyngeal swab resulted positive for SARS-CoV-2; antiviral therapy with darunavir/cobicistat, associated with hydroxychloroquine were started. After 24 h, she was taken to Intensive Care Unit: she was sedated and mechanical ventilation was started. Antiviral plus antibiotic therapies were continued for 10 days. After 23 days bronchial aspirate turned negative for SARS-CoV-2.

On day 25 she woke up when sedation was weaned; she was drowsy and complained of blurred vision. She showed an altered mental status, a decreased left nasolabial fold, the tone and the strength were slightly decreased in the legs, and all deep tendon reflexes were reduced symmetrically. Brain CT and CTA were consistent with hemorrhagic Posterior Reversible Encephalopathy Syndrome (PRES; Fig. 1a, b).

Fig.1
figure 1

Radiological findings. a Brain axial CT on day 25 shows posterior frontal and temporo-parieto-occipital symmetric bilateral hypodensity of the subcortical white matter, and a tiny left occipital parenchymal hemorrhage. b Para-axial CTA scan confirms the absence of vascular malformation and alterations of posterior circle vessel caliber, suggestive of vasoconstriction mechanism. c Axial T2 Flair image on day 56 shows that vasogenic edema is reduced but still detectable and d T2 Gradient-Echo reveals the onset of right temporal hypodensity, correlated to hemorrhagic process

In the following days spontaneous breathing was restored. No epileptic seizures were reported during hospitalization.

On day 56 a brain MRI showed a reduction of the bilateral edema with bilateral occipital foci of subacute hemorrhage (Fig. 1c, d). A second nasopharyngeal swab was negative for SARS-CoV-2, and she was alert and fully oriented with a normalization of blurred vision.

Discussion

PRES is characterized by acute impairment in level of consciousness, headache, visual disturbances and seizures, with cortical/subcortical vasogenic edema, involving predominantly the parietal and occipital regions bilaterally [1]. PRES is commonly associated with blood pressure fluctuations, renal failure, autoimmune conditions, sepsis, preeclampsia or eclampsia and immunosuppressive-cytotoxic drugs. In our patient the sepsis (Table 1) was due to Staph. Epidermidis, that has never been associated with PRES, and did not induce a shock condition as is usually the case in septic PRES [2,3,4]. None of the drugs given to our patient has been associated with PRES [5].

Several studies suggested a key role of endothelial dysfunction (ED), combined with hemodynamic stress (hypertensive crisis) and immunological activation with release of cytokines (TNF-α, IFN-γ, IL-1) able to activate endothelial cells, thus increasing vascular permeability. ED is a principal determinant of microvascular perfusion: by shifting the vascular equilibrium towards a more pro-inflammatory, pro-coagulant and proliferative state, it leads to ischaemia and inflammation with edema [6].

This is the second report of hemorrhagic PRES in COVID-19, and these other two patients were very similar to ours.[7].

Mounting evidence suggests that the SARS-Cov2 directly infects endothelial cells causing diffuse inflammation [8,9,10]. The pivotal host cell receptor for the entry of SARS-CoV-2 into the cells is the Angiotensin-Converting Enzyme 2, which is also expressed by the brain endothelium [9, 11]. Varga et al. [10] showed the presence of viral elements within endothelial cells in different vascular beds, suggesting a role of an ED in the systemic toxicity caused by the virus.

In our patient we can rule out the causes of PRES listed above. A contribution from the respiratory distress was unlikely since PRES developed during mechanical ventilation. We hypothesize that SARS-CoV-2 may have caused a cerebrovascular ED which in turn was responsible for both the hemorrhagic lesions and the for the disruption of the blood brain barrier with vasogenic edema.

Availability of data and material

Our data are available upon request to the corresponding author.