Recent evidence highlights a relatively high percentage of central nervous system symptoms including headache, altered mental status, acute cerebrovascular disease and epilepsy in patients with COVID-19
SARS-CoV-2 has caused an outbreak of severe pneumonia (COVID-19) in China that rapidly spread around the globe. Recent evidence highlights a relatively high percentage (36 per cent) of central nervous system symptoms including headache, altered mental status, acute cerebrovascular disease and epilepsy in patients with COVID-19 (1). The rate of neurological symptoms is higher in patients with more severe respiratory disease status (1). The relatively high percentage of neurologic symptoms is concordant with studies showing neurotropism of coronavirus (2).
The current literature is limited regarding neuroimaging findings of patients with COVID-19 including acute hemorrhagic necrotising encephalopathy and meningoencephalitis (3–5). The purpose of this study was to describe brain MRI findings in the evaluation of patients in the intensive care unit with COVID-19 pneumonia.
Materials and Methods
Local institutional review board approval was obtained for this retrospective study for patients evaluated from between March 1 and April 18, 2020. The requirement for informed consent was waived. The clinical course, neurological findings, laboratory data (including CSF analysis) and neuroimaging findings were retrospectively reviewed using a structured research form.
Indications and timing for brain MRI in patients with mechanic ventilation was decided on a protocol established by ICU teams. Full details are in the supplement at the end of this article (Appendix E1). MRIs were initially analysed by institution’s own neuroradiologists. Subsequently, all images were reviewed by two neuroradiologists (AD, 29 years of experience in neuroradiology and NK, 29 years of experience in neuroradiology) in consensus.
Of 749 inpatients with COVID-19 infection at eight hospitals (two university, six university affiliated hospitals), 235 patients (31 per cent) required intensive care unit (ICU) admission during hospitalisation. Fifty of 235 ICU patients (21 per cent, 95 per cent CI 16-27 per cent) developed neurological symptoms.
Brain MRI was performed in 27 / 50 (54 per cent) patients with neurologic symptoms (Fig 1). The median age of patients with MRI was 63 years (range 34-87 years, 21 males) (Table). 12 / 27 (44 per cent, 95 per cent CI 25-65 per cent) patients who had MRI had acute findings. In 10/27 (37 per cent) patients, cortical FLAIR signal abnormality (Fig 2; Appendix E1, Figs E1-E4) was present. Accompanying subcortical and deep white matter signal abnormality on FLAIR images were each present in three patients. Abnormalities involved the frontal lobe in 4, parietal lobe in 3, occipital lobe in 4, temporal lobe in 1, insular cortex in 3 and cingulate gyrus in 3 patients.
Cerobrospinal fluid (CSF) was obtained in five out of ten patients with cortical signal abnormalities. Total protein was elevated (mean 79.9 mg/dL, range 59.9 – 109.7 mg/dL) in four of these patients. The cell count, glucose levels, IgG index, albumin were within normal limits, and RT-PCR for HSV DNA and SARS-CoV-2 were negative in all five specimens. Oligoclonal bands were checked in three specimens and were negative.
Other acute intracranial findings in the absence of cortical signal abnormality included one patient with acute transverse sinus thrombosis and one patient with acute infarction in right middle cerebral artery territory.
In 15 / 27 cases (56 per cent), MR did not reveal any COVID-19 related or acute intracranial findings. CSF was obtained in two of these cases which showed elevated CSF protein (mean 98 mg/dL) despite negative MRI. A full description of MRI findings is in the supplement at the end of this article (Appendix E1).
Current evidence suggests an association of neurologic manifestations with COVID-19 infection including acute stroke (6 per cent) and altered mental status (15 per cent) (1). Neurotropism of coronavirus may account for the relatively high percentage of neurologic involvement (6, 7). In addition to neurotropism, another potential mechanism for neurologic manifestations might be related to cytokine storm syndrome (8). In addition to findings of encephalitis, increased thrombosis rates in coronavirus infection has been reported. In patients with SARS-CoV, increased incidence of deep venous thrombosis and pulmonary embolism was observed despite optimal anticoagulant therapy (9). Additionally, intracranial arterial stroke cases have been reported in SARS patients receiving IVIG treatment (9).
A recent series from France reported 84 per cent neurologic signs in 58 COVID-19 patients admitted to ICU. Out of the 13 cranial MRIs performed, leptomeningeal enhancement was noted in eight cases (5). In our series, the most common imaging finding was cortical signal abnormalities on FLAIR images 10 / 27 (37 per cent), accompanied by cortical diffusion restriction, leptomeningeal enhancement or cortical blooming artefact in some of these cases. The main differential diagnosis for this constellation of findings is infectious or autoimmune encephalitis, seizure, hypoglycemia and hypoxia. (10–16) The cases with bilateral frontal involvement may have hypoxia as underlying pathogenesis given the underlying respiratory distress and frontotemporal hypoperfusion as demonstrated by Helms et al., in COVID-19 patients admitted to ICU (5). Cortical microhemorrhages and breakdown of blood-brain barrier can accompany hypoxia which can result in such an imaging pattern. Postictal state is also a plausible etiology for our imaging findings, however the relative symmetry and deep white matter involvement in our cases don’t support postictal changes.
Hypoglycaemia can act as a potential mimicker, however no episode of hypoglycaemia occurred during the ICU course of patients. COVID-19 with its neurotropic potential may result in infectious or autoimmune encephalitis (3, 4). Certain viral and autoimmune encephalitis can have specific pattern of involvement that is helpful to establish a differential list, however nonspecific imaging pattern in our series hinders achieving a specific diagnosis based on MRI (10). In addition, the complex clinical course including comorbid conditions like diabetes mellitus, long ICU stay with multi-drug regimens, respiratory distress with hypoxia episodes can all act as confounding factors and a clear cause-effect relationship between COVID-19 infection and MRI findings is hard to establish in the absence of more specific CSF findings. More data is needed to determine which imaging findings are related to neurotropism of COVID-19 and which are related to other etiologies like cytokine storm syndrome, hypoxia, subclinical seizures and critical illness–related encephalopathy.
Limitations of the current study are the retrospective and multi-centre nature of the study, lack of standardisation of indications across hospitals.
This report may help increase awareness for possible neurological involvement of SARS-CoV-2 for patients in the ICU and especially for patients who do not tolerate extubation despite improvement of respiratory findings.
* Equal contribution: Ibrahim O Akinci and Alp Dincer
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