In the Wuhan series, 27 of 88 patients hospitalized with severe COVID–19 infection (30.7%) had CNS symptoms (1). 13 of them (48.1%) suffered from impaired consciousness, five from acute cerebrovascular disease (18.5%), one from ataxia and one from seizure. Neurological features were found in 58 of 64 consecutive hospitalized patients in Strasbourg (4). Most of them occurred when sedation was withheld (67%) and consisted of agitation (69%), confusion (65%) and diffuse corticospinal tract signs (67%).
In the present patient population of 32 ICU patients with COVID–19, eight (25%) had severe CNS symptoms, among them two with hemiparesis and lacunar ischemic stroke and one with status epilepticus in the early phase. As most common presentation, six patients presented with prolonged impaired consciousness after termination of analgosedation, three with temporarily delirious state.
The different patterns of our cases suggest that variable pathogenesis may lead to CNS disorders in COVID–19. Evaluating and summarizing the published small series and individual cases (1–3, 5–11), neurologic sequelae can be assigned to the following pathophysiological groups:
Unspecific, related to severity of disease
In one case hypoxic encephalopathy, presenting as status epilepticus and myoclonic movements, and in another case, metabolic-toxic encephalopathy, associated with uraemia, might be unspecific cerebral complications in two of our critically ill COVID–19 patients. In both patients neuroimaging showed no specific findings but frontotemporal brain atrophy, which might be associated with sepsis-induced brain dysfunction (15). Sepsis-associated encephalopathy, which typically presents as confusion and coma, is reported in up to 70% of patients with sepsis (16). All our patients’ EEG examinations showed severe generalized background slowing, indicating global cognitive dysfunction and occurring in patients after recovery from severe sepsis (17). In the Beijing series, critically ill COVID–19 patients developing septic shock and multiorgan failure have been described (18). In 76% of the cases cultures for bacteria and fungus were negative. The authors, therefore, used the term “viral sepsis”. As in sepsis induced by other microorganisms, hyperactivation of proinflammatory cytokines and chemokines play an important role in severe COVID–19 and may be associated with septic encephalopathy. Finally, epileptic activity seems to occur only rarely in COVID–19 patients (0.5% in the Wuhan series) (1) and might be related to hypoxia, multiorgan failure, and metabolic disorder rather than to CNS infection (19). In agreement, also in our series the occurrence of epileptic activity and myoclonic status in patient 3 was most probably caused by hypoxic brain injury.
Large and small cerebral vessel disease
Two of our patients presented with acute ischemic stroke in the early phase of their disease. A series of five cases of large -vessel stroke in patients younger than 50 years has been described in New York City (6). In the Wuhan series, the incidence of stroke in hospitalized patients was about 5% (1). Severe infections, especially respiratory-related, are known to trigger acute cerebrovascular events (20). Severe COVID–19 mostly develops in patients with cardiovascular risk factors and is characterized by a pronounced proinflammatory early phase (18), both factors even aggravating the risk for stroke at disease onset. In Strasbourg, 23 patients with neurological symptoms were examined with MR imaging (4). Three asymptomatic patients had small ischemic strokes and bilateral frontotemporal hypoperfusion was noted in all 11 patients who underwent perfusion imaging (4). Contrast -enhanced perfusion MR was not performed in our series. However, the unspecific EEG patterns in our patients with background slowing and occasional anterior rhythmic delta activity, consistent with unspecific encephalopathy, might also reflect frontal hypoperfusion.
Further extraordinary findings in our series were detected later in the course of the disease. In all but one patient with delayed wake-up, neuroimaging or autopsy showed multiple cerebral microbleeds, in three of them with additional subarachnoid haemorrhage and in another two with additional small ischemic lesions, indicating CNS small vessel disease. Different factors might explain the involvement of small cerebral vessels. All patients had cardiovascular risk factors, most of them hypertension. The distribution of the microbleeds, however, was typical for hypertension in only one patient. None of our patients had a history of cerebral amyloid angiopathy. As in other series, all our patients had a hypercoagulable state with increased fibrinogen and D-dimer levels (11, 21), which might lead to thrombosis of small cerebral vessels. Only one patient, however, fulfilled the criteria of disseminated intravascular coagulation disorder (> 5 points according to the International Society on Thrombosis and Haemostasis criteria) (22), which is known to be associated with acute cerebral micro-angiopathy. Immune-mediated and infectious vasculitis may cause CNS small vessel disease (23) and a certain type of vasculitis involving cerebral vessels might be induced by COVID–19 as well.
In three patients with severe COVID–19 intracranial vessel wall sequence MRI scans were performed, for the first time to our knowledge. MR vessel wall imaging showed contrast -enhancement of vessel walls in large and middle-sized cerebral arteries, suggesting vascular wall pathologies with an inflammatory component. However, MRI vessel wall contrast- enhancement is not specific for vasculitis involving cerebral vessels. None of our patients showed inflammatory signs in the CSF or characteristic autoantibodies indicating systemic vasculitis. Chen et al. found vessel wall contrast -enhancement in 45.8% of the patients with reversible cerebral vasoconstriction syndrome (RCVS) (24). The authors suggest that, among other factors, endothelial dysfunction might contribute to vascular wall inflammation in RCVS. However, none of our patients had typical signs of RCVS such as thunderclap headache and/or reversible multifocal cerebral vasoconstrictions.
Contrast -enhancement of vessel walls as well as the pattern of micro-bleedings and multiple small infarctions indicate that large, middle-sized as well as small cerebral vessels are involved. An autopsy study in patients with severe COVID–19 revealed vascular involvement in multiple organs (25). Lymphocytic endotheliitis was found in lung, heart, kidney, liver and small intestine. Furthermore, viral inclusion structures, could be found in endothelial cells. The angiotensin-converting enzyme 2 (ACE2), as the main host cell receptor of SARS-CoV–2 (26), albeit at lower concentrations, is also expressed in the endothelium and vascular smooth muscle cells of the brain (27). It might be hypothesized that the endothelium of brain vessels might be directly affected by the virus or that the virus induces a parainfectious immune-mediated inflammation of the endothelium. However, we did not find any inflammatory CSF syndrome as a sign of infectious cerebral vasculitis in our patients or signs of perivascular inflammatory cell infiltration in the one post-mortem analysis performed. Another mechanism might be, that the cerebral vessels might be affected by the inflammatory state in the peripheral blood. Prolonged increased levels of IL–6, IL–10, IL–2 and IFN γ have been described in severe cases and may play an important role in the immunopathology of COVID–19 (28). In our patients, serum IL–6 was elevated in all but one patient up to levels of 594 ng/L. However, in all of them IL–6 values in the serum were higher than in CSF, which contradicts its intrathecal synthesis. Still, these observations do not exclude the possibility of damage to cerebral vessels induced by the hyperinflammatory state in the peripheral blood. Cytokines or inflammation-induced metabolic changes leaking from peripheral blood to the CNS micromilieu might lead to disseminated focal disturbances of the blood brain barrier and dysfunction of the respective surrounding brain tissue.
Singles cases with COVID–19 and meningo-encephalitis, one case with acute necrotizing encephalopathy and one with acute disseminated encephalomyelitis (ADEM) have been described (2, 3, 5, 7–11). Neuroinvasion is hypothesized to occur via hematogenous or neuronal route as over the olfactory nerve (29). In two cases with neuropsychological symptoms, one of them with status epilepticus, lymphocytic pleocytosis but negative RT-PCR for SARS-CoV–2 was found in the CSF (2). In another case suffering from disorientation and hallucinations, CSF analysis also revealed lymphocytosis (3). To our knowledge, up to date, gene sequencing confirmed the presence of SARS-CoV–2 in the CSF in Beijing in only one case (30) and RT-PCR was positive in only one patient in Japan (5). None of our patients, not even those with status epilepticus, showed inflammatory signs neither in neuroimaging nor in the CSF. RT-PCR for SARS-CoV–2 in the CSF was negative in all patients. Intrathecal IgG production against the SARS-CoV–2 could not be demonstrated and even metagenomic virus sequencing was negative in two patients. Therefore, neither direct neuroinvasive potential nor directly CNS-directed parainfectious injury could be demonstrated in our patients.
Only eight patients were studied. All were severely ill, entering the ICU with respiratory failure. Mild neurological symptoms at disease onset as headache, dizziness and taste or smell impairment could no longer be reliably evaluated. Furthermore, CNS symptoms might have remained undetected in patients who were under analgosedation. Diagnostics with neuroimaging and CSF analysis might not have been performed at the time of the occurrence of cerebral complications. Therefore, inflammatory signs in the CSF, might have been missed. Furthermore, RT-PCR tests for SARS-CoV–2 in the CSF are not yet sufficiently clinically validated regarding sensitivity and timing of lumbar puncture after onset of symptoms. We cannot exclude the possibilities of (i) transient SARS-CoV–2 RT-PCR positivity in the CSF through true invasion of CNS with SARS-CoV–2, which turned out to be negative at the time of lumbar puncture, or (ii) concentrations of SARS-CoV–2 in the CSF below detection limit of our RT-PCR assay. Additional search for intrathecal SARS-CoV–2-specific IgG production as a sign of humoral immune reaction against viral infection of CSF space turned out negative. In other viral CNS infections such as herpes encephalitis or tick-borne encephalitis, intrathecal antiviral IgG production usually consistently occurs 10–14 days after onset of symptoms, but may occur occasionally as early as 3 days after disease onset (31–33). Our observation of no intrathecal SARS-CoV–2 IgG production may be explained by the possibilities, that SARS-CoV–2 never entered CNS and therefore no intrathecal immune response was mounted or because intrathecal SARS-CoV–2-specific IgG synthesis occurred after lumbar puncture. In analogy to other human viral CNS infections, the consistent combination of negative SARS-CoV–2 RT-PCR and absence of intrathecal SARS-CoV–2 IgG production 2 days (range 0—31) after onset of CNS disorder argues relatively against a direct invasion of CNS by SARS-CoV–2, but we cannot exclude the possibility of a differential diagnostic window, which might have been missed.