Presentations and mechanisms of CNS disorders related to COVID-19

Overview of CNS complications of SARS-CoV-2

Observational series have reported the presence of CNS symptoms in 31%⁶ to 69%² of patients with severe COVID-19 vs 21% in patients with nonsevere COVID-19 (severity being established according to respiratory status). Dizziness (17%), headache (13%), impaired level of consciousness (8%), acute stroke (3%), ataxia (<1.0%), and seizures (<1.0%) were the main symptoms or syndromes reported in hospitalized patients.⁶ Agitation (69%), confusion (65%), signs of corticospinal tract dysfunction (67%), and impairment of executive functions (36%) were frequent symptoms in an observational series of 64 consecutive patients admitted to 2 intensive care units (ICUs) due to acute respiratory distress syndrome caused by COVID-19.² In this series, at the time of hospital discharge, 33% of patients had a dysexecutive syndrome consisting of inattention, disorientation, and poorly organized responses to commands.²

In patients with COVID-19 admitted in the ICU with neurologic symptoms, the main MRI abnormalities include cortical FLAIR signal abnormalities¹² and silent ischemic strokes.² In one of these series,¹² only 7 of the 58 patients (12%) underwent real-time PCR for SARS-CoV-2 in CSF, and all were negative. In the other series the patients who underwent EEG, only nonspecific changes were detected.² A recent single case report of a patient with COVID-19 who needed extracorporeal membrane oxygenation (ECMO) had documented brain microbleeds as seen in other critical illness cases requiring ECMO and previously associated with influenza virus. The authors suggested an underlying endotheliopathy.¹³

A retrospective multicenter case series from France showed that stroke, leptomeningeal enhancement, and encephalitis were the 3 most frequent neuroimaging findings among 64 patients with COVID-19.¹⁴ Confusion, impaired consciousness, agitation, corticospinal tract signs, and headache were the most common clinical features. Encephalitis occurred more frequently in younger patients, and agitation was associated with leptomeningeal enhancement.¹⁴

Finally, in a case series from the United Kingdom that included 43 patients with definitive (n = 29), probable (8), and possible (6) COVID-19, 5 categories of neurologic involvement emerged, with 3 specifically affecting the CNS: encephalopathies (n = 10); inflammatory CNS syndromes (n = 12) including encephalitis, acute disseminated encephalomyelitis (ADEM), and myelitis; and ischemic strokes (n = 8).¹⁵

Other than these series, well-characterized case reports with predominant CNS involvement other than stroke (reviewed separately) are scarce and are summarized in the table. In short, these include 14 cases, 9 of them (75%) were women, with age ranging from 24 to 69 years. Three were diagnosed with encephalitis, 4 with acute necrotizing encephalopathy, 2 with a clinicoradiologic picture compatible with endotheliitis (without pathologic confirmation), 2 with toxic-metabolic or vitamin deficiency–like encephalopathy, 2 with ADEM, and 1 with necrotizing myelitis.^{8,9,16,–,25} Of these 14 cases, only 3 had positive SARS-CoV-2 PCR in CSF (2 with negative nasopharyngeal swabs). In the remaining 10 cases, SARS-CoV-2 infection was demonstrated with nasopharyngeal PCR.

Acute necrotizing encephalopathy (n = 4)

The 4 cases reported so far with acute necrotizing encephalopathy resemble those seen after other viral infections, mainly influenza. All these cases had negative PCR for SARS-CoV-2 in CSF.^19,22,25,26 Systemic inflammatory response syndrome (SIRS) and cytokine storm are also thought to underlie this condition. One of the patients also developed myocarditis.^16,17 Two of the patients did not respond to treatment and died.¹⁶ An additional case without data on sex and age but with positive PCR in CSF and improvement with IV immunoglobulins (IVIgs) and plasma exchange has been reported.²⁶

Encephalitis (n = 3)

The 3 reported cases with encephalitis differ in terms of clinical severity and CSF and MRI features.^8,18 Thus, although all 3 showed CSF lymphocytic pleocytosis with increased protein concentration, 1 was severely ill, had positive PCR for SARS-CoV-2 in CSF, and showed structural lesions (mostly in the mesial right temporal lobe) on brain MRI.⁸ By contrast, the other 2 patients had rapid recovery, negative CSF PCR for SARS-CoV-2, and normal MRI.¹⁸ Of interest, these 2 patients were the first reported cases in whom CSF levels of interleukins (ILs) and angiotensin-converting enzyme (ACE) were measured, showing increased levels of IL-1β (in both), IL-6 (in 1), and ACE (both).¹⁸ Accordingly, encephalitis of the former case might be related to direct CNS infection,⁸ whereas in the other 2, it could be linked to cytokine storm and endothelial inflammation as suggested by increased ILs and ACE levels in CSF.¹⁸

ADEM (n = 2) and acute necrotizing myelitis (n = 1)

ADEM is a clinicoradiologic condition that requires a multifocal CNS event of presumed inflammatory demyelinating cause, with an encephalopathic picture that cannot be explained by fever or other causes. It requires the presence on MRI of diffuse, poorly demarcated, large (>1–2 cm) lesions mostly involving the white matter, rarely with T1 hypointense white matter lesions.²⁷ Deep gray nuclei (thalami and basal ganglia) lesions can be seen, without additional clinical and MRI findings in the ensuing 3 months. ADEM is not associated with aquaporin 4 (AQP4) antibodies, but up to 60% of patients have myelin oligodendrocyte glycoprotein (MOG) antibodies.

To the best of our knowledge, there are 2 single case reports of ADEM associated with COVID-19.^9,21 One had positive SARS-CoV-2 PCR in CSF and a clinical picture that resembled neuromyelitis optica and was treated with IV methylprednisolone and IVIg.¹⁰ The other patient had a negative PCR in CSF and developed decreased level of consciousness and impaired oculocephalic response after a stay in the ICU due to respiratory distress. Despite the diagnosis of ADEM, findings of spinal MRI were not reported. This patient was treated with IVIg.²¹ Both patients had partial clinical and radiologic responses. A single case report of a patient with longitudinal extensive transverse necrotizing myelitis who again had a negative PCR for SARS-CoV-2 in CSF, was also negative for AQP4 and anti-MOG antibodies, and responded to methylprednisolone and plasmapheresis.²⁵

Overall, in these 3 cases, the different evidence of the infectious status makes it difficult to infer the underlying pathophysiology. Although in 2 of the patients, the CSF PCR can potentially be considered a false-negative result, the clinical and radiologic features of these cases are suggestive of an inflammatory postinfectious process.

Endotheliitis-like involvement (n = 2)

The 2 reported cases of endotheliitis-like involvement include 1 patient with focal neurologic signs and the other with impaired level of consciousness. Both had marked perivascular enhancement on MRI, were negative for SARS-CoV-2 PCR in CSF, and had rapid clinical and radiologic recovery after treatment with IV methylprednisolone and plasma exchange, supporting the notion of an inflammatory mechanism.^20,23 Although no pathologic studies were available, the MRI findings led to the diagnosis of endotheliitis. The inflammatory endothelial reaction might be related to cytokine storm or the ACE pathway, but neither of these mechanisms was studied in blood or CSF.

More recently, Pugin et al.²⁸ reported 5 cases of COVID-19–related encephalopathy responsive to corticosteroids that the authors suggested were caused by endotheliitis based on the MR angiography features.

Toxic/Wernicke-like encephalopathy (n = 2)

Two patients were identified at a single institution with COVID-19 who had developed clinical and brain MRI features that resembled Wernicke encephalopathy, prompting supplementation of vitamins despite having normal blood levels.²⁴ The patients showed partial improvement. The authors considered the symptoms as related to SARS-CoV-2, either by direct viral involvement or secondary to the systemic inflammatory response to the virus.

Stroke

In a series of 388 patients, thromboembolic events occurred in 28 patients (8%) including 9 cases with ischemic stroke (2.5%).²⁹ Likewise, in a study of ischemic events in critically ill patients with COVID-19, 28 of 184 cases had thrombotic events (15%), including 3 with stroke.³⁰ In another series of 1,683 COVID-19 cases, 23 (1.4%) developed cerebrovascular disease.³¹ Cerebral and chest CT scans were performed in all cases and MRI in 6, with histologic samples available for 6/23 cases (2 brain biopsies and 4 arterial thrombi). Cerebral ischemia occurred in 17 cases (74%), including 2 cases with arterial dissection (9%), whereas intracerebral hemorrhage happened in 5 (22%), and 1 (4%) had posterior reversible encephalopathy. Ischemic strokes were frequent in the vertebrobasilar territory. In the hemorrhagic group, subarachnoid hemorrhage, parieto-occipital leukoencephalopathy, microbleeds, and single or multiple focal hematomas were characteristic. Brain biopsies showed thrombotic microangiopathy and endothelial injury, with no evidence of vasculitis or necrotizing encephalitis. Outcome was poor, 8 died, and 17 had a median Rankin scale score of 4–6 at hospital discharge.³¹

In another study, Al Saiegh et al. reported 2 patients with cerebrovascular disease in the setting of COVID-19. One was a 31-year-old man with a Hunt & Hess grade 3 subarachnoid hemorrhage and the other a 62-year-old woman with ischemic stroke with massive hemorrhagic transformation.³² Oxley et al. reported 5 patients with COVID-19 younger than 50 years with large vessel ischemic stroke,³³ and Gonzalez-Pinto et al.³⁴ described a 36-year-old man with malignant ischemic stroke of the middle cerebral artery and a free-floating thrombus in the ascending aorta. Overall, these reports suggest that stroke is more frequent than expected in patients with COVID-19 younger than 50 years.

Other CNS involvement

There are other case reports difficult to classify. For example, Méndez-Guerrero et al. described a 50-year-old man presenting with a hypokinetic syndrome, hyposmia, opsoclonus, and myoclonus after a severe COVID-19 infection with positive nasopharyngeal but negative CSF PCR. The MRI was normal, but there was impaired presynaptic dopamine imaging. The patient spontaneously recovered.³⁵ In another report, Rabano-Suarez and colleagues^33,36 described 3 cases (2 men, 63 and 76 years and a woman of 88 years) with COVID-19 who had generalized myoclonus with normal CSF, imaging (MRI or CT), and EEG. They slowly improved with either corticosteroids or plasma exchange, leading the authors to conclude that the myoclonus was postinfectious and immune mediated.

Direct viral injury

Like other well-recognized neuroinvasive human viruses, coronavirus might invade the CNS, via trans-synaptic propagation from the olfactory epithelium or through systemic circulation, entering the CNS using the endothelial ACE2 receptors expressed in brain vessels, or crossing a leaky blood-brain barrier affected by systemically produced cytokines (figure).³⁷

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Figure Proposed CNS entry routes, mechanisms and their respective associated clinical pictures

Therefore, SARS-CoV-2 might reach the CNS by different routes and induce short-term illnesses, such as viral encephalitis. On the other hand, SARS-CoV-2 might persist in resident cells of the CNS and be involved in long-term neurologic sequelae in genetically or otherwise predisposed individuals.³⁷

There are case reports of the detection of human coronavirus OC43 RNA in brain biopsies by metagenomic sequencing in immunosuppressed children with encephalitis.^38,39 Moreover, SARS-CoV-1 has also been detected at autopsy in brain tissue of patients with SARS.^40,–,42 However, as previously indicated, there are limited data suggesting the presence of SARS-CoV-2 in the CNS of patients with COVID-19. In an autopsy series of patients with COVID-19 without neurologic symptoms, SARS-CoV-2 was detected in the brain of 8 (38%) of 21 patients with low levels of SARS-CoV-2 copies per cell.⁴³ In another autopsy study of 10 patients,⁴⁴ no signs of encephalitis or CNS vasculitis were found, and the PCR in CSF was negative.

Only 2 of the 11 patients who underwent PCR testing in CSF (table) were positive (1 case of encephalitis and 1 ADEM), suggesting that the virus can directly invade the nervous system in some cases.^8,9

Inflammatory-mediated injury

Thrombotic injury

Increased levels of circulating prothrombotic factors have been reported in patients with severe COVID-19, reflecting a hypercoagulable state.^7,62 Proinflammatory cytokines can induce endothelial and mononuclear cell activation with expression of tissue factor leading to activation of the coagulation cascade and thrombin generation. Circulation of free thrombin can activate platelets and lead to thrombosis. It has been postulated that the binding of SARS-CoV-2 to the ACE2 receptor causes an imbalance of the renin angiotensin system favoring the ACE1-angiotensin axis and contributing to endothelial dysfunction, organ damage, and clot formation.⁶³

Hypoxia-mediated injury and encephalopathy of the critically ill

The diffuse alveolar and interstitial inflammatory edema in COVID-19 leads to impairment of alveolar gas exchange and CNS hypoxia. Anerobic metabolism in the mitochondria of brain cells results in acidosis, vasodilatation, increased interstitial edema, obstruction of cerebral blood flow, intracranial hypertension, and coma.

Between 5%^1,2 and 14%³ of patients with COVID-19 require admission to the ICU. A high number of patients in the ICU develop symptoms of acute cerebral dysfunction described as delirium, acute confusional state, acute brain failure, organic brain syndrome, acute organic reaction, cerebral insufficiency, and ICU psychosis and grouped under the term “encephalopathy of the critically ill” or “critical illness brain syndrome.” This encephalopathy is an independent predictor of mortality and is associated with long-term cognitive dysfunction.⁶⁴ The mechanisms underlying this encephalopathy are heterogeneous and multifactorial, including direct brain injury, respiratory, heart, renal or liver failure, sepsis, endocrine or electrolyte imbalance, and pharmacologic agents.⁶⁵

In a series of 18 patients with COVID-19 who died in the ICU and underwent autopsy, acute hypoxic ischemic damage was identified in all. Nevertheless, the clinical description is very limited, and none of the cases underwent MRI, EEG, or CSF examination.