Neurologic manifestations of COVID-19

Neurologic Manifestations

• CNS: dizziness, headache, impaired consciousness, acute cerebrovascular accident, ataxia, seizure
• PNS: hypogeusia, hyposmia, hypopnia, neuralgia
• Muscle injury

A retrospective study of 213 COVID-19 positive patients in the Wuhan region assessed the symptoms listed above in patients with both severe and non-severe COVID-19 infection, finding that 36.4% (78/214) patients with COVID-19 developed at least 1 of these neurologic symptoms. They additionally found that patients with severe systemic and respiratory symptoms were more likely to develop CNS neurological symptoms than patients with moderate or mild disease. A small portion of these patients initially presented with their neurological symptoms.[1] The presence of hypogeusia and hyposmia has been further evaluated as a potential early sign of disease in otherwise asymptomatic patients.[2]

There have been multiple reports of meningitis/encephalitis related to COVID-19. One case report detailed a patient with neck stiffness and transient generalized seizures, CNS serologic testing positive for SARS-CoV-2 RNA (and negative for other CNS pathogens including HSV and VZV), and brain MRI showing temporal lobe hyperintensities in the absence of brain edema.[4] Another case report demonstrated altered mental status in a patient with severe COVID-19 and brain MRI consistent with acute necrotizing hemorrhagic encephalopathy, although CSF testing for SARS-CoV-2 RNA was unable to be performed.[5] Media sources also report a case of COVID-19 related viral encephalitis in the Beijing Ditan Hospital,[3][6] although this is unconfirmed by peer-reviewed literature. Viral encephalopathy is thought to be due to intracranial cytokine storms resulting in blood-brain-barrier breakdown but without direct viral invasion. Evidence suggests that some patients with severe COVID-19 may have cytokine storm syndrome,[7] which could serve as a trigger for the development of encephalitis in these patients. Although this suggests that immunosuppressive therapies may be helpful for the treatment of this specific presentation, no data on this subject is currently available.

A retrospective study of 725 COVID-19 hospitalizations from Italy aimed to complement the aforementioned Wuhan study by further characterizing neurological symptoms and neuroimaging features[8]. Of the 725 patients reviewed, 108 met eligibility criteria for the study (criteria being hospitalization, a positive COVID-19real time reverse-transcriptase PCR test of respiratory secretions, presence of neurological symptoms during hospitalization, and neuroimaging studies). Acute ischemic infarcts, present in 34 out of 108 patients with the majority occurring in large vascular territory, and intracranial hemorrhages, present in 6 out of 108 patients, were the most common neurological sequelae. Other symptoms, including cranial nerve enhancement and encephalopathy, were far less common. The authors highlighted the case of a 60 year old COVID-19 positive male with a history of seizures who presented with acute encephalopathy. Neuroimaging studies revealed hyperintensity in the right cerebellum, left anterior cingulate cortex, and superior frontal gyrus. Overall, Mahammedi et al. found a lower prevalence of CNS symptoms among COVID-19 hospitalizations in their population of interest than the preceding Wuhan study by Mao et. al[1][8].

Several case reports exist concerning a possible connection between the development of Guillain-Barre Syndrome (GBS) and COVID-19 infection. For example, between February 28 and March 31 2020, 5 cases of GBS were seen among COVID-19 patients in 3 hospitals across Northern Italy[9]. For 4 of these patients, onset of GBS began with lower limb weakness and paresthesia; for 1, facial diplegia, ataxia, and paresthesia were the first symptoms. Eventually all patients began to develop flaccid tetraparesis or tetraplegia. 3 eventually needed ventilation. The average interval between the onset of COVID-19 symptoms and onset of GBS symptoms across all 5 patients was 5 to 10 days. RT-PCR analysis of CSF in all 5 patients was negative for CSF infiltration of COVID-19. Given reported associations between GBS and other coronavirus infections, it is possible that a connection could exist between GBS and COVID-19, although more work will need to be done to elucidate any potential relationships.

A growing body of evidence points to stroke as a significant and potentially lethal consequence of COVID-19, especially in young adults not otherwise severely ill[10]. Consider 5 patients under 50 treated in the Mt. Sinai Health System. Each patient exhibited either mild symptoms or none whatsoever, and each patient presented with a stroke. It is increasingly likely that COVID-19 appears to increase clotting in large arteries, contributing to severe strokes. Additional work is necessary to better understand the mechanisms by which COVID-19 could contribute to acute vascular injury.

Mechanism of Neurologic Damage Related to COVID-19

Current theories for mechanisms underpinning COVID-19 induced nervous system pathology derive from genetic and structural similarities between SARS-CoV and COVID-19.

SARS-CoV invades human cells through interaction with angiotensin-converting enzyme 2 (ACE2) present on cell surfaces. In addition, the priming protein TMPRSS2 helps to facilitate SARs-CoV uptake by cells[11]. In this vein, the prevailing model for COVID-19 cell invasion centers on COVID-19 spike protein interaction with ACE2, followed by TMPRSS2 activation of the spike protein to allow the virus to penetrate its target cell.

Studies have shown that ACE2 is expressed in neurons and glia of the brain; therefore, it is theoretically plausible that COVID-19 could target neurons if it reaches the brain[12]. Indeed, in mouse studies SARS-CoV can kill neurons by invading the brain through the olfactory epithelium[12]. Furthermore, SARS-CoV has been found in CSF samples.

However, it is an open question as to how exactly COVID-19 enters the brain, especially because COVID-19 has yet to be definitively confirmed to invade the CSF system. In one model, it does so in a manner similar to SARS-CoV, penetrating olfactory neurons and hijacking retrograde axonal transport to move from the periphery into the brain[13]. Once in the brain, COVID-19 can bind to neuronal ACE2 and trigger neurological pathology. Unfortunately, this proposal is challenged by findings that suggest olfactory receptor neurons lack significant expression levels of ACE2 and TMPRSS2[11][14].

Instead, sustentacular cells of the olfactory epithelium appear to express high levels of both proteins[11]. It may be that COVID-19 accumulation in olfactory epithelium sustentacular cells disrupts their metabolic processes, which in turn may affect the function of olfactory receptor neurons[11]. This could explain hyposmia and anosmia observed in many COVID-19 patients. In addition, given that sustentacular cells wrap around the dendrites of olfactory receptor neurons, and that reciprocal communication between the two may occur through exosomes, it may be possible for COVID-19 to move from sustentacular cells to olfactory receptor neurons through an exosome sent from the former to the latter[11]. Once inside the neuron, perhaps COVID-19 can use retrograde axoplasmic transport to move deeper into the CNS.

A second possibility for COVID-19 CNS invasion is penetration of the Blood Brain Barrier (BBB). Blood vessel endothelial cells are known to have high levels of ACE2 expression[13]. Therefore, it could be possible for COVID-19 to attack endothelial cells of the BBB, thereby passing from the general circulation into cerebral circulation[12][13]. Such a process would disrupt BBB integrity, leading to cerebral edema, intracranial hypertension, and other potentially fatal consequences.

Finally, neuropathologies induced by COVID-19 may not be due to direct neuronal invasion at all. Instead, it could be the consequence of systemic, long-lasting chronic inflammatory state throughout the body, induced by ordinary COVID-19 infection[15]. Cytokine storms have been noted as significant drivers of general COVID-19 pathology in severe infections. Systemic inflammation can initiate a process that compromises the integrity of the BBB (e.g. by weakening tight junctions, increasing permeability). This in turn could allow peripheral cytokines to flow into the CNS, triggering neuroinflammation. Note that such a neuroinflammatory response in acute/chronic COVID-19 infection could in theory exacerbate mechanisms that drive early stages of neurodegeneration5. Therefore, a possible long-term study looking for the onset of neurodegenerative diseases on patients with severe neurological symptoms of COVID-19 could be quite relevant.

It may be difficult to distinguish whether the neurologic symptoms associated with COVID-19 are due to the direct effects of virus invasion on neurons and surrounding tissue, or factors related to the process of acute infection such as metabolic disorders, hypoxia, and systemic toxemia. Continued study of patients with COVID-19-related neurologic disease, including CSF analysis and pathologic evaluation of brain tissues, will be required to better understand these mechanisms.

Neurologic Manifestations of Coronaviruses Related to COVID-19

Many other coronaviruses related to COVID-19 have shared a similar ability to affect the nervous system, including SARS-CoV and MERS-CoV. SARS-CoV specifically shares highly homological sequences with COVID-19 (SARS-CoV-2),[16] suggesting they may have similar neurologic manifestations. SARS-CoV has been shown to induce neurological diseases such as encephalitis, aortic ischemic stroke, and polyneuropathy, among others, with associated findings of cerebral edema and meningeal vasodilation on autopsy.[17] Additionally, SARS-CoV has been demonstrated able to spread via a synapse-connected route from the respiratory airways to the medullary cardiorespiratory center, where virus-mediated damage may lead to decreased respiratory drive and be partially responsible for SARS-CoV-related respiratory failure. With the high similarity between SARS-CoV and SARS-CoV-2, it may be important to consider the role of this neuroinvasion in the respiratory failure of COVID-19 patients,[18] although the clinical implications of this knowledge remain to be seen.