Limited reports described neurologic complications of SARS-CoV-1 and MERS-CoV, mainly restricted to axonal peripheral neuropathy, acute disseminated encephalomyelitis, and stroke[22, 23]. Our systematic review of 2499 patients reported the occurrence of a wide spectrum of neurologic complications in hospitalized patients with laboratory-confirmed COVID-19 infection, supporting the possible neuroinvasive potential of SARS-CoV-2.
The potential neurotropism of SARS-CoV-2
A growing body of evidence suggests that SARS-CoV-2, similarly to SARS-CoV-1, has neuroinvasive potential, possibly through the retrograde neuronal route[24, 25]. Recent studies reported that the expression level of angiotensin converting enzyme 2 (ACE2) is critical for the susceptibility of SARS-CoV-1 and SARS-CoV-2 infection. The cellular receptor ACE2 is expressed in different tissues and organs including the nervous system and skeletal muscles. Autopsy samples from patients with SARS clearly demonstrated the presence of SARS-CoV-1 in brain samples[28, 29]. Interestingly, laboratory investigations on transgenic mice for the SARS-CoV receptor (ACE2) demonstrated that the virus enters the brain via the olfactory bulb with resultant rapid transneuronal spread to different brain regions including cortical areas (piriform and infralimbic cortices), basal ganglia (ventral pallidum and lateral preoptic regions), and midbrain (dorsal raphe). In these regions, a significant neuronal death occurs. A recent report confirmed the presence of SARS-CoV-2 in cerebrospinal fluid by genome sequencing in a patient with viral encephalitis, confirming the neurotropism of SARS-CoV2[31, 32]. They proposed that the respiratory failure in patients with COVID-19 is related to the neuronal loss at the level of the cardiorespiratory center in the brainstem. However, type 1 respiratory failure with low CO2 levels and raised respiratory rate observed in patients with COVD-19 is more likely related to pneumonia instead of brainstem dysfunction that leads to failure of breathing associated with reduced respiratory rate and high C02 levels (type 2 respiratory failure).
Symptoms related to skeletal muscle injury are generally associated with elevated creatine kinase and lactate dehydrogenase levels. It was initially suspected that this injury was related to the presence of ACE-2 in skeletal muscle. However, immunohistochemistry and in situ hybridization failed to detect SARS-CoV in the skeletal muscle of patients who died of SARS, suggesting a putative role of a systemic inflammatory response syndrome (SIRS) in the pathogenesis of muscular damage. It is supposed that SIRS can occur in pneumonia caused by COVID-19 infection and promotes multiple organ failures in patients with severe infection. Further clinical and laboratory investigations are required to clarify the neurotropism of SARS-COV-2 and its neuroinvasive potential.
Neurologic Manifestations of SARS-CoV-2 Infection
Neurologic manifestations in patients with COVID-19 are common. In a recent retrospective study, Mao et al. reported nervous system-related clinical findings in 78 of 214 hospitalized patients (36.4%) and categorized neurological disturbances into three groups: CNS manifestations, PNS manifestations, and skeletal muscular injury manifestations. Interestingly, their report suggested that patients with severe infection were more likely to develop CNS and muscular injury symptoms. The results of our analysis are consistent with their findings, demonstrating a significant difference among severe and non-severe patients. Nonetheless, the two groups were not homogeneous in terms of clinical comorbidity, and severe patients were characterized by a significant higher rate of concomitant hypertension, cardiovascular disease, malignancy, and diabetes. Accordingly, as previously discussed, a direct link between the occurrence of neurological symptoms and the clinical condition cannot be drawn at the current state of knowledge. However, the occurrence of multiorgan damage in patients with muscle injury suggests that infection-mediated immune response probably plays a role as a causative factor of skeletal muscle damage. In fact, these patients present not only significantly higher levels of creatine kinase but also higher neutrophil counts, lower lymphocyte counts, higher C-reactive protein levels, and higher D-dimer levels indicating increased inflammatory response and coagulation activation[7, 24]. Similar findings were reported in patients with MERS and SARS-CoV-1 infection[35, 36]. Our study demonstrated that olfactory and gustatory function impairment were the most common neurologic manifestations in patients with COVD-19 and were detected in more than 50% of patients. Lechien et al. extensively examined this topic in a multicentric investigation and reported an overall rate of olfactory and gustatory dysfunctions of roughly 85 and 88%, respectively. In this study, olfactory and gustatory dysfunction were both prevalent in patients with mild-to-moderate COVID-19 infection and hyposmia was generally observed in patients without nasal obstruction or rhinorrhea before, during or after the general symptoms. It is worth noting that the prevalence of olfactory and gustatory dysfunction was substantially higher in European cohorts compared with the Asian cohorts[4, 15]. This difference is poorly understood and requires further investigation. Scant information is available on MRI investigations of the brain in patients with COVID-19. In the series of Helms at al., an MRI was performed in 13 patients because of encephalopathic features and demonstrated two asymptomatic acute ischemic strokes and one subacute ischemic stroke.
Limitations of the study
Our study has limitations. The series are often small, retrospective, and single-institution experiences. Furthermore, due to the contemporaneity of the outbreak, the follow-up is short, and the occurrence of late onset neurological deficits cannot be analyzed. Furthermore, only two studies[7, 8] have analyzed, as primary outcome, the neurological characteristics of their patients. In addition, advanced neuroimaging (MRI) and diagnostic procedures (lumbar puncture, electromyography/nerve conduction velocity) were rarely reported in the studies included. However, our review is the largest study to date that provides a representation of data concerning neurological symptoms among laboratory-confirmed COVID-19 population.