Introduction

The infamous COVID-19 pandemic has drastically involved everyone in a hit or miss manner. The world is currently fighting against a highly infectious novel coronavirus, known as SARS-CoV2. What began as an outbreak of pneumonia in Wuhan, China, has rapidly engulfed the entire world [1]. As of August 31, 2020, this virus has infected approximately 25 million people and caused 844 thousand deaths globally [2]. The pandemic has posed severe challenges to public health, and the medical community continues to struggle in hitherto mysterious zones, especially in terms of reliable therapeutic interventions. In one study, health care providers utilized extracorporeal membrane oxygenation (ECMO) for patients with acute respiratory distress syndrome secondary to COVID-19, although early reports seem to have a high mortality rate due to devastating neurological insult [3].

Though the respiratory symptoms are the most common, there have been studies which highlight the potential neurotropism of the virus. The incubation period of COVID-19 infected patients, whether asymptomatic or possessing wide spread signs and symptoms, varies from 2 to 11 days with an approximate mortality rate of 2-4% [4]. In an observational study in Wuhan, 36.4% of the patients had neurological involvement such as impaired consciousness, acute cerebrovascular events, headache, seizure, hyposmia, and hypogeusia [5]. There have also been several reports on patients presenting with neurological involvement as the initial symptoms [6, 7].

This initial data reflects that the brain seems to be a target organ for various infections and critical diseases, either due to direct insult or through secondary involvement. The peripheral nervous system (PNS) is also particularly susceptible during infection-related immune-mediated diseases [8].

Even though there is extensive data on the respiratory involvement of SARS-CoV2, documentation of its neurological aspect has been limited to observational studies and case reports. There is a further lack of information on the neuroimaging findings of COVID-19. In this rapidly evolving situation, it has become essential for healthcare providers to stay updated on the various atypical presentations of SARS-CoV2 and keep in mind COVID-19 as a potential diagnosis when encountering such cases. Therefore, we performed a comprehensive literature search in this systematic review to ascertain the different neurological manifestations and neuroimaging findings linked with COVID-19 infection.

Objective

To evaluate and correlate the neuro-radiological and neurological manifestations in patients diagnosed with SARS-CoV2.

To identify neuro-invasive pathways of COVID infection.

Methods

A comprehensive search of the literature was performed from the following databases: PubMed, Web of Science, Cochrane Library, and Science Direct. The following search terms were used in combination with the Boolean operators AND and OR; “COVID-19,” “SARS-CoV2,” “neurological manifestations,” “neuroimaging,” “MRI,” and “CT.” We selected for analysis only articles in which the title and abstract contained the aforementioned search terms. In an initial screen, we excluded articles which were duplicates, and those in which title and abstract were not relevant to our search terminology. Of the remaining studies, screening was done based on the full text of the article under the following inclusion criteria: (1) Studies reporting patients with laboratory confirmation of SARS-CoV2, (2) case reports, case series, cohort studies, and case-control studies, (3) studies in which subjects were above the age of 18, (4) studies containing neuroimaging (CT or MRI) of the brain, (5) studies performed between December 2019 and August 2020. The exclusion criteria were as follows: (1) reviews, editorials, or commentaries. (2) Studies in which subjects were in the pediatric age group, were pregnant, or had prior neurological conditions. (3) Studies with no neurological evaluation, (4) studies published in any language other than English, without available English translations. The articles were screened in their entirety, by two independent readers, in each of the aforementioned scientific databases, to determine eligibility for inclusion. Discrepancies were discussed among all authors, and a collective effort was undertaken to resolve them.

The search strategy and article selection process are depicted in the flowchart in Fig. 1 as per the PRISMA statement.

Fig. 1
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PRSIMA flow chart summarizing search strategy for the articles included in the study

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Results

Through the search strategy, we identified 63 articles with neurological and neuroimaging manifestations in patients infected with COVID-19. We included 584 patients who presented with neurological manifestations and underwent different neuroimaging modalities. The age of patients ranged from 24-88 years.

In terms of neuroimaging findings (Table 1), among these 63 articles, 584 patients underwent neuroimaging. Four hundred and twenty eight (67.61%) patients that underwent neuroimaging did not have any abnormality on CT or MRI. For the remaining 156 patients, neuroimaging findings were in descending order as follows: ischemic changes (17.85%), with the middle cerebral artery (MCA) being the most frequent anatomical location; hemorrhagic changes (6.31%), diffuse edema (1.57%), encephalitis (1.57%), herniation (with uncal and subfalcine as the most common) (1.26%), venous thrombosis (0.7%), atrophy (0.4%), inflammatory process (0.4%), and constriction (0.4%). The absence of flow and signal changes was 0.3% each. The least common findings were acute myelitis, high-grade glioma, calcification of the proximal left internal carotid artery (ICA), a demyelinating lesion in left temporal and right occipital lobes, dissection of the left vertebral artery, and small-vessel disease comprised the remaining 0.6% (0.1% each) (Fig. 2).

Table 1 Reported studies on COVID-19 patients with neurological manifestations with positive findings on major imaging modalities
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Fig. 2
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Evaluation of positive neurological findings on CT scan and MRI of COVID-19 infected patients. To demonstrate positive neuroimaging findings, patients with normal findings on imaging or findings unrelated to COVID-19 were not included

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Out of the 157 distinct neurological manifestations presented in the 63 articles (Table 2), we were able to identify 5 possible groups. Patients were only included once per group. In order of prevalence: altered mental status (52.5%), sensory alterations (19.7%), motor alterations (17.7%), others (5.5%), and seizures (4.6%) (Fig. 3). Certain articles with a larger patient population did not specify its prevalence for the different neurological manifestations. The only group with a female predominance was sensory alterations (51.7%). No group had a defined male predominance. Altered mental status and others had a greater representation of un-specified sex (79.8% and 80% respectively) (Fig. 4).

Table 2 General signs and symptoms, and associated neurological manifestations reported in the studies on COVID-19 infected patients
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Fig. 3
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Neurological manifestations in patients infected with SARS-CoV2

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Fig. 4
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Gender wise allocation of neurological manifestations in patients with COVID-19

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Discussion

Since the outbreak of the SARS-CoV2 virus in December 2019, the majority of research has been centered around respiratory pathogenesis and manifestations of the virus. However, recent focus has shifted toward its invasive nature and complications in the nervous system. There has been a surge in the number of cases documenting the nervous system involvement in COVID-19 positive patients with minimal respiratory involvement. Some studies reported absence of SARS-CoV-2 RNA in the nasal and throat swabs even though it was found to be present in the cerebrospinal fluid upon further investigations [10]. However, our understanding of the pathophysiology behind such neurological manifestations and the data on neuroimaging still remains limited.

Pathogenesis

Currently, there are 4 mechanisms of neuro-invasion that have been hypothesized.

Receptor modulation

The body has a traditional angiotensin-converting enzyme (ACE) in lung capillaries which is a part of the renin-angiotensin-aldosterone system (RAAS) and is involved in regulating blood pressure. COVID-19 is known to use ACE2 receptors, present in the endothelium of the heart, kidneys, and alveolar cells, especially alveolar type 2 (AT2), for cell entry. Binding to these receptors, the virus hampers the body’s natural mechanism of decreasing blood pressure thus increasing the likelihood of intracranial hemorrhages and stroke [69,70,71]. The neurons and glial cells are known to have ACE2 receptors, possibly explaining the neurotropism of the virus [72]. The mechanism of entry hypothesized is that the spikes present on the virus might link with ACE2 on the capillary endothelium, damaging the blood-brain barrier (BBB) and thus gaining entry into CNS [71]. The two areas are involved in the central regulation of respiration—nucleus of the tractus solitarius and ventrolateral medulla also express ACE2 receptors.

Trans-cribrial transmission

The anosmia in many cases points toward viral entry via olfactory bulb and across the cribriform plate [71]. This mechanism has been linked with murine experiments which led to the detection of the virus in the midbrain, basal ganglia, infralimbic cortex, and the piriform via intranasal inoculation of COVID-19 [69, 73]. SARS-CoV-2 may use ACE2 or trans-membrane protease serine 2 (TMPRSS2) receptors to infect olfactory receptor neurons in the olfactory epithelium [74].

Blood-brain barrier spread

Prior research of SARS-CoV and MERS has shown that cytokines like tumor necrosis factor (TNF-α) and interleukins (IL-6 and IL-1) led to direct death of neurons in the respiratory center in the medulla [73, 75]. The prolific response of the immune system leads to an enormous release of these cytokines and chemokines. They lead to increased permeability and breakdown of the BBB resulting in increased entry of leukocytes. They can also precipitate glutamate receptor-induced neuronal hyperexcitability which may be the reason behind acute seizures linked with the virus. Furthermore, hyperinflammatory and immune responses can result in cytokine storm syndrome which is a severe manifestation of COVID-19 [72].

Trans-synaptic transmission

The entry of the virus into CNS through the peripheral nerves is another hypothesized secondary pathway. The alveoli in the lungs have sensory innervations that detect changes in O2 and CO2. These pathways run-up to the respiratory centers in the brainstem and send signals to the pre-synapses there. Porcine hepatitis E virus studies depict a similar pathway of transmission and since HEV is almost homologous to hCoV-OC432, a close relative of SARS-CoV-2, it might be the same case here [76].

The neuropathological mechanisms reported to play a role in the development of neurological disorders in COVID-19 are—hypoxic brain injury and immune-mediated damage. The hypoxic brain injury is believed to be due to the alveolar gas exchange disorders caused by proliferation of virus in the alveolar cells [71]. As mentioned above, severe immune response resulting in a cytokine storm can also lead to the development of neurological manifestations [72].

Neuro-radiological manifestations

About 17.85% patients who underwent neuroimaging were found to be having ischemic changes suggestive of a stroke. Rajan Jain [27] and colleagues found that the inpatient COVID-19 positive population with stroke had a poor outcome. Similarly, in a systematic review by Sebastian Fredman [77] and colleagues, mortality rate of 45% was reported in the admitted COVID-19 positive patients affected with ischemic stroke. Large vessel involvement was found to be the most common, particularly the MCA. The association of COVID-19 and cerebrovascular disease has been well established but it is still unclear whether this is a de novo occurrence or a complication of already existing atheromatous plaques [78]. The role of stenotic lesions resulting in ischemic changes is also unclear. Hemorrhagic changes were found to be the second most common positive imaging finding particularly involving the corpus callosum and subcortical parenchyma. Aikaterini Fitsiori [68] and colleagues reported that COVID-19 or its treatment may cause unusual microbleeds, predominantly affecting the corpus callosum. All these patients were suffering from severe or moderate acute respiratory distress. This could be due to microangiopathic changes resulting from the cytokine-induced pathogenesis discussed above. Simon Pao [79] and colleagues concluded that ischemic changes were seen in both mild and severe infections whereas hemorrhagic changes were more prevalent in severely affected patients.

Neurological findings

In this study, we observe that COVID-19 patients presented with a variety of neurological complications. In our review, the most prevalent finding has been altered mental status (52.5%). Among the earliest articles about COVID-19 by Mao [5] and colleagues was a retrospective study that showed that 36.4% of patients presented with nervous system abnormalities, and among them, patients who had severe disease were more vulnerable to acute cerebrovascular disease and altered consciousness. The neurotropism of the virus leading to inflammation in the CNS may be a cause of altered mental status. Macrophages and microglia which proliferate to the areas concentrated by viral antigen have shown to cause demyelination leading to memory and cognitive deficits. This was observed in a murine study conducted with several strains of the virus [80, 81]. Nepal G [80]. and colleagues mention the importance of early identification of altered mental status in SARS-CoV-2 patients to check for a possible reversible cause leading to its early management. Confusion, agitation, drowsiness, lethargy, and psychotic symptoms were some of the most commonly observed subsets of symptoms included in altered mental status (Table 2).

Stroke has been observed to be the most frequent finding in neuroimaging of patients affected by COVID-19. A peculiar thing about COVID-19 related strokes is that they can be found in younger patients as observed in a case series by Ashrafi [33] which explores this association in patients younger than the age of 55, where the youngest patient, a 33-year-old, was without any previous comorbidities. Several studies have mentioned the prothrombotic and inflammatory nature of COVID-19, and some reports mention stroke symptoms being the first presentation in many cases. Lee SG [82] and Spence JD [83] mention that about 20-55% of SARS-CoV-2 patients exhibited laboratory values indicating coagulopathies. The prevalence of ischemic strokes is slightly higher than that of hemorrhagic strokes as seen in a 6-patient case series by Morassi [64] where 4 were affected by ischemic stroke and 2 by hemorrhagic. Other frequently seen manifestations include paralysis, headaches, and altered speech.

As far as we know, this is the only study with documentation of reports published until August 2020 which is based on the nervous system involvement and neuroradiological findings of COVID-19 patients. The limitations of our study were that a subset of reported neurological or neuroimaging findings in severely ill and elderly patients may be incidental. The radiological findings might have been susceptible to clinical bias hence it is difficult to standardize them. Radiological imaging presumably is performed selectively on those presenting with notable neurological involvement, leaving out the probable findings in those diseases which are milder in nature, as routine imaging may increase the risk of transmission of the virus. Our study only included articles published in the English language.

Conclusion

In the past few months of the global pandemic, the connection between COVID-19 and neurological manifestations has been growing substantially. Having strong knowledge about such associations will prove to be instrumental in early detection, isolation, and care of patients who present with unusual neurologic symptoms, especially during the ongoing pandemic. Focus on long-term neurologic sequelae and neuroimaging findings is necessary to further the research on the neurotropic involvement of SARS-CoV-2.