Neurological manifestations and neuroimaging findings in patients with SARS-CoV2—a systematic review

Background The COVID-19 pandemic has drastically affected everyone in a hit or miss manner. Since it began, evidence of the neuro-invasive potential of the virus has been intensifying significantly. Several pathways have been hypothesized to elucidate the neurotropic nature of SARS-CoV2. It is the need of the hour to collect vital information. 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 Relevant studies were identified through four databases—the Cochrane Library, PubMed, Science Direct, and Web of Science. These were searched using relevant keywords—“COVID-19,” “SARS-CoV2,” “neurological manifestations,” “neuroimaging,” “CT,” and “MRI.” Relevant articles were screened according to a pre-defined inclusion and exclusion criteria from December 2019 to August 2020. Results Our review included a total of 63 full text publications with 584 patients, composed mainly of observational studies, case reports, and case series. The most common neurological manifestations associated with COVID-19 were altered mental status, stroke, and paralysis. About 17.85% patients who underwent neuroimaging were found to be having ischemic changes suggestive of a stroke. This was followed by hemorrhagic changes as the second most common finding. The most commonly involved vessel was the Middle Cerebral Artery. Besides stroke, we found that SARS-CoV2 could be the cause for new-onset seizures, Guillain-Barre Syndrome, encephalitis, and many other severe neurological diseases. Conclusion The information that we have obtained so far will prove dynamic to healthcare providers working against the COVID-19 pandemic. It is necessary to be aware of these atypical neurological findings for the early diagnosis and treatment of COVID-19 infected patients. However, to completely understand the connection between SARS-CoV2 and the nervous system, further research is necessary.


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 immunemediated 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.

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.
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).

Discussion
Since the outbreak of the SARS-CoV2 virus in December 2019, the majority of research has been  MRI-brain and spine 6 enhancing lesions, most with ring enhancement and some with nodular enhancement Hyperintense signal of the optic nerves bilaterally Hyperintense spindle-like T8 lesion 6 Acute myelitis as a neurological complication of COVID-19: a case report and MRI findings [13] Gadolinium-enhanced MRI-spine Extensive diffuse hyperintense signal of the gray matter of cervical, dorsal, and lumbar regions of the spinal cord Mild enlargement and swelling of the cervical cord Areas of restricted diffusion on DWI and apparent diffusion coefficient (ADC) 7 Acute polyradiculoneuritis with locked-in syndrome in a patient with COVID-19 [14] MRI-spine Massive symmetrical contrast enhancement of the spinal nerve roots at all levels of the spine including the cauda equina 8 Acute profound sensorineural hearing loss after COVID-19 pneumonia [15] MRI-brain Pronounced contrast enhancement in the right cochlea and a partially decreased fluid signal in the basal turn of the right cochlea Adjacent to the temporal bone, meningeal contrast enhancement was seen at the base of the right temporal lobe Signs of an inflammatory process in the cochlea 9 Basal ganglia involvement and altered mental status: a unique neurological manifestation of coronavirus disease 2019 [16] CT-head MRI-brain B/L basal ganglia hyper-density suggestive of subacute hemorrhagic event Involvement of basal ganglia in subacute bleeding 10 Bilateral posterior cerebral artery territory infarction in a SARS-Cov-2 infected patient: discussion about an unusual case [17] MRI-brain B/L and asymmetric acute occipito-temporal infarction of the posterior cerebral arteries (PCA) with occlusion of P3 segments Hemorrhagic transformation of the previous lesions 11 Bilateral trochlear nerve palsy due to cerebral vasculitis related to COVID-19 infection [18] MRI-brain Signs of vasculitis of the vertebrobasilar system Inflammatory signs in the periaqueductal region, along the topography of the trochlear nuclei 12 Cerebral microhemorrhage and purpuric rash in COVID-19: the case for a secondary microangiopathy [19] MRI-brain Multiple areas of micro-hemorrhage throughout the corpus callosum, B/L juxtacortical white matter, basal ganglia, cerebellum, and brain-stem, without clear asymmetry Discrete areas of FLAIR hyperintensity correlating with some of the larger areas of SWI changes suggesting larger macro-hemorrhage Areas of diffusion restriction 13 Cerebral nervous system vasculitis in a COVID-19 patient with pneumonia [20] CT-headMRI-brain Cortical-subcortical blood-related hyperdensities in the right occipital lobes and B/L fronto-parietal Signal restriction of the cortex in a parietal and parieto-occipital region and at the pons level suggestive of subacute phase of cortical inflammation and ischemia 14 Cerebral venous thrombosis: a typical presentation of COVID-19 in the young [21] CT-head MRI-brain  CT-head MRI-brain Hypodensity of bilateral thalami Signal changes of brain parenchyma including insula, B/L dorsal frontal lobes, and thalamus with restricted diffusion of globus pallidus (features of encephalopathy) 23 COVID-19-associated ophthalmoparesis and hypothalamic involvement [30] MRI-brain T2/FLAIR Hyperintensity (HI) in the brainstem, including the medial temporal lobes, mammillary bodies, CN VI nuclei, thalami, and hypothalamus 24 COVID-19-associated pulmonary and cerebral thromboembolic disease [31] CT-head MRI-brain Partial right Sylvian segment (M2), superior division occlusion and right opercular (M3), parietal segment occlusions Multiple, discrete, peripheral acute infarctions of the right MCA territory with some hemorrhagic conversion 25 COVID-19-related acute necrotizing encephalopathy with brain stem involvement in a patient with aplastic anemia [32] CT-head MRI-brain Increased hypodensity and swelling of the brain stem, and a new area of cortical and subcortical hypodensity in the left occipital lobe suggestive of an acute posterior circulation infarct Extensive, symmetrical changes in the supratentorial and infratentorial compartments. Hemorrhage and diffuse swelling in the amygdalae and brain stem Microhemorrhage and extensive abnormal signal were found in a symmetrical distribution within the dorsolateral putamina, ventrolateral thalamic nuclei, sub-insular regions, splenium of the corpus callosum, cingulate gyri, and subcortical perirolandic regions 26 COVID-19-related strokes in adults below 55 years of age: a case series [33] CT-head Right MCA, Left MCA, and left basal ganglia infarction 27 COVID-19-associated encephalitis mimicking glial tumor [34] MRI-brain Hyperintense signal in the left temporal lobe in T2 and T2 FLAIR imaging suggestive of high-grade glioma 28 De novo status epilepticus in patients with COVID-19 [35] CT-head MRI-brain   CT-head MRI-brain  MRI-brain Normal 63 COVID-19 is associated with an unusual pattern of brain microbleeds in critically ill patients [68] MRI-brain Microbleeds in unusual distribution, particularly involving the anterior/posterior limbs of internal capsule (five patients), middle cerebellar peduncles (5/9 patients), and the corpus callosum

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 O 2 and CO 2 . 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-OC43 2 , 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 immunemediated 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 longterm neurologic sequelae and neuroimaging findings is necessary to further the research on the neurotropic involvement of SARS-CoV-2.