Skip to main content
The Egyptian Journal of Neurology, Psychiatry and Neurosurgery
Download PDF

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

The Egyptian Journal of Neurology, Psychiatry and Neurosurgery volume 57, Article number: 68 (2021) Cite this article

Abstract

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 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
figure 1

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

Full size image

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
Full size table
Fig. 2
figure 2

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

Full size image

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
Full size table
Fig. 3
figure 3

Neurological manifestations in patients infected with SARS-CoV2

Full size image
Fig. 4
figure 4

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

Full size image

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.

Availability of data and materials

The authors declare that the data supporting the findings of this study are available within the article [and its supplementary information files].

Abbreviations

ACE:

Angiotensin-converting enzyme

ACE2:

Angiotensin-converting enzyme 2

AT2:

Alveolar type 2 cells

BBB:

Blood-brain barrier

CNS:

Central nervous system

CT:

Computed tomography

HEV:

Hepatitis E virus

ICA:

Internal carotid artery

IL-1:

Interleukin 1

IL-6:

Interleukin 6

MCA:

Middle cerebral artery

MRA:

Magnetic resonance angiography

MRI:

Magnetic resonance imaging

RAAS:

Renin angiotensin aldosterone system

SARS-CoV2:

Severe acute respiratory syndrome-coronavirus 2

TMPRSS2:

Transmembrane protease serine 2

TNF:

Tumor necrosis factor

References

  1. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 2020;382(8):727–33. https://doi.org/10.1056/NEJMoa2001017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. WHO Coronavirus Disease (COVID-19) Dashboard. 2020 [cited 2020 2020-08-31]; Available from: https://covid19.who.int/.

    Google Scholar 

  3. Usman AA, Han J, Acker A, Olia SE, Bermudez C, Cucchiara B, et al. A case series of devastating intracranial hemorrhage during venovenous extracorporeal membrane oxygenation for COVID-19. J Cardiothorac Vasc Anesth. 2020;34(11):3006–12. https://doi.org/10.1053/j.jvca.2020.07.063.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Niazkar HR, Zibaee B, Nasimi A, Bahri N. The neurological manifestations of COVID-19: a review article. Neurol Sci. 2020;41(7):1667–71. https://doi.org/10.1007/s10072-020-04486-3.

    Article  PubMed  Google Scholar 

  5. Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan. China. JAMA Neurol. 2020;77(6):683–90. https://doi.org/10.1001/jamaneurol.2020.1127.

    Article  PubMed  Google Scholar 

  6. Butt I, Sawlani V, Geberhiwot T. Prolonged confusional state as first manifestation of COVID-19. Annals of Clinical and Translational Neurology. 2020;7(8):1450–2. https://doi.org/10.1002/acn3.51067.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Gonzalez-Pinto T, Luna-Rodriguez A, Moreno-Estebanez A, Agirre-Beitia G, Rodriguez-Antiguedad A, Ruiz-Lopez M. Emergency room neurology in times of COVID-19: malignant ischaemic stroke and SARS-CoV-2 infection. Eur J Neurol. 2020;27(9):e35–6. https://doi.org/10.1111/ene.14286.

    Article  CAS  PubMed  Google Scholar 

  8. Tsivgoulis G, Palaiodimou L, Katsanos AH, Caso V, Kohrmann M, Molina C, et al. Neurological manifestations and implications of COVID-19 pandemic. Ther Adv Neurol Disord. 2020;13:1756286420932036.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Hamidi A, Sabayan B, Sorond F, Nemeth AJ, Borhani-haghighi A. A case of Covid-19 respiratory illness with subsequent seizure and hemiparesis. Galen Medical Journal. 2020;9:1915. https://doi.org/10.31661/gmj.v9i0.1915.

    Article  Google Scholar 

  10. Moriguchi T, Harii N, Goto J, Harada D, Sugawara H, Takamino J, et al. A first case of meningitis/encephalitis associated with SARS-coronavirus-2. Int J Infect Dis. 2020;94:55–8. https://doi.org/10.1016/j.ijid.2020.03.062.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Falcone MM, Rong AJ, Salazar H, Redick DW, Falcone S, Cavuoto KM. Acute abducens nerve palsy in a patient with the novel coronavirus disease (COVID-19). J AAPOS. 2020;24(4):216–7. https://doi.org/10.1016/j.jaapos.2020.06.001.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Novi G, Rossi T, Pedemonte E, Saitta L, Rolla C, Roccatagliata L, et al. Acute disseminated encephalomyelitis after SARS-CoV-2 infection. Neurol Neuroimmunol Neuroinflamm. 2020;7(5):e797. https://doi.org/10.1212/NXI.0000000000000797.

  13. AlKetbi R, AlNuaimi D, AlMulla M, AlTalai N, Samir M, Kumar N, et al. Acute myelitis as a neurological complication of Covid-19: a case report and MRI findings. Radiology Case Reports. 2020;15(9):1591–5.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Pfefferkorn T, Dabitz R, von Wernitz-Keibel T, Aufenanger J, Nowak-Machen M, Janssen H. Acute polyradiculoneuritis with locked-in syndrome in a patient with Covid-19. J Neurol. 2020;267(7):1883–4. https://doi.org/10.1007/s00415-020-09897-y.

    Article  CAS  PubMed  Google Scholar 

  15. Degen C, Lenarz T, Willenborg K. Acute profound sensorineural hearing loss after COVID-19 pneumonia. Mayo Clin Proc. 2020;95(8):1801–3. https://doi.org/10.1016/j.mayocp.2020.05.034.

    Article  CAS  PubMed  Google Scholar 

  16. Haddadi K, Ghasemian R, Shafizad M. Basal ganglia involvement and altered mental status: a unique neurological manifestation of coronavirus disease 2019. Cureus. 2020;12(4):e7869. https://doi.org/10.7759/cureus.7869.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Bonardel C, Bonnerot M, Ludwig M, Vadot W, Beaune G, Chanzy B, et al. Bilateral posterior cerebral artery territory infarction in a SARS-Cov-2 infected patient: discussion about an unusual case. Journal of Stroke and Cerebrovascular Diseases. 2020;29(9):105095. https://doi.org/10.1016/j.jstrokecerebrovasdis.2020.105095.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Oliveira RdMC d, Santos DH, Olivetti BC, Takahashi JT. Bilateral trochlear nerve palsy due to cerebral vasculitis related to covid-19 infection. Arquivos de Neuro-Psiquiatria. 2020;78(7):385–6. https://doi.org/10.1590/0004-282x20200052.

    Article  Google Scholar 

  19. Shoskes A, Migdady I, Fernandez A, Ruggieri P, Rae-Grant A. Cerebral microhemorrhage and purpuric rash in COVID-19: the case for a secondary microangiopathy. J Stroke Cerebrovasc Dis. 2020;29(10):105111. https://doi.org/10.1016/j.jstrokecerebrovasdis.2020.105111.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Vaschetto R, Cena T, Sainaghi PP, Meneghetti G, Bazzano S, Vecchio D, et al. Cerebral nervous system vasculitis in a Covid-19 patient with pneumonia. J Clin Neurosci. 2020;79:71–3. https://doi.org/10.1016/j.jocn.2020.07.032.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Klein DE, Libman R, Kirsch C, Arora R. Cerebral venous thrombosis: a typical presentation of COVID-19 in the young. J Stroke Cerebrovasc Dis. 2020;29(8):104989. https://doi.org/10.1016/j.jstrokecerebrovasdis.2020.104989.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Tun CA, UnlUba SY, Alemdar M, AkyUz E. Coexistence of COVID-19 and acute ischemic stroke report of four cases. J Clin Neurosci. 2020;77:227–9.

    Article  Google Scholar 

  23. Yin R, Feng W, Wang T, Chen G, Wu T, Chen D, et al. Concomitant neurological symptoms observed in a patient diagnosed with coronavirus disease 2019. J Med Virol. 2020;92(10):1782–4. https://doi.org/10.1002/jmv.25888.

  24. Scullen T, Keen J, Mathkour M, Dumont AS, Kahn L. Coronavirus 2019 (COVID-19)-associated encephalopathies and cerebrovascular disease: the New Orleans experience. World Neurosurg. 2020;141:e437–e46. https://doi.org/10.1016/j.wneu.2020.05.192.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Avula A, Nalleballe K, Narula N, Sapozhnikov S, Dandu V, Toom S, et al. COVID-19 presenting as stroke. Brain, Behavior, and Immunity. 2020;87:115–9. https://doi.org/10.1016/j.bbi.2020.04.077.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sohal S, Mansur M. COVID-19 presenting with seizures. IDCases. 2020;20:e00782. https://doi.org/10.1016/j.idcr.2020.e00782.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Jain R, Young M, Dogra S, Kennedy H, Nguyen V, Jones S, et al. COVID-19 related neuroimaging findings: a signal of thromboembolic complications and a strong prognostic marker of poor patient outcome. J Neurol Sci. 2020;414:116923. https://doi.org/10.1016/j.jns.2020.116923.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Sirous R, Taghvaei R, Hellinger JC, Krauthamer AV, Mirfendereski S. COVID-19-associated encephalopathy with fulminant cerebral vasoconstriction: CT and MRI findings. Radiol Case Rep. 2020;15(11):2208–12. https://doi.org/10.1016/j.radcr.2020.08.024.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Al Mazrouei SS, Saeed GA, Al Helali AA, Ahmed M. COVID-19-associated encephalopathy: neurological manifestation of COVID-19. Radiol Case Rep. 2020;15(9):1646–9. https://doi.org/10.1016/j.radcr.2020.07.009.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Pascual-Goni E, Fortea J, Martinez-Domeno A, Rabella N, Tecame M, Gomez-Oliva C, et al. COVID-19-associated ophthalmoparesis and hypothalamic involvement. Neurol Neuroimmunol Neuroinflamm. 2020;7(5):e823. https://doi.org/10.1212/NXI.0000000000000823.

  31. Gill I, Chan S, Fitzpatrick D. COVID-19-associated pulmonary and cerebral thromboembolic disease. Radiol Case Rep. 2020;15(8):1242–9. https://doi.org/10.1016/j.radcr.2020.05.034.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Dixon L, Varley J, Gontsarova A, Mallon D, Tona F, Muir D, et al. COVID-19-related acute necrotizing encephalopathy with brain stem involvement in a patient with aplastic anemia. Neurol Neuroimmunol Neuroinflamm. 2020;7(5):e789. https://doi.org/10.1212/NXI.0000000000000789.

  33. Ashrafi F, Zali A, Ommi D, Salari M, Fatemi A, Arab-Ahmadi M, et al. COVID-19-related strokes in adults below 55 years of age: a case series. Neurol Sci. 2020;41(8):1985–9. https://doi.org/10.1007/s10072-020-04521-3.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Efe IE, Aydin OU, Alabulut A, Celik O, Aydin K. COVID-19-associated encephalitis mimicking glial tumor. World Neurosurg. 2020;140:46–8. https://doi.org/10.1016/j.wneu.2020.05.194.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Somani S, Pati S, Gaston T, Chitlangia A, Agnihotri S. De novo status epilepticus in patients with COVID-19. Ann Clin Transl Neurol. 2020;7(7):1240–4. https://doi.org/10.1002/acn3.51071.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hosseini AA, Shetty AK, Sprigg N, Auer DP, Constantinescu CS. Delirium as a presenting feature in COVID-19: neuroinvasive infection or autoimmune encephalopathy? Brain Behav Immun. 2020;88:68–70. https://doi.org/10.1016/j.bbi.2020.06.012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Haddad S, Tayyar R, Risch L, Churchill G, Fares E, Choe M, et al. Encephalopathy and seizure activity in a COVID-19 well controlled HIV patient. IDCases. 2020;21:e00814. https://doi.org/10.1016/j.idcr.2020.e00814.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zhang H, Charmchi Z, Seidman RJ, Anziska Y, Velayudhan V, Perk J. COVID-19-associated myositis with severe proximal and bulbar weakness. Muscle Nerve. 2020;62(3):E57–60. https://doi.org/10.1002/mus.27003.

    Article  CAS  PubMed  Google Scholar 

  39. Afshar H, Yassin Z, Kalantari S, Aloosh O, Lotfi T, Moghaddasi M, et al. Evolution and resolution of brain involvement associated with SARS- CoV2 infection: a close clinical - paraclinical follow up study of a case. Mult Scler Relat Disord. 2020;43:102216. https://doi.org/10.1016/j.msard.2020.102216.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Elgamasy S, Kamel MG, Ghozy S, Khalil A, Morra ME, Islam SMS. First case of focal epilepsy associated with SARS-coronavirus-2. J Med Virol. 2020;92(10):2238–42. https://doi.org/10.1002/jmv.26113.

    Article  CAS  PubMed  Google Scholar 

  41. Domingues RB, Mendes-Correa MC, de Moura Leite FBV, Sabino EC, Salarini DZ, Claro I, et al. First case of SARS-COV-2 sequencing in cerebrospinal fluid of a patient with suspected demyelinating disease. J Neurol. 2020;267(11):3154–6. https://doi.org/10.1007/s00415-020-09996-w.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Fasano A, Cavallieri F, Canali E, Valzania F. First motor seizure as presenting symptom of SARS-CoV-2 infection. Neurol Sci. 2020;41(7):1651–3. https://doi.org/10.1007/s10072-020-04460-z.

    Article  PubMed  PubMed Central  Google Scholar 

  43. De Stefano P, Nencha U, De Stefano L, Megevand P, Seeck M. Focal EEG changes indicating critical illness associated cerebral microbleeds in a Covid-19 patient. Clin Neurophysiol Pract. 2020;5:125–9. https://doi.org/10.1016/j.cnp.2020.05.004.

    Article  PubMed  PubMed Central  Google Scholar 

  44. van den Enden AJM, van Gils L, Labout JAM, van der Jagt M, Moudrous W. Fulminant cerebral edema as a lethal manifestation of COVID-19. Radiol Case Rep. 2020;15(9):1705–8. https://doi.org/10.1016/j.radcr.2020.06.053.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Khattar NK, Sharma M, McCallum AP, Oxford BG, Zeb H, Suliman SA, et al. Intracranial hemorrhage in a young COVID-19 patient. Interdiscip Neurosurg. 2020;22:100878. https://doi.org/10.1016/j.inat.2020.100878.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Sharifi-Razavi A, Karimi N, Zarvani A, Cheraghmakani H, Baghbanian SM. Ischemic stroke associated with novel coronavirus 2019: a report of three cases. Int J Neurosci. 2020:1–5. https://doi.org/10.1080/00207454.2020.1782902.

  47. Avula A, Gill A, Nassar R, Nalleballe K, Siddamreddy S, Chalhoub M. Locked-in with COVID-19. J Clin Neurosci. 2020;79:80–3. https://doi.org/10.1016/j.jocn.2020.07.014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Fara MG, Stein LK, Skliut M, Morgello S, Fifi JT, Dhamoon MS. Macrothrombosis and stroke in patients with mild Covid-19 infection. J Thromb Haemost. 2020;18(8):2031–3. https://doi.org/10.1111/jth.14938.

    Article  CAS  PubMed  Google Scholar 

  49. Patel SD, Kollar R, Troy P, Song X, Khaled M, Parra A, et al. Malignant cerebral ischemia in a COVID-19 infected patient: case review and histopathological findings. J Stroke Cerebrovasc Dis. 2020;29(11):105231. https://doi.org/10.1016/j.jstrokecerebrovasdis.2020.105231.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Palao M, Fernandez-Diaz E, Gracia-Gil J, Romero-Sanchez CM, Diaz-Maroto I, Segura T. Multiple sclerosis following SARS-CoV-2 infection. Mult Scler Relat Disord. 2020;45:102377. https://doi.org/10.1016/j.msard.2020.102377.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Mohammad LM, Botros JA, Chohan MO. Necessity of brain imaging in COVID-19 infected patients presenting with acute neurological deficits. Interdiscip Neurosurg. 2020;22:100883. https://doi.org/10.1016/j.inat.2020.100883.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Siepmann T, Kitzler HH, Lueck C, Platzek I, Reichmann H, Barlinn K. Neuralgic amyotrophy following infection with SARS-CoV-2. Muscle Nerve. 2020;62(4):E68–70. https://doi.org/10.1002/mus.27035.

    Article  CAS  PubMed  Google Scholar 

  53. Fan S, Xiao M, Han F, Xia P, Bai X, Chen H, et al. Neurological manifestations in critically ill patients with COVID-19: a retrospective study. Front Neurol. 2020;11:806. https://doi.org/10.3389/fneur.2020.00806.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Rana S, Lima AA, Chandra R, Valeriano J, Desai T, Freiberg W, et al. Novel coronavirus (COVID-19)-associated Guillain-Barre syndrome: case report. J Clin Neuromuscul Dis. 2020;21(4):240–2. https://doi.org/10.1097/CND.0000000000000309.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Thu SS, Matin N, Levine SR. Olfactory gyrus intracerebral hemorrhage in a patient with COVID-19 infection. J Clin Neurosci. 2020;79:275–6. https://doi.org/10.1016/j.jocn.2020.07.033.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Le Guennec L, Devianne J, Jalin L, Cao A, Galanaud D, Navarro V, et al. Orbitofrontal involvement in a neuroCOVID-19 patient. Epilepsia. 2020;61(8):e90–4. https://doi.org/10.1111/epi.16612.

  57. Rogg J, Baker A, Tung G. Posterior reversible encephalopathy syndrome (PRES): another imaging manifestation of COVID-19. Interdiscip Neurosurg. 2020;22:100808. https://doi.org/10.1016/j.inat.2020.100808.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Dakay K, Kaur G, Gulko E, Santarelli J, Bowers C, Mayer SA, et al. Reversible cerebral vasoconstriction syndrome and dissection in the setting of COVID-19 infection. J Stroke Cerebrovasc Dis. 2020;29(9):105011. https://doi.org/10.1016/j.jstrokecerebrovasdis.2020.105011.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Princiotta Cariddi L, Tabaee Damavandi P, Carimati F, Banfi P, Clemenzi A, Marelli M, et al. Reversible encephalopathy syndrome (PRES) in a COVID-19 patient. J Neurol. 2020;267(11):3157–60. https://doi.org/10.1007/s00415-020-10001-7.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Su XW, Palka SV, Rao RR, Chen FS, Brackney CR, Cambi F. SARS-CoV-2-associated Guillain-Barre syndrome with dysautonomia. Muscle Nerve. 2020;62(2):E48–E9. https://doi.org/10.1002/mus.26988.

    Article  CAS  PubMed  Google Scholar 

  61. Kimambo H, Chin JH, Mnacho M, Punatar P, Msilanga D, Chagula AC. Severe headache as the sole presenting symptom of COVID-19 pneumonia: a case report. Interdiscip Neurosurg. 2020;22:100882. https://doi.org/10.1016/j.inat.2020.100882.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Pilotto A, Odolini S, Masciocchi S, Comelli A, Volonghi I, Gazzina S, et al. Steroid-responsive encephalitis in coronavirus disease 2019. Ann Neurol. 2020;88(2):423–7. https://doi.org/10.1002/ana.25783.

  63. Frisullo G, Bellavia S, Scala I, Piano C, Morosetti R, Brunetti V, et al. Stroke and COVID19: not only a large-vessel disease. J Stroke Cerebrovasc Dis. 2020;29(10):105074. https://doi.org/10.1016/j.jstrokecerebrovasdis.2020.105074.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Morassi M, Bagatto D, Cobelli M, D’Agostini S, Gigli GL, Bna C, et al. Stroke in patients with SARS-CoV-2 infection: case series. J Neurol. 2020;267(8):2185–92. https://doi.org/10.1007/s00415-020-09885-2.

    Article  CAS  PubMed  Google Scholar 

  65. Muccioli L, Rondelli F, Ferri L, Rossini G, Cortelli P, Guarino M. Subcortical myoclonus in COVID-19: comprehensive evaluation of a patient. Mov Disord Clin Pract. 2020;7(8):971–3. https://doi.org/10.1002/mdc3.13046.

  66. Rudilosso S, Esteller D, Urra X, Chamorro A. Thalamic perforating artery stroke on computed tomography perfusion in a patient with coronavirus disease 2019. J Stroke Cerebrovasc Dis. 2020;29(8):104974. https://doi.org/10.1016/j.jstrokecerebrovasdis.2020.104974.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Bernard-Valnet R, Pizzarotti B, Anichini A, Demars Y, Russo E, Schmidhauser M, et al. Two patients with acute meningoencephalitis concomitant with SARS-CoV-2 infection. Eur J Neurol. 2020;27(9):e43–4. https://doi.org/10.1111/ene.14298.

    Article  CAS  PubMed  Google Scholar 

  68. Fitsiori A, Pugin D, Thieffry C, Lalive P, Vargas MI. COVID-19 is associated with an unusual pattern of brain microbleeds in critically ill patients. J Neuroimaging. 2020;30(5):593–7. https://doi.org/10.1111/jon.12755.

    Article  PubMed  Google Scholar 

  69. Doobay MF, Talman LS, Obr TD, Tian X, Davisson RL, Lazartigues E. Differential expression of neuronal ACE2 in transgenic mice with overexpression of the brain renin-angiotensin system. Am J Physiol Regul Integr Comp Physiol. 2007;292(1):R373–81. https://doi.org/10.1152/ajpregu.00292.2006.

    Article  CAS  PubMed  Google Scholar 

  70. Zheng YY, Ma YT, Zhang JY, Xie X. COVID-19 and the cardiovascular system. Nat Rev Cardiol. 2020;17(5):259–60. https://doi.org/10.1038/s41569-020-0360-5.

    Article  CAS  PubMed  Google Scholar 

  71. Abboud H, Abboud FZ, Kharbouch H, Arkha Y, El Abbadi N, El Ouahabi A. COVID-19 and SARS-Cov-2 infection: pathophysiology and clinical effects on the nervous system. World Neurosurg. 2020;140:49–53. https://doi.org/10.1016/j.wneu.2020.05.193.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Katal S, Balakrishnan S, Gholamrezanezhad A. Neuroimaging and neurologic findings in COVID-19 and other coronavirus infections: a systematic review in 116 patients. J Neuroradiol. 2021;48(1):43–50. https://doi.org/10.1016/j.neurad.2020.06.007.

  73. Netland J, Meyerholz DK, Moore S, Cassell M, Perlman S. Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2. J Virol. 2008;82(15):7264–75. https://doi.org/10.1128/JVI.00737-08.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Yavarpour-Bali H, Ghasemi-Kasman M. Update on neurological manifestations of COVID-19. Life Sci. 2020;257:118063. https://doi.org/10.1016/j.lfs.2020.118063.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Li K, Wohlford-Lenane C, Perlman S, Zhao J, Jewell AK, Reznikov LR, et al. Middle East respiratory syndrome coronavirus causes multiple organ damage and lethal disease in mice transgenic for human dipeptidyl peptidase 4. J Infect Dis. 2016;213(5):712–22. https://doi.org/10.1093/infdis/jiv499.

    Article  CAS  PubMed  Google Scholar 

  76. Das M, Penn C, Martinez T, Mayilsamy K, McGill A, Wiling A, et al. COVID-19 neurotropism and implications for therapy. Neuroimmunology and Neuroinflammation. 2020;2020(2):141–9.

    Google Scholar 

  77. Fridman S, Bullrich MB, Jimenez-Ruiz A, Costantini P, Shah P, Just C, et al. Stroke risk, phenotypes, and death in COVID-19: systematic review and newly reported cases. Neurology. 2020;95(24):e3373–85. https://doi.org/10.1212/WNL.0000000000010851.

    Article  PubMed  Google Scholar 

  78. Gulko E, Oleksk ML, Gomes W, Ali S, Mehta H, Overby P, et al. MRI brain findings in 126 patients with COVID-19: initial observations from a descriptive literature review. AJNR Am J Neuroradiol. 2020;41(12):2199–203. https://doi.org/10.3174/ajnr.A6805.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Pan S, Chen WC, Baal JD, Sugrue LP. Neuroradiological features of mild and severe SARS-CoV-2 infection. Acad Radiol. 2020;27(11):1507–14. https://doi.org/10.1016/j.acra.2020.08.026.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Nepal G, Rehrig JH, Shrestha GS, Shing YK, Yadav JK, Ojha R, et al. Neurological manifestations of COVID-19: a systematic review. Crit Care. 2020;24(1):421. https://doi.org/10.1186/s13054-020-03121-z.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Templeton SP, Kim TS, O’Malley K, Perlman S. Maturation and localization of macrophages and microglia during infection with a neurotropic murine coronavirus. Brain Pathol. 2008;18(1):40–51. https://doi.org/10.1111/j.1750-3639.2007.00098.x.

    Article  PubMed  Google Scholar 

  82. Lee SG, Fralick M, Sholzberg M. Coagulopathy associated with COVID-19. CMAJ. 2020;192(21):E583. https://doi.org/10.1503/cmaj.200685.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Spence JD, de Freitas GR, Pettigrew LC, Ay H, Liebeskind DS, Kase CS, et al. Mechanisms of stroke in COVID-19. Cerebrovasc Dis. 2020;49(4):451–8. https://doi.org/10.1159/000509581.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Not applicable

Funding

The authors declare that no funding was received for this research.

Author information

Authors and Affiliations

  1. Jawaharlal Nehru Medical College, Belagavi, Karnataka, India

    Nikita Mohan

  2. Quaid e Azam Medical College, Bahawalpur, Pakistan

    Muhammad Ali Fayyaz

  3. Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey Nuevo Leon, Mexico

    Christopher del Rio & Esteban Salazar

  4. Indira Gandhi Government Medical College & Mayo Hospital, Nagpur, Maharashtra, India

    Navpreet Kaur Rajinder Singh Khurana

  5. Kazan State Medical University, Kazan, Russia

    Sampada Sandip Vaidya

  6. M.S Ramaiah Medical College, Bangalore, Karnataka, India

    John Joyce

  7. Liaquat University of Medical and Health Sciences, Jamshoro, Pakistan

    Amrat Ayaz Ali

Authors
  1. Nikita Mohan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Muhammad Ali Fayyaz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christopher del Rio
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Navpreet Kaur Rajinder Singh Khurana
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sampada Sandip Vaidya
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Esteban Salazar
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. John Joyce
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Amrat Ayaz Ali
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

NM contributed to the conception, design, acquisition, analysis of data, drafted the work and approved the submitted version, and has agreed to be personally accountable for their contributions. MAF contributed to the conception, design, acquisition, analysis of data, drafted the work and approved the submitted version, and has agreed to be personally accountable for their contributions. CR contributed to the conception, design, acquisition, analysis of data, drafted the work and approved the submitted version, and has agreed to be personally accountable for their contributions. NK contributed to the conception, design, acquisition, analysis of data, drafted the work and approved the submitted version, and has agreed to be personally accountable for their contributions. SV contributed to the conception, design, acquisition, analysis of data, drafted the work and approved the submitted version, and has agreed to be personally accountable for their contributions. ES contributed to the conception, design, acquisition, analysis of data, drafted the work and approved the submitted version, and has agreed to be personally accountable for their contributions. JJ contributed to the conception, design, acquisition, analysis of data, drafted the work and approved the submitted version, and has agreed to be personally accountable for their contributions. AA contributed to the conception, design, acquisition, analysis of data, drafted the work and approved the submitted version, and has agreed to be personally accountable for their contributions. The authors read and approved the final manuscript.

Corresponding author

Correspondence to Navpreet Kaur Rajinder Singh Khurana.

Ethics declarations

Ethics approval and consent to participate

Not applicable

Consent for publication

Not applicable

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mohan, N., Fayyaz, M.A., del Rio, C. et al. Neurological manifestations and neuroimaging findings in patients with SARS-CoV2—a systematic review. Egypt J Neurol Psychiatry Neurosurg 57, 68 (2021). https://doi.org/10.1186/s41983-021-00322-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s41983-021-00322-3

Keywords

  • SARS-CoV 2
  • Stroke
  • Neuro-invasive
  • COVID-19
  • Neuroimaging