COVID-19 and Brain complications in adult and pediatric patients: A review on neuroimaging findings

, intraventricular and subarachnoid hemorrhage, infarction, leukoencephalopathy, acute ischemic strokes and posterior reversible encephalopathy syndrome (PRES) in adult patients and severe encephalopathy, stroke, infarction, CNS infection/demyelination, neuritis or polyradiculitis, venous thrombosis, Guillain-Barré syndrome, and longitudinally extensive myelitis, and myositis in pediatric patients. Our findings showed that the most important complication of the coronavirus is not just respiratory complications, because although transiently, COVID - 19-related brain complications are seen in pediatrics as well as adults, and families should pay more attention to health care.


Introduction
Coronaviruses belong to the family of coronaviridae and the order Nidovirales [1,2]. These viruses have a single-strand, positivesense RNA genome (encapsulated within a membrane) that is between 16 and 32 kilobases in length and have a variety of hosts including camels, dogs, cats, bats and mice [3]. Previous research has shown that most human coronavirus infections are moderate because, in the last two decades, the rate of infection with both SARS and MERS has been around 10,000 cases, with mortality rates of 10% and 37%, respectively [4]. Novel coronavirus-2019 is now a pandemic worldwide and poses a serious threat to global public health [5]. Coronavirus disease  has attracted the attention of the whole world because of its widespread, especially as human-to-human transmission has been confirmed [6]. However, with the higher outbreak of the disease, the mortality rate is increasing; more clinical findings could be effective in preventing and managing the disease [7]. Although at first the articles focused more on respiratory complications, in later articles various brain complications were discussed [8]. In several studies, various neurological symptoms have been reported for patients with COVID-19 including dizziness, headache, ataxia, and confusion [9]. Brain imaging of patients with COVID-19 makes the neurologic complications of the disease more apparent [10]. Therefore, this study aimed to review the imaging findings of pediatric and adult patients with COVID-19 and their brain complications.

Search strategy
The systematic search for related articles was performed on different databases including PubMed, Scopus, Google Scholar, Science Direct, ProQuest, Web of Science and the World Health Organization database. The published articles were restricted from January 01, 2020, to October 30, 2021. This study was done using a combination of several keywords including: 'COVID-19', 'coronavirus disease 2019', 'brain MRI', 'brain magnetic resonance imaging', 'brain CT', and 'neuroimaging'.

Data collection
All clinical studies in which patients with COVID-19 underwent brain CT/MRI were included. Furthermore, to ensure the comprehensiveness of the results, we also searched the reference lists of the selected articles. We included articles in the English language. The exclusion criteria in this study were as: Review articles. The outcome of interest was a different type of brain lesions and complications caused by coronavirus disease 2019 in patients who underwent brain imaging. A total of 175 studies were retrieved through the search, of which 142 were excluded after the full-text screening, leaving 33 studies that were included.

Results
Based on the results, approximately 30% of the studied patients were female and the others were male. The age range of patients was between 22-96 years and 9 days to 16 years for adults and pediatrics, respectively. According to the results, it can be founded that brain complications are more common in patients over 50 years of age and their frequency is lower in younger patients. In addition, it is more common in male patients than in women. The neuroimaging findings of 1550 patients with positive RT-PCR tests are summarized in (Table 1).  Hyperintensity in the right mesial lobe and hippocampus -meningitis/encephalitis. [12] Male USA/CT-MRI 59 The patient was found to be encephalopathic so brain imaging was requested Hyperintensity in the subcortical [ [41]

Discussion
Covid 19 disease caused by the new coronavirus was initially diagnosed with clinical symptoms similar to influenza and respiratory distress [42]. However, subsequent research showed that various neurological symptoms such as headache, inability to walk, cerebral hemorrhage, cerebral infections, etc. can be seen in patients with COVID-19 [43,44]. It should be noted that most recent research has shown that SARS covid 19 infection is not limited to the respiratory system [45]. Therefore, due to the importance of neurological damage, any neurological signs and symptoms related to COVID-19 patients should be monitored and evaluated by MRI and CT scan [46]. Based on the results of this study, it was found that in patients with symptoms of confusion, agitation, delayed recovery of consciousness, abnormal or altered mental status, deranged coagulation parameters and markedly elevated D-dimer levels, the neuroimaging indication was necessary. In addition, it was found that a negative PCR test and also no chest complications did not indicate patients have COVID-19, because some studies have shown that the patient's brain CT/MRI shows signs of coronavirus infection. Neuroimaging findings in patients with COVID-19 indeed have similarities in most cases, but it is not possible to say with certainty which complication is more common in these patients, because in every patient CT and MRI, have a range of findings. Cortical CVT is one of the rare causes of stroke with an annual incidence of 15.7 per million. Factors contributing to this complication include acquired or genetic thrombophilia, infections of the face, neck and head, and some systemic diseases [47]. In the absence of the above factors, based on MRI findings in a patient with COVID-19, CVT complications were observed, so Baudar et al. suggested that coronavirus infection as a trigger co-factor for CVT [11]. Hyperintensity seems to be one of the most common brain complications of COVID-19, which indicates lesions that are widely produced by demyelination and loss of axons, impairing the transmission of neural messages. Meningitis is another complication of coronavirus which was observed with increasing hyperintensity. Meningitis is an inflammation of the meninges. The most common causes of meningitis are viral and bacterial infections [48,49]. Moriguchi et al, reported that hyperintensity along the wall of the right lateral ventricle and hyperintense signal changes in the right mesial temporal lobe and hippocampus, suggesting meningitis/encephalitis [12]. Intraventricular and subarachnoid hemorrhage is another brain complication of COVID-19 which is common in older patients and so far it has not been reported in pediatric patients. Posterior reversible encephalopathy syndrome (PRES) is another complication of COVID-19. PRES is more commonly used as a complication in systemic hypertension, toxemia pregnancy, uremia, and chemotherapy. It has also been reported with infection and sepsis [50]. Numerous researchers stated that although there was no evidence of hypertension and other factors contributing to the development of PRES in patients with COVID-19, typical PRES symptoms in CT/MRI findings included confluent predominantly posterior subcortical and external capsule edema signal, with increased diffusivity and no associated contrast enhancement was found [30,33]. Another complication of COVID-19 is acute ischemic strokes which are related to possible underlying causes including coagulopathy, endothelial dysfunction, cardioembolism, and direct viral-mediated neuronal injury [51]. Infarction is also a brain complication that has been reported in both adult and pediatric patients [36,37]. As a result of this complication, the blood supply to the target tissues is disrupted and there is a decrease in oxygen supply, edema, and finally necrosis or death in the tissues. Another complication of COVID-19 is leukoencephalopathy. Hyperintensity in the white matter is associated with leukoencephalopathy [52]. Lang et al. reported that COVID-19-associated leukoencephalopathy may be due to hypoxia. They announced there was evidence of damage to the white matter of the brain in the studied patients, which may be due to the hypoxia of COVID-19 disease. It should be noted that severe or prolonged hypoxia causes problems in the process of secretion and production of myelin, which in turn causes brain damage [14]. Encephalopathy is another complication of COVID-19 [53]. One of the most important clinical signs of COVID-19 encephalopathy is altered consciousness. Also, changes in cortical and subcortical T2/FLAIR signals are common neuroimaging abnormalities [54]. Other CT/MRI findings especially in pediatric patients with COVID-19 include an unusual DWI pattern with ring and nodular spots in the periventricular and white matter of the brain. such imaging findings could have potentially suggested inflammatory lesions such as acute disseminated encephalomyelitis, which is thought to occur from cross-reactivity in immunity to viral antigens, triggering an autoimmune attack on the CNS [38, 41].

Conclusion
Contrary to popular belief, the most important complication of the coronavirus is not just respiratory complications. Since the outbreak of the COVID-19 pandemic, several articles have addressed a possible relationship between SARS-CoV-2 virus infection and neurologic symptoms. It seems that coronavirus can have short-term, longterm and even lifelong brain complications in patients, especially in adults.
Since complications related to COVID-19 have been reported in children and even infants, families should pay more attention to health issues. Also, physicians and radiologists if they encounter unexplained neurological findings during the COVID period, should consider infection with this virus. However, many studies still need to be done to determine the long-term brain complications of this disease.

Conflict of Interest
The authors hereby declare that they have no conflict of interest.

Author's contributions
All authors equally participated in designing experiment analysis and interpretation of data. All authors read and approved the final manuscript.

Consent for publications
All authors have read and approved the final manuscript for publication.

Availability of data and material
The authors have embedded all data in the manuscript.

Informed Consent
The authors declare not used any patients in this research.

Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.