The coronavirus family neurological effects: A literature review

All the lethal coronaviruses like the middle east respiratory syndrome, severe acute respiratory syndrome coronavirus, or the new coronavirus have showed similar and non-similar effects on the central nerves system. The aim of this paper is to summarize the published findings as neurological effects of the most dangerous three viruses in the coronavirus family and to find the common neuropathological patterns among the three viruses.


Introduction
The most lethal viruses in the coronavirus family (i.e. MERS-CoV, SARS-CoV, SARS-CoV-2) showed different effects on the nervous system ranging from mild to life-threatening conditions. The following is an overview of these neurological effects: Page: 30 www.raftpubs.com

Medullary cardiopulmonary centers in the brainstem
Probably the most difficult symptom on the coronavirus patient is not the fever, but it's the short breath (respiratory distress). Some of the patients required ventilators, so they can breathe. The lethal coronaviruses are usually associated with pneumonia which makes the breathing very difficult. But it has been proved that SARS-CoV passes through Records identified through database searching (n =14)

Included Eligibility Identification
Additional records identified through other sources (in other articles) (n =1) Records after duplicates removed (n =15)

Records screened (n = 15)
Records excluded non peer reviewed journals (n =3) Full-text articles assessed for eligibility (n = 12) Full-text articles excluded, non-radiology, neurology related, or published out of (2002-2020) (n = 3) Studies included in review (n = 9) Page: 31 www.raftpubs.com chemoreceptors and mechanoreceptors of the lungs from one neuron to another neuron to attack the medullary cardiopulmonary centers in the brainstem through synaptic connections [1]. The breathing becomes more difficult due to the infection in the brainstem. Similarly, SARS-CoV-2 could be transmitted to the brainstem through synaptic connections similar to SARS-CoV [1].

Intracranial hemorrhage
MERS-CoV can cause platelet dysfunction, thrombocytopenia, and disseminated intravenous coagulation which leads to prolonged coagulation profile then will cause a multi-organ failure then irreversible brainstem damage which eventually will lead to death. Polyneuropathy has been reported as non-direct consequences of the MERS-CoV [2]. The brain damage in SARS-CoV case due to hyper-dense lesions has been proven see ( Figure 2). There is a SARS-CoV-2 case with thalamic hemorrhage which is a common finding in among the lethal viruses of the coronavirus family see ( Figure 2).

Figure 2:
Three medical imaging study of three patients. The patient (A) is 34-year-old female patient with brain hemorrhage (a confirmed case of MERS-COV disease). The patient (B) is 50-year-old female patient with diffuse brain edema and multiple hyper densities lesions suggestive of ischemic and necrotic changes (a confirmed case of SARS-COV disease). The patient (C) is 50 year old female patient with bilateral thalamic hemorrhage (a confirmed case of SARS-COV-2 disease). Findings: The patient (A) study is axial CT scan for the brain show left intracranial hemorrhage, interventricular extension, midline shift, and brain edema (white arrow). The patient (B) study is axial CT scan show multiple hyper-densities -in different slices located upper and lower than the showed slice, but has the same features of the presented scan-with diffuse brain edema (white arrow). The patient (C) study is axial T2 MRI scan show bilateral thalamic hemorrhage that was confirmed as hypo-intense susceptibility weighted images (white arrow). Technique: (A) axial CT, cerebrum window. (B) axial CT, cerebrum window. (C) axial MRI, T2.

Long term neurological sequelae
It has been proven that SARS-CoV mostly enter the brain through the olfactory bulb leading to neurons death. The infection was detected in the brain mostly attacking the cardiopulmonary centers in the brainstem, while a minimal infection presented in the lungs [3].

Extent of the infection in the brain parts
MERS-CoV affect the corticospinal tract, ventricles (causing inter-ventricular hemorrhage), subcortical, basal ganglia, corpus callosum, temporal lobe, parietal lobe, and frontal lobe by different lesions. As well, Page: 32 www.raftpubs.com SARS-CoV affect the olfactory bulb, cerebrum, and cardiopulmonary centers in the brainstem. Similarly, SARS-CoV-2affect the brainstem, thalamus, olfactory bulb, and cerebrum, while the cerebellum remains as the uninfected part of the brain by SARS-CoV-2 [3].

Acute necrotizing encephalopathy (cytokine storm syndrome)
There isa confirmed case of SARS-CoV-2 of a women with bilateral thalamic and temporal lobe damage on both CT and MRI scans [4]. The findings are bilateral medial temporal lobe and thalamic bleedings on FLAIR and they were confirmed by susceptibility weighted images [4]. These findings are similar to another published case of influenza A virus subtype H3 with a fatal acute necrotic encephalitis [5]. The disruption of blood-brain barrier is associated with cytokine release which causes the bleeding.

Hyperthermia vs. brain
The normal body temperature is 37.7 •C (99.9 •F) and any temperature beyond 40 •C can be life-threatening temperature. The developing brain is at risk form hyperthermia. As well, the developed brain can have some effects which depends on the degree of the temperature and the duration of the exposure. In case of a severe hyperthermia, it could induce neuronal necrotic death. Even with lower temperatures, hyperthermia-induced damage can cause neurons to show a late apoptotic characteristic.
The mechanism of hyperthermia-induced damage is done by depolarizing the mitochondria in the neurons which would lead to cell damage [7].

Low oxygen saturation vs. brain
The normal oxygen level in the blood is 75 to 100 mm HG and if the oxygen level dropped below 60 mm HG, the patient will need a ventilator. The decrease in oxygen level in the blood will lead to a hypoxia. Brain hypoxia can be categorizing into 4 categories; diffuse cerebral hypoxia, focal cerebral ischemia, massive cerebral infarction, and global cerebral hypoxia. Similar to the body temperature, the low oxygen saturation effect on the nervous system has two important factors; the amount of oxygen in the blood and the period of shortage. The categories of hypoxia are associated with the previously mentioned two factors. The world health organization report claim that the mean incubation time for SARS-CoV-2 is 5.2 days based on a study among 425 patients in Wuhan and it may widely vary among patients which depends on their immune systems [8]. Another paper claims that the SARS-CoV-2 incubation period is 6.4 days [9]. If a patient have a low oxygen saturation for a long time, it could lead to white matter periventricular lesions, infarctions, or cognitive impairments. It is similar to chronic obstructive pulmonary diseases (COPD). The COPD patients with low oxygen saturation, they could develop white matter periventricular and subcortical lesions which will lead to cognitive impairments and mental illness [10].

Meningitis and encephalitis
One SARS-CoV-2 case was reported to be associated with Meningitis and encephalitis [11]. In the report, the patient brought to the hospital due to convulsion and loss of conciseness not because of fever or respiratory issues. The patient's MRI scan revealed ventricular hyper-intensities on DWI, partially atrophied hippocampus, high signal intensity in the temporal lobe and hippocampus on FLAIR, and pan sinusitis on T2 [11]. Page: 33 www.raftpubs.com

White matter lesions
MERS-CoV can causes lesions in the white matter in different regions like; subcortical, basal ganglia, corpus callosum, temporal lobe, parietal lobe, and frontal lobe see (Figure 3). The white matter lesions will cause ataxia, focal motor deficit, and coma [12]. All the brain lesions in the MERS-CoV patient did not show any gadolinium enhancement on MRI [12].

Olfactory nerve
It has been proven that the olfactory nerve is affected by SARS-CoV-2 in acute stages with no nasal congestion [13]. In such cases, the MRI images will show a high signal intensity in the olfactory bulb see ( Figure 4). As well, anosmia and olfactory neuropathy was reported in SARS-CoV with no abnormal Page: 34 www.raftpubs.com MRI finding in the olfactory bulb 14 , but a temporal epidermoid cyst was found in the scan see ( Figure  5).

Conclusion
Coronaviruses have a huge effect that is targeting the central nervous system which leads to other symptoms like; vomiting, anosmia, ageusia, respiratory distress, etc. The real issue is happening in the brainstem more than the lungs or the gastrointestinal system which is primarily led to death in some vulnerable cases with chronic conditions. Medical imaging investigation of the central nervous system must be done like the chest CT or swab test for confirmed coronavirus cases. To tackle the issue, an MRI must be done for the confirmed cases to detect any abnormality in the brain and especially the brainstem of the corona patients. A post-mortem pan CT can help in identifying other affected systems and our understanding of these viruses' mechanisms in damaging the human body. The etiology of coronavirus family summarized see (Table 2).

SARS-CoV
Intracranial hemorrhage Multiple hyper−densities and diffuse brain edema. Olfactory neuropathy N/A.
Olfactory neuropathy High signal olfactory bulb on T2 wighted images. Normal nasal volume (no congestion).

Teaching points
There is a large similarity between the lethal viruses in the coronavirus family especially in their effects on the nervous system. The central nervous system is largely involved in the coronavirus infection and we must pay more attention to this system which could help in saving lives.