Neurology Research International

Review Article

Neurological Components in Coronavirus Induced Disease: A Review of the Literature Related to SARS, MERS, and COVID-19

Table 2

Neurologic findings reported in SARS, MERS, and COVID-19.


Reference	Title	Type of study	Virus	Virus confirmation	Host	Age	Comorbidities	Initial clinical manifestation	Neurologic symptoms/findings	Neurological clinical test/techniques	Disease type/final conclusion

[70]	Possible central nervous system infection by SARS coronavirus	Clinic case report	SARS-CoV	RT-PCR of CSF	Humans (n = 1)	32	—	Myalgia, fever, chills and rigor for 2 days, and unproductive cough	Generalized tonic-clonic convulsion loss of consciousness	CSF test, EEG, and RMI showed no abnormalities	The results suggest that the central nervous system (CNS) is affected by SARS-CoV

[51]	Detection of severe acute respiratory syndrome coronavirus in the brain: potential role of the chemokine MIG in pathogenesis	Clinic case report/experimental study	SARS-CoV	RT-PCR	Humans (n = 1)	39	—	Fever, chills, malaise, headache, dizziness, and myalgia	Headache, dizziness	Immunohistochemistry and immunofluorescence staining;	Brain tissue revealed necrosis of neuron cells and broad hyperplasia of gliocytes
										isolation and identification of SARS-CoV	Immunostaining demonstrated that monokine induced by interferon-g (MIG) was expressed in gliocytes with the infiltration of CD68+ monocytes/macrophages and CD3+ T lymphocytes in the brain mesenchyme
										Infection of 2 human cell lines with the previous virus isolated	The cytokine/chemokine assay revealed that levels of interferon-g-inducible protein 10 and MIG in the blood were highly elevated, although the levels of other cytokines and chemokines were close to normal
[52]	Organ distribution of severe acute respiratory syndrome- (SARS-) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways	Histopathological examination/autopsy study	SARS-CoV	RT-PCR of tissue selected	Human experimental group (n = 4)	Mean: 45.5 SD: 17.13	—	The initial symptoms were related to pyrexia, followed by chills, generalized aching pains, nonproductive cough, and sputum with a small quantity of blood (in one case)	—	IHC RT-PCR ISH Transmission electron microscopy	SARS-CoV was found in the brain and other tissues. The pathological changes in these organs may be caused directly by the cytopathic effect mediated by local replication of SARS-CoV

[71]	Severe acute respiratory syndrome coronavirus as an agent of emerging and reemerging infection	Review	SARS-CoV	—	Transgenic mice expressing hACE2 (K18-hACE2) Transgenic mice expressing hACE2 (AC70)	—	—	Weight loss by 3–5 DPI and died by 7 DPI; infection begins in airway epithelia with subsequent alveolar involvement and extrapulmonary virus; developed acute wasting syndrome and died within 4–8 DPI	Macrophage and lymphocyte infiltration into the lungs and upregulation of proinflammatory cytokines and chemokines in both the lung and the brain	Histological and immunohistochemical analyses	Extensive involvement of the central nervous system likely contributed to the death of mice; even though viral pneumonia was present, transgenic mice expressing human ACE2 receptors also developed fatal disease, with extrapulmonary dissemination to many organs including the brain

[72]	Pathology and pathogenesis of severe acute respiratory syndrome	Review	SARS-CoV	—	Various	—	—	Patients present with flu-like symptoms including fever, chills, cough, and malaise	IHC, ISH, and EM have confirmed the viral infection of neurons.13, 15, and 42; gliocytes have also been found infected by SARS-CoV	IHC ISH CT Genomic sequences in cerebral spinal fluid and in brain tissue specimens	Edema and degeneration of neurons and several neurons in situ hybridization showed positive results
[63]	Severe neurologic syndrome associated with Middle East respiratory syndrome corona virus (MERS-CoV)	Clinic case report	MERS-CoV	Tracheal aspirate tested positive for MERS-CoV	Humans (n = 3)	C1: 73	Case 1: diabetes, hypertension, and dyslipidemia	C1: Fever	C1: ataxia, vomiting, and confusion	C1: brain CT, brain MR, and CSF test	Altered level of consciousness ranging from confusion to coma, ataxia, and focal
						C2: 57	Case 2: diabetes and hypertension	C2: Acute myocardial ischemia with pulmonary edema	Also, dysmetria and decreased motor power on the left side	C2: brain CT and CT angiography	Motor deficit
						C3: 43	Case 3: diabetic and hypertensive with chronic kidney disease and ischemic heart disease	C3: 10-day history of productive cough, dyspnea, rigors, fever, and diarrhea	Case 2: at HD 4, the patient was unresponsive and hypotensive with left-sided facial paralysis	C3: MRI and CSF	MERS-CoV infection may be responsible for the extensive CNS injury observed in our patients

[54]	Neurological complications of Middle East respiratory syndrome coronavirus: a report of two cases and review of the literature	Clinic case report	MERS-CoV	RT-PCR of sputum	Human postmortem (n = 2)	C1: 34	C1: diabetes mellitus	C1: fever	C1: severe headache, nausea, and vomiting	C1: chest imaging and brain CT	C1: multiorgan failure and signs of irreversible brain stem dysfunction
[54]		Clinic case report	MERS-CoV	RT-PCR of sputum	Human postmortem (n = 2)	C2: 28	C2: does not report any comorbidities	C2: fever, generalized myalgia, dizziness, productive cough, and then development of bronchitis	C2: weakness in both legs and inability to walk with numbness and tingling in stocking distribution	C2: MRI and CSF tests were normal	C2: axonal polyneuropathy
[73]	Neurological complications during treatment of Middle East respiratory syndrome	Clinic case report	MERS-CoV	RT-PCR of sputum	Humans (n = 4)	Mean: 45.5 SD:7.14	C1: atrial fibrillation, diabetes mellitus, hypertension, chronic kidney disease, hypothyroidism, and tuberculosis	C1: cough, dyspnea, and chest discomfort	C1: complete external ophthalmoplegia and mild limb ataxia; suspected weakness in all four limbs	C1: MRI and CSF was normal; EEG exhibited diffuse slow-wave activity; RT-PCR of CSF was negative	C1: BBE overlapping with GBS
							C2: no underlying medical problems	C2: severe myalgia, chills, fever, cough, and headache; after a week, the patient presented with gastrointestinal symptoms, including nausea, vomiting, and anorexia	C2: deep tendon reflexes were mildly diminished in both legs; tingling and pain in the four distal limbs were also present	C2: EMG and evoked potential studies were normal	C2: ICU-acquired weakness or GBS
							C3: pulmonary	C3: fever, coughing, chest discomfort, dyspnea, and stool loss	C3: tingling present in the distal parts of the patient’s hands and feet; also, reflexes were decreased in both knees but were normal in both upper extremities	C3: only neurological evaluation	C3: infectious or toxic polyneuropathy and the patient’s sensory symptoms gradually improved over 6 months
							C4: no reported	C4: cough, sore throat, and fever	C4: tingling in both hands	C4: only neurological evaluation	C4: acute sensory neuropathy caused by a toxin or infection

[74]	Histopathology of Middle East respiratory syndrome coronavirus (MERS-CoV) infection: clinicopathological and ultrastructural study	Histopathological examination/case report	MERS-CoV	RT-PCR of sputum	Humans (n = 1)	33	T-cell lymphoma, thrombocytopenia, and neutropenia	Fever and productive cough with new infiltrate on chest radiograph	No significant inflammatory infiltrate	Light microscopy, electron microscopy (EM), and immunohistochemistry	The brain was histologically unremarkable
[75]	Middle East respiratory syndrome coronavirus causes multiple organ damage and lethal disease in mice transgenic for human dipeptidyl peptidase 4	Experimental study	MERS-CoV	Real-time quantitative PCR	Transgenic mice DPP4	—	—	MERS-CoV: infected lungs revealed mononuclear cell infiltration, alveolar edema, and microvascular thrombosis, with airways generally unaffected	—	Histologic and immunohistochemical analyses; infection of human cell lines; and primary porcine astrocytes	Brain disease was observed, with the greatest involvement noted in the thalamus and brain stem; animals immunized with a vaccine candidate were uniformly protected from lethal infection

[9]	Clinical characteristics of 82 death cases with COVID-19	Clinic case report	SARS-CoV-2	—	Humans (n = 82)	66 of 82 (80.5%) of patients were older than 60 years median age: 72.5 years.	Comorbidities (75.6%) including hypertension (56.1%), heart disease (20.7%), diabetes (18.3%), cerebrovascular disease (12.2%), and cancer (7.3%)	Fever, cough, and fatigue; the great proportion of them were diagnosed with severe illness when admitted; incubation period: 3–7 days	A majority of patients (75.6%) had 3 or more damaged organs or systems following the infection with SARS-CoV-2	Laboratory analyses: blood count, liver function, renal function, electrolyte test, coagulation function, C-reactive protein, lactate dehydrogenase, myocardial enzymes, procalcitonin, and status of other virus infection; radiological analyses: X-ray and computed tomography	A majority of patients (75.6%) had 3 or more damaged organs or systems following the infection with SARS-CoV-2; CNS not mentioned

[76]	COVID-19-associated acute hemorrhagic necrotizing encephalopathy: CT and MRI features	Clinic case report	SARS-CoV-2	Real-time quantitative PCR	Humans (n = 1)	Young female	No mention	3-day history of cough, fever, and altered mental status	aCT angiogram demonstrates normal appearance of the basilar artery and proximal posterior cerebral arteries; CT demonstrates symmetric hypoattenuation within the bilateral medial thalami	aCT CT CSF analysis RT-PCR	Acute necrotizing encephalopathy
[77]	Coincidence of COVID-19 epidemic and olfactory dysfunction outbreak	Cross-sectional study	SARS-CoV-2	Only online form	Humans (n = 10069)	32.5 ± 8.6 (7–78) years	No mention	Fever, cough, and dyspnea were less common in the participants with anosmia/hyposmia compliant in some period of time in the last four weeks	Sudden onset of anosmia: 76.24%; decreased sense of smell was constant: 60.90%; decreased taste sensation in association with anosmia: 83.38%	Online checklist, which was distributed in social networks	Postviral epidemic olfactory dysfunction

[12]	Neurological manifestations of hospitalized patients with COVID-19 in Wuhan, China: a Retrospective case series study	Retrospective case series	SARS-CoV-2	RT-PCR	Humans (n = 214)	Average age: 52.7 ± 15.5	83 (38.8%) had at least one disorder: hypertension (51, 23.8%), diabetes (30, 14.0%), cardiovascular disease (15, 7.0%), and malignancy (13, 6.1%)	Fever (132, 61.7%), dry cough (107, 50%), anorexia (68, 31.8%)	78 patients had nervous system symptoms: CNS: dizziness (16, 8%); headache (13.1%); PNS: hypogeusia (5.6%), hyposmia (5.1%); common in severe cases	Positive result to real-time reverse transcriptase polymerase chain reaction (RT-PCR) assay	Cerebrovascular disease impairment consciousness and muscle injury

[78]	Metabolic disturbances and inflammatory dysfunction predict severity of coronavirus disease 2019 (COVID-19): a Retrospective study	Retrospective study	SARS-CoV-2	RT-PCR	Humans (n = 97)	Median age: 39 years (range 23–82 years) Mild group: 37 years (29–55) Severe group: 58 years (47–67).	Mild group: hypertension (5, 6.9%), diabetes (2, 8%), cardiovascular disease (2, 8%), and cerebrovascular disease (2, 8%)	Fever (58.8%), cough (55.7%), fatigue (33%), sputum production (15.5%), vomiting and diarrhea (12.4%), and nasal congestion (10.3%)	Dizziness and headache (7.2%)	Positive results for fluorescence reverse transcription polymerase chain reaction (RT-PCR) chest computed tomography	Metabolic disturbances and immune-inflammatory dysfunction were found in patients with COVID-19
[78]		Retrospective study	SARS-CoV-2	RT-PCR	Humans (n = 97)		Severe group: hypertension (10, 40%), diabetes (3, 4.2%), cardiovascular disease (0, 0%), and cerebrovascular disease (1, 1.4%)		Dizziness and headache (7.2%)

[79]	Retrospective analysis of clinical features in 101 death cases with COVID-19	Retrospective study	SARS-CoV-2	RT-PCR	Humans (n = 101)	Average age: 65.46 years. 24–83 years	Hypertension (42.57%), diabetes (22.77%), neurological disease (9.90%), malignant tumor (4.95%), and respiratory disease (4.95%)	Fever (90.10%), cough (68.32%), dyspnea (74.26%), white sputum (30.69)%, myalgia, general weakness, dizziness, headache, and nausea and vomiting (85.15%)	Dizziness and headache	Positive RT-PCR or highly homologous gene sequencing with known coronavirus	Fatal respiratory distress syndrome and multiple-organ failure; The heart may be the second damaged organ; the median time from onset to death was 21.00 days; CNS not mentioned
[80]	Understanding COVID-19 new diagnostic guidelines: a message of reassurance from an internal medicine doctor in Shanghai	Review	SARS-CoV-2	—	Humans	—	—	(1) Fever and/or respiratory symptoms; (2) chest CT features of multiple small patchy shadows and interstitial changes and obvious extrapulmonary bands (early stage); multiple ground glass infiltration and infiltrates in both lungs (later stages). (3) Early stage of the disease: Total white blood cell count is normal or decreased, or the lymphocyte count is decreased	—	(1) Real-time fluorescent RT-PCR detected a nucleic acid of novel coronavirus in respiratory or blood samples or (2) sequencing of virus genes in respiratory or blood samples, highly homologous with SARS- CoV-2	Pneumonia syndrome and other symptoms

[53]	The neuroinvasive potential of SARS‐CoV2 may play a role in the respiratory failure of COVID‐19 patients	Review	SARS-CoV-2	—	—	—	—	—	Patients with COVID‐19 also showed neurologic signs, such as headache, nausea, and vomiting	—	Patients with COVID‐19 display clinical symptoms similar to those reported for SARS‐CoV and MERS‐CoV; the infection of SARS‐CoV has been reported in the brains from both patients and experimental animals, where the brainstem was heavily infected

aCT: computer tomography angiogram; CT: computer tomography; MRI: magnetic resonance imaging; BBE: Bickerstaff’s encephalitis; GBS: Guillain–Barre syndrome; ICU: intensive care unit; HD: hospital day; RT-PCR: reverse transcriptase polymerase chain reaction; IHC: immunohistochemistry; ISH: in situ hybridization; EM: electron microscopy.