Results
Far more is known and reported on neurological complications with SARS and MERS than for COVID-19 although the nature of the pandemic and the clinicians reporting from the front lines is rapidly generating a large body of literature. In a systematic review that identified COVID-19 cases with neurological complications (n = 82), the mean age of the patient was 62.3 years, 37.8% were female, and 48.8% developed cerebrovascular insults, 28% neuromuscular disorders, and 23% encephalitis or encephalopathy [16].

Viral entry and potential neurological consequences
The viruses associated with both SARS and COVID-19 enter the brain via a process involving the angiotensin-converting enzyme (ACE)-2 receptors located in the CNS [17–19], unlike the MERS virus, which gains entry via the plasma membrane or in the endosomes [20]. ACE-2 receptors are expressed in many parts of the body and are particularly densely expressed in the nasal mucosa. Coronaviruses that enter the body via the nasal mucosa may disrupt the nasal endothelium, cross the epithelial barrier, and then directly enter the lymphatic or circulatory system, accessing the CNS [21]. The SARS-CoV has been detected in the brain, and it is thought entry occurred by way of the olfactory nerve. Since there have been studies that located the SARS-CoV virus in the CNS but not the lung, it suggests that there is a direct pathway from the olfactory point of entry into the CNS [22]. Alternatively, a high viral load in the brain following a pulmonary infection might mean the virus entered the brain from the respiratory system; e.g., the vagus nerve links the respiratory system to the nucleus ambiguous and solitary tract nuclei of the brainstem. It has been speculated that the cardiorespiratory center of the brain may be involved in the severe acute respiratory distress in some patients with COVID-19 [23]. The more common form of respiratory failure in COVID-19 patients is Type 1 (gas exchange dysfunction resulting in hypoxia and low levels of carbon dioxide), which is more likely to be associated with pneumonia than brain dysfunction [24]. Type 2 respiratory failure, which involves both hypoxia and high levels of carbon dioxide due to ventilatory failure would be more suggestive of neurological dysfunction, and this occurs less frequently in COVID-19 patients [25].
Any viral invader of the CNS creates stress within the body, because the host must balance its natural immune response to destroy the pathogen while, at the same time, minimizing damage to nearby nonrenewable cells [26]. Once in the CNS, viruses that affect neurons are far more dangerous than viruses that target the leptomeninges, which can restore themselves. The CNS has a highly nuanced system of responses to viruses, which can cause considerable harm to the body should it become uncontrolled.
Coronaviruses such as the SARS-CoV-2 can enter the body via the nasal mucosa and may disrupt the nasal endothelium, cross the epithelial barrier, and then enter the CNS via the lymphatic or circulatory system [21]. The blood-brain barrier has a pore size of about 1 nm and coronaviruses are substantially larger [9], and this likely protects the brain from coronavirus invasion in many individuals. However, neuroinvasive viruses can cross the blood-brain barrier by brain viremia, inflammatory processes (making microvascular endothelial cells vulnerable), or infecting leukocytes that then cross the blood-brain barrier in the manner of a Trojan horse [27]. The entry of the virus via the olfactory endothelium with transit of the virus across the cribriform plate would allow the virus to enter the brain by circumventing the blood-brain barrier entirely [27].
In theory at least, the coronavirus could invade the CNS using a passive mechanism such as hematogenous spread; in this case, the virus goes dormant and is carried toward the CNS, only to re-activate at some point to infect endothelial cells of the blood-brain barrier or infect leukocytes that then act as the reservoir for further viral dissemination [28]. The neurological symptoms associated with the H1N1 influenza virus had earlier been explained by an autoimmunity model [29]. The autoimmunity model of coronavirus infection of the CNS, likewise unproven, maintains that neural tissues and blood vessels perceive both viral and myelin antigens as the same because of autoreactive T-cells. Autoimmunity would be limited to patients who were genetically predisposed [29].
The SARS-CoV-2 associated with COVID-19 belongs to the same clade of beta-coronaviruses as the MERS-CoV and the SARS-CoV viruses, although its homological sequence more closely resembles SARS-CoV than MERS-CoV [2]. The respiratory symptoms that occur in genetically related beta-coronaviruses, such as MERS-CoV and SARS-CoV are similar, two infections with which the global healthcare community has had years of clinical experience [30]. While it cannot be stated unequivocally that the neurological symptoms of these viral infections will be the same, it forms a good starting point.

Middle eastern respiratory syndrome
MERS was first identified in September 2012 in a 60-year-old man in Jeddah, Saudi Arabia, who presented with pneumonia complicated by renal failure [31]. Sporadic cases were reported outside of the Middle East up until 2015, when an outbreak in South Korea occurred with 186 confirmed infections and 38 deaths [32]. MERS has established associations with encephalomyelitis, vasculitis, Guillain-Barré syndrome (GBS), and encephalitis of the brain stem [21].
The clinical course of MERS ranges from asymptomatic cases (about 4%) to severe pneumonia with multiorgan involvement and negative patient outcomes [15]. While pulmonary, gastrointestinal, renal, and hematological complications have been reported in MERS patients, there are fewer reports of neurological complications [15]. In fact, the MERS-CoV virus has never been isolated from neural tissue in human beings [28].
In a study of 737 hospitalized MERS patients in South Korea, the most commonly reported symptoms were respiratory symptoms (13.6%), fever (11.1%), fatigue (11.1%), myalgia (9.2%), and gastrointestinal symptoms (7.5%) [32]. In a study of 23 MERS patients from South Korea, 17.4% experienced neurological symptoms either during or following MERS treatment [33]. These neurological complications occurred about two to three weeks after the onset of respiratory symptoms [33]. A study from Saudi Arabia (n = 70) reported that 24.7% of MERS patients experienced confusion and 8.6% had a seizure [34]. In this study, fever was present in 61.4% of patients, dyspnea occurred in 60%, an 54.3% had a cough. MERS symptoms were typically severe with 70% of those hospitalized in this study requiring intensive care and 60% of this cohort died [34].
The literature reports a fatal case of a 34-year-old woman with diabetes hospitalized for MERS, who two weeks after diagnosis developed a headache with nausea and vomiting [15]. An urgent computed tomography scan showed right frontal lobe intracerebral hemorrhage with massive brain edema; laboratory findings showed disseminated intravascular coagulation, including thrombocytopenia and a prolonged coagulation profile. In another case, a 28-year-old man was hospitalized in the intensive care unit for MERS complicated by bacterial pneumonia and had to be put on a ventilator for respiratory distress. Unfortunately, after initial improvement, he reported weakness and tingling in his legs that made it impossible for him to walk. Using neuroimaging scans, cerebrospinal fluid analysis, nerve conduction velocity studies, and spinal imaging, a diagnosis was made of critical-illness polyneuropathy. He was treated with intravenous (IV) immunoglobulin 400 mg/kg daily for five days and was discharged in 40 days; gradual improvement was noted over the next 6 months [15].

Severe acute respiratory syndrome
SARS broke out in Hong Kong, Taiwan, Canada, and other locations in 2003. It has been reported to be associated with encephalitis, ischemic stroke, and polyneuropathy [35]. Seizures have been mentioned as the first symptom of SARS-related encephalitis [36]. In a necropsy study of eight patients who died of SARS, there was evidence of SARS-CoV infection in the brain cortex and hypothalamus [37]. Particles from the SARS-CoV virus have been found in the brains of patients infected with SARS, most frequently in brain neurons [37–39]. Murine studies found that intranasal injections of both MERS-CoV and SARS-CoV could enter the brain, presumably via the olfactory nerves [40,41]. Among the areas of the brain infected, the brain stem was a primary, but not exclusive, target for both MERS-CoV [41] and SARS-CoV [40,42].
Neurological sequelae of SARS have been only sporadically reported. Acute olfactory neuropathy has been reported in a case study of a 27-year-old female SARS patient who was diagnosed with SARS in 2003, hospitalized, and recovered with combination therapy of antiviral therapy (ribivarin plus steroids) [43]. Fever persisted for about three weeks from onset of symptoms. She was discharged from the hospital at around the same time she reported the paroxysmal bilateral loss of her sense of smell. An otolaryngologic examination, biochemistry tests, and subsequent magnetic resonance imaging scans showed nothing unusual with no lesions that might account for her loss of olfaction. Now 2 years after her recovery from SARS, she still has not regained her sense of smell [43]. The common causes of anosmia include structural defects in the nasal cavity or sinuses, head injury, brain trauma, brain lesions, or drug-induced loss of olfaction, and in her case, these could all be ruled out. It was postulated that her anosmia was a coronavirus-induced form of olfactory neuropathy [43].
Neuromuscular symptoms associated with SARS have also been reported. A 51-year-old woman in Taiwan developed probable SARS shortly after her husband was diagnosed [44]. She was hospitalized and intubated and had no evidence of respiratory syncytial virus; however, a bone-marrow biopsy showed evidence of infection-related hemophagocytic syndrome. Her condition gradually improved and she was extubated, but she complained of weakness, numbness, and paresthesia in her legs. Ten days after extubation, a neurological examination showed good mental clarity with intact cranial nerves, but symmetric loss of muscle strength in her legs and mild weakness in the hands. These conditions improved slowly and two months later, a neurological examination reported only mild loss of leg strength and slight numbness in the toes of her right foot [44].
A case report from Hong Kong describes a 59-year-old woman with severe SARS who developed status epilepticus; evidence of the virus was found in her cerebrospinal fluid [45]. Another case report describes a pregnant patient with SARS who experienced a generalized convulsion with suspected nervous system invasion by the virus [46].
The neurological manifestations observed in SARS include peripheral axonal neuropathy and elevated muscle enzymes, which might be caused by extensive virus-driven vasculitis [38,47]. These were considered to be polyneuropathic and/or myopathic symptoms associated with critical illness [47].

COVID-19
Neurological symptoms have been sporadically reported in COVID-19 patients but have not yet been well studied [48,49]. The current body of evidence suggests that the SARS-CoV-2 can affect the nervous system in previously unsuspected ways [50]. The neuroinvasive capabilities of the SARS-CoV-2 doubtless exist but remain to be elucidated. Observed neurological symptoms of COVID-19 include febrile seizures, convulsions, mental status changes, and encephalitis [51]. Among the most commonly reported possibly neurological symptoms of COVID-19 are nonspecific symptoms, such as headache, myalgia, dizziness, and fatigue [21]. In a study at a single center in China (n = 214), 36.4% (n = 78) of hospitalized COVID-19 patients had what were identified as neurological symptoms[52]. In a multicenter retrospective study from Europe of 417 patients who recovered from mild to moderate COVID-19, 86% reported olfactory dysfunction and 88% problems with taste. In fact, in 12% of patients, the loss of the sense of smell was the first symptom of COVID-19 [53]. The loss of smell has emerged as being more prevalent among patients infected with COVID-19 than patients infected with other viruses or with other types of respiratory conditions [54] and has been recommended as a symptom that may help guide earlier diagnosis and treatment of COVID-19 [55]. In a meta-analysis (n = 1,627 patients, 10 studies), a loss of the sense of smell was reported in 53% of COVID-19 patients [55].
It appears that the frequency of neurological symptoms is associated with COVID-19 disease severity. In the aforementioned study of 214 hospitalized patients with COVID-19 infection (41% severe and 59% non-severe disease), severe patients were more likely than non-severe patients to have neurologically related manifestations (45.5% vs. 30.2%, respectively). In this study, the most frequently reported neurological manifestations for severe and non-severe patients, respectively, were acute cerebrovascular disease (5.7% vs. 0.8%), impaired consciousness (14.8% vs. 2.4%) and skeletal muscle injury (19.3% vs. 4.8%) [52]. This does not take into account more diffuse symptoms, such as confusion or headache, which may also be neurological [51].
Most COVID-19 patients seem to exhibit pulmonary symptoms before neurological ones [49]. About a third of diagnosed COVID-19 patients have some form of symptomology of suspected neurological origin, which might include headache, dizziness, impaired consciousness, ataxia, epilepsy, and cerebrovascular disease [49]. Besides an impaired or absent sense of smell or taste, vision disturbances, neuralgia, and skeletal muscle damage have also been reported [49]. Nucleic acid from the SARS-CoV-2 virus has been detected in the cerebrospinal fluid of patients, and the virus itself has been identified in brain tissue on autopsy of patients who died of COVID-19 [49]. Such findings are rare but confirm that the SARS-CoV-2 virus can enter the CNS. A 24-year-old Japanese man with COVID-19 presented with generalized epileptic seizures and decreased consciousness; RNA from the SARS-CoV-2 was not detectable in his nasopharynx but was identified in the cerebrospinal fluid [56]. Using a polymerase chain reaction (PCR) assay, the SARS-CoV-2 was likewise detected in the cerebrospinal fluid of an obese 40-year-old female COVID-19 patient with diabetes [57].