Introduction
In December 2019, pneumonia cases of unknown etiology were identified in Wuhan city, Hubei Province of China. The cause, a novel enveloped RNA betacoronavirus which was isolated on January 7, 2020, later named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). On February 11th, The World Health Organization (WHO) defined the condition caused by this pathogen as “Coronavirus disease 2019” (COVID-19) (1). On February 27th, the first case in South America was confirmed in Brazil (2) and two days later, Ecuador’s (3) first case was reported as well. On March 11th, the WHO declared COVID-19 as a pandemic (4). During this outbreak, numerous studies have mainly described respiratory and gastrointestinal symptoms, distinctive laboratory findings, and characteristic pulmonary radiological abnormalities. But recently, Mao et al reported the first description (preprint) in February 2020 (now published in JAMA Neurology in April), focusing on neurological manifestations of SARS-CoV-2 infection (5).
Methods
Three independent searches by authors (DMZ, MAM, and AFB) of articles published in English and Spanish in electronic databases, including Medline, EMBASE, BEI, Cochrane Library, Dialog Datastar, EBSCO Biomedical, ERIC, First Search, Scholar Google, BioRxiv, MedRxiv, and the surveillance system of the World Health Organization (WHO), the Pan American Health Organization (PAHO), the European Center for Disease Prevention and Control (CEPCE). Using the following keywords: "SARS-CoV-2", "COVID-19", "neurological manifestations", and "neurological associations"; between December 2019 and April 2020. The reference list of the selected articles was manually searched for any relevant data. There was no restriction for the review of the study in the articles searched. The bibliographic search was iterative, that is, finding materials until reaching theoretical saturation.
Results
We found a total of 24 relevant articles in our search. Huang et al. (6) were the first to report the clinical characteristics of 41 patients with confirmed COVID-19 on January 24, 2020, 8% of which presented with headache. Later in the month, Chen et al. (7) described a sample of 99 patients in which 8% exhibited headache, 9% consciousness impairment, and 11% myalgia. Eleven more studies were published by February; the most common manifestation reported was headache (4 - 34%), followed by myalgia (3.36 - 52%) (1)(5)(8)(9)(10)(11)(12)(13)(14)(15)(16); within these studies, Mao et al (5) published on February 25 a preprint (not peer reviewed) which was later published in JAMA Neurology on April, the first report with a neurological focus. The report consisted of 214 patients, 36.4% of which had neurological manifestations displaying a direct proportional relation to the severity of the clinical presentations; these included: dizziness (16.8%), headache (13.1%), muscle injury (10.7%), consciousness impairment (7.5%), hypogeusia (5.6%), hyposmia (5.1%), acute cerebrovascular event (2.8%), neuralgia (2.3%), visual impairment (1.4%), ataxia (0.5%), and seizures (0.5%). In March, 6 other similar studies (17)(18)(19)(20)(21)(22) reported muscular compromise as the most common symptom (5.49 - 61%), followed by headache (7.69 - 13%), and dizziness (2.4%). Among these, Li et al (17) described in an abstract preprint of the Lancet journal, the development of cerebrovascular events in patients with COVID-19; where 5% of the 221 subjects included presented with an ischemic stroke, 0.5% with cavernous sinus thrombosis, and 0.5% with a cerebral hemorrhage. These patients were more likely to present with cardiovascular risk factors and severe SARS-CoV-2. In April, Lechien et al, showed that up to 85.6% and 88% of patients could present olfactory and gustatory dysfunction respectively (23). These findings are summarized in Table 1. Recently, Li et al mentioned a possible Central Hypoventilation Syndrome in a 24-year-old female patient (24), Jin et al presented a case of rhabdomyolysis in a 60 year old male (25), Filatov et al a case of encephalopathy in a 74-year-old man (26), Poyiadji et al reported a female that developed acute hemorrhagic necrotizing encephalopathy (27), Zhao et al reported a 61 year old female with GBS during COVID-19 (28), and Moriguchi et al presented the first case of meningitis and encephalitis associated to SARS-CoV-2 infection (29). These cases are presented in Table 2. (Table 1)
Discussion
In October 2007, Cheng et al warned about the importance of public health preparedness for a coronavirus outbreak similar to the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and the Middle East Respiratory Syndrome Coronavirus (MERS-CoV); this is due to the recombinant genetic capacity of these viruses, the presence of reservoirs in horseshoe bats, and the tradition of exotic mammal consumption in the southern China. He called it a “time bomb” and stressed on the need to be prepared for such an event should not be ignored (30). Today, 13 years later, we face a pandemic caused by the novel coronavirus SARS-CoV-2. Even though the main clinical manifestations are respiratory, there are reports on other clinical presentations such as the gastrointestinal (6.1%) (31) and cardiac as well (32). However, as the infection toll rises, other less common clinical presentations may surface, including those of neurological characteristics in nature.
The neuroinvasive potential of SARS-CoV-2 has been previously postulated (24)(33), but not demonstrated. Once transmitted through respiratory droplets, aerosol, or by direct contact, SARS-CoV-2 enters the host's cells through the angiotensin-converting enzyme receptor 2 (ACE 2); which is widely expressed in various tissues including the respiratory tract, lungs, endothelium, and the central nervous system (CNS). Animal studies have shown various pathways by which coronaviruses could enter the CNS. Either through the olfactory nerves, invading areas such as the brainstem and thalamus; or by invading peripheral nerve terminals and then gaining access to the CNS using a synaptic pathway through the respiratory system, once it has already established contact with the ACE 2 receptor (33). Available evidence cites similar coronaviruses such as SARS-CoV and MERS-CoV, Hemagglutinating Encephalomyelitis Virus 67 (HEV67), Human Coronavirus OC43 (HCV-OC43) or Avian Bronchitis Virus (ABV). In these studies, viral antigens have been detected in the brainstem, especially in regions that include the solitary tract and the ambiguous nucleus. The nucleus of the solitary tract receives sensory information from lung mechanoreceptors and chemoreceptors, and the respiratory tract; while efferent fibers from the nucleus ambiguous and the solitary tract nucleus provide innervation to glands, airway smooth muscle and blood vessels.
Such neuroanatomical interconnections could indicate that the death of infected animals or even humans may be due to dysfunction of the cardiorespiratory centers in the brainstem, pointing out that the respiratory dysfunction in COVID-19 may have a neurogenic component. (24)
Although there is no abundant evidence to date regarding neuroinvasion by SARS-CoV-2, reports of neurological manifestations in hospitalized patients with COVID-19 have begun to emerge (5)(17)(23)(24)(25)(26)(27)(28)(29). These manifestations seem to more likely present in patients with risk factors such as high blood pressure, diabetes mellitus, previous cerebrovascular disease, advanced age, severe clinical conditions, lymphopenia, elevated C-reactive protein and D-Dimer. These patients may have fewer typical symptoms such as fever and cough, but are more likely to have muscle injury, impaired consciousness, and acute cerebrovascular disease; the latter could be associated with a hypercoagulable state demonstrated by D-Dimer elevations. (5)(17) (Table 2)
Reports | Authors and Date | Sex | Age | Comorbidities |
---|---|---|---|---|
Central Hypoventilation Syndrome± | Li et al Feb 27 2020 | Female | 24 | Not reported |
Encephalopathy | Filatov et al Mar 21 2020 | Male | 74 | Multiple** |
Rhabdomyolysis | Jin et al Mar 20 2020 | Male | 60 | Not reported |
Acute Hemorrhagic Necrotizing Encephalopathy | Poyiadji et al Mar 31 2020 | Female | Not reported | Not reported |
Guillain Barre syndrome | Zhao et al Apr 1 2020 | Female | 61 | Not reported |
Meningitis | Moriguchi et al Apr 3 2020 | Male | 24 | Not reported |
Encephalitis | Moriguchi et al Apr 3 2020 | Male | 24 | Not reported |
* Severe Acute Respiratory Syndrome Coronavirus 2. ± Possible. ** Atrial Fibrillation, Ischemic Cerebrovascular Disease, Parkinson's Disease, Chronic Obstructive Pulmonary Disease.
Musculoskeletal manifestations are common in COVID-19. Muscle injury with elevated creatine kinase and lactate dehydrogenase levels was observed in severely ill patients; (5) its presence becomes important since it is known that a possible complication is rhabdomyolysis (25). Hyposmia and dysgeusia have recently been reported by the Spanish Society of Neurology and other medical societies as symptoms of SARS-CoV-2 infection (34), and that their presence could reach 85.6% and 88% respectively (23). The first could be explained by CoVs’ tendency to invade the olfactory bulbs (23) and it’s potential to compromise the CNS. Consciousness impairment has been demonstrated as another manifestation of COVID-19; it could be due to direct or indirect involvement, since there are reports in which the virus was detected in the cerebrospinal fluid in a patient with meningoencephalitis (29) and not in the other (26). In these cases, headache could be a symptom of meningeal involvement (35), especially if it presents with neck stiffness (NS) (29); an interesting clinical manifestation since most viral meningitis do not present NS and this sign has been observed in SARS-CoV-2 meningitis. COVID-19 has been associated with epileptogenic activity (0.5%) (5) that could indicate direct injury to the temporal lobe due to encephalitis (29). In addition to being found in tears, there is evidence that SARS-CoV-2 can compromise the conjunctiva (36), which in turn could be the origin of hypopsy (decreased visual acuity).
Although to the moment, injury to the retina and optic nerve has only been demonstrated by other CoVs. (37) Also, ataxia and dizziness have previously been described in similar CoVs infections. (38)
A significant fact is that SARS-CoV-2 has been associated with cases of Acute Hemorrhagic Necrotizing Encephalopathy (27) and GBS (28). Other associated and post-infectious complications have already been reported with other CoVs such as encephalitis, Critical Illness Polyneuromyopathy, myopathy, Refractory Epileptic Status, Indeterminate Acute Flaccid Paralysis, Brainstem Encephalitis, Acute Disseminated Encephalomyelitis, and GBS (Table 3) (38)(39)(40)(41)(42)(43)(44)(45)(46). The latter takes on special importance, since neuralgia (5) is a peripheral neurological manifestation observed in COVID-19. Proposing that in addition to acute virulence, there could be chronic complications; this is in accordance with existing evidence that has demonstrated the persistent presence in glia and possibly in similar CoVs neurons that would be related to perennial neuropathological changes (47).
Reports | Authors and Date | Sex | Age ⨥ | Comorbidities | Coronavirus |
---|---|---|---|---|---|
Encephalitis | Hung et al 2003 & Morfopoulou et al 2016 | Female & Male | 59 & 11 months | IgA Nephropathy & SCID. * | SARS - CoV** & HCoV-OC43∑ |
Critical Illness Polyneuromyopathy | Tsai et al 2004 | Female | 51, 48 & 42 | Not reported | SARS - CoV** |
Myopathy | Tsai et al 2004 | Male | 31 | Not reported | SARS - CoV** |
Refractory Epileptic Status | Lau et al 2004 | Female | 32 | 26 Week Pregnancy | SARS - CoV** |
Indeterminate Acute Flaccid Paralysis | Turgay et al 2015 | Female | 3 | Not reported | HCoV-OC43∑ & HCoV-229E⨍ |
Severe Acute Disseminated Encephalomyelitis | Yeh et al 2004 & Arabi et al 2017 | Male | 15 & 74; 45 | Not reported & DM, HTN, HLD; DM, HTN, CKD, IHD. * | HCoV-229E⨍ & MERS-CoV⋕ |
Central Nervous System Vasculopathy | Arabi et al 2017 | Male | 57 | DM, HTN, PVD* | MERS-CoV⋕ |
Post-Infectious Brain Stem Encephalitis | Kim et al 2017 | Male | 55 | AF, DM, HTN, ERC, HT* | MERS-CoV⋕ |
Guillain Barré Syndrome | Kim et al 2017 & Sharma et al 2019 | Male | 55 & 5 | FA, DM, HTN, ERC, HT* & Not reported | MERS-CoV⋕ & HCoV-OC43∑ |
*⨥Expressed in years unless otherwise stated. *SCID (Severe Combined Immunodeficiency Disease), DM (Diabetes Mellitus), HTN (Hypertension), HLD (Hyperlipidemia), CKD (Chronic Kidney Disease), IHD (Ischemic Heart Disease), FA (Atrial Fibrillation), HT (Hypothyroidism), PVD (Peripheral Vascular Disease); **SARS-CoV (Severe Acute Respiratory Syndrome Coronavirus); ∑ Human Coronavirus OC43, ⨍ Human Coronavirus 229E ⋕ Middle East Respiratory Syndrome Coronavirus.
Reports of neurological compromise on COVID-19 are on the rise. Timely recognition is significant since it is more common in patients with severe and atypical clinical conditions, (5) which could occur in the absence of respiratory or gastrointestinal manifestations. Healthcare providers and neurologists should pay close attention to this and should have a high index of suspicion when evaluating patients in an endemic area; especially since the knowledge of this is evolving. Effective identification could initiate early treatment and early isolation; preventing a clinical aggravation and spread of the virus (48). Currently, due to mobility restrictions and lack of service provided by outpatient clinics, elective care is not extensively available. Because of this, the use of telemedicine is a growing need and guidelines for the management of COVID-19 have currently been developed for this purpose (49). This pandemic is likely to catalyze the widespread adoption of teleneurology during and after the public control of this disease has been achieved (50); since specialists in neurology may not always be readily available in person for the evaluation of cases. Detailed knowledge of these manifestations and associations will help to provide better care to patients, either through telemedicine or inpatient care.
Conclusion
SARS-CoV-2 infection is associated with neurological compromise. It is mainly observed in severe cases, in patients with comorbidities, and atypical presentations. General healthcare providers and neurologists should pay close attention to this and have a high index of suspicion due to the fluency with which new information is reported. Timely recognition could help initiate early treatment and isolation, preventing clinical aggravation and spread of the virus.