by Christopher Moulton, PhD
With what seems to be breakneck speed, the world continues to learn about the myriad manifestations of SARS-CoV-2 infection. Although much attention has been paid to the hallmark respiratory dysfunction in COVID-19, it’s becoming increasingly clear that the virus can target multiple organ systems, including the central nervous system. Although coronaviruses (including SARS-Cov-2) typically manifest as respiratory illnesses, neurological complications including neuropathy, delirium, and acute cerebrovascular events were seen in the recent 21st century SARS-CoV-1 and MERS epidemics.1
It’s been hypothesized that the common labored breathing, as well as less frequent instances of asymptomatic hypoxemia in COVID-19, may be linked to SARS-CoV-2 invasion of the CNS, as virulence studies in animal models and human autopsy samples reveal high viral infection rates in the brainstem.2 Here we’ll briefly consider the evolving aspects of neurological involvement and consequences of COVID-19.
A recent systematic review of 67 case reports, case series, and cohort studies shows that SARS-CoV-2 infection is associated with a variety of neurological symptoms, including headaches, hyposomia, asthenia, and altered consciousness.3 Additionally, stroke, neuropathy, demyelination, and various forms of encephalitis have been noted in COVID-19 patients.3
One of the first reports to consistently observe these signals came from Mao et al. in JAMA Neurology.4 This was a retrospective case series of patients that were admitted to one of three different medical centers in Wuhan, China. Positive cases were confirmed by RT-PCR and further classified as severe or nonsevere according to the American Thoracic Society guidelines for community-acquired pneumonia. Neurological symptoms were primarily recorded as subjective complaints in order to limit cross-infection during the outbreak; however, limited imaging studies and advanced workups were considered.
The authors found neurologic symptoms (including headache, dizziness, impaired consciousness, and cerebrovascular events) in 78 of 214 patients (36.4%), and these were more common in patients with severe COVID-19. Additionally, severe cases were older and had more comorbidities than nonsevere cases and intriguingly were less likely to present with cough or fever. Anosmia was uncommon (5.1%) in this cohort, and neuropathy was reported in only 1 patient.
SARS-CoV-2 gains entry through the ACE2 receptor, which is found in a variety of organ systems including lung, the digestive tract, and the CNS.5 Correspondingly, it’s been proposed that this constellation of varied neurological symptoms may be a direct consequence of neuronal attack by the virus or of secondary impairment via neuroinflammatory or autoimmune mechanisms.6
Loss of smell and taste
The CDC has now included new loss of taste or smell to the list of COVID-19 symptoms.7 Although Mao et al. only noted once instance of olfactory impairment in 214 patients,4 it has become increasingly clear that novel anosmia and ageusia are common symptoms of the viral infection.8,9 ACE2 receptors are abundant in the olfactory epithelium, which suggests that SARS-CoV-2 may access the olfactory bulb, leading to sensory dysfunction and potentially further invasion via the forebrain.10
Internet search trend data suggests that new loss of smell or taste may precede appearance of other symptoms and foreshadow advancing clinical severity. For example, a management professor at the University of Toronto noted that in Italy, web searches for “non sento odori” spiked prior to this symptom being recorded in hospitals or medical centers.11 A consortium of researchers at King’s College London and Massachusetts General Hospital in Boston have developed a phone-based tracking app with which 3.5 million globally are self-reporting COVID-related symptoms. The group has just conveyed in Nature Medicine that, among 18,401 individuals who received a SARS-CoV-2 test, those who tested positive were substantially more likely to have self-reported loss of smell and taste than those who tested negative (65.0% vs. 21.7%; OR =6.74).12
Strokes, emboli, and abnormal thrombosis
As COVID-related morbidity and mortality skew toward older population segments, concern has been expressed regarding relatively young (< 50 years) and otherwise healthy patients experiencing large-vessel ischemic stroke.13 Mao et al. identified acute cerebrovascular disease in 2.8% of patients (age not reported), which was more likely to occur in severe vs. nonsevere cases.4 Stroke, deep vein thrombosis, and pulmonary embolisms were present in some SARS-CoV-1 patients,14 so it is conceivable that similarities exist in the underlying pathophysiology among these similar coronaviruses.
Remarkably, a Dutch study reported that 31% of critically ill COVID-19 patients experienced thrombotic complications, which were associated with coagulopathies identified by prolongation of prothrombin time or activated partial thromboplastin time.15 Early data from China indicated that abnormal coagulation parameters, including elevated D-dimer, were associated with poor prognosis in COVID-19,16 and lung tissue from patient autopsies has revealed substantial microvascular injury and systemic activation of the complement pathway.17 These findings suggest that activation of the immune response may be implicated in irregular hematologic responses that precipitate macrovascular consequences.
Immune response involvement
Like many other respiratory viral infections, SARS-CoV-2 activates the adaptive immune response; however, there appear to be immunopathological consequences that are unique to COVID-19, including severe lymphopenia and eosinopenia.18 Similarly, Mao et al. found that neutrophilia and lymphopenia was more common in severe cases, and lymphopenia was more likely to be associated with neurologic symptoms.4 A rare case of acute hemorrhagic necrotizing encephalopathy, in which the blood brain barrier degrades without direct viral invasion, has been attributed to COVID-19.19 Certain manifestations of acute encephalopathy are associated with viral infections precipitating immune-mediated cytokine storms,20 as have been reported with SARS-CoV-2.
Three separate case reports published in May have identified development of SARS-CoV-2 associated Guillain Barré syndrome (GBS) in patients from Germany, Italy, and Iran.21–23 GBS is mediated by an overactive immune response that damages the myelin sheath of peripheral nerves. During the 2015 Zika virus epidemic, approximately 1% of infected adults developed GBS,24 so it’s suggestive that in a subset of COVID-19 patients, the systemic hyperinflammatory response to the virus provokes autoimmune activity against neuronal tissue. Whether SARS-CoV-2 is involved precipitating other immune-involved neurological conditions such as multiple sclerosis and Parkinson’s disease remains to be seen.
- A variety of neurological symptoms may be primary or secondary indicators of SARS-CoV-2 infection
- New loss of smell and taste is increasingly common and may be an early sign of COVID-19
- Thrombotic events and neuro-autoimmune activity are possible outcomes
- Chong Ng Kee Kwong K et al. COVID-19, SARS and MERS: A neurological perspective. J Clin Neurosci. 2020. (Epub ahead of print).
- Li Y-C et al. The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients. J Med Virol. 2020. (Epub ahead of print).
- Montalvan V et al. Neurological manifestations of COVID-19 and other coronavirus infections: A systematic review. Clin Neurol Neurosurg. 2020;194:105921.
- Mao L et al. Neurologic Manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol. 2020. Published online April 10, 2020.
- Hamming I et al. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004;203(2):631-637.
- Vonck K et al. Neurological manifestations and neuro-invasive mechanisms of the severe acute respiratory syndrome coronavirus type 2. Eur J Neurol. 2020. (Epub ahead of print).
- CDC. Coronavirus Disease 2019 (COVID-19) – Symptoms. Centers for Disease Control and Prevention. https://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/symptoms.html. Published April 4, 2020. Accessed April 11, 2020.
- Lechien JR et al. Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study. Eur Arch Otorhinolaryngol. 2020:1-11.
- Tong JY et al. The prevalence of olfactory and gustatory dysfunction in COVID-19 patients: A systematic review and meta-analysis. Otolaryngol Head Neck Surg. 2020:194599820926473.
- Soler ZM et al. A primer on viral-associated olfactory loss in the era of COVID-19. Int Forum Allergy Rhinol. 2020. Published online April 9, 2020.
- Stephens-Davidowitz S. Opinion | Google searches can help us find emerging Covid-19 outbreaks. The New York Times. https://www.nytimes.com/2020/04/05/opinion/coronavirus-google-searches.html. Published April 5, 2020. Accessed May 21, 2020.
- Menni C et al. Real-time tracking of self-reported symptoms to predict potential COVID-19. Nature Medicine. 2020:1-4. 2
- Oxley TJ et al. Large-vessel stroke as a presenting feature of Covid-19 in the young. N Engl J Med. 2020;0(0):e60.
- Umapathi T et al. Large artery ischaemic stroke in severe acute respiratory syndrome (SARS). J Neurol. 2004;251(10):1227-1231.
- Klok FA et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thrombosis Research. 2020. (Epub ahead of print).
- Tang N et al. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020;18(4):844-847.
- Magro C et al. Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases. Transl Res. 2020. (Epub ahead of print).
- Azkur AK et al. Immune response to SARS-CoV-2 and mechanisms of immunopathological changes in COVID-19. Allergy. 2020. (Epub ahead of print).
- Poyiadji N et al. COVID-19–associated acute hemorrhagic necrotizing encephalopathy: CT and MRI features. Radiology. 2020:201187.
- Mizuguchi M et al. Acute encephalopathy associated with influenza and other viral infections. Acta Neurol Scand, Suppl. 2007;186:45-56.
- Sedaghat Z et al. Guillain Barre syndrome associated with COVID-19 infection: A case report. J Clin Neurosci. 2020. (Epub ahead of print).
- Ottaviani D et al. Early Guillain-Barré syndrome in coronavirus disease 2019 (COVID-19): a case report from an Italian COVID-hospital. Neurol Sci. 2020:1-4. (Epub ahead of print).
- Scheidl E et al. Guillain-Barre syndrome during SARS-CoV-2 pandemic: a case report and review of recent literature. J Peripher Nerv Syst. 2020. Published online May 10, 2020.
- Barbi L et al. Prevalence of Guillain-Barré syndrome among Zika virus infected cases: a systematic review and meta-analysis. Braz J Infect Dis. 2018;22(2):137-141.
Christopher Moulton, PhD is the Therapeutic Platform Lead for Cognition & Special Projects at Metagenics. Dr. Moulton endeavors to develop innovative, science-based solutions for practitioners to improve and enhance the well-being of their patients. Relatedly, he engages with the scientific & medical communities to better understand the potential of personalized nutrition to advance health care. Dr. Moulton completed a PhD in Nutritional Sciences at the University of Illinois in Urbana-Champaign. He also holds a Master’s degree in Exercise Physiology and a Bachelor’s degree in Biochemistry. Prior to joining Metagenics, Dr. Moulton managed the Center for Nutrition, Learning, & Memory, a public-private partnership focused at the intersection of nutrition & neuroscience.