COVID-19 and Neurological Symptoms: Do We Know Enough?

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 21^st 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.

Neurologic symptoms

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.

Bottom line

• 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

Citations

1. Chong Ng Kee Kwong K et al. COVID-19, SARS and MERS: A neurological perspective. J Clin Neurosci. 2020. (Epub ahead of print).
2. 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).
3. Montalvan V et al. Neurological manifestations of COVID-19 and other coronavirus infections: A systematic review. Clin Neurol Neurosurg. 2020;194:105921.
4. Mao L et al. Neurologic Manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol. 2020. Published online April 10, 2020.
5. 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.
6. 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).
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. Menni C et al. Real-time tracking of self-reported symptoms to predict potential COVID-19. Nature Medicine. 2020:1-4. 2
13. 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.
14. Umapathi T et al. Large artery ischaemic stroke in severe acute respiratory syndrome (SARS). J Neurol. 2004;251(10):1227-1231.
15. Klok FA et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thrombosis Research. 2020. (Epub ahead of print).
16. 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.
17. 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).
18. Azkur AK et al. Immune response to SARS-CoV-2 and mechanisms of immunopathological changes in COVID-19. Allergy. 2020. (Epub ahead of print).
19. Poyiadji N et al. COVID-19–associated acute hemorrhagic necrotizing encephalopathy: CT and MRI features. Radiology. 2020:201187.
20. Mizuguchi M et al. Acute encephalopathy associated with influenza and other viral infections. Acta Neurol Scand, Suppl. 2007;186:45-56.
21. Sedaghat Z et al. Guillain Barre syndrome associated with COVID-19 infection: A case report. J Clin Neurosci. 2020. (Epub ahead of print).
22. 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).
23. 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.
24. 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.