Long COVID Effects in Neurology

COVID-19 has undoubtably had a pervasive and noticeable impact on day-to-day life. Trying to understand the effects of a global pandemic in real time has highlighted several challenges and has proven to be like organizing drops of rain during a downpour. There is a flood of information to wade through, and it is not always clear where the safe high ground is to get the strongest vantage point. This metaphor is especially true for understanding the persistent, long-term neurological symptoms associated with COVID-19.

The Evolution of COVID Symptoms

In the spring of 2020, research on SARS-CoV-2 primarily centered around understanding how the virus was transmitted and the prominent respiratory effects of the virus. As hospitalization numbers grew globally, there seemed to be a focus on the extreme outcomes, i.e., whether the virus resulted in asymptomatic presentation, or for the unluckiest, ventilator assistance or loss of life. As the pandemic progressed, however, patients who had other presentations – those with milder, but prolonged illnesses – started to receive attention. Researchers highlighted neurological symptoms associated with COVID as early as May 2020¹, and the term “long COVID” started appearing in new articles in the summer of 2020.

Though there is much still unknown about long COVID and its neurological symptoms, this syndrome is concerning to the medical community as it does not seem to be related to the severity of initial infection.² Thus, it can result from both the most severe and the most mild of cases. For COVID patients that did not need hospital treatment, 20 – 30% still experience at least one symptom of COVID a month after acute illness, and 10% three months later.² These persistent symptoms indicate that the impact of COVID can reach far beyond those that ever required inpatient hospitalization.

Chronic Neurological Presentations in COVID

The most prominent symptoms of long COVID (e.g., extreme fatigue, brain fog, joint pain) are similar to myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS). Although the causes for ME/CFS are unknown, viral and bacterial infections are believed to be potential triggers.

Many viral infections can result in chronic neurological presentations (e.g., Epstein Barr, herpes type 6, ebola). Specifically, other known coronavirus outbreaks (i.e., SARS in 2002 and MERS in 2012) resulted in prolonged neuronal disturbances.³ 50% of SARS patients reported fatigue and sleep disturbances up to 12 months after infection, with a substantial portion reporting chronic fatigue symptoms up to four years after infection. Similarly, around a third of MERS patients report anxiety, depression, and symptoms of PTSD one year after infection.

The inconsistent definitions of long COVID have included new symptoms that arise between 3 to 12 weeks after infection, as well as symptoms that persist throughout the infection or worsened several weeks after infection. Some definitions include symptoms that are secondary to other organ dysfunction impacted by SARS-CoV-2, or an interaction with previous pathology or disability. Critics argue that these imprecise working definitions of long COVID blur what is being studied and can lead to more confusion than clarity.^3,4

COVID Challenges in Research

This global pandemic has introduced a natural experiment impacting almost every aspect of life. Researchers have examined these impacts in their individual fields with studies using those resources readily available. This has led to multiple potential issues with the research process, including:

Decisions on who to include in the analyses
- often those conveniently available, either already in clinic/hospital, or those seeking medical care
What symptoms to focus on
- often prioritizing those within the specialty of the lead researcher
How to define the variables studied
- often based on tests that were included in routine care for that clinic/hospital system

Limited resources and sporadic testing created potential bias in studies during the early months of the pandemic. For long COVID, this has led to criticism of the imprecise definitions and defined methods of systematic data collection.^{3, 4}

What are the Impacts of Long COVID?

Mounting evidence strongly suggests that COVID has a tangible impact on long term neurologic and psychiatric health. The following symptoms have been reported in patients post hospitalization:⁵

fatigue
myalgia
headache
dysautonomia
cognitive impairment (i.e., “brain fog”)

Over half of hospitalized patients report fatigue several months to a year after diagnosis.^{3, 6} Fatigue and muscle weakness remained the most prevalent reported symptom at both 6 months (1 in 2 reporting) and 1 year (1 in 5 reporting)⁷. Cognitive impairment (“brain fog”) can either be persistent or fluctuating, and can include problems with concentration, memory, language, and executive functioning.⁵ One in ten patients also report loss of taste and smell persisting 6 months after acute recovery.⁵ Between 30-40% of COVID survivors report persistent anxiety, depression, sleep disruptions and PTSD, similar to survivors of other coronavirus outbreaks.⁵ Patients with higher levels of anxiety and depression also showed persistent physical symptoms, such as shortness of breath and general weakness, ⁸ though a causal relationship remains indeterminate.

What is Still Unknown?

The causes of these symptoms are unknown and are most likely complex. Since the disease manifests a wide variety of neurological symptoms, the likely pathological mechanisms are probably diverse. Proposed theories range from direct infection to immune dysregulation, secondary inflammation, microvascular dysfunction, iatrogenic effects of medications, as well as psychosocial effects.⁵

Psychological symptoms such as depression and anxiety may be most reflective of social consequences of COVID, arising from isolation, grief, or other socio-economic factors.⁴ However, the cause of longer term cognitive symptoms such as brain fog and chronic fatigue are not as clear. The duration of the symptoms, the impact on individual function, and best evidence-based treatments for long COVID remain unknown.

As we are still in the midst of an ongoing pandemic, the need for prospective treatment studies remains critical. Scientists and treating physicians need to be thoughtful in their research design and critical data review, given the potential bias posed by data collection practices. Examples of this are reports on long COVID that tracked patient outcomes after inpatient hospitalizations¹. This leaves out non-hospitalized patients who may suffer long COVID effects. Persistent symptoms associated with post-ICU care and recovery may differ significantly from milder but persistent long COVID symptoms in patients who did not require hospitalization.

How easy it will be to generalize research findings with the changing dynamics of the pandemic, such as novel variants and variable vaccination rates, remains unclear. It will be critical for scientists and treating physicians to be aware of how cognitive biases may influence our understanding of this disease. In the rush to consume new findings and novel case studies, it is possible to overestimate associations between atypical presentations and COVID – especially if incidence rates are not compared to the population as a whole.⁴

With large portions of the population at risk of exposure to the virus and impacted by the societal adjustments, any new finding or unique presentation should be compared to the possibility of a random or chance medical event occurring outside of infection. With new variants of SARS-CoV-2 impacting patient risk,⁹ it is important to place findings in the context of similar disease states (see ¹⁰ for comparisons with other respiratory infections), or chance presentation within the greater population, to truly understand novel risks.

How do Clinicians and Researchers Proceed?

At this stage of the pandemic, controlling the spread of SARS-CoV-2 is always the first step in care. FDA approval for the Pfizer vaccine, and pending approvals for alternate COVID vaccines provide a valuable tool in controlling the spread. Although breakthrough cases may occur post-vaccination, vaccinated individuals have shown lower risk of infection (for both alpha and delta variants),⁹ less severe symptomatology,¹¹ and a lowered risk of prolonged symptoms.¹¹ Furthermore, data suggests that there is no elevated risk of any neurological complications associated with vaccinations¹² (for a podcast discussion on that topic, click here).

Controlling the spread of the disease may provide relief to our medical and research institutions stretched for resources due to the pandemic and improve the ability to proactively study and understand the impact of long COVID. Further, physicians and researchers can do better listening to, and directly addressing the concerns of those being impacted by long COVID. The Atlantic recently published an article highlighting the role patient advocacy groups have played in directing attention to this syndrome. Using first person reports, as well as examining connections between long COVID to known chronic conditions like ME/CFS, may direct novel research hypotheses and targets for treatment.

*NOTE* This blog is valid as of 12/14/21 due to the ongoing and evolving nature of the COVID-19 pandemic.

About the Author Hans Klein, Ph.D., is the Manager of Scientific Publications for Stratus. Dr. Klein is a social neuroscientist by training and received his doctorate at the University of Texas at Dallas, where his research focused on the neural underpinnings of social cognitive deficits within schizophrenia spectrum disorders, as well as methods for improving measurement and research design.

References

Li H, Xue Q, Xu X. Involvement of the Nervous System in SARS-CoV-2 Infection. Neurotox Res. 2020;38(1):1-7. doi:10.1007/s12640-020-00219-8
Review NT. Living with Covid19 – Second review 2021 [updated March 2021].
Carod-Artal FJ. Post-COVID-19 syndrome: epidemiology, diagnostic criteria and pathogenic mechanisms involved. (1576-6578 (Electronic)).
Beghi E, Michael BD, Solomon T, Westenberg E, Winkler AS, Coalition C-NR. Approaches to understanding COVID-19 and its neurological associations. Ann Neurol. 2021. doi:10.1002/ana.26076
Nalbandian A, Sehgal K, Gupta A, Madhavan MV, McGroder C, Stevens JS, et al. Post-acute COVID-19 syndrome. Nat Med. 2021;27(4):601-15. doi:10.1038/s41591-021-01283-z
Tabacof L, Tosto-Mancuso J Fau – Wood J, Wood J Fau – Cortes M, Cortes M Fau – Kontorovich A, Kontorovich A Fau – McCarthy D, McCarthy D Fau – Rizk D, et al. Post-acute COVID-19 syndrome negatively impacts physical function, cognitive function, health-related quality of life and participation. LID – 10.1097/PHM.0000000000001910 [doi]. (1537-7385 (Electronic)).
Huang L, Yao Q, Gu X, Wang Q, Ren L, Wang Y, et al. 1-year outcomes in hospital survivors with COVID-19: a longitudinal cohort study. Lancet. 2021;398(10302):747-58. doi:10.1016/S0140-6736(21)01755-4
Tomasoni D, Bai F, Castoldi R, Barbanotti D, Falcinella C, Mule G, et al. Anxiety and depression symptoms after virological clearance of COVID-19: A cross-sectional study in Milan, Italy. J Med Virol. 2021;93(2):1175-9. doi:10.1002/jmv.26459
Twohig KA, Nyberg T, Zaidi A, Thelwall S, Sinnathamby MA, Aliabadi S, et al. Hospital admission and emergency care attendance risk for SARS-CoV-2 delta (B.1.617.2) compared with alpha (B.1.1.7) variants of concern: a cohort study. Lancet Infect Dis. 2021. doi:10.1016/S1473-3099(21)00475-8
Taquet M, Geddes JR, Husain M, Luciano S, Harrison PJ. 6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: a retrospective cohort study using electronic health records. Lancet Psychiatry. 2021;8(5):416-27. doi:10.1016/S2215-0366(21)00084-5
Antonelli M, Penfold RS, Merino J, Sudre CH, Molteni E, Berry S, et al. Risk factors and disease profile of post-vaccination SARS-CoV-2 infection in UK users of the COVID Symptom Study app: a prospective, community-based, nested, case-control study. Lancet Infect Dis. 2021. doi:10.1016/S1473-3099(21)00460-6
Goss AA-O, Samudralwar RA-O, Das RA-O, Nath AA-O. ANA Investigates: Neurological Complications of COVID-19 Vaccines. (1531-8249 (Electronic)).