Several studies provide evidence for neurologic and neuropsychiatric morbidity during and after COVID-19 infection—a phenomenon known as “long-haul COVID.”1 People with long-haul COVID are likely to experience health conditions that are either new, returning, or ongoing for 4 weeks or more following SARS-CoV-2 infection, the virus that causes COVID-19. New or ongoing symptoms of long-haul COVID include but are not limited to: difficulty breathing or shortness of breath, and neurologic symptoms such as brain fog and sleep problems.
Evidence suggests that on entering the central nervous system (CNS), SARS-CoV-2 may infect the brain, directly causing a variety of disorders that can vary from mild to severe.2 Once in the brain, SARS-CoV-2 can cause neuroinflammation resulting from microglial activation. It can also cause synucleinopathy, which spreads to other parts of the brain through the vagus nerve.
Risk factors for long-haul COVID are diverse and include severity of initial infection, comorbidities, age, sex and ethnicity. In one systematic review that included longitudinal studies, female patients were more at risk of post-acute SARS-CoV2 sequelae (23.6% versus 20.7%).3,4 Although older adults have been known to be more at risk of contracting COVID, the greatest prevalence rates of long-haul COVID were identified in adults between the ages of 35-69 years.
The presence of pre-existing comorbidities was also a highly significant factor. Several studies suggest reduced pulmonary diffusion capacities, cardiovascular disease, asthma, hypertension, and obesity to be some of the key comorbidities in patients developing symptoms of long-term sequelae.4,5 In addition, ethnicity and socio-economic conditions such as living in deprived areas were found to be highly culpable in the development of long-haul COVID.
Given the increased prevalence of long-haul COVID cases with a manifestation of neurologic symptoms, also known as “long-neuro COVID,” we talked with 3 neurology experts to learn more about this post-COVID phenomenon and its neurologic significance: Lavanya Visvabharathy, PhD, postdoctoral fellow of neurology at the Northwestern University in Chicago, Anna Cervantes-Arslanian, MD, director of neurocritical care at the Boston University School of Medicine, and Jonathan Rogers, PhD, specialty registrar in general adult and old age psychiatry at South London and Maudsley NHS Foundation Trust.
What is the neurologic significance of long-haul COVID?
Dr Visvabharathy: The main quality of life markers affected in [patients with long-haul COVID neurologic symptoms] seem to involve depression, anxiety, and pain. These are clearly issues combining both psychological factors and physical factors and are distinct from measures of cognitive dysfunction.
The significance of this in long-haul COVID is based on data showing lack of a [T lymphocyte] T-cell memory response, plus the persistence of anti-SARS-Cov-2 antibodies over long periods of time. Compared with healthy COVID convalescents, [patients presenting with long-neuro COVID] might have a persistent infection that leads to long-term symptoms and eventually, perhaps, autoimmunity.
How does COVID gain access to the CNS and consequently the brain?
Dr Cervantes-Arslanian: SARS-CoV-2 can gain access to the CNS either directly or indirectly. Direct infection can occur via the olfactory nerves by retrograde transport across the cribriform plate into the olfactory bulb, followed in some rarer cases by contiguous spread. Indirect infection can be hematologic by binding onto [angiotensin converting enzyme-2] ACE 2 receptors.
Dr Rogers: There is some evidence that the indirect effect of infection occurs via inflammation—that is, the virus causes the immune system to activate, and this inflammation affects the brain. In addition, COVID infection may cause failure in the respiratory system, reducing the supply of oxygen to the brain.
How serious is the threat of developing Guillain-Barré Syndrome (GBS) for long-haul COVID patients?
Dr Rogers: “While GBS may be linked to cases of COVID-19, it is a rare occurrence. In fact, evidence suggests incidence of GBS actually dropped during the pandemic, probably because lockdowns resulted in reduced transmission of other pathogens linked to GBS.”
How can we ascertain whether the presence of neurologic syndrome after COVID infection is long-haul COVID?
Dr Rogers: At the population level, studies have found a higher incidence of neurologic and neuropsychiatric disorders among individuals infected with COVID-19 than among healthy control [individuals] or those with other respiratory tract infections. At an individual level, it can be quite difficult. With rare but serious manifestations such as stroke, there can be a clear temporal link to COVID-19, but other neurologic or neuropsychiatric syndromes such as headache or depression are very common in the population, so it is hard to know when to attribute them to COVID.”
What is the difference in severity of long-term symptoms between vaccinated and unvaccinated patients with long-neuro COVID?
Dr Visvabharathy: Although we haven’t seen a difference in the severity of long-term symptoms between vaccinated and unvaccinated [patients with neuro-long], recent data from the UK suggests that the incidence of long-haul COVID is reduced by up to 40% in vaccinated patients who get COVID for the first time.6 This may still result in long COVID rates of up to 20%, but that is less than the 33% that we estimate on the conservative end from the beginning of the pandemic.
What are some of the most severe neurologic complications following COVID-19 infection?
Dr Cervantes-Arslanian: COVID-19 acute infection has been associated with severe neurologic complications in a minority of patients, including stroke, seizure, and even more rare—encephalitis, cranial nerve palsies, peripheral nerve problems, and movement disorders. These conditions may bring on long-haul neurologic symptoms. In addition, some [patients with long-haul COVID] have been seen to have autonomic changes reminiscent of postural tachycardia syndrome.
How do new variants like Omicron impact the nervous system?
Dr Cervantes-Arslanian:There is some very early data suggesting that Omicron may be associated with less neurologic symptoms, but this research is ongoing.
Are there any drug interactions and potential neurologic effects that have been reported secondary to the medications used to treat COVID-19 that could be risk factors for long-haul COVID?
Dr Cervantes-Arslanian: It is very rare that medications used in treating severe COVID infections are themselves associated with neurologic problems. Moreover, a large number of patients with long-haul COVID never require hospitalization or never receive treatment as they don’t have severe COVID or underlying risk factors.
What should clinicians tell their patients when it comes to managing long-haul COVID symptoms?
Dr Cervantes-Arslanian: The majority of [patients with] COVID, even those with long-haul COVID, will have improvement in symptoms with time. However, continued attention to well-being, exercise, and keeping mentally active are important in supporting good health and hygiene to maximize potential for symptomatic improvement. Patients experiencing new headaches that are not resolving, focal weakness or sensory loss, loss of balance, or persistent memory problems should bring these to the attention of a specialist.
What type of research do you believe needs to be done to better understand long-neuro COVID?
Dr Visvabharathy: One of these is the development of long-term autoimmune disease after the initial viral infection. I think we need to further study whether T-cells from [patients with] long-haul COVID can cross-react to a variety of neuronal auto antigens and further decipher what this might mean for neuronal pathology. This is something I am actively pursuing and I know other researchers are doing this as well.
1. Post-COVID conditions. Centers for Disease Control and Prevention website. Updated September 16, 2021. Accessed February 7, 2022. https://www.cdc.gov/coronavirus/2019-ncov/long-term-effects/index.html
2. Wildwing T and Holt N. The neurological symptoms of COVID-19: a systematic overview of systematic reviews, comparison with other neurological conditions and implications for healthcare services. Ther Adv Chronic Dis. Published online January 28, 2021. doi:https://doi.org/10.1177/2040622320976979
3. Michelen M, Manoharan L, Elkheir N, Cheng V, Dagens D, Hastie C, et al. Characterising long-term COVID-19: a rapid living systematic review. medRxiv. Posted May 31, 2021. doi:https://doi.org/10.1101/2020.12.08.20246025
4. Crook H, Raza S, Nowell J, Young M and Edison P. Long covid—mechanisms, risk factors, and management. BMJ. Published online July 26, 2021. doi:http://dx.doi.org/10.1136/bmj.n1648
5. Sudre CH, Murray B, Varsavsky T, et al. Attributes and predictors of long COVID. Nat Med. Published online May 27, 2021. doi:10.1038/s41591-021-01292-y
6. Antonelli M, Penfold RS, Merino J, 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. Published online September 1, 2021. doi:https://doi.org/10.1016/S1473-3099(21)00460-6