Neurological Consequences of COVID-19 & Post-Acute Sequelae of COVID (PASC)

Learning Objectives

As a result of participating in this activity, learners will be better able to:

• Recognize the symptoms of post-acute COVID and how best to manage the symptoms
• evaluate patients for post-COVID pain symptoms
• make appropriate referrals to provide treatment for patients experiencing Post-Acute Sequelae of COVID (PASC)

Abstract

Among evaluated patients with long COVID, prolonged, often disabling, small-fiber neuropathy after mild SARS-CoV-2 was most common, beginning within 1 month of COVID-19 onset. Various evidence suggested infection-triggered immune dysregulation as a common mechanism. - Nath, 2022

Symptoms of long COVID are reported to be on-and-off, cyclic or multiphasic. A meta-analysis of pain-related symptoms reported for patients with long-term PASC determined that every one month of follow-up corresponded to a 45% increase in prevalence in patients who developed neuralgia after acute COVID-19 infection.

Weakness, often accompanied by myalgia and arthralgia, is a musculoskeletal manifestation of SARS-CoV-2 infection.

Central and peripheral nerve systems are one of the most susceptible targets for SARS-CoV-2 virus (neurotropism).

As well, a prolonged period of mechanical ventilation in the ICU may cause what is called “post intensive care syndrome” or “ICU-acquired weakness”, manifesting as cognitive dysfunction, muscle atrophy, sensory disruption and joint-related pain.

Residual effects from SARS-CoV-2 virus include fatigue, dyspnea, chest pain, persistent loss of taste and/or smell, cognitive changes, arthralgias, and decreased quality of life.

Accreditation & Designation

Release date: This activity was released 8/20/2022.

Termination date: The content of this activity remains eligible for CME Credit until 8/19/2025, unless reviewed or amended prior to this date.

Claiming Credit: Watch the entire presentation and complete the Improvement Plan/Evaluation.

Neurovations Education is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

Neurovations Education designates this other activity (blended learning) for a maximum of 0.75 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Disclosure of Financial Relationships

Neither the presenter, reviewers nor any other person with control of, or responsibility for, the planning, delivery, or evaluation of accredited continuing education has, or has had within the past 24 months, any financial relationship(s) to disclose with ineligible companies whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.

Additional Reading

• Spudich, S., & Nath, A. (2022). Nervous system consequences of COVID-19. Science, 375(6578), 267-269.
• Oaklander, A. L., Mills, A. J., Kelley, M., Toran, L. S., Smith, B., Dalakas, M. C., & Nath, A. (2022). Peripheral Neuropathy Evaluations of Patients With Prolonged Long COVID. Neurology-Neuroimmunology Neuroinflammation, 9(3).
• Chrousos, G. P., & Kaltsas, G. (2005). Post‐SARS sickness syndrome manifestations and endocrinopathy: how, why, and so what?. Clinical Endocrinology, 63(4), 363.
• Nath, A. (2020). Long-haul COVID. Neurology, 95(13), 559-560.
• Shiers, S., Ray, P. R., Wangzhou, A., Sankaranarayanan, I., Tatsui, C. E., Rhines, L. D., ... & Price, T. J. (2020). ACE2 and SCARF expression in human DRG nociceptors: implications for SARS-CoV-2 virus neurological effects. Pain, 161(11), 2494.
• Attal, N., Martinez, V., & Bouhassira, D. (2021). Potential for increased prevalence of neuropathic pain after the COVID-19 pandemic. Pain reports, 6(1).
• Lancet, T. (2021). Understanding long COVID: a modern medical challenge. Lancet (London, England), 398(10302), 725.
• Cascella, M., Del Gaudio, A., Vittori, A., Bimonte, S., Del Prete, P., Forte, C. A., ... & De Blasio, E. (2021). COVID-Pain: Acute and Late-Onset Painful Clinical Manifestations in COVID-19–Molecular Mechanisms and Research Perspectives. Journal of Pain Research, 14, 2403.
• Dani, M., Dirksen, A., Taraborrelli, P., Torocastro, M., Panagopoulos, D., Sutton, R., & Lim, P. B. (2021). Autonomic dysfunction in ‘long COVID’: rationale, physiology and management strategies. Clinical Medicine, 21(1), e63.
• Raveendran, A. V., Rajeev Jayadevan, and S. Sashidharan. "Long COVID: an overview." Diabetes & Metabolic Syndrome: Clinical Research & Reviews 15, no. 3 (2021): 869-875.
• Nath, A., & Smith, B. (2021). Neurological issues during COVID-19: An overview. Neuroscience Letters, 742, 135533.
• Goss, A. L., Samudralwar, R. D., Das, R. R., & Nath, A. (2021). ANA investigates: neurological complications of COVID‐19 vaccines. Annals of Neurology, 89(5), 856.
• Bierle, D. M., Aakre, C. A., Grach, S. L., Salonen, B. R., Croghan, I. T., Hurt, R. T., & Ganesh, R. (2021). Central sensitization phenotypes in post acute sequelae of SARS-CoV-2 infection (PASC): defining the post COVID syndrome. Journal of Primary Care & Community Health, 12, 21501327211030826.
• Groff, D., Sun, A., Ssentongo, A. E., Ba, D. M., Parsons, N., Poudel, G. R., ... & Chinchilli, V. M. (2021). Short-term and long-term rates of postacute sequelae of SARS-CoV-2 infection: a systematic review. JAMA Network Open, 4(10)
• Hoshijima, H., Mihara, T., Seki, H., Hyuga, S., Kuratani, N., & Shiga, T. (2021). Incidence of Long-term Post-acute Sequelae of SARS-CoV-2 Infection Related to Pain and Other Symptoms: A Living Systematic Review and Meta-analysis. medRxiv.
• Totura, A. L., & Bavari, S. (2019). Broad-spectrum coronavirus antiviral drug discovery. Expert opinion on drug discovery, 14(4), 397-412.
• Berlin, D. A., Gulick, R. M., & Martinez, F. J. (2020). Severe COVID-19 [published online ahead of print May 15, 2020]. N Engl J Med, 10.
• Abdalkader, M., Shaikh, S. P., Siegler, J. E., Cervantes-Arslanian, A. M., Tiu, C., Radu, R. A., ... & Jovin, T. G. (2021). Cerebral venous sinus thrombosis in COVID-19 patients: a multicenter study and review of literature. Journal of Stroke and Cerebrovascular Diseases, 30(6), 105733.
• Ross Russell, A. L., Hardwick, M., Jeyanantham, A., White, L. M., Deb, S., Burnside, G., ... & Galea, I. (2021). Spectrum, risk factors and outcomes of neurological and psychiatric complications of COVID-19: a UK-wide cross-sectional surveillance study. Brain communications, 3(3), fcab168.
• Zuo, Y., Estes, S. K., Ali, R. A., Gandhi, A. A., Yalavarthi, S., Shi, H., ... & Knight, J. S. (2020). Prothrombotic autoantibodies in serum from patients hospitalized with COVID-19. Science translational medicine, 12(570), eabd3876.
• Novi, G., Rossi, T., Pedemonte, E., Saitta, L., Rolla, C., Roccatagliata, L., ... & Farinini, D. (2020). Acute disseminated encephalomyelitis after SARS-CoV-2 infection. Neurology-Neuroimmunology Neuroinflammation, 7(5).
• Poyiadji, N., Shahin, G., Noujaim, D., Stone, M., Patel, S. C., & Griffith, B. (2020). COVID-19-associated acute hemorrhagic necrotizing encephalopathy: imaging features. Radiology, 296(2), 119.
• LaRovere, K. L., Riggs, B. J., Poussaint, T. Y., Young, C. C., Newhams, M. M., Maamari, M., ... & Overcoming COVID-19 Investigators. (2021). Neurologic involvement in children and adolescents hospitalized in the United States for COVID-19 or multisystem inflammatory syndrome. JAMA neurology, 78(5), 536-547.
• Abdel-Mannan, O., Eyre, M., Löbel, U., Bamford, A., Eltze, C., Hameed, B., ... & Hacohen, Y. (2020). Neurologic and radiographic findings associated with COVID-19 infection in children. JAMA neurology, 77(11), 1440-1445.
• Khedr, E. M., Abo-Elfetoh, N., Deaf, E., Hassan, H. M., Amin, M. T., Soliman, R. K., ... & Saber, M. (2021). Surveillance study of acute neurological manifestations among 439 Egyptian patients with COVID-19 in Assiut and Aswan University Hospitals. Neuroepidemiology, 55(2), 109-118.
• Ward, H., Atchison, C., Whitaker, M., Ainslie, K. E., Elliott, J., Okell, L., ... & Elliott, P. (2021). SARS-CoV-2 antibody prevalence in England following the first peak of the pandemic. Nature communications, 12(1), 1-8.
• Elliott, J., Whitaker, M., Bodinier, B., Eales, O., Riley, S., Ward, H., ... & Elliott, P. (2021). Predictive symptoms for COVID-19 in the community: REACT-1 study of over 1 million people. PLoS medicine, 18(9), e1003777.
• Balcom, E. F., Nath, A., & Power, C. (2021). Acute and chronic neurological disorders in COVID-19: potential mechanisms of disease. Brain, 144(12), 3576-3588.
• Christensen, P. A., Olsen, R. J., Long, S. W., Subedi, S., Davis, J. J., Hodjat, P., ... & Musser, J. M. (2021). Delta variants of SARS-CoV-2 cause significantly increased vaccine breakthrough COVID-19 cases in Houston, Texas. MedRxiv.
• Hosp, J. A., Dressing, A., Blazhenets, G., Bormann, T., Rau, A., Schwabenland, M., ... & Meyer, P. T. (2021). Cognitive impairment and altered cerebral glucose metabolism in the subacute stage of COVID-19. Brain, 144(4), 1263-1276.
• Guedj, E., Campion, J. Y., Dudouet, P., Kaphan, E., Bregeon, F., Tissot-Dupont, H., ... & Eldin, C. (2021). 18F-FDG brain PET hypometabolism in patients with long COVID. European journal of nuclear medicine and molecular imaging, 48(9), 2823-2833.
• Douaud, G., Lee, S., Alfaro-Almagro, F., Arthofer, C., Wang, C., McCarthy, P., ... & Smith, S. M. (2022). SARS-CoV-2 is associated with changes in brain structure in UK Biobank. Nature, 604(7907), 697-707.
• Brann, D. H., Tsukahara, T., Weinreb, C., Lipovsek, M., Van den Berge, K., Gong, B., ... & Datta, S. R. (2020). Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia. Science advances, 6(31), eabc5801.
• Evangelho, V. G. O., Bello, M. L., Castro, H. C., & Amorim, M. R. (2022). Down syndrome: the aggravation of COVID-19 may be partially justified by the expression of TMPRSS2. Neurological Sciences, 43(2), 789-790.
• Lee, M. H., Perl, D. P., Nair, G., Li, W., Maric, D., Murray, H., ... & Nath, A. (2021). Microvascular injury in the brains of patients with Covid-19. New England Journal of Medicine, 384(5), 481-483.
• Chertow, D., Stein, S., Ramelli, S., Grazioli, A., Chung, J. Y., Singh, M., ... & Kleiner, D. (2021). SARS-CoV-2 infection and persistence throughout the human body and brain.
• Jolobe, O. M. (2022). Post-COVID-19 diabetes in the context of long COVID. The American Journal of Emergency Medicine.
• Noval Rivas, M., Porritt, R. A., Cheng, M. H., Bahar, I., & Arditi, M. (2022). Multisystem Inflammatory Syndrome in Children and Long COVID: The SARS-CoV-2 Viral Superantigen Hypothesis. Frontiers in Immunology, 3480.
• Geers, D., Sablerolles, R., van Baarle, D., Kootstra, N., Rietdijk, W., Schmitz, K., ... & de Vries, R. D. (2022). Ad26. COV2. S priming provides a solid immunological base for mRNA-based COVID-19 booster vaccination. medRxiv.
• Heming, M., Li, X., Räuber, S., Mausberg, A. K., Börsch, A. L., Hartlehnert, M., ... & Zu Hörste, G. M. (2021). Neurological manifestations of COVID-19 feature T cell exhaustion and dedifferentiated monocytes in cerebrospinal fluid. Immunity, 54(1), 164-175.
• Hosaka, T., Tsuji, H., & Kwak, S. (2021). RNA editing: A new therapeutic target in amyotrophic lateral sclerosis and other neurological diseases. International Journal of Molecular Sciences, 22(20), 10958.
• Johansson, M., Ståhlberg, M., Runold, M., Nygren-Bonnier, M., Nilsson, J., Olshansky, B., ... & Fedorowski, A. (2021). Long-haul post–COVID-19 symptoms presenting as a variant of postural orthostatic tachycardia syndrome: the Swedish experience. Case Reports, 3(4), 573-580.
• Oaklander, A. L., Mills, A. J., Kelley, M., Toran, L. S., Smith, B., Dalakas, M. C., & Nath, A. (2022). Peripheral neuropathy evaluations of patients with prolonged long COVID. Neurology-Neuroimmunology Neuroinflammation, 9(3).
• Novak, P., Mukerji, S. S., Alabsi, H. S., Systrom, D., Marciano, S. P., Felsenstein, D., ... & Pilgrim, D. M. (2022). Multisystem Involvement in Post‐Acute Sequelae of Coronavirus Disease 19. Annals of neurology, 91(3), 367-379.
• Shiers, S., Ray, P. R., Wangzhou, A., Sankaranarayanan, I., Tatsui, C. E., Rhines, L. D., ... & Price, T. J. (2020). ACE2 and SCARF expression in human DRG nociceptors: implications for SARS-CoV-2 virus neurological effects. Pain, 161(11), 2494.
• Ballering, A. V., van Zon, S. K., Olde Hartman, T. C., Rosmalen, J. G., & Lifelines Corona Research Initiative. (2022). Persistence of somatic symptoms after COVID-19 in the Netherlands: an observational cohort study. The Lancet, 400(10350), 452-461.
• Moutal, A., Martin, L. F., Boinon, L., Gomez, K., Ran, D., Zhou, Y., ... & Khanna, R. (2021). SARS-CoV-2 spike protein co-opts VEGF-A/neuropilin-1 receptor signaling to induce analgesia. Pain, 162(1), 243.