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May 18, 2021

Designated, “Long COVID”, there is significant concern over the potential long-term effects among COVID-19 survivors. The most prominent end-organ systems at risk for long-term effects are pulmonary, cardiovascular, and central nervous system (CNS). The CNS effects can result either from primary involvement by COVID, like hyposmia, or risk from secondary morbidity, such as hypercoagulability causing a stroke.

Neurologic Effects of Viruses

Previous human coronaviruses have resulted in CNS effects. The first Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) infection was first reported in China in February 2002, infecting individuals in North America, South America, Europe and Asia before the infection was contained in 2003. The neurological manifestations included epilepsy, ischemic stroke, and polyneuropathy and myopathy. Unlike COVID-19, anosmia was anecdotal. Chronic post-SARS autonomic dysfunction, occurring in up to half of patients who recovered, was characterized by persistent fatigue, diffuse myalgia, myopathy, weakness, and non-restorative sleep associated with apnea/hypopnea.

The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) was first identified in 2012, causing severe respiratory infection that was often associated with shock, acute kidney injury and coagulopathy but neurologic effects were not immediately known. The first report of MERS-CoV neurotoxicity occurred in 2015 when three patients presented with a severe neurologic syndrome consisting of confusion or coma, ataxia, and a focal motor deficit. Brain magnetic resonance imaging (MRI) revealed widespread bilateral hyperintense lesions (T2-weighted images) within the white matter and subcortical areas, and none of the lesions were enhanced by gadolinium. A retrospective study identified that 25% of MERS patients developed confusion and 8.6% experienced a seizure.

Neurological manifestations are among the first symptoms of COVID-19 infection including anosmia, hyposmia, hypogeusia, and dysgeusia. Cardiovascular morbidity, exacerbated by hypercoagulability, is related to ischemic stroke. Cerebrovascular disease includes large-vessel ischemic strokes, cerebral venous sinus thrombosis, intracerebral and subarachnoid bleeding. Acute hemorrhagic necrotizing encephalopathy is associated with cytokine storm. A frontal hypoperfusion syndrome also has been identified. Over 70% of hospitalized COVID-19 patients had neurological symptoms including headache, myalgias, and impaired consciousness. Stroke in COVID-19 patients was significantly more severe with poorer outcomes.

New onset seizure activity occurs in approximately 20% of critically ill COVID-19 patients with multi-organ failure, 70% of whom are intubated. Altered mental status and seizure-like activity account for over 60% and 30%, respectively, are the most common indications to perform an electroencephalogram (EEG) among COVID-19 patients. Conducted after a CNS event, EEG findings and disease outcomes are correlated. Over 25% of critically ill patients who recovered without disability from COVID-19 have a normal EEG.  By contrast, EEG findings are generally abnormal among critically ill COVID-19 patients who either die in the hospital or recover from COVID-19 with a disability. Over 70% of COVID-19 patients with abnormal EEG findings will also have abnormal findings on brain magnetic resonance imaging (MRI). MRI and perfusion brain imaging has revealed bilateral frontotemporal hypoperfusion and leptomeningeal enhancement.

Pathophysiology Differences

The pathophysiology of these coronavirus variants differs. SARS-CoV acts via the angiotensin-converting enzyme-2 (ACE2) receptor, while MERS-CoV infects cells by binding to the dipeptidyl peptidase 4 (DPP4) receptor. The binding affinity of the spike protein of SARS-CoV-2 is significantly higher than that of the SARS-CoV spike protein. Coronaviruses can access the CNS through axonal transport and viral migration through neurons to the brain. Other potential mechanisms of CNS entry include the olfactory bulb and in breaching the blood-brain-barrier.

Designated as “Neuro-COVID”, the cerebrospinal fluid (CSF) of COVID-19 patients has shown an expansion of dedifferentiated monocytes, and “exhausted” or inefficient T cell-driven antiviral immunity within the CSF. Additionally, the interferon-signaling transcript (STAT1, IRF7, MX1, ISG15) response is less pronounced than in viral encephalitis, resulting in a relative lack of anti-viral interferon-producing CD4+ T cells. While viral encephalitis causes a strong antiviral immune response within the CSF, the response of Neuro-COVID is either weaker or ineffective.  Compared with mild Neuro-COVID, severe Neuro-COVID exhibited a broad clonal T cell expansion and a curtailed interferon response. Similar to results in blood, the CSF also exhibited differences based on the severity of the COVID-19 infection. In blood, T cell exhaustion, an increase in proinflammatory macrophages, and a reduced interferon-dominated transcriptional response has been observed in severe COVID-19.

The neurological effects of COVID-19 result either directly from the disease’s pathophysiology or indirectly from hypoxia, sepsis and/or multi-organ failure. Neurological effects may result from an inflammatory cytokine storm syndrome or an immune pathway that includes lymphopenia and raised C-reactive protein (CRP) levels. COVID-19 patients presenting with CNS involvement tend to also have CNS symptoms compared to reportedly lower lymphocyte levels and lower platelet counts. Elevated D-dimer levels are a marker of a hypercoagulable state and of endogenous fibrinolysis. Coronaviruses are also associated with CNS diseases including disseminated encephalomyelitis, multiple sclerosis, febrile seizures, and encephalitis epilepsy.

Early in 2020, without known therapeutics or a vaccine, the COVID-19 cytokine storm was responsible for most of the acute cardiopulmonary morbidity and mortality. While Neuro-COVID was later recognized as a significant acute COVID-19 morbidity, its long-term impact on functional outcomes may prove as significant as the cardiopulmonary aspects of the disease.

Long COVID: Challenges and Implications

  1. Determining COVID-19’s impact on life expectancy of survivors

Real-world data will be needed to evaluate:

  • Long-term disease-related sequelae
  • Impact of COVID-19 on comorbidities (with particular attention to cardiopulmonary and neurological morbidities)
  • Death rates of COVID-19 survivors compared to a group of demographically matched peers who did not contract COVID-19, using a synthetic control arm
  1. Closely monitor COVID-19 survivors for existing and new COVID-19-related sequelae

Especially important is the pace of progression among known and/or existing comorbidities:

  1. Dementia among COVID-19 survivors
  2. Neurological compromise resulting from:
    • Primary effects: EEG and/or MRI evidence of CNS involvement by COVID-19
    • Secondary effects: Stroke due to hypercoagulability, cardiopulmonary compromise, hypoxemia

Index COVID-19 morbidities to:

  • Patient’s underlying comorbidities
  • Age at which COVID-19 was contracted
  • Severity of the infection
  • Sequelae experienced during the acute phase of the disease
  1. Sociodemographic details within outcomes analytics:
  • Type of health insurance
  • Place of residence (nursing facility vs. living independently at home)

Much like the medical follow-up required after infections and exposures, such as polio and for the first responders involved in 9/11, it is an obligation to continue to care for patients through expanded knowledge of the disease. Understanding the mechanism of action for COVID-19, this knowledge can then be applied to a better understanding of the pathogenesis of existing chronic diseases and future coronavirus outbreaks.

Unlike its predecessor SARS infections over the past two decades, COVID-19 has invoked significant mortality and morbidity to at least 10% of the US population. The elderly and patients with persistent sequelae of COVID-19 must be followed closely for Neuro-COVID.

Unknowns

  • True prevalence of COVID-19 in the general population, as not everyone was tested for COVID-19, including asymptomatic COVID-19 carriers 
  • Potential interval between COVID-19 infection and the development of Late COVID-19-related morbidity 
  • Development of late effects influenced by the type of COVID-19 sequelae, patient’s age and comorbidities, and the severity of the COVID infection

Neuro-COVID outcomes may be more immediate and age agnostic than anticipated. More accelerated dementia may occur among elderly COVID-19 survivors, especially if neurological complications occurred during the acute phase of the disease. Other factors, however, may prove to be age-independent for Neuro-COVID sequelae, including presenting symptoms (such as anosmia and dysgeusia), or seizures that developed during the acute phase of COVID-19 infection.

As in past long-term public health follow-up efforts, much will be learned about the pathogenesis of COVID-19. Unlike past long-term follow-up initiatives, the significant numbers of COVID-19 survivors, constituting approximately 10% of the US population, will provide significant insight into the pathogenesis of coronavirus infections.

Nora Janjan, MD, MPSA, MBA
FACP, FACR, FASTRO, FASCO
Chief Medical Officer

Dr. Janjan enhances our team with her broad experience in regulatory affairs, development of national and international standards for healthcare, and unique academic credentials to enrich our knowledge base and provide high-quality clinical expertise to our team. As one of a few physicians nationally with a master’s degree in public service administration and business administration, her expertise includes clinical trials, health economics and outcomes research, healthcare policy, and patient-reported outcomes.

References

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Lambrecq, et. al. Association of clinical, biological, and brain magnetic resonance imaging findings with electroencephalographic findings for patients with COVID-19.  JAMA Network Open. 2021;4(3):e211489.

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