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Disponible online el 20 de Febrero de 2024
Unseen scars: Unraveling the neurological manifestations of COVID-19
Cicatrices invisibles: desentrañando las manifestaciones neurológicas de la COVID-19
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Julián Benito-Leóna,b,c,d
a Department of Neurology, University Hospital “12 de Octubre”, Madrid, Spain
b Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain
c Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
d Department of Medicine, Faculty of Medicine, Complutense University, Madrid, Spain
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Coronavirus disease 2019 (COVID-19), a global health crisis ignited by the novel Severe Acute Respiratory Syndrome (SARS-CoV-2), has transcended its initial identification as a respiratory ailment to reveal far-reaching neurological implications.1,2 The pandemic has swept across nations since its emergence in late 2019, leaving a trail of profound health, economic, and social disruptions.2 The rapid spread and severity of the virus have overwhelmed healthcare systems, altered daily life, and triggered a global economic downturn, illustrating its pervasive impact.

This editorial aims to shed light on the spectrum of neurological symptoms experienced by patients, explore the potential mechanisms behind these manifestations, and discuss the long-term implications for individuals and healthcare systems. Understanding these neurological effects is crucial for providing comprehensive care to those affected and preparing healthcare systems and societies for these challenges and future pandemics.

Neurological symptoms can manifest not only in individuals with severe COVID-19 but also in mild cases. These manifestations vary from relatively mild symptoms such as anosmia, ageusia, and headaches, which are often holocranial, hemicranial, or occipital, pressing, to a myriad of severe central and peripheral nervous system complications such as impairment of consciousness, Guillain-Barré syndrome and its variants, movement disorders, spinal cord involvement, acute disseminated encephalomyelitis, neuromyelitis optica spectrum disorder, ischemic and hemorrhagic stroke, including cerebral venous thrombosis, posterior reversible encephalopathy syndrome, seizure, and encephalopathy among others.1–13

According to a study published in the JAMA Netw Open that included more than 3700 adults hospitalized with clinically diagnosed or laboratory-confirmed COVID-19 at 28 centers representing 13 countries and four continents, 82% had any neurological manifestation (self-reported neurological symptoms and/or clinically captured neurological sign and/or syndrome), which were associated with higher in-hospital mortality.13 The most common self-reported symptoms included headache (37%) and anosmia or ageusia (26%).13 The most prevalent neurological signs and/or syndromes were acute encephalopathy (49%), coma (17%), and stroke (6%), while meningitis and/or encephalitis were infrequent (0.5%).13 The presence of clinically captured neurologic signs and/or syndromes was associated with an increased risk of in-hospital death. Of interest was that the presence of preexisting neurological disorders was associated with an increased risk of developing neurological signs and/or syndromes with COVID-19.13

These figures underscore the importance of recognizing and addressing neurological manifestations of COVID-19, not only in the acute phase but also long after the acute phase of the infection. They also highlight the need for further research into understanding the mechanisms behind these symptoms, their long-term implications, and the development of effective treatment strategies to manage these neurological effects in patients.

While diverse and complex, the neurological manifestations of COVID-19 are thought to arise from several potential mechanisms through which the virus impacts the nervous system. Understanding these mechanisms is crucial for developing targeted treatments and supporting recovery in affected patients.

One primary mechanism is the direct viral invasion of the nervous system. The SARS-CoV-2 virus may enter the brain through the olfactory nerve, the nerve responsible for the sense of smell, which may explain the common symptom of anosmia in COVID-19 patients.1 Once in the central nervous system, the virus may cause inflammation and damage neural tissues, leading to neurological symptoms.1 However, in contrast to this hypothesis, few studies have confirmed the presence of SARS-CoV-2 antigens in brain tissue samples.14

Another mechanism involves the immune response to the infection.1 In some patients, COVID-19 triggers an excessive immune reaction known as a cytokine storm.1 This hyperactive immune response can lead to inflammation throughout the body, including the brain, and is associated with neurological complications such as encephalitis and acute disseminated encephalomyelitis.1

The virus also affects the vascular system, leading to blood clotting abnormalities.1,13 This can result in strokes, even in younger patients and those without traditional stroke risk factors.1,13

Additionally, the systemic effects of COVID-19, such as hypoxic/ischemic alterations, can indirectly harm the brain.14 It is known that prolonged periods of hypoxia can lead to cognitive issues like memory problems and difficulty concentrating.

Case studies have provided real-world insights into these mechanisms. For instance, a report published in Neurology detailed the case of a 58-year-old man who, following a severe SARS-CoV-2 infection, developed neurologic signs and symptoms such as hyposmia, generalized myoclonus, fluctuating changes in level of consciousness, opsoclonus, and an asymmetric hypokinetic-rigid syndrome with ocular abnormalities.6 [123I]-ioflupane dopamine transporter SPECT imaging confirmed a bilateral decrease in presynaptic dopamine uptake in the brain, asymmetrically involving both putamina.6 This case suggests that SARS-CoV-2 may gain access to the central nervous system and affected midbrain structures, leading to neurologic manifestations.6 The significant improvement in parkinsonian symptoms without specific treatment further supported the involvement of the central nervous system by SARS-CoV-2. Another case involved a 34-year-old woman who was diagnosed with COVID-19-induced acute disseminated encephalomyelitis, which is an autoimmune disorder of the central nervous system.8 The patient experienced a constellation of movement disorders (predominantly myoclonus) followed by encephalopathy. She was finally diagnosed with COVID-19-induced acute disseminated encephalomyelitis, which responded to intravenous methylprednisolone and intravenous immunoglobulin.8 These two cases highlight the varied and potential mechanisms behind the neurological manifestations.

Long COVID, also known as post-COVID-19 condition, is a term used for symptoms persisting long after the acute phase of the infection. It refers to a range of symptoms that persist long after the acute phase of the infection has resolved. These symptoms have been reported even in patients who experienced mild initial infections. A cross-sectional cohort study conducted across two urban Spanish hospitals and general practitioner centers from March 20 to April 30, 2020, involving 360 hospitalized and 308 non-hospitalized patients with acute SARS-CoV-2 infection during the pandemic's first wave, found that 59.7% of hospitalized and 67.5% of non-hospitalized patients experienced at least one post-COVID-19 symptom two years following the infection.15

Headaches and sleep disturbances are frequently reported among long COVID sufferers. These symptoms can be debilitating and considerably impact individuals’ well-being. Other neurological symptoms include dizziness, a loss of taste and smell that persists long after other symptoms have subsided, and neuropathic pain or tingling sensations. Notably, the cognitive impairment observed in some patients, colloquially termed ‘brain fog’ or ‘FADE-IN MEMORY’ (i.e., Fatigue, decreased Fluency, Attention deficit, Depression, Executive dysfunction, slowed INformation processing speed, and subcortical MEMORY impairment), is currently considered COVID-19's most devastating sequelae.16,17 It is characterized by decreased attention and concentration, executive dysfunction, memory impairment, and delayed information processing speed.16,17 Although we are still in the infancy of knowledge about the pathogenesis and treatment of this complication, cognitive exercises, memory training, and other rehabilitation techniques might help improve cognitive functions affected by brain fog. We should encourage patients to adopt a healthy lifestyle, including regular physical activity, a balanced diet, adequate sleep, and stress reduction techniques. Ongoing research into the pathophysiology of post-COVID brain fog is essential. Understanding the underlying mechanisms will aid in developing targeted therapies and improving patient outcomes.

Emerging theories in the field explore various aspects of the post-COVID-19 neurological manifestations. One theory posits that the virus may have a long-term effect on the brain's vascular system, contributing to an increased risk of neurological disorders in the future.18 Another theory, based on preliminary studies, suggests that COVID-19 might accelerate the onset of neurodegenerative diseases such as Alzheimer's in susceptible individuals.17 The potential for ‘viral persistence’ in the brain is another area of investigation.19 Some researchers are exploring the possibility that remnants of the virus or its RNA might remain in the brain, leading to chronic inflammation or other neurological issues over time.19

One significant study published in Brain, Behavior, and Immunity delved into the mechanisms behind these neurological impacts.20 The researchers found the ability of SARS-CoV-2 to cross the blood–brain barrier and induce neuroinflammation, a significant mechanism underlying cognitive impairments.20 The study also showed that two non-infective models of SARS-CoV-2 could cross the blood–brain barrier and induce neuroinflammation, even without productive infection.20 The ability of SARS-CoV-2 to cross the blood–brain barrier and induce neuroinflammation may place individuals at risk for long-term cognitive impairments.20

These studies and emerging theories highlight the complexity of COVID-19s impact on the nervous system. They underscore the need for ongoing research to fully understand the long-term neurological consequences of the virus and develop effective strategies for prevention and treatment. The evolution of these research findings will be crucial in guiding healthcare professionals in managing the neurological aspects of COVID-19 and preparing for potential long-term effects on public health.

Long COVID's neurological symptoms underscore the need for comprehensive care strategies that address not only the immediate impact of COVID-19 but also its long-term effects. As our understanding of long COVID evolves, it will be crucial for healthcare systems to adapt and support the growing number of individuals dealing with these chronic neurological consequences.

COVID-19s neurological manifestations present significant challenges for healthcare systems, such as:

  • a.

    Increased demand for neurological care: The surge in patients experiencing neurological symptoms, both acute and long-term, requires more resources and specialized care. Healthcare systems must adapt to address these needs, potentially straining already overburdened services.

  • b.

    Multidisciplinary approach: Managing the neurological effects of COVID-19 calls for a multidisciplinary approach involving internists, neurologists, psychiatrists, rehabilitation specialists, and primary care providers. This approach necessitates enhanced coordination and communication within healthcare systems.

  • c.

    Long-term monitoring and research: The long-term nature of some neurological symptoms means that patients may require ongoing monitoring and treatment. This scenario demands sustained research and the development of long-term care models.

  • d.

    Training and awareness: There is a need for increased training and awareness among healthcare professionals regarding the neurological manifestations of COVID-19 to ensure accurate diagnosis and appropriate management.

On the other hand, the neurological effects of COVID-19 extend beyond the healthcare system, influencing various societal aspects:

  • a.

    Workforce impact: Neurological symptoms like cognitive impairment and chronic fatigue significantly affect individuals’ ability to work. This impact can lead to decreased productivity, increased sick leaves, and challenges in workplace accommodations, impacting the overall economy.

  • b.

    Health-related quality of life: Persistent neurological symptoms can severely impact individuals, leading to difficulties in daily functioning, mental health issues, and reduced social interactions.

  • c.

    Mental health burden: The increased prevalence of neuropsychiatric conditions like anxiety and depression due to COVID-19 adds to the overall mental health burden on society. This burden necessitates expanded mental health services and support systems.

  • d.

    Public health policies: Understanding the neurological effects of COVID-19 is critical for shaping public health policies. These policies must encompass acute care, rehabilitation, and support for long-term conditions. Integrating mental health and neurological care into public health planning and emergency preparedness is essential.

Addressing all these challenges requires a holistic approach that integrates medical, psychological, and social support, ensuring that the needs of those affected are adequately met.

In conclusion, the neurological manifestations of COVID-19 have emerged as a significant aspect of the pandemic, extending far beyond the initial understanding of the virus as a primarily respiratory illness. Studies have highlighted a range of neurological symptoms associated with COVID-19, from headaches and dizziness to more severe conditions like strokes and cognitive impairments. These findings underscore the virus's profound impact on the nervous system, both in the acute phase and as part of long COVID, where symptoms persist long after the initial recovery.

The challenges these neurological effects pose are multifaceted, affecting healthcare systems and broader societal aspects. The need for a multidisciplinary approach in healthcare, increased research, and long-term patient monitoring is evident. Healthcare systems must adapt to address the rising demand for neurological and mental health care, and there is a pressing need for enhanced training and awareness among healthcare professionals.

Continued research is crucial for a deeper understanding of the mechanisms behind these neurological impacts and for developing effective treatments. These insights must inform public health policies, incorporating long-term care and rehabilitation strategies. Advocacy for greater public awareness and understanding of these issues is vital. As we navigate the ongoing challenges of the pandemic, a comprehensive approach that addresses both the physical and neurological health of individuals will be essential in mitigating the long-term impacts of COVID-19 on our societies.

Ethical approval

This article does not imply or imply studies in humans or animals.

Funding

There was no funding for the preparation of this article.

Conflict of interests

None declared.

Acknowledgments

J. Benito-León is supported by the National Institutes of Health, Bethesda, MD, USA (NINDS #R01 NS39422), the European Commission (grant ICT-2011-287739, NeuroTREMOR), the Spanish Health Research Agency (grant FIS PI12/01602 and grant FIS PI16/00451), the Recovery, Transformation and Resilience Plan of the Spanish Ministry of Science and Innovation (grant TED2021-130174B-C33, NETremor), and the Spanish Ministry of Science and Innovation (grant PID2022-138585OB-C33, Resonate).

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