A new study by Houston Methodist researchers reviews the emerging insights and evidence that suggest COVID-19 infections may have both short- and long-term neurological effects.
Led by corresponding authors Joy Mitra, Ph.D., Instructor, and Muralidhar L. Hegde, Ph.D., Professor of Neurosurgery, with the Division of DNA Repair within the Center for Neuroregeneration at the Houston Methodist Research Institute, the research team described their findings in an article titled “SARS-CoV-2 and the Central Nervous System: Emerging Insights into Hemorrhage-Associated Neurological Consequences and Therapeutic Considerations” in the journal Ageing Research Reviews.
COVID-19 is known to invade and infect the brain, among other major organs. While a lot of research has been done to help us understand the evolution, infection and pathology of the disease, there is still a great deal that remains unclear about the long-term effects, especially on the brain.
The coronavirus infection can cause long-term and irreversible neurodegenerative diseases, particularly in the elderly and other vulnerable populations. Several brain imaging studies on COVID-19 victims and survivors have confirmed the formation of microbleed lesions in deeper brain regions related to our cognitive and memory functions.
In this review study, researchers have critically evaluated the possible chronic neuropathological outcomes in aging and comorbid populations if timely therapeutic intervention is not implemented.
Microbleeds are emerging neuropathological signatures frequently identified in people suffering from chronic stress, depressive disorders, diabetes and age-associated comorbidities. Based on their earlier findings, the investigators discuss how COVID-19-induced microhemorrhagic lesions may exacerbate DNA damage in affected brain cells, resulting in neuronal senescence and activation of cell death mechanisms, which ultimately impact brain microstructure-vasculature.
These pathological phenomena resemble hallmarks of neurodegenerative conditions like Alzheimer’s and Parkinson’s diseases and are likely to aggravate advanced-stage dementia, as well as cognitive and motor deficits.
The effects of COVID-19 infection on various aspects of the central nervous system are currently being studied. For instance, 20-30% of COVID-19 patients report a lingering psychological condition known as “brain fog” where individuals suffer from symptoms such as memory loss, difficulty in concentrating, forgetting daily activities, difficulty in selecting the right words, taking longer than usual time to complete a regular task, disoriented thought processes and emotional numbness.
More severe long-term effects analyzed in the Houston Methodist review article include predispositions for Alzheimer’s, Parkinson’s and related neurodegenerative diseases, as well as cardiovascular disorders due to internal bleeding and blood clotting-induced lesions in the part of the brain that regulates our respiratory system, following the COVID-19 symptoms.
The study also suggests various strategies to improve some of these long-term neuropsychiatric and neurodegenerative outcomes, as well as outlines the importance of the therapeutic regimen of the “nanozyme” in combination with various FDA-approved drugs that may prove successful to fight against this catastrophic disease.
However, given the ever-evolving nature of this field, associations like the ones described in this review show the fight against COVID-19 is far from over, say the investigators, and reinforce the message that getting vaccinated and maintaining proper hygiene are key in trying to prevent such long-term and detrimental consequences.
Neurological clinical manifestations of SARS-CoV-2 infection
Despite not being in the list of the main diagnostic criteria, in the bibliography were reported considerable neurological clinical manifestations as consequence of the SARS-CoV-2 infection, being currently most of them under study. In order to summarized these neurological symptoms, first there were extracted the most reported and best cited. Second, these were organized in the following categories: neurological diffuse or miscellaneous, cerebrovascular, motor, sensorial, cognitive symptoms (Fig. 1). The information regarding each category is summarized in the following paragraphs.
Leading neurological manifestations in COVID-19. Symptoms are classified in miscellaneous, cerebrovascular, motor, sensorial and cognitive.
Diffuse or miscellaneous neurological symptoms in SARS-CoV-2 infection
Retrospective and prospective case series about patients with COVID-19 reported the presence of diffuse neurological symptoms in levels up to 36,4% of them (L. Mao et al., 2020), being the headache, encephalopathies, encephalitis, confusion, dizziness and seizure the most cited. Following, it is summarized the information about these symptoms:
a) Headache: Although there is not a concern about their exact prevalence, it has been pointed to be a frequent symptom in COVID-19 patients. The maximum percentage reported was in a prospective study, which included 130 patients and described 74.6% of presence of headache in these infected patients, having the 24.7% of them severe headache (Caronna et al., 2020). The published frequencies are varied, for example a meta-analysis with 104.751 infected patients from 17 studies indicates a headache rate of 25.2%. These studies are based in samples of patients with moderate severity of COVID-19.
However, in severe COVID-19 patients the headache frequency reported was about 27.83%, including 309 COVID-19 cases from 15 studies (Mutiawati et al., 2020). Surprisingly, in relation with this symptom it was also indicated that the duration of the clinical symptoms of COVID-19 in patients with headache is shorter (23.9 ± 11.6 days) than in infected patients without headache (31.2 ± 12.0 days), being significant (p = 0.028) and suggesting that the headache could be an alarm sign, to protect the body against the virus through the activation of the immune system (Caronna et al., 2020). It was also described an increase in mortality concomitant to the onset of the headache in severe infected patients (Shapiro et al., 2021).
Physiologically, the headache has migraine-like features, probably reflecting an activation of the trigeminovascular system, direct by the virus or indirect as a consequence of the systemic inflammation. Authors suggest a relationship with the symptom of anosmia frequently cited. Because the virus would act not only in the olfactory epithelium causing loss of smell, but also in the branches of the trigeminal nerve, very close to the nostrils through which the virus could cross brain barrier causing neuroinvasion (Bolay et al., 2020). Therefore, the direct invasion of trigeminal nerve endings in the nasal or oral cavity by the virus seems one of the most reasonable mechanisms underlying headache and anosmia/ageusia connection. Besides, SARS-CoV-2 is a neurotropic virus and viral particles have been observed in the human brain (Ding et al., 2004)(Gu et al., 2005).
Therefore, it is highly likely that SARS-CoV-2 may also enter to the nervous system via the cranial nerves (Izquierdo-Dominguez et al., 2020)(Baysal-Kirac and Uysal, 2020). Although the SARS-COV-2 trans-synaptic transfer has not been still proven, the possibility of a trans-synaptic route was documented for other coronaviruses (Mengeling et al., 1972). Entrance from the nasal cavity to the olfactory bulb, then spreading to the brainstem via the piriform cortex with both passive diffusion and axonal transport has been demonstrated (Desforges et al., 2019)(Uygun et al., 2020).
Therefore, although there is still matter of study, the neurotropic ability of the virus, could not only affect the trigeminal nerve but also the other olfactive nerves, by their anatomical proximity, together with the loss of sensitive functionality when there is a trigeminal inflammation in presence of nasal congestion symptoms due to the respiratory infection, supporting altogether the relationship between nasal sensitive symptoms and headache. Besides, nasal obstruction and rhinorrhea were frequently reported accompanied by anosmia and ageusia. Accordingly, there were found significant levels of anosmia and ageusia in patients with headache (54.6% vs. 18.2% in headache vs control group; p < 0.0001) (Caronna et al., 2020).
b) Encephalopathy and encephalitis: encephalopathy is defined as an alteration of one or more brain functions (e.g. altered level of consciousness, seizures, confusional state, acute focal deficits) caused by a systemic disease (e.g. anoxia, ischemia, metabolic disorders, etc.), and is typically reversible (Al Mazrouei et al., 2020). Encephalitis is characterized by typically focal brain alterations, with or without meningeal involvement, with different possible causes (infectious, inflammatory, autoimmune, paraneoplastic, etc.), and can be confirmed with histology studies or through the detection of inflammatory cells in the cerebrospinal fluid (CSF) (Blinder and Lewerenz, 2019). The clinical features are fever, headache and symptoms of brain dysfunction.
Infectious etiology is common, therefore in patients with COVID-19 there was also observed the presence of this neurological complication with these cited manifestations, being frequently classified insight the category of infectious toxic encephalopathy, also known as acute toxic encephalitis. In this sense, in a Spanish registry of 232 COVID-19 patients, there was found a frequency of 21.9% of encephalopathy. Manifesting mild or moderate confusion (33% of cases) in moderated infected patients and severe encephalopathy or coma (9.8% of cases) in Intensive Care Unit (ICU) patients, being these symptoms detected after 8.02 days of infection (Abenza Abildúa et al., 2021). Brain MRI studies were performed in 47% of these patients, detecting alterations in 7.8% of them. Besides, EEG studies were also performed in 41.3% of these patients, indicating alterations in 61.9% of them (Abenza Abildúa et al., 2021).
However, other smallest studies pointed encephalopathies in lower frequencies, as for example in a retrospective study developed in Geneva, it is reported 4,4% (Uginet et al., 2021). The Spanish registry cited before found viral RNA of SARS-CoV-2 in cerebrospinal fluid (CSF) of patients with encephalitis in only one case (Abenza Abildúa et al., 2021) and the study from Geneve did not find in any of the patient (Uginet et al., 2021). In agreement, other studies that identified cases of encephalopathies did not detected the virus in CSF, or detected it with low frequencies 7%, suggesting that viral neuroinvasion by SARS-CoV-2 it is not the exclusive mechanism of action (Helms et al., 2020). This point should be studied with accuracy, because there is not already consensus. In this regard, researchers suggest the hypothesis that the neurological manifestations due to COVID-19 infection are triggered by a combination of direct and an indirect mechanisms (Lucchese, 2020), pointed the disturbed brain homeostasis, the inflammatory state and the vascular dysfunction, the main causes for example of the endotheliitis (Uginet et al., 2021).
c) Confusion: signs of confusion were also detected in COVID-19 patients, involving delirium, acute or chronic confusional state, acute brain failure or acute encephalopathy impaired consciousness, disorientation, lack of attention, agitation and other cognitive problems (Soiza and Myint, 2019). One sign of encephalopathy reported was mild or moderate confusion (Abenza Abildúa et al., 2021). The frequencies arrive up to levels of 27% (Pranata et al., 2021) or 33% (Abenza Abildúa et al., 2021). As it is described delirious patients are more likely to have longer hospital stay and to develop in-hospital complications and ICU hospitalization comparing with non-delirious patients that are ambulatory or hospitalized in infectious departments prepared for COVID-19 patients (Cipriani et al., 2020). In some cases delirium may precede symptoms as headache, fever and cough, being the presence of delirium associated with an increased risk of mortality in ICU or not ICU hospitalized older adults with COVID-19 (Pranata et al., 2021).
d) Dizziness: it is also presented in COVID-19 infected patients, although it is not a specific COVID-19 symptom, because its leading cause include, acute labyrinthitis, vestibular neuritis, acute otitis media or secondary to stroke following COVID-19. Furthermore, this symptom is reported as the initial presentation of COVID-19 illness, thereupon during a moderate severity phase, with frequencies from 2.13% (Saniasiaya and Kulasegarah, 2021), arriving also up to a maximum of 17% in a series of 214 infected patients (Mao Li et al., 2020, Li et al., 2020, Li et al., 2020).
Therefore, dizziness requires a deep investigation to determine its leading cause. Among the postulated mechanisms causing dizziness are the direct neuroinvasion by the union of the virus with the angiotensin-converting enzyme 2 receptors (ACE2) found in the capillary endothelium of the brain (Baig et al., 2020). ACE2 is expressed in a wide variety of tissues, including the brain and most of the cardiovascular-relevant tissues, and the current consensus is that the distribution of this protein is ubiquitous. In brain ACE2 is widespread throughout different regions, for example present in nuclei involved in the central regulation of cardiovascular functions like the cardio-respiratory neurons of the brainstem, as well as in non-cardiovascular areas such as the motor cortex and raphe. Activation of ACE2 receptor promotes vasodilation, antiproliferation and antihypertrophy.
Therefore, it constitutes a target in the treatment of the hypertension and other cardiovascular diseases with impact in brain functionality (Xia and Lazartigues, 2008). Other postulated cause of dizziness is the indirect effect of the hypoxia, hypercoagulopathy, as well as immune-mediated insult during COVID-19 infection (Saniasiaya and Kulasegarah, 2021). These authors emphasize that dizziness should not be taken lightly as it has been proven to be a notable clinical manifestation among COVID-19 patients. Dizziness also occurs in patients with encephalopathy, concomitant with headache (Romero-Sánchez et al., 2020), possibly because the virus affects mechanisms involved in the triggering of all these symptoms, such as the inflammation of the neural nerves, hypoxia, hypercoagulopathy and the general replay of the brain against the pathogen (Saniasiaya and Kulasegarah, 2021).
e) Seizure: is a paroxysmal alteration of the neurologic function caused by the excessive, hypersynchronous discharge of neurons in the brain. The term epileptic seizure is used to distinguish a seizure caused by abnormal neuronal firing from a nonepileptic event, such as a psychogenic seizure (Stafstrom and Carmant, 2015). In COVID-19 the onset of seizures seems to be occasional and reported with low frequencies, beginning from 0.5% (Mao Li et al., 2020) up to 9% in small series (Liu et al., 2020). These studies pointed an indirect effect, arguing that the seizure could be triggered by fever and hyperthermia, which can disrupt the blood brain barrier (BBB) (Nikbakht et al., 2020). Because extreme hyperthermia increases the acute activation of glial cells and the BBB permeability (Kiyatkin and Sharma, 2009). Furthermore, a severe disease course or the advanced disease stages for example in ICU hospitalized patients could result for example in hypoxic encephalopathy, cerebrovascular events and cytokine storm, which may trigger the development of acute seizure (Sohal and Mansur, 2020). Patients who had seizure needed to be hospitalized not necessarily in ICU, but usually for a long in-hospital stay. Besides, they had four times more probability to die than patients without seizures, suggesting that this kind of neurological complication may be an important contributor to the morbidity and mortality associated with COVID-19 (Kuroda, 2021). This aspect is under study principally in the context of epilepsy, because the effect of COVID-19 on individuals with this neurological disease remains unclear.
Cerebrovascular symptoms in SARS-CoV-2 infection
Acute cerebrovascular symptoms remain one of the most serious neurologic complications observed in COVID-19 patients, being more frequent in severe or ICU hospitalized than in non-severe or not hospitalized patients (Bridwell et al., 2020). Although some cases were reported, fortunately it seems that their onset is infrequent, being published low level of frequency, e.g. 0.2% in a study of 21.483 hospitalized patients with COVID-19 registered in the COVID-19 Cardiovascular Disease registry of the American Heart Association (Leasure et al., 2021), and also 0.2% in a retrospective study with a sample size of 85.645 patients in the USA (Qureshi et al., 2021). In severe patients are also reported low levels 1.3% (Qureshi et al., 2021), up to a maximum of 6% of frequency of acute cerebrovascular diseases (Yaghi et al., 2020).
The type of cerebrovascular symptoms published so far are ischemic stroke, intracerebral hemorrhage, and cerebral venous thrombosis; being the stroke one of the most reported, with frequency rates from 2.5% to 6%, with a large majority of them being acute ischemic stroke, causing ICU hospitalization (Leasure et al., 2021). It is suggested that the comorbidities like hypertension, atrial fibrillation, hyperlipidemia, congestive heart failure or diabetes, were present in patients with acute ischemic stroke. In fact, COVID-19 is characterized as a predominantly prothrombotic disease with elevated D-dimer, higher Sequential Organ Failure Assessment (SOFA) score, high fibrinogen levels, but only mildly decreased antithrombin levels and microvascular thrombosis rather than a bleeding diathesis (Gao et al., 2020)(C. Wu et al., 2020)(Yang et al., 2020). Therefore, the plausible mechanism that causes these ischemic processes is the so called “sepsis-induced coagulopathy” (Abbas et al., 2021).
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. For clinical operationalization, organ dysfunction can be represented by an increase in the SOFA score of 2 points or more (Singer et al., 2016). Early phase of sepsis is characterized by hypercoagulability due to tissue factor expression on circulating monocytes and microparticles, increased fibrinogen plasma concentration, platelet activation and subsequent dysfunction, and hypofibrinolysis/fibrinolysis shutdown (Sun, 2006)(Adamzik et al., 2012). Tissue factor expression on circulating monocytes and microparticles is triggered by pathogen toxins and other pathogen-associated molecular patterns via NF-kB activation and subsequent induction of plasminogen activator inhibitor type 1 and proinflammatory cytokines such as interleukin-6 (IL-6) (Mussbacher et al., 2019)(Liu et al., 2017) and neutrophil extracellular traps (NETs). NETs are extracellular webs of chromatin, microbicidal proteins, and oxidant enzymes that are released by neutrophils to contain infections, including cell-free DNA. All these molecules are elevated in severe COVID-19 patients receiving mechanical ventilation in ICU hospitalized, and it strongly correlates with acute phase reactants, including CRP, D-dimer and LDH.
These NETs have the potential to propagate inflammation and microvascular thrombosis (Zuo et al., 2020). Whether extracellular RNA derived from SARS-CoV-2 contributes to the hypercoagulability seen in COVID-19 is not still known (Görlinger et al., 2020). Furthermore, other authors affirm that the risk of mortality increase with the occurrence of acute ischemic stroke in patients with COVID-19 (Abbas et al., 2021), especially when comorbidities are present (Qureshi et al., 2021). Intracerebral hemorrhage has been also reported (Agarwal et al., 2020), with emphasis in the elderly and in ICU hospitalized COVID-19 patients, being categorized as a rare manifestation with a high risk of mortality (Abboud et al., 2020; Yanan Li et al., 2020), and described up to rates of 59% of lethality (Abbas et al., 2021). This symptom in some cases is accompanied by severe immune thrombocytopenia following upper respiratory tract infection (Magdi and Rahil, 2019) or multiple microhemorrhages (e.g. intraparenchymal hemorrhage, subarachnoid hemorrhage and subdural hematoma), and finally sometimes accompanied by cognitive declined (Magdi and Rahil, 2019). It is required to elucidate the causes, the risk and the outcome of the cerebrovascular complications through studies using large sample sizes.
reference link :https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8629776/
Original Research: Open access.
“SARS-CoV-2 and the central nervous system: Emerging insights into hemorrhage-associated neurological consequences and therapeutic considerations” by Joy Mitra et al. Ageing Research Reviews
