COVID-19 Associated Brain Fog and Neurocognitive Assessment

BACKGROUND/AIMS: In this study, we aimed to make detailed neurocognitive assessments of patients who presented with brain fog after coronavirus disease-2019 (COVID-19) infection and to investigate their complaints after one-year of follow-up. MATERIALS AND METHODS: Patients who had COVID-19, which was not severe enough to require intensive care, and who subsequently applied to neurology due to cognitive complaints were included in this study. A neurocognitive test battery was applied to those patients who agreed to detailed examination (n=16). This battery consisted of the following tests: mini-mental test, enhanced cued recall test, phonemic fluency, categorical fluency, digit span, counting the months backwards, clock-drawing, arithmetic operations, trail-making, cube copying, intersecting pentagons, and the interpretation of proverbs and similes. At one year, the patients were called by phone and questioned as to whether their cognitive complaints had persisted. Those patients with ongoing complaints were invited to the hospital and re-evaluated via cognitive tests. The results are presented in comparison with age-matched healthy controls (n=15). RESULTS: Almost all of the patients' scores were within the "normal" range. The Spontaneous recall of the patients was statistically significantly lower than the controls (p=0.03). Although there were decreases in executive functions and central processing speed (trail making-A, trail making-B and reciting the months backwards tests) in the patient group, these differences were not statistically significant (p=0.07;p=0.14 and p=0.22, respectively) compared to the controls. We observed that the cognitive complaints of the patients had disappeared by the one-year follow-up. CONCLUSION: In our patients with brain fog, most of whom had mild COVID-19, we observed that among all cognitive functions, memory domain was most affected compared to the controls. At the one-year follow-up, COVID-related brain fog had disappeared.

Near-infrared photobiomodulation therapy for rehabilitation of patients with long COVID

About 80% of the patients recovering from COVID-19 have inflammation symptoms, like brain fog, myopathy, myalgia, muscle weariness, headache, mental tiredness, asthenia, adynamia, dizziness, tinnitus, hearing loss, telogenic effluvium and mood disturbances. Here, we demonstrate how transcranial and systemic photobiomodulation using near-infrared LEDs emitting 850 nm wavelength light enhanced cognition and reduced pain. Participants were separated into transcranial photobiomodulation with near-infrared LEDs (850 nm, 10W, 10 minutes), photobiomodulation with a punctual cutaneous application (850nm, 10W, 10-40 minutes), and both treatments. All patients underwent 10-day treatments at least. © 2023 SPIE.

Effects of Multidisciplinary Rehabilitation Enhanced with Neuropsychological Treatment on Post-Acute SARS-CoV-2 Cognitive Impairment (Brain Fog): An Observational Study.

Concentration and memory impairment (named "brain fog") represents a frequent and disabling neuropsychological sequela in post-acute COVID-19 syndrome (PACS) patients. The aim of this study was to assess whether neurocognitive function could improve after a multidisciplinary rehabilitation program enhanced with individualized neuropsychological treatment. A prospective monocentric registry of PACS patients consecutively admitted to our Rehabilitation Unit was created. The Montreal Cognitive Assessment (MoCA) was used to assess cognitive impairment at admission and discharge. A total of sixty-four (64) PACS patients, fifty-six (56) of them with brain fog, were treated with a day-by-day individualized psychological intervention of cognitive stimulation (45 min) on top of a standard in-hospital rehabilitation program. The mean duration of the acute-phase hospitalization was 55.8 ± 25.8 days and the mean in-hospital rehabilitation duration was 30 ± 10 days. The mean age of the patients was 67.3 ± 10.4 years, 66% of them were male, none had a previous diagnosis of dementia, and 66% of the entire sample had experienced severe COVID-19. At admission, only 12% of the patients had normal cognitive function, while 57% showed mild, 28% moderate, and 3% severe cognitive impairment. After psychological treatment, a significant improvement in the MoCA score was found (20.4 ± 5 vs. 24.7 ± 3.7; p < 0.0001) as a result of significant amelioration in the following domains: attention task (p = 0.014), abstract reasoning (p = 0.003), language repetition (p = 0.002), memory recall (p < 0.0001), orientation (p < 0.0001), and visuospatial abilities (p < 0.0001). Moreover, the improvement remained significant after multivariate analysis adjusted for several confounding factors. Finally, at discharge, 43% of the patients with cognitive impairment normalized their cognitive function, while 4.7% were discharged with residual moderate cognitive impairment. In conclusion, our study provides evidence of the effects of multidisciplinary rehabilitation enhanced with neuropsychological treatment on improvement in the cognitive function of post-acute COVID-19 patients.

Brain fog in long COVID limits function and health status, independently of hospital severity and preexisting conditions.

Importance: The U.S. government has named post-acute sequelae of COVID-19 (longCOVID) as influential on disability rates. We previously showed that COVID-19 carries a medical/functional burden at 1 year, and that age and other risk factors of severe COVID-19 were not associated with increased longCOVID risk. Long-term longCOVID brain fog (BF) prevalence, risk factors and associated medical/functional factors are poorly understood, especially after mild SARS-CoV-2 infection. Methods: A retrospective observational cohort study was conducted at an urban tertiary-care hospital. Of 1,032 acute COVID-19 survivors from March 3-May 15, 2020, 633 were called, 530 responded (59.2 ± 16.3 years, 44.5% female, 51.5% non-White) about BF prevalence, other longCOVID, post-acute ED/hospital utilization, perceived health/social network, effort tolerance, disability. Results: At approximately 1-year, 31.9% (n = 169) experienced BF. Acute COVID-19 severity, age, and premorbid cardiopulmonary comorbidities did not differ between those with/without BF at 1 year. Patients with respiratory longCOVID had 54% higher risk of BF than those without respiratory longCOVID. BF associated with sleep disturbance (63% with BF vs.29% without BF, p < 0.0001), shortness of breath (46% vs.18%, p < 0.0001), weakness (49% vs.22%, p < 0.0001), dysosmia/dysgeusia (12% vs.5%, p < 0.004), activity limitations (p < 0.001), disability/leave (11% vs.3%, p < 0.0001), worsened perceived health since acute COVID-19 (66% vs.30%, p < 0.001) and social isolation (40% vs.29%, p < 0.02), despite no differences in premorbid comorbidities and age. Conclusions and relevance: A year after COVID-19 infection, BF persists in a third of patients. COVID-19 severity is not a predictive risk factor. BF associates with other longCOVID and independently associates with persistent debility.

Reported neurological symptoms after severe acute respiratory syndrome coronavirus type 2 infection: A systematic diagnostic approach.

BACKGROUND AND PURPOSE: Following increasing demands of patients with suspected neurological symptoms after infection with severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), the Department of Neurology at the Medical University of Vienna established a new outpatient clinic to systematically assess, diagnose, and document neurological complaints potentially associated with a prior SARS-CoV-2 infection. METHODS: The data presented here include prospectively collected 156 outpatients from May 2021 to April 2022. Patients underwent semistandardized interviewing about symptoms with reported onset after SARS-CoV-2 infection, neurological examination, and comprehensive diagnostic workup. RESULTS: Reported new onset symptoms after infection included fatigue (77.6%), subjective cognitive impairment (72.4%), headache (47.7%), loss of smell and/or taste (43.2%), and sleep disturbances (42.2%). Most patients had a mild coronavirus disease (COVID-19) disease course (84%) and reported comorbidities (71%), of which the most frequent were psychiatric disorders (34%). Frequency of symptoms was not associated with age, sex, or severity of COVID-19 course. A comprehensive diagnostic workup revealed no neurological abnormalities in the clinical examination, or electrophysiological or imaging assessments in the majority of patients (n = 143, 91.7%). Neuropsychological assessment of a subgroup of patients (n = 28, 17.9%) showed that cognitive impairments in executive functions and attention, anxiety, depression, and somatization symptoms were highly common. CONCLUSIONS: In this systematic registry, we identified fatigue, cognitive impairment, and headache as the most frequently reported persisting complaints after SARS-CoV-2 infection. Structural neurological findings were rare. We also suspect a link between the growing burden of the COVID-19 pandemic on personal lives and the increase in reported neurological and psychiatric complaints.

Long COVID brain fog and muscle pain are associated with longer time to clearance of SARS-CoV-2 RNA from the upper respiratory tract during acute infection.

Introduction: The incidence of long COVID is substantial, even in people with mild to moderate acute COVID-19. The role of early viral kinetics in the subsequent development of long COVID is largely unknown, especially in individuals who were not hospitalized for acute COVID-19. Methods: Seventy-three non-hospitalized adult participants were enrolled within approximately 48 hours of their first positive SARS-CoV-2 RT-PCR test, and mid-turbinate nasal and saliva samples were collected up to 9 times within the first 45 days after enrollment. Samples were assayed for SARS-CoV-2 using RT-PCR and additional SARS-CoV-2 test results were abstracted from the clinical record. Each participant indicated the presence and severity of 49 long COVID symptoms at 1-, 3-, 6-, 12-, and 18-months post-COVID-19 diagnosis. Time from acute COVID-19 illness onset to SARS-CoV-2 RNA clearance greater or less than 28 days was tested for association with the presence or absence of each of 49 long COVID symptoms at 90+ days from acute COVID-19 symptom onset. Results: Self-reported brain fog and muscle pain at 90+ days after acute COVID-19 onset were negatively associated with viral RNA clearance within 28 days of acute COVID-19 onset with adjustment for age, sex, BMI ≥ 25, and COVID vaccination status prior to COVID-19 (brain fog: aRR 0.46, 95% CI 0.22-0.95; muscle pain: aRR 0.28, 95% CI 0.08-0.94). Participants reporting higher severity brain fog or muscle pain at 90+ days after acute COVID-19 onset were less likely to have cleared SARS-CoV-2 RNA within 28 days. The acute viral RNA decay trajectories of participants who did and did not later go on to experience brain fog 90+ days after acute COVID-19 onset were distinct. Discussion: This work indicates that at least two long COVID symptoms - brain fog and muscle pain - at 90+ days from acute COVID-19 onset are specifically associated with prolonged time to clearance of SARS-CoV-2 RNA from the upper respiratory tract during acute COVID-19. This finding provides evidence that delayed immune clearance of SARS-CoV-2 antigen or greater amount or duration of viral antigen burden in the upper respiratory tract during acute COVID-19 are directly linked to long COVID. This work suggests that host-pathogen interactions during the first few weeks after acute COVID-19 onset have an impact on long COVID risk months later.

Autonomic Dysfunction Related to Postacute SARS-CoV-2 Syndrome.

Persistence of symptoms beyond the initial acute phase of coronavirus disease-2019 (COVID-19) is termed postacute SARS-CoV-2 (PASC) and includes neurologic, autonomic, pulmonary, cardiac, psychiatric, gastrointestinal, and functional impairment. PASC autonomic dysfunction can present with dizziness, tachycardia, sweating, headache, syncope, labile blood pressure, exercise intolerance, and "brain fog." A multidisciplinary team can help manage this complex syndrome with nonpharmacologic and pharmacologic interventions.

Persistent olfactory dysfunction in mild COVID-19 patients: A descriptive study of the characteristics and association with other symptoms.

Introduction: Post-COVID olfactory dysfunction continues to be studied due to the controversy of the mechanisms involved. The aim was to investigate the olfactory dysfunctions in association with other post-COVID symptoms. Material and methods: Observational, descriptive and single-center study. The patients had confirmed mild COVID-19 and subjective olfactory dysfunction of more than a month of evolution, which was assessed by Sniffin' Sticks Olfactory Test. Results: A total of 86 patients participated. The mean age was 37.2 years (SD 9.82). 70.9% reported parosmia and 46.5% symptoms of brain fog. A pathological test result was obtained in 72.1% of the participants. The most failed pen was 11 (apple) in 76.7%. Anosmia of pen 15 (anise) was reported more frequently in 24.4% and cacosmia of pen 9 (garlic) in 27.9%. We observed a significant association between patients who reported parosmias and brain fog (RR 2.18; p = 0.018), also between parosmia and phantosmia (RR 6.042; p < 0.001). Conclusion: There is some pathological selectivity for certain test pens, a higher prevalence of cognitive symptoms and many patients with combined parosmia and brain fog.

Introducción: La alteración olfatoria post-COVID continúa en estudio por la controversia sobre los mecanismos implicados. El objetivo de este estudio es caracterizar las alteraciones olfatorias y su relación con otros síntomas post-COVID. Material y métodos: Estudio unicéntrico, observacional y descriptivo. Los pacientes tuvieron infección por COVID-19 leve confirmada y disfunción olfatoria subjetiva de más de un mes de evolución, evaluada con el Sniffin' Sticks Olfatory Test. Resultados: Se seleccionaron 86 pacientes. La edad media fue de 37,2 años (DE 9,82). El 70,9% refirieron parosmia y el 46,5% niebla mental. Se obtuvo un test patológico en el 72,1% de los participantes. El lápiz más fallado fue el número 11 (manzana), en el 76,7%. La anosmia fue reportada más frecuentemente con el lápiz 15 (anís) y la cacosmia con el lápiz 9 (ajo) en el 27,9%. Observamos una asociación significativa entre pacientes que refieren parosmias y niebla mental (RR 2,18; p = 0,018) y entre parosmia y fantosmia (RR 6,042; p < 0,001). Conclusión: Se observa anosmia y cacosmia selectiva para algunos olores testados. Hay una alta prevalencia de síntomas cognitivos, más frecuentes en pacientes con parosmia.

Successful Treatment of Post-COVID-19 ADHD-like Syndrome: A Case Report.

Despite inattention being one of the most common symptoms of Post-COVID-19 Syndrome (PCS), there is a gap in the literature regarding its treatment. This report presents a case of attentional symptoms and fatigue that emerged after the SARS-CoV-2 infection. The symptoms were similar to ADHD in adults, although the 61-year-old patient had never experienced inattention symptoms before. The patient was initially treated with Methylphenidate and then Lisdexamfetamine. Both were adapted to the needs and treatment response presented by the patient. After several changes in the therapeutic regimen, including the addition of Bupropion, the patient achieved remission of his symptoms. This case highlights the importance of treating PCS inattention and fatigue as an ADHD-like syndrome, despite the evident different etiology of symptoms. It would be necessary to replicate these findings to confirm our results, thus benefiting other patients currently affected by this syndrome.

Depression and brain fog as long-COVID mental health consequences: Difficult, complex and partially successful treatment of a 72-year-old patient-A case report.

SARS-CoV-2 (COVID-19) infection can result in long-term health consequences i.e., long COVID. The clinical manifestations of long COVID include depression, anxiety, brain fog with cognitive dysfunction, memory issues, and fatigue. These delayed effects of COVID-19 occur in up to 30% of people who have had an acute case of COVID-19. In this case report, a 72-year-old, fully vaccinated patient without pre-existing somatic or mental illnesses, or other relevant risk factors was diagnosed with long COVID. Nine months following an acute COVID-19 infection, the patient's depressive symptoms improved, but memory and concentration difficulties persisted, and the patient remains unable to resume work. These long-term symptoms are possibly linked to micro-hemorrhages detected during examinations of the patient's brain following COVID-19 infection. Patient treatment was complex, and positive results were attained via antidepressants and non-drug therapies e.g., art, music, drama, dance and movement therapy, physiotherapy, occupational therapy, and psychotherapy.

An Unusual Case of Blackout in a COVID-19 Patient: COVID-19 Brain Fog.

This case report highlights a unique case of brain fog in a COVID-19 patient suggesting COVID-19's neurotropic nature. COVID-19 is associated with a long-COVID syndrome that presents with cognitive decline and fatigue. Recent studies show the emergence of a novel syndrome known as post-acute COVID syndrome or long COVID, which constitutes a variety of symptoms that continue for four weeks following the onset of a COVID-19 diagnosis. Numerous post-COVID patients experience both short and long-lasting symptoms affecting several organs, including the brain, which includes being unconscious, bradyphrenia, or amnesia. This long COVID status comprises of "brain fog", which, coupled with neuro-cognitive effects, has a significant role in prolonging the recovery phase. The pathogenesis of brain fog is currently unknown. One of the leading causes might be the involvement of neuroinflammation due to mast cells stimulated by pathogenic and stress stimuli. This in turn, triggers the release of mediators that activate microglia, causing inflammation in the hypothalamus. Its ability to invade the nervous system through trans-neural or hematogenous mechanisms is possibly the chief cause behind the presenting symptoms. This case report highlights a unique case of brain fog in a COVID-19 patient suggesting COVID-19's neurotropic nature and how it may lead to neurologic complications such as meningitis, encephalitis, and Guillain-Barré syndrome.

Clinical experience with the alpha2A-adrenoceptor agonist, guanfacine, and N-acetylcysteine for the treatment of cognitive deficits in "Long-COVID19"

Background: Prolonged cognitive deficits ("brain fog") following COVID19 infection (long-COVID) are common and debilitating, yet there are currently no approved treatments. Cognitive impairment particularly targets the working memory and executive functions of the prefrontal cortex (PFC). The PFC has unusual neurotransmission and neuromodulation that render it vulnerable to stressors, and basic research has identified mechanisms that protect PFC connections. Based on the basic neuroscience data, we tried a combined open label treatment to bolster prefrontal function: the alpha2A-adrenoceptor agonist, guanfacine, which strengthens prefrontal connectivity, and the anti-oxidant, N- acetylcysteine (NAC), which protects mitochondria and reduces kynurenic acid blockade of NMDA receptors. Case report: Twelve patients with "brain fog" including difficulties in executive functions were treated with guanfacine (1mg, PO bedtime for the first month, increased to 2mg after 1 month, if well-tolerated) and 600 mg NAC daily. Guanfacine+NAC improved cognitive abilities in eight of the twelve patients;four patients discontinued therapy, two for unspecified reasons and two due to hypotension and/or dizziness, common side effects of guanfacine. Those who stayed on guanfacine+NAC reported improved working memory, concentration, and executive functions, including a resumption of normal workloads. One patient briefly stopped taking guanfacine due to a hypotensive episode and reported a return of cognitive deficits that abated with resumed guanfacine treatment. Conclusion(s): Although placebo-controlled trials will be needed to more rigorously demonstrate efficacy, as these agents have established safety, they may be immediately helpful in treating the large number of patients suffering from prolonged cognitive deficits following COVID19 infection.Copyright © 2022 The Author(s)

Cognitive symptoms after COVID-19

Introduction: SARS-CoV-2 infection frequently causes neurological symptoms. Cognitive alterations are among the most frequent symptoms, and may persist beyond the acute phase of infection. Method(s): We conducted a narrative review of the literature. Result(s): Hospitalised patients, and especially critically ill patients, are at greater risk of developing cognitive symptoms. Post-COVID-19 cognitive symptoms, unlike those associated with other viral illnesses, have been observed in patients with mild infection, and present some atypical features. Cognitive symptoms may last longer in COVID-19 than in other infectious processes, and more frequently affect young people. Post-COVID-19 cognitive symptoms share common features with those described in chronic fatigue syndrome, including a similar profile with affective symptoms. Brief screening tests for cognitive impairment present suboptimal diagnostic performance, and standardised criteria are needed to ensure correct diagnosis. Post-COVID-19 cognitive impairment can have a significant impact on the patient's quality of life and functional independence, regardless of other post-COVID-19 symptoms. Currently, no specific treatments have been approved for post-COVID-19 cognitive impairment, although cognitive stimulation may be useful in some patients. Conclusion(s): Post-COVID-19 cognitive symptoms are common and are often associated with other systemic symptoms. Neuropsychological evaluation may be useful for diagnosis and to quantify their severity and long-term prognosis. Detailed, and individualised assessment of cognitive impairment may enable the design of treatment plans.Copyright © 2021 Sociedad Espanola de Neurologia

Neurological complications of SARS-CoV-2 infection.

SARS-CoV-2 virus was first identified in 2019 in Wuhan (China) and is responsible for the ongoing COVID-19 pandemic. Although the virus causes mild, transient symptoms of an upper respiratory tract infection in most cases, it can also lead to severe pneumonia, respiratory failure and/or death. Approximately 85% of patients experience central and peripheral neurological symptoms. In the acute phase of the disease, ischaemic strokes, intracranial haemorrhages, meningitis and encephalitis, acute demyelinating diseases and acute inflammatory polyneuropathies may occur. However, mild neurological symptoms that can persist for months and significantly affect daily functioning are much more common. These include headache and dizziness, olfactory and gustatory dysfunction, mild cognitive disturbances, as well as depressive, anxiety, and sleep disorders. Some of them are encompassed by popular terms "post-covid syndrome" and "brain fog." The pathogenesis of neurological complications of SARS-CoV-2 infection is still not fully understood;overproduction of cytokines induced by viral infection may be of great importance. There is no causal treatment, while symptomatic treatment is of limited effectiveness. Primary prevention in the form of SARS-CoV-2 vaccinations is of great importance. In the following review, we would like to present the current knowledge on epidemiology, pathology, pathogenesis and treatment of neurological complications after SARS-CoV-2 infection. Further multi-centre, large-scale clinical studies are necessary to identify the exact pathogenetic mechanismsCopyright © 2022 Sawicka et al.

COVID-19 and cognitive functions.

COVID-19 affects not only somatic, but also psychological functions of a person. Cognitive disorder appears to be one of the most striking, although it is very inconsistent and there is a considerable interindividual variability in the cognitive impairment of different patients. The symptoms of cognitive disorder and fatigue syndrome are strongly intertwined with each other. The condition is often described as "brain fog". In most cases, it has a reversible character of a type of a mild disorder of cognitive functions. The causes are discussed - primarily inflammation, but also factors of a psychosocial nature.Copyright © 2023, Czech Medical Association J.E. Purkyne. All rights reserved.

Investigating brain cortical activity in patients with post-COVID-19 brain fog.

Brain fog is a kind of mental problem, similar to chronic fatigue syndrome, and appears about 3 months after the infection with COVID-19 and lasts up to 9 months. The maximum magnitude of the third wave of COVID-19 in Poland was in April 2021. The research referred here aimed at carrying out the investigation comprising the electrophysiological analysis of the patients who suffered from COVID-19 and had symptoms of brain fog (sub-cohort A), suffered from COVID-19 and did not have symptoms of brain fog (sub-cohort B), and the control group that had no COVID-19 and no symptoms (sub-cohort C). The aim of this article was to examine whether there are differences in the brain cortical activity of these three sub-cohorts and, if possible differentiate and classify them using the machine-learning tools. he dense array electroencephalographic amplifier with 256 electrodes was used for recordings. The event-related potentials were chosen as we expected to find the differences in the patients' responses to three different mental tasks arranged in the experiments commonly known in experimental psychology: face recognition, digit span, and task switching. These potentials were plotted for all three patients' sub-cohorts and all three experiments. The cross-correlation method was used to find differences, and, in fact, such differences manifested themselves in the shape of event-related potentials on the cognitive electrodes. The discussion of such differences will be presented; however, an explanation of such differences would require the recruitment of a much larger cohort. In the classification problem, the avalanche analysis for feature extractions from the resting state signal and linear discriminant analysis for classification were used. The differences between sub-cohorts in such signals were expected to be found. Machine-learning tools were used, as finding the differences with eyes seemed impossible. Indeed, the A&B vs. C, B&C vs. A, A vs. B, A vs. C, and B vs. C classification tasks were performed, and the efficiency of around 60-70% was achieved. In future, probably there will be pandemics again due to the imbalance in the natural environment, resulting in the decreasing number of species, temperature increase, and climate change-generated migrations. The research can help to predict brain fog after the COVID-19 recovery and prepare the patients for better convalescence. Shortening the time of brain fog recovery will be beneficial not only for the patients but also for social conditions.

Persistent olfactory dysfunction in mild COVID-19 patients: A descriptive study of the characteristics and association with other symptoms.

INTRODUCTION: Post-COVID olfactory dysfunction continues to be studied due to the controversy of the mechanisms involved. The aim was to investigate the olfactory dysfunctions in association with other post-COVID symptoms. MATERIAL AND METHODS: Observational, descriptive and single-center study. The patients had confirmed mild COVID-19 and subjective olfactory dysfunction of more than a month of evolution, which was assessed by Sniffin' Sticks Olfactory Test. RESULTS: A total of 86 patients participated. The mean age was 37.2 years (SD 9.82). 70.9% reported parosmia and 46.5% symptoms of brain fog. A pathological test result was obtained in 72.1% of the participants. The most failed pen was 11 (apple) in 76.7%. Anosmia of pen 15 (anise) was reported more frequently in 24.4% and cacosmia of pen 9 (garlic) in 27.9%. We observed a significant association between patients who reported parosmias and brain fog (RR 2.18; p=0.018), also between parosmia and phantosmia (RR 6.042; p<0.001). CONCLUSION: There is some pathological selectivity for certain test pens, a higher prevalence of cognitive symptoms and many patients with combined parosmia and brain fog.

Pathogenesis Underlying Neurological Manifestations of Long COVID Syndrome and Potential Therapeutics.

The development of long-term symptoms of coronavirus disease 2019 (COVID-19) more than four weeks after primary infection, termed "long COVID" or post-acute sequela of COVID-19 (PASC), can implicate persistent neurological complications in up to one third of patients and present as fatigue, "brain fog", headaches, cognitive impairment, dysautonomia, neuropsychiatric symptoms, anosmia, hypogeusia, and peripheral neuropathy. Pathogenic mechanisms of these symptoms of long COVID remain largely unclear; however, several hypotheses implicate both nervous system and systemic pathogenic mechanisms such as SARS-CoV2 viral persistence and neuroinvasion, abnormal immunological response, autoimmunity, coagulopathies, and endotheliopathy. Outside of the CNS, SARS-CoV-2 can invade the support and stem cells of the olfactory epithelium leading to persistent alterations to olfactory function. SARS-CoV-2 infection may induce abnormalities in innate and adaptive immunity including monocyte expansion, T-cell exhaustion, and prolonged cytokine release, which may cause neuroinflammatory responses and microglia activation, white matter abnormalities, and microvascular changes. Additionally, microvascular clot formation can occlude capillaries and endotheliopathy, due to SARS-CoV-2 protease activity and complement activation, can contribute to hypoxic neuronal injury and blood-brain barrier dysfunction, respectively. Current therapeutics target pathological mechanisms by employing antivirals, decreasing inflammation, and promoting olfactory epithelium regeneration. Thus, from laboratory evidence and clinical trials in the literature, we sought to synthesize the pathophysiological pathways underlying neurological symptoms of long COVID and potential therapeutics.