Tag: long covid neurology

Immunometabolic rewiring in long COVID patients with chronic headache

Abstract:

Almost 20% of patients with COVID-19 experience long-term effects, known as post-COVID condition or long COVID. Among many lingering neurologic symptoms, chronic headache is the most common. Despite this health concern, the etiology of long COVID headache is still not well characterized. Here, we present a longitudinal multi-omics analysis of blood leukocyte transcriptomics, plasma proteomics and metabolomics of long COVID patients with chronic headache. L

ong COVID patients experienced a state of hyper-inflammation prior to chronic headache onset and maintained persistent inflammatory activation throughout the progression of chronic headache. Metabolomic analysis also revealed augmented arginine and lipid metabolisms, skewing towards a nitric oxide-based pro-inflammation. Furthermore, metabolisms of neurotransmitters including serotonin, dopamine, glutamate, and GABA were markedly dysregulated during the progression of long COVID headache.

Overall, these findings illustrate the immuno-metabolomics landscape of long COVID patients with chronic headache, which may provide insights to potential therapeutic interventions.

Source: Foo SS, Chen W, Jung KL, Azamor T, Choi UY, Zhang P, Comhair SA, Erzurum SC, Jehi L, Jung JU. Immunometabolic rewiring in long COVID patients with chronic headache. bioRxiv [Preprint]. 2023 Mar 6:2023.03.06.531302. doi: 10.1101/2023.03.06.531302. PMID: 36945569; PMCID: PMC10028820. https://www.biorxiv.org/content/10.1101/2023.03.06.531302v1.full (Full text)

Neurological Dysfunction in Long COVID Should Not Be Labelled as Functional Neurological Disorder

Abstract:

There have been suggestions that Long COVID might be purely functional (meaning psychological) in origin. Labelling patients with neurological dysfunction in Long COVID as having functional neurological disorder (FND) in the absence of proper testing may be symptomatic of that line of thought. This practice is problematic for Long COVID patients, as motor and balance symptoms have been reported to occur in Long COVID frequently.
FND is characterized by the presentation of symptoms that seem neurological but lack compatibility of the symptom with a neurological substrate. Although diagnostic classification according to the ICD-11 and DSM-5-TR is dependent predominantly on the exclusion of any other medical condition that could account for the symptoms, current neurological practice of FND classification allows for such comorbidity. As a consequence, Long COVID patients with motor and balance symptoms mislabeled as FND have no longer access to Long COVID care, whereas treatment for FND is seldom provided and is ineffective.
Research into underlying mechanisms and diagnostic methods should explore how to determine whether motor and balance symptoms currently diagnosed as FND should be considered one part of Long COVID symptoms, in other words, one component of symptomatology, and in which cases they correctly represent FND. Research into rehabilitation models, treatment and integrated care are needed, which should take into account biological underpinnings as well as possible psychological mechanisms and the patient perspective.
Source: Van der Feltz-Cornelis CM, Moriarty AS, Strain WD. Neurological Dysfunction in Long COVID Should Not Be Labelled as Functional Neurological Disorder. Viruses. 2023; 15(3):783. https://doi.org/10.3390/v15030783 https://www.mdpi.com/1999-4915/15/3/783 (Full text)

Severe Course of COVID-19 and Long-COVID-19 in Children: Difficulties in Diagnosis

Abstract:

The question of COVID-19 and long-COVID-19 course in children remains unsolved. This infection in children, which is associated with COVID-19, can vary from asymptomatic to systemic damage of various systems. Multisystem inflammatory syndrome in children, associated with SARS-CoV-2 (MIS-C), is a serious condition in children and adolescents after experiencing COVID-19.
Published data on MIS-C have indicated that the inflammation can be registered in the gastrointestinal tract (60–100%), as well as in cardiovascular (80%), nervous (29–58%), and respiratory (21–65%) systems. However, with the changing characteristics of SARS-CoV-2, the manifestations of COVID-19 and long-COVID-19 in children have also been changing. Currently, there is no clear understanding of the development of severe COVID-19 and MIS-C in children, especially after being exposed to patients with COVID-19.
We presented two new clinical courses of multisystem inflammatory syndrome in children with severe multisystem damage after close contact to relatives with COVID-19 or long-COVID-19. Thus, high-risk children, who are positive for SARS-CoV-2 infection after contact with COVID-19 patients, should be clinically managed during the first few months. The identification of the disease complexity requires the involvement of neurologists, cardiologists, and other specialists.
Source: Vasichkina E, Kofeynikova O, Fetisova S, Starshinova AY, Sheyanova E, Vershinina T, Ryzhkov A, Skripnik A, Alekseeva D, Nechaeva E, Glushkova A, Kudlay D, Pervunina T, Starshinova A. Severe Course of COVID-19 and Long-COVID-19 in Children: Difficulties in Diagnosis. Life. 2023; 13(3):781. https://doi.org/10.3390/life13030781 https://www.mdpi.com/2075-1729/13/3/781 (Full text)

Not myopathic, but autonomic changes in patients with long-COVID syndrome: a case series

Abstract:

Introduction: Neurological sequelae following SARS-CoV-2 infection still represent a serious concern both for neurologists and neuroscientists. In our paper, we investigated pain, myalgia, and fatigue as symptoms in long-COVID patients with an electrophysiological approach, comprising the evaluation of sympathetic skin responses (SSRs) and quantitative electromyography (qEMG).

Materials and methods: Twelve patients were enrolled (mean age, 47.7 ± 11.6 years), referred to our attention because of myalgia, pain, or muscle cramps, which persisted about 6 months after the diagnosis of SARS-CoV-2 infection. They underwent conventional electroneurography (ENG), needle electromyography (EMG), and SSRs; moreover, qEMG was performed by sampling at least 20 motor unit potentials (20-30 MUPs) during weak voluntary contraction in deltoid and tibialis anterior muscles. The mean duration, amplitude, and percentage of polyphasic potentials were assessed and compared with healthy and age-matched volunteers.

Results: ENG did not disclose significant changes compared to healthy subjects; needle EMG did not reveal denervation activity. In addition, qEMG showed MUPs similar to those recorded in healthy volunteers in terms of polyphasia (deltoid: p = 0.24; TA: p = 0.35), MUP area (deltoid: p = 0.45; TA: p = 0.44), mean duration (deltoid: p = 0.06; TA: p = 0.45), and amplitude (deltoid: p = 0.27; TA: p = 0.63). SSRs were not recordable from lower limbs in seven patients (58%) and from the upper ones in three of them (25%).

Conclusion: Our data suggest an involvement of the autonomic system, with a focus on cholinergic efferent sympathetic activity, without any evidence of myopathic changes.

Source: Bocci T, Bertini A, Campiglio L, Botta S, Libelli G, Guidetti M, Priori A. Not myopathic, but autonomic changes in patients with long-COVID syndrome: a case series. Neurol Sci. 2023 Apr;44(4):1147-1153. doi: 10.1007/s10072-023-06637-8. Epub 2023 Feb 3. PMID: 36735149; PMCID: PMC9896447. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9896447/ (Full study)

Neuropathology and Neurological Manifestations in ME/CFS and Long COVID with focus on Post-Exertional Symptom Exacerbation: a Literature Review

Summary:

Many of the people that get infected with the Coronavirus develop long-lasting complaints and are diagnosed with Long COVID after the acute infection is gone. These complains can last several months or years and include fatigue, cognitive impairment, sleeping problems and post-exertional symptom exacerbation (PESE). Research shows that COVID-19 patients with an acute infection have abnormalities in their brain, which could potentially lead to long-lasting neurological problems and symptoms. However, although many researchers are trying to uncover the underlying mechanisms, Long COVID is still very new.
The underlying mechanisms causing and maintaining the disease are therefore unclear. A large group of Long COVID patients resembles patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) in terms of symptoms and, in many cases, the viral trigger of the disease. A core symptom of ME/CFS is PESE, which is uncommon in other fatiguing illnesses, but frequently seen in Long COVID patients. PESE involves an abnormal worsening of symptoms and cognitive and physical functions after any type of normal activity. Because of the large symptom overlap and lack of knowledge regarding PESE, underlying brain-mechanisms associated with Long COVID and ME/CFS in general as well as after physical exertion were investigated.
The findings of this review indicate that ME/CFS is associated with several abnormalities in the brain which are also proposed to be present in Long COVID patients. Such abnormalities include inflammation of the brain, shrinkage of the brain and less blood flow to the brain. After physical exertion, these abnormalities might be exacerbated in ME/CFS patients. This results in a brain that needs to work harder than the healthy brain to complete a task. It is demonstrated by increased brain activity in several brain regions after physical exertion and general symptom exacerbation. Since the two diseases seem to have a large overlap in symptoms and underlying brain-mechanisms, this finding might apply to patients with long COVID as well. Importantly, Long COVID seems to consist of different subgroups of which a large part fulfills the criteria for ME/CFS.
Treatment and therapy for ME/CFS patients is therefore likely transferable to this subgroup of Long COVID patients, with explicit attention towards the PESE phenomenon. More research is needed to uncover the underlying mechanisms as well as correct treatment approach of these diseases. Future research should take subgroups of Long COVID into account.
Source: Rodenburg, Sanne. Neuropathology and Neurological Manifestations in ME/CFS and Long COVID with focus on Post-Exertional Symptom Exacerbation: a Literature Review. Master Thesis, Utrecht University. March 14, 2023. https://studenttheses.uu.nl/bitstream/handle/20.500.12932/43647/Rodenburg_7433050_Neuropathology%20and%20neurological%20manifestations%20in%20MECFS%20and%20Long%20COVID%20with%20focus%20on%20PESE.pdf (Full text)

Pathogenesis Underlying Neurological Manifestations of Long COVID Syndrome and Potential Therapeutics

Abstract:

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.
Source: Leng A, Shah M, Ahmad SA, Premraj L, Wildi K, Li Bassi G, Pardo CA, Choi A, Cho S-M. Pathogenesis Underlying Neurological Manifestations of Long COVID Syndrome and Potential Therapeutics. Cells. 2023; 12(5):816. https://doi.org/10.3390/cells12050816 (Full text)

Effect of Repetitive Transcranial Magnetic Stimulation on Long Coronavirus Disease 2019 with Fatigue and Cognitive Dysfunction

Abstract:

Objectives: There is no established treatment for chronic fatigue and various cognitive dysfunctions (brain fog) caused by long coronavirus disease 2019 (COVID-19). We aimed to clarify the effectiveness of repetitive transcranial magnetic stimulation (rTMS) for treating these symptoms.

Methods: High-frequency rTMS was applied to occipital and frontal lobes in 12 patients with chronic fatigue and cognitive dysfunction 3 months after severe acute respiratory syndrome coronavirus 2 infection. Before and after ten sessions of rTMS, Brief Fatigue Inventory (BFI), Apathy Scale (AS), and Wechsler Adult Intelligence Scale-fourth edition (WAIS4) were determined and N-isopropyl-p-[123I]iodoamphetamine single photon emission computed tomography (SPECT) was performed.

Results: Twelve subjects completed ten sessions of rTMS without adverse events. The mean age of the subjects was 44.3 ± 10.7 years, and the mean duration of illness was 202.4 ± 114.5 days. BFI, which was 5.7 ± 2.3 before the intervention, decreased significantly to 1.9 ± 1.8 after the intervention. The AS was significantly decreased after the intervention from 19.2 ± 8.7 to 10.3 ± 7.2. All WAIS4 sub-items were significantly improved after rTMS intervention, and the full-scale intelligence quotient increased from 94.6 ± 10.9 to 104.4 ± 13.0. Hypoperfusion in the bilateral occipital and frontal lobes observed on SPECT improved in extent and severity after ten sessions of rTMS.

Conclusions: Although we are still in the early stages of exploring the effects of rTMS, the procedure has the potential for use as a new non-invasive treatment for the symptoms of long COVID.

Source: Sasaki N, Yamatoku M, Tsuchida T, Sato H, Yamaguchi K. Effect of Repetitive Transcranial Magnetic Stimulation on Long Coronavirus Disease 2019 with Fatigue and Cognitive Dysfunction. Prog Rehabil Med. 2023 Feb 28;8:20230004. doi: 10.2490/prm.20230004. PMID: 36861061; PMCID: PMC9968785. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9968785/ (Full text)

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

Abstract:

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. The 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.

Source: Wojcik GM, Shriki O, Kwasniewicz L, Kawiak A, Ben-Horin Y, Furman S, Wróbel K, Bartosik B, Panas E. Investigating brain cortical activity in patients with post-COVID-19 brain fog. Front Neurosci. 2023 Feb 9;17:1019778. doi: 10.3389/fnins.2023.1019778. PMID: 36845422; PMCID: PMC9947499. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9947499/ (Full text)

Identification of the pathogenic relationship between Long COVID and Alzheimer’s disease by bioinformatics methods

Abstract:

Background: The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused an unprecedented global health crisis. Although many Corona Virus Disease 2019 (COVID-19) patients have recovered, the long-term consequences of SARS-CoV-2 infection are unclear. Several independent epidemiological surveys and clinical studies have found that SARS-CoV-2 infection and Long COVID are closely related to Alzheimer’s disease (AD). This could lead to long-term medical challenges and social burdens following this health crisis. However, the mechanism between Long COVID and AD is unknown.

Methods: Genes associated with Long COVID were collected from the database. Two sets of AD-related clinical sample datasets were collected in the Gene Expression Omnibus (GEO) database by limiting screening conditions. After identifying the differentially expressed genes (DEGs) of AD, the significant overlapping genes of AD and Long COVID were obtained by taking the intersection. Then, four kinds of analyses were performed, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analysis, protein-protein interaction (PPI) analysis, identification of hub genes, hub gene verification and transcription factors (TFs) prediction.

Results: A total of 197 common genes were selected for subsequent analysis. GO and KEGG enrichment analysis showed that these genes were mainly enriched in multiple neurodegenerative disease related pathways. In addition, 20 important hub genes were identified using cytoHubba. At the same time, these hub genes were verified in another data set, where 19 hub gene expressions were significantly different in the two diseases and 6 hub genes were significantly different in AD patients of different genders. Finally, we collected 9 TFs that may regulate the expression of these hub genes in the Transcriptional Regulatory Relationships Unraveled by Sentence-based Text mining (TRUSST) database and verified them in the current data set.

Conclusion: This work reveals the common pathways and hub genes of AD and Long COVID, providing new ideas for
the pathogenic relationship between these two diseases and further mechanism research.

Source:

Structural brain changes in patients with post-COVID fatigue: a prospective observational study

Summary:

Background: Post-COVID syndrome is a severe long-term complication of COVID-19. Although fatigue and cognitive complaints are the most prominent symptoms, it is unclear whether they have structural correlates in the brain. We therefore explored the clinical characteristics of post-COVID fatigue, describe associated structural imaging changes, and determine what influences fatigue severity.

Methods: We prospectively recruited 50 patients from neurological post-COVID outpatient clinics (age 18–69 years, 39f/8m) and matched non-COVID healthy controls between April 15 and December 31, 2021. Assessments included diffusion and volumetric MR imaging, neuropsychiatric, and cognitive testing. At 7.5 months (median, IQR 6.5–9.2) after the acute SARS-CoV-2 infection, moderate or severe fatigue was identified in 47/50 patients with post-COVID syndrome who were included in the analyses. As a clinical control group, we included 47 matched multiple sclerosis patients with fatigue.

Findings: Our diffusion imaging analyses revealed aberrant fractional anisotropy of the thalamus. Diffusion markers correlated with fatigue severity, such as physical fatigue, fatigue-related impairment in everyday life (Bell score) and daytime sleepiness. Moreover, we observed shape deformations and decreased volumes of the left thalamus, putamen, and pallidum. These overlapped with the more extensive subcortical changes in MS and were associated with impaired short-term memory. While fatigue severity was not related to COVID-19 disease courses (6/47 hospitalised, 2/47 with ICU treatment), post-acute sleep quality and depressiveness emerged as associated factors and were accompanied by increased levels of anxiety and daytime sleepiness.

Interpretation: Characteristic structural imaging changes of the thalamus and basal ganglia underlie the persistent fatigue experienced by patients with post-COVID syndrome. Evidence for pathological changes to these subcortical motor and cognitive hubs provides a key to the understanding of post-COVID fatigue and related neuropsychiatric complications.

Source: Josephine Heine, et al. Structural brain changes in patients with post-COVID fatigue: a prospective observational study. The Lancet, VOLUME 58, 101874, APRIL 2023.  Published: February 27, 2023 DOI: https://doi.org/10.1016/j.eclinm.2023.101874 (Full text)