Tag: long covid neurology

Stuttering-Like Dysfluencies as a Consequence of Long COVID-19

Abstract:

Purpose: We present two patients who developed neurogenic stuttering after long COVID-19 related to SARS-CoV-2 infection.

Methods and results: Both patients experienced both physical (e.g., fatigue) and cognitive difficulties, which led to impaired function of attention, lexical retrieval, and memory consolidation. Both patients had new-onset stuttering-like speech dysfluencies: Blocks and repetitions were especially evident at the initial part of words and sentences, sometimes accompanied by effortful and associated movements (e.g., facial grimaces and oro-facial movements). Neuropsychological evaluations confirmed the presence of difficulties in cognitive tasks, while neurophysiological evaluations (i.e., electroencephalography) suggested the presence of “slowed” patterns of brain activity. Neurogenic stuttering and cognitive difficulties were evident for 4-5 months after negativization of SARS-CoV-2 nasopharyngeal swab, with gradual improvement and near-to-complete recovery.

Conclusions: It is now evident that SARS-CoV-2 infection may significantly involve the central nervous system, also resulting in severe and long-term consequences, even if the precise mechanisms are still unknown. In the present report, long COVID-19 resulted in neurogenic stuttering, as the likely consequence of a “slowed” metabolism of (pre)frontal and sensorimotor brain regions (as suggested by the present and previous clinical evidence). As a consequence, the pathophysiological mechanisms related to the appearance of neurogenic stuttering have been hypothesized, which help to better understand the broader and possible neurological consequences of COVID-19.

Source: Furlanis G, Busan P, Formaggio E, Menichelli A, Lunardelli A, Ajcevic M, Pesavento V, Manganotti P. Stuttering-Like Dysfluencies as a Consequence of Long COVID-19. J Speech Lang Hear Res. 2023 Feb 7:1-16. doi: 10.1044/2022_JSLHR-22-00381. Epub ahead of print. PMID: 36749838. https://pubs.asha.org/doi/10.1044/2022_JSLHR-22-00381 (Full text)

Autonomic dysfunction and postural orthostatic tachycardia syndrome in post-acute COVID-19 syndrome

Abstract:

The post-acute sequelae of COVID-19 present major problems for many patients, their physicians and the health-care system. They are unrelated to the severity of the initial infection, are often highly symptomatic and can occur after vaccination. Many sequelae involve cardiovascular autonomic dysfunction, with postural orthostatic tachycardia syndrome in 30% of individuals. Prognosis is unknown, and treatment is still unsatisfactory.

Source: Fedorowski A, Sutton R. Autonomic dysfunction and postural orthostatic tachycardia syndrome in post-acute COVID-19 syndrome. Nat Rev Cardiol. 2023 Feb 2:1–2. doi: 10.1038/s41569-023-00842-w. Epub ahead of print. PMID: 36732397; PMCID: PMC9893964. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9893964/ (Full text)

Long Covid and Neurodegenerative Disease

Abstract:

Brain fog with compromised ability to concentrate has been the most frequent Long Covid (LC) complaint. This is due to an increased TGF beta/IFN gamma with consequently increased bradykinin (BKN), especially in Caucasian females. Brain and lung blood vessels “leak.” This same ratio is increased in Alzheimer’s disease (AD), but decreased in Parkinson’s disease (PD), because CD4+ and CD8+ T cells are differentially affected by the invading associated viruses, e.g., SARS CoV2, HIV, ….

In Covid-19 CD147 receptors on immune cells are critical in generating the increased TGF beta/IFN gamma and those on endothelial cells, platelets, and erythrocytes are critical to the abnormal microvascular blood flow. ACE2 receptors on pneumocytes and enterocytes enable pulmonary and GI entry, initiating gut dysbiosis.

Epigenetics, methylation, magnesium, vitamin D, the B vitamins, and antioxidants suggest that these issues can be surmounted. Biochemical, physiologic, and epidemiologic data are analyzed to answer these questions. An LC model is presented and discussed in the context of the most recent research. Suggestions to avoid these and other worrisome concerns are included. Other topics discussed include estrogen, the gut microbiome, type 2 diabetes (T2D), and homocysteine.

Source: Chambers, P. Long Covid and Neurodegenerative Disease. Preprints 2023, 2023020027 (doi: 10.20944/preprints202302.0027.v1) https://www.preprints.org/manuscript/202302.0027/v1 (Full text available as PDF file)

 

Functional Neurological Disorder in people with Long-Covid: A Systematic Review

Abstract:

Background: Acute health events, including infections, can trigger the onset of functional neurological disorder (FND). We hypothesised that a proportion of people with long-COVID might be experiencing functional symptoms.

Methods: We performed a systematic review of studies containing original data on long-COVID. We reviewed the frequency and characteristics of neurological symptoms, looking for positive evidence suggesting an underlying functional disorder, and the hypothesised causes of long-COVID.

Results: We included 102 studies in our narrative synthesis. The most consistently reported neurological symptoms were cognitive difficulties, headaches, pain, dizziness, fatigue, sleep-related symptoms, and ageusia/anosmia. Overall, we found no evidence that any authors had systematically looked for positive features of FND. An exception were three studies describing temporal inconsistency. In general, the neurological symptoms were insufficiently characterised in order to support or refute a diagnosis of FND. Moreover, only 13 studies specifically focussed on long-COVID after mild infection, where the impact of confounders from the general effects of severe illness would be mitigated. Only one study hypothesised that some people with long-COVID might have a functional disorder, and another 8 studies a chronic fatigue syndrome-like response.

Discussion: Neurological symptoms are prevalent in long-COVID, but poorly characterised. We are struck by the similarities between some manifestations of long-COVID and functional disorders triggered by acute illnesses. Unfortunately, the current literature is plagued by confounders, including the mixing of patients with initial mild infection with those with severe acute medical complications. The hypothesis that long-COVID might in part correspond to a functional disorder remains untested.

Source: Teodoro T, Chen J, Gelauff J, Edwards MJ. Functional Neurological Disorder in people with Long-Covid: A Systematic Review. Eur J Neurol. 2023 Jan 31. doi: 10.1111/ene.15721. Epub ahead of print. PMID: 36719069. https://onlinelibrary.wiley.com/doi/10.1111/ene.15721 (Full text available as PDF file)

Mechanisms, Effects, and Management of Neurological Complications of Post-Acute Sequelae of COVID-19 (NC-PASC)

Abstract:

With a growing number of patients entering the recovery phase following infection with SARS-CoV-2, understanding the long-term neurological consequences of the disease is important to their care. The neurological complications of post-acute sequelae of SARS-CoV-2 infection (NC-PASC) represent a myriad of symptoms including headaches, brain fog, numbness/tingling, and other neurological symptoms that many people report long after their acute infection has resolved.
Emerging reports are being published concerning COVID-19 and its chronic effects, yet limited knowledge of disease mechanisms has challenged therapeutic efforts. To address these issues, we review broadly the literature spanning 2020–2022 concerning the proposed mechanisms underlying NC-PASC, outline the long-term neurological sequelae associated with COVID-19, and discuss potential clinical interventions.
Source: Ong IZ, Kolson DL, Schindler MK. Mechanisms, Effects, and Management of Neurological Complications of Post-Acute Sequelae of COVID-19 (NC-PASC). Biomedicines. 2023; 11(2):377. https://doi.org/10.3390/biomedicines11020377 https://www.mdpi.com/2227-9059/11/2/377

Long-COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): Potential neurophysiological biomarkers for these enigmatic entities

Since early in the pandemic, fatigue has been recognized as one of the most common persistent complaints in individuals infected with SARS-CoV-2, and constitutes one main symptom of the so-called long-COVID syndrome. The term fatigue refers to a sustained feeling of tiredness, which can be present at rest; it is not directly related to physical activity, but can be exacerbated disproportionally by exertion.

Survivors of other recent coronavirus outbreaks, such as severe acute respiratory syndrome (SARS) in 2002 and Middle East respiratory syndrome (MERS) in 2012 also developed chronic fatigue. These ‘post-infectious’ fatigue syndromes, including long-COVID, resemble myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a chronic disorder of unknown physiopathology characterized by fatigue, post-exertional malaise, chronic muscle or skeletal pain, and cognitive impairment (‘brain fog’).

Despite it being an extremely disabling symptom, the results of routine examinations are often normal in patients complaining of lingering fatigue, a phenomenon that has also led the medical-scientific community to view this condition with skepticism.

In physiology, fatigue is defined as a decrease in the maximal force-generating capacity of a muscle during exercise. It may result from peripheral processes distal to the neuromuscular junction and from central processes controlling the discharge rate of motoneurons.

Physical fatigue related to both central and peripheral nervous system dysfunction can be assessed with neurophysiological techniques including transcranial magnetic stimulation (TMS) of the motor cortex, electrical stimulation of nerve trunks or intramuscular nerve fibers, and electromyography (EMG) recordings.

In August 2021, the first study showing myopathic changes in quantitative EMG (qEMG) in long-COVID patients with musculoskeletal symptoms was published (). The same authors demonstrated myopathic qEMG features and histopathological changes in skeletal muscle biopsies in 16 patients with complaints of fatigue, myalgia, and/or weakness persisting for up to 14 months after mild to moderate COVID-19 (). The wide variety of histological changes in this study, including muscle fiber atrophy, mitochondrial changes, subsarcolemmal accumulation, inflammation, capillaries alteration, suggests that skeletal muscle may be a major target of SARS-CoV-2.

On the opposite side of the neuroaxis, dysfunction in the activity of the primary motor cortex and reduced corticomotor output may underlie fatigue.

The first TMS study on motor cortex physiology was conducted on 12 patients with long-term fatigue and ‘brain fog’ after severe COVID-19 (). It showed disruption of the physiological mechanism of post-contraction depression, i.e., the transient decrease in the amplitude of motor evoked potentials and prolongation of the cortical silent period after a fatiguing motor task, which depends on cortical inhibitory mechanisms and has the protective purpose of preventing muscle overload. Impairment of intracortical GABAergic activity, as indicated by disrupted long-interval intracortical inhibition, together with reduced excitability of the primary motor cortex was subsequently demonstrated in 67 patients with fatigue and cognitive difficulties after mild COVID-19 (). These patients also presented selective deficits in executive functions. Based on these findings, the authors proposed that fatigue depends on altered excitability and neurotransmission within the motor cortex at rest, and on abnormal reactivity to muscular exercise. In addition, reduced executive control may contribute to exacerbating poor physical performance and fatigue tolerance ().

These objective neurophysiological and histopathological findings showed for the first time that fatigue may due both to pathological processes in the muscle (the effector of the motor command) and/or at the site of motor command processing. The mechanisms of chronic dysfunction of neural and muscle cells may be sustained by inflammation or dysimmunity, triggered by SARS-COV-2 in predisposed individuals.

Immune-inflammatory and neuroendocrine mechanisms have also been implicated in ME/CFS. In particular, increased production of autoantibodies against CNS and autonomic nervous system targets, such as the ß2 adrenergic receptor (ß2AdR), have been documented (). As ß2AdR are important vasodilators, their functional disturbance may result in vasoconstriction and hypoxemia with chronic muscular and cerebral hypoperfusion.

The COVID-19 pandemic is likely to greatly increase the incidence of ME/CFS, so that the intense research on the pathophysiological mechanisms of fatigue in long-COVID can help to shed light on a poorly understood and underestimated syndrome.

Source: Versace V, Tankisi H. Long-COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): Potential neurophysiological biomarkers for these enigmatic entities. Clin Neurophysiol. 2023 Jan 13;147:58-59. doi: 10.1016/j.clinph.2023.01.001. Epub ahead of print. PMID: 36657309; PMCID: PMC9838078. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9838078/ (Full text)

Cortical Grey matter volume depletion links to neurological sequelae in post COVID-19 “long haulers”

Abstract:

Objective: COVID-19 (SARS-CoV-2) has been associated with neurological sequelae even in those patients with mild respiratory symptoms. Patients experiencing cognitive symptoms such as “brain fog” and other neurologic sequelae for 8 or more weeks define “long haulers”. There is limited information regarding damage to grey matter (GM) structures occurring in COVID-19 “long haulers”. Advanced imaging techniques can quantify brain volume depletions related to COVID-19 infection which is important as conventional Brain MRI often fails to identify disease correlates. 3-dimensional voxel-based morphometry (3D VBM) analyzes, segments and quantifies key brain volumes allowing comparisons between COVID-19 “long haulers” and normative data drawn from healthy controls, with values based on percentages of intracranial volume.

Methods: This is a retrospective single center study which analyzed 24 consecutive COVID-19 infected patients with long term neurologic symptoms. Each patient underwent Brain MRI with 3D VBM at median time of 85 days following laboratory confirmation. All patients had relatively mild respiratory symptoms not requiring oxygen supplementation, hospitalization, or assisted ventilation. 3D VBM was obtained for whole brain and forebrain parenchyma, cortical grey matter (CGM), hippocampus, and thalamus.

Results: The results demonstrate a statistically significant depletion of CGM volume in 24 COVID-19 infected patients. Reduced CGM volume likely influences their long term neurological sequelae and may impair post COVID-19 patient’s quality of life and productivity.

Conclusion: This study contributes to understanding effects of COVID-19 infection on patient’s neurocognitive and neurological function, with potential for producing serious long term personal and economic consequences, and ongoing challenges to public health systems.

Source: Rothstein TL. Cortical Grey matter volume depletion links to neurological sequelae in post COVID-19 “long haulers”. BMC Neurol. 2023 Jan 17;23(1):22. doi: 10.1186/s12883-023-03049-1. PMID: 36647063; PMCID: PMC9843113. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9843113/ (Full text)

Long COVID: Is There a Role for Antidepressants?

Abstract:

Two years into this historic pandemic, the scientific and healthcare communities continue to learn a great deal regarding COVID-19. The most urgent and immediate focus has been on vaccine development for disease prevention/mitigation and on identification of effective therapeutic interventions for acute phase of illness. However, attention is increasingly being placed on formulating treatment strategies for individuals who are post-COVID-19 and experiencing a syndrome of persistent symptoms that is being referred to as long COVID.

One strategy is to repurpose drugs which have been approved for other conditions and subsequently assess their safety and efficacy when applied to COVID-19. In this light, antidepressant medications have garnered attention amidst evidence supporting anti-inflammatory and anti-viral properties.

In this article, we present purported anti-inflammatory mechanisms of antidepressants, review studies appearing in the literature to date regarding antidepressants and acute COVID-19, and discuss the utility of antidepressants as a potential therapeutic resource for long COVID.

Source: Rivas-Vázquez R, Carrazana EJ, Blais MA, Rey GJ, RivasVázquez E, Quintana AA. Long COVID: Is There a Role for Antidepressants? Neurol Curr Res. 2022;2(3):1019. https://www.medtextpublications.com/open-access/long-covid-is-there-a-role-for-antidepressants-1249.pdf (Full text)

The relationship between chronic immune response and neurodegenerative damage in long COVID-19

Abstract:

In the past two years, the world has faced the pandemic caused by the severe acute respiratory syndrome 2 coronavirus (SARS-CoV-2), which by August of 2022 has infected around 619 million people and caused the death of 6.55 million individuals globally. Although SARS-CoV-2 mainly affects the respiratory tract level, there are several reports, indicating that other organs such as the heart, kidney, pancreas, and brain can also be damaged.

A characteristic observed in blood serum samples of patients suffering COVID-19 disease in moderate and severe stages, is a significant increase in proinflammatory cytokines such as interferon-α (IFN-α), interleukin-1β (IL-1β), interleukin-2 (IL-2), interleukin-6 (IL-6) and interleukin-18 (IL-18), as well as the presence of autoantibodies against interferon-α (IFN-α), interferon-λ (IFN-λ), C-C motif chemokine ligand 26 (CCL26), CXC motif chemokine ligand 12 (CXCL12), family with sequence similarity 19 (chemokine (C-C motif)-like) member A4 (FAM19A4), and C-C motif chemokine ligand 1 (CCL1). Interestingly, it has been described that the chronic cytokinemia is related to alterations of blood-brain barrier (BBB) permeability and induction of neurotoxicity.

Furthermore, the generation of autoantibodies affects processes such as neurogenesis, neuronal repair, chemotaxis and the optimal microglia function. These observations support the notion that COVID-19 patients who survived the disease present neurological sequelae and neuropsychiatric disorders. The goal of this review is to explore the relationship between inflammatory and humoral immune markers and the major neurological damage manifested in post-COVID-19 patients.

Source: Elizalde-Díaz JP, Miranda-Narváez CL, Martínez-Lazcano JC, Martínez-Martínez E. The relationship between chronic immune response and neurodegenerative damage in long COVID-19. Front Immunol. 2022 Dec 16;13:1039427. doi: 10.3389/fimmu.2022.1039427. PMID: 36591299; PMCID: PMC9800881. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9800881/ (Full text)

Brain correlates of subjective cognitive complaints in COVID-19 survivors: A multimodal magnetic resonance imaging study

Abstract:

Cognitive impairment represents a leading residual symptom of COVID-19 infection, which lasts for months after the virus clearance. Up-to-date scientific reports documented a wide spectrum of brain changes in COVID-19 survivors following the illness’s resolution, mainly related to neurological and neuropsychiatric consequences.

Preliminary insights suggest abnormal brain metabolism, microstructure, and functionality as neural under-layer of post-acute cognitive dysfunction. While previous works focused on brain correlates of impaired cognition as objectively assessed, herein we investigated long-term neural correlates of subjective cognitive decline in a sample of 58 COVID-19 survivors with a multimodal imaging approach.

Diffusion Tensor Imaging (DTI) analyses revealed widespread white matter disruption in the sub-group of cognitive complainers compared to the non-complainer one, as indexed by increased axial, radial, and mean diffusivity in several commissural, projection and associative fibres. Likewise, the Multivoxel Pattern Connectivity analysis (MVPA) revealed highly discriminant patterns of functional connectivity in resting-state among the two groups in the right frontal pole and in the middle temporal gyrus, suggestive of inefficient dynamic modulation of frontal brain activity and possible metacognitive dysfunction at rest.

Beyond COVID-19 actual pathophysiological brain processes, our findings point toward brain connectome disruption conceivably translating into clinical post-COVID cognitive symptomatology. Our results could pave the way for a potential brain signature of cognitive complaints experienced by COVID-19 survivors, possibly leading to identify early therapeutic targets and thus mitigating its detrimental long-term impact on quality of life in the post-COVID-19 stages.

Source: Paolini M, Palladini M, Mazza MG, Colombo F, Vai B, Rovere-Querini P, Falini A, Poletti S, Benedetti F. Brain correlates of subjective cognitive complaints in COVID-19 survivors: A multimodal magnetic resonance imaging study. Eur Neuropsychopharmacol. 2022 Dec 12;68:1-10. doi: 10.1016/j.euroneuro.2022.12.002. Epub ahead of print. PMID: 36640728. https://www.sciencedirect.com/science/article/pii/S0924977X22009130 (Full study)