Tag: long covid neurology

Deficient GABABergic and glutamatergic excitability in the motor cortex of patients with long-COVID and cognitive impairment

Abstract:

Objective: Attention, working memory and executive processing have been reported to be consistently impaired in Neuro-Long coronavirus disease (COVID). On the hypothesis of abnormal cortical excitability, we investigated the functional state of inhibitory and excitatory cortical regulatory circuits by single “paired-pulse” transcranial magnetic stimulation (ppTMS) and Short-latency Afferent Inhibition (SAI).

Methods: We compared clinical and neurophysiological data of 18 Long COVID patients complaining of persistent cognitive impairment with 16 Healthy control (HC) subjects. Cognitive status was evaluated by means of the Montreal Cognitive Assessment (MoCA) and a neuropsychological evaluation of the executive function domain; fatigue was scored by the Fatigue Severity Scale (FSS). Resting motor threshold (RMT), the amplitude of the motor evoked potential (MEP), Short Intra-cortical Inhibition (SICI), Intra-cortical Facilitation (ICF), Long-interval Intracortical Inhibition (LICI) and Short-afferent inhibition (SAI) were investigated over the motor (M1) cortex.

Results: MoCA corrected scores were significantly different between the two groups (p = 0.023). The majority of the patients’ performed sub-optimally in the neuropsychological assessment of the executive functions. The majority (77.80%) of the patients reported high levels of perceived fatigue in the FSS. RMT, MEPs, SICI and SAI were not significantly different between the two groups. On the other hand, Long COVID patients showed a reduced amount of inhibition in LICI (p = 0.003) and a significant reduction in ICF (p < 0.001).

Conclusions: Neuro-Long COVID patients performing sub-optimally in the executive functions showed a reduction of LICI related to GABAb inhibition and a reduction of ICF related to glutamatergic regulation. No alteration in cholinergic circuits was found.

Significance: These findings can help to better understand the neurophysiological characteristics of Neuro-Long COVID, and in particular, motor cortex regulation in people with “brain fog”.

Source: Manganotti P, Michelutti M, Furlanis G, Deodato M, Buoite Stella A. Deficient GABABergic and glutamatergic excitability in the motor cortex of patients with long-COVID and cognitive impairment. Clin Neurophysiol. 2023 May 10;151:83-91. doi: 10.1016/j.clinph.2023.04.010. Epub ahead of print. PMID: 37210757; PMCID: PMC10170904. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10170904/ (Full text)

Long-Term Effects of SARS-CoV-2 in the Brain: Clinical Consequences and Molecular Mechanisms

Abstract:

Numerous investigations have demonstrated significant and long-lasting neurological manifestations of COVID-19. It has been suggested that as many as four out of five patients who sustained COVID-19 will show one or several neurological symptoms that can last months after the infection has run its course. Neurological symptoms are most common in people who are less than 60 years of age, while encephalopathy is more common in those over 60. Biological mechanisms for these neurological symptoms need to be investigated and may include both direct and indirect effects of the virus on the brain and spinal cord. Individuals with Alzheimer’s disease (AD) and related dementia, as well as persons with Down syndrome (DS), are especially vulnerable to COVID-19, but the biological reasons for this are not clear.
Investigating the neurological consequences of COVID-19 is an urgent emerging medical need, since close to 700 million people worldwide have now had COVID-19 at least once. It is likely that there will be a new burden on healthcare and the economy dealing with the long-term neurological consequences of severe SARS-CoV-2 infections and long COVID, even in younger generations. Interestingly, neurological symptoms after an acute infection are strikingly similar to the symptoms observed after a mild traumatic brain injury (mTBI) or concussion, including dizziness, balance issues, anosmia, and headaches. The possible convergence of biological pathways involved in both will be discussed. The current review is focused on the most commonly described neurological symptoms, as well as the possible molecular mechanisms involved.
Source: Granholm A-C. Long-Term Effects of SARS-CoV-2 in the Brain: Clinical Consequences and Molecular Mechanisms. Journal of Clinical Medicine. 2023; 12(9):3190. https://doi.org/10.3390/jcm12093190 https://www.mdpi.com/2077-0383/12/9/3190 (Full text)

Brain imaging and neuropsychological assessment of individuals recovered from a mild to moderate SARS-CoV-2 infection

Abstract:

As severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infections have been shown to affect the central nervous system, the investigation of associated alterations of brain structure and neuropsychological sequelae is crucial to help address future health care needs. Therefore, we performed a comprehensive neuroimaging and neuropsychological assessment of 223 nonvaccinated individuals recovered from a mild to moderate SARS-CoV-2 infection (100 female/123 male, age [years], mean ± SD, 55.54 ± 7.07; median 9.7 mo after infection) in comparison with 223 matched controls (93 female/130 male, 55.74 ± 6.60) within the framework of the Hamburg City Health Study.
Primary study outcomes were advanced diffusion MRI measures of white matter microstructure, cortical thickness, white matter hyperintensity load, and neuropsychological test scores. Among all 11 MRI markers tested, significant differences were found in global measures of mean diffusivity (MD) and extracellular free water which were elevated in the white matter of post-SARS-CoV-2 individuals compared to matched controls (free water: 0.148 ± 0.018 vs. 0.142 ± 0.017, P < 0.001; MD [10−3 mm2/s]: 0.747 ± 0.021 vs. 0.740 ± 0.020, P < 0.001). Group classification accuracy based on diffusion imaging markers was up to 80%. Neuropsychological test scores did not significantly differ between groups.
Collectively, our findings suggest that subtle changes in white matter extracellular water content last beyond the acute infection with SARS-CoV-2. However, in our sample, a mild to moderate SARS-CoV-2 infection was not associated with neuropsychological deficits, significant changes in cortical structure, or vascular lesions several months after recovery. External validation of our findings and longitudinal follow-up investigations are needed.

Significance:

In this case–control study, we demonstrate that non-vaccinated individuals recovered from a mild to moderate severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection show significant alterations of the cerebral white matter identified by diffusion-weighted imaging, such as global increases in extracellular free water and mean diffusivity. Despite the observed brain white matter alterations in this sample, a mild to moderate SARS-CoV-2 infection was not associated with worse cognitive functions within the first year after recovery. Collectively, our findings indicate the presence of a prolonged neuroinflammatory response to the initial viral infection. Further longitudinal research is necessary to elucidate the link between brain alterations and clinical features of post-SARS-CoV-2 individuals.
Source: Marvin Petersen, Felix Leonard Nägele, Carola Mayer, and Bastian Cheng. Brain imaging and neuropsychological assessment of individuals recovered from a mild to moderate SARS-CoV-2 infection. Neuroscience, May 23, 2023, 120 (22) e2217232120 https://doi.org/10.1073/pnas.2217232120 (Full text)

Perceived Cognitive Deficits in Patients With Symptomatic SARS-CoV-2 and Their Association With Post-COVID-19 Condition

Abstract:

Importance: Neuropsychiatric symptoms are common in acute SARS-CoV-2 infection and in post-COVID-19 condition (PCC; colloquially known as long COVID), but the association between early presenting neuropsychiatric symptoms and PCC is unknown.

Objective: To describe the characteristics of patients with perceived cognitive deficits within the first 4 weeks of SARS-CoV-2 infection and the association of those deficits with PCC symptoms.

Design, setting, and participants: This prospective cohort study was conducted from April 2020 to February 2021, with follow-up of 60 to 90 days. The cohort consisted of adults enrolled in the University of California, Los Angeles, SARS-CoV-2 Ambulatory Program who had a laboratory-confirmed symptomatic SARS-CoV-2 infection and were either hospitalized in a University of California, Los Angeles, hospital or one of 20 local health care facilities, or were outpatients referred by a primary care clinician. Data analysis was performed from March 2022 to February 2023.

Exposure: Laboratory-confirmed SARS-CoV-2 infection.

Main outcomes and measures: Patients responded to surveys that included questions about perceived cognitive deficits modified from the Perceived Deficits Questionnaire, Fifth Edition, (ie, trouble being organized, trouble concentrating, and forgetfulness) and symptoms of PCC at 30, 60, and 90 days after hospital discharge or initial laboratory-confirmed infection of SARS-CoV-2. Perceived cognitive deficits were scored on a scale from 0 to 4. Development of PCC was determined by patient self-report of persistent symptoms 60 or 90 days after initial SARS-CoV-2 infection or hospital discharge.

Results: Of 1296 patients enrolled in the program, 766 (59.1%) (mean [SD] age, 60.0 [16.7] years; 399 men [52.1%]; 317 Hispanic/Latinx patients [41.4%]) completed the perceived cognitive deficit items at 30 days after hospital discharge or outpatient diagnosis. Of the 766 patients, 276 (36.1%) perceived a cognitive deficit, with 164 (21.4%) having a mean score of greater than 0 to 1.5 and 112 patients (14.6 %) having a mean score greater than 1.5. Prior cognitive difficulties (odds ratio [OR], 1.46; 95% CI, 1.16-1.83) and diagnosis of depressive disorder (OR, 1.51; 95% CI, 1.23-1.86) were associated with report of a perceived cognitive deficit. Patients reporting perceived cognitive deficits in the first 4 weeks of SARS-CoV-2 infection were more likely to report symptoms of PCC than those without perceived cognitive deficits (118 of 276 patients [42.8%] vs 105 of 490 patients [21.4%]; χ21, 38.9; P < .001). Adjusting for demographic and clinical factors, perceived cognitive deficits in the first 4 weeks of SARS-CoV-2 were associated with PCC symptoms (patients with a cognitive deficit score of >0 to 1.5: OR, 2.42; 95% CI, 1.62-3.60; patients with cognitive deficit score >1.5: OR, 2.97; 95% CI, 1.86-4.75) compared to patients who reported no perceived cognitive deficits.

Conclusions and relevance: These findings suggest that patient-reported perceived cognitive deficits in the first 4 weeks of SARS-CoV-2 infection are associated with PCC symptoms and that there may be an affective component to PCC in some patients. The underlying reasons for PCC merit additional exploration.

Source: Turner GM, McMullan C, Aiyegbusi OL, Hughes SE, Walker A, Jeyes F, Adler Y, Chong A, Buckland L, Stanton D, Davies EH, Haroon S, Calvert M. Co-production of a feasibility trial of pacing interventions for Long COVID. Res Involv Engagem. 2023 Mar 30;9(1):18. doi: 10.1186/s40900-023-00429-2. PMID: 36997975; PMCID: PMC10061378. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10061378/ (Full text)

Long-COVID and its Physical and Neurological Symptoms in Adults: A Systematic Review

Abstract:

This review was carried out with the objective to study patterns of neurological, psychological and other physical consequences of COVID-19 in the long term. The guidelines of PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) had been followed; 22 articles, published during January 2020 to September 2021, were selected. Original research, review articles, editorial and viewpoints were included. Google Scholar, Medline, and PubMed were searched through 2020 till 2021.

Data collection in selected studies was performed mainly through the online survey, telephone survey, use of medical records, and patient interviews. This systematic review contains the studies conducted in the American, Asian and European countries. The major outcomes identified were the neurological, psychological, and other long-term chronic manifestations of COVID‐19.

This review demonstrates that long-COVID has started to bring a huge wave of patients, the count of them being millions now, who can enter a phase of disability due to neurological damages if not treated during the early course of illness. Though more disabling than lethal, long-COVID patients with a neurological deficit is expected to overburden the healthcare system globally which is already been struggling to handle acute COVID-19 patients in this once-in-a-lifetime pandemic.

Source: Abdul Mannan Baig, Sameera Rizvi, Shahla Pardhan, Joachim Gerlach, Tazeen Saeed Ali. Long-COVID and its Physical and Neurological Symptoms in Adults: A Systematic Review. Vol. 17 No. 04 (2023): Pakistan Journal of Medical & Health Sciences. https://pjmhsonline.com/index.php/pjmhs/article/view/4549/4498 (Full text)

Review of Neurological Manifestations of SARS-CoV-2

Abstract:

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can affect any part of the neuraxis. Many neurological conditions have been attributed to be caused by SARS-CoV-2, namely encephalopathy (acute necrotizing encephalopathy and encephalopathy with reversible splenial lesions), seizures, stroke, cranial nerve palsies, meningoencephalitis, acute disseminated encephalomyelitis (ADEM), transverse myelitis (long and short segment), Guillain-Barré syndrome (GBS) and its variants, polyneuritis cranialis, optic neuritis (ON), plexopathy, myasthenia gravis (MG), and myositis.

The pathophysiology differs depending on the time frame of presentation. In patients with concomitant pulmonary disease, for instance, acute neurological illness appears to be caused by endotheliopathy and cytokine storm. Autoimmunity and molecular mimicry are causative for post-coronavirus disease 2019 (COVID-19)-sequelae. It has not yet been shown that the virus can penetrate the central nervous system (CNS) directly.

This review aims to describe the disease and root pathogenic cause of the various neurological manifestations of COVID-19. We searched Pubmed/Medline and Google Scholar using the keywords “SARS-CoV-2” and “neurological illness” for articles published between January 2020 and November 2022. Then, we used the SWIFT-Review (Sciome LLC, North Carolina, United States), a text-mining workbench for systematic review, to classify the 1383 articles into MeSH hierarchical tree codes for articles on various parts of the nervous system, such as the CNS, peripheral nervous system, autonomic nervous system, neuromuscular junction, sensory system, and musculoskeletal system. Finally, we reviewed 152 articles in full text. SARS-CoV-2 RNA has been found in multiple brain areas without any histopathological changes.

Despite the absence of in vivo virions or virus-infected cells, CNS inflammation has been reported, especially in the olfactory bulb and brain stem. SARS-CoV-2 genomes and proteins have been found in affected individuals’ brain tissues, but corresponding neuropathologic changes are seldom found in these cases. Additionally, viral RNA can rarely be identified in neurological patients’ CSF post hoc SARS-CoV-2 infection.

Most patients with neurological symptoms do not have active viral replication in the nervous system and infrequently have typical clinical and laboratory characteristics of viral CNS infections. Endotheliopathy and the systemic inflammatory response to SARS-CoV-2 infection play a crucial role in developing neuro-COVID-19, with proinflammatory cytokine release mediating both pathological pathways. The systemic inflammatory mediators likely activate astrocytes and microglia across the blood-brain barrier, indirectly affecting CNS-specific immune activation and tissue injury. The management differs according to co-morbidities and the neurological disorder.

Source: P, Sehgal V, Kapila S, et al. (April 27, 2023) Review of Neurological Manifestations of SARS-CoV-2. Cureus 15(4): e38194. doi:10.7759/cureus.38194 https://www.cureus.com/articles/149269-review-of-neurological-manifestations-of-sars-cov-2#!/ (Full text)

Long COVID and especially headache syndromes

Abstract:

Purpose of review: This is an expert overview on recent literature about the complex relationship between coronavirus disease 2019 (COVID-19) and headache.

Recent findings: Long COVID is a clinical syndrome characterized by the presence of persistent symptoms following the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Headache is one of the most common symptoms and is described most often as throbbing pain, associated with photo and phonofobia and worsening with physical exercise. In acute COVID-19, headache is usually described as moderate or severe, diffuse and oppressive although sometimes it has been described with a migraine-like phenotype, especially in patients with a previous history of migraine.

Headache intensity during acute phase seems to be the most important predictor of duration of headache over time. Some COVID-19 cases can be associated with cerebrovascular complications, and red flags of secondary headaches (e.g. new worsening or unresponsive headache, or new onset of neurological focal signs) should be urgently investigated with imaging. Treatment goals are the reduction of number and intensity of headache crises, and the prevention of chronic forms.

Summary: This review can help clinicians to approach patients with headache and infection from SARS-CoV-2, with particular attention to persistent headache in long COVID.

Source: Tana C, Giamberardino MA, Martelletti P. Long COVID and especially headache syndromes. Curr Opin Neurol. 2023 Jun 1;36(3):168-174. doi: 10.1097/WCO.0000000000001153. Epub 2023 Apr 4. PMID: 37078648. https://pubmed.ncbi.nlm.nih.gov/37078648/

Exaggerated blood pressure elevation in response to orthostatic challenge, a post-acute sequelae of SARS-CoV-2 infection (PASC) after hospitalization

Abstract:

Objective: Post-acute sequelae of SARS-COV-2 (PASC) are emerging as a major health challenge. Orthostatic intolerance secondary to autonomic failure has been found in PASC patients. This study investigated the effect of COVID-19 after recovery on blood pressure (BP) during the orthostatic challenge.

Research design and methods: Thirty-one out of 45 patients hospitalized due to COVID-19-related pneumonia that developed PASC and did not have hypertension at discharge were studied. They underwent a head-up tilt test (HUTT) at 10.8 ± 1.9 months from discharge. All met the PASC clinical criteria, and an alternative diagnosis did not explain the symptoms. This population was compared with 32 historical asymptomatic healthy controls.

Results: Exaggerated orthostatic blood pressure response (EOPR)/orthostatic hypertension (OHT) was detected in 8 out of 23 (34.7 %) patients, representing a significantly increased prevalence (7.67-fold increase p = 0.009) compared to 2 out of 32 (6.4 %) asymptomatic healthy controls matched by age, who underwent HUTT and were not infected with SARS-CoV-2.

Conclusions: This prospective evaluation in patients with PASC revealed abnormal blood pressure rise during the orthostatic challenge, suggesting of autonomic dysfunction in a third of the studied subjects. Our findings support the hypothesis that EOPR/OHT may be a phenotype of neurogenic hypertension. Hypertension in PASC patients may adversely affect the cardiovascular burden in the world.

Source: González-Hermosillo G JA, Galarza EJ, Fermín OV, González JMN, Tostado LMFÁ, Lozano MAE, Rabasa CR, Martínez Alvarado MDR. Exaggerated blood pressure elevation in response to orthostatic challenge, a post-acute sequelae of SARS-CoV-2 infection (PASC) after hospitalization. Auton Neurosci. 2023 Apr 21;247:103094. doi: 10.1016/j.autneu.2023.103094. Epub ahead of print. PMID: 37137186; PMCID: PMC10121145. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10121145/ (Full text)

Effect of Post-COVID-19 on Brain Volume and Glucose Metabolism: Influence of Time Since Infection and Fatigue Status

Abstract:

Post-COVID-19 syndrome (PCS) fatigue is typically most severe <6 months post-infection. Combining magnetic resonance imaging (MRI) and positron emission tomography (PET) imaging with the glucose analog [18F]-Fluorodeoxyglucose (FDG) provides a comprehensive overview of the effects of PCS on regional brain volumes and metabolism, respectively. The primary purpose of this exploratory study was to investigate differences in MRI/PET outcomes between people < 6 months (N = 18, 11 female) and > 6 months (N = 15, 6 female) after COVID-19.
The secondary purpose was to assess if any differences in MRI/PET outcomes were associated with fatigue symptoms. Subjects > 6 months showed smaller volumes in the putamen, pallidum, and thalamus compared to subjects < 6 months. In subjects > 6 months, fatigued subjects had smaller volumes in frontal areas compared to non-fatigued subjects. Moreover, worse fatigue was associated with smaller volumes in several frontal areas in subjects > 6 months.
The results revealed no brain metabolism differences between subjects > 6 and < 6 months. However, both groups exhibited both regional hypo- and hypermetabolism compared to a normative database. These results suggest that PCS may alter regional brain volumes but not metabolism in people > 6 months, particularly those experiencing fatigue symptoms.
Source: Deters JR, Fietsam AC, Gander PE, Boles Ponto LL, Rudroff T. Effect of Post-COVID-19 on Brain Volume and Glucose Metabolism: Influence of Time Since Infection and Fatigue Status. Brain Sciences. 2023; 13(4):675. https://doi.org/10.3390/brainsci13040675 https://www.mdpi.com/2076-3425/13/4/675 (Full text)

Autonomic Dysfunction related to Post-Acute SARS-CoV-2 Syndrome

Introduction:

The SARS-CoV-2 virus, a member of the coronavirus family, has been responsible for the Coronavirus Disease-19 (COVID-19) pandemic with an acute phase causing pneumonia and pulmonary disorders, but it has been shown to extrapulmonary manifestations including cardiovascular and neurological diseases. Moreover, residual symptoms have been reported to persist past the acute phase. In a cross-sectional study of SARS-CoV-2 positive patients, at 48 days post-discharge the most common persistent symptoms were fatigue, difficulty breathing, and psychological distress.
 In a cohort study of 1,733 COVID-19 patients from Wuhan, China, patients reported persistence of fatigue, muscle weakness, sleeping difficulties, palpitations, anxiety, or depression at 6 months after initial onset.
 Numerous other studies now indicate the presence of persistent symptoms following COVID-19 infection, with over 200 symptoms reported. This syndrome has been coined as the Post-Acute SARS-CoV-2 Syndrome (PASC) and has been defined as the persistence of symptoms or development of new symptoms after the time of infection, which can include fatigue, brain fog, palpitations, and a plethora of other manifestations.
Source: Justin Haloot, DO, MS, MS, Ratna Bhavaraju-Sanka, MD, Jayasree Pillarisetti, MD Msc, Monica Verduzco-Gutierrez, MD. Autonomic Dysfunction related to Post-Acute SARS-CoV-2 Syndrome. Physical Medicine and Rehabiliation Clinics. Published: April 18, 2023. DOI:https://doi.org/10.1016/j.pmr.2023.04.003 (Full text)