Tag: long covid neurology

High-density EEG sleep correlates of cognitive and affective impairment at 12-month follow-up after COVID-19

Abstract:

Objective: To disentangle the pathophysiology of cognitive/affective impairment in Coronavirus Disease-2019 (COVID-19), we studied long-term cognitive and affective sequelae and sleep high-density electroencephalography (EEG) at 12-month follow-up in people with a previous hospital admission for acute COVID-19.

Methods: People discharged from an intensive care unit (ICU) and a sub-intensive ward (nonICU) between March and May 2020 were contacted between March and June 2021. Participants underwent cognitive, psychological, and sleep assessment. High-density EEG recording was acquired during a nap. Slow and fast spindles density/amplitude/frequency and source reconstruction in brain gray matter were extracted. The relationship between psychological and cognitive findings was explored with Pearson correlation.

Results: We enrolled 33 participants ( 17 nonICU) and 12 controls. We observed a lower Physical Quality of Life index, higher post-traumatic stress disorder (PTSD) score, and a worse executive function performance in nonICU participants. Higher PTSD and Beck Depression Inventory scores correlated with lower executive performance. The same group showed a reorganization of spindle cortical generators.

Conclusions: Our results show executive and psycho-affective deficits and spindle alterations in COVID-19 survivors – especially in nonICU participants – after 12 months from discharge.

Significance: These findings may be suggestive of a crucial contribution of stress experienced during hospital admission on long-term cognitive functioning.

Source: Rubega M, Ciringione L, Bertuccelli M, Paramento M, Sparacino G, Vianello A, Masiero S, Vallesi A, Formaggio E, Del Felice A. High-density EEG sleep correlates of cognitive and affective impairment at 12-month follow-up after COVID-19. Clin Neurophysiol. 2022 Jun 15;140:126-135. doi: 10.1016/j.clinph.2022.05.017. Epub ahead of print. PMID: 35763985; PMCID: PMC9292469. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9292469/ (Full text)

COVID fog demystified

Abstract:

Acute mild respiratory SARS-CoV-2 infection can lead to a more chronic cognitive syndrome known as “COVID fog.” New findings from Fernández-Castañeda et al. reveal how glial dysregulation and consequent neural circuit dysfunction may contribute to cognitive impairments in long COVID.

Source: Kao J, Frankland PW. COVID fog demystified. Cell. 2022 Jul 7;185(14):2391-2393. doi: 10.1016/j.cell.2022.06.020. Epub 2022 Jun 15. PMID: 35768007; PMCID: PMC9197953. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9197953/ (Full text)

Bridging Knowledge Gaps in the Diagnosis and Management of Neuropsychiatric Sequelae of COVID-19

Abstract:

Importance: Neuropsychiatric symptoms have been reported as a prominent feature of postacute sequelae of COVID-19 (PASC), with common symptoms that include cognitive impairment, sleep difficulties, depression, posttraumatic stress, and substance use disorders. A primary challenge of parsing PASC epidemiology and pathophysiology is the lack of a standard definition of the syndrome, and little is known regarding mechanisms of neuropsychiatric PASC.

Observations: Rates of symptom prevalence vary, but at least 1 PASC neuropsychiatric symptom has been reported in as many as 90% of patients 6 months after COVID-19 hospitalization and in approximately 25% of nonhospitalized adults with COVID-19. Mechanisms of neuropsychiatric sequelae of COVID-19 are still being elucidated. They may include static brain injury accrued during acute COVID-19, neurodegeneration triggered by secondary effects of acute COVID-19, autoimmune mechanisms with chronic inflammation, viral persistence in tissue reservoirs, or reactivation of other latent viruses. Despite rapidly emerging data, many gaps in knowledge persist related to the variable definitions of PASC, lack of standardized phenotyping or biomarkers, variability in virus genotypes, ascertainment biases, and limited accounting for social determinants of health and pandemic-related stressors.

Conclusions and relevance: Growing data support a high prevalence of PASC neuropsychiatric symptoms, but the current literature is heterogeneous with variable assessments of critical epidemiological factors. By enrolling large patient samples and conducting state-of-the-art assessments, the Researching COVID to Enhance Recovery (RECOVER), a multicenter research initiative funded by the National Institutes of Health, will help clarify PASC epidemiology, pathophysiology, and mechanisms of injury, as well as identify targets for therapeutic intervention.

Source: Frontera JA, Simon NM. Bridging Knowledge Gaps in the Diagnosis and Management of Neuropsychiatric Sequelae of COVID-19. JAMA Psychiatry. 2022 Jun 29. doi: 10.1001/jamapsychiatry.2022.1616. Epub ahead of print. PMID: 35767287.  https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2793903 (Full text)

Neurovascular injury with complement activation and inflammation in COVID-19

Abstract:

The underlying mechanisms by which severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to acute and long-term neurological manifestations remains obscure. We aimed to characterize the neuropathological changes in patients with coronavirus disease 2019 and determine the underlying pathophysiological mechanisms. In this autopsy study of the brain, we characterized the vascular pathology, the neuroinflammatory changes and cellular and humoral immune responses by immunohistochemistry.

All patients died during the first wave of the pandemic from March to July 2020. All patients were adults who died after a short duration of the infection, some had died suddenly with minimal respiratory involvement. Infection with SARS-CoV-2 was confirmed on ante-mortem or post-mortem testing. Descriptive analysis of the pathological changes and quantitative analyses of the infiltrates and vascular changes were performed.

All patients had multifocal vascular damage as determined by leakage of serum proteins into the brain parenchyma. This was accompanied by widespread endothelial cell activation. Platelet aggregates and microthrombi were found adherent to the endothelial cells along vascular lumina. Immune complexes with activation of the classical complement pathway were found on the endothelial cells and platelets. Perivascular infiltrates consisted of predominantly macrophages and some CD8+ T cells. Only rare CD4+ T cells and CD20+ B cells were present. Astrogliosis was also prominent in the perivascular regions. Microglial nodules were predominant in the hindbrain, which were associated with focal neuronal loss and neuronophagia.

Antibody-mediated cytotoxicity directed against the endothelial cells is the most likely initiating event that leads to vascular leakage, platelet aggregation, neuroinflammation and neuronal injury. Therapeutic modalities directed against immune complexes should be considered.

Source: Lee MH, Perl DP, Steiner J, Pasternack N, Li W, Maric D, Safavi F, Horkayne-Szakaly I, Jones R, Stram MN, Moncur JT, Hefti M, Folkerth RD, Nath A. Neurovascular injury with complement activation and inflammation in COVID-19. Brain. 2022 Jul 5:awac151. doi: 10.1093/brain/awac151. Epub ahead of print. PMID: 35788639; PMCID: PMC9278212. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9278212/ (Full text)

Microvascular Injury in the Brains of Patients with Covid-19

To the Editor:

We conducted postmortem high-resolution magnetic resonance imaging (magnetic resonance microscopy) of the brains of patients with coronavirus disease 2019 (Covid-19) (median age, 50 years) and histopathological examination that focused on microvascular changes in the olfactory bulb and brain stem. (See the Materials and Methods section in the Supplementary Appendix, available with the full text of this letter at NEJM.org.) Images were obtained from the brains of 13 patients with the use of an 11.7-Tesla scanner at a resolution of 25 μm for the olfactory bulb and at a resolution of 100 μm for the brain. Abnormalities were seen in the brains of 10 patients.

We examined the brains of patients that showed abnormalities by means of multiplex fluorescence imaging (in 5 patients) and by means of chromogenic immunostaining (in 10 patients). We performed conventional histopathological examination of the brains of 18 patients. Fourteen patients had chronic illnesses, including diabetes and hypertension, and 11 had been found dead or had died suddenly and unexpectedly. Of the 16 patients with available medical histories, 1 had delirium, 5 had mild respiratory symptoms, 4 had acute respiratory distress syndrome, 2 had pulmonary embolism, and the symptoms were not known in 3.

Read the rest of this letter HERE.

Source: Lee MH, Perl DP, Nair G, Li W, Maric D, Murray H, Dodd SJ, Koretsky AP, Watts JA, Cheung V, Masliah E, Horkayne-Szakaly I, Jones R, Stram MN, Moncur J, Hefti M, Folkerth RD, Nath A. Microvascular Injury in the Brains of Patients with Covid-19. N Engl J Med. 2021 Feb 4;384(5):481-483. doi: 10.1056/NEJMc2033369. Epub 2020 Dec 30. PMID: 33378608; PMCID: PMC7787217. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787217/ (Full text)

Mild respiratory SARS-CoV-2 infection can cause multi-lineage cellular dysregulation and myelin loss in the brain

Abstract:

Survivors of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection frequently experience lingering neurological symptoms, including impairment in attention, concentration, speed of information processing and memory. This long-COVID cognitive syndrome shares many features with the syndrome of cancer therapy-related cognitive impairment (CRCI). Neuroinflammation, particularly microglial reactivity and consequent dysregulation of hippocampal neurogenesis and oligodendrocyte lineage cells, is central to CRCI. We hypothesized that similar cellular mechanisms may contribute to the persistent neurological symptoms associated with even mild SARS-CoV-2 respiratory infection.

Here, we explored neuroinflammation caused by mild respiratory SARS-CoV-2 infection – without neuroinvasion – and effects on hippocampal neurogenesis and the oligodendroglial lineage. Using a mouse model of mild respiratory SARS-CoV-2 infection induced by intranasal SARS-CoV-2 delivery, we found white matter-selective microglial reactivity, a pattern observed in CRCI. Human brain tissue from 9 individuals with COVID-19 or SARS-CoV-2 infection exhibits the same pattern of prominent white matter-selective microglial reactivity. In mice, pro-inflammatory CSF cytokines/chemokines were elevated for at least 7-weeks post-infection; among the chemokines demonstrating persistent elevation is CCL11, which is associated with impairments in neurogenesis and cognitive function.

Humans experiencing long-COVID with cognitive symptoms (48 subjects) similarly demonstrate elevated CCL11 levels compared to those with long-COVID who lack cognitive symptoms (15 subjects). Impaired hippocampal neurogenesis, decreased oligodendrocytes and myelin loss in subcortical white matter were evident at 1 week, and persisted until at least 7 weeks, following mild respiratory SARS-CoV-2 infection in mice. Taken together, the findings presented here illustrate striking similarities between neuropathophysiology after cancer therapy and after SARS-CoV-2 infection, and elucidate cellular deficits that may contribute to lasting neurological symptoms following even mild SARS-CoV-2 infection.

Source: Fernández-Castañeda A, Lu P, Geraghty AC, Song E, Lee MH, Wood J, Yalçın B, Taylor KR, Dutton S, Acosta-Alvarez L, Ni L, Contreras-Esquivel D, Gehlhausen JR, Klein J, Lucas C, Mao T, Silva J, Peña-Hernández MA, Tabachnikova A, Takahashi T, Tabacof L, Tosto-Mancuso J, Breyman E, Kontorovich A, McCarthy D, Quezado M, Hefti M, Perl D, Folkerth R, Putrino D, Nath A, Iwasaki A, Monje M. Mild respiratory SARS-CoV-2 infection can cause multi-lineage cellular dysregulation and myelin loss in the brain. bioRxiv [Preprint]. 2022 Jan 10:2022.01.07.475453. doi: 10.1101/2022.01.07.475453. PMID: 35043113; PMCID: PMC8764721.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8764721/ (Full text)

Rapid improvement in severe long COVID following perispinal etanercept

Abstract:

Background: This study aimed to describe the neurological improvements in a patient with severe long COVID brain dysfunction following perispinal etanercept administration. Perispinal administration of etanercept, a novel method designed to enhance its brain delivery via carriage in the cerebrospinal venous system, has previously been shown to reduce chronic neurological dysfunction after stroke. Etanercept is a recombinant biologic that is capable of ameliorating two components of neuroinflammation: microglial activation and the excess bioactivity of tumor necrosis factor (TNF), a proinflammatory cytokine that is a key neuromodulator in the brain. Optimal synaptic and brain network function require physiological levels of TNF. Neuroinflammation, including brain microglial activation and excess central TNF, can be a consequence of stroke or peripheral infection, including infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19.

Methods: Standardized, validated measures, including the Montreal Cognitive Assessment, Beck Depression Index-II (BDI-II), Fatigue Assessment Scale, Controlled Oral Word Association Test, Trail Making Tests, Timed Finger-to-Nose Test, 20 meter Self-Paced Walk Test, 5 Times Sit-to-Stand Test and Grip Strength measured with a Jamar Dynamometer were used to quantitate changes in cognition, depression, fatigue and neurological function after a single 25mg perispinal etanercept dose in a patient with severe long COVID of 12 months duration.

Results: Following perispinal etanercept administration there was immediate neurological improvement. At 24 hours there were remarkable reductions in chronic post-COVID-19 fatigue and depression, and significant measureable improvements in cognition, executive function, phonemic verbal fluency, balance, gait, upper limb coordination and grip strength. Cognition, depression and fatigue were examined at 29 days; each remained substantially improved.

Conclusion: Perispinal etanercept is a promising treatment for the chronic neurologic dysfunction that may persist after resolution of acute COVID-19, including chronic cognitive dysfunction, fatigue, and depression. These results suggest that long COVID brain neuroinflammation is a potentially reversible pathology and viable treatment target. In view of the increasing unmet medical need, clinical trials of perispinal etanercept for long COVID are urgently necessary. The robust results of the present case suggest that perispinal etanercept clinical trials studying long COVID populations with severe fatigue, depression and cognitive dysfunction may have improved ability to detect a treatment effect. Positron emission tomographic methods that image brain microglial activation and measurements of cerebrospinal fluid proinflammatory cytokines may be useful for patient selection and correlation with treatment effects, as well as provide insight into the underlying pathophysiology.

Source: Tobinick E, Spengler RN, Ignatowski TA, Wassel M, Laborde S. Rapid improvement in severe long COVID following perispinal etanercept. Curr Med Res Opin. 2022 Jul 6:1-23. doi: 10.1080/03007995.2022.2096351. Epub ahead of print. PMID: 35791687.  https://pubmed.ncbi.nlm.nih.gov/35791687/

Neurological long-COVID in the outpatient clinic: Two subtypes, two courses

Abstract:

Introduction: Symptoms referable to central and peripheral nervous system involvement are often evident both during the acute phase of COVID-19 infection and during long-COVID. In this study, we evaluated a population of patients with prior COVID-19 infection who showed signs and symptoms consistent with neurological long-COVID.

Methods: We prospectively collected demographic and acute phase course data from patients with prior COVID-19 infection who showed symptoms related to neurological involvement in the long-COVID phase. Firstly, we performed a multivariate logistic linear regression analysis to investigate the impact of demographic and clinical data, the severity of the acute COVID-19 infection and hospitalization course, on the post-COVID neurological symptoms at three months follow-up. Secondly, we performed an unsupervised clustering analysis to investigate whether there was evidence of different subtypes of neurological long COVID-19.

Results: One hundred and nine patients referred to the neurological post-COVID outpatient clinic. Clustering analysis on the most common neurological symptoms returned two well-separated and well-balanced clusters: long-COVID type 1 contains the subjects with memory disturbances, psychological impairment, headache, anosmia and ageusia, while long-COVID type 2 contains all the subjects with reported symptoms related to PNS involvement. The analysis of potential risk-factors among the demographic, clinical presentation, COVID 19 severity and hospitalization course variables showed that the number of comorbidities at onset, the BMI, the number of COVID-19 symptoms, the number of non-neurological complications and a more severe course of the acute infection were all, on average, higher for the cluster of subjects with reported symptoms related to PNS involvement.

Conclusion: We analyzed the characteristics of neurological long-COVID and presented a method to identify well-defined patient groups with distinct symptoms and risk factors. The proposed method could potentially enable treatment deployment by identifying the optimal interventions and services for well-defined patient groups, so alleviating long-COVID and easing recovery.

Source: Grisanti SG, Garbarino S, Barisione E, Aloè T, Grosso M, Schenone C, Pardini M, Biassoni E, Zaottini F, Picasso R, Morbelli S, Campi C, Pesce G, Massa F, Girtler N, Battaglini D, Cabona C, Bassetti M, Uccelli A, Schenone A, Piana M, Benedetti L. Neurological long-COVID in the outpatient clinic: Two subtypes, two courses. J Neurol Sci. 2022 Jun 3;439:120315. doi: 10.1016/j.jns.2022.120315. Epub ahead of print. PMID: 35717880; PMCID: PMC9212262. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9212262/ (Full text)

A systematic review and meta-analysis of long term physical and mental sequelae of COVID-19 pandemic: call for research priority and action

Abstract:

The long-term physical and mental sequelae of COVID-19 are a growing public health concern, yet there is considerable uncertainty about their prevalence, persistence and predictors. We conducted a comprehensive, up-to-date meta-analysis of survivors’ health consequences and sequelae for COVID-19. PubMed, Embase and the Cochrane Library were searched through Sep 30th, 2021. Observational studies that reported the prevalence of sequelae of COVID-19 were included. Two reviewers independently undertook the data extraction and quality assessment.

Of the 36,625 records identified, a total of 151 studies were included involving 1,285,407 participants from thirty-two countries. At least one sequelae symptom occurred in 50.1% (95% CI 45.4-54.8) of COVID-19 survivors for up to 12 months after infection. The most common investigation findings included abnormalities on lung CT (56.9%, 95% CI 46.2–67.3) and abnormal pulmonary function tests (45.6%, 95% CI 36.3–55.0), followed by generalized symptoms, such as fatigue (28.7%, 95% CI 21.0–37.0), psychiatric symptoms (19.7%, 95% CI 16.1–23.6) mainly depression (18.3%, 95% CI 13.3–23.8) and PTSD (17.9%, 95% CI 11.6–25.3), and neurological symptoms (18.7%, 95% CI 16.2–21.4), such as cognitive deficits (19.7%, 95% CI 8.8–33.4) and memory impairment (17.5%, 95% CI 8.1–29.6).

Subgroup analysis showed that participants with a higher risk of long-term sequelae were older, mostly male, living in a high-income country, with more severe status at acute infection. Individuals with severe infection suffered more from PTSD, sleep disturbance, cognitive deficits, concentration impairment, and gustatory dysfunction. Survivors with mild infection had high burden of anxiety and memory impairment after recovery.

Our findings suggest that after recovery from acute COVID-19, half of survivors still have a high burden of either physical or mental sequelae up to at least 12 months. It is important to provide urgent and appropriate prevention and intervention management to preclude persistent or emerging long-term sequelae and to promote the physical and psychiatric wellbeing of COVID-19 survivors.

Source: Zeng N, Zhao YM, Yan W, Li C, Lu QD, Liu L, Ni SY, Mei H, Yuan K, Shi L, Li P, Fan TT, Yuan JL, Vitiello MV, Kosten T, Kondratiuk AL, Sun HQ, Tang XD, Liu MY, Lalvani A, Shi J, Bao YP, Lu L. A systematic review and meta-analysis of long term physical and mental sequelae of COVID-19 pandemic: call for research priority and action. Mol Psychiatry. 2022 Jun 6:1–11. doi: 10.1038/s41380-022-01614-7. Epub ahead of print. PMID: 35668159; PMCID: PMC9168643. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9168643/ (Full text)

Comprehensive clinical assessment identifies specific neurocognitive deficits in working-age patients with long-COVID

Abstract:

Introduction: There have been more than 425 million COVID-19 infections worldwide. Post-COVID illness has become a common, disabling complication of this infection. Therefore, it presents a significant challenge to global public health and economic activity.

Methods: Comprehensive clinical assessment (symptoms, WHO performance status, cognitive testing, CPET, lung function, high-resolution CT chest, CT pulmonary angiogram and cardiac MRI) of previously well, working-age adults in full-time employment was conducted to identify physical and neurocognitive deficits in those with severe or prolonged COVID-19 illness.

Results: 205 consecutive patients, age 39 (IQR30.0-46.7) years, 84% male, were assessed 24 (IQR17.1-34.0) weeks after acute illness. 69% reported ≥3 ongoing symptoms. Shortness of breath (61%), fatigue (54%) and cognitive problems (47%) were the most frequent symptoms, 17% met criteria for anxiety and 24% depression. 67% remained below pre-COVID performance status at 24 weeks. One third of lung function tests were abnormal, (reduced lung volume and transfer factor, and obstructive spirometry). HRCT lung was clinically indicated in <50% of patients, with COVID-associated pathology found in 25% of these. In all but three HRCTs, changes were graded ‘mild’. There was an extremely low incidence of pulmonary thromboembolic disease or significant cardiac pathology. A specific, focal cognitive deficit was identified in those with ongoing symptoms of fatigue, poor concentration, poor memory, low mood, and anxiety. This was notably more common in patients managed in the community during their acute illness.

Conclusion: Despite low rates of residual cardiopulmonary pathology, in this cohort, with low rates of premorbid illness, there is a high burden of symptoms and failure to regain pre-COVID performance 6-months after acute illness. Cognitive assessment identified a specific deficit of the same magnitude as intoxication at the UK drink driving limit or the deterioration expected with 10 years ageing, which appears to contribute significantly to the symptomatology of long-COVID.

Source: Holdsworth DA, Chamley R, Barker-Davies R, O’Sullivan O, Ladlow P, Mitchell JL, Dewson D, Mills D, May SLJ, Cranley M, Xie C, Sellon E, Mulae J, Naylor J, Raman B, Talbot NP, Rider OJ, Bennett AN, Nicol ED. Comprehensive clinical assessment identifies specific neurocognitive deficits in working-age patients with long-COVID. PLoS One. 2022 Jun 10;17(6):e0267392. doi: 10.1371/journal.pone.0267392. PMID: 35687603; PMCID: PMC9187094. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9187094/ (Full text)