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

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. Funding 10.13039/501100001659Deutsche Forschungsgemeinschaft (DFG) and German Ministry of Education and Research (BMBF).

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

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. Funding: Deutsche Forschungsgemeinschaft (DFG) and German Ministry of Education and Research (BMBF).

Multidomain cognitive impairment in non-hospitalized patients with the post-COVID-19 syndrome: results from a prospective monocentric cohort.

BACKGROUND: A fraction of patients with asymptomatic to mild/moderate acute COVID-19 disease report cognitive deficits as part of the post-COVID-19 syndrome. This study aimed to assess the neuropsychological profile of these patients. METHODS: Assessment at baseline (three months or more following acute COVID-19) of a monocentric prospective cohort of patients with post-COVID-19 syndrome. Multidomain neuropsychological tests were performed, and questionnaires on depression, anxiety, fatigue, sleep, and general health status were administered. RESULTS: Of the 58 patients screened, six were excluded due to possible alternative causes of cognitive impairment (major depression, neurodegenerative disease). Of the remaining 52 individuals, only one had a below-threshold screening result on Mini-Mental State Examination, and 13 scored below the cut-off on Montreal Cognitive Assessment. Extended neuropsychological testing revealed a neurocognitive disorder (NCD) in 31 (59.6%) participants with minor NCD in the majority of cases (n = 26). In patients with NCD, the cognitive domains learning/memory and executive functions were impaired in 60.7%, complex attention in 51.6%, language in 35.5%, and perceptual-motor function in 29.0%. Cognitive profiles were associated with daytime sleepiness but not with depression, anxiety, sleep quality, total general health status, or fatigue. CONCLUSION: Neurocognitive impairment can be confirmed in around 60% of individuals with self-reported deficits as part of post-COVID-19 syndrome following a mild acute COVID-19 disease course. Notably, screening tests cannot reliably detect this dysfunction. Standard psychiatric assessments showed no association with cognitive profiles. Longitudinal studies are needed to further evaluate the course of neurocognitive deficits and clarify pathophysiology.

Association of cerebrospinal fluid brain-binding autoantibodies with cognitive impairment in post-COVID-19 syndrome.

BACKGROUND: Neurological symptoms, in particular cognitive deficits, are common in post-COVID-19 syndrome (PCS). There is no approved therapy available, and the underlying disease mechanisms are largely unknown. Besides others, autoimmune processes may play a key role. DESIGN: We here present data of a prospective study conducted between September 2020 and December 2021 and performed at two German University hospitals with specialized Neurology outpatient clinics. Fifty patients with self-reported cognitive deficits as main complaint of PCS and available serum and CSF samples were included. Cell-based assays and indirect immunofluorescence on murine brain sections were used to detect autoantibodies against intracellular and surface antigens in serum and CSF and analyzed for associations with cognitive screening assessment. RESULTS: Clearly abnormal cognitive status (MoCA ≤ 25/30 points) was only seen in 18/50 patients with self-reported cognitive deficits. Most patients (46/50) had normal routine CSF parameters. anti-neuronal autoantibodies were found in 52 % of all patients: n = 9 in serum only, n = 3 in CSF only and n = 14 in both, including those against myelin, Yo, Ma2/Ta, GAD65 and NMDA receptor, but also a variety of undetermined epitopes on brain sections. These included cerebral vessel endothelium, Purkinje neurons, granule cells, axon initial segments, astrocytic proteins and neuropil of basal ganglia or hippocampus as well as a formerly unknown perinuclear rim pattern. Pathological MoCA results were associated with the presence of anti-neuronal antibodies in CSF (p = 0.0004). CONCLUSIONS: Autoantibodies targeting brain epitopes are common in PCS patients and strongly associate with pathological cognitive screening tests, in particular when found in CSF. Several underlying autoantigens still await experimental identification. Further research is needed to inform on the clinical relevance of these autoantibodies, including controlled studies that explore the potential efficacy of antibody-depleting immunotherapy in PCS.

Anti-neuronal antibodies against brainstem antigens are associated with COVID-19.

BACKGROUND: Understanding how SARS-CoV-2 affects respiratory centres in the brainstem may help to preclude assisted ventilation for patients in intensive care setting. Viral invasion appears unlikely, although autoimmunity has been implicated, the responsible antigens remain unknown. We previously predicted the involvement of three epitopes within distinct brainstem proteins: disabled homolog 1 (DAB1), apoptosis-inducing-factor-1 (AIFM1), and surfeit-locus-protein-1 (SURF1). METHODS: Here, we used microarrays to screen serum from COVID-19 patients admitted to intensive care and compared those with controls who experienced mild course of the disease. FINDINGS: The results confirm the occurrence of IgG and IgM antibodies against the hypothesised epitopes in COVID-19 patients. Importantly, while IgM levels were similar in both groups, IgG levels were significantly elevated in severely ill patients compared to controls, suggesting a pathogenic role of IgG. INTERPRETATION: The newly discovered anti-neuronal antibodies might be promising markers of severe disease and the targeted peptide epitopes might be used for targeted immunomodulation. Further work is needed to determine whether these antibodies may play a role in long-COVID. FUNDING: AF, CF and PR received support from the German Research Foundation (grants FL 379/22-1, 327654276-SFB 1315, FR 4479/1-1, PR 1274/8-1). SH, DR, and DB received support from the Ministry of Economy, State of Mecklenburg Western Pomerania, Germany (grant COVIDPROTECT: "Optimisation of diagnostic and therapeutic pathways for COVID-19 patients in MV"). SH received support from the Research Group Molecular Medicine University of Greifswald (FVMM, seed funding FOVB-2021-01). AV received support from the Else Kröner Fresenius Foundation and the Alzheimer Research Initiative.

Neurological manifestations of post-COVID-19 syndrome S1-guideline of the German society of neurology.

Infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to COVID-19 (COrona VIrus Disease-2019). SARS-CoV-2 acute infection may be associated with an increased incidence of neurological manifestations such as encephalopathy and encephalomyelitis, ischemic stroke and intracerebral hemorrhage, anosmia and neuromuscular diseases. Neurological manifestations are commonly reported during the post-acute phase and are also present in Long-COVID (LCS) and post-COVID-19 syndrome (PCS). In October 2020, the German Society of Neurology (DGN, Deutsche Gesellschaft für Neurologie) published the first guideline on the neurological manifestations of COVID-19. In December 2021 this S1 guideline was revised and guidance for the care of patients with post-COVID-19 syndrome regarding neurological manifestations was added. This is an abbreviated version of the post-COVID-19 syndrome chapter of the guideline issued by the German Neurological society and published in the Guideline repository of the AWMF (Working Group of Scientific Medical Societies; Arbeitsgemeinschaft wissenschaftlicher Medizinischer Fachgesellschaften).

Manifestationen im Zentralnervensystem nach COVID-19 Manifestations of the central nervous system after COVID-19

Zahlreiche Erkrankungen des Zentralnervensystems sind insbesondere in der Postakutphase nach einer Infektion mit SARS-CoV‑2 („severe acute respiratory syndrome coronavirus 2“) beschrieben. Diese umfassen neuroimmunologisch vermittelte Erkrankungen wie Enzephalopathien, Enzephalitiden, Myelitiden, ADEM (akute disseminierte Enzephalomyelitis), ANHLE (akute nekrotisierende hämorrhagische Leukoenzephalitis) und NMOSD (Neuromyelitis-optica-Spektrum-Erkrankungen), aber auch andere wie PRES (posteriores reversibles Enzephalopathiesyndrom), OMAS (Opsoklonus-Myoklonus-Ataxie-Syndrom) sowie zerebrovaskuläre Erkrankungen. Ein para- oder postinfektiöser Zusammenhang wird diskutiert, jedoch sind pathophysiologische Mechanismen bislang unbekannt. Ursächlich könnte eine virusgetriggerte Überaktivierung des Immunsystems mit Hyperinflammation und Zytokinsturm, aber möglicherweise auch die Bildung spezifischer Autoantikörper gegen Gewebe des Zentralnervensystems sein. Eine direkte Schädigung durch die Invasion von SARS-CoV‑2 in das Gehirn oder das Rückenmark scheint keine relevante Rolle zu spielen. Eine exakte klinische Phänotypisierung und Einleitung von Zusatzdiagnostik, auch zum Ausschluss anderer Ursachen, ist empfohlen. Bislang existieren noch keine medikamentösen Therapieoptionen zur Behandlung von ZNS-Manifestationen beim Long-COVID(„coronavirus disease“)-Syndrom. Erste Befunde zu Inflammation und Autoimmunität sind jedoch vielversprechend und könnten zu neuen Therapieansätzen führen.

Cerebrospinal Fluid Analysis Post-COVID-19 Is Not Suggestive of Persistent Central Nervous System Infection.

This study was undertaken to assess whether SARS-CoV-2 causes a persistent central nervous system infection. SARS-CoV-2-specific antibody index and SARS-CoV-2 RNA were studied in cerebrospinal fluid following COVID-19. Cerebrospinal fluid was assessed between days 1 and 30 (n = 12), between days 31 and 90 (n = 8), or later than 90 days (post-COVID-19, n = 20) after COVID-19 diagnosis. SARS-CoV-2 RNA was absent in all patients, and in none of the 20 patients with post-COVID-19 syndrome were intrathecally produced anti-SARS-CoV-2 antibodies detected. The absence of evidence of SARS-CoV-2 in cerebrospinal fluid argues against a persistent central nervous system infection as a cause of neurological or neuropsychiatric post-COVID-19 syndrome. ANN NEUROL 2022;91:150-157.

Neurological symptoms and complications in predominantly hospitalized COVID-19 patients: Results of the European multinational Lean European Open Survey on SARS-Infected Patients (LEOSS).

BACKGROUND AND PURPOSE: During acute coronavirus disease 2019 (COVID-19) infection, neurological signs, symptoms and complications occur. We aimed to assess their clinical relevance by evaluating real-world data from a multinational registry. METHODS: We analyzed COVID-19 patients from 127 centers, diagnosed between January 2020 and February 2021, and registered in the European multinational LEOSS (Lean European Open Survey on SARS-Infected Patients) registry. The effects of prior neurological diseases and the effect of neurological symptoms on outcome were studied using multivariate logistic regression. RESULTS: A total of 6537 COVID-19 patients (97.7% PCR-confirmed) were analyzed, of whom 92.1% were hospitalized and 14.7% died. Commonly, excessive tiredness (28.0%), headache (18.5%), nausea/emesis (16.6%), muscular weakness (17.0%), impaired sense of smell (9.0%) and taste (12.8%), and delirium (6.7%) were reported. In patients with a complicated or critical disease course (53%) the most frequent neurological complications were ischemic stroke (1.0%) and intracerebral bleeding (ICB; 2.2%). ICB peaked in the critical disease phase (5%) and was associated with the administration of anticoagulation and extracorporeal membrane oxygenation (ECMO). Excessive tiredness (odds ratio [OR] 1.42, 95% confidence interval [CI] 1.20-1.68) and prior neurodegenerative diseases (OR 1.32, 95% CI 1.07-1.63) were associated with an increased risk of an unfavorable outcome. Prior cerebrovascular and neuroimmunological diseases were not associated with an unfavorable short-term outcome of COVID-19. CONCLUSION: Our data on mostly hospitalized COVID-19 patients show that excessive tiredness or prior neurodegenerative disease at first presentation increase the risk of an unfavorable short-term outcome. ICB in critical COVID-19 was associated with therapeutic interventions, such as anticoagulation and ECMO, and thus may be an indirect complication of a life-threatening systemic viral infection.

A Neurological Outpatient Clinic for Patients With Post-COVID-19 Syndrome - A Report on the Clinical Presentations of the First 100 Patients.

Background and Objectives: Neurological and psychiatric symptoms are frequent in patients with post-COVID-19 syndrome (PCS). Here, we report on the clinical presentation of the first 100 patients who presented to our PCS Neurology outpatient clinic ≥12 weeks after the acute infection with SARS-CoV-2. To date, PCS is only defined by temporal connection to SARS-CoV-2 infection. Identification of clinical phenotypes and subgroups of PCS is urgently needed. Design: We assessed clinical data of our first 100 ambulatory patients regarding clinical presentations; self-questionnaires focusing on daytime sleepiness, mood, and fatigue; and a screening assessment for detecting cognitive impairment. Results: A total of 89% of the patients presenting to the Neurology outpatient clinic had an initially mild course of COVID-19 and had not been hospitalized. The majority of the patients were female (67 vs. 33% male). The most frequent symptom reported was cognitive impairment (72%). There were 30% of patients who reported cognitive deficits and scored below 26 points on the Montreal Cognitive Assessment Scale. Fatigue (67%), headache (36%), and persisting hyposmia (36%) were also frequently reported; 5.5% of all patients showed signs of severe depression. Discussion: To our knowledge, this is the first report of patient data of a PCS Neurology outpatient clinic. Neurological sequelae also exist for more than 3 months after mainly mild SARS-CoV-2 acute infections. The reported symptoms are in accordance with recently published data of hospitalized patients.

Neuro-COVID-19 is more than anosmia: clinical presentation, neurodiagnostics, therapies, and prognosis.

PURPOSE OF REVIEW: To provide an overview on current knowledge of neurological symptoms and complications of COVID-19, and to suggest management concepts. RECENT FINDINGS: Headache, dizziness, excessive tiredness, myalgia, anosmia/hyposmia, and ageusia/dysgeusia are common nonspecific neurological manifestations during early COVID-19 disease found in the majority of patients. Less frequent but more severe and specific neurological manifestations include Guillain--Barré syndrome, encephalopathy, encephalitis/meningitis, epileptic seizures, and cerebrovascular events. Beyond standard neurological examination, these require a more extensive work-up, including cerebrospinal fluid assessment, neurophysiological evaluation, neuroimaging, and cognitive testing. Symptomatic treatment is advisable unless the neurological complication's immune pathogenesis is proven. SUMMARY: Neurological manifestations of COVID-19 occur during the acute, para-infectious, and 'recovery' phase. Therapeutic management depends on the clinical presentation and neurological work-up.

[Neuroimmunology of COVID-19]. / Neuroimmunologie von COVID­19.

Many neuroimmunological diseases, such as encephalopathy, encephalitis, myelitis and acute disseminated encephalomyelitis (ADEM) have occurred more frequently after infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which indicates a parainfectious or postinfectious association. The most likely underlying mechanisms include virus-triggered overactivation of the immune system with hyperinflammation and cytokine storm but potentially also the development of specific autoantibodies against central nervous system (CNS) tissue. These were predominantly detected in the cerebrospinal fluid of severely ill coronavirus disease 2019 (COVID-19) patients. In contrast, direct damage after invasion of SARS-CoV­2 into the brain and spinal cord does not seem to play a relevant role. Susceptibility to infection with SARS-CoV­2 in patients with multiple sclerosis, myasthenia or other neuroimmunological diseases including the risk for severe disease courses, is not determined by the administered immunotherapy but by known risk factors, such as age, comorbidities and the disease-related degree of disability. Therefore, immunotherapy in these patients should not be delayed or discontinued. The contribution of neuroimmunological mechanisms to long-term sequelae after survival of a COVID-19 illness, such as fatigue, impairment of memory, sleep dysfunction or anxiety, will require long-term clinical follow-up, preferentially in COVID-19 register studies.

Stroke Admissions, Stroke Severity, and Treatment Rates in Urban and Rural Areas During the COVID-19 Pandemic.

Background: Many regions worldwide reported a decline of stroke admissions during the early phase of the coronavirus disease 2019 (COVID-19) pandemic. It remains unclear whether urban and rural regions experienced similar declines and whether deviations from historical admission numbers were more pronounced among specific age, stroke severity or treatment groups. Methods: We used registry datasets from (a) nine acute stroke hospitals in Berlin, and (b) nine hospitals from a rural TeleNeurology network in Northeastern Germany for primary analysis of 3-week-rolling average of stroke/TIA admissions before and during the COVID-19 pandemic. We compared course of stroke admission numbers with regional cumulative severe acute respiratory syndrome coronavirus 2 (Sars-CoV-2) infections. In secondary analyses, we used emergency department logs of the Berlin Charité University hospital to investigate changes in age, stroke severity, and thrombolysis/thrombectomy frequencies during the early regional Sars-CoV-2 spread (March and April 2020) and compared them with preceding years. Results: Compared to past years, stroke admissions decreased by 20% in urban and 20-25% in rural hospitals. Deviations from historical averages were observable starting in early March and peaked when numbers of regional Sars-CoV-2 infections were still low. At the same time, average admission stroke severity and proportions of moderate/severe strokes (NIHSS >5) were 20 and 20-40% higher, respectively. There were no relevant deviations observed in proportions of younger patients (<65 years), proportions of patients with thrombolysis, or number of thrombectomy procedures. Stroke admissions at Charité subsequently rebounded and reached near-normal levels after 4 weeks when the number of new Sars-CoV-2 infections started to decrease. Conclusions: During the early pandemic, deviations of stroke-related admissions from historical averages were observed in both urban and rural regions of Northeastern Germany and appear to have been mainly driven by avoidance of admissions of mildly affected stroke patients.

High frequency of cerebrospinal fluid autoantibodies in COVID-19 patients with neurological symptoms.

BACKGROUND: COVID-19 intensive care patients can present with neurological syndromes, usually in the absence of SARS-CoV-2 in cerebrospinal fluid (CSF). The recent finding of some virus-neutralizing antibodies cross-reacting with brain tissue suggests the possible involvement of specific autoimmunity. DESIGN: Blood and CSF samples from eleven critically ill COVID-19 patients presenting with unexplained neurological symptoms including myoclonus, oculomotor disturbance, delirium, dystonia and epileptic seizures, were analyzed for anti-neuronal and anti-glial autoantibodies. RESULTS: Using cell-based assays and indirect immunofluorescence on unfixed murine brain sections, all patients showed anti-neuronal autoantibodies in serum or CSF. Antigens included intracellular and neuronal surface proteins, such as Yo or NMDA receptor, but also various specific undetermined epitopes, reminiscent of the brain tissue binding observed with certain human monoclonal SARS-CoV-2 antibodies. These included vessel endothelium, astrocytic proteins and neuropil of basal ganglia, hippocampus or olfactory bulb. CONCLUSION: The high frequency of autoantibodies targeting the brain in the absence of other explanations suggests a causal relationship to clinical symptoms, in particular to hyperexcitability (myoclonus, seizures). Several underlying autoantigens and their potential molecular mimicry with SARS-CoV-2 still await identification. However, autoantibodies may already now explain some aspects of multi-organ disease in COVID-19 and can guide immunotherapy in selected cases.

A Therapeutic Non-self-reactive SARS-CoV-2 Antibody Protects from Lung Pathology in a COVID-19 Hamster Model.

The emergence of SARS-CoV-2 led to pandemic spread of coronavirus disease 2019 (COVID-19), manifesting with respiratory symptoms and multi-organ dysfunction. Detailed characterization of virus-neutralizing antibodies and target epitopes is needed to understand COVID-19 pathophysiology and guide immunization strategies. Among 598 human monoclonal antibodies (mAbs) from 10 COVID-19 patients, we identified 40 strongly neutralizing mAbs. The most potent mAb, CV07-209, neutralized authentic SARS-CoV-2 with an IC50 value of 3.1 ng/mL. Crystal structures of two mAbs in complex with the SARS-CoV-2 receptor-binding domain at 2.55 and 2.70 Å revealed a direct block of ACE2 attachment. Interestingly, some of the near-germline SARS-CoV-2-neutralizing mAbs reacted with mammalian self-antigens. Prophylactic and therapeutic application of CV07-209 protected hamsters from SARS-CoV-2 infection, weight loss, and lung pathology. Our results show that non-self-reactive virus-neutralizing mAbs elicited during SARS-CoV-2 infection are a promising therapeutic strategy.