Since the first description of the coronavirus disease 2019 (COVID-19), more than 500,000,000 infections with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been verified as of May 2022 [1
]. Initially thought to mainly present as respiratory tract infection, COVID-19 has been identified as a multiorgan disease, among others, affecting the kidneys, the heart, and the nervous system in many patients [2
Following the acute infection, symptoms in some individuals persist while others develop new symptoms, a phenomenon that the World Health Organization (WHO) had recently named post-COVID-19 condition or ‘long’ COVID-19 [3
]. Even though varying definitions exist for these two terms, they are used equivalently in clinical practice. Reported frequency of post-COVID-19 syndrome ranges between 10 and 35% [4
]. However, these numbers mainly have been collected during the pre-vaccination era and at a time when the alpha and delta variants of SARS-CoV-2 were still dominant. Whether they also apply to the omicron variant of the virus or vaccinated individuals remains unknown. Recent studies suggest that post-COVID-19 syndrome can also occur following infection with omicron [6
] or even as a result of the vaccination against the corona virus [7
]. Interestingly, even asymptomatic individuals or those with only mild COVID-19 symptoms seem to be at risk of developing post-COVID-19 syndrome. Of note, even children can develop post-COVID-19 syndrome, although the risk appears to be lower compared to adults. However, with the increased transmissibility of novel SARS-CoV-2 variants, pediatric post-COVID-19 might occur more frequently [2
According to previous descriptions, disturbances related to nearly every organ system can occur in individuals with post-COVID-19 syndrome, making the classification of this symptom complex and a challenging task in clinical practice [5
]. However, neurological and/or neuropsychological deficits such as memory loss, “brain fog”, fatigue, dizziness, headaches, or generalized pain [5
] are frequent complaints, thus placing the nervous system at the center of interest when studying this condition.
The pathophysiological mechanisms triggering post-COVID-19 are still under debate. Several groups have suggested virus persistence, long-lasting overactivation of the immune system including autoimmune phenomena or ongoing thrombus formation in the microvasculature as potential factors [11
]. With respect to the nervous system, distinct patterns of brain atrophy have recently been reported in post-COVID-19 patients suffering from impaired cognition [12
] and cerebral spinal fluid (CSF) analyses suggested dysfunctional inflammatory processes as the underlying cause of the disease [13
However, the clinical significance of these often selective findings-in relation to the broad and heterogeneous symptomatology—remains unclear, and so does the validity of the diagnostic tests performed, many of which can be considered rather experimental or not established in routine practice [14
]. Therefore, an increasing number of research groups have recently stressed the potential importance of psychosomatic factors in the emergence and perpetuation of post-COVID-19 syndrome [16
]. This idea is further supported by similarities between post-COVID-19 syndrome and the presentation of posttraumatic distress syndrome, depression, anxiety disorder, or poorly defined disease entities such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) [18
]. Coherently, supportive psychotherapy appears to be effective in alleviating the symptoms of post-COVID-19 [20
In an attempt to further put into context the manifold complaints brought forward by post-COVID-19 patients, we performed a prospective observational cohort study encompassing a comprehensive neurological diagnostic work-up.
The study was conducted in accordance with the Declaration of Helsinki. A total of 171 participants fulfilling the WHO Delphi consensus criteria for post-COVID-19 syndrome [4
] were included in this prospective observational cohort study. Individuals were recruited from the post-COVID-19 outpatient center at the Department of Neurology, University Medicine Essen, Germany between January 2021 and February 2022.
The cohort represents a typical “real-world” cohort in a German tertiary COVID-19 and neurology center. A broad range of patients with post-COVID-19 syndrome including those with previous cerebrovascular disease has been included into our study. Patients with comorbidities, in particular cerebrovascular disease, did not present any severe physical or mental deficits at the time of study entry and all patients were able to undergo the full set of diagnostic tests including neurocognitive assessment.
All patients were of legal age and gave written informed consent prior to study inclusion. The study was approved by the local ethics committee of the University Duisburg-Essen, Germany (reference numbers 20-9284-BO, 20-9307-BO).
Information on demographics, previous medical history, the severity of the preceding COVID-19 infection, and the profession were collected via structured interviews. All patients underwent full neurological and physical examination according to standards recommended by the European Academy of Neurology [21
]. If clinically indicated or if more specific complaints were brought forward by the patient, additional diagnostics such as MRI or lumbar puncture were performed to substantiate or exclude diagnoses.
In 171 patients, extensive nerve conduction studies were performed (tibial nerve, sural nerve, median and ulnar nerve), recording motor distal latency, motor conduction velocity, compound muscle action potential amplitude, F-waves, temporal dispersion and compound muscle action potential duration in motor nerves and sensory nerve action potential amplitude, and conduction velocity in sensory nerves. Furthermore, sensory and motor evoked potentials (SEP, MEP), blink reflex, and masseter reflex were conducted. Electrophysiological studies were expanded at the physicians’ discretion (n = 12 patients). Ultrasound examination of the extra- and intracranial head and neck arteries was performed in 76 patients. In 41 patients, clinical findings justified brain MRI and nine patients underwent lumbar puncture. In addition, all patients received pulmonary function tests (vital capacity, forced 1-s capacity) using a handheld spirometer (Micro Spirometer, Vitalograph), and peripheral oxygen saturation was measured using a finger clip (Pulox, PO-200). Blood was collected from all patients and analyzed for routine parameters, full blood count, and analysis of inflammatory parameters.
= 146) underwent structured neuropsychological testing by trained personnel. Patients were asked for self-perceived current cognitive status and subjective cognitive decline after COVID-19. A standardized cognitive assessment was performed using the following neuropsychological tests: word list of ten words to assess immediate and delayed verbal memory [22
], d2 test to assess selective attention [23
], verbal fluency (words with the letter “S” at the beginning) as executive function [24
], Trail Making Test A to assess processing speed and Trail Making Test B to assess cognitive flexibility as executive function [25
], digit span forward to assess verbal short-term memory and digit span backwards to assess verbal working-memory [26
] and symbol digit modalities test to assess attention, processing speed, visual scanning and memory [27
Results were transferred to z-scores using the age-appropriate mean and standard deviation (SD) of the corresponding test. If the performance was more than 1 SD below the mean, it was considered impaired. Results were depicted as a radar plot to visualize the proportion of individuals with impaired results.
Assessment of Fatigue and Somatization
In addition, study participants completed the German adaptation of the Fatigue Inventory Scale (FIS, n
= 128) to evaluate fatigue [28
]. FIS scores 40 items, ranging from 0 (no problem) to 4 (severe problem), adding up to a maximum score of 160. In addition, subdimensions for cognitive, physical, and psychosocial domains were calculated.
The severity of individual somatic symptoms was evaluated using the Patient Health Questionnaire-15 (PHQ-15, n
= 128). The survey is a valid and reliable screening tool for detecting patients at risk for somatoform disorders [21
] and requests 15 symptoms, accountable for more than 90% symptoms reported in somatoform disorders. PHQ-15 also records severity of somatization [30
], scoring from 0 (“not bothered at all”) to 2 (“bothered a lot”) [31
All statistical analyses were performed using SPSS (IBM Corp. Released 2020. IBM SPSS Statistics for Windows, Version 27.0. IBM Corp. Armonk, NY, USA).
The two-step clustering method was performed to identify underlying clusters of complaints using SPSS (IBM Corp. Released 2020. IBM SPSS Statistics for Windows, Version 27.0. IBM Corp. Armonk, NY, USA). Clusters were identified using log-likelihood distance measure and Schwarz’s Bayesian clustering criterion.
Odds ratios (OR) for the complaints were calculated and Cramer's V test for statistical significance was performed. We used logistic regression analyses to examine the association of risk factors (“no” as reference) with patients’ symptoms resulting in odds ratios (OR) and 95% confidence interval (CI). Comparison of means was performed using Mann–Whitney U test, and analysis of multiple groups was performed using Kruskal–Wallis ANOVA with Dunn’s post hoc test after testing for parametric distribution with Shapiro–Wilk test. Influencing factors on somatization (PHQ-15) and cognitive dimensions were identified with linear regression calculation with the method enter. Correlations were analyzed by bivariate correlation and spearman’s rho. The level of significance was set at p < 0.05.
Our study showed that patients with post-COVID-19 syndrome suffer from a great variety of neuropsychiatric syndromes. However, damage of the central or peripheral nervous system could only be rarely objectified or, if present, was attributable to a distinct neurological disease rather than post-COVID-19 syndrome. Moreover, we found evidence of significant psychiatric comorbidities and high levels of somatization, pointing towards the possibility that psychosomatic mechanisms like somato-sensoric amplification might play a substantial role in the pathogenesis of post-COVID-19 syndrome.
The majority of our patients were female and reported multiple complaints of which fatigue, difficulties in concentration, and headache were most frequently expressed. This observation underlines that neurological and neuropsychiatric symptoms represent key features of post-COVID-19 syndrome and is in accordance with several previous reports on the symptomatology and female predominance in post-COVID-19 syndrome [10
]. Most of the patients included in our study had only a mild-to-moderate COVID-19 course, with only 5% requiring hospitalization. This underrepresentation of severe COVID-19 cases might have biased the findings in post-COVID-19 syndrome afterwards. On the other hand, it is well established that there is no clear correlation between the severity of acute COVID-19 and the risk of developing post-COVID-19 syndrome, since only mildly affected COVID-19 patients or even asymptomatic SARS-CoV-2-positive individuals can develop persisting symptoms [38
Interestingly, stratification according to different occupational groups revealed that professions requiring academic qualifications or from the administrative and teaching field were more frequently represented in our cohort in comparison to professions going along with physical activity. We are not aware of any other study on post-COVID-19 that has captured the occupational status of the study participants and the reasons for this specific distribution are unknown. However, different educational levels of the study participants leading to a higher interest in health issues in academics, in particular women [41
], or disparities in social security and the job situation between the different professions might play a role.
Fatigue was the most prominent complaint in our cohort, which is in line with previous observations [5
]. The degree of post-COVID-19 fatigue observed here was much higher than in healthy individuals and similar to the extent of fatigue in patients with multiple sclerosis [28
], further underlining that fatigue is one of the most disturbing symptoms in post-COVID-19 syndrome, although we cannot completely rule out from our findings that some neurological comorbidities present in our study participants, in particular former stroke and multiple sclerosis amplified fatigue levels. The mechanisms causing extensive fatigue in post-COVID-19 syndrome are still not fully understood. Albeit post-infectious fatigue is a common and sometimes long-lasting clinical phenomenon, e.g., following EBV infections or tick-borne encephalitis [45
], the high frequency, the strong manifestation, and the persistence of fatigue in patients with post-COVID-19 argue in favor of distinct mechanisms. In addition, significant tissue hypoxemia as another potential cause of fatigue [47
] appeared unlikely in our cohort since the assessment of blood oxygenation was normal in all patients. Also, cranial MRI did not reveal any structural abnormalities, e.g., strategic lesions that could have accounted for the occurrence of fatigue. In the absence of any specific measurements in our study and evidence from the literature, we cannot exclude that continuously elevated levels of certain proinflammatory cytokines (e.g., IL-6) or the re-composition of different immune cell subsets in the CSF are involved in the occurrence of post-COVID-19 fatigue, as it has also been suggested for acute COVID-19 [48
]. Finally, we did not routinely assess iron metabolism (e.g., ferritin and transferrin levels) in our study participants, which has been described to affect the frequency and severity of fatigue [50
]. However, hemoglobin levels, which are linked to iron metabolism [51
], were normal in 97.7% of patients, therefore arguing against a severe iron deficit in our cohort.
Interestingly, patients with pre-existing psychiatric conditions most often reported fatigue in our study. It is well known that the perception of fatigue also depends on emotional factors such as mood and motivation [52
], and it can sometimes be challenging in clinical practice to strictly distinguish fatigue from depression [54
Some groups suggested that patients having recovered from COVID-19 are at a higher risk of developing dementia afterwards. For instance, neurofilament and amyloid-beta serum levels were increased in elderly and severely affected COVID-19 patients, as was the extent of brain atrophy [55
]. In line with these findings, the feeling of suffering from cognitive deficits, e.g., difficulties in recalling names or word finding difficulties, was also frequently reported by our study participants. Indeed, the structured neuropsychological assessment revealed low performance in cognition in these patients. However, the deficits did not follow any specific pattern, but were distributed across all measured cognitive domains, resembling neuropsychological patterns in individuals with mood disorders such as depression [57
], conditions which are well known for their reduced impetus to perform exhausting tests [60
]. Also, MRI assessment in our study did not reveal remarkable brain atrophy, albeit we might have missed subtle changes in brain volumes since we did not perform volumetric brain measurements and the cross-sectional study design did not allow for collecting longitudinal MRI data. Patients were examined according to common clinical standards, which in Germany do not include brain volumetry. According to the best possible clinical judgement also from our neuroradiologists we did not observe any ‘obvious’ brain atrophy in our study patients. In addition, we were not able to detect SARS-CoV-2 RNA in the CSF of any of our study participants, which is in accordance with our larger CSF studies on COVID-19 [49
], arguing against an excessive neurotropism of SARS-CoV-2 or virus persistence in the CNS. Moreover, most patients with post-COVID-19 syndrome spontaneously recover after several months [42
], a phenomenon that explicitly excludes the diagnosis of dementia [64
]. In addition, elevated neurofilament serum levels have also been reported in hospitalized COVID-19 patients without CNS involvement, and in non-hospitalized COVID-19 patients, biomarker levels of neurodegeneration were found to be normal [55
]. Interestingly, study participants comorbid of stroke and multiple sclerosis did not perform worse in neurocognitive testing in comparison to the other participants. Nevertheless, we cannot fully exclude the possibility that in some of our post-COVID-19 patients pre-existing neuropsychiatric diseases might have negatively impacted cognitive results.
Despite the multitude of diagnostic tests and examinations applied, findings were normal in most of our patients. Although we did not perform some of the diagnostic tests that have recently been claimed to be specifically or causally linked to post-COVID-19 syndrome, such as autoantibodies against g-protein-coupled receptors [15
] or Xenon CT of the chest [14
], the diagnostic armamentarium used in our study well represents the current standard in clinical neurology. Apart from that, most current experimental tests and diagnostics offered to patients with post-COVID-19 syndrome have not been validated independently or in larger groups of patients, and their actual pathophysiological relevance is unknown. Of note, some of the reported abnormal findings, for instance related to the autonomic nervous system, might even be triggered through conditioning mechanisms (fear conditioning) rather than structural organ changes [66
]. Moreover, from a clinical perspective, it is questionable that any single abnormal finding can explain the large heterogeneity of post-COVID-19 symptoms. Accordingly, specific neurological diagnoses plausibly linked to preceding COVID-19 could be established only in single patients in our study. GBS, transverse myelitis, and cerebellitis have been described in temporal proximity to the infection with SARS-CoV-2 [67
Considering the absence of any specific abnormalities in the CNS and PNS, evidence of high somatization scores, and a higher frequency of neuropsychiatric symptoms in individuals with pre-existing psychiatric disorder in our cohort, one should consider that in some individuals post-COVID-19 syndrome might be a rather psychosomatic provenance. Indeed, symptoms of post-COVID-19 syndrome even occurred in patients with retrospectively falsified diagnosis of SARS-CoV-2 infection [71
]. In contrast, patients aware of a previous infection reported higher rates of post-COVID-19 syndrome than those not being aware. Furthermore, the predisposition of developing symptoms of post-COVID-19 in patients with comorbid psychiatric disorders has already been reported by other groups [72
] and psychiatric medications such as antidepressants have been described to relieve symptoms of post-COVID-19 [74
]. Finally, the observed gender and age distribution in post-COVID-19 is typical for patient populations suffering from psychosomatic disorders [75
], and there seems to be considerable overlap in terms of symptomatology and postulated pathophysiological concepts with similarly enigmatic disease entities such as chronic fatigue syndrome or ME/CFS [19
Nevertheless, we cannot exclude from our findings that post-COVID-19 syndrome represents a spectrum of different entities and that subgroups of post-COVID-19 patients exist with more specific organotypic abnormalities that could be of causal relevance. In any case, it is crucial to take the complaints of patients with alleged post-COVID-19 syndrome seriously, since in 18.2% of our study participants we were finally able to secure a neurological diagnosis unrelated to post-COVID-19 including multiple sclerosis, migraine, and encephalitis. In particular, individuals presenting with sensory or motor symptoms should be thoroughly examined since they were at a higher risk of suffering from a neurological disease rather than from post-COVID-19, although we cannot fully exclude self-reporting of symptoms related to previous disease states (e.g., stroke) or re-activation of neurological symptoms as a consequence of SARS-CoV-2 infection.
Our study has several limitations. First, we did not collect longitudinal data. Therefore, we cannot make any firm statement regarding the natural course of post-COVID-19 or the possible development of brain atrophy over time in our cohort. Nevertheless, previous studies have shown that symptoms in populations with post-COVID-19 significantly improve or even completely resolve in the majority of patients after 6 months [42
]. Furthermore, due to the monocentric and observational study design, we cannot fully rule out selection bias or unidentified confounders. Moreover, infection of our study participants happened during a time of the pandemic when the alpha and delta variants of SARS-CoV-2 were still dominant, and vaccination was not broadly available. Hence, our data do not allow for conclusions as to whether symptoms of post-COVID-19 are different according to virus variants or vaccination status. For ethical reasons, we were not able to apply all diagnostics, e.g., lumbar puncture, to each study participant, and our population was probably biased towards ‘Neuro post-COVID-19’ rather than pulmonary or cardiac disturbances, for instance. Hence, we might have missed specific findings in some individuals. However, our approach reflects common clinical practice and diagnostic decisions were strictly based on the results from patient interviews and neurological examination. Also, most of the patients suffering from post-COVID-19 report neuropsychiatric symptoms [5
]. Another limitation of our study is that psychosomatic assessment was solely based on the PHQ15 score. Yet, PHQ15 is a well-established test in psychosomatic medicine and can detect psychosomatic disorders with a high level of sensitivity and specificity [78
]. Nevertheless, further investigations are warranted to better characterize how psychosomatic factors contribute to the pathophysiology of post-COVID-19 syndrome.
We thank the participants of the study. We acknowledge support by the Open Access Publication Fund of the University of Duisburg-Essen.
No funding or sponsorship was received for this study or publication of this article. The Rapid Service Fee was funded by the authors.
Mark Stettner, Christoph Kleinschnitz, and Martin Teufel concepted the study. Data collection was performed by Michael Fleischer, Muriel Tovar, Hannah Dinse, Klaas Herchert, Daniel Jokisch, and Julia Stögbauer. Analysis and figure preparation was performed by Michael Fleischer, Mark Stettner, Adam Schweda, Daniel Jokisch, Martha Jokisch, and Hannah Dinse. The first draft of the manuscript was written by Mark Stettner, Christoph Kleinschnitz, Michael Fleischer, and Fabian Szepanowski. All authors commented on previous versions of the manuscript. Supervision and critical revision were done by Martin Köhrmann, Martha Jokisch, Anne K. Mausberg, Eva-Maria Skoda, Cornelius Deuschl, Dagny Holle-Lee, Martin Teufel, Christoph Kleinschnitz, and Mark Stettner. All authors read and approved the final manuscript.
Michael Fleischer, Fabian Szepanowski, Muriel Tovar, Klaas Herchert, Hannah Dinse, Adam Schweda, Anne K. Mausberg, Dagny Holle-Lee, Martin Köhrmann, Julia Stögbauer, Daniel Jokisch, Martha Jokisch, Cornelius Deuschl, Eva-Maria Skoda, Martin Teufel, Mark Stettner, and Christoph Kleinschnitz declare that they have no competing interest in connection with the submitted material.
Compliance with Ethics Guidelines
The study was conducted in accordance with the Declaration of Helsinki. All patients were of legal age and gave written informed consent prior to study inclusion. The study was approved by the local ethics committee of the University Duisburg-Essen, Germany (reference numbers 20-9284-BO, 20-9307-BO).
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.