Post-COVID-19 Syndrome is Rarely Associated with Damage of the Nervous System: Findings from a Prospective Observational Cohort Study in 171 Patients

Abstract

Introduction: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can affect multiple organs. Reports of persistent or newly emergent symptoms, including those related to the nervous system, have increased over the course of the pandemic, leading to the introduction of post-COVID-19 syndrome. However, this novel syndrome is still ill-defined and structured objectification of complaints is scarce. Therefore, we performed a prospective observational cohort study to better define and validate subjective neurological disturbances in patients with post-COVID-19 syndrome.

Methods: A total of 171 patients fulfilling the post-COVID-19 WHO Delphi consensus criteria underwent a comprehensive neurological diagnostic work-up including neurovascular, electrophysiological, and blood analysis. In addition, magnetic resonance imaging (MRI) and lumbar puncture were conducted in subgroups of patients. Furthermore, patients underwent neuropsychological, psychosomatic, and fatigue assessment.

Results: Patients were predominantly female, middle-aged, and had incurred mostly mild-to-moderate acute COVID-19. The most frequent post-COVID-19 complaints included fatigue, difficulties in concentration, and memory deficits. In most patients (85.8%), in-depth neurological assessment yielded no pathological findings. In 97.7% of the cases, either no diagnosis other than post COVID-19 syndrome, or no diagnosis likely related to preceding acute COVID-19 could be established. Sensory or motor complaints were more often associated with a neurological diagnosis other than post-COVID-19 syndrome. Previous psychiatric conditions were identified as a risk factor for developing post-COVID-19 syndrome. We found high somatization scores in our patient group that correlated with cognitive deficits and the extent of fatigue.

Conclusions: Albeit frequently reported by patients, objectifiable affection of the nervous system is rare in post-COVID-19 syndrome. Instead, elevated levels of somatization point towards a pathogenesis potentially involving psychosomatic factors. However, thorough neurological assessment is important in this patient group in order to not miss neurological diseases other than post-COVID-19.

Keywords: COVID-19; Fatigue; Long COVID; Neurological deficits; Neuropsychological assessment; Post-COVID; Somatization.

Fig. 1

Timeline of SARS-CoV-2 infections and self-reported complaints. A Number of SARS-CoV-2 infections per month of the study participants in comparison to the different SARS-CoV-2 infection waves in Germany. All study participants had been infected during the first two infection waves in Germany between March 2020 and August 2021. B Frequency of complaints reported by patients with fatigue and difficulties in concentration as most prevalent complaints. C Clusters of complaints. Complaints brought forward by the participants were clustered with a two-step clustering method. Three distinct clusters could be identified. Diameter indicates the number of patients reporting the respective complaint. Cluster 1: Headache (n = 46) is defined by the complaint of headaches and fatigue. Cluster 2: Psycho-Fatigue (n = 34) is predominated by psychiatric complaints and fatigue. In Cluster 3: Fatigue-Concentration (n = 60), fatigue and difficulties in concentration constitute most frequent complaints

Fig. 2

Evaluation of risk factors by calculation of odds ratios (OR) and 95% confidence interval (CI) for presenting a particular complaint. A Patients with a history of psychiatric conditions were more likely to complain of fatigue (OR 2.43, CI 1.11–5.82, p < 0.05), difficulties in concentration (OR 2.58, CI 1.01–6.19, p < 0.05), and to report psychiatric complaints (OR 4.50, CI 1.47–8.32, p < 0.01). B Patients with a history of neurological conditions more frequently reported sensor and motor disturbances (OR 2.49, CI 1.10–5.62, p < 0.05) as well as dizziness (OR 2.13, CI 1.02–4.42, p < 0.05). C History of headaches was a risk factor for reporting headache as part of post-COVID-19 syndrome (OR 3.52, CI 1.34–9.36, p < 0.01). OR are given with respective 95% confidence intervals (95% CI), x-axis is depicted in logarithmic scale. Only OR that reached a level of significance p < 0.05 are reported *p < 0.05, **p < 0.01, ***p < 0.001

Fig. 3

Fatigue Impact Scale (FIS), neuropsychological assessment and Patient Health Questionnaire 15 (PHQ15) for clusters of complaints and previous neurological and psychiatric conditions. A Highest levels of fatigue (95.7 ± 33.2) were found in the “Fatigue-Concentration cluster” while lowest levels were found in the “Headache cluster” (62.3 ± 42.0, p < 0.001). Range of reference encompassed fatigue levels of MS patients (high fatigue levels, 93.2) and patients with high blood pressure (HBP; low fatigue levels, 31.2) [28]. The presence of a previous psychiatric condition was associated with markedly higher FIS (110 ± 27.4 vs. 79.8 ± 38.0, p < 0.01) while previous neurological conditions did not influence levels of fatigue. B The proportion of patients having abnormal neuropsychological test results is depicted as radar plot. For the total cohort, assessment revealed deficits in all tested qualities of neurocognition. “Fatigue-concentration cluster” and patients with previous psychiatric conditions displayed the highest frequency of abnormal test results. C Assessment of PHQ15 revealed the strongest tendency towards somatization in the “Fatigue-concentration cluster” as compared to “Headache cluster” (p < 0.01; PHQ15 > 15, dotted line). Patients with a previous psychiatric condition had significantly higher PHQ15 scores, whereas those with previous neurological conditions showed the lowest levels of somatization (Dotted line: mean score of the total cohort (PHQ15: 14.0)). *p < 0.05, **p < 0.01, ***p < 0.001, ns: not significant

Fig. 4

Results of neurological diagnostics. Findings evaluated as to whether they were able to explain at least one reported complaint. A In 85.8%, the neurological examination (n = 171) revealed no abnormalities. Sensory and motor deficits (11.8%), tremor (1.2%) and ataxia (1.2%) added up to 14.2% of cases with focal neurological deficits; 10.0% of these findings could be attributed to one complaint brought forward by the patient. B Electrophysiological assessment in 89.2% yielded normal and in 10.8% pathological findings; 6.3% of these findings explained a reported complaint, in 4.5% the electrophysiological finding was incidental and not related to any complaints. C 41 MRI scans were performed, revealing no pathological findings in 85.0% of the cases. Of 15.0% noticeable findings, 5.0% (stable MS lesions) were considered explanatory for the complaints of the patients. D In 81.9% of patients, cerebrospinal fluid analysis (n = 11) yielded no pathological findings; in 18.1% of cases either elevated cell count or oligoclonal bands (new MS diagnosis) were found

Fig. 5

Neurological diagnoses explaining at least one subjective complaint and the possible association with COVID-19. A For the total cohort, 20.5% of participants received a neurological diagnosis apart from post-COVID-19, of which 18.2% were not associated with COVID-19. B 47.2% of individuals with sensory or motor dysfunction were finally found with a neurological diagnosis and in 36.1% this diagnosis was not associated with COVID-19. C In 17.0% of individuals complaining of fatigue, a neurological diagnosis was found explaining at least one subjective complaint; 1.2% of these were related to COVID-19