The coronavirus disease 2019 (SARS-CoV-2) is a viral strain first reported in China in 2019, which rapidly evolved into a global pandemic responsible for more than 700 million infections and more than 7 million deaths reported worldwide as of April 2024 (1, 2). Infection-associated symptoms are multisystemic, possibly affecting the respiratory, cardiovascular, gastrointestinal, musculoskeletal, and neurologic systems. Most infected patients exhibit mild symptoms not requiring hospitalization (3). Although symptoms fully resolve in most cases, in over 10% of cases patients will experience lingering complications of infection, such as chronic fatigue and headaches, months after the initial infection (4–6). The finding of post-COVID-19 syndrome has been defined as “persistent, new, or recurrent symptoms and conditions more than 4 weeks after initial COVID-19 diagnosis” (7, 8).

Neurologic effects of COVID-19 on the central nervous system (CNS) have been reported since the start of the pandemic (9) and may be related to various mechanisms such as underlying systemic disease, immune dysfunction, vasculopathy, and complications of prolonged illness or hospitalization (6, 10, 11). The most common sequelae include chronic fatigue, headaches, sleep disorders, and depression (12, 13). A number of questionnaires have been validated for the clinical evaluation of these conditions, including the Fatigue Severity Scale (FSS), the Fatigue Scale for Motor and Cognitive Functions (FSMC) (14, 15), the Epworth Sleepiness Scale (ESS) (16, 17) and the Beck Depression Inventory (BDI-II) (18, 19). Some of these have also been applied to patients diagnosed with post-COVID-19 syndrome (20).

Overall, post-COVID-19 syndrome is associated with more than 60 heterogeneous physical and psychological symptoms affecting multiple organ systems (21). This heterogeneity has led to controversial and confusing findings in medical imaging research. In a large longitudinal brain imaging study, significant effects of SARS-CoV-2 infection, including a reduction in gray matter thickness and global brain size were reported (22). In contrast, Yiping et al. reported higher bilateral gray matter volume with no significant change in white matter volume in COVID-positive patients (23). Imaging findings tend to be nonspecific and are often seen as T2-hyperintense white matter lesions or supratentorial susceptibility abnormalities suggestive of microvascular pathology (24, 25). T2-hyperintense lesions are associated with small vessel disease, inflammatory processes and post-infectious sequelae, which may play a role in the pathophysiology of post-COVID-19 syndrome (26, 27). Despite conflicting reports in the literature, such as differences in lesion prevalence and significance in symptomatic patients (28), these lesions remain a widely studied marker of neurological abnormalities in post-viral syndromes.

The McDonald diagnostic criteria are commonly used in clinical practice as a way to standardize and provide diagnostic accuracy in the identification of multiple sclerosis (MS) (29). The revised McDonald criteria (2024) are expected to place more emphasis on early diagnosis. This will be achieved through advanced imaging techniques such as susceptibility-weighted imaging (SWI) and diffusion-weighted imaging (DWI), as well as certain imaging and laboratory biomarkers, such as the central vein sign (CVS) and paramagnetic rim lesions, among others (30, 31). The CVS represents the imaging manifestation of the perivenular nature of demyelinating plaques and has been defined as a hypointensity appearing at the center of a surrounding hyperintense lesion in at least 2 of 3 orthogonal planes. Although not pathognomonic for MS, the CVS can help differentiate between MS and other demyelinating diseases of the CNS (32, 33).

The exact relationship between these imaging findings and different post-COVID-19 syndrome symptoms remains unclear. The aim of this study was therefore to compare the number of T2-hyperintense white matter lesions in the brain and within the spinal cord among patients with post-COVID-19 syndrome exhibiting either chronic fatigue and/or headaches after initial infection.

This study considered the 2 most reported symptoms persisting after SARS-CoV-2 infection—headache and fatigue—and tried to determine the relationship between the prevalence of these symptoms and the number and location of T2-hyperintense lesions identified on brain MRI in this cohort of patients. The statistical analysis is depicted in Table 8.

Due to the small number of patients with T2-hyperintense lesions identified on spine MRI, a similar statistical analysis was not possible for these data.

This study focused on radiological evaluation with brain/spine MRI in participants with post-COVID-19 syndrome in single-center cohort in Switzerland. In our cohort, the majority of patients suffering from Post-COVID-19 Syndrome were female (73%; 70/96). This gender predominance aligns with findings from previous studies on long COVID, which have shown that women are disproportionately affected by persistent symptoms (34). Several factors may contribute to this gender disparity: biological differences, such as sex-specific variations in immune response are well-documented with women tending to have stronger immune responses making them more prone to immune-mediated conditions, which could influence susceptibility to long COVID (35). Additionally, hormonal differences, particularly the modulatory effects of estrogen on immune and vascular function, may play a role in the manifestation of chronic post-viral symptoms (35). Beyond biological factors, gender-specific reporting and healthcare-seeking behaviors may further contribute to the observed differences, as women may be more likely to report symptoms and seek medical attention for chronic conditions like Post-COVID-19 Syndrome (36). These considerations underscore the need to account for gender differences when interpreting findings and developing management strategies for long COVID.

Our study underscores the complexity of interpreting radiological findings in patients with post-COVID-19 syndrome. This is particularly evident with respect to structural brain alterations seen on MRI and their relationship with the most commonly identified symptoms such as chronic fatigue, headaches and depression. MRI is often used to identify possible structural causes for persistent neurological symptoms. The most common finding in brain MRI in our study was the presence of T2-hyperintense lesions in subcortical and periventricular areas, which is in line with the current literature (37). These lesions have previously been reported in patients suffering from persistent fatigue after hospitalization for COVID-19 (26), as well as in those with post-COVID-19 “brain fog” (28). However, these lesions tend to be frequently encountered in other unrelated settings such as post-infectious and inflammatory conditions, as well as in cases of chronic hypertension and small vessel disease. Advanced MRI techniques, such as diffusion tensor imaging and functional MRI (fMRI) have been shown to help in identifying imaging alterations that seem to be more prevalent in patients exhibiting neurological symptoms in the setting of post-COVID-19 syndrome (23, 38). However, our study did not find a significant correlation between reported radiological abnormalities and the most common symptoms reported by our patient cohort.

Symptoms such as chronic fatigue could be influenced by a range of physiological and psychological factors, including immune dysregulation, hormonal imbalances, and mental health conditions like depression or anxiety (21). The findings of our study suggest that these complex factors may not manifest as detectable structural changes in the brain, at least not in ways that are visible using conventional MRI protocols. While more complex imaging protocols such as fMRI or advanced diffusion techniques may be more sensitive to subtle brain changes, in our experience their application in clinical practice remains limited. Other options, such as detailed clinical assessments and the use of validated questionnaires for symptom tracking, may be a more effective strategy in guiding therapy for patients presenting with post-COVID-19 syndrome (39), than using MRI as a routine follow-up tool. This could shift the focus of treatment strategies from purely neurological investigations to a more multidisciplinary approach including neuropsychiatric, psychological, and rehabilitative care.

Transverse myelitis, while uncommon, has been documented in the literature as a severe complication of viral infections, including COVID-19 (27). In our study, only 3 patients demonstrated spine lesions consistent with post-infectious myelitis. This low prevalence aligns with current findings that transverse myelitis is a rare but serious post-COVID-19 complication, typically linked to more severe neurological symptoms such as motor weakness and sensory deficits (27). This suggests reserving spine MRI for cases where more specific neurological deficits are present, rather than incorporating it as part of the routine post-COVID-19 workup.

Our findings suggest a need to re-evaluate the role of MRI in managing patients with post-COVID-19 syndrome. The absence of a clear structural correlation with common symptoms such as fatigue and headaches indicates that MRI findings, while useful in excluding structural brain abnormalities, may not provide actionable insights for guiding therapeutic interventions. As such, the nonspecific nature of white matter lesions calls for a cautious approach when attributing patient symptoms to these findings. Instead, functional and neuropsychological assessments, including cognitive testing and fatigue scales, might yield more direct information about the patient’s condition and better inform therapeutic strategies.

Our study has some limitations. Firstly, the sample size is relatively small, particularly that for the analysis of spine MRI data, which limits the statistical power of the findings. Secondly, this study is retrospective and single-center, which may limit the generalizability of the results. The subjective nature of self-report questionnaires could introduce bias in the evaluation of symptoms. Additionally, the study did not adjust for other potential confounding factors such as treatment received during acute COVID-19 infection. Furthermore, this study relies on a single time-point for imaging and symptom assessment. Whilst previous studies suggest that some imaging abnormalities, such as those associated with inflammation or microvascular injury, may resolve or change with symptom recovery (38, 39), additional longitudinal studies with repeated imaging at multiple timepoints—such as 1, 3, and 6 months post-infection—are needed to evaluate the progression and resolution of T2-hyperintense lesions over time and to validate our findings.

While T2-hyperintense lesions are commonly observed in patients with post-COVID-19 syndrome, their presence does not seem to significantly correlate with symptoms of fatigue or headaches. These findings suggest that T2-hyperintense lesions may not be directly related to the subjective experience of these symptoms in patients with post-COVID-19 syndrome. Further research with larger sample sizes and adjustment for potential confounding factors is necessary to better understand the relationship between MRI findings and post-COVID-19 syndrome.