Review Long-term neurological and cognitive impact of COVID-19: a systematic review and meta-analysis in over 4 million patients, 2025, Elboraay et al

[forestglip]

Long-term neurological and cognitive impact of COVID-19: a systematic review and meta-analysis in over 4 million patients

Toka Elboraay, Mahmoud A. Ebada, Maged Elsayed, Heba Ahmed Aboeldahab, Hazem Mohamed Salamah, Omar Rageh, Mohamed Elmallahy, Hadeer Elsaeed AboElfarh, Lena Said Mansour, Yehia Nabil, Ahmed Khaled Abd Eltawab, Hany Atwan, Souad Alkanj

[Line breaks added]

Background
Neuropsychiatric symptoms emerged early in the COVID-19 pandemic as a key feature of the virus, with research confirming a range of neuropsychiatric manifestations linked to acute SARS-CoV-2 infection. However, the persistence of neurological symptoms in the post-acute and chronic phases remains unclear. This meta-analysis assesses the long-term neurological effects of COVID-19 in recovered patients, providing insights for mental health service planning.

Methods
A comprehensive literature search was conducted across five electronic databases: PubMed, Scopus, Web of Science, EBSCO, and CENTRAL, up to March 22, 2024. Studies evaluating the prevalence of long-term neurological symptoms in COVID-19 survivors with at least six months of follow-up were included. Pooled prevalence estimates, subgroup analyses, and meta-regression were performed, and publication bias was assessed.

Results
The prevalence rates for the different symptoms were as follows: fatigue 43.3% (95% CI [36.1-50.9%]), memory disorders 27.8% (95% CI [20.1-37.1%]), cognitive impairment 27.1% (95% CI [20.4-34.9%]), sleep disorders 24.4% (95% CI [18.1-32.1%]), concentration impairment 23.8% (95% CI [17.2-31.9%]), headache 20.3% (95% CI [15-26.9%]), dizziness 16% (95% CI [9.5-25.7%]), stress 15.9% (95% CI [10.2-24%]), depression 14.0% (95% CI [10.1-19.2%]), anxiety 13.2% (95% CI [9.6-17.9%]), and migraine 13% (95% CI [2.2-49.8%]).

Significant heterogeneity was observed across all symptoms. Meta-regression analysis showed higher stress, fatigue, and headache in females, and increased stress and concentration impairment with higher BMI.

Conclusions
Neurological symptoms are common and persistent in COVID-19 survivors. This meta-analysis highlights the significant burden these symptoms place on individuals, emphasizing the need for well-resourced multidisciplinary healthcare services to support post-COVID recovery.

Registration and protocol
This meta-analysis was registered in PROSPERO with registration number CRD42024576237 [link].

Link | PDF (BMC Neurology) [Open Access]

 

[Utsikt]

Quality assessment​

The risk of bias in the included studies was evaluated using the Newcastle–Ottawa Quality Assessment Scale (NOS) [23]. According to the NOS criteria, we assigned a maximum of four stars for selection bias, two stars for comparability evaluation, and three stars for exposure and outcome assessment. Studies were categorized based on their total star count: fewer than five stars indicated low quality; five to seven stars indicated moderate quality; and more than seven stars indicated high quality. Four investigators (OR, ME, LE, and ME) independently assessed each item on the scale. A fifth author (TE) facilitated a joint review to resolve any disagreements.

Quality assessment and publication Bias​

The quality scores of the studies show a range primarily between 3 and 9, with the majority of scores clustering around the middle values of 5, 6, and 7. This suggests a moderate level of quality across most studies, with some achieving higher marks, reflecting a strong methodological approach, and a few scoring lower, indicating areas for potential improvement in study design or execution (Table S1).

The analysis indicated that small study sizes significantly influenced the estimation of the prevalence of sleep disorders, fatigue, memory disorders, and cognitive impairment (Egger’s test: p < 0.001), as well as headache (Egger’s test: p = 0.03). However, no significant publication bias was observed for other symptoms, including dizziness, stress, anxiety, concentration impairment, and depression (Egger’s test: p > 0.05) (Table S2 and funnel plot in Figs. S12.1 to 12.10).

I get an error message when trying to dowload the supplemental materials.

They go on to write a lot of nonsense about multidiciplinary treatments, CBT, exercise, etc:

Despite increasing recognition of these sequelae, effective management strategies remain limited, and further research is needed to develop targeted interventions. Pharmacological management is an active area of investigation, with ongoing trials evaluating the efficacy of antidepressants, anti-inflammatory agents, and neuromodulatory drugs for treating neuropsychiatric symptoms in long COVID [190]. However, these trials are still in their early phases, and no standardized treatment protocol has been established.

Given this uncertainty, a multidisciplinary approach integrating cognitive rehabilitation, psychological support, and pharmacological interventions is emerging as a promising strategy. A comprehensive neuropsychological intervention program incorporating psychoeducation, restorative techniques, and compensatory strategies has demonstrated potential in addressing cognitive deficits and associated neuropsychiatric symptoms [191]. Similarly, neuropsychiatric associations emphasize the need for a structured clinical framework for assessing and managing post-COVID neuropsychiatric sequelae, with a focus on symptom-based treatment approaches [165]. A recent systematic review by Zeraatkar et al. (2024) further supports the role of multidisciplinary interventions in managing long COVID neuropsychiatric symptoms [192]. The analysis of 24 trials (n = 3,695) found that online cognitive behavioral therapy (CBT) effectively reduced fatigue and improved concentration, while a supervised rehabilitation program integrating physical and mental health interventions enhanced overall health, reduced depression, and improved quality of life [192]. Intermittent aerobic exercise (3–5 times per week for 4–6 weeks) also showed greater benefits for physical function than continuous exercise. However, no compelling evidence was found for pharmacological treatments, reinforcing the importance of psychological and rehabilitative approaches in long COVID management.

In addition to cognitive and psychological interventions, neuromodulatory approaches are gaining attention. A pilot randomized controlled trial assessing transcutaneous auricular vagus nerve stimulation demonstrated its feasibility as a noninvasive home-based intervention, with preliminary findings suggesting potential improvements in mental fatigue and related symptoms [193].

The limitations are noteable:

Despite these strengths, this meta-analysis has notable limitations that warrant careful consideration. One significant limitation is the heterogeneity observed across the included studies, which varied in design, populations, and methodologies. This variability complicates direct comparisons and limits the generalizability of the findings. Furthermore, differences in follow-up periods across studies may have affected symptom prevalence rates. Standardizing follow-up periods in future research would enhance clarity and comparability. Publication bias also poses a challenge, as studies with positive findings are more likely to be published, potentially skewing the results. Additionally, the quality of data extracted from the included studies varied, with inconsistencies in how symptoms were defined, measured, and reported. Reliance on self-reported data in some studies introduces variability and may limit accuracy due to measurement bias that can affect prevalence estimates; therefore, future studies should strive to incorporate objective assessments where possible. While the study accounted for several demographic and health-related factors, residual confounding remains a possibility, as unmeasured variables such as socioeconomic status, comorbid conditions, and lifestyle factors could influence symptom prevalence. Lastly, the predominance of cross-sectional data limits the ability to infer causal relationships between COVID-19 and the reported symptoms. Longitudinal studies are necessary to establish temporal relationships and better understand symptom progression in post-COVID patients.