Current update on the neurological manifestations of long COVID: more questions than answers

Abstract

Since the outbreak of the COVID-19 pandemic, there has been a global surge in patients presenting with prolonged or late-onset debilitating sequelae of SARS-CoV-2 infection, colloquially termed long COVID. This narrative review provides an updated synthesis of the latest evidence on the neurological manifestations of long COVID, discussing its clinical phenotypes, underlying pathophysiology, while also presenting the current state of diagnostic and therapeutic approaches. Approximately one-third of COVID-19 survivors experience prolonged neurological sequelae that persist for at least 12-months post-infection, adversely affecting patients' quality of life. Core neurological manifestations comprise fatigue, post-exertional malaise, cognitive impairment, headache, lightheadedness ('brain fog'), sleep disturbances, taste or smell disorders, dysautonomia, anxiety, and depression. Some of these features overlap substantially with those reported in post-intensive-care syndrome, myalgic encephalomyelitis/chronic fatigue syndrome, fibromyalgia, and postural-orthostatic-tachycardia syndrome. Advances in data-driven research utilizing electronic-health-records combined with machine learning and artificial intelligence have propelled the identification of long COVID sub-phenotypes. Furthermore, the evolving definitions reflect the dynamic conceptualization of long COVID in both research and clinical contexts. Although the underlying pathophysiology remains incompletely elucidated, neuroinflammatory responses, endotheliopathy, and metabolic imbalances, rather than direct viral neuroinvasion, are implicated in neurological sequelae. Genetic susceptibility has also emerged as a potential risk factor. While major limitations remain with existing definitions, collaborative strategies to standardize diagnostic approaches are needed. Current therapeutic paradigms advocate for multimodal approaches, integrating pharmacological and non-pharmacological interventions along with comprehensive rehabilitation programs. Although preliminary evidence of therapeutic efficacy has been provided by a number of clinical trials, methodological constraints limit the generalizability of this evidence. Preventive measures, notably vaccination, have proven integral for reducing the global burden of long COVID. Considering the healthcare and socioeconomic repercussions incurred by long COVID worldwide, international collaborative initiatives are warranted to address the remaining challenges in diagnosing and managing patients presenting with neurological sequelae. See also the graphical abstract(Fig. 1).

Keywords: COVID-19; PACS; SARS-CoV-2; brain fog; long COVID; long-haul.

Table 1. Comparative analysis of terminology and definitions of long COVID (Chou et al., 2024; Ely et al., 2024; Soriano et al., 2022)

Table 2. Average duration and prevalence of neurological manifestations of long COVID at 6- and 12-months post-infection (Arnold et al., 2021; Badenoch et al., 2022; Dorobisz et al., 2023; Li et al., 2023; Păunescu et al., 2023; Peter et al., 2022; Rivera-Izquierdo et al., 2022; Tana et al., 2022; Vaira et al., 2020)

Table 3. Summary of randomized-controlled clinical trials on pharmacological interventions for neurological manifestations of long COVID

Table 4. Summary of randomized-controlled clinical trials on non-pharmacological interventions for neurological manifestations of long COVID

Figure 1. Graphical abstract

Figure 2. Pathophysiological mechanisms implicated in neurological manifestations of long COVID. The pathophysiology of long COVID is multifactorial, with several mechanisms contributing to its neurological manifestations. Neuroinflammation is a key feature, driven by persistent immune activation involving elevated levels of pro-inflammatory cytokines and autoantibodies, leading to chronic inflammation in both the central and peripheral nervous systems. Reactivation of latent viruses, such as Epstein-Barr virus, may further exacerbate these inflammatory processes. Endothelial dysfunction plays a critical role, characterized by damage to the blood-brain barrier (BBB), which increases its permeability, allowing inflammatory mediators and immune cells to infiltrate the CNS, potentially leading to cognitive deficits such as brain fog. Metabolic disturbances are observed in regions with a high density of ACE2 receptors, such as the olfactory bulb, hippocampus, and brainstem, where hypometabolism likely results from mitochondrial dysfunction and oxidative stress, disrupting cognitive function, mood regulation, and autonomic processes. Autonomic dysfunction is another significant component, marked by dysregulation of autonomic nervous system functions, including impaired heart rate variability, possibly due to damage to the brainstem and vagus nerve. The viral reservoir hypothesis posits that while direct viral persistence in the CNS is rare, SARS-CoV-2 reservoirs in peripheral organs, such as the lungs and gastrointestinal tract, may perpetuate systemic inflammation, indirectly affecting both the CNS and PNS. This inflammation can disrupt the brain-gut axis, potentially exacerbating neurological symptoms by influencing neuroinflammation and gut-derived inflammatory mediators. Finally, genetic susceptibility may influence the risk of developing long COVID, with variants in immune-regulatory genes such as OAS1 and TLR4 potentially contributing to prolonged immune responses and viral persistence, though the exact genetic determinants remain to be fully elucidated. This image was created with BioRender (https://biorender.com).

ACE2: Angiotensin-Converting Enzyme 2; BBB: Blood-Brain Barrier; CNS: Central Nervous System; COVID: Coronavirus Disease; EBV: Epstein-Barr Virus; PNS: Peripheral Nervous System; SARS-CoV-2: Severe Acute Respiratory Syndrome Coronavirus 2; TLR4: Toll-Like Receptor 4; OAS1: 2'-5'-Oligoadenylate Synthetase 1

Figure 3. Proposed diagnostic and therapeutic algorithm for patients presenting with neurological manifestations of long COVID.

PICS: post intensive care unit syndrome; ME/CFS: myalgic encephalomyelitis/chronic fatigue syndrome; FM: fibromyalgia; POTS: postural orthostatic tachycardia syndrome.

Figure 4. Activation of neuroinflammatory pathways induced by SARS-CoV-2 viral infection. This figure illustrates the sequential mechanisms involved in neuroinflammation following viral entry into host cells, highlighting the immune and inflammatory signaling cascades activated.

1. Viral Entry via ACE2 Receptor: The SARS-CoV-2 viral particle binds to the angiotensin-converting enzyme 2 (ACE2) receptor on the cell surface, allowing viral RNA to enter the host cell and initiate infection. 2. Recognition by Innate Immune Sensors: Viral RNA within the cell is detected by pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) and RIG-I-like receptors, which recognize viral genetic material and activate innate immune responses. 3. Activation of Inflammatory Signaling Pathways: The binding of viral RNA to PRRs initiates signaling cascades, including the NF-κB and MAPK pathways, which are critical for the host's inflammatory response. These pathways ultimately lead to the production of inflammatory mediators. 4. Cytokine Production and Release: The activated NF-κB and MAPK pathways drive the production and release of pro-inflammatory cytokines, including IL-6, IL-1β, and TNF-α. These cytokines promote local and systemic inflammation, and their upregulation is characteristic of the cytokine storm. 5. Renin-Angiotensin System (RAS) Involvement: Viral binding to ACE2 reduces its normal function, causing an imbalance in the RAS. Angiotensin II, acting primarily through the AT1 receptor, promotes inflammation and oxidative stress. In contrast, the AT2 receptor counteracts these effects by exhibiting anti-inflammatory actions. 6. Nuclear Translocation and Gene Expression: Activated transcriptional factors, including NF-κB and STAT, translocate to the nucleus, where they bind to DNA and initiate transcription of inflammatory genes. 7. Sustained Inflammatory Gene Expression: The continuous expression of inflammatory genes contributes to chronic inflammation, potentially leading to neurological damage and exacerbating disease severity in cases of severe infection. This image was created with BioRender (https://biorender.com). ACE2: Angiotensin-Converting Enzyme 2; AT1: Angiotensin II Type 1 Receptor; AT2: Angiotensin II Type 2 Receptor; IL-6: Interleukin-6; IL-1β: Interleukin-1 beta; MAPK: Mitogen-Activated Protein Kinase; NF-κB: Nuclear Factor kappa-light-chain-enhancer of activated B cells; PRR: Pattern Recognition Receptor; RAS: Renin-Angiotensin System; STAT: Signal Transducer and Activator of Transcription; TLR: Toll-Like Receptor; TNF-α: Tumor Necrosis Factor-alpha