Long COVID-19 and the Unveiled Impact on Corneal Innervation


The Coronavirus Disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2), has been a global health crisis with far-reaching consequences.

While COVID-19 primarily affects the respiratory system, it has manifested in various organ systems, including the nervous system.

Among the multitude of symptoms associated with COVID-19, neurological symptoms have emerged as a significant and perplexing aspect of the disease, encompassing manifestations such as headache, fatigue, loss of taste and smell, brain fog, and neuropathic pain [1].

Long COVID-19 (LC-19), a condition also known as post-COVID conditions (PCC), post-acute sequelae of SARS-CoV-2 infection (PASC), long-haul COVID, or chronic COVID, has garnered considerable attention. It refers to the long-term health effects experienced by individuals who have previously contracted COVID-19.

These effects typically manifest within three months of the initial infection and persist for at least two months, defying explanation by an alternative diagnosis [2]. LC-19 is marked by complex and highly diverse symptoms, with fatigue, respiratory distress, and cognitive dysfunction being the most commonly reported complaints. Furthermore, these symptoms can vary in intensity and reoccur over time, making LC-19 a challenging condition to define [2].

Recent studies have drawn attention to the profound impact of LC-19 on cognitive function, with significant linguistic-cognitive and visual attention impairment reported [3,4]. This cognitive decline, coupled with intense daily fatigue that can arise even during routine activities, contributes to a reduced quality of life for LC-19 patients [5].

The mechanism by which SARS-CoV-2 affects the nervous system remains an enigma, although it is believed to involve both innate and adaptive immune responses [6]. Recent research has established a link between LC-19 and small fiber neuropathy (SFN) and peripheral neuropathy.

These conditions are characterized by the selective damage to small, thinly myelinated A-fibers and unmyelinated C-fibers. The loss of corneal nerve fibers, indicative of neurodegeneration, has also been linked to other diseases such as fibromyalgia, diabetic neuropathy, and even Alzheimer’s disease [7,8,9].

The cornea, as one of the most innervated tissues in the human body, plays a crucial role in transmitting sensory information. It is supplied by sensory nerves from the ophthalmic branch of the trigeminal nerve and a small number of autonomic sympathetic nerve fibers. In vivo confocal microscopy (IVCM) is an invaluable tool for assessing the peripheral nervous system, even in neurodegenerative diseases. Additionally, the cornea is home to dendritic cells (DCs), which act as immune sentinels and contribute to maintaining corneal nerve homeostasis [15,16,17].

Recent studies have identified microneuromas in the sub-basal nerve plexus and stromal nerves in patients recovering from SARS-CoV-2 infection [18]. These microneuromas may signify nerve damage and subsequent regeneration [19].

COVID-19 vaccines have been a critical tool in controlling the pandemic. While these vaccines have proven highly effective in preventing severe disease and death, concerns have arisen about potential neurological complications [20]. It is vital to understand how COVID-19 vaccines impact neuroinflammation, especially in patients with LC-19, to optimize clinical management and patient outcomes.

To date, only a limited number of studies have evaluated corneal innervation in COVID-19 patients. Some have revealed reduced corneal nerve fibers and increased DCs in patients with active COVID-19 and LC-19 patients 3-4 months after infection [21]. However, none of these studies have investigated patients with persistent LC-19 symptoms nearly two years post-infection.

Hence, the aim of this study is to present corneal confocal microscopy findings in LC-19 patients with enduring symptoms over 20 months after their initial COVID-19 infection. This research will contribute to the growing body of knowledge surrounding the long-term effects of COVID-19 and its impact on the nervous system, offering potential insights into the complex interplay between SARS-CoV-2 and the human body.


Long COVID-19 (LC-19), a complex and perplexing condition, continues to be an enigma that has profound implications on the nervous system. Our study delves into the impact of LC-19 on corneal innervation, as revealed through corneal confocal microscopy. We found distinct differences in corneal nerve parameters and dendritic cell (DC) activation among LC-19 patients, with a noteworthy presence of microneuromas. Additionally, we explored the influence of COVID-19 vaccination on these parameters, although this yielded non-significant results.

Our study uncovered a notable reduction in corneal nerve density, shorter corneal nerves, and lower branch densities in LC-19 patients. This supports findings from previous studies, which have reported similar reductions in post-COVID-19 patients, even one month after infection, regardless of the presence of neurological symptoms [26]. While the reasons behind these changes remain unclear, subclinical alterations in the corneal nerve plexus are evident. Interestingly, the duration of these alterations in LC-19 patients persists far longer, with our study revealing these effects up to 20 months post-infection, contrasting the findings of Mirza et al. [26] and Bitirgen et al. [22] at earlier time points.

The underlying mechanisms for corneal nerve involvement are still elusive, but inflammation and biochemical cascades have been implicated. Neuropathological studies have indicated the presence of SARS-CoV-2 in various parts of the nervous system, with associated inflammation and immune responses [27]. This viral impact has also been linked to post-infectious immune-mediated peripheral neuropathy [28], with some improvement observed following plasma exchange [29].

One remarkable discovery in our study is the presence of microneuromas in nine LC-19 patients, constituting 15% of the study population. The formation of microneuromas remains a subject of ongoing research, with links to sprouting from proximal nerve stumps and neuroinflammatory processes [19,30]. These findings add to the growing body of evidence that microneuromas may signify nerve damage and subsequent regeneration. The positive correlation observed between months after infection and corneal nerve fiber density (CNFD) in LC-19 patients suggests that this may be a sign of recovery, although further studies are required to establish this relationship more definitively.

The increased activation of DCs in LC-19 patients, as evidenced by a larger DC area, is consistent with an inflammatory and innate immune response. DCs, which are immune sentinels, play a pivotal role in corneal nerve homeostasis [16,17]. This evidence suggests that immune and inflammatory pathways may contribute to the nerve degeneration seen in LC-19 patients, even 20-24 months after acute infection. Additional research is imperative to explore this theory further.

Notably, there has been limited research on the direct relationship between unvaccinated LC-19 patients and an increase in DCs in the cornea. Our study revealed lower corneal nerve density, higher DC density, and more active DCs in unvaccinated patients, although these findings did not reach statistical significance. Some research suggests that COVID-19 vaccination might increase DCs in the cornea, potentially enhancing local immune responses and viral infection protection [20]. However, it is important to interpret the connection between LC-19 and unvaccinated individuals with caution, considering the small sample size in our study.

In vivo confocal microscopy (IVCM) has proven to be a valuable tool for identifying damage in small fiber neuropathy (SFN) and various disorders of the peripheral and central nervous systems. This noninvasive imaging technique offers a direct visualization of the corneal structure, including the sub-basal nerve plexus, providing invaluable insights into the changes induced by LC-19.

Despite its contributions, our study carries certain limitations. It is a cross-sectional study, which necessitates a longer follow-up to assess potential changes in corneal confocal findings. Additionally, investigating the effects of treatment on these parameters could be a promising avenue for future research.

In conclusion, our study sheds light on the intricate and long-lasting impact of LC-19 on corneal innervation and immune responses, unveiling the complexity of this post-infectious condition. Further research is needed to elucidate the underlying mechanisms and potential therapeutic strategies to alleviate the burden experienced by LC-19 patients. As the world grapples with the ongoing challenges of COVID-19, understanding its long-term effects on the nervous system remains a critical area of investigation.

reference link : https://www.mdpi.com/2075-4418/13/20/3188



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