1. Introduction
Coronavirus disease (COVID-19) is an infectious disease caused by the SARS-CoV-2 virus [
1]. In Croatia, approximately 1.27 million cases of COVID-19 infection and 18,230 deaths caused by COVID-19 were reported. To this day, approximately 5.36 million doses of the vaccine have been administered, with 2.32 million people having received at least one dose of the vaccine (57.60% of the population) and 2.25 million people who were fully vaccinated (55.87% of the population). The vaccination rate in Croatia is below average, considering that the average percentage of the fully vaccinated population in Europe is 66.24% [
2]. More strikingly, the death per capita rates put Croatia in seventh place in the world, with approximately 4523 deaths per 1 million inhabitants, highlighting the great toll that the pandemic had on society [
3]. The burden of COVID-19 is not measured only in deaths, and unfortunately, a large proportion of patients have continuous post-COVID-19 problems [
4].
Post-COVID-19 syndrome is a multisystemic disorder that includes about 50 symptoms [
5]. Due to the lack of a definition for post-COVID-19 syndrome, the WHO issued the Delphi guidelines, which define post-COVID-19 syndrome as a condition that occurs in individuals with a history of SARS-CoV-2 infection, usually 3 months after the onset of infection, with symptoms that last at least 2 months and cannot be explained by an alternative diagnosis. Common symptoms include fatigue, shortness of breath, and cognitive dysfunction. Symptoms may persist from the initial infection or may arise de novo after recovery from the disease [
6]. Although COVID-19 is primarily presented with respiratory symptoms, neurological manifestations of this disease are being increasingly recognized [
7].
There are two ways for the entry of theSARS-CoV-2 virus into the central nervous system (CNS). The first viable way of invasion into the CNS is through the olfactory nerve. It is thought that SARS-CoV-2 can enter the nervous system by crossing the neural-mucosal barrier in the olfactory mucosa and penetrating the neuroanatomical areas, including the primary respiratory and cardiovascular centers in the medulla oblongata [
8,
9]. There is clear evidence that SARS-CoV-2 can cause significant morphological and functional changes in the CNS, which could be the basis for the development of long-term post-COVID-19 syndromes [
10,
11].
It has been suggested that the chronic neurological symptoms of post-COVID-19 syndrome be classified into four groups: (I) cognition, mood, and sleep disorders; (II) dysautonomia; (III) pain syndromes; and (IV) exercise intolerance [
12]. The prevalence of the most common neurological COVID-19 symptoms included fatigue (32%), myalgia (20%), taste impairment (21%), smell impairment (19%), and headache (13%) [
13]. Brain fog and depression/anxiety also occur frequently during follow-up, suggesting their relevance to long-term COVID syndrome [
14].
Studies have shown that neurological post-COVID-19 symptoms can persist for even a year after the initial infection. When symptoms are compared between the 3-month follow-up and 1-year follow-up examination, there is an improvement in patient outcomes. However, a portion of patients experience new-onset neurological symptoms [
15]. There is still not enough data on the outcomes of the neurological post-COVID-19 syndrome.
Due to the significant burden of COVID-19 in Croatia and large patient numbers during previous pandemic waves, we have established a separate post-COVID-19 outpatient clinic to facilitate faster examinations and follow-ups. The large number of patients and the variety of symptoms led to the aim of this study, which was to retrospectively assess the frequency and characteristics of neurological symptoms of post-COVID-19 syndrome in our outpatient clinic, including the diagnostic and therapeutic measures that were taken in the treatment of these patients and what outcomes the patients had.
4. Discussion
We present the results from the neurological post-COVID-19 outpatient clinic of CHC Rijeka for the period of 11 May 2021 to 22 June 2022. An analysis of 227 patients revealed that headache (30%) and cognitive impairments (29%) were the most common neurological post-COVID-19 symptoms. Such results are expected, considering that these are one of the most common neurological disorders in the general population. According to some studies, 46% of the population suffers from headaches [
16], while cognitive problems predominantly affect the elderly population and can affect up to 70% of the population over 60 years of age [
17]. Additionally, a significant portion of patients complained about smell disorders (17%), paresthesia (16%), chronic fatigue (15%), and dizziness, accompanied by nausea and vomiting (15%). According to the meta-analysis by Lopez-Leone and colleagues, the most common neurological symptoms of the post-COVID-19-syndrome are, precisely, chronic fatigue, headache, cognitive complaints, and smell disorders, which is in accordance with the data obtained in our research [
18]. Most studies support chronic fatigue as the most common symptom of post-COVID-19 syndrome, which is present in 32% to 58% of post-COVID-19 patients [
18,
19,
20,
21], while according to the results of our research, it is the fifth most frequent symptom in the Rijeka Clinical Hospital Center, present in only 15% of patients. Sykes et al. concluded that the symptoms of neurological post-COVID-19 syndrome can be divided into three groups. Group A includes myalgia and chronic fatigue, group B low mood, anxiety and sleep disorders, while group C consists of patients with cognitive impairments [
22].
From the data analysis, it is evident that twice as many women were examined in the post-COVID-19 neurological outpatient clinic, which could indicate a higher frequency of post-COVID-19 syndrome in women. A multicenter study by Fernández-de-las-Peñas et al. indicated that the female gender is associated with a higher risk of developing post-COVID-19 syndrome, with an emphasis on depression, anxiety, and sleep disorders [
23]. According to the research of Bai et al., women even have a three times greater risk of being diagnosed with post-COVID-19 syndrome [
24]. Finally, a recent review by Sylvester et al. highlighted that there are present sex-disaggregated differences for COVID-19 sequelae and long-COVID syndrome, with a higher frequency found in women [
25]. The fact that the post-COVID-19 syndrome is more frequent in women may indicate a potential contribution of autoimmunity in the development of this complication of SARS-CoV-2 infection [
26]. However, it is important to highlight that the magnitude of the difference could be impacted by the propensity of women to seek healthcare more often, especially in the ages found in our study [
27,
28]. According to the obtained results, there is a clear difference in the frequency of individual symptoms between genders. For example, in women, headaches were almost twice as common as in men, taste disorders were three times more common, while psychiatric disorders were even four times more common. On the other hand, symptoms such as neuropathic pain, balance disorders, syncope, presyncope, and collapse were two times more common in men. According to the research published so far, there is a difference in the distribution of symptoms between the genders, which does not fully agree with the results obtained in our research. According to previous data, chronic fatigue and psychiatric problems occur more often in women [
29,
30]. On the other hand, there are studies in which the gender distribution of symptoms is not present, however, they occur in equal proportions in both sexes [
31,
32]. So far, a small number of studies investigating gender differences in neurological post-COVID-19 syndrome have been conducted, and there is room for research on this topic.
The diagnostic procedures included a very wide range of tests, the most common of which were consultative examinations by specialists from other branches of medicine, which is expected due to the polymorphism of post-COVID-19 syndrome symptoms. Neuroradiological methods, EEG, and neurosonological tests were the next most frequent. Since the most common neurological symptoms of post-COVID-19 syndrome are headaches and cognitive problems, these diagnostic methods are justifiably more frequent. Neuroradiological methods are recommended in all patients with headaches, new neurological deficits, new and sudden severe headaches, HIV-positive patients with a new type of headache, and patients over 50 years old with a new headache [
33], and they are undoubtedly indicated in patients with an acute onset of cognitive impairment and/or rapid neurological deterioration [
34]. Neuropsychological damage is not always associated with abnormal MRI findings, however, in a subset of patients with post-COVID syndrome, the MRI shows white matter lesions that are not limited to patients with severe disease. Therefore, changes associated with the disease of COVID-19 could be considered in the differential diagnosis of white matter lesions [
35,
36]. EEG abnormalities are common in patients with COVID-19 and include a wide range of findings, such as background abnormalities, periodic and rhythmic activity, and other epileptiform abnormalities [
37]. The surprising result is the relatively low frequency of psychological testing, to which only 14% of patients were referred, as many patients have rejected further diagnostics for the present cognitive dysfunction. Psychological testing is among the main diagnostic tools for the evaluation of cognitive functions [
38], and given the relatively high proportion of patients who complained of cognitive impairment, it was expected that this would be one of the most common diagnostic procedures.
Therapy was most often not prescribed and was recommended in 23% of patients, indicating a lack of a clear therapeutic plan in post-COVID-19 patients. Since the etiology of the post-COVID-19 syndrome is still not fully known, therapy is usually limited to symptomatic treatment. Therefore, the prescribed therapy mostly depends on the manifestations of the post-COVID-19 syndrome. The most frequently prescribed therapy was vitamin supplements, followed by antidepressants, analgesics, and anxiolytics. Research by Naureen et al. indicates the possible benefits of using multivitamin dietary supplements in patients suffering from post-COVID-19 syndrome. Vitamin complexes containing B vitamins, vitamin C, vitamin D, acetyl L-carnitine, and hydroxytyrosol could be crucial in the treatment of chronic fatigue [
39]. Currently, no pharmaceutical drugs have been shown to alleviate the symptoms of post-COVID-19 syndrome, however, paracetamol and NSAIDs can be used to treat specific symptoms, such as fever and pain [
40]. Creating a rehabilitation plan can be helpful for some patients and may include physical and occupational therapy, speech and language therapy, and neurologic rehabilitation of cognitive symptoms. A gradual return to exercise has been hypothesized to have a beneficial effect on post-COVID-19 symptom relief [
41]. Early rehabilitation has been shown to be critical for improving patients’ long-term recovery and functional independence, so rehabilitation should begin as soon as possible. The rehabilitation program must be personalized and focused on solving the specific problems of the patient [
42].
To the best of our knowledge, only a few prospective studies monitoring the outcome of patients with neurological post-COVID-19 syndrome were published. According to Jennifer A. Frontera et al., patients with neurological complications of COVID-19 had significantly worse outcomes at 6 months [
43]. In a 3-month follow-up study conducted in Italy, there was no significant change in the symptoms between the 1-month and 3-month follow-up examinations, which is similar to our results, as no change in the symptoms is the most common outcome [
44]. Physical therapy and rehabilitation have been shown to benefit the patient’s recovery and increase the probability of positive functional outcomes [
45,
46]. It is important to highlight that most patients did not come to follow-up visits, which could indicate a positive outcome and alleviation of symptoms, although this is speculative and cannot be confirmed by this study. There is much to learn about this syndrome, especially relating to the outcomes, and further follow-up is required.
This study has several limitations. First, the time frame for patient assessment was not standardized, so the study included patients with different time intervals since recovering from COVID-19. For this reason, it is not possible to assess whether there is a difference in the frequency of occurrence of post-COVID-19 symptoms regarding the time that has passed since the infection. Secondly, data on pre-existing comorbidities were not collected from the patients. This is very significant because research has shown that people with a greater number of comorbidities have a higher risk of developing post-COVID-19 syndrome [
47]. Furthermore, due to the retrospective nature of the study, we were not able to discern which COVID-19 variant was present in our patients and whether this might impact the nature of the symptoms. We have decided not to include patients who had symptoms appear after vaccination with one of the approved vaccines against the SARS-CoV-2 virus, which limits the possibility of assessing the potentiated impact of vaccination on the frequency and intensity of the symptoms.