Most of the publications included in the present review report an impaired sense of smell and taste (43%). Moreover, evidence suggests that between 51% and 67% of patients with mild COVID-19 report impairment of these senses. However, only one study⁸⁰ conducted in South Korea in 3 191 patients reported the prevalence of acute anosmia or ageusia in 15.3% (n=488/3 191) of patients in the early stages of COVID-19 and 15.7% (n=367/2 342) of patients with asymptomatic-to-mild disease severity. It should be noted that the main limitation of this research is that it studied the complete impairment of these senses, omitting the review of partial alterations.

On the other hand, a lower prevalence of these disorders was observed in patients with moderate and severe COVID-19 (23%-40%, respectively), since most of the analytical studies reviewed reported that the presence of these neurological manifestations was significantly more frequent in young people, women, patients without comorbidities, and patients with mild COVID-19. Furthermore, the only publication suggesting that there might be a direct association between disease severity and olfactory impairment is the study by Vaira et al., ⁶⁶ in which a statistically significant correlation was found between the severity of olfactory or gustatory impairment and the presence of fever, altered oxygen saturation, and requirement for hospitalization in patients with severe SARS-CoV-2 infection.

Studies using standardized tools for measuring smell and taste impairment (such as the SinoNasal Outcome Test 22 [SNOT-22] and the Quick Smell Identification Test [Q-SIT]) confirm that COVID-19 patients experience these impairments more frequently than the general population.^75,82,87 Likewise, these studies suggest that the duration of sensory impairment is proportional to its severity. These papers also report that smell and taste disorders cannot be objectively confirmed in 26-51% of the patients who report them.

Regarding the usefulness of smell and taste impairment as a marker for COVID-19, three aspects stand out. First, case-control studies clearly showed that these disorders are significantly more frequent in patients with COVID-19 than in the general population.^86,87 Second, individuals who report the presence of smell and taste impairment are more likely to have COVID-19 if they also have other symptoms of infection; for example, Menni et al.⁸⁵ report that smell and taste impairment, fatigue, persistent cough, and loss of appetite were significantly associated with SARS-CoV-2 infection. Thirdly, it has been reported that the main differential diagnosis in cases of sudden smell and taste impairment is nasal obstruction due to other causes, such as allergic rhinitis.⁷²

Concerning the onset and duration of symptoms, data are quite heterogeneous. The reviewed publications report that between 9% and 15% of patients presented anosmia as the first symptom of the disease.^73,81 Also, most patients report partial smell and taste impairment and a recovery time of 10 to 14 days, although some cases may require up to 1 month to recover.^71,73,80

It is noteworthy that recovery seems to be related to the degree of smell and taste disorder, since patients with anosmia took longer to recover than those with hyposmia.^66,70,76,82

Likewise, a prolonged duration of these impairments could be associated with the severity of COVID-19; however, the correlation between the severity of smell and taste impairment and the severity of COVID-19 has not been clearly established.⁶⁶ The most relevant aspects of this disorder are presented in Figure 2.

Figure 2 Source: Own elaboration.

Sixteen articles (case studies and case series) were retrieved, reporting 20 COVID-19 patients with neuropathies, polyneuropathies, and polyradiculopathies. In general, these patients were younger than 60 years of age (only 7 were older) and had few comorbidities since only three of them had hypertension and one had paranoid schizophrenia (a 48-year-old man). Additionally, more than half of these patients had mild COVID-19, while only 3 had severe COVID-19, and no participant died. This may be related to the moment of neuropathy onset because, in most cases, the neuropathy occurred after the acute stage of the disease.

Regarding the type of neuropathy, most cases corresponded to Guillain-Barré syndrome (GBS) or one of its variants, and its onset occurred between 6 and 21 days after the onset of signs and symptoms; it was also reported that these neurological manifestations usually occurred after the onset of respiratory and systemic symptoms of COVID-19. This is consistent with reports in similar studies.⁹⁰

Other types of neuropathy found were facial paralysis, hearing impairment, and supranuclear ophthalmoplegia. In general, the prognosis of patients with peripheral nerve involvement was good and chronic symptoms were reported in only one case. This case involved a 72-year-old man who had had mild COVID-19 (which manifested only with diarrhea) and whose comorbidities included hypertension, coronary artery disease, and alcoholism. This patient presented a very severe form of GBS and dysautonomia and had an unfavorable progression, requiring tracheostomy and percutaneous endoscopic gastrostomy tube placement.²⁸

While only one of the retrieved analytical articles focuses on investigating the association between headache and COVID-19, 11 publications report data on this symptom (Table 3).^{69-71,75,77,79,82-84,86,89} In 8 of them, the prevalence of headache in patients with COVID-19 exceeds 50% and even reaches 82%. Importantly, most of these patients had mild SARS-CoV-2 infection. In fact, prevalence data below 50% is for patients with moderate and severe disease.

Despite the above, headache is considered a nonspecific symptom and is not included in the items considered in the diagnostic algorithms for COVID-19. In general terms, this symptom seems to be more frequent in women and in patients with a history of primary headache.⁸⁹

The behavior of neurological manifestations in patients with SARS-CoV-2 infection had a different distribution across extremes of age. One of the conditions presenting in elderly patients is delirium. In the case reports and case series in which this disorder was reported,^30,31,57,62 all patients (n=8) were older than 65 years and, at the same time, they had more comorbidities than the patients described in the other case reports included in the present review. In addition, half of these patients had mild COVID-19 (n=4), but it is striking that 3 of these participants had dementia and the other had paranoid schizophrenia. These findings confirm that patients with dementia, even if they have mild COVID-19, are at increased risk of developing delirium. Moreover, case reports reporting data on symptoms of delirium or mental confusion indicate that these symptoms appeared within the first four days from the onset of disease symptoms,^31,62 suggesting that delirium may be an early neurological manifestation in older adults.

On the other hand, it was found that the presence of delirium is a marker for poor prognosis in older adults with severe COVID-19. In this regard, in the study by Helms et al.,⁸⁸ patients with delirium required invasive mechanical ventilation for a longer time and had a longer stay in the intensive care unit (ICU) than those without delirium and with a normal neurological examination.

At the other extreme of age, very few articles reported data on pediatric patients, which is a limitation for the representativeness of all population groups. On this point, only four of the publications reviewed explicitly refer to children; actually, being of legal age is one of the inclusion criteria in most of the studies reviewed. In particular, two of the four articles report smell and taste impairment. On the one hand, in the study by Somekh et al.,⁶⁸ in which 31 of the patients were between 5 and 17 years of age, it was found that these symptoms were less frequent in this age group (children: 26%; adults: 71%). On the other hand, in the United Kingdom, Mak et al., ⁵⁵ described three cases of adolescents between 14 and 17 years of age with COVID-19 who presented loss of smell and/or taste.

The other two articles are individual case reports. The first reports the case of a previously healthy 11-year-old boy who presented status epilepticus and was subsequently diagnosed with encephalitis based on the findings of cerebrospinal fluid analysis. Based on what was reported, the patient tested positive for COVID-19 as well as for rhinovirus/ enterovirus on nasal swab test, although no evidence of the latter was found in this fluid, and finally, the child recovered completely in 6 days without the need for treatment.⁴¹

The second reports a case of COVID-19-associated rhabdomyolysis in a 16-year-old patient with autism spectrum disorder, attention deficit hyperactivity disorder, morbid obesity, obstructive sleep apnea, and eczema. According to this report, the patient, who tested positive for COVID-19, presented with myalgia, fever, mild shortness of breath, and dark-colored urine, and his creatine phosphokinase level was 427 656U/L, leading to a diagnosis of rhabdomyolysis. Finally, the child progressed satisfactorily during hospitalization and was discharged after 12 days with creatine phosphokinase levels of 6526U/L.⁴⁵

In addition to severe forms of GBS and cases of delirium that were associated with extubation difficulties and longer ICU stay, other severe neurological manifestations associated with COVID-19 have been described. Although the case of a pediatric patient with encephalitis was mentioned above, inflammatory involvement of the central nervous system was also reported in five other patients in the publications reviewed. Of these, a case of acute disseminated encephalomyelitis following SARS-CoV-2 infection in a 64-year-old woman with hypertension and vitiligo stands out.⁴² Also, 3 patients between 35 and 59 years of age (2 with severe COVID-19 and 1 with mild COVID-19) were reported to have encephalitis in the second week after symptom onset.^37-39 It is noteworthy that only 1 of these 3 patients had comorbidities and, in fact, was the only one who died.

Likewise, a series of three cases of patients aged 33, 77 and 55 years with mild COVID-19 from the United States, who were admitted to the emergency department due to clinical symptoms of stroke, was retrieved. In these three cases, internal carotid artery thrombosis was documented.⁶⁰

In addition, epileptic seizures associated with SARS-CoV-2 infection were reported in 6 patients, of whom 1 had severe infection and 2 had a previous diagnosis of epilepsy.^{32,33,35,36,64} In 5 of these patients, the onset of seizures was focal, while in the other one it was described as generalized tonic-clonic. In turn, 4 of the 6 patients presented status epilepticus, of which 2 had de novo status epilepticus, 1 had sequelae of herpetic encephalitis, and the other had thrombosis of the venous sinuses requiring craniotomy. Besides epileptiform activity, electroencephalogram monitoring reported encephalopathic tracing and graphoelements, such as periodic lateralized epileptiform discharges.

Other non-epileptic paroxysmal disorders were also described in some patients. The occurrence of vasovagal syncope was reported in 5 patients, most of whom were over 65 years of age,^34,65and only 1 of them reported the presence of convulsive epileptic seizures associated with vasovagal syncope, as well as autonomic dysfunction.³⁴ Finally, a series of three patients with generalized non-epileptic myoclonus, similar to the startle reflex, was interpreted as a para-infectious immune-mediated disorder.⁶³ None of the patients with vasovagal syncope or myoclonus had severe COVID-19.

Regarding the limitations of this literature review, two aspects should be mentioned that could have affected the inclusion of all the articles published on this topic in the period analyzed.

First, there is an underreporting of clinical manifestations that may be interpreted as general manifestations, but which, in other contexts, may be considered neurological. Such is the case of symptoms like myalgias, which are not the main objective of any of the articles retrieved, but are reported in at least 12 of the patients described, of which only 3 presented rhabdomyolysis.^{16,17,23,35,37,44-47,50,63,64} In addition, some of the descriptive articles reviewed report prevalence figures of myalgia in patients with COVID-19 between 25% and 57%,^84,86,89 which is similar to those described in patients with headache, as mentioned above.

Second, some articles may not have been identified because, although they address this topic, they do not meet the parameters of the proposed search strategy, for example, those that do not include the selected keywords. Despite the above, the results obtained in this literature review allow us to establish an overview of the neurological manifestations in patients with COVID-19 infection.