Statistical Analysis
Data analysis was performed using IBM SPSS Statistics version 17.0 (IBM
Corporation, Armonk, NY, USA). Whether the distribution of continuous
variables was normal was determined using the Kolmogorov-Smirnov test.
Descriptive statistics for continuous variables were expressed as mean ±
SD or median (min-max), where appropriate. Numbers and percentages were
used for categorical data. While the mean differences between the groups
were determined using Student’s t-test, the Mann-Whitney U test was
applied for the comparison of non-normally distributed variables.
Pearson’s χ2 test was used in the analysis of
categorical data unless otherwise stated. In all 2 x 2 contingency
tables, to compare categorical variables, the continuity-corrected
χ2 test was used when one or more of the cells had an
expected frequency of 5-25 while Fisher’s exact test was used when one
or more of the cells had an expected frequency of 5 or less. Multiple
logistic regression analyses were performed to determine the best
predictor of cranial nerve involvement after the adjustment of data for
age and gender. Odds ratios, 95% confidence intervals, and Wald
statistics for each independent variable were also calculated. A p value
of less than 0.05 was considered as statistically significant.
Results:
Of the 356 patients included in the study, 47 below 18 years were
excluded due to unreliable examination and anamnesis findings. In
addition, seven patients who died in hospital were also excluded from
the study because of the lack of long-term results. The data of the
remaining 302 patients were statistically evaluated.
The cranial nerve involvement of the cases included in the study and
their incidence are shown in Table 1. The demographic and clinical
characteristics of the cases with and without cranial nerve involvement
are summarized in Table 2. There was no significant difference between
the groups with and without cranial nerve involvement in terms of age,
female-male distribution, body mass index, comorbidities, intensive care
requirement, median length of stay in intensive care unit, and median
length of hospital stay (p > 0.05). However, the rate of
the patients diagnosed upon complaint was significantly higher in the
group with cranial nerve involvement compared to the group without
involvement, while the rate of those diagnosed by screening was
significantly lower (p < 0.001) (Figure 2).
The frequency distribution of the cases in terms of presentation
complaints is shown in Table 3. No significant difference was observed
between the groups in terms of cough, diarrhea, respiratory distress,
and hoarseness (p > 0.05). However, the rates of patients
presenting with fever, sore throat, tiredness, headache, and joint pain
complaints were statistically significantly higher in the group with
cranial nerve involvement compared to the group without this involvement
(p < 0.05).
The probability of having cranial nerve involvement was statistically
7.714 times (95% CI: 4.309-13.811) higher in patients diagnosed upon
complaint than those diagnosed by screening (p < 0.001) (Table
4). The most determinant complaint in distinguishing between the cases
with and without cranial involvement was headache, followed by sore
throat and joint pain (p < 0.001, p = 0.003 and p = 0.016,
respectively). According to the age- and gender-adjusted data, the
probability of cranial nerve involvement was 4.062 times (95% CI:
1.904-8.667) greater for the patients presenting with the headache
complaint, 2.357 times greater for those with a sore throat (95% CI:
1.337-4.155), and 4.216 times greater for those with joint pain (95%
CI: 1.305-13.623) (Table 4).
In 135 of the 302 patients, symptoms of various cranial nerves were
detected over the 40-day period from the time of diagnosis. Although
many patients had more than one symptom associated with nerve
involvement, isolated involvement was also detected, albeit rarely.
While most symptoms, such as loss of vision, sudden hearing loss,
vertigo, tinnitus, facial paresthesia, and trigeminal neuralgia rapidly
regressed with the initiation of the treatment, it was determined that
smell problems were the last symptom to be relieved (3-60 days). The
latest emerging cranial nerve findings were related to the trigeminal
nerve (facial hypoesthesia and weakness in chewing muscles). In all
seven patients with the complaints of the trigeminal nerve, the symptoms
began to emerge after discharge from hospital (7-13 days). The most
resistant nerve to the virus, with no symptoms, was N. hypoglossus.
Sudden loss of vision developed in one patient during the follow-up.
Pathological contrast enhancement and edema were detected in bilateral
optic nerves in the MRI of the patient. Diplopia, decreased visual
acuity, and eye movement disorder were the other eye symptoms seen among
the patients. Vestibulocochlear nerve involvement was also very common.
Dizziness and tinnitus were observed frequently, and sudden hearing loss
was seen in two patients.
The main problem in all but three patients with facial nerve symptoms
was the loss of the sense of taste. In the remaining three patients,
vague facial paresis findings not exceeding grade 3 were detected.
After discharge from hospital, the patients were called and questioned
about their complaints, and 37 patients with complaints that lasted more
than one month after discharge were called back to the hospital for
re-examination. In one patient, there was no reduction in the severity
of smell loss that was present at the time of presentation, and this
symptom persisted for more than 40 days. A nasal mucosa biopsy was taken
from this patient, and oral and nasal steroids were prescribed. Moderate
epithelial damage was observed in the biopsy (Figures 3 and 4).
Among the 37 patients with symptoms lasting for more than one month,
reduced visual acuity was seen in one patient, tinnitus in four,
numbness of the tongue and loss of taste in 12, hoarseness in one, and
loss of smell in 19.
Discussion:
There are many studies showing that COVID-19 infection is neurotrophic
and neuroinvasive (5-10). The most common
neurological symptoms in COVID-19 are encephalopathy, acute
cerebrovascular diseases, and acute polyradiculopathy or neuropathies
(6, 11).
Neurological symptoms may occur as direct effects of SARS-CoV-2 virus
neurotropism on central and peripheral nervous systems (CNS and PNS), or
as a systemic consequence of a para-infectious or post-infectious
immune-mediated mechanism (6,
12). It is considered that the virus
reaches CNS via neuronal retrograde transmission or hematological
spread. In addition, the effects on CNS and PNS are thought to occur
through the virus entering the cell using ACE-2 receptors
(9, 13).
However, it is not known whether cranial nerve involvement is directly
caused by CNS or the direct invasion of peripheral nerves nor is it
clear whether this damage is caused directly by the virus or the immune
system response triggered by the virus. There are many publications
reporting that the carnal nerves are affected by COVID-19. Mao et al.
evaluated neurological symptoms in 214 patients infected with COVID-19.
It was observed that 36.4% of these 214 patients who were hospitalized
had nervous system findings such as dizziness, headache, taste
disturbance, hyposmia, muscle damage, and hemorrhagic and ischemic brain
damage (8). However, Mao et al. observed
the effects of the virus on peripheral nerves and CNS rather than
cranial nerves. We consider that the emergence of neurological findings
alone is not an indicator of poor prognosis, as previously assumed
because we did not determine a statistically significant difference
between the groups with and without cranial nerve involvement in terms
of length of hospital stay and intensive care requirement. In
particular, both in our study and among the reported cases, the presence
of patients with complaints such as sudden vision loss, sudden hearing
loss, sudden-onset severe peripheral vertigo, and sudden movement
limitation in the eye suggests that COVID-19 involves aggressive
neurotropism and neuroinvasion. The current literature contains reports
on cranial nerve involvement in patients with COVID-19; e.g., dysphagia
caused by N. glossofarengeus, N. vagus and N. hypoglossus damage
(12), as well as presence of damage to N.
vestibulocochlearis (14), N. facialis
(15-17), N. oculomotorius
(18, 19),
N. abducens (20,
21), N. trochlearis
(22), N. opticus
(23) and N. olfactorius
(14, 15,
17, 24).
COVID-19 has also been reported to cause neurological syndromes such as
Guillain–Barré syndrome and Miller Fisher syndrome
(6, 20,
25). Despite all these data, we did not
find any study on the prevalence of these cranial nerve symptoms in
patients in the current literature. In a study conducted by Mao et al.,
damage to the peripheral nervous system and CNS was discussed in the
majority of patients, but cranial nerve functions were not emphasized,
except for taste and smell disorders (8).
Bagheri et al. investigated olfactory disorders in people infected with
COVID-19, but only used an online survey to identify patients
(24). In the current study, we tried to
evaluate all cranial nerve involvements together in people infected with
COVID-19 and to reveal their prevalence in infected patients. For this
purpose, we deemed it appropriate to make a diagnosis based on a direct
examination. Only after the patients’ discharge from the hospital, we
administered the survey through phone calls to determine the development
or regression of existing symptoms. However, we can state that there are
still some important points that have not yet been fully explained.
Although we still cannot explain the exact mechanism, some cranial
nerves are affected more frequently in the very early period while
others occur later. For example, while patients had symptoms of a very
high degree of loss of taste and smell at the time of direct
presentation, they rarely presented with ophthalmoparesis, dysphagia, or
vision and hearing loss. In a multicentric survey study conducted in 12
hospitals from different regions of Europe, the rate of loss of smell
and taste in COVID-19-infected patients was found to be 85.6% and
88.0%, respectively(26). This led us to
consider that the most important factors for this virus settled in the
respiratory tract to cause cranial nerve damage are the response it
triggers in local immunity and direct nerve invasion. As we mentioned
earlier, if the most common symptoms of loss of smell (27.2%) and taste
(30.8%) had occurred as a result of damage caused by the virus in CNS
or systemic immune response, we would expect it to occur at a frequency
close to other cranial nerve involvement. However, while N. facialis and
N. ophthalmicus, the cranial nerves that are closest to the respiratory
tract and branch into this region, are frequently affected, N.
hypoglossus, N. glossopharyngeus, N. vagus, and N. trigeminus were less
frequently involved, which raises further questions that need to be
answered. Nevertheless, we believe that the size of the areas in which
these nerves innervate in the respiratory tract will naturally increase
their exposure, which is a factor to be considered in explaining this
situation. Another important finding of our study was that among the
patients hospitalized due to COVID-19, those with swallowing disorders
due to glossopharyngeal and vagal nerve involvement had a more severe
disease process and required a longer hospital stay since their food
intake was impaired.
Limitations: The major limiting factor of our study is that we did not
have any evidence (such as pathological examination or nerve biopsy
sample) to show the direct damage of the virus on the nerves. Although
we are not sure, we cannot go beyond predicting whether this damage
occurs as a result of the direct effect of the virus or the development
of an immune response-mediated mechanism. In addition, there are
publications indicating that that the virus is frequently mutated, but
we did not know whether the virus type in the patients we evaluated was
mutated or whether all patients were infected with the same strain,
which can be considered as another limitation.
In conclusion, the COVID-19 disease caused by the SARS-CoV2 virus
commonly leads to cranial nerve symptoms. During our study, we observed
symptoms of the involvement of very different cranial nerves apart from
taste and smell disorders reported in previous studies. However, further
studies are needed to provide more definitive results concerning whether
these nerve damages are permanent or temporary. Our first impression is
that symptoms such as smell, taste, vision and sudden hearing loss,
vertigo, swallowing disorders, hoarseness, eye symptoms, and facial
hypoesthesia completely disappear within the first month of the
infection. Taste and smell disorders rarely last more than one month.
Therefore, we consider that these symptoms often do not require any
special treatment, and cranial nerve symptoms regress with the current
COVID-19 treatment protocol. In addition, as an interesting finding, we
determined the dominant effect of cranial nerve involvement on sensory
dysfunction compared to motor functions, suggesting that the virus
causes more sensory dysfunction. While the negative effects of the virus
on sensory functions are evident, motor functions are less frequently
affected.