key: cord-0948001-trzklu4c authors: Yuksel, Hatice; Tutal Gursoy, Gorkem; Bilge Dirik, Ebru; Gül Kenar, Safiye; Bektaş, Hesna; Yamanel, Levent; Rahmet Güner, Hatice title: Neurological Manifestations of COVID-19 in Confirmed and Probable Cases: A Descriptive Study from a Large Tertiary Care Center date: 2021-01-22 journal: J Clin Neurosci DOI: 10.1016/j.jocn.2021.01.002 sha: 3a078fe2019f481e433232f1025bcd980fba8abb doc_id: 948001 cord_uid: trzklu4c During the early phase of the COVID-19 pandemic, it was thought that virus affects only the respiratory system. However, now it is clear that it can affect other systems too, particularly the nervous system. We aimed to identify the most common neurological symptoms and findings of COVID-19 in hospitalized patients and investigate the relationship between these symptoms and clinical, radiological, and laboratory findings. A total of 307 patients, including 125 women and 182 men, were included in the study. They were classified as “confirmed cases” or “probable cases” based on confirmatory tests, including polymerase chain reaction testing of a nasopharyngeal sample or validated antibody test. All medical records, including medical history, clinical course, laboratory data, and radiographic studies, were evaluated by two expert neurologists. Altered mental status (AMS) is the most common neurological finding in both confirmed (68.1%) and probable cases (71.8%). Pre-existing neurological diseases were detected as an independent risk factor for AMS. The mortality rate of patients with AMS was dramatically higher than normal mental status in both confirmed (43.9% vs. 6.2%) and probable cases (47.3% vs. 6.9%)(for both p:0.001). The frequency of seizure attacks was 13.2% in confirmed and 17.5% in probable cases (p:0.321). The mortality rate was higher in patients with a seizure attack in both groups. We conclude that AMS was one of the most common neurological manifestations in this cohort of COVID-19 patients. The development of mental deterioration increases mortality dramatically. Also, the existence of seizure attacks was associated with a high mortality rate. Although the frequency of having "at least one medical comorbidity" and "at least one neurological comorbidity" in probable cases was higher than the confirmed cases, there were no significant differences between them (p:0.064, p:0.150, respectively). The frequencies of history of stroke, atrial fibrillation, and chronic pulmonary disease were higher in probable cases than in confirmed cases (p:0.038, p:0.016, and p:0.021, respectively) ( Table 1) . The most common neurological symptom in both confirmed and probable cases was impaired consciousness (p:0.570). The other neurological symptoms were shown in Table 2 . AMS is the most common neurological findings in both groups. There was no difference between the two groups in terms of the level of consciousness (p:0.171) ( Table 2) . On neuroimaging findings, the frequency of infarct, edema, and hemorrhage was higher in probable cases (p:0.003, p:0.001, and p:0.023, respectively). In addition, cerebral venous thrombosis was detected in 4 of the confirmed cases, while brain abscess was observed in one of the probable cases (Table 2) . On chest CT findings, bilateral involvement of the lungs in confirmed cases (75.0%) was more common than probable cases (60.2%) (p:0.001). White blood cell (WBC) count and creatinine level were higher in probable cases than confirmed cases (p:0.001 and p:0.019), whereas hemoglobin was lower (p:0.02). There was no difference between the two groups regarding all other biochemical, hematological, and coagulation parameters ( Table 2) . The mean age in the AMS group was higher than the NMS group (p:0.001). AMS and NMS groups were similar in terms of gender (p:0.780) ( Table 3) . While the mortality rate in the AMS group was 43.9%, it was only 6.2% in the NMS group (p:0.001). Also, the number of patients requiring intensive care and intubation in the AMS group was higher than in the NMS group (for both p:0.001) ( Table 3 ). The existence of "at least one medical comorbidity" in the AMS group was substantially more frequent than in the NMS group (p:0.042). Although the presence of "at least one neurological comorbidity" was more common in the AMS group than in the NMS group, the difference was not significant (p:0.173) ( Table 3) . On neuroimaging findings, frequencies of infarction, edema and hemorrhage were comparable in the AMS and NMS groups (p:0.104, p:0.107, and p:0.735, respectively) ( Table 3 ). The AMS group and NMS group were similar in terms of lung involvement on chest CT (p: 0.844). Biochemical and inflammatory parameters in the AMS and NMS groups are presented in Table3. In binary logistic regression analysis, brain edema, brain hemorrhage, presence of neurological comorbidity, and age were determined as independent risk factors for AMS in the confirmed cases (Table 4 ). The AMS and NMS groups were similar in terms of age (p:0.175). The AMS group included more women than the NMS (p:0.010) (Table5). The mortality rate, number of patients requiring intensive care, and intubation in the AMS group was higher (p:0.001, p:0.001 and 0.012, respectively) ( Table 5 ). The frequency of having "at least one neurological comorbidity" in the AMS group was higher than in the NMS group (p:0.005). Although the presence of "at least one medical comorbidity" was more common in the AMS group than in the NMS group, the difference was not significant (p:0.381) ( Table 5) . On neuroimaging findings, edema was present more frequently in the AMS group when compared to the NMS group (p:0.006). Infarct in the AMS group was lower than in the NMS group, although the difference was not significant (p: 0.307) ( Table 5) . Bilateral lung involvement in the AMS group was higher than the NMS group on chest CT (p:0.021) ( Table 5 ). Biochemical and inflammatory parameters in the AMS and NMS groups are shown in Table 5 . In binary logistic regression analysis, brain edema, the severity of lung involvement, presence of neurological comorbidity, and gender were determined as independent risk factors for AMS in the probable cases (Table 4) . Twenty-seven patients (13.2%) in confirmed cases and 18 patients (17.5%) in probable cases had seizure attacks. The characteristics of patients with seizure attacks in confirmed and probable cases are shown in Table 6 . Our results demonstrated that the most prominent neurological manifestation in both confirmed and probable cases was altered mental status. Infarct was the most common neuroimaging finding. The mortality rate for confirmed and probable cases was similar. In the case of mental deterioration, the mortality rate was found to increase dramatically. Brain edema, hemorrhage, neurological comorbidity, the severity of lung involvement, and age were independent risk factors for mental deterioration. The altered mental state has been reported as the most common neurological problem in COVID-19 [4, 13] . In accordance with these studies, our findings showed that AMS might be the most common neurological problem in COVID-19. Although current information on COVID-19 infection is insufficient, it is suggested that the main mechanism responsible for manifestations of the central nervous system is not due to direct viral invasion. Given the lack of comprehensive diagnostic neurological investigations due to pandemic limitations, studies could not clearly establish the cause of AMS and encephalopathy [4, 7, 8] . However, AMS can occur as a result of a wide variety of causes, including toxic-metabolic status, cerebral vascular events, autoimmune mechanisms, encephalitis, and meningitis [2, 5, 8] . Some of our patients had neuroimaging findings that could explain AMS. Although we cannot clearly identify the reasons for the mental status change in our other cases, we can suggest that it is due to metabolic and hypoxic causes. Neurological disorders are more common in elderly patients [8, 14] . Consistent with this, our patients with AMS were about one decade older than patients with NMS. Pre-existing medical comorbidities play an important role in the development of neurological disorders [11, 12] . In our study, pre-existing medical comorbidities were higher in patients with AMS. At the same time, we have demonstrated that pre-existing neurological comorbidities are independent risk factors for AMS. Given the available information, altered mental status in COVID-19 has been associated with increased mortality and morbidity [4, 7, 8] . We also observed that the development of mental deterioration increases mortality dramatically. Seizure attack has been reported as one of the central nervous system manifestations of COVID- 19 . The frequency of seizures reported in the studies was between 0.5% and 4% [4, [6] [7] [8] . In our study, the frequency of seizure attacks was determined as 13.2% in confirmed and 17.5% in probable cases. Compared to other studies, the frequency of seizure attacks was higher in our study. This high frequency in our cases was that our study population consisted of patients who developed neurological symptoms. Besides, a history of pre-existing epilepsy and comorbidities may be responsible for this high seizure rate. The frequency, causes, and pathogenesis of seizures in COVID-19 infection have not yet been clearly revealed [15] . The virus entering the central nervous system can disrupt the blood-brain barrier. This process may trigger epileptic activity. Also, hypoxia, electrolyte imbalances, mitochondrial dysfunction, thrombotic state, metabolic disorders, and medications can initiate seizure attacks [15, 16] . In our study, we detected electrolyte imbalance, deterioration in renal functions, fulminant liver failure, and cerebrovascular events in patients with seizure. Sun et al. reported high mortality in COVID-19 patients with seizure [15] . We also demonstrated that the mortality rate in patients with seizure was very high. We demonstrated some patients with infrequent neurological disorders, including Myasthenia gravis (MG), Multiple sclerosis (MS), Parkinson's disease (PD), and Guillain-Barré syndrome (GBS) in our study population. Given the lack of well-designed studies, the approach to these diseases in COVID-19 is shaped based on case reports and authors' opinions [17] [18] [19] . In the COVID-19 period, the problem of how to approach autoimmune based neurological diseases such as MG has not been clarified yet. MG patients may become at risk for COVID-19 due to immunosuppressive therapy and existing respiratory system problems. On the other hand, COVID-19 can make MG more severe [17, 20] . In light of the available data, when immunosuppressives are used carefully, they seem to not increase the risk of COVID-19, and may even have a protective role [17, 21, 22] . There were two MG patients in our study. Our first patient had a recently diagnosed severe form of MG. The patient did not respond to COVID-19 and MG treatments including IVIG, plasmapheresis, and tocilizumab, and died. The second patient with stable MG developed respiratory distress after COVID-19, and the steroid dose was increased. The patient, whose complaints improved, was discharged. Disease-modifying drugs (DMDs) used in MS treatment have been associated with an increased risk of infection. [23] [24] [25] . Nevertheless, studies have not shown a significant relationship between the use of DMDs and an increased risk of COVID-19 [23, 26, 27] . Since the clinical worsening of MS patients who are left untreated or not effectively treated would cause poor outcomes, some authors have suggested that MS patients should continue the treatment with the drugs they took before the pandemic [19, 27, 28] . There were two MS patients in our study. While PD is a neurological problem that deserves consideration in the COVID-19 pandemic. Recent studies reported that advanced age and long-term disease increase mortality in advanced PH [18, 29] . In one study, it was emphasized that COVID-19 worsened motor symptoms and that the dopaminergic treatment may need to be increased [29] . We had 10 PD patients, and mental deterioration developed in seven, speech impairment in two, and paresthesia in one. All but one of our patients was over 65 years old, and all had concomitant diseases. Two of the patients who presented with AMS died. We adjusted the medication dosage in one patient who developed dyskinesia. COVID-19 affects the peripheral nervous system as well as the central nervous system. GBS is thought to be the peripheral nervous system manifestation of COVID-19 [12, 30] . The first cases demonstrating the relationship between COVID-19 and GBS appeared in the early pandemic period [31, 32] . Several valuable, detailed reviews have been published analyzing cases of GBS in COVID-19 patients [33] [34] [35] [36] . However, the available information is insufficient to reveal whether COVID-19 is an important risk factor for GBS. More well-designed studies are needed to clarify the relationship between GBS and COVID-19 [33] [34] [35] [36] [37] . In our study population of over 300 patients with COVID-19, we only had one newly diagnosed GBS patient. The strengths of our study were as follows; firstly, our study population included a significant number of confirmed cases, as well as probable cases. In this way, besides evaluating the characteristics and data of two groups separately, it was the first study in the literature comparing the two groups with each other, as far as we know. Secondly, compared to the literature, we had a large number of patients with seizure attacks in both confirmed cases and probable cases, which allowed for the evaluation of the etiology of seizure attacks in COVID-19. Thirdly, we presented the data of patients with rare neurological diseases in our study groups, accompanied by publications in the literature. One of the weak points of the study was that our evaluations were limited to recorded data, as the study was designed retrospectively, and the other was that some detailed neurological investigations could not be performed due to COVID-19 pandemic limitations. In conclusion, our data showed that one of the most common neurological findings in COVID-19 patients is AMS. Age, the patient's current comorbid diseases, and the severity of infection increase the risk of developing AMS. Mortality increases dramatically in patients who develop AMS. However, one point to keep in mind is that our data reflect moderate and severe Covid-19 disease rather than the entire spectrum of COVID-19 disease, since our study population consists of patients who develop neurological complaints and symptoms while being treated in the hospital. 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Guillain Barre syndrome associated with COVID-19 infection: A case report Syndrome: a systematic review of case reports Guillain-Barré syndrome spectrum associated with COVID-19: an up-to-date systematic review of 73 cases Guillain-Barré syndrome in SARS-CoV-2 infection: an instant systematic review of the first six months of pandemic Guillain-Barré syndrome associated with SARS-CoV-2 infection. A systematic review Guillain-Barre syndrome during COVID-19 pandemic: an overview of the Liver failure Hypernatremia Hyponatremia Acute impairment of kidney function -4 (14.8%) 1 (3.7%) 4 (14.8%) 2 (11.1%) 1 (5.5%) -1 (5.5%) Mental deterioration is the most common neurological finding in the moderate-severe COVID- Pre-existing neurological diseases are independent risk factors for mental deterioration Mental deterioration increases mortality dramatically.Emerging of seizure attacks is linked with a high mortality rate.