Clinical Spectrum of Neurological Complaints in COVID-19: Experiences from a COVID-19 Referral Hospital in Indonesia

Citation : Rocksy Fransisca V. Situmeang, Astra Dea Simanungkalita, Anyeliria Sutanto, Aristo Pangestu. Clinical Spectrum of Neurological Complaints in COVID-19: Experiences from a COVID-19 Referral Hospital in Indonesia Medicinus. 2021 February; 9(1): 14-26

Although the primary manifestations of COVID-19 involve the respiratory system, there has been increasing reports of neurological symptoms in COVID-19 patients. 8 Nervous system involvement may be caused by direct invasion of the central nervous system (CNS) by the virus, immune-mediated inflammation, or as complications due to the systemic effects of COVID-19. 8,9 A systematic review conducted by Nepal et al revealed that the most frequently encountered neurological symptoms include disorders of smell (59%), taste (56%), myalgia (25%), and headaches (20%). Research that studies neurological manifestations in confirmed COVID-19 cases in Indonesia is very lacking. Therefore, we conduct this study in order to identify clinical, laboratory, and imaging findings on COVID-19 patients with neurological complaints.

Study design and population
This study was a cross-sectional observational study conducted at Siloam Hospitals Mampang, a COVID-19 referral hospital in South Jakarta. The patients included in this study were confirmed COVID-19 patients with complaints of neurological symptoms, and were referred to a neurologist during that period. We analyzed medical records belonging to COVID-19 patients confirmed by real-time reverse transcriptase polymerase-chainreaction (rt-PCR), collected via nasopharyngeal swab, during the period of April -July 2020.

Data collection
The data obtained were secondary data from medical records. Demographic data collected include age, gender, presence of pre-existing comorbidities, and past medical history.
The neurological symptoms described were complaints that necessitated a referral to neurology, or the chief complaint that resulted in patient admission. Examination of vital signs were obtained from the emergency department, or the last examination done at the isolation ward.
Neurological evaluation and examination was conducted by a neurologist. Laboratory test results included complete blood count and other significant results.
Imaging examinations were performed according to the anatomical sites of the neurological complaint. Neurological diagnosis was made by a neurologist according to clinical, laboratory, and radiological findings.
(81.8%) had comorbid conditions or past medical history associated with neurological symptoms.

Altered mental status
The most frequently encountered neurological complaint was altered mental status (50%), followed by hemiparesis (27.3%) and tremors (22.7%). This result is similar to the study conducted by Helms et al, in which altered mental status was found in 69% of confirmed COVID-19 patients admitted to the ICU. 10 The mechanism of altered mental status in COVID-19 is still unclear. SARS-CoV-2 has been shown to have neurotropic features that enable it to invade the CNS directly via attachment to ACE2 receptors in capillaries, or via penetration of the cribriform plate through the olfactory nerve. 11,12 However, direct invasion as the cause of COVID-19 encephalopathy is still doubtful, as several studies report that positive CSF-PCR examinations were only found in less than 10% of cases. 13 An interesting theory is the possibility of severe systemic inflammation caused by cytokine storm as the main mechanism of cerebral damage in COVID-19. 14 Several studies showed that there was a significant increase in pro-inflammatory cytokines in the CSF of COVID-19 patients with encephalopathy 15,16,17 , as well as a significant improvement in response to intravenous steroids. 15,18,19 The possibility of autoimmune mechanisms can also be considered, given the relationship between COVID-19 and GBS (Guillain Barre syndrome) 20 and clinical improvement with the administration of immunotherapy (intravenous immunoglobulin 15 ,18,19 and plasmapheresis 17 ).

Ischemic stroke
Ischemic stroke occurs in 27.3% of patients, with the most common clinical feature of altered mental status and hemiparesis. The results of our study revealed a higher incidence of stroke than in the study conducted by Mao et al, which showed that acute cerebrovascular disease occurred only in 6% of COVID-19 cases. 21 This difference may be due to variations in the study sample, in which our sample was COVID-19 patients who complained of neurological symptoms (n = 22), while the study conducted by Mao et al included all COVID-19 patients in general (n = 214). This made our sample more likely to have more severe conditions, as evidenced by the examination of inflammatory markers that tend to be higher in our study. The number of subjects with pre-existing comorbidities were higher in our sample compared to the study by Mao et al (81% vs 38%). 21 The underlying cause of ischemic stroke in COVID-19 is thought to be COVID-19-associated-coagulopathy (CAC), which appears in acute systemic inflammatory response, mediated by cytokines and proinflammatory agents. The CAC is characterized by an increase in blood coagulant markers (D-dimers, fibrinogen degradation products, fibrinogen), as well as peripheral inflammation markers (CRP), and mild thrombocytopenia. 22 In severe conditions of COVID-19, coagulopathy can also occur with a pattern similar to disseminated intravascular coagulation (DIC), due to excessive consumption and activation of coagulation factors, characterized by increased PT, aPTT, and D-dimer, and thrombocytopenia.

22.23
Anemia Anemia was present in 45.5% of cases, with a mean hemoglobin value of 10.29 (SD: 1.61). SARS-CoV-2 can cause anemia through various mechanisms. The interaction of SARS-CoV-2 with hemoglobin receptor molecules such as ACE2, CD147, and CD26 will induce a reaction between spike protein and membrane receptors, triggering viral endocytosis. 24 Further hemolysis occurs through damage to the heme on 1-betachain of hemoglobin. 25 By activating CD147 and CD26, SARS-CoV-2 can attack erythroblasts in bone marrow, causing progressive anemia. 24 Free circulating heme caused by hemolysis may damage endothelial, resulting in diffuse endocellitis. 24,26 Previous studies also reported several case reports of autoimmune hemolytic anemia associated with COVID-19, so that the possibility of an autoimmune process should also be considered. 27,28 In this study we were unable to further explore the causes and pathomechanisms of anemia due to limited laboratorium facilities.

Increased NLR Ratio
Out of 22 cases, an increased NLR ratio was found in 11 cases (50%). Increased NLR ratio was associated with severe COVID-19 and a poor prognostic factor. The study conducted by Yan et al showed that the NLR ratio tended to be higher in the non survival group (median: 49.06, interquartile range (IQR): 25.71-69.70) compared to the survival group (median: 4.11, interquartile range (IQR): 2.44-8.12, p <0.01). The study also stated that an NLR more than 11.74 had a significant correlation with hospital mortality (odds ratio = 44,351; 95% confidence interval = 4,627-425,088). 30 The mechanism of increased NLR ratio in COVID-19 is still unclear. The increase in neutrophils occurs due to a hyperinflammatory process in COVID-19, evidenced by an increase of classic neutrophil chemoattractant (CXCL1, CXCL2, CXCL3, CXCL5, CXCL20, and interleukin-8 ) in cells infected with SARS-CoV-2. 31,32 Lymphopenia can occur due to bone marrow suppression, immunemediated-destruction, as well as sequestration due to activation of the ACE2 receptor by SARS-CoV2. 33,34 The mean NLR ratio in our study was quite high (16.99, SD: 15.23), but we could not compare the outcome in our sample with that previous study due to lack of data and most of the patients were still in treatment.

Electrolyte imbalance
Electrolyte imbalance was present in 7 cases (31.8%), with the most common abnormality being hyponatremia (6 cases, 28.6%), followed by hypokalemia (4 cases, 18.2%), and hyperkalemia (2 cases, 9.1%). A study conducted by Lippi et al showed that sodium and potassium levels were found to be lower significantly in severe COVID-19. 35 The mechanism of hyponatremia in COVID-19 is still unclear. Previous studies linked syndrome of inappropriate antidiuretic hormone secretion (SIADH) as a cause of hyponatremia in COVID-19 pneumoniae. 36 A study by Berni et al showed that levels of interleukin-6, a pro-inflammatory cytokine core in the COVID-19 cytokine storm, was inversely related with sodium. 37 This suggests that the systemic inflammatory system may also play a role in the development of hyponatremia. Hypokalemia is thought to occur due to activation of the ACE2 receptor, resulting in decreased ACE2 expression, which in turn triggers an upregulation in angiotensin II, leading to increased excretion of potassium by the kidneys. 37,38 Hypokalemia can also be caused by gastrointestinal loss, such as vomiting and diarrhea, which are common in COVID-19. 37,39 Correlation of pre-existing comorbidities with neurologic complaint on COVID-19 More than half (81.8%) of the study sample in this study had pre-existing comorbidities or past history associated with the neurological complaint. These results indicate that it is likely that COVID-19 does not cause direct nervous system damage, but induces dysfunction through the exacerbation of pre-existing neurological disorders, presumably via the hyperinflammation mechanisms. SARS-CoV-2 can cause a widespread inflammatory cascade condition through activation of the ACE2 receptor, leading to severe acute systemic inflammation mediated by interleukin (IL)-6, which increases the number and response of proinflammatory cytokines such as IL-17, IL-21, and IL-22. 40,41 The cytokine storm causes widespread endothelial dysfunction, including damage to the blood-brainbarrier. 14 SARS-CoV-2 infection, accompanied by comorbidities, tended to be more severe than without comorbidities (p <0.03) 21 43 , so there may be decline in cognitive function, especially in patients with pre-existing dementia.

Limitation
The limitation of our study is that we cannot perform more specific laboratory tests, so we could not further investigate the causes of abnormal laboratory results. Furthermore, neuroimaging and some laboratory tests were not performed in all patients, so we could not compare and describe the data.

Conclusion
We have found that neurological complaints in COVID-19 patients are mostly associated with exacerbation of pre-existing comorbidities as a result of the severe inflammatory process triggered by COVID-19. Further research is needed to establish the mechanism of nervous system dysfunction in COVID-19.