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Background: New onset or worsening of a headache disorder substantially contributes to the disease burden of post-COVID-19. Its management poses a suitable means to enhance patients' participation in professional, social, and personal activities. Unfortunately, the pathophysiology of post-COVID-19 headaches is poorly understood. This study aims to investigate the role of (neuro-) inflammatory mechanisms in order to guide the development of anti-inflammatory treatment strategies. Methods: We included patients from the interdisciplinary post-COVID-19 Rehabilitation Study (PoCoRe, n = 184 patients) run at a tertiary care university hospital, comprising patients with PCR-confirmed SARS-CoV-2 infection ≥ 6 weeks prior to their initial consultation. Patients reporting any headache since their infection were considered for this study (n = 93). These were interviewed and classified according to the International Classification of Headache Disorders, Third Edition (ICHD-3) by headache specialists. Patient sera were additionally analysed for levels of VILIP-1, MCP-1 (CCL2), sTREM-2, BDNF, TGF-ß1, VEGF, IL-6, sTREM-1, ß-NGF, IL-18, TNF-alpha, sRAGE, and CX3CL1 (Fractalkine). Markers of inflammation were compared between four groups of patients (none, unchanged, worsened, or new headache disorder). Results: Patients reported experiencing more severe headaches (n = 17), new onset headaches (n = 46), unchanged headaches (n = 18), and surprisingly, some patients denied having any headaches (n = 12) despite self-reports. Serum levels of CX3CL1 were increased in the worsened (2145 [811–4866] pg/ml) and new onset (1668 [0-7357] pg/ml) headache group as compared to patients with no (1129 [0-5379] pg/ml) or unchanged (1478 [346–4332] pg/ml) headaches. Other markers also differed between groups, but most significantly between patients with worsened (TGF-ß1: 60 [0-310] pg/ml, VEGF: 328 [86–842] pg/ml, ß-NGF: 6 [3–38] pg/ml) as compared to unchanged headaches (TGF-ß1: 29 [0–77] pg/ml, VEGF: 183 [72–380] pg/ml, ß-NGF: 3 [2–89] pg/ml). The results did not differ between headache phenotypes. Discussion: This study provides evidence that worsened or new headaches following COVID-19 are associated with pro-(neuro-)inflammatory profiles. This supports the use of anti-inflammatory treatment options in this population, especially in the subacute phase. [ABSTRACT FROM AUTHOR]

Background: The prolonged psychiatric disorders rate following coronavirus disease 2019 (COVID-19) could surpass that of severe acute respiratory syndrome (SARS) as well as Middle East Respiratory Syndrome (MERS) as a result of variations in viral disease treatment as well as societal circumstances throughout the outbreaks. This work aimed to investigate the COVID-19 prolonged psychiatric effects on survivors without psychiatric diseases before infection. Methods: This cross-sectional research was conducted on 1254 patients of which 700 patients (55.8%) were positive for psychiatric complications based on the general health (GHQ-28) questionnaire and 554 patients (44.1%) were negative, aged above 18 years old who had been infected with COVID19 (PCR swab confirmed) and recovered since less than 6 months without previous history of any psychiatric disease. Results: Smoking, medical comorbidities, hospitalization, and cortisone in treatment were significantly higher in GHQ-28 positive than GHQ-28 negative (p < 0.05). Psychiatric disorders and Beck's Depression Inventory (BDI) grades showed a significant association between smoking and hospitalization and Taylor Manifest Anxiety scales and smoking, hospitalization, and treatment with cortisone). Smoking, medical comorbidities, hospitalization, and cortisone in treatment were the most significant predictors of positive GHQ-28. However, multivariate analysis demonstrated that medical comorbidities, hospitalization, and cortisone in treatment were the best independent predictors of GHQ-28 positive (p = 7.055, p = 0.007, p = 0.043, p = 0.047, respectively). Conclusions: COVID-19 cases without pre-existing psychological disorders exhibited a significant increase in psychiatric disorders occurrence 6 months following recovery. Anxiety disorders represented the predominant mental diagnoses documented. [ABSTRACT FROM AUTHOR]

Background: Accumulating evidence on the neurological sequelae of COVID-19 is a serious concern, with patients possibly being at risk of permanent debilitation if not managed appropriately. We aimed to determine the prevalence and pattern of neurological manifestations and diagnostic and therapeutic findings among hospitalized COVID-19 patients consulted with the neurology service for neurological disorders. We conducted a retrospective, observational study at the Golestan Hospital of Ahvaz, Iran, between March 20, 2020, and March 19, 2021. Patients' demographic, clinical, paraclinical, and therapeutic characteristics were extracted from medical records and then subjected to statistical analysis. Results: Overall, 6.7% (157/2340) of COVID-19 patients at Golestan Hospital had a neurological disorder. Most of the patients (90/157) were men, and the mean age of patients was 62.91 ± 91 years. A total of 56.68% of patients (89/157) were SARS-CoV-2 RT-PCR positive. The mean chest CT severity score was 8.26 ± 4.4, ranging from 1 to 19. The most common neurologic disorders were cerebrovascular disease (72.6%), encephalopathy (8.9%), and Guillain–Barre syndrome (6.4%). The CSF SARS-CoV-2 PCR test was positive in one patient with Guillain–Barre syndrome. The in-hospital mortality rate was 43.9%. Definite COVID-19, ICU admission, history of stroke and dementia, and comorbidities were associated with an increased mortality risk in these patients. Conclusions: Patients with COVID-19 can present with serious neurological disorders such as cerebrovascular disease and impaired consciousness, even without typical COVID-19 symptoms. Close monitoring for neurological symptoms may help improve prognosis in hospitalized COVID-19 patients. [ABSTRACT FROM AUTHOR]

Current definitions of migraine that are based mainly on clinical characteristics do not account for other patient's features such as those related to an impaired quality of life, due to loss of social life and productivity, and the differences related to the geographical distribution of the disease and cultural misconceptions which tend to underestimate migraine as a psychosocial rather than neurobiological disorder. Global differences definition, care access, and health equity for headache disorders, especially migraine are reported in this paper from a collaborative group of the editorial board members of the Journal of Headache and Pain. Other components that affect patients with migraine, in addition to the impact promoted by the migraine symptoms such as stigma and social determinants, are also reported. [ABSTRACT FROM AUTHOR]

Background: The novel coronavirus disease (COVID-19) has claimed innumerable lives globally since its onset and several extrapulmonary manifestations of the disease have been reported in association with COVID-19. Although optic neuropathy has been previously linked to a variety of infections, neuro-ophthalmological associations of SARS-CoV-2 have been sparsely reported till date. Our aim was to report the clinical profile and outcome of patients diagnosed with parainfectious/postinfectious optic neuritis (ON) associated with COVID-19. Case presentation: In this case series, we have discussed the clinical presentation, laboratory parameters and outcome in a series of three patients of ON associated with COVID-19 and also compared those findings against existing literature. Among the three patients, two patients (Case 1, 3) were incidentally diagnosed with COVID-19 during the course of hospital admission and contributed to a parainfectious association with ON, while one patient (Case 2) had an antecedent history of COVID-19 as evidenced by her antibody titers thus contributing to a postinfectious association. Notably, all these patients were asymptomatic or had mild manifestations of COVID-19 and all of them tested negative for myelin oligodendrocyte glycoprotein (MOG) antibodies. They were treated accordingly and their visual outcomes were noted in follow-up. Conclusion: ON with or without MOG seropositivity, probably attributed to molecular mimicry has surfaced up considerably in association with COVID-19. This article provides a comprehensive overview of clinical presentation and outcome of ON associated with parainfectious/postinfectious COVID-19 in three cases and a critical analysis of existing literature. [ABSTRACT FROM AUTHOR]

Purpose of Review: Headache is one of the most frequent symptoms of the acute and post-acute phase of COVID-19. Specific epidemiology, clinical features, risk factors, pathophysiology, and treatment have been reported in these two scenarios. With this narrative review of the literature, we aim to provide updated knowledge on headache in the COVID-19 setting and give clinicians a practical approach on this topic to guide them in their clinical practice. Recent Findings: Headache mechanisms in COVID-19 are still poorly understood. Strong evidence is also lacking on how to best treat and manage these patients, especially those with persistent and disabling headache after COVID-19. Data are also scarce on the characteristics of headache in COVID-19 caused by the new SARS-CoV-2 (Omicron) variants and how these may influence the acute and persistent symptoms of COVID-19. Patients with pre-existing primary headache disorders remain a particularly concerning population due to their biological predisposition in suffering from headaches and the potential risk of worsening in the setting of SARS-CoV-2 infection. Summary: Although there is an exponential growth of scientific evidence, studies are often controversial and focused on the first wave of the pandemic, making COVID-19 headache still a challenging matter for clinicians. New research is therefore needed. [ABSTRACT FROM AUTHOR]

Current definitions of migraine that are based mainly on clinical characteristics do not account for other patient's features such as those related to an impaired quality of life, due to loss of social life and productivity, and the differences related to the geographical distribution of the disease and cultural misconceptions which tend to underestimate migraine as a psychosocial rather than neurobiological disorder. Global differences definition, care access, and health equity for headache disorders, especially migraine are reported in this paper from a collaborative group of the editorial board members of the Journal of Headache and Pain. Other components that affect patients with migraine, in addition to the impact promoted by the migraine symptoms such as stigma and social determinants, are also reported. [ABSTRACT FROM AUTHOR]

Headache is among the most frequently reported symptoms after resolution of COVID-19. We assessed structural brain changes using T1- and diffusion-weighted MRI processed data from 167 subjects: 40 patients who recovered from COVID-19 but suffered from persistent headache without prior history of headache (COV), 41 healthy controls, 43 patients with episodic migraine and 43 patients with chronic migraine. To evaluate gray matter and white matter changes, morphometry parameters and diffusion tensor imaging-based measures were employed, respectively. COV patients showed significant lower cortical gray matter volume and cortical thickness than healthy subjects (p < 0.05, false discovery rate corrected) in the inferior frontal and the fusiform cortex. Lower fractional anisotropy and higher radial diffusivity (p < 0.05, family-wise error corrected) were observed in COV patients compared to controls, mainly in the corpus callosum and left hemisphere. COV patients showed higher cortical volume and thickness than migraine patients in the cingulate and frontal gyri, paracentral lobule and superior temporal sulcus, lower volume in subcortical regions and lower curvature in the precuneus and cuneus. Lower diffusion metric values in COV patients compared to migraine were identified prominently in the right hemisphere. COV patients present diverse changes in the white matter and gray matter structure. White matter changes seem to be associated with impairment of fiber bundles. Besides, the gray matter changes and other white matter modifications such as axonal integrity loss seemed subtle and less pronounced than those detected in migraine, showing that persistent headache after COVID-19 resolution could be an intermediate state between normality and migraine. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic has led to a radical lifestyle change, which may unintendedly change physical activity levels. We aimed to perform a systematic review to investigate the physical activity changes in people with neurological diseases, and to examine the relationship between physical activity and disease symptoms, and psychosocial factors. The review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. A systematic search of the literature across five databases (PubMed, CINAHL, Web of Science, SCOPUS, and Cochrane Library) was carried out using the keywords relating to COVID-19, physical activity, sedentary behaviour, exercise, and the name of the neurological diseases. The systematic search was updated on 4 February 2021 with the same keywords. Fourteen studies (n = 7662 persons with neurological diseases, n = 1663 healthy controls) were eligible for this review. The study populations were Parkinson disease (n = 7), dementia (n = 1), multiple sclerosis (n = 1), spinal cord injury (n = 1), hereditary spastic paraplegia (n = 1), neuromuscular diseases (n = 1), Charcot-Marie-Tooth neuropathy (n = 1), and epilepsy (n = 1). Thirteen studies reported a decreased physical activity level, one study reported a high interruption rate of physiotherapy/rehabilitation. Furthermore, the physical activity reduction was associated with worse disease symptoms, depression, perceived health, and mental and physical components of quality of life. The COVID-19 pandemic has a negative impact on the physical activity levels of people with neurological diseases, and this change was related to the worsening of disease symptoms and psychosocial factors. Registration number A protocol of the review was registered with the PROSPERO database (CRD42020207676). [ABSTRACT FROM AUTHOR]

Background: Headache is one of the most frequently reported symptoms in post-COVID patients. The clinical phenotype of COVID-19 headache combines phenotypic features of both tension-type headache (TTH) and migraine. We aimed to assess the effectiveness, side effects and predictors of amitriptyline (AMT) response in a real-world study setting. Methods: We performed an observational multicentric study with a retrospective cohort. All consecutive patients with confirmed COVID-19 infection who received AMT for post-COVID headache from March 2020 to May 2021 were included. Response was evaluated by the reduction in the number of headache days per month (HDM) between weeks 8 and 12, compared with the baseline. We explored which variables were associated with a higher probability of response to AMT. Results: Forty-eight patients were eligible for the study, 40/48 (83.3%) females, aged 46.85 (SD: 13.59) years. Patients had history of migraine 15/48 (31.3%) or TTH 5/48 (10.4%). The mean reduction of HDM was 9.6 (SD: 10.9; 95% CI 6.5, 12.7) days. Only 2/48 (5%) of patients discontinued AMT due to poor tolerability. History of TTH (10.9, 95% CI 1.3, 20.6) and nausea (− 8.5, 95% CI − 14.6, − 2.5) were associated with AMT response. Conclusions: This study provides real-world evidence of the potential benefit of AMT in patients with post-COVID-19 headache, especially in patients with history of TTH and without concomitant nausea. [ABSTRACT FROM AUTHOR]

Infection of the CNS with the SARS-CoV-2 can occur via different routes and results in para- or post-infectious manifestations with a variety of neurological symptoms. In patients with neurodegenerative diseases, SARS-CoV-2 is often associated with a higher fatality rate, which is a relevant problem in increasingly older populations. Apart from the direct consequences of an infection in patients with neurodegenerative diseases, indirect consequences of the pandemic such as limited access to care facilities and treatment have negative effects on the course of these chronic disorders. The occurrence of long-lasting neurological symptoms after infection with SARS-CoV-2 indicates a prolonged impact on the CNS. However, while it is known that SARS-CoV-2 affects neuronal populations that are relevant in the pathogenesis of neurodegenerative diseases, it is yet unclear whether an infection with SARS-CoV-2 is sufficient to trigger neurodegeneration. Reflecting on the impact of SARS-CoV-2 on neurodegeneration, we provide a concise overview on the current knowledge of SARS-CoV-2-induced pathology in the CNS and discuss yet open questions in the field. [ABSTRACT FROM AUTHOR]

Introduction: Evidence is emerging about an extra-pulmonary involvement of SARS-CoV-2, including the nervous system. Autonomic dysfunction in patients recovering from acute coronavirus disease 2019 (COVID-19) has been recently described. Dysautonomic symptoms have been reported in the acute phase of the disease, but clear evidence is lacking, especially in the non-critical forms of the infection. Objective: The aim of this study is to assess the prevalence of dysautonomia in acute, non-critically ill COVID-19 patients. Methods: In this observational, cross-sectional study, we compared 38 non-critically ill patients with acute COVID-19 (COVID + group) to 38 healthy volunteers (COVID − group) in order to assess the prevalence of signs and symptoms of dysautonomia through the administration of the composite autonomic symptom score 31 (COMPASS-31) and an active standing test. Comparisons between groups were performed by means of both univariate and multivariate analyses. Results: The prevalence of orthostatic hypotension was significantly higher in the COVID + group. Higher total scores of COMPASS-31 were observed in the COVID + group than controls. Significant differences between groups emerged in the secretomotor, orthostatic intolerance, and gastrointestinal COMPASS-31 domains. All these results maintained the statistical significance after the adjustment for concomitant drugs with a known effect on the autonomic nervous system assumed by the study participants, except for the differences in the gastrointestinal domain of COMPASS-31. Conclusion: Our results suggest that an autonomic dysfunction could be an early manifestation of COVID-19, even in the contest of mild forms of the infection. [ABSTRACT FROM AUTHOR]

Background: Nearly 55 percent of patients are said to be affected by the neurological effects of COVID-19. COVID-19 was shown to be related with stroke in 0.9 to 5% of people. It's critical to assess the impact of COVID-19 on the outcomes of acute ischemic stroke. The goal of this study was to look at the outcomes and characteristics of patients who had an acute ischemic stroke due to covid-19 infection. Results: The participants in this study were 399 people who had had a stroke. COVID-19 positivity was confirmed in 77 cases, while COVID-19 negativity was confirmed in 322. In the COVID-19 and control groups, the average age of the patients was 65.4 ± 10.2 and 65.3 ± 11.8, respectively. The Covid-19 and control groups had a mean stroke onset of 5.2 ± 2.1 and 5.7 ± 3.8 h, respectively (P = 0.12). There was a high in-hospital mortality rate among patients with COVID-19 with a rate of 11.7% compared to 4.04% among the control group (P = 0.02). At discharge, the number of patients with mRS > 2 was higher (P = 0.001) among the COVID-19. There was a correlation between the mean levels of D-Dimer (r = 0.668, P < 0.001), the severity of COVID-19 (r = 0.802, P < 0.001), and mRS > 2. Conclusion: Despite receiving equal acute care as non-COVID-19 patients, COVID-19 patients had more severe strokes and had worse outcomes. This includes a high chance of death while in the hospital as well as a significant level of disability. Neurologists should use timely and effective therapies, particularly for patients who are at a higher risk of having a stroke. This includes elderly patients, patients with severe COVID-19, patients with high levels of D-Dimer, and those with high NIHSS. [ABSTRACT FROM AUTHOR]

Background: Neurological symptoms and complications of Coronavirus disease 2019 (COVID-19) were seldom discussed in the literature initially. Neurological symptoms such as headache, dizziness, anosmia, hypogeusia, and neuralgia are, however, now being reported commonly. Mononeuropathies are rare complications of COVID-19, with most cases associated with prolonged intensive care stay. Case presentation: A 61-year-old gentleman with prior history of well-controlled diabetes and hypertension was recently treated for COVID-19 pneumonia with supplemental oxygen and positive pressure ventilation. He now presented with left-sided foot weakness two weeks after recovering from the viral illness. On examination he had normal bulk and tone and a power of 4/5 in proximal and distal muscles of bilateral lower limbs except for ankle dorsiflexion on the left which was 2/5. He also had absent ankle and knee reflexes bilaterally with bilateral flexor plantar reflexes. Since the patient had no back pain and the sensory system was normal, the lesion was localized to the peripheral nerves and a Nerve Conduction Studies and Electromyography (NCS/EMG) was done. NCS/EMG showed findings suggestive of axonal mononeuropathies. Relevant workup done to identify the cause of mononeuropathy was negative including infectious and autoimmune workup. Since diabetes was well-controlled and he had no intensive care stay his findings were presumed to be associated with resolving COVID-19 infection. The patient underwent aggressive daily physical therapy and has started to show improvement in symptoms. Conclusions: Complications such as mononeuropathies should be kept in mind in patients recovering from COVID-19 infection, since timely diagnosis can improve clinical outcomes in patients. [ABSTRACT FROM AUTHOR]

Symptoms of autonomic dysfunction, particularly those of orthostatic intolerance, continue to represent a major component of the currently recognized post-acute sequelae of SARS-CoV-2 infections. Different pathophysiologic mechanisms can be involved in the development of orthostatic intolerance including hypovolemia due to gastrointestinal dysfunction, fatigue-associated deconditioning, and hyperadrenergic state due to pandemic-related anxiety. Additionally, there has been a well-established association of a common primary autonomic disorder like postural orthostatic tachycardia syndrome, a subtype of orthostatic intolerance, with antecedent viral infections. Here we report a case of neuropathic type postural orthostatic tachycardia syndrome as a form of autonomic neuropathy that developed following COVID-19 infection. [ABSTRACT FROM AUTHOR]

Background: Neurological symptoms are frequent among patients with COVID-19. Little is known regarding the repercussions of neurological symptoms for patients and how these symptoms are related to one another. Objectives: To determine whether there is an association between the neurological symptoms in patients with COVID-19, and to characterize the headache. Method: This was a cross-sectional study. All hospital inpatients and health workers at the Hospital Universitario Oswaldo Cruz with a PCR-confirmed COVID-19 infection between March and June 2020 were considered for the study and were interviewed by telephone at least 2-months after the acute phase of the disease. These patients were identified by the hospital epidemiological surveillance department. A semi-structured questionnaire was used containing sociodemographic and clinical data and the ID-Migraine. Results: A total of 288 patients was interviewed; 53.1% were male; with a median age of 49.9 (41.5–60.5) years; 91.7% presented some neurological symptom; 22.2% reported some neurological symptom as the symptom that troubled them most during COVID-19. Neurological symptoms were: ageusia (69.8%), headache (69.1%), anosmia (67%), myalgia (44.4%), drowsiness (37.2%), agitation (20.8%); mental confusion (14.9%), syncope (4.9%) and epileptic seizures (2.8%). Females, those who presented with fever, sore throat, anosmia/ageusia and myalgia also presented significantly more with headache (logistic regression). The most frequent headache phenotype was a non-migraine phenotype, was of severe intensity and differed from previous headaches. This persisted for more than 30 days in 18% and for more than 90 days in 10% of patients. Thirteen percent of those with anosmia and 11% with ageusia continued with these complaints after more than 90 days of the acute phase of the disease. Aged over 50 years, agitation and epileptic seizures were significantly associated with mental confusion (logistic regression). Conclusion: Headache is frequent in COVID-19, is associated with other symptoms such as fever, sore throat, anosmia, ageusia, and myalgia, and may persist beyond the acute phase of the disease. [ABSTRACT FROM AUTHOR]

Our study aimed to determine the effects of new-onset neurological symptoms (NNS) on clinically relevant outcomes in hospitalized patients with COVID-19 infection. We conducted a nationwide, comparative, retrospective, cohort study among adult, hospitalized COVID-19 patients involving 37 hospital sites from various regions in the Philippines. We included a total of 10,881 patients with confirmed COVID-19 infection (2008 had NNS while 8873 did not have NNS). The adjusted hazard ratios (aHRs) for mortality among the mild and severe cases were significantly higher by 1.660 (95% CI 1.132–2.435) and by 1.352 (95% CI 1.042–1.752), respectively, in the NNS group compared to those in the non-NNS group. The aHRs for respiratory failure in the NNS group were significantly increased by 1.914 (95% CI 1.346–2.722), by 1.614 (95% CI 1.260–2.068), and by 1.234 (95% CI 1.089–1.398) among the mild, severe, and critical cases, respectively. The aHRs for ICU admission in the NNS group were still significantly higher by 1.973 (95% CI 1.457–2.673) and by 1.831 (95% CI 1.506–2.226) among the mild and severe cases, respectively. Patients who had NNS were not significantly associated with a longer duration of ventilator dependence (adjusted odds ratio (aOR) 0.954, 95% CI 0.772–1.179), longer ICU stay (aOR 0.983, 95% CI 0.772–1.252) and longer hospital admission (aOR 1.045, 95% CI 0.947–1.153). The presence of NNS significantly increases the risk of mortality, respiratory failure and ICU admission among COVID-19 patients. Registration and associated protocol publication: ClinicalTrials.gov website (NCT04386083); Espiritu AI, Sy MCC, Anlacan VMM, Jamora RDG. The Philippine COVID-19 Outcomes: a Retrospective study Of Neurological manifestations and Associated symptoms (The Philippine CORONA study): a protocol study. BMJ Open. 2020;10:e040944. [ABSTRACT FROM AUTHOR]

Purpose Of Review: We present biological and psychological factors implicated in psychiatric manifestations of SARS-CoV-2, as well as its neuroinvasive capability and immune pathophysiology.Recent Findings: Preexisting mental illness leads to worse clinical outcomes in COVID-19. The presence of the virus was reported in the cerebrospinal fluid (CSF) and brain tissue post-mortem. Most common psychiatric manifestations include delirium, mood disorders, anxiety disorders, and posttraumatic stress disorder. "Long-COVID" non-syndromal presentations include "brain-fogginess," autonomic instability, fatigue, and insomnia. SARS-CoV-2 infection can trigger prior vulnerabilities based on the priming of microglia and other cells, induced or perpetuated by aging and mental and physical illnesses. COVID-19 could further induce priming of neuroimmunological substrates leading to exacerbated immune response and autoimmunity targeting structures in the central nervous system (CNS), in response to minor immune activating environmental exposures, including stress, minor infections, allergens, pollutants, and traumatic brain injury. [ABSTRACT FROM AUTHOR]

The unremitting coronavirus disease 2019 (COVID-19) pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) marked a year-long phase of public health adversaries and has severely compromised healthcare globally. Early evidence of COVID-19 noted its impact on the pulmonary and cardiovascular functions, while multiple studies in recent time shed light on its substantial neurological complications, though a comprehensive understanding of the cause(s), the mechanism(s), and their neuropathological outcomes is scarce. In the present review, we conferred evidence of neurological complications in COVID-19 patients and shed light on the SARS-CoV-2 infection routes including the hematogenous, direct/neuronal, lymphatic tissue or cerebrospinal fluid, or infiltration through infected immune cells, while the underlying mechanism of SARS-CoV-2 invasion to the central nervous system (CNS) was also discussed. In an up-to-date manner, we further reviewed the impact of COVID-19 in developing diverse neurologic manifestations associated with CNS, peripheral nervous system (PNS), skeletal muscle, and also pre-existing neurological diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, epilepsy, and myasthenia gravis. Furthermore, we discussed the involvement of key factors including age, sex, comorbidity, and disease severity in exacerbating the neurologic manifestations in COVID-19 patients. An outlook of present therapeutic strategies and state of existing challenges in COVID-19 management was also accessed. Conclusively, the present report provides a comprehensive review of COVID-19-related neurological complications and emphasizes the need for their early clinical management in the ongoing COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

Objective: We aim to determine the risk of acute ischemic stroke in patients with severe and non-severe coronavirus disease 2019 (COVID-19). Methods: A literature search was conducted in the PubMed, Embase, Web of Science, and Cochrane Library databases until October 28, 2020. Studies covering COVID-19's severity classification data and COVID-19 patients with acute ischemic stroke were included. Two independent evaluators extracted data, and the random effects model was used to calculate the risk ratios (RR) and 95% confidence interval (95% CI) of acute ischemic stroke associated with COVID-19's severity. Results: A total of 8 studies were included, involving 5266 patients. Among all COVID-19 patients, the total incidence of ischemic stroke was 1.76% (95% CI: 0.82–3.01). Severe patients have an increased risk of acute ischemic stroke compared with non-severe patients (RR = 3.53, 95% CI: 2.06–6.07, P < 0.0001; I2 = 12%). This association was also observed when COVID-19's severity was defined by clinical parameters (RR 2.91, 95% CI: 1.17–7.26, P = 0.02; I2 = 29%) and the need for intensive care (RR 4.47, 95% CI: 2.40–8.31, P < 0.0001; I2 = 0%). Conclusions: This meta-analysis shows that the severe course of COVID-19 is associated with an increased risk of acute ischemic stroke. [ABSTRACT FROM AUTHOR]

The current pandemic of the new human coronavirus (CoV), i.e., severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has created an urgent global condition. The disease, termed coronavirus disease 2019 (COVID-19), is primarily known as a respiratory tract infection. Although SARS-CoV-2 directly invades the lungs, COVID-19 is a complex multi-system disease with varying degrees of severity and affects several human systems including the cardiovascular, respiratory, gastrointestinal, neurological, hematopoietic, and immune systems. From the existing data, most COVID-19 cases develop a mild disease typically presented with fever and respiratory illness. However, in some patients, clinical evidence suggests that COVID-19 might progress to acute respiratory distress syndrome (ARDS), multi-organ dysfunction, and septic shock resulting in a critical condition. Likewise, specific organ dysfunction seems to be related to the disease complication, worsens the condition, and increases the lethality of COVID-19. The neurological manifestations in association with disease severity and mortality have been reported in COVID-19 patients. Despite the continuously increasing reports of the neurological symptoms of SARS-CoV-2, our knowledge about the possible routes of nervous system involvement associated with COVID-19 is limited. Herein, we will primarily describe the critical aspects and clinical features of SARS-CoV-2 related to nervous system impairment and then discuss possible routes of SARS-CoV-2 nervous system involvement based on the current evidence. [ABSTRACT FROM AUTHOR]

Anecdotal evidence suggests that the severity of coronavirus disease of 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is likely to be distinguished by variations in loss of smell (LOS). Thus, we conducted a meta-analysis of 45 articles that include a total of 42,120 COVID-19 patients from 17 different countries to demonstrate that severely ill or hospitalized COVID-19 patients have a lesser chance of experiencing LOS than non-severely ill or non-hospitalized COVID-19 patients (odds ratio = 0.527 [95% CI 0.373–0.744; p < 0.001] and 0.283 [95% CI 0.173–0.462; p < 0.001], respectively). We also proposed a possible mechanism underlying the association of COVID-19 severity with anosmia, which may explain why patients without sense of smell develop severe COVID-19. Variations in LOS according to the severity of COVID-19 is a global phenomenon, with few exceptions. Since severely ill patients have a lower rate of anosmia, patients without anosmia should be monitored more closely in the early stages of COVID-19, for early diagnosis of severity of illness. An understanding of how the severity of COVID-19 infection and LOS are associated has profound implications for the clinical management and mitigation strategies for the disease. [ABSTRACT FROM AUTHOR]

Purpose of Review: The present review discusses the peripheral nervous system (PNS) manifestations associated with coronavirus disease 2019 (COVID-19). Recent Findings: Nerve pain and skeletal muscle injury, Guillain-Barré syndrome, cranial polyneuritis, neuromuscular junction disorders, neuro-ophthalmological disorders, neurosensory hearing loss, and dysautonomia have been reported as PNS manifestations in patients with COVID-19. Summary: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19. COVID-19 has shown syndromic complexity. Not only does SARS-CoV-2 affect the central nervous system but also it involves the PNS. The PNS involvement may be due to dysregulation of the immune system attributable to COVID-19. Here we review the broad spectrum of PNS involvement of COVID-19. [ABSTRACT FROM AUTHOR]

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the infectious agent responsible for coronavirus disease 2019 (COVID-19). Respiratory and gastrointestinal manifestations of SARS-CoV-2 are well described, less defined is the clinical neurological spectrum of COVID-19. We reported a case of COVID-19 patient with acute monophasic Guillain-Barré syndrome (GBS), and a literature review on the SARS-CoV-2 and GBS etiological correlation. Case Description: A 68 years-old man presented to the emergency department with symptoms of acute progressive symmetric ascending flaccid tetraparesis. Oropharyngeal swab for SARS-CoV-2 tested positive. Neurological examination showed bifacial nerve palsy and distal muscular weakness of lower limbs. The cerebrospinal fluid assessment showed an albuminocytologic dissociation. Electrophysiological studies showed delayed distal latencies and absent F waves in early course. A diagnosis of Acute Inflammatory Demyelinating Polyradiculoneuropathy (AIDP) subtype of GBS was then made. Conclusions: Neurological manifestations of COVID-19 are still under study. The case we described of GBS in COVID-19 patient adds to those already reported in the literature, in support of SARS-CoV-2 triggers GBS. COVID-19 associated neurological clinic should probably be seen not as a corollary of classic respiratory and gastrointestinal symptoms, but as SARS-CoV-2-related standalone clinical entities. To date, it is essential for all Specialists, clinicians and surgeons, to direct attention towards the study of this virus, to better clarify the spectrum of its neurological manifestations. [ABSTRACT FROM AUTHOR]

COVID-19 is a highly infectious viral disease caused by the novel coronavirus SARS-CoV-2. While it was initially regarded as a strictly respiratory illness, the impact of COVID-19 on multiple organs is increasingly recognized. The brain is among the targets of COVID-19, and it can be impacted in multiple ways, both directly and indirectly. Direct brain infection by SARS-CoV-2 may occur via axonal transport via the olfactory nerve, eventually infecting the olfactory cortex and other structures in the temporal lobe, and potentially the brain stem. A hematogenous route, which involves viral crossing of blood–brain barrier, is also possible. Secondary mechanisms involve hypoxia due to respiratory failure, as well as aberrant immune response leading to various forms of encephalopathy, white matter damage, and abnormal blood clotting resulting in stroke. Multiple neurological symptoms of COVID-19 have been described. These involve anosmia/ageusia, headaches, seizures, mental confusion and delirium, and coma. There is a growing concern that in a number of patients, long-term or perhaps even permanent cognitive impairment will persist well after the recovery from acute illness. Furthermore, COVID-19 survivors may be at increased risk for developing neurodegenerative diseases years or decades later. Since COVID-19 is a new disease, it will take months or even years to characterize the exact nature, scope, and temporal extent of its long-term neurocognitive sequelae. To that end, rigorous and systematic longitudinal follow-up will be required. For this effort to succeed, appropriate protocols and patient registries should be developed and put in place without delay now. [ABSTRACT FROM AUTHOR]

Background: Emerging evidence suggests that a subset of coronavirus disease 2019 (COVID-19) patients may present with or develop cerebrovascular disease during the course of hospitalization. Whereas ischemic stroke in COVID-19 patients has been well described, data on intracranial hemorrhage (ICH) in these patients is still limited. We, therefore, conducted a rapid systematic review of current scientific literature to identify and consolidate evidence of ICH in COVID-19 patients. Methods: A systematic search of literature was conducted between November 1, 2019, and August 14, 2020, on PubMed and China National Knowledge Infrastructure (CNKI) to identify eligible studies. Results: A total of 23 studies describing ICH in 148 COVID-19 patients were included. The pooled incidence of ICH in COVID-19 patients was 0.7% (95% CI 0.5–0.9), with low levels of inter-study heterogeneity observed (I2 = 33.6%, Cochran's Q = 12.05, p = 0.149). Most of the patients were elderly male patients (65.8%) with comorbidities, the most common being systemic hypertension (54%). Hemorrhage involving multiple cranial compartments was reported in 9.5% of cases. Single compartments were involved in the rest, with intraparenchymal hemorrhage (IPH) being the most common variety (62.6%) and intraventricular hemorrhage (IVH) the least common (1.4%). Half of these patients were on some form of anticoagulation. Overall, the mortality rate in the COVID-19 patients with ICH was about 48.6%. Conclusion: Although relatively uncommon among COVID-19 patients, ICH is associated with a high mortality rate. Early identification of patients at risk of developing ICH, particularly with comorbid conditions and on anticoagulant therapy, may be important to improve outcomes. [ABSTRACT FROM AUTHOR]

Background: The objective of the study was to assess the cerebrospinal fluid (CSF) findings in COVID-19 patients. Aims: This was an observational retrospective cohort from electronic medical records of hospitalized patients (n = 2655) with confirmed COVID-19 between February 15, 2020, and April 15, 2020, in 182 hospitals from a large health system in the USA. The review of data yielded to a total of 79 patients in 20 hospitals who had CSF analysis. Methods: Outcomes during hospitalization, including hospital length of stay, disease severity, ventilator time, and in-hospital death were recorded. Independent variables collected included patient demographics, diagnoses, laboratory values, and procedures. Results: A total of 79 patients underwent CSF analysis. Of these, antigen testing was performed in 73 patients. Ten patients had CSF analysis for general markers such as total protein, cell count, glucose, clarity, and color. Seven of the 10 cases (70%) had normal total cell count and normal white blood cell count in CSF. Sixty-three percent (5/8) had elevated total protein. Two patients had normal levels of lactate dehydrogenase (LDH) and 1 patient had significantly elevated (fourfold) neuron-specific enolase (NSE) level in CSF. Conclusion: Unlike bacterial infections, viral infections are less likely to cause remarkable changes in CSF glucose, cell count, or protein. Our observations showed no pleocytosis, but mild increase in protein in the CSF of the COVID-19 patients. The fourfold elevation of NSE may have diagnostic/prognostic value as a biomarker in CSF for COVID-19 patients who have altered mental status. [ABSTRACT FROM AUTHOR]

First in 2002, severe acute respiratory syndrome coronavirus (SARS-CoV), second in 2012, Middle East respiratory syndrome coronavirus (MERS-CoV), and now the third in the December 2019, emergence of tremendously pathogenic and large-scale epidemic novel coronavirus (SARS-CoV-2) has brought the worst conditions into the human inhabitants of the twenty-first century. The SARS-CoV-2 uses the resembling receptor, angiotensin-converting enzyme 2 (ACE2) as that for SARS-CoV, and mainly feasts through the respiratory tract. The ACE2 receptor appearances have been also detected upon glial cells and neurons, which makes them a potential target of SARS-CoV-2 disease (COVID-19). Consequently, cells expressing ACE2, apart from lung and cardiovascular tissue, neurons and glial cells may act as targets and are thus vulnerable to SARS-CoV-2 systemic infection as well as its central nervous system (CNS) comorbidities. Investigation of the neurological manifestations of COVID-19 is a step towards better understanding the SARS-CoV-2 infections, inhibiting the additional spread and treating patients affected by this pandemic. In this concern, more clinical examinations for CNS involvement of SARS-CoV-2 are warranted. In this article, we have reviewed the neurological characteristic features of COVID-19 patients, latent neurotropic mechanisms of SARS-CoV-2 involvement in the comorbidity associated with CNS disorders, and neurological manifestations associated with COVID-19. Therefore, in the perspective of COVID-19 pandemic, clinicians and healthcare workers should be aware of a wide spectrum of neurological manifestations associated with COVID-19 along with their signs and symptoms for initial diagnosis and isolation of the patients. [ABSTRACT FROM AUTHOR]

Purpose of Review: Coronavirus disease 2019 (COVID-19) has become a global health crisis of our time. The disease arises from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that binds to angiotensin-converting enzyme 2 (ACE2) receptors on host cells for its internalization. COVID-19 has a wide range of respiratory symptoms from mild to severe and affects several other organs, increasing the complexity of the treatment. There is accumulating evidence to suggest that SARS-CoV-2 can target the nervous system. In this review, we provide an account of the COVID-19 central nervous system (CNS) manifestations. Recent Findings: A broad spectrum of the CNS manifestations including headache, impaired consciousness, delirium, loss of smell and taste, encephalitis, seizures, strokes, myelitis, acute disseminated encephalomyelitis, neurogenic respiratory failure, encephalopathy, silent hypoxemia, generalized myoclonus, neuroleptic malignant syndrome and Kawasaki syndrome has been reported in patients with COVID-19. Summary: CNS manifestations associated with COVID-19 should be considered in clinical practice. There is a need for modification of current protocols and standing orders to provide better care for COVID-19 patients presenting with neurological symptoms. [ABSTRACT FROM AUTHOR]

Background: COVID-19 disease affects the nervous system and led to an increase in neurological consults for patients at admission and through the period of hospitalization during the peak of the pandemic. Methods: Patients with clinical and laboratory diagnosis of COVID-19 that required a neurologic consultation or those who presented with neurological problems on admission that led to a diagnosis of SARS-CoV-2 infection during a 2-month period at the peak of the pandemic were included in this study. Demographic and clinical variables were analyzed. Results: Thirty-five patients were included. The presenting neurologic manifestations on admission led to the diagnosis of COVID-19 in 14 patients (40%). The most common reasons for consultation during the hospitalization period were stroke (11), encephalopathy (7), seizures (6), and neuropathies (5) followed by a miscellaneous of syncope (2), migraine (1), anosmia (1), critical illness myopathy (1), and exacerbation of residual dysarthria (1). The most common neurological disturbances were associated with severe disease except for neuropathies. Patients with encephalopathies and seizures had markedly increased D-dimer and ferritin values, even higher than stroke patients. RT-PCR was performed in 8 CSF samples and was negative in all of them. Conclusion: Neurological disturbances represent a significant and severe burden in COVID-19 patients, and they can be the presenting condition that leads to the diagnosis of the viral infection in a high percentage of patients. Evidence of direct viral mechanisms was scarce, but the pathogenesis of the diverse manifestations remains enigmatic. [ABSTRACT FROM AUTHOR]

COVID-19 encephalitis is a rare condition usually presenting with altered mental status. Simultaneous presence of anti-NMDAR antibody and SARS-CoV-2 virus in CSF is a very rare condition described in a few case reports so far. On the other hand, brain edema is an unusual presentation of anti-NMDAR encephalitis. Herein, we reported a case with simultaneous detection of anti-NMDAR antibody and SARS-CoV-2 virus in her cerebrospinal fluid (CSF) presenting with brain edema, altered mental status, seizures, and respiratory symptoms. [ABSTRACT FROM AUTHOR]

Background: Olfactory dysfunction (OD) has been gaining recognition as a symptom of COVID-19, but its clinical utility has not been well defined. Objectives: To quantify the clinical utility of identifying OD in the diagnosis of COVID-19 and determine an estimate of the frequency of OD amongst these patients. Methods: PubMed was searched up to 1 August 2020. Meta-analysis A included studies if they compared the frequency of OD in COVID-19 positive patients (proven by reverse transcription polymerase chain reaction) to COVID-19 negative controls. Meta-analysis B included studies if they described the frequency of OD in COVID-19 positive patients and if OD symptoms were explicitly asked in questionnaires or interviews or if smell tests were performed. Results: The pooled frequency of OD in COVID-19 positive patients (17,401 patients, 60 studies) was 0.56 (0.47–0.64) but differs between detection via smell testing (0.76 [0.51–0.91]) and survey/questionnaire report (0.53 [0.45–0.62]), although not reaching statistical significance (p = 0.089). Patients with reported OD were more likely to test positive for COVID-19 (diagnostic odds ratio 11.5 [8.01–16.5], sensitivity 0.48 (0.40 to 0.56), specificity 0.93 (0.90 to 0.96), positive likelihood ratio 6.10 (4.47–8.32) and negative likelihood ratio 0.58 (0.52–0.64)). There was significant heterogeneity amongst studies with possible publication bias. Conclusion: Frequency of OD in COVID-19 differs greatly across studies. Nevertheless, patients with reported OD were significantly more likely to test positive for COVID-19. Patient-reported OD is a highly specific symptom of COVID-19 which should be included as part of the pre-test screening of suspect patients. [ABSTRACT FROM AUTHOR]

Purpose of Review: To review current literature on endothelial dysfunction with previous coronaviruses, and present available data on the role of endothelial dysfunction in coronavirus disease-2019 (COVID-19) infection in terms of pathophysiology and clinical phenotype Recent Findings: Recent evidence suggests that signs and symptoms of severe COVID-19 infection resemble the clinical phenotype of endothelial dysfunction, implicating mutual pathophysiological pathways. Dysfunction of endothelial cells is believed to mediate a variety of viral infections, including those caused by previous coronaviruses. Experience from previous coronaviruses has triggered hypotheses on the role of endothelial dysfunction in the pathophysiology of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), which are currently being tested in preclinical and clinical studies. Summary: Endothelial dysfunction is the common denominator of multiple clinical aspects of severe COVID-19 infection that have been problematic for treating physicians. Given the global impact of this pandemic, better understanding of the pathophysiology could significantly affect management of patients. [ABSTRACT FROM AUTHOR]