Received 2022-08-05

Revised 2022-08-21

Accepted 2022-08-31

Neurological Symptoms in Coronavirus Disease 2019 Patients: An Updated Literature Review

Somayeh Mohammadi 1, Amirabbas Rostami 2, Fateme Naghdizadeh 3, Mahdie ShojaeiBaghini 4, Nooshin Karami 5, Sohrab Negargar 6, Mohsen Emadi 7, Morteza Jafarinia 8

1 Department of Anesthesiology and Critical Care Medicine, Medical Center, University of Chicago, Chicago, IL, USA

2 Department of Internal Medicine, Faculty of General Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

3 School of Nursing and Midwifery, Yasuj University of Medical Sciences, Yasuj, Iran

4 Medical Informatics Research Center, Institute for Futures Studies in Health, Kerman University of Medical Sciences, Kerman, Iran

5 Department of Clinical Psychology, Shiraz University of Education and Psychology, Shiraz, Iran

6 Cardiovascular Research Center of Tabriz University of Medical Sciences, Tabriz, Iran

7 Faculty of Humanities, Department of Sport Sciences, Jahrom University, Jahrom, Iran

8 Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

Abstract

Several studies have reported that coronavirus disease 2019 (COVID-19) can lead to multi-organ dysfunction. COVID-19 has been linked to a variety of neurological symptoms, according to the literature. The various paths via which the brain can be infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as well as the symptoms of COVID-19 in neurological diseases, are discussed. COVID-19 symptoms have been observed in neurological illnesses such as epilepsy, ischemic stroke, multiple sclerosis, Alzheimer's disease, subarachnoid hemorrhage, Guillain–Barré syndrome, and Parkinson's disease in several investigations. [GMJ.2022;11:e2539] DOI:2539

Keywords: Alzheimer; SARS-CoV-2; Coronavirus Disease 2019; Epilepsy; Multiple
Sclerosis; Parkinson

Introduction

The coronavirus disease 2019
(COVID-19), which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been recognized as a worldwide pandemic and mostly affects the respiratory system [1-3]. Within two weeks of exposure to COVID-19, mild symptoms such as shortness of breath, cough, chills, fever, exhaustion, vomiting, nausea, congestion, sore throat, loss of smell and/or taste, headache, and body aches could appear [4-7]. Many people who survive an acute illness develop chronic and debilitating neurological problems, especially in the central nervous system (CNS), with severe personal and socioeconomic ramifications [8]. During the acute state of COVID-19, one-third of patients reveal neurological involvement, including stroke, altered mental status, seizures, and headache, placing SARS-CoV-2 as a new neuropathogen [9-11]. A post-infectious viral syndrome has been reported in one-third of COVID-19-infected people with several neuropsychiatric symptoms [12]. Neurological problems can appear during viral infections in various ways, such as direct infection of endothelial cells in the nervous system, glia, and neurons in the CNS, which results in acute cellular damage [13, 14]. In this review, we explore the potential paths through which SARS-CoV-2 could infect the nervous systems, as well as the role and effects of
COVID-19 in neurological illnesses.

SARS-CoV-2

The human coronavirus SARS-CoV-2 is a enveloped positive-sense single-stranded RNA (ssRNA) [15, 16]. The respiratory system can be infected by coronaviruses, including the Middle East respiratory syndrome coronavirus (MERS-CoV), SARS-CoV,
HCoV-HKU1, HCoV-NL63, HCoV-OC43, and HCoV-22E [17]. Many human coronaviruses lead to mild diseases; however, some of them, including SARS-CoV-2, MERS-CoV, and SARS-CoV can be extremely lethal [18]. Furthermore, while MERS-CoV and SARS-CoV typically infect the lower respiratory tract, SARS-CoV-2 infects both the lower and upper respiratory tracts [19-21]. SARS-CoV-2 has been shown to infect human cells by interacting with the human angiotensin-converting enzyme 2 (ACE2) receptor [22-24]. The respiratory epithelial cells and the pulmonary type II alveolar cells express high levels of ACE2, which demonstrates that COVID-19 is largely a respiratory disease. On the other hand, this receptor expression is not restricted to the respiratory tract. Bladder urothelial cells, renal proximal tubule cells, esophageal epithelial cells, ileal cells, brain, and myocardial cells have all been discovered to have significant ACE2 expression [25]. As a result, the function and overactivity of ACE2 receptors may increase infection susceptibility and affect such tissues [25, 26].

Mechanism of CNS Invasion

SARS-CoV-2 can enter the CNS by one of two main routes. The virus could first pass via the cribriform plate by retrograde axonal transport. Motor proteins can act as a bridge for SARS-CoV-2, which can help the virus reach the brain via sensory and olfactory
nerves [27]. Loss of smell is one sign of this pathway [28]. SARS-CoV-2 can enter the circulation after the involvement of the respiratory tract as an alternate route to the CNS [29]. With cerebral blood flow, the virus could infect other organs and tissues. Due to the particular physiology of the blood-brain barrier (BBB), the virus cannot easily travel from capillaries to the CNS via endothelial cells. Paracellular migration, transcellular migration, and the trojan horse method are the three main ways a virus might cross the blood-brain barrier [30].

Mechanisms of CNS Damages

SARS-CoV-2 causes neurological injury through a combination of mechanisms, including hypoxic brain injury and immune-mediated CNS damage.

Hypoxic Brain Injury

Systemic hypoxia resulting from severe pneumonia can cause CNS damage. Peripheral vasodilation, hypercarbia, hypoxia, and anaerobic metabolism with hazardous chemical buildup are all contributing causes. These conditions can cause brain edema, leading to nervous system impairment [31].

Immune-Mediated Damage

Activation of endothelial cells, macrophages, and T lymphocytes and elevation of inflammatory mediators are the main causes of immune-mediated damage. Vascular leakage, coagulation cascades, complement activation disseminated intravascular coagulation, and end-organ destruction result from the continued release of Interleukins 6
(IL-6) [32, 33].

CNS-Associated Signs and Complications

COVID-19 has been linked to several CNS symptoms, such as ataxia, epilepsy, acute cerebrovascular illness, altered consciousness, dizziness, and headache [34]. Headache is the most frequent symptom in various studies, with a mean prevalence of 8% [34]. Wang et al. demonstrated that thirteen individuals suffered from dizziness among 138 patients with COVID-19, and nine patients seemed to have a headache [35]. Dizziness was also more common in patients in the intensive care unit (ICU) [35]. In acute infections, older adults were at an increased risk of confusion and encephalopathy [36, 37]. In addition, cerebral hemorrhages can cause confusion or reduced awareness. Intracerebral hemorrhage is also reported in some cases [38]. Cerebrovascular disease is among the most common comorbidities in people with severe epilepsy [39].

Furthermore, viral infections like COVID-19 have been linked to the development of cerebrovascular disorders such as acute ischemic stroke [40]. Some COVID-19-positive critically sick individuals have a high risk of clot formation [41]. In COVID-19 individuals, just a few incidences of ataxia and acute disseminated encephalomyelitis (ADEM) have been reported [29, 42].

Peripheral Nervous System (PNS)-Associated Signs and Complications

Guillain-Barre syndrome (GBS), muscle soreness, hypogeusia/ageusia, and hyposmia/anosmia are far less severe PNS signs and symptoms of COVID-19. Common PNS signs of COVID-19 infection are anosmia and ageusia, which have previously been documented in prior coronaviruses [43]. These symptoms appear rapidly and are frequently accompanied by fewer nasal symptoms [43]. Ageusia and anosmia were the most commonly found in individuals without any symptoms [44]. As a result, some researchers believe that people who exhibit these symptoms could be carriers and should avoid contact with others [45]. The sense of taste and smell are recovered after individuals recover from COVID-19 infection [45]. The exact mechanism of SARS-COV-2 anosmia is unknown. Coronavirus can cause transneuronal spread into the CNS through ACE2 and Transmembrane Serine Protease 2 in olfactory cells [46, 47]. As a result of the disruption of the olfactory neuroepithelium, anosmia develops. However, some researchers suggest that inflammatory reactions are the main culprit of anosmia [48].

Neurological Manifestations

Following SARS-CoV-2 infection, CNS symptoms, including epileptic seizures, encephalopathy, encephalitis, and ischemic stroke may be seen. COVID-19 has been linked to inflammatory-mediated neurological disorders and neurodegenerative diseases. In the following, we provide a brief overview of several neurological illnesses as well as current case studies.

Epilepsy

Unprovoked and recurrent seizures characterize epilepsy caused by an imbalance of excitatory and inhibitory neural
activity [49-51]. Seizures are observed in COVID-19 infection; however, not in large numbers [52-54]. In an observational study [55], a young adult with myalgia, lethargy, and fever was reported. Briefly, following a generalized tonic-clonic seizure, the patient was taken to the hospital, and a cerebrospinal fluid investigation indicated lymphocytic pleocytosis. Except for the sphenoid sinus, where modest mucosal thickening was seen, the rest of the imaging was unremarkable. The presence of SARS-CoV-2 was initially disputed by polymerase chain reaction (PCR) analysis, but a second test proved the patient's infection. However, the patient did not have COVID-19-related respiratory symptoms, the overall clinical course was moderate, and SARS-CoV-2 was not found in the patient's CSF fluid [55]. Another adult guy exhibited numbness of the left hand and face, loss of smell, and bulging of the scalp flap in a recent investigation [55]. The patient experienced a focal conscious seizure. The right temporal lobe was swollen on imaging, but there was no evidence of a cerebral infarction or new vascular obstruction. SARS-CoV-2 infection was verified by PCR analysis [55]. According to Kadono
et al., presence of severe cerebral edema was most likely related to COVID-19 neuroinvasion [56].

Furthermore, another study discovered that 0.7 percent of 1043 COVID-19 patients had a seizure [57]. Four of the seven individuals studied had new-onset seizures. Another epileptic patient had significant leukoencephalopathy with gyriform restricted diffusion imaging, most likely owing to the patient's state or viral encephalitis [57]. Seizures may be caused by SARS-CoV-2 infection through a variety of methods. These symptoms could arise from therapeutic interventions, organ failure, metabolic disturbances, hypoxia, brain injury, and SARS-CoV-2 neuroinvasion [58]. COVID-19-related epilepsy has been linked to the release of granulocyte colony-stimulating factor, tumor necrosis factor (TNF), and inflammatory cytokines [59, 60]. In some circumstances, epilepsy may be linked to antiviral drugs or adverse drug reactions [61].

Ischemic Stroke

Ischemic stroke is described as an episode of neurological impairment induced by focal cerebral, spinal, and/or retinal infarction [62]. It is caused by a reduced brain blood flow and the resulting hypoxia. Thrombosis or embolism can cause blood vessel obstruction and hypoxia [63]. SARS-CoV-2 and stroke have been linked in multiple case
reports [64-68]. For example, an elderly man presented with confusion, weakening of the left upper limb, and dysarthria [69]. Apart from shortness of breath, patients had no symptoms associated with SARS-CoV-2 infection before the onset of neurological signs. Ischemic stroke, atrial fibrillation, and obstructive pulmonary disease were all present in the patient's medical history. Acute anterior cerebral artery infarction was discovered on imaging. SARS-CoV-2 was later validated by PCR analysis [69]. Ischemic stroke was also described in four individuals with different stages of COVID-19 infection in a retrospective analysis [70]. One of the patients arrived with altered mental status, while the other patients acquired stroke symptoms after hospitalization. Bilateral multifocal subcortical infarctions were suggested by the imaging results. Another patient was admitted to the hospital with acute respiratory distress syndrome, septic shock, and organ failure, and imaging revealed a right posterior cerebral artery infarction [70].

Multiple Sclerosis (MS)

MS is an autoimmune disease characterized by gliosis, demyelination, inflammation, and CNS cell damage [71]. Patients with MS are known to have a higher infection risk, which can result in neurological signs due to BBB failure. Since MS patients receive immunosuppressive drugs, they might be more prone to COVID-19 [72, 73]. A previous study discovered that in MS patients, the prevalence of COVID-19 was 2.5 times higher (1%) than in healthy individuals (0.4%) [74]. Another study indicated that people with MS have not an elevated incidence of COVID-19 independent of their disease-modifying medication regimen [75]. Some other studies have reported that there are no relationship between COVID-19 susceptibility and MS [76]. Based on these contradictory reports, the relationship between COVID-19 susceptibility and MS is now debatable [77].

Moreover, previous research has indicated that viral infection might cause MS exacerbations by inducing autoimmunity [78-80]. A young adult, for example, had visual neuritis after contracting SARS-CoV-2 [81]. Hence, more research is required to fully comprehend the intricate link between MS and COVID-19.

Alzheimer’s Disease (AD)

AD is a devastating neurodegenerative disorder caused by neuron damage. Cognitive and behavioral defects are all symptoms of AD [82]. Patients with dementia had a higher mortality rate (62.2%) than patients without dementia in COVID-19-infected individuals, according to recent retrospective research (26.2%) [83]. Patients with AD may be at a higher risk for developing COVID-19. Patients who live alone and do not have access to a caretaker may be unable to follow COVID-19 prevention suggestions such as hand washing, wearing a mask, covering mouth and nose when coughing or sneezing, physical distancing, and/or staying at home [84]. Amyloid fibrils can trigger an inflammatory response and cytokine production [83]. Interferon type 1 could induced genes that be upregulated in AD patients. According to these findings, amyloid fibrils may catch viruses, stimulate glial cells, and initiate interferon production [83, 85, 86]. However, the probable association between AD and COVID-19 remains unknown.

Parkinson’s Disease

Another neurodegenerative disorder is Parkinson's disease, which causes rigidity, resting tremors, and bradykinesia [87]. COVID-19 was discovered to be 0.9 % of people with Parkinson's disease, according to a recent cohort survey [88]. This number is higher than the 0.25 % regional frequency in Tuscany, the study's locale, and the multi-centered survey done [88]. In addition, a cohort research found that patients with Parkinson's disease had a greater COVID-19 death rate than those over 70 years old [89]. Another study [90] found that COVID-19 prevalence in the general population was similar to prevalence among individuals with Parkinson's disease. No difference was found between the two populations regarding mortality and morbidity [90].

Furthermore, pro-inflammatory cytokines such as IL-6, IL-1, and TNF-α are found in increased concentrations in the elderly [85]. These inflammatory markers are crucial participants in the elevated immune response associated with acute illness. As a result, more studies are needed to determine that the reported rise in COVID-19 among people with Parkinson's disease is due to neurodegenerative disease or other factors such as age.

GBS

To our knowledge, the first report of COVID-19-associated GBS was inconclusive [91]. Further research has found significant evidence of a link between COVID-19 and GBS. Five GBS occurrences were recorded among 1000–1200 SARS-CoV-2 infected patients admitted to a hospital in Italy [92]. Finsterer et al. [93] also looked at 24 cases of GBS that could be linked to COVID-19. Male and older patients were the most commonly afflicted, and the bulk of the instances came after the beginning of COVID-19 signs [93]. Acute, inflammatory, and demyelinating polyradiculoneuropathy was the most common disease subtype, accounting for 58% of cases [93]. Viruses were not found in the CSF, which was notable. In general, patients responded well to intravenous (IV) immunoglobulin
therapy [93]. In addition, autonomic dysfunction linked to COVID-19-related GBS was seen in diagnosed patients [94]. The patient had no fever or lung symptoms, which was unusual. The patient proved positive for SARS-CoV-2 infection after undergoing a variety of tests. An X-ray of the chest revealed mild bibasilar atelectasis with scattered consolidations [94]. He was transferred to the ICU three days after his admission due to a deteriorating respiratory state. GBS was diagnosed, and the patient was given IV immunoglobulin to treat it. He had autonomic dysfunction the next day. He developed quadriplegia after six days due to considerable weakness. He had symptoms of inadequate antidiuretic hormone secretion two days later [94]. GBS can have unusual symptoms as well [95]. Two examples of atypical GBS were recorded by
Assini
et al. [95]. A 55-year-old man got GBS/Miller-Fisher overlap syndrome in the first case. After being taken to the hospital for COVID-19, the patient had dysphonia, dysphagia, and acute bilateral eyelid ptosis 12 days later. The results of a motor nerve conduction examination confirmed that he had GBS. Following IV immunoglobulin treatment, the patient's condition significantly improved [95].

Subarachnoid Hemorrhage (SAH)

SAH is a serious disorder characterized by subarachnoid space bleeding [96]. In a study, the authors described SAH in a 66-year-old woman with a history of hyperlipidemia, hypertension, and diabetes [97]. The patient had general malaise, shortness of breath, and dry cough for one week. After arriving at the emergency department, the patient was intubated, and a chest X-ray showed bilateral infiltration. SARS-CoV-2 testing revealed that the patient was positive. The computed tomography (CT) scan of the brain discovered a SAH spreading into the suprasellar cistern, Sylvian and interhemispheric fissures, effacement of the fourth ventricle, and extensive cerebral edema. The patient was unresponsive, with fixed dilated pupils that were not sensitive to light, no corneal or gag reflexes, and no oculocephalic or vestibulocephalic movements. Once more experiencing cardiac arrest, the patient was pronounced dead [97]. Al
Saiegh
et al. described another instance of SAH in a male 31-year-old patient with arthralgia, cough, malaise, moderate fever, and infection in the upper respiratory tract [98]. The patient experienced a strong headache and lost consciousness all of a sudden. A SAH was discovered during a head CT scan. SARS-CoV-2 test was done because of his respiratory symptoms and was confirmed positive. After being intubated the following day, the patient was extubated, his symptoms progressively improved, and he was sent home for rehabilitation [98].

Conclusion

SARS-CoV-2 is largely a respiratory virus; however, some patients may experience brain problems, particularly in advanced disease. Although the underlying processes of illness etiology are unknown, neuroinvasion, neuroinflammation, and BBB disruption have all been implicated in the appearance of various CNS symptoms in investigations. Several inflammatory-mediated neurological disorders may also increase the susceptibility to COVID-19 infection. The majority of the research were case reports. As a result, more research is needed to fully understand the mechanism of COVID-19, which leads to neurological problems. Although vaccine advances offer hope for containing the pandemic, more research and understanding of COVID-19's clinical symptoms and processes are required.

Acknowledgment

This study was financially supported by Shiraz University of Medical Sciences
(grant no: 26718).

Conflict of Interest

The authors declare that there are no conflicts of interest.

Correspondence to:

Morteza Jafarinia, Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

Telephone Number: +987136257497

Email Address: [email protected]

References

  1. Vakili S, Akbari H, Jamalnia S. Clinical and Laboratory findings on the differences between h1n1 influenza and coronavirus disease-2019 (covid-19): focusing on the treatment approach. Clin Pulm Med. 2020;27(4):87-93.
  2. Danesh H, Barzegar F, Maddahi F, Horri E, Abdolrazaghnejad A. Medical and Pharmacological Evaluation of Infection Control in Covid-19 Patients. J Med Chem Sci. 2022;5(2):257-69.
  3. Vakili S, Savardashtaki A, Jamalnia S, Tabrizi R, Nematollahi MH, Jafarinia M, et al. Laboratory findings of COVID-19 infection are conflicting in different age groups and pregnant women: a literature review. Arch Med Res. 2020;51(7):603-7.
  4. Bhattacharyya S, Dey K, Paul AR, Biswas R. A novel CFD analysis to minimize the spread of COVID-19 virus in hospital isolation room. Chaos Solitons Fractals. 2020;139:110294.
  5. Khalifehzadeh-Esfahani Z, Fattahi S, Heidari Haratemeh Z, Jafarinia M. The Role of Immune Regulatory Molecules in COVID-19. Viral Immunol. 2020;35(5):359-64.
  6. Gharayagh-Zandi D, Makouee S. COVID-19 and International Organizations: A Case Study of WHO. Int J Adv Stu Hum Soc Sci. 2022;11(1):1-20.
  7. Harismah K, Mirzaei M. Favipiravir: structural analysis and activity against COVID-19. Adv J Chem B. 2020;2(2):55-60.
  8. Al-Aly Z, Xie Y, Bowe B. High-dimensional characterization of post-acute sequelae of COVID-19. Nature. 2021;594(7862):259-64.
  9. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506.
  10. Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol. 2020;77(6):683-90.
  11. Varatharaj A, Thomas N, Ellul MA, Davies NW, Pollak TA, Tenorio EL, et al. Neurological and neuropsychiatric complications of COVID-19 in 153 patients: a UK-wide surveillance study. Lancet Psychiat. 2020;7(10):875-82.
  12. Taebi M, Tajik A, Zarepur A, Zarepur E, Tavakolimoghadam R, Danesh H. Rhabdomyolysis in Severe Covid19: A Mini Review Study. J Med Chem Sci. 2022:82-8.
  13. Van den Pol AN. Viral infection leading to brain dysfunction: more prevalent than appreciated? Neuron. 2009;64(1):17-20.
  14. Bradshaw MJ, Venkatesan A. Herpes simplex virus-1 encephalitis in adults: pathophysiology, diagnosis, and management. Neurotherapeutics. 2016;13(3):493-508.
  15. Fattahi S, Khalifehzadeh-Esfahani Z, Mohammad-Rezaei M, Mafi S, Jafarinia M. PI3K/Akt/mTOR pathway: a potential target for anti-SARS-CoV-2 therapy. Immunol Res. 2022:1-7.
  16. Jonny J, Violetta L. Coupled Plasma Filtration Adsorption as a Potential Therapy for Critically III Covid-19 Patients. J Med Chem Sci. 2022:197-203.
  17. Matoba Y, Abiko C, Ikeda T, Aoki Y, Suzuki Y, Yahagi K, et al. Detection of the human coronavirus 229E, HKU1, NL63, and OC43 between 2010 and 2013 in Yamagata, Japan. Jpn J Infect Dis. 2015;68(2):138-41.
  18. Ye Z-W, Yuan S, Yuen K-S, Fung S-Y, Chan C-P, Jin D-Y. Zoonotic origins of human coronaviruses. Int J Biol Sci. 2020;16(10):1686.
  19. Tse GM, To K, Chan PK, Lo A, Ng K, Wu A, et al. Pulmonary pathological features in coronavirus associated severe acute respiratory syndrome (SARS). J Clin Pathol. 2004;57(3):260-5.
  20. Widagdo W, Raj VS, Schipper D, Kolijn K, Van Leenders GJ, Bosch BJ, et al. Differential expression of the Middle East respiratory syndrome coronavirus receptor in the upper respiratory tracts of humans and dromedary camels. J Virol. 2016;90(9):4838-42.
  21. Wölfel R, Corman VM, Guggemos W, Seilmaier M, Zange S, Müller MA, et al. Virological assessment of hospitalized patients with COVID-2019. Nature. 2020;581(7809):465-9.
  22. Lan J, Ge J, Yu J, Shan S, Zhou H, Fan S, et al. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature. 2020;581(7807):215-20.
  23. Javadi M. Numerical calculation of necessary distancing regarding SARS-CoV-2 (COVID-19) vs. spherical viruses, based on environmental features. Eurasian Chem Commun. 2021:406-17.
  24. Ara I, Maqbool M, Zehravi M, Gani I. Herbs Boosting Immunity in Covid-19: An Overview. Adv J Chem B. 2020;3(3):289-94.
  25. Zou X, Chen K, Zou J, Han P, Hao J, Han Z. Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection. Front Med. 2020;14(2):185-92.
  26. Li M-Y, Li L, Zhang Y, Wang X-S. Expression of the SARS-CoV-2 cell receptor gene ACE2 in a wide variety of human tissues. Infect Dis Poverty. 2020;9(02):23-9.
  27. Briguglio M, Bona A, Porta M, Dell'Osso B, Pregliasco FE, Banfi G. Disentangling the hypothesis of host dysosmia and SARS-CoV-2: the bait symptom that hides neglected neurophysiological routes. Front Physiol. 2020;11:671.
  28. Eliezer M, Hautefort C, Hamel A-L, Verillaud B, Herman P, Houdart E, et al. Sudden and complete olfactory loss of function as a possible symptom of COVID-19. JAMA Otolaryngol Head Neck Surg. 2020;146(7):674-5.
  29. Baig AM. Neurological manifestations in COVID‐19 caused by SARS‐CoV‐2. CNS Neurosci Ther. 2020;26(5):499.
  30. Dahm T, Rudolph H, Schwerk C, Schroten H, Tenenbaum T. Neuroinvasion and inflammation in viral central nervous system infections. Mediators Inflamm. 2016;2016:8562805.
  31. Tu H, Tu S, Gao S, Shao A, Sheng J. Current epidemiological and clinical features of COVID-19; a global perspective from China. J Infect. 2020;81(1):1-9.
  32. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033-4.
  33. Tveito K. Cytokine storms in COVID-19 cases? Tidsskr Nor Laegeforen. 2020;140.
  34. Rodriguez-Morales AJ, Cardona-Ospina JA, Gutiérrez-Ocampo E, Villamizar-Peña R, Holguin-Rivera Y, Escalera-Antezana JP, et al. Clinical, laboratory and imaging features of COVID-19: A systematic review and meta-analysis. Travel Med Infect Dis. 2020;34:101623.
  35. Wang Y, Wang Y, Chen Y, Qin Q. Unique epidemiological and clinical features of the emerging 2019 novel coronavirus pneumonia (COVID‐19) implicate special control measures. J Med Virol. 2020;92(6):568-76.
  36. Espinosa PS, Rizvi Z, Sharma P, Hindi F, Filatov A. Neurological complications of coronavirus disease (COVID-19): encephalopathy, MRI brain and cerebrospinal fluid findings: case 2. Cureus. 2020;12(5).
  37. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395(10223):507-13.
  38. Sharifi-Razavi A, Karimi N, Rouhani N. COVID-19 and intracerebral haemorrhage: causative or coincidental? New Microbes New Infect. 2020;35:100669.
  39. Wang L, He W, Yu X, Hu D, Bao M, Liu H, et al. Coronavirus disease 2019 in elderly patients: characteristics and prognostic factors based on 4-week follow-up. J Infect. 2020;80(6):639-45.
  40. Morelli N, Rota E, Terracciano C, Immovilli P, Spallazzi M, Colombi D, et al. The baffling case of ischemic stroke disappearance from the casualty department in the COVID-19 era. Eur Neurol. 2020:1.
  41. Violi F, Pastori D, Cangemi R, Pignatelli P, Loffredo L. Hypercoagulation and antithrombotic treatment in coronavirus 2019: a new challenge. Thromb Haemost. 2020;120(6):949-56.
  42. McAbee GN, Brosgol Y, Pavlakis S, Agha R, Gaffoor M. Encephalitis associated with COVID-19 infection in an 11-year-old child. Pediatr Neurol. 2020;109:94.
  43. Vaira LA, Salzano G, Deiana G, De Riu G. Anosmia and ageusia: common findings in COVID‐19 patients. Laryngoscope. 2020;130(7):1787.
  44. Gane SB, Kelly C, Hopkins C. Isolated sudden onset anosmia in COVID-19 infection A novel syndrome. Rhinology. 2020;58(3):299-301.
  45. Ovesen T. COVID-19 anosmia. Tidsskr Nor Laegeforen. 2020;140(7).
  46. Xydakis MS, Dehgani-Mobaraki P, Holbrook EH, Geisthoff UW, Bauer C, Hautefort C, et al. Smell and taste dysfunction in patients with COVID-19. Lancet Infect Dis. 2020;20(9):1015-6.
  47. Moein ST, Hashemian SM, Mansourafshar B, Khorram-Tousi A, Tabarsi P, Doty RL. Smell dysfunction: a biomarker for COVID-19. Int Forum Allergy Rhinol. 2020;10(8):944-50.
  48. Villalba NL, Maouche Y, Ortiz MBA, Sosa ZC, Chahbazian JB, Syrovatkova A, et al. Anosmia and dysgeusia in the absence of other respiratory diseases: should COVID-19 infection be considered? Eur J Case Rep Intern Med. 2020;7(4).
  49. Stafstrom CE, Carmant L. Seizures and epilepsy: an overview for neuroscientists. Cold Spring Harb Perspect. 2015;5(6):a022426.
  50. Scharfman HE. The neurobiology of epilepsy. Curr Neurol Neurosci Rep. 2007;7(4):348-54.
  51. Sirven JI. Epilepsy: a spectrum disorder. Cold Spring Harb Perspect. 2015;5(9):a022848.
  52. Vollono C, Rollo E, Romozzi M, Frisullo G, Servidei S, Borghetti A, et al. Focal status epilepticus as unique clinical feature of COVID-19: a case report. Seizure. 2020;78:109-12.
  53. Karimi N, Razavi AS, Rouhani N. Frequent convulsive seizures in an adult patient with COVID-19: a case report. Iran Red Crescent Med J. 2020;22(3).
  54. Hepburn M, Mullaguri N, George P, Hantus S, Punia V, Bhimraj A, et al. Acute symptomatic seizures in critically ill patients with COVID-19: is there an association? Neurocrit Care. 2021;34(1):139-43.
  55. Lyons S, O’Kelly B, Woods S, Rowan C, Brady D, Sheehan G, et al. Seizure with CSF lymphocytosis as a presenting feature of COVID-19 in an otherwise healthy young man. Seizure-Eur J Epilep. 2020;80:113-4.
  56. Kadono Y, Nakamura Y, Ogawa Y, Yamamoto S, Kajikawa R, Nakajima Y, et al. A case of COVID-19 infection presenting with a seizure following severe brain edema. Seizure-Eur J Epilep. 2020;80:53-5.
  57. Anand P, Al-Faraj A, Sader E, Dashkoff J, Abdennadher M, Murugesan R, et al. Seizure as the presenting symptom of COVID-19: a retrospective case series. Epilepsy Behav. 2020;112:107335.
  58. Asadi-Pooya AA. Seizures associated with coronavirus infections. Seizure. 2020;79:49-52.
  59. Libbey JE, Fujinami RS. Neurotropic viral infections leading to epilepsy: focus on Theiler’s murine encephalomyelitis virus. Future Virol. 2011;6(11):1339-50.
  60. Singhi P. Infectious causes of seizures and epilepsy in the developing world. Dev Med Child Neurol. 2011;53(7):600-9.
  61. Ying W, Qian Y, Kun Z. Drugs supply and pharmaceutical care management practices at a designated hospital during the COVID-19 epidemic. Res Social Adm Pharm. 2021;17(1):1978-83.
  62. Sacco RL, Kasner SE, Broderick JP, Caplan LR, Connors J, Culebras A, et al. An updated definition of stroke for the 21st century: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013;44(7):2064-89.
  63. Hui C, Tadi P, Patti L. Ischemic Stroke. StatPearls. Treasure Island, FL: StatPearls Publishing; 2020.
  64. Zhai P, Ding Y, Li Y. The impact of COVID-19 on ischemic stroke. Diagn Pathol. 2020;15(1):1-5.
  65. Avula A, Nalleballe K, Narula N, Sapozhnikov S, Dandu V, Toom S, et al. COVID-19 presenting as stroke. Brain Behav Immun. 2020;87:115-9.
  66. Beyrouti R, Adams ME, Benjamin L, Cohen H, Farmer SF, Goh YY, et al. Characteristics of ischaemic stroke associated with COVID-19. J Neurol Neurosurg Psychiatry. 2020;91(8):889-91.
  67. Oxley TJ, Mocco J, Majidi S, Kellner CP, Shoirah H, Singh IP, et al. Large-vessel stroke as a presenting feature of Covid-19 in the young. N Engl J Med. 2020;382(20):e60.
  68. Jain R, Young M, Dogra S, Kennedy H, Nguyen V, Jones S, et al. COVID-19 related neuroimaging findings: a signal of thromboembolic complications and a strong prognostic marker of poor patient outcome. J Neurol Sci. 2020;414:116923.
  69. Basi S, Hamdan M, Punekar S. Clinical course of a 66-year-old man with an acute ischaemic stroke in the setting of a COVID-19 infection. BMJ Case Rep. 2020;13(8):e235920.
  70. Diaz-Segarra N, Edmond A, Kunac A, Yonclas P. COVID-19 ischemic strokes as an emerging rehabilitation population: a case series. Am J Phys Med Rehabil. 2020.
  71. Tafti D, Ehsan M, Xixis KL. Multiple Sclerosis. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022.
  72. Willis M, Robertson N. Multiple sclerosis and the risk of infection: considerations in the threat of the novel coronavirus, COVID-19/SARS-CoV-2. J Neurol. 2020;267(5):1567-9.
  73. Winkelmann A, Loebermann M, Reisinger EC, Hartung H-P, Zettl UK. Disease-modifying therapies and infectious risks in multiple sclerosis. Nat Rev Neurol. 2016;12(4):217-33.
  74. Crescenzo F, Marastoni D, Bovo C, Calabrese M. Frequency and severity of COVID-19 in multiple sclerosis: a short single-site report from northern Italy. Mult Scler Relat Disord. 2020;44:102372.
  75. Fan M, Qiu W, Bu B, Xu Y, Yang H, Huang D, et al. Risk of COVID-19 infection in MS and neuromyelitis optica spectrum disorders. Neurol Neuroimmunol. 2020;7(5):e787.
  76. Louapre C, Collongues N, Stankoff B, Giannesini C, Papeix C, Bensa C, et al. Clinical characteristics and outcomes in patients with coronavirus disease 2019 and multiple sclerosis. JAMA Neurol. 2020;77(9):1079-88.
  77. Ferini-Strambi L, Salsone M. COVID-19 and neurological disorders: are neurodegenerative or neuroimmunological diseases more vulnerable? J Neurol. 2021;268(2):409-19.
  78. Sadeghmousavi S, Rezaei N. COVID-19 and multiple sclerosis: predisposition and precautions in treatment. SN Compr Clin Med. 2020;2(10):1802-7.
  79. Buljevac D, Flach H, Hop W, Hijdra D, Laman J, Savelkoul H, et al. Prospective study on the relationship between infections and multiple sclerosis exacerbations. Brain. 2002;125(5):952-60.
  80. Correale J, Fiol M, Gilmore W. The risk of relapses in multiple sclerosis during systemic infections. Neurology. 2006;67(4):652-9.
  81. Palao M, Fernández-Díaz E, Gracia-Gil J, Romero-Sánchez C, Díaz-Maroto I, Segura T. Multiple sclerosis following SARS-CoV-2 infection. Mult Scler Relat Disord. 2020;45:102377.
  82. Ayton S, Lei P, Bush AI. Metallostasis in Alzheimer's disease. Free Radic Biol Med. 2013;62:76-89.
  83. Bianchetti A, Rozzini R, Guerini F, Boffelli S, Ranieri P, Minelli G, et al. Clinical presentation of COVID19 in dementia patients. J Nutr Health Aging. 2020;24(6):560-2.
  84. Fotuhi M, Mian A, Meysami S, Raji CA. Neurobiology of COVID-19. J Alzheimer's Dis. 2020;76(1):3-19.
  85. Naughton SX, Raval U, Pasinetti GM. Potential novel role of COVID-19 in Alzheimer’s disease and preventative mitigation strategies. J Alzheimer's Dis. 2020;76(1):21-5.
  86. Roy ER, Wang B, Wan Y-w, Chiu G, Cole A, Yin Z, et al. Type I interferon response drives neuroinflammation and synapse loss in Alzheimer disease. J Clin Investig. 2020;130(4):1912-30.
  87. Tysnes O-B, Storstein A. Epidemiology of Parkinson’s disease. J Neural Transm. 2017;124(8):901-5.
  88. Del Prete E, Francesconi A, Palermo G, Mazzucchi S, Frosini D, Morganti R, et al. Prevalence and impact of COVID-19 in Parkinson’s disease: evidence from a multi-center survey in Tuscany region. J Neurol. 2021;268(4):1179-87.
  89. Fasano A, Elia AE, Dallocchio C, Canesi M, Alimonti D, Sorbera C, et al. Predictors of COVID-19 outcome in Parkinson's disease. Parkinsonism Relat Disord. 2020;78:134-7.
  90. Fasano A, Cereda E, Barichella M, Cassani E, Ferri V, Zecchinelli AL, et al. COVID‐19 in Parkinson’s disease patients living in Lombardy, Italy. Mov Disord. 2020;35(7):1089-93.
  91. Zhao H, Shen D, Zhou H, Liu J, Chen S. Guillain-Barré syndrome associated with SARS-CoV-2 infection: causality or coincidence? Lancet Neurol. 2020;19(5):383-4.
  92. Toscano G, Palmerini F, Ravaglia S, Ruiz L, Invernizzi P, Cuzzoni MG, et al. Guillain–Barré syndrome associated with SARS-CoV-2. N Engl J Med. 2020;382(26):2574-6.
  93. Finsterer J, Scorza FA, Ghosh R. COVID‐19 polyradiculitis in 24 patients without SARS‐CoV‐2 in the cerebro‐spinal fluid. J Med Virol. 2020;93(1):66-8.
  94. Su XW, Palka SV, Rao RR, Chen FS, Brackney CR, Cambi F. SARS-CoV-2-associated Guillain-Barré syndrome with dysautonomia. Muscle Nerve. 2020;62(2):E48-9.
  95. Assini A, Benedetti L, Di Maio S, Schirinzi E, Del Sette M. New clinical manifestation of COVID-19 related Guillain-Barrè syndrome highly responsive to intravenous immunoglobulins: two Italian cases. Neurol Sci. 2020;41(7):1657-8.
  96. Ziu E, Khan Suheb MZ, Mesfin FB. Subarachnoid Hemorrhage. In Treasure Island (FL). StatPearls Publishing; 2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK441958/.
  97. Craen A, Logan G, Ganti L. Novel coronavirus disease 2019 and subarachnoid hemorrhage: a case report. Cureus. 2020;12(4).
  98. Al Saiegh F, Ghosh R, Leibold A, Avery MB, Schmidt RF, Theofanis T, et al. Status of SARS-CoV-2 in cerebrospinal fluid of patients with COVID-19 and stroke. J Neurol Neurosurg Psychiatry. 2020;91(8):846-8.