LitCovid-sentences  

PMC:7799377 / 1693-45587 JSONTXT 3 Projects

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Id Subject Object Predicate Lexical cue
T18 0-12 Sentence denotes Introduction
T19 13-263 Sentence denotes The neuroinvasive potential of the Severe Acute Respiratory Syndrome novel coronavirus, SARS-CoV-2, is being recognized, with enhanced awareness that the associated infection, Coronavirus Diseases 2019 (COVID-19), might result in neurological injury.
T20 264-419 Sentence denotes Indeed, there is a growing body of evidence to suggest that a subset of COVID-19 patients will experience neurological manifestations of the infection [1].
T21 420-864 Sentence denotes Since genomic studies show that the SARS-CoV-2 virus has similar homological sequences with two of its beta-coronavirus predecessors, the SARS-CoV associated with Severe Acute Respiratory Syndrome (SARS) [2] and the virus associated with Middle Eastern Respiratory Syndrome (MERS) [3], it is helpful to review the neurological symptoms of these two earlier diseases as the plausible link between COVID-19 and neurological symptoms are explored.
T22 865-1001 Sentence denotes Furthermore, the pathophysiological pathways of these three conditions (COVID-19, SARS, and MERS) might be expected to be similar [4–6].
T23 1002-1158 Sentence denotes Neurotropism has been observed in both MERS and SARS [7–9], and there are early findings of certain neurological manifestations in COVID-19 patients [4,10].
T24 1159-1301 Sentence denotes The RNA of the SARS-CoV-2 virus has been identified in the cerebrospinal fluid of a COVID-19 patient, demonstrating its neurotropic potential.
T25 1302-1527 Sentence denotes It is clinically relevant to determine how the SARS-CoV-2 virus can access the central nervous system (CNS) and whether the neuronal injury caused by the virus might be connected to the injury of the autonomic nervous system.
T26 1528-1656 Sentence denotes The transmission of a novel infectious pathogen among humans such as the SARS-CoV-2 may be complicated, but it is far from rare.
T27 1657-1749 Sentence denotes As many as 75% of emerging human infections have some connection to a zoonotic disease [11].
T28 1750-2108 Sentence denotes Typically, viral, bacterial, fungal, or parasitical pathogens may emerge due to one or a combination of factors: human and animal interaction, changes in human or animal behavior, consumption of exotic animal foods, globalization, world travel, or things that disrupt human and animal interactions, such as wars, natural disasters, and environmental changes.
T29 2109-2294 Sentence denotes The pathogen itself may play a role in its pattern of emergence by mutation; in some instances, humans may facilitate the rapid progress of these mutations by the use of antimicrobials.
T30 2295-2412 Sentence denotes Thus, while often multifactorial and complex, the sudden emergence of a novel infectious agent is not a novelty [12].
T31 2413-2559 Sentence denotes The novel SARS-CoV-2 virus, which first appeared in 2019, is just one of several coronaviruses that have caused epidemics in the past two decades.
T32 2560-2754 Sentence denotes These pathogens are sometimes able to adapt to new hosts, as occurred with the zoonotic SARS-CoV-2 virus, which appears to have originated in bats, then rapidly accommodated to human hosts [13].
T33 2755-2922 Sentence denotes Coronaviruses are single-stranded, positive-sense, enveloped RNA viruses in the nidovirales order that are categorized into four genera: alpha, beta, gamma, and delta.
T34 2923-3004 Sentence denotes The SARS-CoV-2 virus associated with the COVID-19 epidemic is a beta-coronavirus.
T35 3005-3125 Sentence denotes Seven known coronaviruses affect humans: HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, MERS-CoV, SARS-CoV, and SARS-CoV-2.
T36 3126-3170 Sentence denotes Many coronavirus-related illnesses are mild.
T37 3171-3266 Sentence denotes In fact, coronaviruses were first studied in the 1960s as being agents of the common cold [14].
T38 3267-3411 Sentence denotes Nevertheless, of these viruses, only MERS-CoV, SARS-CoV, and SARS-CoV-2 are associated with potentially severe symptoms and fatal outcomes [15].
T39 3412-3504 Sentence denotes Once in the body, viruses may invade the CNS through hematogenous spread defined by viremia.
T40 3505-3734 Sentence denotes Viruses may also enter the CNS through retrograde neuronal dissemination, which occurs when the virus infects peripheral neurons, subsequently spreading to the spine and brain by way of the existing neuronal transport mechanisms.
T41 3735-3936 Sentence denotes It is the aim of this narrative review to describe what is known about neurological manifestations of SARS, MERS, and COVID-19, with special emphasis on reports about neurological symptoms in COVID-19.
T42 3938-3945 Sentence denotes Methods
T43 3946-4219 Sentence denotes The authors searched the peer-reviewed medical literature using the PubMed database of the National Institutes of Med for COVID-19 resources searching for ‘neurology,’ ‘neurological symptoms,’ and ‘neuropathy.’ The bibliographies of relevant articles were searched as well.
T44 4220-4353 Sentence denotes The literature on COVID-19 is vast and expanding rapidly, but many articles are short commentaries, case studies, and correspondence.
T45 4354-4415 Sentence denotes The search covers materials published through 17 August 2020.
T46 4416-4570 Sentence denotes This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.
T47 4572-4579 Sentence denotes Results
T48 4580-4813 Sentence denotes Far more is known and reported on neurological complications with SARS and MERS than for COVID-19 although the nature of the pandemic and the clinicians reporting from the front lines is rapidly generating a large body of literature.
T49 4814-5091 Sentence denotes In a systematic review that identified COVID-19 cases with neurological complications (n = 82), the mean age of the patient was 62.3 years, 37.8% were female, and 48.8% developed cerebrovascular insults, 28% neuromuscular disorders, and 23% encephalitis or encephalopathy [16].
T50 5093-5144 Sentence denotes Viral entry and potential neurological consequences
T51 5145-5406 Sentence denotes The viruses associated with both SARS and COVID-19 enter the brain via a process involving the angiotensin-converting enzyme (ACE)-2 receptors located in the CNS [17–19], unlike the MERS virus, which gains entry via the plasma membrane or in the endosomes [20].
T52 5407-5522 Sentence denotes ACE-2 receptors are expressed in many parts of the body and are particularly densely expressed in the nasal mucosa.
T53 5523-5727 Sentence denotes Coronaviruses that enter the body via the nasal mucosa may disrupt the nasal endothelium, cross the epithelial barrier, and then directly enter the lymphatic or circulatory system, accessing the CNS [21].
T54 5728-5836 Sentence denotes The SARS-CoV has been detected in the brain, and it is thought entry occurred by way of the olfactory nerve.
T55 5837-6023 Sentence denotes Since there have been studies that located the SARS-CoV virus in the CNS but not the lung, it suggests that there is a direct pathway from the olfactory point of entry into the CNS [22].
T56 6024-6289 Sentence denotes Alternatively, a high viral load in the brain following a pulmonary infection might mean the virus entered the brain from the respiratory system; e.g., the vagus nerve links the respiratory system to the nucleus ambiguous and solitary tract nuclei of the brainstem.
T57 6290-6453 Sentence denotes It has been speculated that the cardiorespiratory center of the brain may be involved in the severe acute respiratory distress in some patients with COVID-19 [23].
T58 6454-6692 Sentence denotes The more common form of respiratory failure in COVID-19 patients is Type 1 (gas exchange dysfunction resulting in hypoxia and low levels of carbon dioxide), which is more likely to be associated with pneumonia than brain dysfunction [24].
T59 6693-6922 Sentence denotes Type 2 respiratory failure, which involves both hypoxia and high levels of carbon dioxide due to ventilatory failure would be more suggestive of neurological dysfunction, and this occurs less frequently in COVID-19 patients [25].
T60 6923-7143 Sentence denotes Any viral invader of the CNS creates stress within the body, because the host must balance its natural immune response to destroy the pathogen while, at the same time, minimizing damage to nearby nonrenewable cells [26].
T61 7144-7285 Sentence denotes Once in the CNS, viruses that affect neurons are far more dangerous than viruses that target the leptomeninges, which can restore themselves.
T62 7286-7423 Sentence denotes The CNS has a highly nuanced system of responses to viruses, which can cause considerable harm to the body should it become uncontrolled.
T63 7424-7638 Sentence denotes Coronaviruses such as the SARS-CoV-2 can enter the body via the nasal mucosa and may disrupt the nasal endothelium, cross the epithelial barrier, and then enter the CNS via the lymphatic or circulatory system [21].
T64 7639-7822 Sentence denotes The blood-brain barrier has a pore size of about 1 nm and coronaviruses are substantially larger [9], and this likely protects the brain from coronavirus invasion in many individuals.
T65 7823-8083 Sentence denotes However, neuroinvasive viruses can cross the blood-brain barrier by brain viremia, inflammatory processes (making microvascular endothelial cells vulnerable), or infecting leukocytes that then cross the blood-brain barrier in the manner of a Trojan horse [27].
T66 8084-8287 Sentence denotes The entry of the virus via the olfactory endothelium with transit of the virus across the cribriform plate would allow the virus to enter the brain by circumventing the blood-brain barrier entirely [27].
T67 8288-8646 Sentence denotes In theory at least, the coronavirus could invade the CNS using a passive mechanism such as hematogenous spread; in this case, the virus goes dormant and is carried toward the CNS, only to re-activate at some point to infect endothelial cells of the blood-brain barrier or infect leukocytes that then act as the reservoir for further viral dissemination [28].
T68 8647-8771 Sentence denotes The neurological symptoms associated with the H1N1 influenza virus had earlier been explained by an autoimmunity model [29].
T69 8772-8983 Sentence denotes The autoimmunity model of coronavirus infection of the CNS, likewise unproven, maintains that neural tissues and blood vessels perceive both viral and myelin antigens as the same because of autoreactive T-cells.
T70 8984-9064 Sentence denotes Autoimmunity would be limited to patients who were genetically predisposed [29].
T71 9065-9279 Sentence denotes The SARS-CoV-2 associated with COVID-19 belongs to the same clade of beta-coronaviruses as the MERS-CoV and the SARS-CoV viruses, although its homological sequence more closely resembles SARS-CoV than MERS-CoV [2].
T72 9280-9502 Sentence denotes The respiratory symptoms that occur in genetically related beta-coronaviruses, such as MERS-CoV and SARS-CoV are similar, two infections with which the global healthcare community has had years of clinical experience [30].
T73 9503-9649 Sentence denotes While it cannot be stated unequivocally that the neurological symptoms of these viral infections will be the same, it forms a good starting point.
T74 9651-9686 Sentence denotes Middle eastern respiratory syndrome
T75 9687-9840 Sentence denotes MERS was first identified in September 2012 in a 60-year-old man in Jeddah, Saudi Arabia, who presented with pneumonia complicated by renal failure [31].
T76 9841-10002 Sentence denotes Sporadic cases were reported outside of the Middle East up until 2015, when an outbreak in South Korea occurred with 186 confirmed infections and 38 deaths [32].
T77 10003-10144 Sentence denotes MERS has established associations with encephalomyelitis, vasculitis, Guillain-Barré syndrome (GBS), and encephalitis of the brain stem [21].
T78 10145-10298 Sentence denotes The clinical course of MERS ranges from asymptomatic cases (about 4%) to severe pneumonia with multiorgan involvement and negative patient outcomes [15].
T79 10299-10469 Sentence denotes While pulmonary, gastrointestinal, renal, and hematological complications have been reported in MERS patients, there are fewer reports of neurological complications [15].
T80 10470-10562 Sentence denotes In fact, the MERS-CoV virus has never been isolated from neural tissue in human beings [28].
T81 10563-10785 Sentence denotes In a study of 737 hospitalized MERS patients in South Korea, the most commonly reported symptoms were respiratory symptoms (13.6%), fever (11.1%), fatigue (11.1%), myalgia (9.2%), and gastrointestinal symptoms (7.5%) [32].
T82 10786-10922 Sentence denotes In a study of 23 MERS patients from South Korea, 17.4% experienced neurological symptoms either during or following MERS treatment [33].
T83 10923-11035 Sentence denotes These neurological complications occurred about two to three weeks after the onset of respiratory symptoms [33].
T84 11036-11158 Sentence denotes A study from Saudi Arabia (n = 70) reported that 24.7% of MERS patients experienced confusion and 8.6% had a seizure [34].
T85 11159-11260 Sentence denotes In this study, fever was present in 61.4% of patients, dyspnea occurred in 60%, an 54.3% had a cough.
T86 11261-11400 Sentence denotes MERS symptoms were typically severe with 70% of those hospitalized in this study requiring intensive care and 60% of this cohort died [34].
T87 11401-11578 Sentence denotes The literature reports a fatal case of a 34-year-old woman with diabetes hospitalized for MERS, who two weeks after diagnosis developed a headache with nausea and vomiting [15].
T88 11579-11821 Sentence denotes An urgent computed tomography scan showed right frontal lobe intracerebral hemorrhage with massive brain edema; laboratory findings showed disseminated intravascular coagulation, including thrombocytopenia and a prolonged coagulation profile.
T89 11822-12004 Sentence denotes In another case, a 28-year-old man was hospitalized in the intensive care unit for MERS complicated by bacterial pneumonia and had to be put on a ventilator for respiratory distress.
T90 12005-12133 Sentence denotes Unfortunately, after initial improvement, he reported weakness and tingling in his legs that made it impossible for him to walk.
T91 12134-12301 Sentence denotes Using neuroimaging scans, cerebrospinal fluid analysis, nerve conduction velocity studies, and spinal imaging, a diagnosis was made of critical-illness polyneuropathy.
T92 12302-12473 Sentence denotes He was treated with intravenous (IV) immunoglobulin 400 mg/kg daily for five days and was discharged in 40 days; gradual improvement was noted over the next 6 months [15].
T93 12475-12508 Sentence denotes Severe acute respiratory syndrome
T94 12509-12582 Sentence denotes SARS broke out in Hong Kong, Taiwan, Canada, and other locations in 2003.
T95 12583-12681 Sentence denotes It has been reported to be associated with encephalitis, ischemic stroke, and polyneuropathy [35].
T96 12682-12766 Sentence denotes Seizures have been mentioned as the first symptom of SARS-related encephalitis [36].
T97 12767-12906 Sentence denotes In a necropsy study of eight patients who died of SARS, there was evidence of SARS-CoV infection in the brain cortex and hypothalamus [37].
T98 12907-13044 Sentence denotes Particles from the SARS-CoV virus have been found in the brains of patients infected with SARS, most frequently in brain neurons [37–39].
T99 13045-13190 Sentence denotes Murine studies found that intranasal injections of both MERS-CoV and SARS-CoV could enter the brain, presumably via the olfactory nerves [40,41].
T100 13191-13330 Sentence denotes Among the areas of the brain infected, the brain stem was a primary, but not exclusive, target for both MERS-CoV [41] and SARS-CoV [40,42].
T101 13331-13398 Sentence denotes Neurological sequelae of SARS have been only sporadically reported.
T102 13399-13639 Sentence denotes Acute olfactory neuropathy has been reported in a case study of a 27-year-old female SARS patient who was diagnosed with SARS in 2003, hospitalized, and recovered with combination therapy of antiviral therapy (ribivarin plus steroids) [43].
T103 13640-13701 Sentence denotes Fever persisted for about three weeks from onset of symptoms.
T104 13702-13828 Sentence denotes She was discharged from the hospital at around the same time she reported the paroxysmal bilateral loss of her sense of smell.
T105 13829-14013 Sentence denotes An otolaryngologic examination, biochemistry tests, and subsequent magnetic resonance imaging scans showed nothing unusual with no lesions that might account for her loss of olfaction.
T106 14014-14107 Sentence denotes Now 2 years after her recovery from SARS, she still has not regained her sense of smell [43].
T107 14108-14319 Sentence denotes The common causes of anosmia include structural defects in the nasal cavity or sinuses, head injury, brain trauma, brain lesions, or drug-induced loss of olfaction, and in her case, these could all be ruled out.
T108 14320-14415 Sentence denotes It was postulated that her anosmia was a coronavirus-induced form of olfactory neuropathy [43].
T109 14416-14484 Sentence denotes Neuromuscular symptoms associated with SARS have also been reported.
T110 14485-14584 Sentence denotes A 51-year-old woman in Taiwan developed probable SARS shortly after her husband was diagnosed [44].
T111 14585-14763 Sentence denotes She was hospitalized and intubated and had no evidence of respiratory syncytial virus; however, a bone-marrow biopsy showed evidence of infection-related hemophagocytic syndrome.
T112 14764-14890 Sentence denotes Her condition gradually improved and she was extubated, but she complained of weakness, numbness, and paresthesia in her legs.
T113 14891-15081 Sentence denotes Ten days after extubation, a neurological examination showed good mental clarity with intact cranial nerves, but symmetric loss of muscle strength in her legs and mild weakness in the hands.
T114 15082-15259 Sentence denotes These conditions improved slowly and two months later, a neurological examination reported only mild loss of leg strength and slight numbness in the toes of her right foot [44].
T115 15260-15434 Sentence denotes A case report from Hong Kong describes a 59-year-old woman with severe SARS who developed status epilepticus; evidence of the virus was found in her cerebrospinal fluid [45].
T116 15435-15592 Sentence denotes Another case report describes a pregnant patient with SARS who experienced a generalized convulsion with suspected nervous system invasion by the virus [46].
T117 15593-15775 Sentence denotes The neurological manifestations observed in SARS include peripheral axonal neuropathy and elevated muscle enzymes, which might be caused by extensive virus-driven vasculitis [38,47].
T118 15776-15884 Sentence denotes These were considered to be polyneuropathic and/or myopathic symptoms associated with critical illness [47].
T119 15886-15894 Sentence denotes COVID-19
T120 15895-16013 Sentence denotes Neurological symptoms have been sporadically reported in COVID-19 patients but have not yet been well studied [48,49].
T121 16014-16138 Sentence denotes The current body of evidence suggests that the SARS-CoV-2 can affect the nervous system in previously unsuspected ways [50].
T122 16139-16232 Sentence denotes The neuroinvasive capabilities of the SARS-CoV-2 doubtless exist but remain to be elucidated.
T123 16233-16360 Sentence denotes Observed neurological symptoms of COVID-19 include febrile seizures, convulsions, mental status changes, and encephalitis [51].
T124 16361-16518 Sentence denotes Among the most commonly reported possibly neurological symptoms of COVID-19 are nonspecific symptoms, such as headache, myalgia, dizziness, and fatigue [21].
T125 16519-16672 Sentence denotes In a study at a single center in China (n = 214), 36.4% (n = 78) of hospitalized COVID-19 patients had what were identified as neurological symptoms[52].
T126 16673-16847 Sentence denotes In a multicenter retrospective study from Europe of 417 patients who recovered from mild to moderate COVID-19, 86% reported olfactory dysfunction and 88% problems with taste.
T127 16848-16947 Sentence denotes In fact, in 12% of patients, the loss of the sense of smell was the first symptom of COVID-19 [53].
T128 16948-17240 Sentence denotes The loss of smell has emerged as being more prevalent among patients infected with COVID-19 than patients infected with other viruses or with other types of respiratory conditions [54] and has been recommended as a symptom that may help guide earlier diagnosis and treatment of COVID-19 [55].
T129 17241-17369 Sentence denotes In a meta-analysis (n = 1,627 patients, 10 studies), a loss of the sense of smell was reported in 53% of COVID-19 patients [55].
T130 17370-17470 Sentence denotes It appears that the frequency of neurological symptoms is associated with COVID-19 disease severity.
T131 17471-17729 Sentence denotes In the aforementioned study of 214 hospitalized patients with COVID-19 infection (41% severe and 59% non-severe disease), severe patients were more likely than non-severe patients to have neurologically related manifestations (45.5% vs. 30.2%, respectively).
T132 17730-17993 Sentence denotes In this study, the most frequently reported neurological manifestations for severe and non-severe patients, respectively, were acute cerebrovascular disease (5.7% vs. 0.8%), impaired consciousness (14.8% vs. 2.4%) and skeletal muscle injury (19.3% vs. 4.8%) [52].
T133 17994-18116 Sentence denotes This does not take into account more diffuse symptoms, such as confusion or headache, which may also be neurological [51].
T134 18117-18205 Sentence denotes Most COVID-19 patients seem to exhibit pulmonary symptoms before neurological ones [49].
T135 18206-18432 Sentence denotes About a third of diagnosed COVID-19 patients have some form of symptomology of suspected neurological origin, which might include headache, dizziness, impaired consciousness, ataxia, epilepsy, and cerebrovascular disease [49].
T136 18433-18576 Sentence denotes Besides an impaired or absent sense of smell or taste, vision disturbances, neuralgia, and skeletal muscle damage have also been reported [49].
T137 18577-18780 Sentence denotes Nucleic acid from the SARS-CoV-2 virus has been detected in the cerebrospinal fluid of patients, and the virus itself has been identified in brain tissue on autopsy of patients who died of COVID-19 [49].
T138 18781-18860 Sentence denotes Such findings are rare but confirm that the SARS-CoV-2 virus can enter the CNS.
T139 18861-19090 Sentence denotes A 24-year-old Japanese man with COVID-19 presented with generalized epileptic seizures and decreased consciousness; RNA from the SARS-CoV-2 was not detectable in his nasopharynx but was identified in the cerebrospinal fluid [56].
T140 19091-19269 Sentence denotes Using a polymerase chain reaction (PCR) assay, the SARS-CoV-2 was likewise detected in the cerebrospinal fluid of an obese 40-year-old female COVID-19 patient with diabetes [57].
T141 19271-19295 Sentence denotes Neurotropism in COVID-19
T142 19296-19387 Sentence denotes In general, the distribution of the host’s receptor cells determine viral tropisms [58–60].
T143 19388-19527 Sentence denotes Neurotropism appears to be a common feature of coronaviruses in general, as these viruses share similar viral structures and pathways [50].
T144 19528-19777 Sentence denotes Both SARS-CoV and SARS-CoV-2 enter the body via an ACE-2 receptor-facilitated manner; ACE-2 receptors are highly expressed in the epithelial structures of the airway and vessels, lung parenchyma, the kidney, and cells of the small intestine [61,62].
T145 19778-20030 Sentence denotes Unlike its predecessor, the SARS-CoV, however, the SARS-CoV-2 virus, enters human cells in a process involving dipeptidyl peptidase 4 (DPP4), which is most abundant in the lower respiratory tract, kidney, small intestine, liver, and immune system [63].
T146 20031-20149 Sentence denotes The SARS-CoV virus does not utilize the DPP4 system and is not associated with lower respiratory tract infections [4].
T147 20150-20305 Sentence denotes The expression of ACE-2 receptor cells and DPP4 are very low in the CNS [64], and the route by which coronaviruses enter the CNS is subject to speculation.
T148 20306-20460 Sentence denotes It has been suggested that they invade peripheral nerve terminals first, and, in that way, enter onto a synapse-connected pathway into the CNS [23,65–67].
T149 20461-20621 Sentence denotes This so-called ‘trans-synaptic transfer’ has been observed for other lesser-known coronaviruses, such as HEV67N and the avian bronchitis virus [10,23,65,67,68].
T150 20622-20856 Sentence denotes Indeed, the HEV67N virus has been demonstrated in porcine studies to invade the brain; first, it infects the nasal mucosa, lungs, and small intestines and then peripheral nerves transport it retrogradely to the medullary neurons [66].
T151 20857-20956 Sentence denotes The avian bronchitis virus infects the brainstem of mice and may cause neuroanatomical disruptions.
T152 20957-21085 Sentence denotes The mice that died of respiratory failure may have had failure of the cardiorespiratory center within the brain stem [23,64,69].
T153 21087-21132 Sentence denotes COVID-19 and specific neurological conditions
T154 21133-21275 Sentence denotes Neurological manifestations of COVID-19 may be mild and diffuse, such as headache and myalgia or severe, such as intracranial infections [50].
T155 21276-21398 Sentence denotes While severe neurological symptoms have been reported and are associated with worse outcomes, they appear to be rare [50].
T156 21399-21624 Sentence denotes It is important in this connection to note that COVID-19 may cause specific neurological symptoms, exacerbate preexisting neurological conditions, or unmask preexisting neurological conditions that had not yet been diagnosed.
T157 21625-21751 Sentence denotes Any number of infections can unmask an undiagnosed neurological condition, resulting in their overt emergence or exacerbation.
T158 21752-21917 Sentence denotes Thus, a portion of COVID-associated neurological and neuromuscular symptoms may be unmasked in the pandemic rather than directly caused by the SARS-CoV-2 virus [70].
T159 21918-22511 Sentence denotes In a study from the United Kingdom of 43 patients with a confirmed COVID-19 diagnosis or where the diagnosis of COVID-19 was deemed ‘probable’ or ‘possible’ based on World Health Organization criteria, 10/43 patients had encephalopathy with delirium/psychosis and no abnormalities on magnetic resonance imaging or in cerebrospinal fluid, 12/43 exhibited inflammatory syndromes of the central nervous system, including encephalitis, 8/43 had ischemic stroke, 8/43 had peripheral neurological disorders (predominantly Guillain-Barré syndrome), and 5/43 with miscellaneous central disorders [71].
T160 22512-22607 Sentence denotes These neurological disorders were similar to those associated with other coronavirus epidemics.
T161 22608-22809 Sentence denotes An online network of rapid-response case report notifications in the United Kingdom was launched in April and collected 23 days of data in April 2020 about COVID-19 patients with neurological symptoms.
T162 22810-22875 Sentence denotes A total of 153 cases were reported that met clinical definitions.
T163 22876-23115 Sentence denotes The median patient age was 71 years (range 23–94, interquartile range 58–79) with 62% presenting with a cerebrovascular event, 74% with ischemic stroke, 12% with intracerebral hemorrhage, and 1% with central nervous system vasculitis [72].
T164 23116-23448 Sentence denotes In the ALBACOVID registry study of 841 hospitalized COVID-19 patients in Spain evaluated in March 2020, 57% had some neurological symptom(s), with myalgia, headache, and dizziness more likely to occur early in the diseases; neurological complication were the main cause of death in 4% of the decedents in this study population [73].
T165 23449-23643 Sentence denotes Patients with confirmed or suspected COVID-19 may have preexisting neurological conditions or be at elevated risk for them, for example, patients with atrial fibrillation are at risk for stroke.
T166 23644-23773 Sentence denotes Certain motor neuron diseases, such as amyotrophic lateral sclerosis, may put patients at elevated risk for infection in general.
T167 23774-23928 Sentence denotes Of particular concern are patients with muscular dystrophies associated with weakness of ventilator muscles or cardiomyopathy who are exposed to COVID-19.
T168 23929-24044 Sentence denotes In such cases, patients may recover from COVID-19 but not go back to their baseline neuromuscular functioning [70].
T169 24046-24060 Sentence denotes Encephalopathy
T170 24061-24255 Sentence denotes Encephalopathy, which often presents in infectious disease patients as delirium, is a brain disorder that causes acute or subacute dysfunction in terms of consciousness or altered mental states.
T171 24256-24409 Sentence denotes The elderly, people with cognitive deficits, and people with hypertension are elevated risk for developing an altered mental state with COVID-19 [52,74].
T172 24410-24562 Sentence denotes Cerebral edema, a dangerous condition which can cause elevated intracranial pressure and encephalopathy, has been identified in COVID-19 decedents [75].
T173 24563-24726 Sentence denotes Those with a history of neurological damage and acute respiratory distress are at elevated risk for developing encephalopathy as the initial COVID-19 symptom [76].
T174 24727-24875 Sentence denotes The risk becomes greater as the COVID-19 becomes more severe; altered consciousness occurs in 2.4% of mild and 15% of severe COVID-19 patients [52].
T175 24876-24986 Sentence denotes The risk for delirium, like the risk for worse outcomes with COVID-19, is also associated with older age [77].
T176 24987-25111 Sentence denotes The use of sedatives, which is common in critically ill patients, may also be associated with the risk for delirium [78,79].
T177 25112-25375 Sentence denotes Social distancing mandated for COVID-19 may actually contribute to the rate of delirium of certain COVID-19 patients, who may feel desperate and panicked as they are isolated, separated from family, alone, and/or denied religious support from a clergyperson [77].
T178 25376-25696 Sentence denotes Delirium in hospitalized COVID-19 patients may be the result of direct CNS invasion, induction of CNS inflammatory mediators, a secondary effect of other organ system failures, the effect of sedation, the result of prolonged mechanical ventilation, a psychological manifestation, or caused by environmental factors [77].
T179 25697-25963 Sentence denotes In cases of COVID-19, it is thought that delirium caused by direct invasion of the virus into the CNS is relatively rare, but possible, and would likely be accompanied by seizures, altered states of consciousness, or signs of increased intracranial pressure [39,46].
T180 25964-26064 Sentence denotes The rates and presentation of encephalopathy and delirium in COVID-19 patients has not been studied.
T181 26065-26254 Sentence denotes Delirium in COVID-19 patients may be under-reported to date, indeed delirium is thought to be widely under-reported for various conditions unless it is being specifically monitored [79–82].
T182 26255-26333 Sentence denotes Case studies of COVID-19-associated delirium appear in the literature [83,84].
T183 26334-26458 Sentence denotes Acute necrotizing encephalopathy, although relatively rare, has also been diagnosed in a hospitalized COVID-19 patient [85].
T184 26459-26638 Sentence denotes Overall, ICU patients on mechanical ventilation have rates of delirium as high as 70% to 75%, and delirium is associated with mortality and long-term cognitive impairment [86–88].
T185 26639-26772 Sentence denotes The causes of COVID-19-associated encephalopathy may involve multiple factors, including metabolic causes, hypoxia, and drug therapy.
T186 26773-26866 Sentence denotes Symptomatic treatment involves antipyretics, anticonvulsants, and treatment for hypoxia [21].
T187 26867-27026 Sentence denotes Early signs of delirium in COVID-19 patients might suggest CNS involvement and, as such, might indicate heightened risk for impending respiratory failure [77].
T188 27027-27272 Sentence denotes In a study of 27 pediatric COVID-19 patients with multisystem inflammatory syndrome, 15% (n = 4) exhibited new-onset neurological symptoms, such as encephalopathy, headaches, brainstem, and cerebellar signs, weak muscles, and poor reflexes [89].
T189 27273-27463 Sentence denotes Cerebrospinal fluid testing in two patients were acellular; three patients underwent nerve conduction and electromyographical studies, which revealed mild myopathic and neuropathic deficits.
T190 27464-27563 Sentence denotes All four patients improved, two of whom made a complete recovery over the course of the study [89].
T191 27565-27594 Sentence denotes Guillain-Barré syndrome (GBS)
T192 27595-27675 Sentence denotes GBS typically involves demyelination and presents in both upper and lower limbs.
T193 27676-27854 Sentence denotes While there is no clear evidence to date associating the SARS-CoV-2 virus with GBS, other viral infections, such as influenza and the Epstein-Barr virus, have been linked to GBS.
T194 27855-28024 Sentence denotes The association is based on the idea that there can be molecular mimicry between certain viral proteins and the gangliosides and other proteins on the peripheral nerves.
T195 28025-28138 Sentence denotes This can result in an ‘innocent bystander attack’ against the myelin sheath or axon of the peripheral nerve [70].
T196 28139-28334 Sentence denotes GBS is a complex disorder and has been recognized as a para-infectious neurological disease, and has associations with the Zika virus that were documented during the 2015–2016 Zika epidemic [90].
T197 28335-28404 Sentence denotes It is not known if the coronavirus can damage peripheral nerves [44].
T198 28405-28757 Sentence denotes The literature reports on several cases that suggest a link between COVID-19 and GBS [91–94], for example, the case of a 62-year-old COVID patient with GBS; however it is unclear if this patient, who had comorbid lymphopenia and thrombocytopenia, developed GBS and COVID-19 independently but concurrently, or if COVID-19 might have caused the GBS [95].
T199 28758-28881 Sentence denotes It must likewise be considered that COVID-19-associated neurological manifestations may emerge after the initial infection.
T200 28882-29000 Sentence denotes Thus, while there is currently no evidence that COVID-19 can cause GBS, it is an area worthy of further investigation.
T201 29001-29230 Sentence denotes It should be noted in this context that clinicians may sometimes observe peripheral neuropathies, for example based around the ulna, that have to do with prolonged intubation periods in a position that impinges the cubital canal.
T202 29232-29268 Sentence denotes Myopathy and neuromuscular disorders
T203 29269-29466 Sentence denotes Myalgia and fatigue are common symptoms of COVID-19 and a study of COVID-19 patients found 44% to 70% of hospitalized patients had these symptoms and 33% had increased creatine kinase (CK) [10,96].
T204 29467-29694 Sentence denotes However, the nature of the rapid outbreak and spread of the virus did not allow for thorough workup of such COVID-19 patients that might have included electromyography testing, muscle imaging, or histopathological examinations.
T205 29695-29805 Sentence denotes Myalgia occurred in about a third of SARS patients [97], and rhabdomyolysis has been observed as well [47,98].
T206 29807-29819 Sentence denotes Encephalitis
T207 29820-29897 Sentence denotes Encephalitis or inflammation of the brain may be caused by a viral infection.
T208 29898-30010 Sentence denotes The symptoms of encephalitis include fever, headache, seizures, altered consciousness, and behavioral disorders.
T209 30011-30151 Sentence denotes A case report from China describes encephalitis in a male patient with COVID-19 with no traces of the SARS-CoV-2 in his cerebrospinal fluid.
T210 30152-30298 Sentence denotes His main symptom was altered consciousness but the condition was self-limiting and the patient recovered from both COVID-19 and encephalitis [99].
T211 30299-30420 Sentence denotes Although unusual, patients with COVID-19 may present with encephalitis rather than the typical respiratory symptoms [57].
T212 30421-30486 Sentence denotes COVID-19 patients with encephalitis may also experience seizures.
T213 30487-30598 Sentence denotes In particular, it is important to note that nonconvulsive status epilepticus (NCSE) may occur in such patients.
T214 30599-30791 Sentence denotes The Salzburg Consensus Criteria for Nonconvulsive Status Epilepticus was published in 2015 and provides terminology definitions and identified specific EEG tracings associated with NCSE [100].
T215 30792-30943 Sentence denotes NCSE may be evident on electroencephalography (EEG), so that continuous EEG monitoring may be appropriate for critically ill patients in general [101].
T216 30944-31013 Sentence denotes In comatose patients, NCSE has a prevalence between 5% and 48% [102].
T217 31014-31076 Sentence denotes Its prevalence specifically in COVID-19 patients is not known.
T218 31078-31096 Sentence denotes Cephalgia/headache
T219 31097-31289 Sentence denotes Early reports out of Wuhan described headache and decreased responsiveness of patients as an early indicator of potential neurologic involvement associated with the SARS-CoV-2 infection [103].
T220 31290-31373 Sentence denotes Headaches have been reported in 11% to 34% of hospitalized COVID-19 patients [104].
T221 31374-31520 Sentence denotes Among COVID-19 patients who developed symptoms, the incidence of headache is 6% to 10% and headache was often among the presenting symptoms [104].
T222 31521-31698 Sentence denotes Initial reports of the so-called ‘COVID-19 headache’ describe bilateral cephalgia characterized by pulsating pain in the temporoparietal region, forehead, or periorbital region.
T223 31699-31813 Sentence denotes Such headaches were limited to active periods of the COVID-19 infection and resisted conventional analgesia [104].
T224 31814-31968 Sentence denotes While it is plausible that these headaches relate to the viral invasion, they may also be a byproduct of cytokine storm or have some other etiology [105].
T225 31970-32007 Sentence denotes Critical-illness polyneuropathy (CIP)
T226 32008-32095 Sentence denotes Acute neuropathy or CIP may develop in patients suffering a number of severe illnesses.
T227 32096-32163 Sentence denotes CIP typically remits as the patient recovers from the illness [44].
T228 32164-32433 Sentence denotes Signs and symptoms of CIP include reduced compound muscle action potentials amplitude, abnormal spontaneous unilateral activities in the diaphragmatic needle electromyography evaluation, abnormal F responses, and an abnormal H reflex on electrodiagnostic studies [106].
T229 32434-32570 Sentence denotes The pathogenesis of CIP is not well elucidated and may involve a systemic inflammatory response to sepsis that damages the nerves [107].
T230 32571-32623 Sentence denotes Its prevalence among COVID-19 patients is not known.
T231 32625-32651 Sentence denotes Cerebrovascular conditions
T232 32652-32741 Sentence denotes Vascular comorbidities seem to pose a risk factor for worse outcomes with COVID-19 [108].
T233 32742-32825 Sentence denotes Stroke is emerging as an increasingly important adverse event in COVID-19 patients.
T234 32826-33152 Sentence denotes From a retrospective single-center study in China (n = 221), risk factors for stroke in COVID-19 patients appear to be: older age, more severe COVID-19, history of hypertension, diabetes, cerebrovascular diseases, and any marked inflammatory or pro-coagulant response, such as a high C-reactive protein or D-dimer level [108].
T235 33153-33243 Sentence denotes Cerebrovascular conditions may present as neurological symptoms in COVID-19 patients [21].
T236 33245-33292 Sentence denotes Parkinson’s disease (PD) and movement disorders
T237 33293-33476 Sentence denotes The etiology of PD likely involves the interplay of genetic and environmental factors, but viruses have been implicated in causing parkinsonism and other movement disorders [109,110].
T238 33477-33824 Sentence denotes In a study using the cerebrospinal fluid of 67 patients (20 with PD, 29 without PD but with another neurological disorder, and 18 healthy controls), the PD patients had a significantly higher mean cerebrospinal fluid antibody response to two specific coronaviruses (MHV-JHM and MHV-A59) than controls or patients with other neurological disorders.
T239 33825-33941 Sentence denotes It was theorized that some strain of coronavirus might contribute over the long term to the development of PD [110].
T240 33942-34171 Sentence denotes This may relate to the epidemiological observation that people who live on farms or grow up in farming communities have a higher risk of developing PD than others, possible due to zoonotic transmission of coronaviruses [111,112].
T241 34172-34342 Sentence denotes There is no compelling evidence to suggest that patients with PD are more likely to contract COVID-19 or that they are at elevated risk for worse COVID-19 outcomes [113].
T242 34343-34507 Sentence denotes However, PD is associated with decreased respiratory function, which might contribute to respiratory distress in any number of infections, including COVID-19 [114].
T243 34508-34725 Sentence denotes Furthermore, PD is comorbid with a number of disorders, including cerebrovascular disease, heart failure, and coronary artery disease, any of which would elevate risk of worse outcomes if COVID-19 was contracted [22].
T244 34727-34747 Sentence denotes Pulmonary conditions
T245 34748-34968 Sentence denotes It has been postulated that the neuroinvasion of the brain’s medulla oblongata region by the SARS-CoV-2 virus might impair cardiorespiratory control centers and, in that way, lead to respiratory distress and failure [4].
T246 34969-35096 Sentence denotes The literature reports a COVID-19 patient who lost the involuntary process of breathing and suffered respiratory failure [115].
T247 35097-35238 Sentence denotes ACE-2 receptors are expressed abundantly in the body, even in the brain, and particularly in the brain stem which controls respiration [116].
T248 35239-35391 Sentence denotes In the event that the SARS-CoV-2 virus might enter the microcirculatory system of the brain, it may access ACE-2 receptors in the capillary endothelium.
T249 35392-35521 Sentence denotes In such a situation, the virus can cause damage to the endothelium itself, enter the brain, and cause neuronal destruction [116].
T250 35522-35699 Sentence denotes Better understanding is urgently needed to elucidate the role of the SARS-CoV-2 virus in the brain and to risk-stratify patients who may be suffering COVID-related brain damage.
T251 35701-35766 Sentence denotes Clinical management of neurological symptoms in COVID-19 patients
T252 35767-36025 Sentence denotes Symptoms frequently reported by COVID-19 patients, such as headache, dizziness, nausea, vomiting, confusion, and fatigue may be neurological, or they may actually be manifestations of hypoxia, respiratory distress, metabolic acidosis, or drug reactions [84].
T253 36026-36206 Sentence denotes Such generalized symptoms occur with many types of infections, can be vague and diffuse, and may be difficult for the patient to associate specifically with the COVID-19 infection.
T254 36207-36353 Sentence denotes Thus, many neurological manifestations of COVID-19 are overlooked, particularly in a pandemic situation when healthcare resources are overwhelmed.
T255 36354-36458 Sentence denotes For that reason, it is important to consider neurological assessments of hospitalized COVID-19 patients.
T256 36459-36571 Sentence denotes Serum urea, creatinine, electrolyte, and blood gas tests may be helpful to indicate if there is CNS involvement.
T257 36572-36705 Sentence denotes The loss of smell and/or taste early in the course of the disease may be significant and point toward neurological involvement [117].
T258 36706-36966 Sentence denotes Alterations to the senses of taste and smell have been reported in early-stage COVID-19 cases without complications and suggest that the virus is moving toward the olfactory bulb of the brain, which would permit it to enter and possibly affect the brain [118].
T259 36967-37105 Sentence denotes However, it must be noted that anosmia and ageusia can also be reported in the setting of non-COVID-19 upper respiratory tract infections.
T260 37106-37242 Sentence denotes Treating neurological symptoms can be challenging as drugs that suppress the immune system may be contraindicated for COVID-19 patients.
T261 37243-37330 Sentence denotes There is evidence that the use of corticosteroids may prolong viral shedding [119,120].
T262 37331-37653 Sentence denotes Symptoms for neurological problems may be addressed, with first-line strategies such as controlling body temperature, offering anticonvulsants, and treating hypoxia.21 Second-line treatments for neuroinflammation involve IV immunoglobulin or plasma exchange, but IV immunoglobulin may increase the risk of thromboembolism.
T263 37654-37758 Sentence denotes Furthermore, there is emerging concern of the possibility of microthrombosis in COVID-19 patients [121].
T264 37759-37925 Sentence denotes Third-line strategies for neuroinflammation in COVID patients may carry higher risks, and include such pharmacological agents as cyclophosphamide and rituximab [121].
T265 37926-38077 Sentence denotes Typically, COVID-19 patients present with respiratory symptoms before neurological ones, but atypical presentations, although rare, have been reported.
T266 38078-38284 Sentence denotes When neurological symptoms are present in suspected COVID-19 patients, it may be important to test and, if necessary, treat them for COVID-19 first and then address the neurological disorder afterward [49].
T267 38285-38439 Sentence denotes Although not yet fully characterized, neurological symptoms related to COVID-19 are thought to be possible following resolution of the COVID-19 infection.
T268 38440-38708 Sentence denotes In the hospital, distinct and separate areas for neurological emergencies versus COVID-related emergencies may be helpful in order to preclude that a patient with a neurological emergency but not COVID-19 does not come inadvertently in contact with a COVID-19 patient.
T269 38709-38921 Sentence denotes When treating patients with neurological symptoms but no confirmed COVID-19 diagnosis, physicians, and other clinicians should ask about fever, sore throat, exposure history in the past two weeks, and so on [49].
T270 38922-39019 Sentence denotes Testing is important, particularly if there is any reason to suspect possible COVID-19 infection.
T271 39020-39197 Sentence denotes COVID-19 patients who have suffered neurological complications, including stroke, may require acute rehabilitation or, in some cases, long-term residential-skilled nursing care.
T272 39198-39502 Sentence denotes Some patients who undergo prolonged hospitalization with extended periods prone in bed during mechanical ventilation may present following hospitalization with myopathy or neuropathy following acute respiratory distress syndrome, possibly necessitating extracorporeal membrane oxygenation (ECMO) therapy.
T273 39503-39627 Sentence denotes Other presentations may include reversible posterior encephalopathy or the sequela of severe stroke of a large blood vessel.
T274 39628-39872 Sentence denotes Weakness acquired through prolonged stays in intensive care, critical-illness polymyopathy, or polyneuropathy can occur with acute respiratory distress syndrome and may require a multidisciplinary approach for rehabilitation and recovery [122].
T275 39874-39884 Sentence denotes Discussion
T276 39885-40121 Sentence denotes As scientists and clinicians concentrate on the complexities of the SARS-CoV-2 virus and better treatment strategies for COVID-19, it is possible that neurological manifestations of COVID-19 are being overlooked or misinterpreted [117].
T277 40122-40398 Sentence denotes In general, neurological symptoms can be under-diagnosed or even entirely overlooked as neurological manifestations, such as delirium in the critically ill COVID-19 patients or infected outpatients who do not consider a loss of the sense of smell or taste related to COVID-19.
T278 40399-40535 Sentence denotes As such, clinicians on the front lines of COVID-19 care should be cognizant of possible neurological manifestations of this novel virus.
T279 40536-40721 Sentence denotes Patients with suspected or diagnosed COVID-19 should be asked about the loss of smell and taste and educated that this is an important symptom to bring to the attention of the provider.
T280 40722-40828 Sentence denotes Neurological symptoms of COVID-19 have to date mainly be described within the trajectory of the infection.
T281 40829-41041 Sentence denotes However, it is plausible (although far from established) that neurological sequelae from COVID-19 may emerge after the patient has recovered from the primary infection and persist for long periods after recovery.
T282 41042-41206 Sentence denotes For example, it is not known if an elderly patient who recovers from a severe case of COVID-19 with cognitive dysfunction will suffer persistent cognitive deficits.
T283 41207-41467 Sentence denotes The long-term burden on both caregivers and the healthcare system that might be posed by COVID-19 survivors with neurological or cognitive impairment may turn out to be very important, although it is one that is rarely discussed, even hypothetically [123,124].
T284 41468-41612 Sentence denotes There is evidence of neurological complications with SARS and MERS, and a growing body of evidence for neurological complications with COVID-19.
T285 41613-41891 Sentence denotes The etiology of these neurological symptoms is less clear; they may be directly caused by the viral infection or they could be due to other conditions, such as sepsis, coagulation disorders, cytokine release, and vasculitis, all of which have been reported in COVID-19 patients.
T286 41892-42036 Sentence denotes Much more needs to be learned, but clinicians must be aware and prepared for the possibility and potentiality of COVID-19 neurological symptoms.
T287 42037-42100 Sentence denotes The evidence that the SARS-CoV-2 can enter the CNS is alarming.
T288 42101-42259 Sentence denotes While autopsy studies show definitive proof that the earlier SARS-CoV was found in brain tissue, viral levels were lower in the brain than in the lungs [125].
T289 42260-42366 Sentence denotes The route by which the SARS-CoV-2 virus enters the CNS and its effects on the CNS remain to be elucidated.
T290 42367-42459 Sentence denotes It is important to learn more about chronic neurological complications related to COVID-019.
T291 42460-42642 Sentence denotes The blood-brain barrier, which may protect patients from invading pathogens, is a two-way street and could in theory at least prevent viruses from being expelled from the brain [50].
T292 42643-42796 Sentence denotes Further study is needed, particularly as the population of COVID-recovered patients grows and may have to manage long-term consequences of the infection.
T293 42798-42809 Sentence denotes Limitations
T294 42810-42878 Sentence denotes COVID-19 is a complex condition that has yet to be fully elucidated.
T295 42879-42997 Sentence denotes New information appears daily in the medical literature and some earlier concepts about the disease have been revised.
T296 42998-43133 Sentence denotes This article was produced during the pandemic and may reflect an incomplete understanding of the neurological consequences of COVID-19.
T297 43135-43145 Sentence denotes Conclusion
T298 43146-43384 Sentence denotes Neurological impairment has been reported with the coronaviruses related to the earlier SARS and MERS epidemics, and there is growing awareness of what may be potentially serious neurological effects of the virus associated with COVID-19.
T299 43385-43536 Sentence denotes While most COVID-19 patients develop respiratory symptoms prior to or to the exclusion of neurological symptoms, atypical COVID-19 cases have occurred.
T300 43537-43706 Sentence denotes Neurological symptoms may be mild, such as headache, dizziness, or altered consciousness or may include encephalitis, which might also be the result of critical illness.
T301 43707-43823 Sentence denotes The link between neurological involvement and respiratory failure has been suspected but remains to be investigated.
T302 43824-43894 Sentence denotes Clinicians should be aware of neurological symptoms in their patients.