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Id Subject Object Predicate Lexical cue
T1 0-68 Sentence denotes Acute Symptomatic Seizures in Critically Ill Patients with COVID-19:
T2 69-93 Sentence denotes Is There an Association?
T3 95-103 Sentence denotes Abstract
T4 104-114 Sentence denotes Background
T5 115-187 Sentence denotes The coronavirus disease of 2019 (COVID-19) emerged as a global pandemic.
T6 188-420 Sentence denotes Historically, the group of human coronaviruses can also affect the central nervous system leading to neurological symptoms; however, the causative mechanisms of the neurological manifestations of COVID-19 disease are not well known.
T7 421-551 Sentence denotes Seizures have not been directly reported as a part of COVID-19 outside of patients with previously known brain injury or epilepsy.
T8 552-670 Sentence denotes We report two cases of acute symptomatic seizures, in non-epileptic patients, associated with severe COVID-19 disease.
T9 672-690 Sentence denotes Case Presentations
T10 691-835 Sentence denotes Two advanced-age, non-epileptic, male patients presented to our northeast Ohio-based health system with concern for infection in Mid-March 2020.
T11 836-935 Sentence denotes Both had a history of lung disease and during their hospitalization tested positive for SARS-CoV-2.
T12 936-1046 Sentence denotes They developed acute encephalopathy days into their hospitalization with clinical and electrographic seizures.
T13 1047-1102 Sentence denotes Resolution of seizures was achieved with levetiracetam.
T14 1104-1114 Sentence denotes Discussion
T15 1115-1245 Sentence denotes Patients with COVID-19 disease are at an elevated risk for seizures, and the mechanism of these seizures is likely multifactorial.
T16 1246-1420 Sentence denotes Clinical (motor) seizures may not be readily detected in this population due to the expansive utilization of sedatives and paralytics for respiratory optimization strategies.
T17 1421-1607 Sentence denotes Many of these patients are also not electrographically monitored for seizures due to limited resources, multifactorial risk for acute encephalopathy, and the risk of cross-contamination.
T18 1608-1846 Sentence denotes Previously, several neurological symptoms were seen in patients with more advanced COVID-19 disease, and these were thought to be secondary to multi-system organ failure and/or disseminated intravascular coagulopathy-related brain injury.
T19 1847-1986 Sentence denotes However, these patients may also have an advanced breakdown of the blood–brain barrier precipitated by pro-inflammatory cytokine reactions.
T20 1987-2089 Sentence denotes The neurotropic effect and neuroinvasiveness of SARS-Coronavirus-2 have not been directly established.
T21 2091-2102 Sentence denotes Conclusions
T22 2103-2177 Sentence denotes Acute symptomatic seizures are possible in patients with COVID-19 disease.
T23 2178-2369 Sentence denotes These seizures are likely multifactorial in origin, including cortical irritation due to blood–brain barrier breakdown, precipitated by the cytokine reaction as a part of the viral infection.
T24 2370-2540 Sentence denotes Patients with clinical signs of seizures or otherwise unexplained encephalopathy may benefit from electroencephalography monitoring and/or empiric anti-epileptic therapy.
T25 2541-2647 Sentence denotes Further studies are needed to elucidate the risk of seizures and benefit of monitoring in this population.
T26 2649-2661 Sentence denotes Introduction
T27 2662-2833 Sentence denotes Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged first in Wuhan, China, in 2019 and spread rapidly worldwide as a pandemic of the twenty-first century.
T28 2834-2979 Sentence denotes The symptoms and disease manifestations caused by SARS-CoV-2 were named Coronavirus disease 2019 (COVID-19) by the World Health Organization [1].
T29 2980-3211 Sentence denotes The neurological manifestations of this disease are not well known, and there is growing evidence that the disease has effects on the central nervous system (CNS) as detailed in retrospective reports from several centers worldwide.
T30 3212-3358 Sentence denotes An initial retrospective case series from Wuhan, China, showed that neurological manifestations are present in patients with COVID-19 disease [2].
T31 3359-3555 Sentence denotes In that series, 45.5% of patients with COVID-19 disease who had severe systemic disease burden also suffered from acute cerebrovascular disease, acute encephalopathy, and skeletal muscle symptoms.
T32 3556-3662 Sentence denotes These patients also had higher levels of inflammatory markers and greater evidence of multi-organ failure.
T33 3663-3796 Sentence denotes However, the study did not elucidate how many patients with encephalopathy were monitored and treated for acute symptomatic seizures.
T34 3797-3936 Sentence denotes Another series of patients were reported in Strasbourg, France, with neurological features of encephalopathy and corticospinal tract signs.
T35 3937-4099 Sentence denotes Only a small proportion of the patients (8 out of 64) had electroencephalography performed, which demonstrated diffuse slowing consistent with encephalopathy [3].
T36 4100-4238 Sentence denotes Seizures have not been directly reported as a part of COVID-19 disease outside of patients with previously known brain injury or epilepsy.
T37 4239-4496 Sentence denotes There are several barriers to electrographically monitoring patients with SARS-CoV-2 infection such as prone positioning for respiratory compromise as well as the contamination risk which obviates a need for minimizing procedures in this patient population.
T38 4497-4621 Sentence denotes Neurointensivists and neurologists are often consulted for severe COVID-19 patients that present with neurological features.
T39 4622-4886 Sentence denotes In this report, we describe two patients who were electrographically monitored for acute encephalopathy and seizure-like activity, in the setting of normal brain imaging and who were found to have acute symptomatic seizures associated with severe COVID-19 disease.
T40 4888-4895 Sentence denotes Case #1
T41 4896-5240 Sentence denotes A 76-year-old male with history of chronic asthma on benralizumab, hypertension, chronic kidney disease, hyperlipidemia, left bundle branch block, diastolic dysfunction, and cervical fusion presented to the emergency department with the chief complaint of severe right lower extremity pain, fever (102.5 °F on presentation), and encephalopathy.
T42 5241-5350 Sentence denotes He was status post recent L3-S1 laminectomy for acute lumbosacral radiculopathy 5 days prior to presentation.
T43 5351-5421 Sentence denotes Laboratory workup showed neutrophilic leukocytosis (17,200 cells/mm3).
T44 5422-5576 Sentence denotes He had a Glasgow coma scale of 14, was oriented to name only, and exhibited exaggerated deep tendon reflexes but had no other focal neurological deficits.
T45 5577-5643 Sentence denotes A computerized tomography (CT) scan of the brain was unremarkable.
T46 5644-5733 Sentence denotes Magnetic resonance imaging (MRI) of the spine revealed an epidural abscess between L4-S1.
T47 5734-5849 Sentence denotes Surgical drainage was performed, and the patient was started empirically on vancomycin and piperacillin–tazobactam.
T48 5850-5893 Sentence denotes Wound cultures grew Pseudomonas aeruginosa.
T49 5894-6090 Sentence denotes Despite antibiotic therapy, and improved leukocytosis, he continued to have high-grade fevers and acute hypoxemic respiratory failure requiring intensive care unit transfer on postoperative day 1.
T50 6091-6289 Sentence denotes He was initially managed conservatively with diuresis, preload, and afterload optimization; however, his chest X-ray rapidly progressed to bilateral interstitial and airspace opacification (Fig. 1).
T51 6290-6376 Sentence denotes Fig. 1 Chest X-ray showing bilateral lung infiltrates (a) compared to his baseline (b)
T52 6377-6619 Sentence denotes On postoperative day two, the patient suffered several episodes of left upper extremity clonic activity and worsening encephalopathy with decline in level of consciousness as evidenced by increased drowsiness and inability to follow commands.
T53 6620-6777 Sentence denotes Continuous electroencephalography (EEG) confirmed three focal seizures lasting approximately 30 s each arising from the right centroparietal region (Fig. 2).
T54 6778-6869 Sentence denotes Levetiracetam was initiated and both clinical and electrographic seizure activity subsided.
T55 6870-6960 Sentence denotes Antibiotic regimen was broadened to Vancomycin, Meropenem, and Acyclovir for CSF coverage.
T56 6961-7209 Sentence denotes MRI of the brain and cervical spine with and without contrast was remarkable only for chronic white matter hyperintensities, without acute intracranial lesions, meningeal enhancement or venous sinus thrombosis, and C5–C6 myelomalacia, respectively.
T57 7210-7296 Sentence denotes Lumbar puncture was not performed due to the risk of seeding infection into neuroaxis.
T58 7297-7621 Sentence denotes Given persistent high-grade fevers, worsening respiratory status requiring intubation, and recent possible exposures, a respiratory viral panel was sent in addition to separate rapid testing for COVID-19 polymerase chain reaction on postoperative day 4 and COVID-19 testing was confirmed as positive twenty-four hours later.
T59 7622-7766 Sentence denotes His fibrinogen level was elevated at 631 mg/dL (normal range 200–400 mg/dL) and continued to increase to over 860 mg/dL over the following days.
T60 7767-7896 Sentence denotes C-reactive protein increased from 1.7 mg/dL on prior admission to 27.3 mg/dL and remained elevated despite antimicrobial therapy.
T61 7897-7999 Sentence denotes White blood cell count steadily improved over his hospitalization, and platelet count remained stable.
T62 8000-8161 Sentence denotes Our patient ultimately received a tracheostomy and after 30 days of ICU stay was discharged to a long-term acute care hospital for further ventilator management.
T63 8162-8192 Sentence denotes Fig. 2 Electroencephalography.
T64 8193-8341 Sentence denotes Rhythmic discharges noted in the right frontocentral/vertex region (red box) corresponding to clonic movements of the left arm (Color figure online)
T65 8343-8350 Sentence denotes Case #2
T66 8351-8635 Sentence denotes An 82-year-old male patient with chronic obstructive pulmonary disease, venous thromboembolic disease, complete heart block, and chronic kidney disease presented to the emergency department with a 10-day history of progressive dyspnea, altered mental status, and generalized weakness.
T67 8636-8689 Sentence denotes He was found to be hypoxic, febrile, and tachycardic.
T68 8690-8819 Sentence denotes He was intubated for acute hypoxemic respiratory failure with a chest X-ray showing lung infiltrates consistent with pneumonitis.
T69 8820-9251 Sentence denotes The patient’s laboratory results were significant for lymphopenia (WBC 3.26 k/μl, absolute lymphocyte count 0.70), coagulopathy (international normalised ratio (INR) 2.5, partial thromboplastin time (PTT) 53.9), elevated D-dimer (590 ng/mL), thrombocytopenia (132 k/μl), acute kidney injury (blood urea nitrogen (BUN) 47 mg/dL, creatinine 3.96 mg/dL), and elevated C-reactive protein initially 12.5 mg/L and increased to 26.2 mg/L.
T70 9252-9374 Sentence denotes A nasopharyngeal swab polymerase chain reaction (PCR) test for COVID-19 was sent on admission and was positive 24 h later.
T71 9375-9545 Sentence denotes Continuous video electroencephalogram (EEG) monitoring was ordered on day 5 of admission after events of right eyelid and facial twitching were observed by the care team.
T72 9546-9716 Sentence denotes Frequent EEG seizures were captured independently from the left more than right frontal–temporal regions (Fig. 3) which eventually progressed to focal status epilepticus.
T73 9717-9762 Sentence denotes The majority of seizures were non-convulsive.
T74 9763-9825 Sentence denotes Seizure frequency improved after treatment with levetiracetam.
T75 9826-9998 Sentence denotes A non-contrast CT-brain demonstrated hypodensities within the supratentorial white matter, consistent with mild microvascular disease but without acute intracranial lesion.
T76 9999-10085 Sentence denotes He was unable to have an MRI brain performed due to an incompatible cardiac pacemaker.
T77 10086-10183 Sentence denotes Further vessel imaging was unable to be performed due to patients acute on chronic kidney injury.
T78 10184-10279 Sentence denotes A lumbar puncture was unable to be performed due to worsening coagulopathy (INR 3.8, PTT 73.5).
T79 10280-10406 Sentence denotes Patient remained on the ventilator, and after 20 days of ICU stay, the family opted for withdrawal of life-sustaining support.
T80 10407-10437 Sentence denotes Fig. 3 Electroencephalography.
T81 10438-10596 Sentence denotes Rhythmic discharges evolving in the left frontotemporal (a) region and spreading anteriorly and posteriorly (b) corresponding to right facial clonic movements
T82 10598-10608 Sentence denotes Discussion
T83 10609-10792 Sentence denotes The SARS-Coronavirus-2 belongs to the β-coronavirus group which includes several human pathogenic viruses including middle east respiratory syndrome (MERS) coronavirus and SARS-CoV-1.
T84 10793-10863 Sentence denotes These group of coronaviruses are associated with respiratory symptoms.
T85 10864-11037 Sentence denotes Additional neurological symptoms including delirium, dizziness, and headaches have also been reported with other coronavirus infections prior to the SARS-CoV-2 outbreak [4].
T86 11038-11269 Sentence denotes The case series of patients from Wuhan, China, with COVID-19 disease, included both central and peripheral neurological manifestations (i.e., headache, dizziness, impaired consciousness, cerebrovascular disease, and neuralgia) [2].
T87 11270-11347 Sentence denotes Seizures were not reported as a direct manifestation of SARS-CoV-2 infection.
T88 11348-11488 Sentence denotes The patients described in our series developed focal seizures and, in the second case, even progressed to non-convulsive status epilepticus.
T89 11489-11545 Sentence denotes Seizures may be a CNS manifestation of COVID-19 disease.
T90 11546-11656 Sentence denotes Further investigations are needed to elucidate the mechanism of neurological symptoms in SARS-CoV-2 infection.
T91 11657-11909 Sentence denotes Human coronaviruses (HCoV) have been established to infect human astrocytes and microglia in neural cell cultures as well as detection of viral RNA in a study of human brain autopsy samples supporting their neurotropic and neuroinvasive properties [5].
T92 11910-12050 Sentence denotes A case report of SARS-CoV-1 infection with CNS symptoms during the SARS epidemic also isolated the virus within a brain tissue specimen [6].
T93 12051-12430 Sentence denotes Although direct evidence of a neurotropic effect of SARS-Cov-2 has not been reported as yet through either cerebrospinal fluid (CSF) or autopsy studies, the presence of neurological symptoms in patients with COVID-19 disease during this current pandemic, and the similarity between the two strains of human coronaviruses (CoV-1 and CoV-2), makes this mechanism highly suggestive.
T94 12431-12658 Sentence denotes Acute symptomatic seizures may be the result of a possible neurotropic effect of the virus or can be a marker of severity of systemic disease itself since CNS symptoms were found mainly in patients with severe COVID-19 disease.
T95 12659-12812 Sentence denotes After penetration of the blood–brain barrier, the virus can slow the cerebral microcirculation, possibly through the creation of a hypercoagulable state.
T96 12813-12926 Sentence denotes This allows increased interaction of SARS-CoV-2 with the endothelial receptors and receptors on glial tissue [7].
T97 12927-13037 Sentence denotes The interaction at the glia may predispose patients to seizures as seen in other neurological diseases [8, 9].
T98 13038-13276 Sentence denotes Previous studies of SARS-coronaviruses have described the proliferation of pro-inflammatory cytokines that are active in promoting blood–barrier breakdown, namely interleukin-8 (IL8) and monocyte chemoattractant protein-1 (MCP1) [10, 11].
T99 13277-13489 Sentence denotes A description of coronavirus infections in a Japanese encephalitis mouse model demonstrated CNS viral infection induced astrocyte and microglia proliferation, leading to increased release of IL-8 in the CSF [10].
T100 13490-13608 Sentence denotes MCP1 is another pro-inflammatory mediator that is expressed in CNS cells including astrocytes, neurons, and microglia.
T101 13609-13804 Sentence denotes MCP1 may be up-regulated in conditions which target and degrade the blood–brain barrier and can recruit additional inflammatory cells as the monocytes migrate across the blood–brain barrier [11].
T102 13805-13978 Sentence denotes We hypothesize that as a result of the accumulation of inflammatory markers, there may be local cortical irritation that precipitates seizures related to COVID-19 infection.
T103 13979-14268 Sentence denotes Although cerebrospinal fluid may contain markers of inflammation, the treatment of this infection is largely supportive, and with the additional risk of coagulopathy precipitated by SARS-CoV-2, a lumbar puncture may not be justifiable unless there is an alternative diagnosis to be sought.
T104 14269-14507 Sentence denotes A limitation of our case series is that cerebrospinal fluid was unable to be obtained due to patient factors that made a lumbar puncture relatively contraindicated and that a CSF-PCR test for SARS-CoV-2 was not yet commercially available.
T105 14508-14620 Sentence denotes As this disease continues to spread, we will continue to learn about its direct and/or indirect epileptogenesis.
T106 14622-14633 Sentence denotes Conclusions
T107 14634-15013 Sentence denotes Although there are concerns regarding decreasing transmission risk by limiting healthcare interventions in COVID-19 disease, patients with severe infection who demonstrate either clinical signs of seizures or severe encephalopathy may benefit from continuous electroencephalography monitoring to diagnose and treat symptomatic seizures and also non-convulsive status epilepticus.
T108 15014-15257 Sentence denotes The mechanism of seizures precipitated by SARS-CoV-2 infection appears to be multifactorial and may involve a possible neurotropism of SARS-CoV-2 in addition to blood–brain barrier breakdown precipitated by pro-inflammatory cytokine reactions.
T109 15259-15275 Sentence denotes Publisher's Note
T110 15276-15394 Sentence denotes Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
T111 15396-15416 Sentence denotes Author contributions
T112 15417-15510 Sentence denotes The authors listed have contributed equally to the creation and revisions of this manuscript.
T113 15512-15529 Sentence denotes Source of Support
T114 15530-15623 Sentence denotes The authors as listed above have received no source of financial support for this manuscript.
T115 15625-15645 Sentence denotes Conflict of interest
T116 15646-15775 Sentence denotes None of the authors listed have received any financial support for this manuscript and have no conflicts of interest to disclose.
T117 15777-15810 Sentence denotes Ethical approval/Informed consent
T118 15811-15970 Sentence denotes This study was approved by the instiutional board review of the Cleveland Clinic as a minimal risk quality improvement project and informed consent was waived.