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Id Subject Object Predicate Lexical cue
T1 0-65 Sentence denotes Brain microvascular occlusive disorder in COVID-19: a case report
T2 67-75 Sentence denotes Abstract
T3 76-543 Sentence denotes We describe the case of a COVID-19 patient with severely impaired consciousness after sedation hold, showing magnetic resonance imaging (MRI) findings of (i) acute bilateral supratentorial ischemic lesions involving the fronto-parietal white matter and the corpus callosum and (ii) multiple diffuse susceptibility weighted imaging (SWI) hypointense foci, infra and supratentorial, predominantly bithalamic, suggestive of microhemorrhage or alternatively microthrombi.
T4 544-649 Sentence denotes Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) RNA was detected in the cerebrospinal fluid.
T5 650-743 Sentence denotes Our findings suggest the occurrence of vascular damage, predominantly involving microvessels.
T6 744-1001 Sentence denotes The underlying mechanisms, which include direct and indirect penetration of the virus to the central nervous system and systemic cardiorespiratory complications, are yet to be elucidated, and a direct correlation with SARS-CoV-2 infection remains uncertain.
T7 1003-1015 Sentence denotes Introduction
T8 1016-1179 Sentence denotes Neurological manifestations have been observed in a relevant proportion of patients with COVID-19 [1] with different magnetic resonance imaging (MRI) patterns [2].
T9 1180-1544 Sentence denotes We report the case of a patient with severe neurological complications and brain MRI evidence of multiple supratentorial areas of restricted diffusion at diffusion-weighted imaging (DWI), consistent with acute ischemic lesions, and several susceptibility-weighted imaging (SWI) punctate hypointensities, most referable to microbleeds or alternatively microthrombi.
T10 1545-1657 Sentence denotes Collection and scientific use of the patient’s data were approved by the regional ethics committee (CER Liguria:
T11 1658-1680 Sentence denotes 173/2020-DB id 10512).
T12 1681-1752 Sentence denotes Consent to data publication was verbally obtained from the next of kin.
T13 1754-1765 Sentence denotes Case report
T14 1766-1946 Sentence denotes On March 25, a 68-year-old man with previous history of hypertension and diabetes mellitus presented to the emergency department with dyspnea, fever, fatigue, and productive cough.
T15 1947-2099 Sentence denotes Diagnosis of coronavirus 2 (SARS-CoV-2) pneumonia was confirmed by nasopharyngeal swab specimen using the transcriptase-polymerase chain reaction assay.
T16 2100-2346 Sentence denotes Following the development of severe acute respiratory syndrome and acute kidney failure, the patient was admitted to our intensive care unit (ICU) and intubated; mechanical ventilation and continuous veno-venous hemodialysis (CVVHD) were started.
T17 2347-2458 Sentence denotes Table 1 reports the main mechanical ventilation settings, data on respiratory function, and laboratory results.
T18 2459-2523 Sentence denotes He was started on steroids, hydroxychloroquine, and ceftaroline.
T19 2524-2650 Sentence denotes A prophylactic dose of enoxaparin (6000 u once/day) was subsequently switched to 6000 u/bd, due to increase of D-dimer values.
T20 2651-2796 Sentence denotes Respiratory function improved over days, and he was switched to assisted mechanical ventilation, while CVVHD was continued for persistent anuria.
T21 2797-2881 Sentence denotes On day 9, on sedation hold, his Glasgow Coma Score was 3 (Eyes 1,Verbal 1, Motor 1).
T22 2882-2969 Sentence denotes Photomotor reflex was present, and brainstem reflexes (including cough) were preserved.
T23 2970-3232 Sentence denotes After 2 days from sedation hold, an electroencephalography (EEG) revealed a severe voltage attenuation (signal diffusely < 20 μV), with background activity substituted by irregular theta and delta activities widely distributed, without antero-posterior gradient.
T24 3233-3336 Sentence denotes No focal or generalized interictal/ictal epileptiform discharges nor periodic discharges were observed.
T25 3337-3396 Sentence denotes Two days later, a second EEG showed no significant changes.
T26 3397-3647 Sentence denotes At brain MRI (Fig. 1), DWI shows multiple small supratentorial areas of restricted diffusion, consistent with acute ischemic foci, involving the bilateral fronto-parietal deep and subcortical white matter and the genu and body of the corpus callosum.
T27 3648-3766 Sentence denotes SWI revealed several hypointense foci throughout the brain, both infratentorial and supratentorial, mostly bithalamic.
T28 3767-3900 Sentence denotes On T1-weighted images obtained after intravenous gadolinium injection, there was no evidence of parenchymal or meningeal enhancement.
T29 3901-4149 Sentence denotes Cerebrospinal fluid (CSF) analysis showed 0.492 g/L [0.130–0.520 g/L] proteins, 88 mg/dL [44–74 mg/L] glucose, no leukocytes and red blood cells, CSF/serum albumin ratio 7.74 [1.92–7.30], and CSF/serum immunoglobulin G (IgG) ratio 4.48 [0.82–3.26].
T30 4150-4189 Sentence denotes SARS-CoV-2 RNA was detected in the CSF.
T31 4190-4293 Sentence denotes Over the following days, the patient developed a systemic candida and gram-negative bacteria infection.
T32 4294-4399 Sentence denotes His respiratory function significantly worsened, and he developed a septic shock with multiorgan failure.
T33 4400-4418 Sentence denotes He died on day 21.
T34 4419-4493 Sentence denotes Table 1 Laboratory data, respiratory function, and mechanical ventilation†
T35 4494-4570 Sentence denotes Variable Reference range, adults On admission ICU day 3 ICU day 7 ICU day 14
T36 4571-4628 Sentence denotes White blood cell (109/L) 4.50–9.80 9.58 13.99 24.14 23.58
T37 4629-4679 Sentence denotes C-reactive protein (mg/L) 0.0–5.0 137 77.7 138 121
T38 4680-4731 Sentence denotes Procalcitonin (mcg/L) 0.00–0.25 1.37 2.09 1.67 2.07
T39 4732-4778 Sentence denotes IL (interleukin)-6 (ng/L) < 3.4 491 32.7 NA NA
T40 4779-4816 Sentence denotes Ferritin (mcg/L) 30–400 605 378 NA NA
T41 4817-4862 Sentence denotes D-Dimer (mcg/L) 0.00–500.0 1605 810 3497 6941
T42 4863-4909 Sentence denotes Fibrinogen (g/L) 2.00–4.00 6.10 3.84 6.06 8.47
T43 4910-4981 Sentence denotes Activated partial-thromboplastin time (sec) 28.0–40.0 39 27.3 33.6 32.2
T44 4982-5024 Sentence denotes Creatinine (mg/dL) 0.51–0.95 2.4 5 2.9 2.6
T45 5025-5067 Sentence denotes Urea nitrogen (mg/dL) 21–54 90 172 135 167
T46 5068-5119 Sentence denotes Lactate dehydrogenase (U/L) 135–214 425 282 357 265
T47 5120-5161 Sentence denotes Arterial pH 7.35–7.45 7.36 7.35 7.23 7.34
T48 5162-5231 Sentence denotes Arterial partial pressure of oxygen (mmHg) 83–108 71.8 73.3 80.8 56.1
T49 5232-5308 Sentence denotes Arterial partial pressure of carbon dioxide (mmHg) 32–45 42.4 48.1 54.1 55.4
T50 5309-5349 Sentence denotes Lactate (mmol/L) 0.5–1.6 1.1 1.1 1.6 0.8
T51 5350-5444 Sentence denotes Nasopharyngeal swab Positive-quite positive-negative Positive Positive Positive Quite positive
T52 5445-5503 Sentence denotes Ventilation mode Controlled Controlled Controlled Assisted
T53 5504-5547 Sentence denotes Fraction of inspired oxygen 0.8 0.6 0.6 0.6
T54 5548-5600 Sentence denotes Positive end-expiratory pressure (cmH2O) 15 15 13 12
T55 5601-5652 Sentence denotes Continuous renal replacement therapy NO YES YES YES
T56 5653-5737 Sentence denotes †To convert the values for urea nitrogen to millimoles per liter, multiply by 0.357.
T57 5738-5813 Sentence denotes To convert values for creatinine to micromoles per liter, multiply by 88.4.
T58 5814-5838 Sentence denotes NA denotes not available
T59 5839-6103 Sentence denotes Fig. 1 Diffusion-weighted imaging (DWI) b1000 (a) and apparent diffusion coefficient map (b) show multiple areas of restricted diffusion, involving the bilateral fronto-parietal white matter and the genu of the corpus callosum, compatible with acute ischemic foci.
T60 6104-6400 Sentence denotes Susceptibility-weighted imaging (SWI) (c) shows several millimetric hypointense areas, predominantly distributed in the thalami bilaterally, but also in the genu of the corpus callosum and in the parietal iuxtacortical white matter, consistent with microhemorrhages or alternatively microthrombi.
T61 6401-6604 Sentence denotes T1-weighted post-contrast image (d) demonstrates the lack of parenchymal or meningeal enhancement at the level of these lesions (lack of enhancement was also observed in the rest of the brain, not shown)
T62 6606-6616 Sentence denotes Discussion
T63 6617-6891 Sentence denotes We present a patient with pulmonary COVID-19 infection who developed neurological symptoms characterized by severely impaired consciousness, with multiple DWI areas of restricted diffusion and scattered SWI hypointensities at brain MRI and CSF positivity for SARS-CoV-2 RNA.
T64 6892-7048 Sentence denotes Neurological complications following COVID-19 infection are not uncommon [2], and various putative mechanisms for brain involvement have been suggested [3].
T65 7049-7220 Sentence denotes Our patient presented MRI signs of brain vascular injury, characterized by the coexistence of acute ischemic areas and scattered microbleeds or alternatively microthrombi.
T66 7221-7522 Sentence denotes The underlying mechanisms, which include direct and indirect penetration of the virus to the central nervous system and systemic cardiorespiratory complications [4], are yet to be elucidated, and a direct correlation with SARS-CoV-2 infection remains uncertain, but we tried to make some observations.
T67 7523-7729 Sentence denotes First, the multiple supratentorial ischemic lesions seen on DWI, with corpus callosum involvement, do not depict a territorial distribution, inconsistent with COVID-19-associated large vessel occlusion [5].
T68 7730-7809 Sentence denotes Instead, they might reflect diffuse local thrombosis or, less likely, embolism.
T69 7810-8082 Sentence denotes In this setting, high D-dimer values may reflect thrombus formation, but they can also act as acute-phase enhancer of the inflammatory cascade and stimulates monocyte synthesis and release of proinflammatory cytokines, which can contribute to the occurrence of stroke [6].
T70 8083-8186 Sentence denotes We cannot ascertain a specific correlation of the DWI findings with SARS-CoV2 infection in our patient.
T71 8187-8364 Sentence denotes Nevertheless, similar MRI findings of bilateral supratentorial and corpus callosum DWI lesions have been described in COVID-19 patients with similar clinical manifestations [2].
T72 8365-8442 Sentence denotes The SWI hypointense foci in our patient are also of difficult interpretation.
T73 8443-8713 Sentence denotes In fact, SWI hypointensities in the corpus callosum and in the cortical/iuxtacortical regions of COVID-19 patients with neurological impairment have been reported [7], but their pathological correlate is not univocal, as they could represent microbleeds or microthrombi.
T74 8714-8827 Sentence denotes In one pathology study, microhemorrages were detected on brain tissue at the location of SWI hypointensities [8].
T75 8828-9026 Sentence denotes Though a coagulopathic disorder has been reported in COVID-19 patients, diffuse, mostly peripherally distributed brain microbleeds can also be the expression of critical illness in ICU patients [9].
T76 9027-9254 Sentence denotes Acute necrotizing encephalopathy (ANE) [2], with similar bithalamic SWI hypointensities, has been reported in COVID-19 patients, but the MRI picture we describe is different, because no signs of edema and necrosis were evident.
T77 9255-9481 Sentence denotes Our patient did not develop any EEG abnormalities typically related to meningoencephalitis, hypoxic encephalopathy, or renal failure, such as epileptiform focal abnormalities and lateralized or generalized periodic discharges.
T78 9482-9615 Sentence denotes Accordingly, post-contrast MRI showed a lack of parenchymal and meningeal enhancement, and no MRI signs of encephalitis were present.
T79 9616-9694 Sentence denotes The meaning of SARS-CoV-2 RNA positivity in the CSF of our patient is unclear.
T80 9695-9793 Sentence denotes A direct effect of the virus, with normal proteins and no pleocytosis in the CSF, is questionable.
T81 9794-10138 Sentence denotes Viral neurotropism has been largely theorized, and virus particles have been observed to cross the capillary endothelium of the brain blood barrier (BBB) [10], but direct implication of SARS-CoV-2 in neurological manifestations is controversial, and viral RNA in the CSF of patients with neurological complications is only rarely detected [11].
T82 10139-10326 Sentence denotes In a recent study including 31 patients with neurological manifestations, none had CSF viral positivity, but many had signs of disturbance of the blood brain barrier (BBB) integrity [12].
T83 10327-10497 Sentence denotes Our patient showed signs of mild damage of the BBB as well, which might also be a possible consequence of systemic inflammation, in a patient with multiple organ failure.
T84 10498-10655 Sentence denotes Therefore, an indirect mechanism of neurovascular unit breakdown, resulting in a passage of the virus in the CSF through the damaged BBB, cannot be excluded.
T85 10656-10715 Sentence denotes Contamination or artifact could also be a possibility [11].
T86 10716-10964 Sentence denotes In COVID-19 pneumonia, the extensive microvascular damage seems to be related to a macrophage activation syndrome (MAS)-like mechanism [13], which induces a coagulopathic cascade with subsequent local microthrombosis and microbleeding in the lungs.
T87 10965-11080 Sentence denotes A similar mechanism could be responsible for central nervous system manifestations, but supporting data are scarce.
T88 11081-11245 Sentence denotes We consider this case an example of neurological manifestations possibly related to COVID-19, characterized by vascular damage predominantly involving microvessels.
T89 11246-11433 Sentence denotes The absence of pathological confirmation represents a major limitation, but similar MRI patterns [2] and recent pathological correlations seem to support a microangiopathic substrate [8].
T90 11434-11676 Sentence denotes Different mechanisms including a systemic procoagulative status and systemic and local inflammatory processes involving the endothelium, most likely via the ACE2 receptor, and eventual immune-mediated vascular injury could be considered [11].
T91 11677-11824 Sentence denotes Clinicians should be aware of the possible severe neurological complications in COVID-19 patients and of the role of MRI in their characterization.
T92 11826-11842 Sentence denotes Publisher’s note
T93 11843-11961 Sentence denotes Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
T94 11963-11984 Sentence denotes Authors’ contribution
T95 11985-12121 Sentence denotes Laura Saitta, Alexandre Molin, Luca Roccatagliata, Chiara Robba, and Nicolò Patroniti contributed to conception and design of the study.
T96 12122-12310 Sentence denotes Material preparation, data collection, and analysis were performed by Laura Saitta, Alexandre Molin, Flavio Villani, Angelo Insorsi, Luca Roccatagliata, Chiara Robba, and Nicolò Patroniti.
T97 12311-12438 Sentence denotes The first draft of the manuscript was written by Chiara Robba and all authors commented on previous versions of the manuscript.
T98 12439-12490 Sentence denotes All authors read and approved the final manuscript.
T99 12492-12525 Sentence denotes Compliance with ethical standards
T100 12527-12548 Sentence denotes Conflicts of interest
T101 12549-13222 Sentence denotes Dr. Bassetti reports personal fees from Achaogen, personal fees and other from Angelini, personal fees and other from Astellas, personal fees from Bayer, personal fees and other from Basilea, personal fees from Biomerieux, personal fees and other from Cidara, personal fees and other from Gilead, personal fees from Menarini, personal fees and other from MSD, personal fees from Nabiva, personal fees from Paratek, personal fees and other from Pfizer, personal fees from Roche, personal fees and other from Melinta, personal fees and other from Shionogi, personal fees from Tetraphase, personal fees from VenatoRx and Vifor, outside the submitted work; nothing to disclose.
T102 13223-13270 Sentence denotes All the other authors have nothing to disclose.
T103 13272-13288 Sentence denotes Ethical approval
T104 13289-13294 Sentence denotes None.