key: cord-1043620-jnff96ol authors: Canavero, Isabella; Valentino, Francesca; Colombo, Elena; Franciotta, Diego; Ferrandi, Delfina; Mussa, Marco; Schizzi, Rodolfo; Marinou, Kalliopi; Zanferrari, Carla; Businaro, Pietro; Ravaglia, Sabrina; Prunetti, Paolo; Cosentino, Giuseppe; Farina, Lisa.Maria; Rognone, Elisa; Pichiecchio, Anna; Micieli, Giuseppe title: Acute myelopathies associated to SARS-CoV-2 infection: viral or immune-mediated damage? date: 2021-02-25 journal: Travel Med Infect Dis DOI: 10.1016/j.tmaid.2021.102000 sha: d1507a99615a537ce874e02e62c8bc27ea402370 doc_id: 1043620 cord_uid: jnff96ol nan Normal WBC 6, 6/ Motor evoked potentials: no response for lower limbs. EMG/ENG: "polio-like syndrome" in lower limbs (reduced amplitude of compound motor action potentials, reduced recruitment pattern, presence of denervation potentials on needle EMG, absent F wave responses) Negative N.P. Negative Post-infectious encephalomyelitis Para-infectious demyelinating and polio-like encephalomyelitis Treatment M-P 1 g OD for 7 days Ceftriaxone 2 g x 2 for 5 days, Ampicillin 2 g x 6 for 5 days, Acyclovir 750 mg x 3 for 3 days M-P 1 g OD for 5 days, 500 mg OD for 3 days, 250 mg OD for 3 days Ceftriaxone 2 g x 2 for 10 days, acyclovir 750 mg x 3 for 5 days, lopinavir/ritonavir 400/100 mg and HCQ 200 mg x 2 for 14 days M-P 1 g OD for 7 days; IVIg 0.4 g/kg OD for 5 days Clinical follow up After 2 weeks; discharged to rehab with paraplegia and sensory gait ataxia, able to walk with a walker After 3 months: Discharged home, able to walk with a walker, mild sensory gait ataxia None to declare All sources of funding should also be acknowledged and you should declare any involvement of study sponsors in the study design; collection, analysis and interpretation of data; the writing of the manuscript; the decision to submit the manuscript for publication. If the study sponsors had no such involvement, this should be stated. Signature (a scanned signature is acceptable, Print name but each author must sign) Manuscript number (if applicable): Article Title: Acute myelopathies associated to SARS-CoV-2 infection: viral or immune-mediated damage? Author name: ISABELLA CANAVERO J o u r n a l P r e -p r o o f Declarations Travel Medicine and Infectious Disease requires that all authors sign a declaration of conflicting interests. If you have nothing to declare in any of these categories then this should be stated. A conflicting interest exists when professional judgement concerning a primary interest (such as patient's welfare or the validity of research) may be influenced by a secondary interest (such as financial gain or personal rivalry). It may arise for the authors when they have financial interest that may influence their interpretation of their results or those of others. Examples of potential conflicts of interest include employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications/registrations, and grants or other funding. None to declare All sources of funding should also be acknowledged and you should declare any involvement of study sponsors in the study design; collection, analysis and interpretation of data; the writing of the manuscript; the decision to submit the manuscript for publication. If the study sponsors had no such involvement, this should be stated. Signature (a scanned signature is acceptable, Print name but each author must sign) Manuscript number (if applicable): Article Title: Acute myelopathies associated to SARS-CoV-2 infection: viral or immune-mediated damage? Author name: ELENA COLOMBO J o u r n a l P r e -p r o o f Declarations Travel Medicine and Infectious Disease requires that all authors sign a declaration of conflicting interests. If you have nothing to declare in any of these categories then this should be stated. A conflicting interest exists when professional judgement concerning a primary interest (such as patient's welfare or the validity of research) may be influenced by a secondary interest (such as financial gain or personal rivalry). It may arise for the authors when they have financial interest that may influence their interpretation of their results or those of others. Examples of potential conflicts of interest include employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications/registrations, and grants or other funding. None to declare All sources of funding should also be acknowledged and you should declare any involvement of study sponsors in the study design; collection, analysis and interpretation of data; the writing of the manuscript; the decision to submit the manuscript for publication. If the study sponsors had no such involvement, this should be stated. None Signature (a scanned signature is acceptable, Print name but each author must sign) Manuscript number (if applicable): Article Title: Acute myelopathies associated to SARS-CoV-2 infection: viral or immune-mediated damage? Author name: GIUSEPPE COSENTINO J o u r n a l P r e -p r o o f Declarations Travel Medicine and Infectious Disease requires that all authors sign a declaration of conflicting interests. If you have nothing to declare in any of these categories then this should be stated. A conflicting interest exists when professional judgement concerning a primary interest (such as patient's welfare or the validity of research) may be influenced by a secondary interest (such as financial gain or personal rivalry). It may arise for the authors when they have financial interest that may influence their interpretation of their results or those of others. Examples of potential conflicts of interest include employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications/registrations, and grants or other funding. None to declare All sources of funding should also be acknowledged and you should declare any involvement of study sponsors in the study design; collection, analysis and interpretation of data; the writing of the manuscript; the decision to submit the manuscript for publication. If the study sponsors had no such involvement, this should be stated. A conflicting interest exists when professional judgement concerning a primary interest (such as patient's welfare or the validity of research) may be influenced by a secondary interest (such as financial gain or personal rivalry). It may arise for the authors when they have financial interest that may influence their interpretation of their results or those of others. Examples of potential conflicts of interest include employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications/registrations, and grants or other funding. None to declare All sources of funding should also be acknowledged and you should declare any involvement of study sponsors in the study design; collection, analysis and interpretation of data; the writing of the manuscript; the decision to submit the manuscript for publication. If the study sponsors had no such involvement, this should be stated. A conflicting interest exists when professional judgement concerning a primary interest (such as patient's welfare or the validity of research) may be influenced by a secondary interest (such as financial gain or personal rivalry). It may arise for the authors when they have financial interest that may influence their interpretation of their results or those of others. Examples of potential conflicts of interest include employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications/registrations, and grants or other funding. None to declare All sources of funding should also be acknowledged and you should declare any involvement of study sponsors in the study design; collection, analysis and interpretation of data; the writing of the manuscript; the decision to submit the manuscript for publication. If the study sponsors had no such involvement, this should be stated. A conflicting interest exists when professional judgement concerning a primary interest (such as patient's welfare or the validity of research) may be influenced by a secondary interest (such as financial gain or personal rivalry). It may arise for the authors when they have financial interest that may influence their interpretation of their results or those of others. Examples of potential conflicts of interest include employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications/registrations, and grants or other funding. None to declare All sources of funding should also be acknowledged and you should declare any involvement of study sponsors in the study design; collection, analysis and interpretation of data; the writing of the manuscript; the decision to submit the manuscript for publication. If the study sponsors had no such involvement, this should be stated. None Signature (a scanned signature is acceptable, Print name but each author must sign) Pavia, 18 th July 2020 Dear Editor, We are glad to submit to Your Journal our Review article entitled "Acute myelopathies associated to SARS-CoV-2 infection: viral or immune-mediated damage?" for consideration for publication. In the article we present our recent experience with acute myelopathies in COVID-19 patients, a topic that to date has never been specifically addressed in medical literature. Starting from three case reports, we have reviewed and discussed the limited, anecdotal literature on the topic and proposed insights about pathogenesis, treatment and prognosis. Our contribution includes two cases of post-infectious myelitis in patients recently recovering from COVID-19, and an interesting case of COVID-19-related acute flaccid paraplegia with polio-like syndrome, that to our knowledge is unique. Basing our dissertation on clinical, radiological and laboratory findings, we hypothesized a para-infectious mechanism, peculiarly supporting the possibility of a direct viral damage to the spinal cord, as for a major involvement of the spinal grey matter and preeminently of the anterior horns, which resembles the typical pattern of the acquired poliomyelitis and is clearly distinguishable in the performed neuroimaging. The lack of a formal demonstration by means of a pathology study was to some extent counterbalanced by the thorough exclusion of other potential differential diagnosis. In our opinion, our work deals with an interesting "bridging" topic for neurologists and infectologists. We would like to encourage screening COVID-19 patients for clinical and neurophysiological signs of spinal cord involvement, that could be missed especially in the critically ill but could play a major role in determining post-acute functional outcomes. Our experience is in line with the latest reports of neurological complications of COVID-19, supporting and further characterizing the already hypothesized SARS-CoV-2 neurotropic potential. We thought that a Narrative Review format would be potentially fitting for our broad dissertation, but we are sure open to shorten and reformat the paper for other sections according to Your advice, if still engaging Your interest. We are aware that these data are limited, but we have seen that many preliminary data about clinical experiences with COVID-19 complications have already been welcomed in medical literature and can be truly useful for inspiring further studies on the evolving knowledge about COVID-19. The article is solely submitted to Travel Medicine and Infectious Disease and all the presented data have not been published or submitted elsewhere. All coauthors have reviewed and approved the contents of the manuscript, and all the requirements for authorship have been met. No conflicts of interest have to be declared. We thank You for the attention, and are looking forward to hearing from You at Your earliest convenience Isabella Canavero, M.D. We agree that our experience is too limited to enable a reliable, and not only speculative, discussion about pathogenesis, thus we have embraced the Editor-in-Chief's proposal to reformat the work with the "Correspondence" requirements. In the revised manuscript, case reports have been extremely summarized and their features outlined in a table; literature review has been removed due to format standards and the Discussion section has been cut to include only essential topics. We have included also the neuroimaging data in a single Figure To date, spinal cord involvement in association with COVID-19 has been poorly characterized. However, its incidence could have been underestimated, due to the difficulties in performing complete neurological, neurophysiological and neuroimaging tests in a highly contagious, intensivecare setting. Here we report on three cases of COVID-19-related acute myelopathies, as further evidence endorsing SARS-CoV-2 neurotropic potential. 1 Table 1 provides further details to the following case descriptions. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 J o u r n a l P r e -p r o o f III]. CSF disclosed a marked neutrophilic pleocytosis, hyperproteinorrachia, and "mirror pattern" OCBs. Extensive screening on blood and CSF for endemic neurotropic pathogens resulted negative. SARS-CoV-2 RNA was undetectable on CSF. Broad-spectrum antibiotics and antivirals were started. Systemic and neurologic autoimmune and vascular diseases were ruled out. Treatment with i.v. steroids was started within 48 hours from onset and continued for 7 days, with significant sensory improvement. Follow up MRI showed a notable reduction in white matter lesions size, and only slight changes as for the multimetameric dorsal lesion. Subsequent treatment with i.v. immunoglobulin 0.4 g/kg daily for 5 days determined a slight motor improvement. Neurophysiology results were consistent with the clinical and neuroimaging findings. After rehab, he regained ability to stand and walk with a walker. In Case 1 and Case 2 we described a multifocal myelitis and a encephalomyelitis with pre-eminent spinal involvement occurring soon after clinical recovery from COVID-19. The prototypical post infectious neurological syndrome is represented by acute disseminated encephalomyelitis (ADEM), which typically follows a recent (from 1 to 6 weeks prior) viral infection or vaccination and is featured by multifocal demyelinating lesions. 2 Differently from our cases, ADEM lesions usually affect the brain to a greater extent than the spinal cord, although cases of post-infectious siterestricted isolated myelitis have already been reported. 2 In both cases, infectious and neurological course were temporally separated, as outlined by the lack of symptoms or indexes of systemic infection or inflammation at admission tests. Systemic and neurological chronic autoimmune disorders were excluded. CSF lymphomonocytosis, the disseminated pattern of lesions with major white matter involvement, and the dramatic improvement after steroid treatment are consistent with an immune-mediated, inflammatory damage that was reasonably triggered by the previous infection. 2 Conversely, in Case 3 we described an extensive spinal cord damage in a COVID-19 patient where the overlapping infectious and neurological symptoms point to a para-infectious mechanism. The absence of SARS-CoV-2 RNA in the CSF samples, although it does not support a direct pathogenic role of the virus, is consistent with recent reports of COVID-19 patients with CNS involvement. 3 Neuroimaging was distinctive: multiple disseminated lesions without contrast enhancement, mostly affecting the spinal cord, including a dorsal longitudinal elongated transverse myelitis (LETM) with a central "H-shaped" pattern and preeminent involvement of the anterior horns. Interestingly, both LETM and anterior horn myelitis are known to occur also as para-infectious phenomena. 4 The major involvement of the spinal grey matter points to a direct viral damage and is often labeled as "polio-like viral related syndrome", since its similarity with the classical poliomyelitis. 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 J o u r n a l P r e -p r o o f The main pathways played by COVID-19 while affecting the CNS are likely represented by a combination of direct viral pathogenicity, immune-mediated tissue damage, inflammatory vascular involvement and intravascular coagulation. 1, 5 It is important acknowledging that the temporal relationship between COVID-19 and acute myelopathies is not sufficient to prove causation and further data are warranted. To this effect, we encourage searching signs of spinal cord involvement in COVID-19 patients, whose incidence could have been underestimated but could play a major role in determining post-acute functional outcome . 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Giuseppe Micieli: study conception, clinical data collection, data interpretation, literature search, writing, revision *contributed equally None to declare. 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 J o u r n a l P r e -p r o o f Funding This work did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The corresponding author had full access to all the data in the study and takes full and final responsibility for the decision to submit for publication. All clinical procedures were performed in accordance with the national and international ethical standards. Written informed consent was obtained from all the patients . 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 J o u r n a l P r e -p r o o f 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Figure 1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 to D5 with sagittal (a), parasagittal (b) and axial (d) T2 Turbo Spin Echo (TSE) weighted images and post gadolinium sagittal T1-Spin Echo (SE) weighted images (c). Follow-up MRI performed 1month later (e-g), with sagittal T2-SE (e) and axial T2-Fast Field Echo (FFE) sequences (f, g). In the acute phase, a slight diffuse multifocal hyperintensity at the cervical level (a, b) and a blurred hyperintensity at D3 level (b, white arrow, and d) were detectable. No enhancement was evident after gadolinium injection (c). Follow-up MRI better showed multifocal cervical lesions at C3-C5 and C6-C7 (e), mainly involving the cervical lateral (f) and dorsal centro-medullary region (g). Spine MRI (a) shows multiple, predominantly posterior hyperintense cervical lesions at C3, C4-C5 level (arrows) and in the upper dorsal region (T1-T2, arrows), while a more extensive alteration is evident from T5 down to the epiconus (b-e). Axial slices (f, g) detect an "H-shaped" gray matter involvement (f), predominantly affecting the anterior horns (g). Brain MRI shows one single hyperintense lesion in the left superior cerebellar peduncle (h), without contrast enhancement (i). 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 J o u r n a l P r e -p r o o f Does SARS-Cov-2 invade the brain? Translational lessons from animal models International Pediatric MS Study Group. Acute disseminated encephalomyelitis Neurologic Features in Severe SARS-CoV-2 Infection Acute myelopathies associated to SARS-CoV-2 infection: viral or immune-mediated damage? 3 Neuroimmunology Unit, IRCCS C. Mondino Foundation 8 UOC Neurologia / Stroke Unit Francesca Valentino*: study conception and authors' coordination, clinical data collection, data interpretation, literature search, writing Elena Colombo: clinical data collection, data interpretation, literature search, writing Diego Franciotta: data collection, data analysis (CSF), data interpretation, literature search, writing Delfina Ferrandi: clinical data collection, data interpretation, literature search, writing Marco Mussa: clinical data collection, data interpretation, literature search, writing Rodolfo Schizzi: neuroimaging data collection and analysis, data interpretation, figures, literature search, writing Kalliopi Marinou: clinical data collection, data interpretation, literature search, writing Carla Zanferrari: clinical data collection, data interpretation, literature search, writing Pietro Businaro: clinical data collection, data interpretation, literature search, writing Sabrina Ravaglia: clinical and neurophysiological data interpretation, literature search, writing Prunetti: neurophysiological data collection and analysis, data interpretation, figures, literature search, writing Giuseppe Cosentino: neurophysiological data collection and analysis, data interpretation, literature search, writing Lisa Maria Farina: neuroimaging data collection and analysis, data interpretation, figures, literature search, writing Elisa Rognone: neuroimaging data collection and analysis, data interpretaton, figures, literature search, writing Anna Pichiecchio: study conception, neuroimaging data collection, analysis and interpretation, figures, literature search, writing, revision References 1 International Pediatric MS Study Group. Acute disseminated encephalomyelitis Neurologic Features in Severe SARS-CoV-2 Infection Neuropathology of COVID-19: a spectrum of vascular and acute disseminated encephalomyelitis (ADEM)-like pathology Isabella Canavero*: study conception and authors' coordination, clinical data collection, data interpretation, literature search, writing J o u r n a l P r e -p r o o f Declarations Travel Medicine and Infectious Disease requires that all authors sign a declaration of conflicting interests. If you have nothing to declare in any of these categories then this should be stated. A conflicting interest exists when professional judgement concerning a primary interest (such as patient's welfare or the validity of research) may be influenced by a secondary interest (such as financial gain or personal rivalry). It may arise for the authors when they have financial interest that may influence their interpretation of their results or those of others. Examples of potential conflicts of interest include employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications/registrations, and grants or other funding. None to declare All sources of funding should also be acknowledged and you should declare any involvement of study sponsors in the study design; collection, analysis and interpretation of data; the writing of the manuscript; the decision to submit the manuscript for publication. If the study sponsors had no such involvement, this should be stated. None Signature (a scanned signature is acceptable, Print name but each author must sign) A conflicting interest exists when professional judgement concerning a primary interest (such as patient's welfare or the validity of research) may be influenced by a secondary interest (such as financial gain or personal rivalry). It may arise for the authors when they have financial interest that may influence their interpretation of their results or those of others. Examples of potential conflicts of interest include employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications/registrations, and grants or other funding. None to declare All sources of funding should also be acknowledged and you should declare any involvement of study sponsors in the study design; collection, analysis and interpretation of data; the writing of the manuscript; the decision to submit the manuscript for publication. If the study sponsors had no such involvement, this should be stated. None Signature (a scanned signature is acceptable, Print name but each author must sign) CARLA ZANFERRARI Manuscript number (if applicable): Article Title: Acute myelopathies associated to SARS-CoV-2 infection: viral or immune-mediated damage?Author name: CARLA ZANFERRARI