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Multiple internal border zone infarcts in a patient with COVID-19 and CADASIL

2020; Elsevier BV; Volume: 416; Linguagem: Inglês

10.1016/j.jns.2020.116980

1878-5883

O. Williams, Saamir Mohideen, Arup Sen, Olivera Martinovic, Jonathan Hart, Peter Brex, L. Sztriha,

Acute Ischemic Stroke Management

•Novel case report highlighting association of COVID-19 precipitating symptoms of CADASIL•Multiple internal border zone infarcts in a patient with COVID-19 and CADASIL•Proposed mechanism is endothelial injury with microvascular thrombosis and cerebral dysautoregulation•We advise to consider patients with CADASIL a vulnerable group during the pandemic Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the commonest inherited stroke disorder. We report a novel presentation of multiple internal border zone infarcts in a patient with COVID-19 and CADASIL. The clinical significance of this case is to highlight the risk of COVID-19 exacerbating CADASIL. Possible pathophysiological mechanisms are discussed, which may be extrapolated to patients with cerebral small vessel disease and non-CADASIL strokes. A 38-year-old woman presented with sudden onset of a mild dysarthria (NIHSS 1), with a prodrome seven days earlier of fever, myalgia, anosmia and ageusia. Her past medical history was unremarkable. There was a family history of CADASIL, genetically confirmed in her father and sister. A CT brain showed low attenuation within the right corona radiata; CT angiogram of the head and neck vessels was unremarkable. She was commenced on aspirin 300 mg and admitted. Nasopharyngeal swab confirmed infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). An MRI brain demonstrated chronic small vessel disease consistent with a pattern seen in CADASIL and acute infarcts in eleven locations bilaterally within an internal border zone distribution.(Fig. 1. A-C) Her observations on day eight from onset of COVID-19 symptoms saw a spontaneous blood pressure drop from 119/66 mmHg to 89/47 mmHg, with an associated deterioration of her dysarthria and a transient right facial droop. On day eleven she had a sudden deterioration with severe unintelligible dysarthria, mild oro-pharyngeal dysphagia, right hemiparesis and facial weakness with increased tone and past pointing in the left upper limb (NIHSS 9). An MRI brain on day thirteen demonstrated one new acute infarct in the same territory with a confluence of some lesions as they had increased in size.(Fig. 1. D-F) IgM for anticardiolipin antibodies was elevated at 14 U/mL (0−10), whilst all other investigations were within normal parameters. Genetic analysis of the NOTCH3 gene demonstrated a heterozygous pathogenic missense variant c.268C > T (p.Arg90Cys). On discharge she had moderate to severe dysarthria and a mild facial droop whilst all other neurological symptoms had improved (Modified Rankin Score 2), with neurorehabilitation planned in the community. CADASIL is an inherited angiopathy caused by pathogenic mutations in the NOTCH3 gene on chromosome 19, characterised by aberrant protein formation, the presence of granular osmiophilic deposits and fibrosis of the walls of small arteries. Clinical presentation includes solitary ischaemic strokes, cognitive deficits, migraine, psychiatric symptoms, and encephalopathy with characteristic radiological features including T2/FLAIR hyperintensities specifically affecting the anterior temporal lobes [[1]Locatelli M. Padovani A. Pezzini A. Pathophysiological mechanisms and potential therapeutic targets in cerebral autosomal dominant Arteriopathy with subcortical infarcts and Leukoencephalopathy (CADASIL).Front. Pharmacol. 2020 Mar 13; 11: 321Crossref PubMed Scopus (25) Google Scholar]. An association between COVID-19 and strokes have been described with characteristics including large vessel occlusion, multi-territory infarcts, concomitant venous thromboembolism, raised inflammatory markers, antiphospholipid antibody production, younger age of stroke, premorbid vascular co-morbidities, and a higher incidence of stroke with increasing COVID-19 severity [2Beyrouti R. Adams M.E. Benjamin L. Cohen H. Farmer S.F. Goh Y.Y. et al.Characteristics of ischaemic stroke associated with COVID-19.J. Neurol. Neurosurg. Psychiatry. 2020 Apr 30; 0: 1-3https://doi.org/10.1136/jnnp-2020-323586Crossref Scopus (514) Google Scholar, 3Mao L. Jin H. Wang M. et al.Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China.JAMA Neurol. 2020; 77: 683-690https://doi.org/10.1001/jamaneurol.2020.1127Crossref PubMed Scopus (4744) Google Scholar, 4Chen N. Zhou M. Dong X. Qu J. Gong F. Han Y. et al.Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study.Lancet. 2020 15; 395: 507-513Abstract Full Text Full Text PDF PubMed Scopus (14212) Google Scholar]. Small vessel involvement have rarely been described; our case demonstrates multiple internal border zone infarcts, which are subcortical lesions at the junction between two arterial territories, typically attributed to haemodynamic compromise. We propose two main pathophysiological mechanisms secondary to vascular endothelial injury induced by COVID-19. Firstly, microvascular thrombosis secondary to direct or indirect endothelial cell injury. Direct endothelial cell infection by SARS-CoV-2 has been demonstrated with histological evidence of viral elements within endothelial cells and endotheliitis by accumulation of inflammatory cells and apoptosis, but not to date in the cerebrovasculature [[5]Varga Z. Flammer A.J. Steiger P. Haberecker M. Andermatt R. Zinkernagel A.S. et al.Endothelial cell infection and endotheliitis in COVID-19.Lancet. 2020 May; 395: 1417-1418Abstract Full Text Full Text PDF PubMed Scopus (4433) Google Scholar]. SARS-CoV-2 gains entry into the host via the angiotensin-converting enzyme 2 (ACE2) receptor, which is present in all arterial endothelial and smooth muscle cells, and therefore subsequent endothelial dysfunction could trigger a thrombotic cascade. Indirect endothelial dysfunction with secondary thrombosis could be due to a combination or single systemic factors which would include: inflammatory cytokine production, activation of a coagulation cascade, and complement mediated microvascular thrombosis; as evidenced by elevated inflammatory markers and D-dimer levels [[2]Beyrouti R. Adams M.E. Benjamin L. Cohen H. Farmer S.F. Goh Y.Y. et al.Characteristics of ischaemic stroke associated with COVID-19.J. Neurol. Neurosurg. Psychiatry. 2020 Apr 30; 0: 1-3https://doi.org/10.1136/jnnp-2020-323586Crossref Scopus (514) Google Scholar,[4]Chen N. Zhou M. Dong X. Qu J. Gong F. Han Y. et al.Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study.Lancet. 2020 15; 395: 507-513Abstract Full Text Full Text PDF PubMed Scopus (14212) Google Scholar,[6]Oxley T.J. Mocco J. Majidi S. Kellner C.P. Shoirah H. Singh I.P. et al.Large-vessel stroke as a presenting feature of Covid-19 in the young.N. Engl. J. Med. 2020 Apr 28; : e60Crossref PubMed Scopus (1532) Google Scholar]. Additionally, antiphospholipid antibody production have been described with COVID-19, however, such antibodies can be seen in many acute infections transiently without conferring an increased risk of thrombosis [[2]Beyrouti R. Adams M.E. Benjamin L. Cohen H. Farmer S.F. Goh Y.Y. et al.Characteristics of ischaemic stroke associated with COVID-19.J. Neurol. Neurosurg. Psychiatry. 2020 Apr 30; 0: 1-3https://doi.org/10.1136/jnnp-2020-323586Crossref Scopus (514) Google Scholar]. Hypoxia may also trigger endothelial dysfunction but was not documented in this case. A second mechanism proposed is hypoperfusion due to cerebral blood flow dysautoregulation, secondary to disruption of the renin-angiotensin system (RAS) by COVID-19. Given the location of the arteriopathy in the small vessels of patients with CADASIL this would make the internal border zone particularly vulnerable to hypoperfusion. There is evidence of chronic cerebral hypoperfusion in CADASIL, with a proposed mechanism being impairment in the myogenic component of autoregulation where vascular smooth muscle constricts or dilates to transmural pressure changes [[1]Locatelli M. Padovani A. Pezzini A. Pathophysiological mechanisms and potential therapeutic targets in cerebral autosomal dominant Arteriopathy with subcortical infarcts and Leukoencephalopathy (CADASIL).Front. Pharmacol. 2020 Mar 13; 11: 321Crossref PubMed Scopus (25) Google Scholar]. Internal border zone infarcts have been reported in nine patients with CADASIL; whereby six had documented systemic hypotension, one occurring with intercurrent Influenza A infection [[7]Mizutani K. Sakurai K. Mizuta I. Mizuno T. Yuasa H. Multiple border-zone infarcts triggered by influenza a virus infection in a patient with cerebral autosomal dominant Arteriopathy presenting with subcortical infarcts and Leukoencephalopathy.J. Stroke Cerebrovasc. Dis. 2020 Feb 24; 29104701Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar]. In this case, only a minor transient hypotension was documented with associated clinical deterioration. Broadening this mechanism of injury to non-CADASIL strokes, bilateral frontotemporal hypoperfusion has been described in patients with severe COVID-19 [[8]Helms J. Kremer S. Merdji H. Clere-Jehl R. Schenck M. Kummerlen C. et al.Neurologic features in severe SARS-CoV-2 infection.N. Engl. J. Med. 2020 Apr 15; 382 (NEJMc2008597): 2268-2270Crossref PubMed Scopus (1802) Google Scholar]. We propose the mechanism of injury is related to the RAS; which has separate regulatory pathways in both the periphery and the brain. This can be disrupted by SARS-CoV-2 due to the down regulation of ACE2 receptors, causing limitations on vasodilatation [[9]Divani A.A. Andalib S. Di Napoli M. Lattanzi S. Hussain M.S. Biller J. et al.Coronavirus disease 2019 and stroke: clinical manifestations and pathophysiological insights.J. Stroke Cerebrovasc. Dis. 2020 Aug; 29104941Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar]. Additional mechanisms may involve endothelial dysfunction in CADASIL as a predisposing factor with limited reserve when challenged with such an insult as COVID-19 [[1]Locatelli M. Padovani A. Pezzini A. Pathophysiological mechanisms and potential therapeutic targets in cerebral autosomal dominant Arteriopathy with subcortical infarcts and Leukoencephalopathy (CADASIL).Front. Pharmacol. 2020 Mar 13; 11: 321Crossref PubMed Scopus (25) Google Scholar]; or a superimposed secondary parainfectious autoimmune disorder for which there is growing radiological and histological evidence [[10]Reichard R.R. Kashani K.B. Boire N.A. Constantopoulos E. Guo Y. Lucchinetti C.F. Neuropathology of COVID-19: a spectrum of vascular and acute disseminated encephalomyelitis (ADEM)-like pathology.Acta Neuropathol. 2020 May 24; (Available from:)https://doi.org/10.1007/s00401-020-02166-2Crossref PubMed Scopus (359) Google Scholar]. The clinical significance of this case is to highlight for the first time the association of COVID-19 and CADASIL, and given the risk of exacerbation we would advise patients to abide by strict infection prevention measures for the duration of the pandemic. A wider implication of this report is to highlight proposed pathophysiological mechanisms of stroke in the context of CADASIL and COVID-19, which may inform the mechanism of non-CADASIL strokes. We propose that the primary mechanism of infarcts is endothelial injury causing a secondary microvascular thrombosis and also hypoperfusion due to cerebral blood flow dysautoregulation due to impairment of the RAS. We recommend that further research be conducted into the pathophysiology of COVID-19 related stroke and therapies that target stabilising the vascular endothelium. None.