key: cord-0890118-cmi2iopm
authors: Poisson, Kelsey E.; Zygmunt, Alexander; Leino, Daniel; Fuller, Christine E.; Jones, Blaise V.; Haslam, David; Staat, Mary Allen; Clay, Gwendolyn; Ting, Tracy V.; Wesselkamper, Kristen; Hallinan, Barbara; Standridge, Shannon; Day, Melissa E.; McNeal, Monica; Stevenson, Charles B.; Vawter-Lee, Marissa
title: Lethal pediatric cerebral vasculitis triggered by Severe Acute Respiratory Syndrome Coronavirus 2: a case report
date: 2021-11-12
journal: Pediatr Neurol
DOI: 10.1016/j.pediatrneurol.2021.11.003
sha: 8cd4cbdaccea8fbba0d751f655ad1e1aee2b6de6
doc_id: 890118
cord_uid: cmi2iopm

OBJECTIVES: We report the clinical, radiological, laboratory, and neuropathological findings in support of the first diagnosis of lethal, small-vessel cerebral vasculitis triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a pediatric patient. PATIENT DESCRIPTION: A previously healthy, 8-year-old Hispanic female presented with subacute onset left-sided weakness two weeks after a mild febrile illness. SARS-CoV-2 nasopharyngeal swab was positive. Magnetic resonance imaging (MRI) revealed an enhancing right frontal lobe lesion with significant vasogenic edema. Two brain biopsies of the lesion showed perivascular and intraluminal lymphohistiocytic inflammatory infiltrate consistent with vasculitis. Despite extensive treatment with immunomodulatory therapies targeting primary angiitis of the central nervous system, she experienced neurologic decline and died 93 days after presentation. SARS-CoV-2 testing revealed positive serum IgG and positive cerebrospinal fluid IgM. Comprehensive infectious, rheumatologic, hematologic/oncologic, and genetic evaluation did not identify an alternative etiology. Post-mortem brain autopsy remained consistent with vasculitis. DISCUSSION: This is the first pediatric presentation to suggest SARS-CoV-2 can lead to a fatal, post-infectious, inflammatory small-vessel cerebral vasculitis. Our case is unique in including supportive cerebrospinal fluid and post-mortem tissue analysis. While most children recover well from neurologic complications of SARS-CoV-2, we emphasize the potential mortality in a child with no risk factors for severe disease.

Objectives: We report the clinical, radiological, laboratory, and neuropathological findings in support 34

of the first diagnosis of lethal, small-vessel cerebral vasculitis triggered by severe acute respiratory 35 syndrome coronavirus 2 (SARS-CoV-2) in a pediatric patient. 36

Patient description: A previously healthy, 8-year-old Hispanic female presented with subacute onset left-37 sided weakness two weeks after a mild febrile illness. SARS-CoV-2 nasopharyngeal swab was 38

positive. Magnetic resonance imaging (MRI) revealed an enhancing right frontal lobe lesion with 39 significant vasogenic edema. Two brain biopsies of the lesion showed perivascular and 40

intraluminal lymphohistiocytic inflammatory infiltrate consistent with vasculitis. Despite extensive 41 treatment with immunomodulatory therapies targeting primary angiitis of the central nervous system, 42

she experienced neurologic decline and died 93 days after presentation. SARS-CoV-2 testing revealed 43 positive serum IgG and positive cerebrospinal fluid IgM. Comprehensive infectious, rheumatologic, 44

hematologic/oncologic, and genetic evaluation did not identify an alternative etiology. Post-mortem brain 45 autopsy remained consistent with vasculitis. 46

Discussion: This is the first pediatric presentation to suggest SARS-CoV-2 can lead to a fatal, post-47

infectious, inflammatory small-vessel cerebral vasculitis. Our case is unique in including supportive 48

cerebrospinal fluid and post-mortem tissue analysis. While most children recover well from neurologic 49

complications of SARS-CoV-2, we emphasize the potential mortality in a child with no risk factors for 50 severe disease. We describe the comprehensive evaluation and ultimately fatal course of an 8-year-old girl who 66 presented with left-sided weakness and was found to have a brain lesion. After extensive evaluation the 67 brain lesion was felt to be vasculitis triggered by severe acute respiratory syndrome coronavirus 2 (SARS-68

CoV-2). The lesion was progressive and refractory to numerous immunotherapies targeting cerebral 69 vasculitis, and the patient unfortunately passed away. This is the first reported pediatric case of lethal Table 1A and 1B) and was normal except for positive mycoplasma serology which was 94 considered incidental. 95

On hospital day nine serum SARS-CoV-2 IgG qualitative testing was positive. Multiple 96 subsequent nasopharyngeal SARS-CoV-2 PCR tests were negative (Supplemental Table 1D ). SARS-97

CoV-2 testing of fresh frozen brain biopsy tissue was negative. At time of evaluation there was no 98 validated CSF SARS-CoV-2 test. 99 100

Initial suspicion for tumefactive demyelination led to treatment with intravenous (IV) 102 methylprednisolone followed by plasmapheresis. During plasmapheresis, arm weakness worsened and left 103 lower face weakness developed. MRI showed enlarged lesion with extension into the corpus callosum 104 ( Figure 1B ). Given biopsy concern for vasculitis, cyclophosphamide was administered. Weekly MRI 105 studies demonstrated progression of the lesion despite all interventions ( Figure 1C) . Levetiracetam, neuroprotective measures for elevated intracranial pressure, and broad-spectrum 113 antimicrobials (including azithromycin, antifungal and parasitic coverage) were initiated. IV 114 methylprednisolone was restarted, and infliximab was given for presumed treatment-resistant vasculitis. 115

Laboratory testing at that time revealed anemia, leukopenia, thrombocytopenia, and elevated 116 inflammatory markers (Supplemental Table 1C ). Persistent fevers developed. Bone marrow biopsy 117 demonstrated hypocellularity, but no hemophagocytosis nor signs of malignancy. Due to fevers, 118 cytopenias, hyperferritinemia, and elevation in liver enzymes, a diagnosis of secondary macrophage 119 activation syndrome was postulated for which she received a course of anakinra for additional 120 immunosuppression and central nervous system (CNS) penetration. 121

Unrelenting clinical decline and progression of MRI findings ( Figure 1D neuropathies, headache, myositis, and weakness 7-9 . 160

Children with SARS-CoV-2 and neuroimaging findings are reported to recover well, with 161 exceptions being deaths from fatal co-infections (4 patients), acute fulminant cerebral edema in the setting 162 of status epilepticus (3 patients), stroke (4 patients, one of whom is the patient described in this article), 163 and severe encephalopathy (4 patients) 7,9 . CNS vasculitis has been reported in adults with SARS-CoV-2 10 . 164

In pediatrics, isolated vascular events from focal cerebral arteriopathies have been reported 8 . 165

It has been postulated that pro-inflammatory cytokines associated with SARS-CoV-2 lead to 166 enhanced permeability of the blood-brain-barrier, allowing antibodies and other pro-inflammatory 167 mediators into the brain parenchyma, perpetuating a post-infectious CNS inflammatory response 11 . 168 SARS-CoV-2-related neuropathology findings in the literature are described as either 169 hypoxic/ischemic changes secondary to respiratory/cardiovascular compromise, acute thrombotic 170 ischemic and/or hemorrhagic infarcts within the brain parenchyma, or lesions similar to those seen in 171 ADEM. Rare cases in the adult population have shown focal or diffuse perivascular T-lymphocytic 172 infiltrate 10 , similar to what was encountered in our patient 12 . 173

Mycoplasma has been associated with CNS disease including vasculitis, ADEM, Guillain-Barré 174 syndrome and encephalitis mimicking brain mass 13,14 . A mechanism of vasculitic necrosis associated with 175 Mycoplasma has been proposed; however, this has only been reported in the thalamus, basal ganglia, 176 pons, and splenium of the corpus callosum, which is not consistent with our patient's presentation, nor is 177 the enlargement of our patient's lesion after treatment with azithromycin 14 . 178

Although multisystem inflammatory syndrome in children (MIS-C) has arisen during the SARS-179

CoV-2 pandemic, our patient never met diagnostic criteria due to lack of daily fevers, other additional We thank the family for allowing us to report this case, and the kindness and graciousness they 196 showed us throughout their child's illness. Informed consent (written and oral) was obtained from family 197 for this publication. To the inpatient RNs for the wonderful care they gave to the patient. To our medical 198 colleagues in many subspecialities who let us discuss the case with them (particularly Dr. Maureen 

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commercial, or not-for-profit sectors. 212 213 Previous Presentation of the information in this manuscript: Our patient was included in very limited 214 detail in the study "Neurologic Involvement in Children and Adolescents Hospitalized in the United 215States for COVID-19 or Multisystem Inflammatory Syndrome", published in JAMA Neurology in March 216 2021. In that study's text our patient is the fourth stroke patient who died, and her course is summarized 217in one sentence within the body of the manuscript. In supplemental e- Table 4 she is presented as Case 3. 218The authors of that study had limited access to data, and no access to imaging on our patient, and their 219 manuscript was published before our patient's post-mortem autopsy was performed and the CSF SARS-220CoV-2 IgM result was known. Authors have no potential, perceived or real conflicts of interest to report relative to this study. This research was not funded by any sponsor. Study design, collection, analysis and interpretation of data and all subsequent writing as well as decisions on manuscript submission were made at authors' discretion without undue influence. Drafting and revision of manuscript was performed by all study authors without honorarium, grant or other form of payment.

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