key: cord-0995450-pdlgt2u6
authors: Gorgone, Gaetano; Giudice, Francesco Del; David, Piero; Franco, Giovanni; Giofrè, Laura; Grillo, Gaetano; Iellamo, Mattia Anna; Mastrandrea, Carmela; Orlando, Concetta; Vecchio, Antonino; Galati, Franco
title: SERUM NEGATIVE NEUROMYELITIS OPTICA SPECTRUM DISORDER AFTER VAXZEVRIA VACCINATION: A CASE REPORT
date: 2021-09-08
journal: Neuroimmunology Reports
DOI: 10.1016/j.nerep.2021.100016
sha: 223b725331a8e61f1da0b8e227fc323c9a13b324
doc_id: 995450
cord_uid: pdlgt2u6

Background Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disease, targeting the central nervous system, rarely associated with vaccination. Case report we report a case of a 47 year-old healthy woman who presented, ten days after the first dose of SARS-CoV-2 Vaccine AstraZeneca (Vaxzevria), with back pain, tetraplegia, urinary retention, dysarthria and dysphagia. The patient was diagnosed NMOSD. She underwent intravenous-corticosteroids, vein-Immunoglobulin and plasma-exchange without significant improvement . Conclusion The absence of any possible related conditions, the temporal relation with anti-SARS-CoV-2 vaccination, suggest that, in our case, NMOSD may be due to the cross reaction from Vaxzevria.

A 47-year-old right-handed healthy woman with no family history of autoimmune disorders had a 3 days history of back and lower extremity pain with gradual weakness and paresthesias of the legs, accompanied by urinary retention. This progressed to involve all extremities and ultimately an inability to stand. She reported no prior neurological or respiratory or gastrointestinal illness preceding the onset of symptoms. She was receiving no medications. Ten days prior to the onset of symptoms, she received the first dose of Vaxzevria. Examination revealed a severe proximal muscle weakness with a total sensory loss on the trunk, upper and lower extremities with a C3 sensory level. There was diffuse hyporeflexia. Plantar response was silent and no clonus was noted.

The day after the patient became dysarthric and disphagic.

Magnetic resonance imaging (MRI) revealed extensive intramedullary STIR and FLAIR hyperintensity extending from the cervical medullary junction throughout the length of the thoracic cord (Figure 1 A) and an abnormal signals on FLAIR and DWI acquisitions in the right middle cerebellar peduncle and left temporal lobe ( Figure 1B ). Post-gadolinium enhancing was present only in the cerebellar lesion and in a small portion of the thoracic cord ( Figure 1C ). Laboratory testing revealed negative results for serum angiotensin-converting enzyme, antinuclear antibodies, rheumatoid factor, antiphosolipid, anti-aquaporin-4 (Anti-AQP4) and anti-myelin oligodendrocyte glycoprotein (Anti-MOG) antibodies. Laboratory tests for HIV, SARS-CoV-2, Lyme disease, Mycoplasma were also negative. Sedimentation rate and vitamin B 12 levels were normal.

Cerebrospinal fluid had a protein concentration of 4.04 g/mL, glucose concentration of 35 mg/dL and a white blood cell count of 4350/μL, with 80% neuthrophils. No oligoclonal bands were present.

The PCR-multiplex for Herpes Simplex 1-2-6 virus, Epstein-Barr virus, Cytomegalovirus, Streptococcus agalactiae and pneumonia, Parechovirus, Cryptococcus neoformans/gatti, Haemophilus influenciae, Listeria monocytogenes, Neisseria meningitides and Escherichia coli K1 were negative. An empiric antibiotic regimen ( vancomicine 1g/bid, and meropenem 2g/trid) was in anyway started, together with intravenous methylprednisolone (1 g/d for 5 days). Bacterial and fungal culture results were negative, and three days later, vancomicine and meropenem were stopped. Then, intravenous methylprednisolone was slow tapered over the next three weeks, and plasmapheresis treatment was started. Despite these therapies the patient did not significantly improved . A follow up MRI on the day 14, showed a slight improvement of the radiological picture. Because the little effects of the intravenous methylprednisolone and plasmapheresis the patient was treated with vein -Immunoglobulin ( 0.4 g/kg for five days), without benefit.

A second lumbar puncture performed on day 15, showed a protein concentration of 1.37 g/mL glucose concentration of 52 mg/dL and a white blood cell count of 22/μL. On day 32, before the admission to the inpatient rehabilitation facilities, she underwent another MRI, that showed a new hyperintensity of the left middle cerebellar peduncle without post-gadolinium enhancing (figure 1 D).

We report findings in a healthy 47-years-old woman who developed a rapid-onset diffuse motor weakness associated with cerebellar dysfunction and cranial nerve abnormalities, ten days after the first dose of Vaxzevira, a recombinant chimpanzee adenoviral vector encoding the spike glycoprotein of SARS-CoV-2, approved by regulatory authority for vaccination against SARS- (Jarius et al, 2016) . Approximately 70% of patients have Anti-AQP4, while Anti-MOG, are present in less than 10% of cases (Sato et al, 2014) . However, the newly revised nomenclature, includes in the NMOSD umbrella, serum-negative patients for Anti-AQP4 and Anti-MOG , in presence of multiple core clinic characteristics and MRI findings (table one; Wingerchuk et al, 2015) . Our patient presented with acute myelitis and brainsterm syndrome; MR showed the presence of an extensive intramedullary hyperintensity and abnormal signal areas in the cerebellum and left temporal lobe. These findings met the diagnostic criteria of serum-negative NMOSD. In this report we also evidenced a temporal relationship between onset of the symptoms and Vaxzevria, that makes it plausible a causal relationship. Support this hypothesis the increasing number of NMOSD recently described with other vaccines (Jarius et al, 2016) and the two istances of myelitis reported in clinical trials with Vaxzevria (Voysey et al, 2021) . However, unlike these prior efforts, despite steroid therapy and plasmapheresis, patient's outcome remained poor. Although we cannot rule the exact mechanism underling this phenomenon, we speculate that Vaxzevria may induce, in some cases, a widespread inflammatory reaction, probably mediated by the effect of some cytokines, such as tumor necrosis factor, interleukin 1-beta, and interleukine-17 that affects the clinical outcome (Román et al; . In conclusion, although it is difficult, if not impossible, to establish a causal relationship between vaccination and CNS demyelinating disease through the temporal association of rare events described in case reports such as this, we nevertheless believe it is important to make such cases known, both to contribute to the continued development of safe methods of vaccination against SARS-CoV-2, as well as to provoke further investigation into the pathogenesis of NMOSD, which may lead to a more refined nosology of this evolving spectrum of disease.

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Wingerchuk et al, 2015) Diagnosis with Anti-AQP4  at least one core clinical characteristic  positive Anti-AQP4 with best available method  exclusion of alternative diagnosis (eg sarcoidosis, neoplastic/paraneoplastic, vascular, chronic infection). Diagnosis without Anti-AQP4 /unknown status  at least two core clinical characteristics resulting from one or more clinical attacks and fulfilling the following:

 at least one of optic neuritis, longitudinally extensive transverse myelitis, area postrema syndrome  dissemination in space (two or more different core clinical characteristics)

 fulfilment of additional MRI requirements as applicable  negative for Anti-AQP4 with best available method, or testing unavailable  exclusion of alternative diagnoses. Core clinical characteristics  optic neuritis  acute myelitis  area postrema syndrome brainstem syndrome  symptomatic narcolepsy or acute diencephalic syndrome with NMOSD-typical diencephalic MRI lesions  symptomatic cerebral syndrome with NMOSD-typical brain lesions.

Additional MRI requirements for NMOSD without Anti-AQP4 /unknown status  acute optic neuritis: normal or only non-specific white matter lesions on MRI brain; or optic nerve MRI with T2-hyperintense lesion or T1-weighted gadolinium-enhancing lesion extending over >½ optic nerve length or optic chiasm involvement  acute myelitis: MRI spinal cord demonstrating attack-associated lesion spanning ≥3 contiguous vertebral segments or ≥3 contiguous segments of focal cord atrophy with previous history of acute myelitis  area postrema syndrome: dorsal medulla/area postrema lesion on MRI brain  acute brainstem syndrome: periependymal brainstem lesions. 

MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 3: Brainstem involvement -frequency, presentation and outcome

Acute Transverse Myelitis (ATM):Clinical Review of 43 Patients With COVID-19-Associated ATM and 3 Post-Vaccination ATM Serious Adverse Events With the ChAdOx1 nCoV-19 Vaccine (AZD1222). Front Immunol. Epub ahead of print 26

Autoimmune diseases associated with Neuromyelitis Optica Spectrum Disorders: A literature review

Distinction between MOG antibodypositive and AQP4 antibody-positive NMO spectrum disorders

Safety and efficacy of the

vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK

International consensus diagnostic criteria for neuromyelitis optica spectrum disorders