key: cord-1007607-i9kll52m
authors: Vogrig, Alberto; Janes, Francesco; Gigli, Gian Luigi; Curcio, Francesco; Negro, Ilaria Del; D’Agostini, Serena; Fabris, Martina; Valente, Mariarosaria
title: Acute disseminated encephalomyelitis after SARS-CoV-2 vaccination
date: 2021-07-21
journal: Clin Neurol Neurosurg
DOI: 10.1016/j.clineuro.2021.106839
sha: c388f6eeef2dea5abb6b0326675270c406441328
doc_id: 1007607
cord_uid: i9kll52m

Several central and peripheral nervous system complications associated with the severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection have been recently described. An effective mass vaccination program is necessary to effectively reduce infection spread and, consequently, limit long-term sequelae, including those affecting the nervous system. Nevertheless, as more patients gain access to coronavirus disease 2019 (COVID-19) vaccines, it is important to report potential adverse events. Herein, we report a patient with previous history of post-infectious rhombencephalitis who developed an acute disseminated encephalomyelitis (ADEM) two weeks after being vaccinated for COVID-19.

Acute disseminated encephalomyelitis (ADEM) is a demyelinating disorder of the central nervous system (CNS) that typically occurs in close temporal association with either an antecedent infection or, less frequently, following vaccination [1] .

Herein, we report a patient with previous history of post-infectious rhombencephalitis who developed an ADEM-like, severe neuroinflammatory disorder of the CNS shortly after being vaccinated for SARS-CoV-2.

A 56-year-old female patient was referred for subacute onset over one week of unsteadiness of gait, predominantly on the left side, followed by clumsiness of left arm. The day before the onset of the symptoms, she experienced malaise and chills, without fever. Nasopharyngeal swab was negative for SARS-CoV-2 on reverse-transcriptase polymerase chain reaction (RT-PCR) assay. Two weeks prior to presentation, she received the first dose of the Pfizer-BioMTech COVID-19 vaccine (Comirnaty), without any acute allergic reactions.

Her medical history was relevant for a previous clinical episode suggestive for postinfectious rhombencephalitis 5 years before this admission (Figure 1 ). At that time, the patient manifested diplopia, mild ataxia with left-ward deviation of gait, and urinary retention requiring catheterization one week after a febrile episode characterized by gastroenteritis and erythematous rash. Nuchal rigidity was not present. Brain magnetic resonance imaging (MRI), performed 6 days after onset, was unremarkable. Cerebrospinal fluid (CSF) showed pleocytosis (80 cells/mm 3 ), while protein and glucose levels were within reference ranges.

Electroencephalogram (EEG) was abnormal due to the presence of intermittent slowing in the delta range, predominantly over the fronto-temporal regions. A comprehensive microbiological and autoimmune screening was unrevealing. The patient spontaneously J o u r n a l P r e -p r o o f recovered and underwent regular follow-up, including a control brain MRI four months later, also unremarkable. Between 2016-2020 she was seen for recurrent episodes of cutaneous herpes zoster with resulting neuropathic pain, effectively treated with pregabalin.

Neurological examination was normal during all these consultations, and the patient never complained of episodes of weakness, incoordination, sensory abnormalities, or visual loss.

In the current admission, the patient was found to be alert and oriented. No cranial nerve deficits were documented, but horizontal gaze-evoked nystagmus was present on lateral Nevertheless, in a Danish nationwide study it was observed that only 35% of patients with a final diagnosis of ADEM fulfilled the above mentioned International Pediatric Multiple Sclerosis Study Group (IPMSSG) diagnostic criteria, suggesting that incomplete presentations exist [1] . ADEM is characterized by multifocal lesions involving asymmetrically the white matter which can be large and tumefactive, while CSF may be normal in as many as 60% of the cases [3] . In the differential diagnosis, it should be considered that lymphoma can also respond dramatically to corticosteroids, but the lesions J o u r n a l P r e -p r o o f are typically located in the basal ganglia or periventricular white matter and exhibit strong contrast enhancement [3] . In addition, no atypical lymphoid cells were detected in the CSF.

Neuro-Behçet's syndrome may present with scattered, asymmetric, subcortical white matter lesions, without cortical involvement [3] , but in this case the diagnosis was considered less likely due to the absence of orogenital ulcers or uveitis, therefore HLA testing was not performed. Finally, infectious diseases causing rhomboencephalitis (including Listeria monocytogenes) should also be considered, but in this case the lack of meningeal signs, pleocytosis and contrast-enhancing lesions render this diagnosis unlikely [4] .

It is interesting to note that the patient showed an increased serum level of IL-8, the primary chemokine involved in neutrophil recruitment in acute inflammation and viral infection whose levels were demonstrated to be very high in COVID-19-associated Guillain-Barré syndrome and encephalopathy [5] . IL-8 was not significantly increased in CSF.

Surprisingly, levels of IL-6, TNF-alfa and IL-10 were normal or even slightly reduced in serum, while in CSF both pro-inflammatory (IL-6, IFN-gamma) and anti-inflammatory cytokines (IL-10) were elevated with positive CSF/serum ratio, possibly indicating an unbalanced, but predominantly inflammatory process across the blood brain barrier.

Regarding the pathogenesis of this possible adverse event, immunological or genetic specificities of the patient may be relevant, as it was demonstrated for the role of HLA in other neurological autoimmune disorders [6] . Intriguingly, the patient here described had a previous history of recurrent herpes zoster, and it was shown that genetic variants in Toll-like receptor 3 (TLR3) -which are important in the recognition of foreign RNA -are associated with recurrence of zoster ophthalmicus [7] , while TLR polymorphisms significantly affect vaccine response and, possibly, the risk of adverse events [8] . CoV-2, including 6 cases of ADEM in the United States [9] , but no clinical description was published yet regarding these cases. One case of ADEM was recently reported following inactivated SARS-CoV-2 vaccine in China [10] .

Although the link between vaccination and the neurologic condition might have been just fortuitous, the possibility of a post-vaccine neuroinflammatory syndrome is very suggestive in this case. The potential implication is that particular caution may be needed in the vaccination of patients with previous history of post-infectious neurological disorders, but further prospective data is required before drawing definite conclusions. While waiting for large epidemiological data, it is important to keep in mind that a temporal association does not imply causation, and the experience so far is that SARS-CoV-2 vaccination is safe and should be recommended.

Ethical standards: The patient provided informed written consent for publication of this report. All procedures were performed in accordance with the institutional ethics committee (Comitato Etico Unico Regionale, CEUR) and the Declaration of Helsinki. The adverse event described herein was notified to the Italian Medicines Agency (AIFA). 

Implications of the International Paediatric Multiple Sclerosis Study Group consensus criteria for paediatric acute disseminated encephalomyelitis: a nationwide validation study

International Pediatric Multiple Sclerosis Study Group, International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions

Osborn's Brain: Imaging, Pathology, and Anatomy

Clinical Presentation and Cranial MRI Findings of Listeria monocytogenes Encephalitis: A Literature Review of Case Series

HLA and immunological features of SARS-CoV-2-induced Guillain-Barré syndrome

Associations between HLA and autoimmune neurological diseases with autoantibodies

Recurrent Herpes Zoster Ophthalmicus in a Patient With a Novel Toll-Like Receptor 3 Variant Linked to Compromised Activation Capacity in Fibroblasts

The role of Toll-like receptor 4 polymorphisms in vaccine immune response

ANA Investigates: Neurological Complications of COVID-19 Vaccines

Acute disseminated encephalomyelitis after severe acute respiratory syndrome coronavirus 2 vaccination: a case report