Optic neuromyelitis after vaccination against SARS-CoV-2

Background

Neuromyelitis optica (NMO) is defined as a chronic autoimmune inflammatory and demyelinating disease of the central nervous system (CNS)1 characterised by acute optic neuritis and transverse myelitis2 and associated with significant morbidity and disability.3 NMO has a worldwide prevalence of 0.51 and 4.4 cases per 100 000 inhabitants,1 with a female to male ratio of 10:1. Several studies have found a significant association between human leucocyte antigen (HLA) alleles and NMO,2 with class II HLA-DQB1*03:01 alleles showing the most important association with increased risk of NMO in a Mexican cohort.1 NMO may be a monophasic or relapsing disease, with 80%–90% of patients having a relapsing course.4 According to the 2015 diagnostic international consensus for neuromyelitis optica spectrum disorder (NMOSD), diagnosis requires the involvement of one of the six core clinical CNS regions (optic nerve, spinal cord, area postrema, brainstem, diencephalon or cerebellum) and detection of serum aquaporin 4 (AQP4)-IgG, preferably by cell-based assay (CBA).5 Since AQP4-IgG is an IgG₁ isotype antibody, it can activate the classic complement cascade4 so that AQP4-IgG binding to astrocytic AQP4 leads to complement activation and granulocyte and lymphocyte infiltration. Interleukin 6 (IL-6) may also drive disease activity by promoting plasmablast survival, reducing blood–brain barrier (BBB) integrity, and enhancing proinflammatory T lymphocyte differentiation and activation.6 Despite this, AQP4-IgG production might be an epiphenomenon, without direct pathogenic meaning, but as a result of a secondary autoimmune sensitisation to autoantigens.4 Several cases of inflammatory diseases of the CNS have been reported after vaccination against SARS-CoV-2, most frequently acute disseminated encephalomyelitis (ADEM).7 Cases of NMOSD, mostly AQP4+, have also been reported after vaccination with an inactivated vaccine.8 9 We report the case of a woman in her 40s who presented with longitudinally extensive transverse myelitis (LETM) following AstraZeneca SARS-CoV-2 vaccination and was treated with an IL-6 inhibitor. There is no proven association and research is needed to establish whether optic neuromyelitis is related to vaccination; this is a single case report from which no conclusion can be drawn.

Case presentation

A previously healthy woman in her 40s received a dose of the non-replicating vector vaccine AZD1222 against SARS-CoV-2 a day before the onset of symptoms. She developed an intense occipital headache which improved with paracetamol, as well as progressive weakness of the lower limbs until she was incapable of walking 10 metres without support, but without sensory level, bladder or bowel involvement. She went to see a neurosurgeon, who asked for a first MRI of the brain, not including the spinal cord. This found evidence of lesions in the juxtacortical and deep subcortical white matter and corpus callosum on axial T2 Fluid Attenuated Inversion Recovery (FLAIR) sequence (figure 1A). Additionally, there were findings of lesions in both the cerebral peduncles on axial T2 FLAIR sequence with fat suppression (figure 1B) and hyperintense lesions in the splenius of the corpus callosum (figure 2). Treatment was started with oral prednisone 20 mg daily for 20 days, showing complete remission of symptoms. Two months later, after discontinuation of oral prednisone, she presented with progressive quadriplegia and loss of sensitivity in all modalities, with a sensory level at C4 and bladder and bowel involvement. She was admitted to the neurology service. A new MRI was performed and showed an increase in the number and size of white matter lesions in both the cerebral hemispheres (figure 3A), and interestingly a decrease in the number of lesions in both the cerebral peduncles on FLAIR T2 sequence without fat suppression (figure 3B). Furthermore, significant longitudinally extensive signal alterations were observed in the cervical and dorsal spinal cord with increased thickness on sagittal Fast spin echo (FSE) imaging T2 sequence (figure 4). Routine blood tests were within standard limits, lumbar puncture showed no alterations and oligoclonal bands were negative. Therefore, an autoimmune-mediated LETM was suspected. We gave her an acute treatment with methylprednisolone at a dose of 1000 mg/day for 5 days, followed by intravenous immunoglobulin at a dose of 400 mg/kg/day for 5 days. The antinuclear antibodies, classic antineutrophil cytoplasmic antibody (c-ANCA) and perinuclear antineutrophil cytoplasm antibody (p-ANCA), anti-Ro and anti-LA antibodies, were negative, while the AQP4-IgG antibody was positive by CBA. With these findings, the patient met the diagnostic criteria for NMO AQP4+ and a diagnosis of NMO was made. We decided on maintenance therapy with the IL-6 inhibitor tocilizumab.

Differential diagnosis

Differential diagnoses included multiphasic ADEM, myelin oligodendrocyte glycoprotein-associated disease (MOGAD), NMO and NMOSD. In addition, patients with NMOSD can frequently have other autoimmune diseases or autoimmune epiphenomenon based on a history of postimmunisation onset and adequate therapeutic response to glucocorticoids observed after the initial attack, leading us to suspect an immune-mediated disease.

On the first day of admission, a new MRI was performed in search of new demyelinating lesions, finding new white matter lesions and LETM at the cervical level, which explained the characteristics of the spinal cord syndrome that the patient presented. However, although all our differential diagnoses could cause LETM, MOGAD is characterised by lesions affecting the lower segments, with preferential involvement of the thoracolumbar and conus medullaris segments. While there was an adequate clinical response to glucocorticoids at the first attack, lesions seen on the initial MRI persisted; in MOGAD, they tend to disappear.10 11

A lumbar puncture was performed, which was normal, confirming it was not an infectious aetiology. Even if we expected a degree of pleocytosis in both NMO and MOGAD, normal cerebrospinal fluid cellularity does not rule this out.4 10 Oligoclonal bands were negative, supporting the hypothesis that it was a disease with peripheral production of antibodies and not intrathecal, as in multiple sclerosis.12

Although the patient did not present clinical or laboratory characteristics of a systemic disease, the antinuclear antibodies, c-ANCA, p-ANCA, anti-Ro and anti-LA antibodies, were negative, and AQP4-IgG antibody was positive by CBA. With these findings, the diagnosis of NMO was made 5as the patient met the diagnostic criteria for NMO AQP-4+ and for the diagnosis of ADEM, exclusion of other causes is required.13

There is no proven association and research is needed to establish whether optic neuromyelitis is related to vaccination; this is a single case report from which no conclusion can be drawn.

Treatment

We indicated an acute medical treatment with intravenous methylprednisolone 1000 mg daily for 5 days, followed by intravenous immunoglobulin at a dose of 400 mg/kg/day for 5 days, as well as immunosuppressant maintenance therapy with the IL-6 inhibitor tocilizumab at 8 mg/kg once, administered every 4 weeks.

Follow-up

At 3-month follow-up, the patient showed improvement in motor and sensory functions, with sensory level at T10 and recovery of upper extremity strength against gravity and trace muscle activation in the distal right lower extremity. A follow-up MRI is planned in addition to a close monitoring of her clinical course.