Relapsing Encephalomyelitis After COVID-19 Infection and Vaccination

Discussion

We report here a rare case of relapsing encephalomyelitis occurring after SARS-CoV-2 infection and subsequent COVID-19 vaccination. The unique radiologic and clinical findings of our patient could fit with a neuroinflammatory and vasculopathic condition such as the syndrome known as chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). CLIPPERS is a T cell–mediated disorder characterized by widespread punctate perivascular inflammation that is exquisitely responsive to steroid treatment.² On MRI it appears to pepper the pons, but can also involve the supratentorial parenchyma and spinal cord via perivascular inflammation. It can also be associated with an allergic trigger, with several cases demonstrating persistently elevated serum IgE levels.³ Our patient also demonstrated multiple relapses as his corticosteroids were weaned to 20 mg daily, and multiple reports also observed no relapses when chronic corticosteroid dosages were maintained above 20 mg daily.⁴

However, there has been an absence of laboratory biomarkers to recognize CLIPPERS as a specific disease entity, and given the variability in presentation, multiple alternative conditions may mimic the radiologic and clinical findings. Notably, even the latest proposed diagnostic criteria for CLIPPERS, can be fraught with misdiagnoses. A subsequent case series applying these criteria found a misdiagnosis rate of 31% (13/42 cases), with the most common misdiagnosis being CNS lymphoma, followed by primary CNS angiitis.⁶ This raises the question of whether CLIPPERS is indeed a true isolated disease as opposed to a syndrome with overlap across multiple conditions. As such, without a biomarker to confirm a diagnosis, one must carefully exclude these other conditions before diagnosing CLIPPERS and be vigilant in monitoring for conditions that may cause such a clinicoradiologic appearance over time.

Apart from respiratory symptoms, SARS-CoV-2 infection can be associated with a variety of classic autoimmune neurologic manifestations, involving either the central or peripheral nervous system. A literature review identified 173 additional cases of CNS neuroinflammatory disease after either SARS-CoV-2 infection or vaccination, with 65 cases of transverse myelitis, 30 cases of optic neuritis, and 78 cases of encephalomyelitis (Table).^7,-,15 Most of these cases occurred within 2–3 weeks of either the infection or vaccination as with our patient, although the vast majority of cases in the literature (>70% of each phenotype) occurred in association with infection. Transverse myelitis and encephalomyelitis tended to occur closer to the time of vaccination or infection. Some cases of encephalomyelitis occurred as late as 1 month from the time of COVID-19 or vaccinations, and the ages of patients were primarily distributed in 2 groups, with 20 of 59 patients under age 16 years and 30 of 59 patients being 40 years or older. On average, optic neuritis tended to occur later than transverse myelitis and encephalomyelitis. Notably, among the cases associated with vaccination, 60% (26/43) occurred in the setting of a positive MOG or AQP4 antibody, and these patients were eventually diagnosed with unmasking of MOGAD or NMOSD. Regardless of the type of demyelinating event, all events were far more likely (73% of transverse myelitis, 77% of optic neuritis, and 74% of encephalomyelitis) to occur in association with SARS-CoV-2 infection in comparison to vaccination.^7,-,18 Our case was unusual in the degree of brain and spinal cord involvement, particularly the perivascular distribution of the inflammation, as well as the insidious degree of inflammation, with symptoms progressing over several months. Vascular complications and endothelial dysfunction have become increasingly identified in COVID-19, possibly mediated by SARS-CoV-2 targeting angiotensin-converting enzyme 2 receptors that are expressed in multiple organs, including the brain, although the exact pathogenesis remains unknown.¹⁹

Our patient's steroid dependency and relapsing course suggest an unmasking of an underlying CNS neuroinflammatory condition, rather than due to direct SARS-CoV-2 CNS infection or a vaccine-related adverse event. Similar courses have been identified with post–SARS-CoV-2 infection or COVID-19 vaccination demyelinating events in patients who were eventually identified to have MS, MOGAD, and NMOSD.²⁰ The initial neuroimaging observations of multifocality and innumerable punctate enhancement in the pons, cerebellum, and spinal cord may suggest a vasculocentric neuroinflammatory process triggered either by systemic immune reactions to SARS-CoV2 epitopes or overactivation of inflammatory responses in a genetically susceptible subject. Similar cases posit that the blood-brain barrier breakdown secondary to endothelial inflammation could facilitate antibodies to initiate and sustain the disease process, with subsequent epitope spreading leading to a relapsing course.²¹ This hypothesis could be supported by the temporary nature of the patient's matched oligoclonal bands on his initial CSF testing. Despite unrevealing biomarkers for a specific disease entity, the recurrent nature of his relapses with weaning of his steroid treatment necessitated a steroid-sparing agent. We ultimately chose mycophenolate mofetil because it can treat a broad spectrum of neuroinflammatory diseases.

Temporal associations of neurologic conditions with vaccinations and/or infections do not prove causality despite previous reports of such sequelae. Vaccines containing SARS-CoV-2 antigens may enhance autoimmunity by mechanisms including polyclonal activation, epitope spreading, or molecular mimicry in susceptible individuals.²² Our case highlights that the resulting inflammation may be insidious and extensive, though treatable. A literature search of post–COVID-19 vaccination-related CNS complications, as reported in the Vaccine Adverse Event Reporting System, found a total of 185 cases of either transverse myelitis or optic neuritis in association with the Pfizer, Moderna, and Janssen vaccines, underscoring its relative rarity, especially in comparison to approximately 5.2 billion total vaccine doses given by these manufacturers in that time frame (August 27, 2021).²³ Alvarez et al.²⁴ published a global report of confirmed postvaccination optic neuritis from December 2020 to June 2021 and identified a total of 55 cases, finding no difference in severity or clinical outcomes by the type of vaccine, although most cases (38/55) were associated with the AstraZeneca vaccine. Other studies have posited that there may be an association between the AstraZeneca vaccine and neurologic autoimmunity, possibly attributable to the viral vector of this vaccine, although it must be noted that these studies did not demonstrate an increase in the incidence of such events after the roll out of the mass vaccination program.^16,-,18 Weighing the results of our findings and those in the literature, as COVID-19 constitutes a life-threatening infection in some patients, we feel that the benefits of vaccination outweigh the extremely rare event of unmasking an immune-related condition or leading to another neuroinflammatory event.

Our case represents a rare case of relapsing encephalomyelitis with the appearance of vasculocentric appearance or CLIPPERS-like radiologic findings after a one-two-punch of SARS-CoV-2 infection followed by COVID-19 vaccination. Prompt treatment of these conditions and understanding when patients may require long-term immune therapy may help prevent accrual of neurologic disability.