Introduction

SARS-CoV-2 is known to cause Coronavirus Disease 2019 (COVID-19), which has extremely variable clinical manifestations ranging from asymptomatic carriers to seriously ill patients with fever, breathing difficulty, acute respiratory distress, and multiple organ complications, eventually leading to death.

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is an inflammatory central nervous system (CNS) disorder, prominently involving the brainstem and, more importantly, the pons with variable supratentorial or spinal cord involvement with immune-mediated or other inflammatory pathogenesis [1].

Case report

A 71-year-old man with no previous medical history was diagnosed with COVID-19 pneumonia in March 2020. Chest computed tomography (CT) indicated mild bilateral interstitial pneumonia, and real-time polymerase chain reaction on nasopharyngeal swab for SARS-CoV-2 returned positive. The patient needed no oxygen therapy. He was treated with hydroxychloroquine, azithromycin, and cefexime. The infection outcome was good, and the patient had a full recovery without sequels in a month.

Three months later, the patient sought medical attention for a subacute onset of diplopia in the left gaze, general malaise, and fatigue. Neurological evaluation revealed diplopia in the left gaze with left abducens nerve deficit but no other extraocular muscle deficits or other focal signs. Non-contrast head CT was unremarkable, while brain MRI was characterized by bilateral fluid-attenuated inversion recovery (FLAIR) hyperintensities with punctate, perivascular, and confluent post-gadolinium enhancement in the pons, mesencephalon, hypothalamus, internal capsules, and right hippocampus (Fig. 1).

Fig. 1
figure 1

Pre-treatment brain MRI was characterized by bilateral fluid-attenuated inversion recovery (FLAIR) hyperintensities in the pons, mesencephalon, hypothalamus, internal capsules, and right hippocampus (A) with punctate, peppering, perivascular, and confluent post-gadolinium enhancement in these sites (B-C-D). After treatment, brain MRI demonstrated partial regression of FLAIR hyperintensities (E) with almost disappearance of post-gadolinium enhancement (F-G-H)

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Cerebrospinal fluid (CSF) analysis was normal (2 cells/µL), with no evidence of oligoclonal bands or atypical cells. The screening panel for autoimmune and infectious aetiologies was negative. Epstein-Barr virus viral capsid antigen IgG and IgM antibodies were negative on serum. Whole-body contrast-enhanced CT was unremarkable. Partial spontaneous remission of symptoms occurred within few weeks, persisting only mild fatigue but no diplopia or general malaise. The patient was referred for a stereotactic temporal lobe brain biopsy, which showed non-specific chronic perivascular lymphocytic inflammation (Fig. 2). No therapy was prescribed.

Fig. 2
figure 2

A, B, C Histological slides of formalin-fixed paraffin-embedded (FFPE) tumor specimen haematoxylin and eosin (H&E) stained (A, B 40×, C 20 ×). Figures show brain tissue with inflammatory cell infiltration made by small lymphocytes mostly with perivascular arrangement. D–G Histological slides of FFPE tumor sample immunostained with anti-CD3 (D, F, G) and anti-CD20 (E) antibodies. Inflammatory cell component is made by small T and B lymphocytes equally represented. They show perivascular distribution (F, G) but they are also present as isolated or as small intraparenchymal clusters (D, E)

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At three-month follow-up, the patient felt well, reporting only mild fatigue. Clinical examination showed bilateral distal leg apallesthesia, and mild left leg drift on the Mingazzini maneuver, which the patient was not aware of. A new brain MRI demonstrated an extension of FLAIR hyperintensities with punctate, perivascular, and confluent post-gadolinium enhancement, especially in the pons. He was treated with intravenous high-dose methylprednisolone with almost complete enhancement regression on MRI and then with daily oral steroid tapering and monthly cycles of intravenous cyclophosphamide with persistent clinical and neuroradiological stability.

Collected data were suggestive of CLIPPERS with diffuse bilateral supratentorial involvement.

Discussion

Apart from respiratory symptoms, COVID-19 can be associated with a wide array of neurological manifestations, involving the central and the peripheral nervous systems [2].

Neurological involvement depends on direct cytopathic effects mediated by SARS-CoV-2 infection and the indirect effects secondary to the infection-related inflammatory response [3]. Neuropathologic findings in patients with SARS-CoV-2 infection include hypoxic mechanisms, endovascular microthrombi, microbleeds, necrosis, diffuse cerebral edema, gliosis with diffuse activation of microglia and astrocytes, causing various stages of inflammation with cellular components infiltrating into perivascular areas of the brain [3].

In reaction to SARS-CoV-2 infection, the immune system can produce high cytokine levels [4], leading to a hyperinflammatory response and T-cell activation [4]. Such an inflammatory response can cause blood-brain barrier damage as well. CSF analysis of COVID-19 patients [5] showed differentiated monocytes and exhausted T-cells with consequent broad clonal T-cell expansion.

CLIPPERS is a T-cell-mediated disorder with an infiltrate characterized by an abundance of CD4+ T-cell infiltration with less CD8+ and CD20+ cells, without demyelination [6, 7] with relative widespread perivascular inflammation and postinflammatory axonal injury [7]. T-cell broad clonal expansion is present in CLIPPERS disease.

CLIPPERS aetiology is unknown. Autoimmunity development is multifactorial and complex, requiring time to evolve [8]. Post-infectious phenomena tend to occur usually few weeks following infection, but they can become clinically evident months or years after the triggering event [8].

A several months delayed autoimmune disease onset has already been described in different conditions, among the others CLIPPERS [9] and Mystenia Gravis [10].

The overall process leading to this condition may have been triggered by COVID-19 infection in our 71-year-old patient, without any previous immunological disease.

CLIPPERS is so far considered an idiopathic rare disease. This is the first report after COVID-19 disease with a diffuse involvement of brainstem and supratentorial regions. Even though a single case is not enough to suggest a causal link, future reports could support this association.