CLIPPERS and its mimics: evaluation of new criteria for the diagnosis of CLIPPERS

Abstract

ObjectiveTo evaluate the accuracy of the recently proposed diagnostic criteria for chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS).MethodsWe enrolled 42 patients with hindbrain punctate and/or linear enhancements (<3 mm in diameter) and tested the CLIPPERS criteria.ResultsAfter a median follow-up of 50 months (IQR 25–82), 13 out of 42 patients were CLIPPERS-mimics: systemic and central nervous system lymphomas (n=7), primary central nervous system angiitis (n=4) and autoimmune gliopathies (n=2). The sensitivity and specificity of the CLIPPERS criteria were 93% and 69%, respectively. Nodular enhancement ( ≥ 3 mm in diameter), considered as a red flag in CLIPPERS criteria, was present in 4 out of 13 CLIPPERS-mimics but also in 2 out of 29 patients with CLIPPERS, explaining the lack of sensitivity. Four out of 13 CLIPPERS-mimics who initially met the CLIPPERS criteria displayed red flags at the second attack with a median time of 5.5 months (min 3, max 18), explaining the lack of specificity. One of these four patients had antimyelin oligodendrocyte glycoprotein antibodies, and the three remaining patients relapsed despite a daily dose of prednisone/prednisolone ≥ 30 mg and a biopsy targeting atypical enhancing lesions revealed a lymphoma.ConclusionsOur study highlights that (1) nodular enhancement should be considered more as an unusual finding than a red flag excluding the diagnosis of CLIPPERS; (2) red flags may occur up to 18 months after disease onset; (3) as opposed to CLIPPERS-mimics, no relapse occurs when the daily dose of prednisone/prednisolone is ≥ 30 mg; and (4) brain biopsy should target an atypical enhancing lesion when non-invasive investigations remain inconclusive.

Increased Number of Perivascular CD20-Positive B Lymphocytes in the Neuropathology of CLIPPERS: Findings of 6 Patients from Mainland China

“…Brain MRI showed multiple punctuate and nodular gadolinium enhancement centered on the pons and cerebellar white matter in all patients. Consistent with previous reports, supratentorial Gd+ lesions were observed in more than half of our patients with CLIPPERS [4, 5]. On the other hand, atypical MRI features including nodular Gd+ (i.e., 3–9 mm) and large T2 hypersignal lesions in 3 patients in this series challenged the 2017 diagnostic criterion that gadolinium-enhancing nodules of CLIPPERS should be <3 mm in diameter, supporting the view that nodular Gd+ and large T2 hypersignal lesions should be considered as an atypical MRI feature more than an MRI red flag [4, 5].…”

“…Consistent with previous reports, supratentorial Gd+ lesions were observed in more than half of our patients with CLIPPERS [4, 5]. On the other hand, atypical MRI features including nodular Gd+ (i.e., 3–9 mm) and large T2 hypersignal lesions in 3 patients in this series challenged the 2017 diagnostic criterion that gadolinium-enhancing nodules of CLIPPERS should be <3 mm in diameter, supporting the view that nodular Gd+ and large T2 hypersignal lesions should be considered as an atypical MRI feature more than an MRI red flag [4, 5]. Notably, these nodular Gd+ lesions (i.e., 3–9 mm) were isointense/hyperintense on DWI and hyperintense on ADC maps, somewhat comparable to demyelinating lesions, which can help to differentiate CLIPPERS from other diseases such as lymphoma.…”

Area Postrema Syndrome: A Rare Feature of Chronic Lymphocytic Inflammation With Pontine Perivascular Enhancement Responsive to Steroids

“…However, other well-characterized diseases such as CNS lymphoma and some autoimmune diseases may mimic the clinical and radiological features of CLIPPERS. In addition, a definitive diagnosis of CLIPPERS is typically challenging owing to the absence of specific biomarkers and the lack of availability of pathological materials for most patients (3). In this study, we report on a patient who presented with intractable vomiting and hiccups (IVH) and area postrema (AP) lesion, but without serum aquaporin 4 antibodies (AQP4-IgG).…”

A Case Report of Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy Diagnosed After Long Term Diagnosis of Chronic Lymphocytic Inflammation With Pontine Perivascular Enhancement Responsive to Steroids

“…In the largest reported case series of GFAP astrocytopathy (4), relapses occurred in approximately 20% of patients during steroid taper, making it hard to differentiate GFAP astrocytopathy from CLIPPERS based on treatment response. However, it is proposed that relapse with atypical symptoms or radiological features should be a "red flag" to the diagnosis of CLIPPERS (5), and the patient in our case showed unusual relapse, which made the diagnosis revised. It is a pity that the blood or CSF sample of the patient's previous attacks was not available for antibody tests; therefore, it is difficult to conclude that the patient had GFAP astrocytopathy from the beginning.…”