CLIPPERS with chronic small vessel damage: more overlap with small vessel vasculitis?

In 2010, Pittock et al (1) published a seminal report on an entity they entitled ‘‘Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS).’’ After this, other reports of the entity quickly appeared (2Y22) (Table). A recently presented abstract reviews several more unpublished nonYEnglish language cases (19). Despite this, most reports have emphasized neuroimaging or clinical features and neuropathologists may not be familiar with the syndrome. As discussed in commentaries by Kira (23), and Keegan and Pittock (24), the essential feature of the disease is seen on magnetic resonance imaging (MRI) scans. These show punctate and curvilinear gadolinium enhancement that ‘‘peppers’’ the pons; the enhancement is almost always symmetric (with only 1 of 8 asymmetric in the original series [1] and 1 asymmetric in a recent case report [17]). Signal abnormalities often extend into contiguous cerebellum, brainstem, or even thalami and cerebral cortex, as emphasized by others after the original report (3, 4, 10). Simon et al (10) even suggested a nomenclature modification from ‘‘pontine’’ to ‘‘pontocerebellar’’ to reflect the more widespread features. Clinically, patients present with fluctuating brainstem symptoms and show response to steroids, although it has become increasingly clear that relapses are frequent (8) and immunosuppressive therapy often needs to be prolonged; nonsteroidal drugs such as cyclophosphamide, azathioprine, or rituximab have been required (18, 19). Stereotypic neuroimaging features were felt from the initial report to obviate the need for brain biopsy (1), leading to fewer histologic than clinical/ neuroimaging descriptions of the syndrome (Table). Nevertheless, neuropathologic features of CLIPPERS, even when biopsied from nonpontine sites (Table), have been fairly uniform. Most cases have shown perivascular and parenchymal lymphocytic collections associated with macrophages, microglia, and occasionally plasma cells or neutrophils; true tight granulomas and demyelination are not present (Table). When lymphocytic subsets have been phenotyped, CD4-positive cells were more frequent than CD8-positive lymphocytes or CD20-positive B cells (4, 10). The original authors carefully considered, and excluded on clinicalserologic-histologic grounds, several possible confounding conditions, particularly Bickerstaff brainstem encephalitis, neuroBeh0et disease, and Sjögren syndrome but also neurosarcoidosis, Langerhans cell histiocytosis, and paraneoplastic brainstem encephalitis (1). Bickerstaff brainstem encephalitis was thought unlikely because of the absence of antecedent viral infection or microglial clusters; several subsequent CLIPPERS patients have taken the opportunity to further provide negative testing for the GQ1b IgG antibodies coassociated with Bickerstaff brainstem encephalitis (5, 7, 14). Workup for Sjögren syndrome (when performed) has been negative, although, of the 5 patients in the series by Simon et al (10), one had biopsy-proven chronic lymphocytic sialadenitis and one had lymphocytic conjunctival infiltrates without granulomas. Salivary gland biopsy in the case reported by Biotti et al (11) was normal. Other unusual individual patients with otherwise radiographically typical CLIPPERS have manifested elevated IgE (4, 12), peripheral nerve abnormalities on nerve conduction studies (12), multiple sclerosis with onset of CLIPPERS after withdrawal of drug therapies (15, 21), temporal association with influenza vaccination (13), primary central nervous system lymphoma (9, 17), or even glioma-like biopsy features (6). Kira (23) has questioned whether CLIPPERS is a single disease or a syndrome and Keegan made the critical point that until specific markers are identified for CLIPPERS, it may be impossible to answer the question (24). We recently encountered a case that adds new information, that is, that small vessel injury, which was chronic in our case, can be seen in at least a subset of radiographically typical CLIPPERS patients. We put our case in the context of the fact that, since the original description emphasizing the absence of vasculitis (1), Simon et al (10) reported focal transmural lymphocytic inflammation in 3 of 5 cases and axonal injury in 3 of 3 assessable cases; the very recent report by Buttmann et al (16) showed overlap with angiitis based on digital subtraction angiography and biopsy findings. A 49-year-old woman with no significant past personal or family medical history and an absence of chronic hypertension presented with 3 weeks of left facial numbness, dysphagia, dysarthria, and right upper extremity weakness associated with occipital headache. Neurologic examination further demonstrated decreased sensation in the V1 to V3 distribution of the left cranial nerve V, 4/5 weakness in the right upper extremity, and a mildly ataxic gait. Magnetic resonance imaging scan of the brain with and without gadolinium contrast demonstrated a homogeneously enhancing left cerebellopontine angle mass (thought to be meningioma) and abnormal T2 hyperintensities ‘‘peppering’’ the pons associated with enhancement (Fig. 1A). Cerebrospinal fluid (CSF) showed lymphocytic pleocytosis (94% lymphocytes), normal glucose, normal protein, and normal cytology with smalland medium-sized lymphoid cells. Workup was negative for syphilis (CSF VDRL), Lyme disease, viruses by CSF polymerase chain reaction (PCR) testing (cytomegalovirus, herpes simplex, HHV-6, varicella zoster, JC viruses), human immunodeficiency virus 1/2, and fungi. Serologic testing was negative for the following antibodies: anti-DNA, anti-centromere, antiYN-RNP, anti-Smith, anti-SSA, anti-SSB, anti-nuclear, C-antineutrophil, P-anti-neutrophil, rheumatoid factor, neuromyelitis optica (repeated twice), and paraneoplastic panel. Also negative or normal were tests for lupus anticoagulant, Russell viper venom, angiotensin converting enzyme, and vitamin B12. Complement components (C1 esterase inhibitor, C3a, C3c, C4, C5a, complement 2) were