Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is an inflammatory disease of the central nervous system that predominantly affects the brainstem. Apart from corticosteroids, there are few reported treatment options for CLIPPERS, and there is no standard therapy. A 77-year-old man presented with diplopia that had persisted for 5 months. Dysarthria and numbness of the distal right upper extremity and right lips were also observed. Brain magnetic resonance imaging (MRI) revealed a hyperintense area around the brainstem. Symptoms were relieved immediately following intravenous methylprednisolone (IVMP) administration. However, after gradual tapering of oral prednisolone to 5 mg/day, the symptoms relapsed, and brain imaging revealed that the condition had worsened. Intravenous immunoglobulins (IVIg) were administered for recurrence, with no clinical improvement. After each IVMP treatment, the patient recovered promptly. Based on the patient’s symptoms and characteristic MRI findings, exclusion of other diseases, and the significant efficacy of corticosteroids, he was diagnosed with CLIPPERS. There was no recurrence at a maintenance prednisolone dose of 8 mg/day. IVIg had a poor effect on the acute phase of CLIPPERS symptoms. Compared with other immunosuppressants, IVIg is less effective in suppressing the relapse of CLIPPERS.

© 2023 The Author(s). Published by S. Karger AG, Basel

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) was first reported by Pittock et al. [1]. The main lesion in CLIPPERS occurs in the brainstem, but it may progress to the cerebellar peduncle, cerebellar hemisphere, thalamus, basal ganglia, cerebral white matter, and spinal cord. Thus, patients with CLIPPERS can present with various symptoms, including diplopia, nystagmus, dysarthria, dysphagia, paraplegia, and the bladder-rectal disorder. Brain magnetic resonance imaging (MRI) usually reveals nodular or punctate gadolinium enhancement in the pons [1].

The pathological characteristic of CLIPPERS is cellular infiltration (mainly comprising T cells) into the perivascular space. Given the efficacy of corticosteroids in treating CLIPPERS, its etiology has been attributed to immunological mechanisms and inflammatory reactions [1].

A biomarker specific to CLIPPERS has not yet been identified. Furthermore, since there is currently no consensus on the diagnostic criteria for CLIPPERS, it is diagnosed by referring to dysfunctions of the brainstem, cranial nerves, and cerebellum after excluding other diseases [2]. Additionally, there is no standard treatment regimen for CLIPPERS. Corticosteroids are the first-line drugs for CLIPPERS; however, symptoms recur easily if the corticosteroid dose is reduced or a relatively high dose is not administered for long term. In an effort to minimize the corticosteroid dosage and avoid side effects, many physicians have tried to combine corticosteroids with other immunomodulators.

Currently, there is only one report on intravenous immunoglobulin (IVIg) administration for CLIPPERS, and the efficacy of IVIg is not fully known [3]. Herein, we report the use of IVIg for relapse in a patient with CLIPPERS after tapering oral prednisolone.

This case report is based on the CARE Checklist. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see www.karger.com/doi/10.1159/000529121).

A 77-year-old man with no medical history presented with diplopia that had persisted for 5 months. Neurological examination revealed dysarthria and numbness of the distal right upper extremity and right lips. The patient’s clinical course is summarized in Figure 1.

The clinical course of the patient. Day 0 indicates the first hospitalization day, when initial brain MRI was performed. IVMP, intravenous methylprednisolone; IVIg, intravenous immunoglobulins.

Brain MRI on day 0 revealed a hyperintense area around the brainstem that included the cerebellar peduncles and cerebellum (Fig. 2a–c). However, the blood test results were normal. In parallel, cerebrospinal fluid (CSF) analysis, including standard biochemistry, oligoclonal band analysis, cytology, and Herpesviridae and cytomegalovirus tests, revealed no significant findings except for a mildly elevated CSF protein level (92.8 mg/dL). Serum and CSF soluble interleukin-2 receptor levels were also within normal ranges. The patient was seronegative for the antinuclear, anti-ribonucleoprotein, anti-SS-A, anti-SS-B, anti-neutrophil cytoplasmic, and anti-ganglioside antibodies. Whole-body computed tomography and positron emission tomography findings were also normal. Because the lesion was almost entirely localized in the brainstem, a biopsy could not be performed.

Brain magnetic resonance imaging (MRI) in a patient with chronic lymphocytic inflammation and pontine perivascular enhancement responsive to steroids (CLIPPERS). a, b Initial brain MRI axial fluid-attenuated inversion recovery (FLAIR) images show symmetric hyperintense areas, mainly in the midbrain, pons, basal ganglia, medulla oblongata, and superior and middle cerebellar peduncles. Swelling of the hyperintense areas and punctate dispersal lesions, which are characteristic of CLIPPERS, are not evident. c Initial brain MRI axial gadolinium-enhancing T1-weighted images show strong gadolinium enhancement in the pons. d, e Brain MRI axial FLAIR images taken after intravenous methylprednisolone (IVMP) treatment show significant improvement in the hyperintense areas and swelling in the brainstem. f Brain MRI axial gadolinium-enhancing T1-weighted images taken after IVMP treatment show improvement in the irregular gadolinium enhancement.

Intravenous methylprednisolone (IVMP) was administered from days 10–12 due to progression of symptoms such as dysarthria and gait ataxia. IVMP was exceptionally effective, and the symptoms were relieved immediately, although mild ataxia persisted. The imaging findings were also improved by IVMP (Fig. 2d, e). A second IVMP course was administered 14 days after the first course to resolve the mild ataxia. The ataxia disappeared almost completely, and we succeeded in gradually tapering the dose of oral prednisolone to 5 mg/day after the second IVMP course. However, 1 month after the first IVMP administration, dysarthria and numbness recurred in the distal upper extremities.

IVIg was administered for the recurrent symptoms with no clinical improvement; furthermore, it led to loss of consciousness and dysfunction of the vestibulo-ocular reflex. The patient recovered promptly after the third course of IVMP, and oral prednisolone was gradually tapered over a period of 10 months. Based on the patient’s symptoms and characteristic MRI findings, exclusion of other diseases, and the significant efficacy of corticosteroids, we diagnosed him with CLIPPERS. Although slight ataxia persisted, there was no recurrence of symptoms for 10 months with a maintenance dose of 8 mg/day of prednisolone.

The administration of a maintenance prednisolone dose of 8 mg/day inhibited the recurrence of symptoms of CLIPPERS in our patient. Additionally, our observations show that IVIg administration did not produce any clinical improvement.

IVIg has many immunomodulatory actions, such as inhibition of complement activation, modulation of antibody production, neutralization of autoantibodies via anti-idiotypic antibodies, and interference with co-stimulatory molecules [4]. Because IVIg suppresses excessive inflammation by modulating the immune network, it is administered to many patients with autoimmune neurological diseases.

Corticosteroids elicit anti-inflammatory effects by translocating into the nucleus of leukocytes via intracellular glucocorticoid receptors. Corticosteroids passively cross the blood-brain barrier, block the promoter sites of pro-inflammatory genes (such as those encoding interleukins) [5], and recruit transcription factors to promoter sequences of genes coding for anti-inflammatory products in leukocytes [6].

The transmural infiltration of lymphocytes, mainly CD3-positive or CD4-positive cells, into the perivascular region is the key pathological hallmark of CLIPPERS [1, 7, 8]. Recent reports suggest that the perivascular infiltration of CD20-positive B lymphocytes is another pathological characteristic of CLIPPERS and is the first sign of its possible transformation into a lymphoma [9, 10]. The detailed mechanism of how white blood cells (mainly T cells) infiltrate the perivascular space of the brainstem is currently unknown. However, various cytokines are thought to play a role in the absence of the histological features of vessel-wall destruction secondary to fibrin thrombi, fibrinoid necrosis, and leukocytoclasia, which represent vasculitis [8, 11]. Thus, IVIg may be less effective than corticosteroids because it cannot cross the blood-brain barrier into the brain tissue and control the function of lymphocytes outside undamaged blood vessels [12].

Prolonged inflammation leads to neuro-axonal injury, which causes atrophy and disability [8]. Rapid abatement of the inflammatory reaction is important for the treatment of CLIPPERS. Steroid therapy (especially IVMP) is a key treatment strategy for CLIPPERS, particularly during the acute and chronic phases. When the steroid dosage must be reduced to counteract its side effects, a combination of other immunosuppressants, such as azathioprine [3], hydroxychloroquine [13], interferon beta-1a [14], methotrexate [15], and cyclophosphamide [15], may be effective. In fact, methotrexate (15 mg/week), azathioprine (150 mg/day), hydroxychloroquine (400 mg/day), or cyclophosphamide (1 g/month) are the currently recommended immunosuppressants that should be initiated before tapering steroids [15]. Furthermore, cyclophosphamide and methotrexate have been reported to prolong the time to relapse [16].

Gabilondo et al. [3] have presented the only report on IVIg administration for the treatment of CLIPPERS; they stated that IVIg was not as effective as azathioprine. In their case, IVIg was administered for recurrent symptoms after the dose of oral prednisolone was tapered from 10 mg/day to 5 mg/day; however, the cerebellar symptoms persisted after the last dose of IVIg. When the prednisolone dose was increased to 30 mg/day, the symptoms disappeared. Gabilondo et al. [3] eventually succeeded in keeping the patient asymptomatic with maintenance doses of 5 mg/day of prednisolone and 150 mg/day of azathioprine (which was administered to reduce the quantity of prednisolone required). Our case study corroborated these findings in that IVIg showed no efficacy during the acute phase. Thus, our results highlighted the efficacy of prednisolone as a first-line drug for CLIPPERS and of azathioprine for relapse and progression.

Although IVIg has fewer side effects than steroid therapy, we recommend against IVIg administration to patients with CLIPPERS, at least during the acute phase, as it is less effective for suppressing relapse than other immunosuppressants. However, IVIg may effectively control lymphocyte infiltration into the central nervous system via an intravascular mechanism, thereby preventing disease recurrence. The current case illustrated successful long-term management of CLIPPERS using a relatively low dose of oral prednisolone (8 mg/day, tapered to 5 mg/day) after IVIg.

In conclusion, IVIg had little effect on the acute-phase symptoms of CLIPPERS. Further research is required to evaluate the long-term effects of IVIg therapy.

All procedures were performed in accordance with the World Medical Association Declaration of Helsinki. Written informed consent was obtained from the patient prior to the study. Ethical approval was obtained from the Ethics Committee of the Asahikawa Red Cross Hospital, Japan (approval number: 201722-3). Written informed consent was obtained from the patient for publication of this case report and any accompanying images.

The authors have no conflicts of interest to declare.

The authors have not received funding.

Takumi Tsuchida drafted the manuscript and collected the patient’s data. Shigehisa Ura and Ichiro Yabe interpreted the data and edited the manuscript. Takumi Tsuchida, Shigehisa Ura, and Ichiro Yabe have read and approved the final manuscript.

All data generated or analyzed during this study are included in this article and its online supplementary material. Further inquiries can be directed to the corresponding author.

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