Need for prolonged immunosupressive therapy in CLIPPERS-a case report

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) was first described in 2010 by Pittock et al. [1] They described eight patients presenting with similar clinical and MRI-findings: sub-acute diplopia, gait ataxia and punctiform gadolinium enhancement “peppering” the pons. As distance from the pons increased, lesions became less numerous. Other accompanying clinical symptoms included dysartria, dysesthesia of the face and finally paraparesis and urine retention. The main manifestations of CLIPPERS are summarized in Table 1.

Since 2010, several new possible cases have been published (Table 2). Despite extensive diagnostic work-up so far, the pathogenesis had not been elucidated. An immune-mediated process has been postulated on the basis of the establishment of T-cell predominant infiltrates of the affected brain lesions and radiologic resolution of the lesions upon immunosuppressive treatment.

All patients described so far (Table 2) were treated with intravenous and subsequent oral corticosteroids with gradually improvement of the clinical condition. Unfortunately, almost all patients relapsed following glucocorticoid tapering and required maintenance glucocorticoid or other immunosuppressive therapy. We present this new case of CLIPPERS to underline the importance of introducing maintenance immunosuppressive therapy after glucocorticoid treatment and the need to closely monitor for side effects during this prolonged therapy.

A 63-year-old male presented with a five week history of double vision, rotational vertigo with tinnitus, progressive gait imbalance and apathy. One month earlier he had undergone tibia osteotomy surgery because of varus deformity. He used no medication. He had a history of alcohol abuse and did not smoke. He had no history of international traveling. There was no family history of neurological disease.

Except from postsurgical findings at his right knee general physical examination was normal. The blood pressure was 130/70 mmHg, pulse rate 78/minute, and he was afebrile. On initial neurological examination he was alert and cognitive functions were normal. His speech was dysarthric, chantering. Examination of the cranial nerves revealed a right abducens nerve paresis and an upbeat nystagmus. The pinprick sensation in the V3 distribution of the trigeminal nerve was symmetrically decreased. Other cranial nerve functions were normal. Strength was normal in muscles of the arms and legs and sensation was preserved. Vibration sense on both legs was diminished. The arms and legs on both sides showed atactic, dysmetric movements. Tendon reflexes were normal and the plantar reflexes were normal. He had an impressive gait ataxia and he was unable to walk without aid. His gait was further impaired due to the recent surgery.

As he was known with alcohol abuse, Wernicke’s syndrome was firstly assumed and he was promptly treated with intravenous thiamine.

However, the neurological condition of the patient further deteriorated. He developed difficulties swallowing and became incontinent for urine. His gait ataxia worsened and a slight spastic paraparesis developed.

In this patient with progressive cranial nerve dysfunction with ocular signs, ataxia and pyramidal tract signs, brain stem dysfunction with a variety of causes should be considered. The broad differential diagnosis included CNS lymphoma, primary CNS vasculitis, demyelinating diseases, paraneoplastic syndromes, sarcoidosis, tuberculosis and neurolues. The diagnosis of Wernicke’s syndrome was rejected as the clinical picture deteriorated and the pre-treatment thiamine level showed to be 118 nmol/L (normal range: 60–200 nmol/L).

MRI T2-weighted and fluid-attenuated inversion recovery (FLAIR) images of the brain demonstrated distinct hyperintensity abnormalities consisting of punctuate lesions in the pons, brachium pontis and cerebellum (Figure 1A). The lesions were gadolinium enhancing but had no significant mass effect.

Blood levels of C-reactive protein, ESR, Vit B12 and Angiotensine Converting Enzyme levels were normal. Liver parameters were normal except for a slightly elevated gamma-GT of 65 U/L (reference <55 U/L). Thyroid functions were normal.

Antinuclear antibodies, double-stranded DNA antibodies, extractable nuclear antigens, antineutrophil cytoplasmic antibodies and antineuronal antibodies (anti-Hu, anti-Yo, anti-Ri, anti-Tr, anti-amphiphysine, anti-CV2 and anti-Ma2) were not detected.

Serologic tests on Syphilis, HIV, Borrelia Burgdorferi, anti-DNase B and anti-streptolysine titer were negative. Auramine staining and PCR for M.tuberculosis complex DNA were negative.

Analysis of the cerebrospinal fluid showed a raised protein level (protein 1.3 g/L, reference range 0.2–0.5) and a slight pleiocytosis (6,0 E06, reference <5 E06). Red cell count and glucose levels were normal. The IgG index was marginally increased (0.62, reference range 0.3–0.6), no oligoclonal bands were found. Cytology study reports showed normal amounts of lymphocytes, granulocytes monocytes and erythrocytes. Malignant cells were not detected.

Cultures of urine, blood and cerebral spine fluid were all negative.

MRI of the spinal cord and CT scanning of the chest, abdomen and pelvis showed no abnormalities. Total body PET CT scanning was negative for malignancies.

On the base of the typical MRI findings and exclusion of other possible diagnoses the diagnosis of CLIPPERS was presumed. The patient was treated with 1000 mg intravenous methylprednisolone daily for a period of three days, followed by oral prednisolone 80 mg per day. Within a week from starting treatment the symptoms gradually improved and on MRI two weeks from starting treatment the pontine lesions decreased in number and intensity (Figure 1B).

Maintenance immunosupressive therapy by oral prednisolone 80 mg per day was continued, adding methotrexate 2.5 mg weekly to the regimen as long-lasting immunosuppressive therapy was probably needed.

However, the therapy was complicated in several ways. Firstly, by the end of the first month of therapy our patient developed diabetes mellitus and deep venous thrombosis. Subsequently, severe liver function abnormalities developed after methotrexate was started (Table 3). Therefore, this drug was substituted by azathioprine in a step up dosage regimen up to 100 mg daily. Hereafter, a severe and long-lasting pancytopenia developed (Table 3). Bone marrow analysis showed hyperplastic erythropoiesis and hypoplastic granulopoiesis compatible with a side effect of the immunosuppressive therapy. The azathioprine was therefore stopped and prednisone 20 mg per day was continued.

After recovering from the pancytopenia, mycofenolaatmofetil was added starting at 500 mg daily and in increased dosage to 1000 mg bid. During this whole episode prednisone treatment was maintained at a dosage of 20 mg daily. A severe intercurrent herpes infection was treated with intravenous valcyclovir.

After a course of 18 months, our patient has not had any relapse of his neurological deficits. There were no cranial nerve deficits, no pareses and his gait was normal.

CLIPPERS presents with distinctive clinical and MRI-findings and can be diagnosed after exclusion other differential diagnoses [1, 3]. Our patient confirmed the appropriateness of the initiation of treatment without histopathological confirmation.

A favourable clinical response to corticoid treatment lends further support to the diagnosis of CLIPPERS. We stress that careful clinical and laboratory monitoring is warranted because of the side effects of longstanding glucocorticosteroid and additional immunosuppressive therapy. Follow-up studies to determine the duration of treatment are necessary.