CLIPPERS Responsive to Cladribine as a Durable Steroid-Sparing Agent

Case Presentation

A 25-year-old man presented to the emergency department with a reduced level of consciousness after a fall. Four months prior, he experienced intensifying headaches, episodic vertigo lasting seconds, and polydipsia consuming 5L of fluids daily. One month prior, the vertiginous paroxysms worsened in frequency, duration, and severity, lasting several hours, and were associated with vomiting, intractable hiccups, and double vision with left exotropia.

On initial examination, he was hypertensive (190 mm Hg systolic) and had dysarthria, left ptosis, and facial droop. Laboratory testing demonstrated life-threatening hypo-osmolar hyponatremia (105 mmol/L) and markedly elevated leukocytes (36.1 × 10⁹ cells/L) and CRP (138 µg/mL). MRI revealed diffuse serpiginous and nodular enhancement accompanied areas of T2 fluid attenuated inversion recovery (FLAIR) hyperintensity in the midbrain, pons, right cerebellum (Figure 1), and adjacent to the hypothalamus. A lumbar puncture showed mildly elevated protein (0.47g/L), T-cell–predominant lymphocytic pleocytosis (53 cells per µL) with an elevated CD4:CD8 ratio and no CSF-specific oligoclonal bands. CSF glucose, cytology, and flow cytometry were otherwise normal. Serum antibody screening was negative, including aquaporin-4, myelin oligodendrocyte glycoprotein, glial fibrillary acidic protein, tissue transglutaminase immunoglobulin A, rheumatoid factor, lupus anticoagulant, cardiolipin, double-stranded DNA, and antinuclear and antineutrophil cytoplasmic antibodies.

Figure 1 Brainstem and Cerebellar MRI Hyperintensities and Punctate Enhancement at First Presentation

Pontine and cerebellar hyperintensities (A, axial T2-weighted FLAIR sequence) with a perivascular pattern of punctate enhancement (B, axial T1 post gadolinium contrast), extending into the medulla and midbrain (C, parasagittal T1 post gadolinium contrast).

Due to progressive obtundation and respiratory compromise within hours of presentation, he was intubated. He completed empiric treatment for an infectious cause of encephalitis; however, blood cultures, sputum cultures, cardiac ultrasound, and serologies for syphilis, Legionella, West Nile, HSV, HIV, VZV, and hepatitis B/C were negative. Toxicology was negative. With concern for an autoimmune process, he received a 3-day pulse of methylprednisolone 1g/d followed by prednisone 80 mg/d. His clinical condition rapidly improved, and he was extubated and transferred to the ward on Day 3 of hospitalization. The hyponatremia corrected over 4 days. Follow-up imaging on Day 7 showed reduced abnormal T2 FLAIR hyperintensity and enhancement (Figure 2). A prednisone taper (10 mg week) was initiated. Neurologic deficits progressively improved, although there were persistent bilateral VI nerve palsies at discharge on day 13. The eye findings persisted on 1-month outpatient follow-up. Given the presentation with a steroid-responsive lymphocytosis and perivascular pontine involvement, CLIPPER syndrome was favored, although hypothalamic involvement driving hyponatremia and abrupt level of consciousness change was appreciated to be unusual. Neurosarcoidosis was also considered but not supported by the absence of systemic activity after CT screen of the chest/abdomen/pelvis.

Figure 2 Repeat MRI on Day 7 After Presentation Showed Improvements in Abnormalities After Steroids

Following initiation of steroids, there were improvements in the pontine and cerebellar hyperintensities (A, axial T2-weighted FLAIR sequence) and perivascular pattern of punctate enhancement (B, axial T1 post gadolinium contrast; C, parasagittal T1 post gadolinium contrast).

Unfortunately, 2 attempts to wean prednisone lower than 30 mg daily at 6 months and 1 year after diagnosis resulted in worsening of diplopia, at which point MRI scans were repeated, demonstrating persistent gadolinium enhancement similar to the initial presentation depicted in Figure 1. Over this time, steroid side effects had become incapacitating with marked weight gain of more than 50 kg, impaired glucose tolerance, low bone density, tremor interfering with writing, and anxiety so severe that he had to interrupt his studies. Having demonstrated a risk of relapse with steroid taper, steroid-sparing agents were considered including cyclophosphamide and cladribine. Based on the more favorable side effect profile including lower risks of malignancy and infertility and the potential for a long-lasting effect, cladribine was chosen through shared decision-making. Each cladribine treatment cycle consisted of 0.0875 mg/kg of IV cladribine infused over 2 hours on 4 consecutive days. He received a total of 4 cycles at 0, 4, 8, and 16 months. The only reported side effect was short-term fatigue in the days after the infusion. He remained on shingles prophylaxis for the full course of his treatments. MRI scans at 6, 12, 18, and 32 months and clinical visits at similar intervals after initiating cladribine have demonstrated no ongoing enhancement or diplopia. The patient completely weaned-off prednisone by 20 months. At the time of this submission, 33 months since cladribine initiation and off all treatments for more than 1 year, his CLIPPERS remains in clinical and radiographic remission. Despite modest weight loss, he remains clinically obese with impaired glucose tolerance. He had completed his Bar examinations and was looking forward to starting his career as a lawyer.