Response to immunotherapy in CLIPPERS syndrome

Abstract

Dear Sirs,Chronic lymphocytic inflammation with pontine perivas-cular enhancement responsive to steroids (CLIPPERS) is arecently described treatable, brainstem-predominant, clin-ical and radiological entity [1]. Patients with this conditionpresent with an episodic brainstem syndrome and showcharacteristic scattered and punctate gadolinium (Gd)enhancement in the pons and adjacent CNS structures.They prototypically respond to high dose glucocorticos-teroids and may require chronic steroid or immunosup-pressive treatment, although the effect of intravenousimmunoglobulins (IVIG) in this disease is unknown. Herewe report a patient with CLIPPERS that experienced aclinical rebound of the disease after a short pulse of IVIG.A 28-year-old woman with subacute gait ataxia anddiplopia was admitted to the hospital. Neurologicalexamination revealed internuclear ophthalmoplegia, hori-zontal bidirectional nystagmus and gait and four-limbataxia. Brain and spinal MRI showed multiple punctate Gdenhancing lesions in the mesencephalon, cerebellum andcervical spinal cord. The patient was tested for the presenceof systemic auto-antibodies, anti-neuronal antibodies,infectious pathogens (HIV, T. Pallidum, Brucella spp., B.burgdorferi) and tumoral serum biomarkers. CSF analysisincluded standard biochemistry, cytology and bacteriolog-ical cultures, oligoclonal bands and tests for Tropherymawhippelii and Herpesviridae, with no significant findingsexcept for mildly raised CSF protein. Body-CT and bodyand brain PET-CT were also normal. The patient wastreated with intravenous methylprednisolone for 3 days(1 g/day) followed by oral prednisone tapering startingfrom a dose of 60 mg/day. One week after starting meth-ylprednisolone, she had completely recovered and wascontinued on a slow reduction of oral steroid dose. How-ever, any attempt to taper the oral steroid dose below12.5 mg/day led to neurological relapse of the symptomsand, therefore this dose was maintained for the next6 months. After this period (1 year after disease onset), shewas asymptomatic and physical examination was normal,and therefore treatment discontinuation was reassessed.After she stopped steroids for a few days she suffered arebound of her symptoms: she had new onset mild gaitataxia and brisk symmetric ankle- and knee-jerks. Newbrain and spinal cord MRI disclosed multiple scatteredpunctuate and non-confluent enhancing lesions of a maxi-mum diameter of 0.7 cm visible mainly in the white matterof both cerebellar hemispheres, cerebellar peduncles and inthe cervical spinal cord. (Fig. 1a). At that moment, pontineGd enhancement was relatively scarce compared with thecerebellar hemispheres. Additionally, mild but appreciableamount of diffuse Gd peppering was visible in the whitematter of the whole brain adjacent to the cortico-subcor-tical border. Prednisone dose was increased to 30 mg/dayand the patient recovered to normal in 3 days. Thereafter, a12.5 mg/day dose was maintained for the following9 months and the patient remained asymptomatic. A newMRI 3 months after restoration of steroid therapy showedclear improvement of Gd lesions (Fig. 1b). Notwithstand-ing, steroid side-effects became evident with amenorrhea,hirsutism, mild weight gain and acne. Any attempt to tapersteroid dose below 10 mg/day resulted in a blooming ofneurological symptoms. After assuring 2 weeks of clinicalstability, a short attack pulse of intravenous immunoglob-ulins (IVIG) was administered (0.4 g/kg/day for 5 days)