Severe CNS manifestations as the clinical hallmark in generalized Wegener's granulomatosis consistently negative for antineutrophil cytoplasmic antibodies (ANCA). A report of 3 cases and a review of the literature.

OBJECTIVE: Antineutrophil cytoplasmic antibodies (ANCA) directed against proteinase 3 are highly specific for Wegener's granulomatosis (WG); their sensitivity for active generalized WG is nearly 100%. There are patients, however, who fulfill both the ACR 1990 criteria and the CHC 1992 definition for WG but who remain ANCA negative. The authors report 3 young patients with biopsy-proven active generalized WG who were consistently negative for ANCA over observation times ranging from 58 to 114 months.

METHODS: ANCA titers were determined serially every 3 months. ANCA-negativity was defined by the absence of any fluorescence pattern on IFT plus the absence of any specific ELISA reactions. This included negative results for the antibody classes IgG, IgM and IgA. The sera of all patients were also tested in a capture PR3-ANCA ELISA. At 1- to 6-month intervals each patient underwent a standardized set of interdisciplinary examinations.

RESULTS: Although CNS involvement in large WG cohorts is about 10%, severe CNS manifestations were the clinical hallmark in all 3 patients. One patient suffered from both intraspinal and intracerebral disease with fatal outcome; the other 2 had meningeal manifestations that responded favorably to immunosuppressive therapy.

CONCLUSION: Severe CNS manifestations could represent a clinical hallmark of patients with generalized Wegener's granulomatosis who are consistently negative for antineutrophil cytoplasmic antibodies (ANCA).