A 62 year-old woman was admitted after 4 months history of intermittent frontal headache, nausea, and gait and balance disturbances. She had a 3 year history of IgM-RF and anti-CCP positive RA, with a previously episode of pleuritis. Within the last year, she had been treated with Leflunomide, Infliximab, and was currently treated with Methotrexate and Salazopyrine entabs. Neurological examination was normal, except for a mild gait ataxia and her RA was well-controlled with no symptoms of active synovitis at time of admission.
Due to chronic headache a brain MRI was performed. This showed patchy interhemispheric pachy- and leptomenigeal enhancement adjacent to the parietal- and occipital lobes (Figure 1A). Blood tests revealed signs of inflammation with high levels of IgM RF (56 IU/mL), anti-CCP (>1,600 U/mL), Interleukin-2 receptor (ILR-2-1,065 kU/L) (Table 1), c-reactive protein (43 mg/L), and erythrocyte sedimentation rate (106 mm). Remaining systemic antibody examinations were negative (anti-DNA antibody, anti-nuclear antibody (ANA) IgG, anti-neutropil cytoplasmatic antibody (ANCA) IgG, Anti-Ro (SSA)/La (SSB), anti-cardiolipin antibody, phospholipid antibody, and lupus anticoagulant). Immunoglobulin A, G, and M levels were normal.
Cerebrospinal Fluid (CSF) analysis revealed a mononuclear pleocytosis (170 E6/L) and elevated protein level (1.16 g/L). Due to the pleocytosis, intravenous ceftriaxone, and aciclovir were administered, to cover for bacterial meningitis and Herpes Simplex Virus (HSV) encephalitis. Subsequent CSF cultures revealed no growth of bacteria, no Borrelia antibodies, and viral/bacterial PCR (E. coli, hemophilus influenzae, Listeria monocytogenes, Neisseria meningitidis, hemolytic streptococcus, streptococcus pneumoniae, cytomegalovirus, enterovirus, herpes simplex virus, varicella zoster, Cryptococcus, and micromiome 16S/18S), and flowcytometry, and cytological analysis for malignancy were negative. Therefore, antiviral- and antibiotic- treatment was terminated.
The following days the patient displayed sporadic confusion, delusions, and fever (38.5 C). Subsequent tests, including HIV, syphilis, and tuberculosis were negative. Re-examination of CSF showed continuous mononuclear pleocytosis (130 E6/L), high IgG index (1.45) and presence of oligoclonal bands, suggestive of inflammation. Repeated cultures for bacteria were negative and cytological analysis showed an inflammatory pattern with an elevated number of B-lymphocytes (7.8 %) and plasma cells (1.8%, Table 1).
To investigate possible systemic inflammation or malignancy whole-body FDG-PET CT was performed. This showed hypermetabolism of the cerebral cortex, adjacent to the meningeal enhancement found on MRI, and a right medial lobe infiltrate of the lung. CT of thorax and abdomen confirmed an infiltrate, slight pleural effusion, and pleural thickening. Endobronchial ultrasound with biopsy was performed revealing no malignancy or infection.
On suspicion of RM, we performed analysis on undiluted CSF showing moderately positive IgM RF (92.7 IU/mL) and strongly positive anti-CCP (19,600 IU/mL) and CXCL-13 (>500 ng/L, Table 1).
Subsequent, biopsy of meninges (Figure 1C) confirmed chronic inflammation dominated by CD138 positive plasma cells and a limited number of CD3 positive T-lymphocytes with limited infiltration into the underlying gray matter (Figures 1E,F). Additionally, granulomatous inflammation with dense infiltration of CD68+ histiocytes and the presence of rheumatoid nodules were found (Figures 1D,G). Microbial stains, PCR, and cultures of biopsy tissue for fungi, parasites, acid-fast bacilli, HSV 1, HSV 2, CMV, SV40, M. tuberculosis, and toxoplasmosis were negative.
Based on the (i) MRI findings with patchy meningeal enhancement, (ii) high titer of IgM-RF and anti-CCP in CSF and (iii) histopathological chronic inflammation of meninges with plasma cells and rheumatic nodules, the diagnosis RM was established. Concurrently, the patient displayed extra articular manifestations of RA in her lungs.
Intravenous high dose methylprednisolone (750 + 1,000 + 1,000 mg on three consecutive days) followed by oral tapering was administered in addition to current treatment with methotrexate. Within days symptoms improved, but did not completely resolve. The following weeks, the patient received Rituximab (1,000 mg intravenous, repeated after 14 days). CSF levels of IgM RF, anti-CCP, and CXCL-13 decreased accordingly to the patient reporting significant treatment response (Table 1). A 6 month follow-up MRI showed regression of meningeal enhancement (Figure 1B) and follow-up FDG-PET CT showed almost complete regression of pulmonary findings. Neurological examination at 6 month follow up confirmed resolution of clinical symptoms.