Rheumatoid meningitis developed in patient with stable rheumatoid arthritis and myasthenia gravis—detailed analysis of intracranial inflammation using flow cytometry

Development of rheumatoid meningitis (RM), a rare autoimmune inflammatory disease of the central nervous system (CNS), is often seen in well-controlled rheumatoid arthritis (RA) patients [1, 2] or even manifested as the first symptom in patients with RA [3, 4]. We treated a young woman diagnosed with myasthenia gravis (MG) and RA, who presented with meningitis and transient sensory disturbance during a remission phase of both disorders. A flow cytometry investigation of cellular immunity using cerebrospinal fluid (CSF) and blood samples showed differences in regard to the pathogenesis of inflammation in the CSF and outside of the CNS.

A 36-year-old woman with a 13-year history of generalized MG was diagnosed with RA 8 years prior to the present episode. The patient had undergone a thymectomy, and both diseases were stable with alternate-day administrations of prednisolone (8 mg) and weekly doses of methotrexate (12 mg) until she exhibited new neurological complications. At the time of the initial visit, the patient reported a 10-day history of headache in the left parietal region and also had a moderate fever of 38 °C. On the sixth day after developing the headache, a transient sensory disturbance (dysesthesia) over the right face developed and then spread to the right upper extremity for 30 min, which recurred twice that day; thus, she came to us and also noted headache and fever but no pain in any joints. Neurological examination findings were negative for meningeal irritation signs, and there were no symptoms of MG including ptosis, diplopia, dysarthria, or weakness in the four extremities. Mental state, deep tendon reflexes, and coordination were normal, and there was no sensory disturbance. The patient had no past history of hypertension, diabetes, or smoking.

Routine laboratory tests revealed elevated C-reactive protein (CRP) (6.09 mg/dl, normal < 0.3 mg/dl) and erythrocyte sedimentation rate (ESR) (56 mm in 1 h, normal < 3–11 mm), while white blood cells were normal (7980/μl, normal 3040–8720/ μl; neutrophils, 76.8%, normal 40–77%; lymphocytes, 11.6%, normal 16–44%). Serum electrolytes, creatine, liver enzymes, and the coagulation system were also normal, while titers for anti-acetylcholine receptor (AChR) (12 nmol/l, normal < 0.2 nmol/l) and anti-ribonucleoprotein (RNP) (15 U/ml, normal < 0.5 U/ml) antibodies were elevated, though to the same extent as seen in previous examinations. Complements, as well as cytoplasmic and perinuclear anti-neutrophil cytoplasmic antibodies, were normal. The CSF sample obtained at admission was lymphocytic (white cell count 19/μl, normal < 5, predominance of mononuclear cells) with elevated levels of protein (57 mg/dl, normal 15–45 mg/dl) and IgG (7.0 mg/dl, normal 0.5–4.0 mg/dl; IgG index 0.80, normal < 0.7) and a normal glucose level (51 mg/dl, normal 50–80; serum glucose 116 mg/dl; CSF:serum ratio 0.81). The oligoclonal IgG band was positive (seven bands), and intrathecal IgG synthesis was elevated (6.0 mg/day, normal < 3.3 according to previous report [5]). Furthermore, interleukin-6 (IL-6) was markedly elevated in the CSF (843 pg/ml, normal < 12.1 pg/ml according to previous report [6]). Other CSF examination results were negative, including polymerase chain reaction analysis for infectious agents (herpes simplex, varicella zoster, cytomegalovirus, tuberculosis), cultures for bacteria and acid-fast bacilli, India ink capsule staining, and cytology for malignant cells. Brain magnetic resonance imaging (MRI) using fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted imaging (DWI) showed hyperintense lesions in the subarachnoid space over the left parietal lobe and cortex adjacent to the meningeal lesion (Fig. 1a, b). The meningeal lesion was enhanced by gadolinium (Gd) (Fig. 1c). Moreover, DWI revealed a spot lesion suggesting the presence of an ischemic lesion in the left parietal cortex (Fig. 1d). No abnormalities were seen in magnetic resonance angiogram findings.

We treated a patient with RM who had a long history of MG and RA. This case showed reported features of RM, which were manifested independently of RA activity [1, 2], as well as neurological symptoms, including transient sensory disturbance [2, 11, 12]. Although most reported cases of RM include brain/meningeal biopsy findings, asymmetrical meningeal involvement revealed by MRI [1, 2, 6, 11‐13] has been found helpful for an early diagnosis of RM, which contributes to improvement of treatment outcome [13, 14]. Indeed, some recent cases were diagnosed without biopsy findings, including the present [3, 6, 15]. The presence of vasculitis was reported in a biopsy specimen obtained from a case of RM [13], and cortical lesions likely develop as a consequence of impaired blood flow beneath the restricted area of inflammatory meningeal lesions. It is also conceivable that minor damage or ischemia in the cortex is manifested as transient ischemic attacks or seizure-like episodes. Furthermore, the fever noted in the present patient deserves mention, as this symptom has been reported only rarely even when the feeling of chills is included [6, 12, 14]. Interestingly, a previously reported patient with a fever of 38.2 °C [6] showed extremely high levels of IL-6 in the CSF the same as the present patient, suggesting an ongoing intense inflammatory process in the CSF/meninges.

In the present case, it is noteworthy that RM developed during a phase of remission of both RA and generalized MG. If an extrinsic factor is present, such as an infectious event that can induce general T and/or B cell activation before development of RM, symptoms related to RA and MG will likely worsen along with elevation of immunological markers for those disorders. The good response of clinical symptoms, as well as improvement in ESR and CRP following administration of a moderate dose of corticosteroids alone in the present case and others [4], is similar to polymyalgia rheumatica. However, in our patient, no painful symptoms except for headache were noted during the entire course of illness. Instead, we found a marked increase in the CD4-positive helper T cell population, especially CCR3-positive Th2 cells, as well as marked decrease in CD8-positive cells in the CSF, in contrast to modest changes in those cells in blood. A subset of CD8-positive cells is known to have a role as suppressor T cells [16]; thus, we concluded that immunoregulation in the CSF was disturbed in the present case. Although B cells were increased along with a relative decrease in CD3-positive mature T cells in blood as compared to the results of our previous study of viral meningitis and non-inflammatory neurological diseases [10], these findings may have been due to the effects of long-term immunosuppressive therapy with methotrexate. Furthermore, CSF samples showed an elevated IgG index, positive oligoclonal bands, and excessive intrathecal IgG synthesis. In light of the marked increase in Th2 cells in the CSF, these results indicate the presence of CSF-specific activation of humoral immunity resulting in propagation of meningeal inflammation, though the triggering factor or precise mechanism was not addressed in the present study. Another limitation is that we did not measure the level of IgG4 in serum. However, IgG4-related disease seems to be less likely in cases of asymmetric leptomeningitis [13].

In summary, we performed flow cytometric analysis of cellular immunity in a patient with RM, which showed that immunoregulatory disturbance associated with elevated Th2-type response in the CSF may have stimulated intrathecal IgG synthesis. Results obtained in this case indicate that the pathogenesis of RM differs from that of a systemic manifestation of RA and MG.