Focal Motor Seizures as a Manifestation of Rheumatoid Meningitis

Abstract

We describe a 65-year-old man with rheumatoid arthritis presenting with focal motor seizures and progressive right frontoparietal leptomeningeal enhancement. Biopsy was consistent with an inflammatory process. He improved with corticosteroids and rituximab. Our case highlights consideration of CNS involvement of rheumatoid arthritis in patients presenting with new neurologic symptoms.

Introduction

Rheumatoid meningitis (RM) is a rare manifestation of rheumatoid arthritis (RA) that primarily involves leptomeninges, pachymeninges, or both.¹ It has been described in patients with longstanding RA, patients with newly diagnosed RA, and, in rare instances, patients without a prior diagnosis of RA.² The clinical manifestations are heterogeneous, and may be nonspecific,³ making the diagnosis challenging. Common manifestations include headache, focal neurologic deficits, and seizures, as illustrated in our case.^3,4 The differential diagnosis for RM is broad and encompasses infectious etiologies such as Mycobacterium tuberculosis, endemic mycoses, and syphilis; inflammatory conditions including neurosarcoidosis, immunoglobulin G4 (IgG4)–related hypertrophic meningitis, granulomatosis with polyangiitis, myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD); and neoplastic process including lymphoma and metastatic leptomeningeal disease.³ The absence of a definitive diagnostic biomarker further complicates recognition and frequently leads to delays in diagnosis and treatment, with potential adverse outcomes.

We report the case of a 65-year-old man with a longstanding history of RA who presented with focal motor seizures and was found to have right frontoparietal leptomeningeal enhancement on MRI.

Case Report

In September 2024, a 65-year-old man with a 9-year history of untreated RA, gout, and uveitis/scleritis presented to the emergency department (ED) with rhythmic jerking movements of the left leg, arm, and face, accompanied by impaired awareness lasting approximately 15 minutes. He had no history of malignancy. Neurologic examination was unremarkable. Serum studies revealed an elevated C-reactive protein of 40 mg/L, positive anti–cyclic citrullinated peptide (CCP) antibodies, and a positive rheumatoid factor (RF). Additional serologies—including myelin oligodendrocyte glycoprotein (MOG) antibody, IgG4 level, autoimmune encephalopathy panel, angiotensin-converting enzyme, antinuclear antibody, and antineutrophil cytoplasmic antibody—were normal or negative. Infectious serologies for Epstein-Barr virus, West Nile virus, histoplasma, syphilis, Lyme disease, and tuberculosis (QuantiFERON TB) were negative. CSF analysis revealed elevated protein at 52 mg/dL with normal glucose, total nucleated cell count, and cytology. Oligoclonal bands were absent, and both the autoimmune encephalopathy panel and infectious studies were negative, including viral (cytomegalovirus, herpes simplex virus types 1 and 2, varicella-zoster virus, JC and BK polyomaviruses, Epstein-Barr virus), bacterial (Hemophilus influenzae, Neisseria meningitidis, Listeria monocytogenes, Toxoplasma gondii, and syphilis by VDRL), and fungal (Cryptococcus and histoplasma) pathogens. CSF culture showed no growth, and immunophenotyping demonstrated no abnormal lymphoid population. MRI of the brain with and without contrast revealed T2 FLAIR hyperintensity in the right frontoparietal region, with associated leptomeningeal enhancement on T1 postcontrast images (Figure 1, A and B). Cervical and thoracic spine MRI scans were unremarkable. He was started on levetiracetam 500 mg twice daily, and an outpatient biopsy was planned; however, he was lost to follow-up.

Figure 1. MRI Brain With and Without Contrast at Presentation and 6 Months Later.

(A) MRI September 2024: axial T2/FLAIR image demonstrates right frontoparietal hyperintensity related to vasogenic edema. (B) MRI September 2024: sagittal T1 postcontrast image demonstrates parasagittal frontoparietal leptomeningeal enhancement. (C) MRI February 2025: axial FLAIR image demonstrates slight anterior extension of right frontoparietal edema with improved edema posteriorly. (D) MRI February 2025: sagittal T1 postcontrast image shows worsening or more diffuse right frontoparietal leptomeningeal enhancement in the parasagittal sulci.

In February 2025, he re-presented to the ED with a second episode of rhythmic jerking movements of the left arm and leg, with preserved awareness after discontinuing levetiracetam for a week. Routine electroencephalography (EEG) demonstrated intermittent slowing over the right hemisphere. Repeat serum and CSF studies remained unremarkable. Follow-up brain MRI demonstrated worsening leptomeningeal and pachymeningeal enhancement in the right frontoparietal region with new areas of edema (Figure 1, C and D). Fluorodeoxyglucose PET-CT of head to thigh demonstrated hypermetabolic activity corresponding to the areas of leptomeningeal enhancement, with no other hypermetabolic lesions identified.

He subsequently underwent biopsy of the right parietal lobe and dura. The histologic sections stained with H&E revealed a dural lesion characterized by central fibrinoid necrosis, surrounded by numerous macrophages, lymphocytes, and Touton giant cells. No granulomas were present. Most of the lymphocytes were CD3-positive T cells, with a smaller population of CD20-positive B lymphocytes. The gray matter fragments showed reactive astrocytes and foamy macrophage. There was no evidence of neoplasm, demyelinating disease, IgG4-related disease, or vasculitis. The histologic findings are consistent with an inflammatory process (Figure 2).

Figure 2. Histopathologic Findings of Brain and Dural Biopsy.

(A) H&E stain demonstrating lymphocytes (predominantly CD3⁻positive T cells), plasma cells, and macrophage infiltrating dura (×2). (B) H&E stain showing foamy macrophages, Touton-like giant cells, and areas of necrosis (×10). (C) CD 163 immunostain highlighting a dense collection of macrophages within the dura and extension into the gray matter (×2). (D) Luxol fast blue special stain showing preserved myelin within both white and gray matter (×2).

He was treated with IV methylprednisolone 1 g daily for three days, followed by an oral steroid taper for 6–8 weeks. Rituximab was subsequently initiated as maintenance therapy to prevent subsequent relapses of rheumatoid meningitis. There was interval improvement in leptomeningeal enhancement noted on follow-up MRI three months after treatment initiation in June 2025 (Figure 3).

Figure 3. MRI Brain With and Without Contrast After Treatment With Corticosteroids.

(A) MRI June 2025: sagittal T1 postcontrast sequence demonstrates improvement in right frontoparietal leptomeningeal enhancement. (B) MRI June 2025: axial T1 postcontrast image demonstrates interval improvement in right frontoparietal leptomeningeal enhancement. (C) MRI June 2025: axial T2/FLAIR image shows partial resolution of right frontoparietal edema-related hyperintensity.

Differential Diagnosis

Leptomeningeal enhancement warrants evaluation for inflammatory conditions (neurosarcoidosis, IgG4-related disease, MOGAD), CNS infection, and malignancy (lymphoma and leptomeningeal carcinomatosis).^4,5 In this case, histopathology was critical in excluding alternative diagnoses. In neurosarcoidosis, a positive PET scan with or without systemic involvement is typically seen, with noncaseating granulomas on pathology. IgG4-related disease is suggested by elevated serum IgG4 levels and increased IgG4⁺ plasma cells on biopsy.⁴ However, our case showed rare IgG4-positive cells with the IgG4: IgG ratio less than 5%.

In MOGAD, particularly the entity described as FLAIR-hyperintense lesions in anti-MOG–associated encephalitis with seizures, characteristic unilateral or bilateral cortical T2/FLAIR hyperintensities with seizures are observed.⁵ A positive serum MOG antibody is typically seen with presence of demyelination on histopathology, which was not seen in our patient. With malignancy, atypical lymphocytes on CSF immunophenotyping with confirmatory histopathology are present. A negative infectious panel including normal CSF total nucleated cells makes infection unlikely.

Collectively, the clinical, radiologic, and histopathologic findings supported a diagnosis of RM.

Discussion

RM, an uncommon extra-articular manifestation of RA, is an inflammatory condition of the CNS that can involve leptomeninges and pachymeninges.⁶ Although its precise pathogenesis remains unclear, current evidence suggests perivascular infiltration of immune cells or deposition of antibodies within the meningeal microvasculature.⁶ The clinical presentation often varies depending on the area of involvement. Stroke-like episodes and seizures are the most common manifestations.⁷ In our case, the patient experienced recurrent seizures. It is important to note that, in some cases, CNS involvement may precede the diagnosis of RA.² While our patient had uncontrolled RA, the development of RM can occur independent of underlying RA disease activity.⁶

CSF findings in RM, although variable, most commonly demonstrate elevated protein levels and mononuclear-predominant pleocytosis.⁶ Although CSF RF was not obtained in our case, the diagnosis of rheumatoid arthritis had been established previously based on serum RF positivity and clinical findings. Prior reports have described cases showing elevated CSF RF relative to serum levels, suggesting intrathecal RF synthesis.⁶ Conversely, a low CSF-to-serum RF ratio may be seen depending on the lesion's location in relation to the lumbar puncture site.¹ Inflammatory cytokines, such as TNF-α, IL-1β, and IL-6, are implicated in the pathogenesis of RA and have been proposed as potential CSF biomarkers.¹ Other useful CSF markers include anti-CCP antibodies and B-cell chemoattractant (CXCL-13).⁸ On brain imaging, unilateral or bilateral meningeal involvement is often observed, most commonly in the frontoparietal regions, as in our patient. In cases of bilateral involvement, the findings are usually focal and asymmetric, although diffuse involvement may also occur.^2,6 Histopathologic findings in RM typically demonstrate meningeal inflammation, rheumatoid nodules (localized granulomatous tissue), and vasculitis with a poorer prognosis in cases with nodules or vasculitis.^3,6 In some instances, nonspecific inflammation or granulomatous necrosis may be present, complicating the diagnosis.⁵

Given the wide range of clinical presentation, RM is often a diagnosis of exclusion, with alternative causes such as infectious, neoplastic, or autoimmune processes needing to be excluded.^3,6 Although evidence remains limited, high-dose IV corticosteroids (1 g/d methylprednisolone for 3–5 days) followed by a taper have proven beneficial in acute management.⁶ There are no standardized guidelines on the duration of steroid taper. However, a gradual taper over several weeks is generally recommended to minimize the risk of relapse.⁶ For long-term management, steroid-sparing agents such as cyclophosphamide, methotrexate, rituximab, tocilizumab, and azathioprine have demonstrated therapeutic benefit.⁶ By contrast, anti-TNF agents, although effective for systemic RA, are not recommended for RM. This is due to their implication in CNS demyelination and reported cases of poorer outcomes compared with other immunotherapies.⁶ Notably, development of RM has been reported in patients already on anti-TNF therapy.⁶ Rituximab, a B cell–depleting agent, has demonstrated favorable outcomes with relatively low adverse events.^6,9 In our patient, rituximab was selected for long-term management, leading to improvement in leptomeningeal enhancement.

Early recognition and initiation of immunotherapy remain critical determinants of prognosis. While antiseizure therapy controlled his focal motor seizures, corticosteroids and disease-modifying therapy were essential to prevent progression, as reflected by radiographic improvement after immunotherapy. This case highlights the importance of early recognition, exclusion of mimics, and timely initiation of immunotherapy in improving outcomes in RM.

Conclusion

This case highlights focal motor seizures as a manifestation of RM, a rare but important extra-articular complication of RA. Diagnosis requires exclusion of mimics because of the absence of definitive biomarkers and nonspecific clinical and radiologic findings. While leptomeningeal or pachymeningeal involvement may be evident on imaging, meningeal biopsy remains the diagnostic gold standard. Early recognition and timely immunotherapy initiation are crucial for improving patient outcomes. Corticosteroids remain the cornerstone of acute management, whereas long-term immunotherapy has demonstrated sustained clinical benefit. Future studies are needed to establish evidence-based diagnostic criteria and therapeutic protocols for RM.

Glossary

CCP

cyclic citrullinated peptide

ED

emergency department

IgG4

immunoglobulin G4

MOG

myelin oligodendrocyte glycoprotein

MOGAD

myelin oligodendrocyte glycoprotein antibody–associated disease

RA

rheumatoid arthritis

RF

rheumatoid factor

RM

rheumatoid meningitis

Author Contributions

I.G. Moninuola: drafting/revision of the manuscript for content, including medical writing for content. M.T. Shujaat: drafting/revision of the manuscript for content, including medical writing for content. S. Ahmadian: drafting/revision of the manuscript for content, including medical writing for content. S.S. Zamvil: drafting/revision of the manuscript for content, including medical writing for content. C. Riley: drafting/revision of the manuscript for content, including medical writing for content. M.D. Goldman: drafting/revision of the manuscript for content, including medical writing for content. T.V. Gyang: drafting/revision of the manuscript for content, including medical writing for content.

Study Funding

This work was funded by the National MS Society.

Disclosure

I. Moninuola, M.T. Shujaat, and S. Ahmadian have nothing to disclose. S.S. Zamvil has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Sanofi-Genzyme; $500-$4,999 for serving on a Speakers Bureau for Alexion; $500-$4,999 for serving on a speakers bureau for Genzyme; $10,000-$49,999 for serving on a Speakers Bureau for Horizon; $5,000-$9,999 for serving on an advisory board with Genzyme; $500-$4,999 for serving on an advisory board with Genentech; and $500-$4,999 for serving on an advisory board with Alexion. The institution of S.S. Zamvil has received personal compensation in the range of $10,000-$49,999 for serving as an editor, associate editor, or editorial advisory board member for AAN and has received research support from Sumaira Foundation. C. Riley has received personal compensation in the range of $500-$4,999 for serving as a consultant for Genentech; $10,000-$49,999 for serving on a scientific advisory or data safety monitoring board for EMD Serono, TG Therapeutics, and Horizon; $500-$4,999 for serving on a scientific advisory or data safety monitoring board for Roche, Amgen, Immunic AG, Cabaletta Bio, Bristol Myers Squibb, and Novartis; and $10,000-$49,999 for serving on a scientific advisory or data safety monitoring board for TG Therapeutics. M. Goldman has received personal compensation in the range of $5,000-$9,999 for serving as a consultant for Genentec, Immunic, and Novartis Pharmaceuticals; $500-$4,999 for serving as a consultant for Kiniska and TG Therapeutics; $500-$4,999 for serving on a scientific advisory or data safety monitoring board for Brainstorm Cell Therapeutics Ltd and as a study section member with the NIH. M. Goldman has received personal compensation in the range of $0-$499 for serving as a grant review committee member with the Department of Defense. T. Gyang has received personal compensation for consulting with EMD Serono. Go to Neurology.org/NN for full disclosures.