Edited by: Fernando Testai, University of Illinois at Chicago, United States
Reviewed by: Benjamin Aaron Emanuel, University of Southern California, United States; Rick Gill, Loyola University Chicago, United States
This article was submitted to Neurocritical and Neurohospitalist Care, a section of the journal Frontiers in Neurology
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Rheumatoid meningitis is a rare complication of rheumatoid arthritis (RA). It is associated with substantial morbidity and mortality. The condition may present in a variety of ways and is therefore diagnostically challenging. Uncertainty still exists regarding the optimal treatment strategy. Herein, we describe the case of a 74-year-old man with a history of well-controlled seropositive RA on low-dose prednisone, hydroxychloroquine, and methotrexate. The patient presented with a several-month history of multiple prolonged episodes of expressive aphasia, right hemiparesis, and encephalopathy. Although no epileptiform activity was recorded on repeated electroencephalography, the symptoms fully resolved following treatment with antiepileptic drugs. He subsequently developed acute asymmetrical parkinsonism of the right hemibody. Magnetic resonance imaging revealed subtle enhancement of the leptomeninges over the left frontoparietal convexity. Cerebrospinal fluid analysis revealed a mild lymphocytic pleocytosis and elevated proteins. Histopathologic analysis of a meningeal biopsy revealed nodular rheumatoid meningitis. The patient was treated with corticosteroids and cyclophosphamide, following which he incompletely recovered. This is the first description of rheumatoid meningitis manifesting with acute parkinsonism and protracted non-convulsive seizures. A summary of cases reported since 2005, including data on pathology, therapy and outcomes, along with a discussion on the efficacy of different treatment strategies are provided.
Rheumatoid arthritis (RA) may be associated with various neurological complications, most commonly compressive cervical myelopathy from atlantoaxial subluxation and entrapment neuropathies (
A 74-year-old man was admitted to our institution for investigation of progressive neurological symptoms. The patient was diagnosed with seropositive RA in 2015, which was quiescent on maintenance methotrexate, hydroxychloroquine and low-dose prednisone (10 mg daily). Titers of both rheumatoid factor and antibodies to cyclic citrullinated peptide were elevated. One week prior to admission, the patient developed fluctuating confusion, apathy, word-finding difficulty, right-sided weakness and gait imbalance. He had also experienced several other similar self-limited episodes within the 3 preceding months. The initial neurological examination was remarkable for decreased attention span, severe expressive aphasia, bilateral postural tremor, right hemiparesis and hypoesthesia, as well as a shuffling and wide-based gait. Clinical evaluation by rheumatology confirmed absence of synovitis and no evidence of extra-articular RA involvement. Gadolinium-enhanced head magnetic resonance imaging (MRI) showed finite areas of scattered restricted diffusion and enhancement within the cortex and leptomeninges of the left hemisphere near the vertex, suspicious for meningoencephalitis (
Brain magnetic resonance imaging (MRI)—Rheumatoid meningitis.
Shortly after admission, the patient experienced two brief generalized tonic-clonic seizures. Following treatment with phenytoin, the patient's mental status and neurological examinations normalized completely. Electroencephalography (EEG) revealed nonspecific diffuse cortical slowing without interictal epileptiform activity. Two weeks later, the patient developed recurrence of his presenting neurological symptoms, in addition to new asymmetrical acute parkinsonism of the right hemibody (rigidity, bradykinesia, and resting tremor). Titration of his antiepileptic medication and addition of levetiracetam, lacosamide, and clobazam allowed for control of the symptoms, except for parkinsonism. The patient subsequently developed marked fluctuations of his mental status, ranging from an apathetic state to a confused and combative state. Repeat EEG and CSF analysis were essentially unchanged from previous. CSF cytology showed occasional atypical lymphocytes negative for CD3 and CD20. Additional analyses on CSF, including
An open meningeal biopsy was performed and gross examination revealed thickening and opacification of the meninges. Hematoxylin and eosin (H&E) stained sections demonstrated meningothelial hyperplasia (
Meningeal histologic sections—Rheumatoid meningitis. Representative hematoxylin and eosin (H&E) stained sections.
Following histopathological confirmation of the diagnosis, immunosuppressive therapy with monthly cyclophosphamide (500–750 mg/m2 for 6 months) and high-dose corticosteroids was initiated. Corticosteroid regimen consisted of methylprednisolone 1,000 mg IV daily for 5 days, then prednisone 80 mg daily (1 mg/kg) tapered by 10 mg every 2 weeks up to a dose of 40 mg daily, at which point the dose was tapered by 5 mg every 2 weeks for 2 months then by 5 mg every 4 weeks for 4 months. Methotrexate was discontinued due to its failure to prevent disease progression, while hydroxychloroquine was continued. One month following treatment initiation, the patient's neurological examination improved, although confusion and bilateral postural tremor persisted. Furthermore, most parkinsonian features, except for mild leg rigidity, largely resolved following immunosuppressive therapy. Residual parkinsonism was not felt to be severe enough to warrant dopamine-replacement therapy, especially as it was felt that the parkinsonism was most likely secondary to the underlying RM and not due to a primary neurodegenerative process. Additionally, dopamine-replacement therapy was withheld as it was previously reported to be ineffective in a case of rheumatoid meningitis-induced parkinsonism (
Three main histopathological findings characteristic of rheumatoid meningitis may be observed on pathologic examination of the meninges, including nonspecific inflammation, rheumatoid nodules and vasculitis (
Pathological findings, treatment regimens, and outcome of rheumatoid meningitis cases reported since 2005.
Chowdhry et al. ( |
2005 | 78F | + | + | − | CS, MTX, leflunomide | CS | Improvement |
Jones et al. ( |
2006 | 58F | + | − | − | None | CS, CYC | Improvement |
Ahmed et al. ( |
2006 | 77M | + | − | − | MTX, HCQ, sulfasalazine, minocycline, leflunomide | CS | Improvement |
Chou et al. ( |
2006 | 58F | + | − | − | None | CS, CYC, infliximab | Improvement, then relapsed, then improvement |
Starosta et al. ( |
2007 | 67M | + | + | − | None | CS, MTX | Incomplete improvement |
2007 | 76F | + | + | − | CS, MTX, infliximab | CS | Incomplete improvement | |
Schmid et al. ( |
2009 | 64M | + | − | + | MTX, infiximab | CS, rituximab, d/c infliximab | Improvement |
Shimada et al. ( |
2009 | 53F | + | − | − | CS, MTX | CS | Incomplete improvement |
Ii et al. ( |
2009 | 68M | + | − | − | None | CS | Improvement |
Koide et al. ( |
2009 | 74F | + | − | − | Not reported | CS | Improvement |
Luessi et al. ( |
2009 | 64F | + | + | + | MTX, azulfidine | CS, AZA, CYC, infliximab, MTX | Worsening |
Cianfoni et al. ( |
2010 | 74F | + | + | − | CS, MTX | CS, IT MTX | Worsening |
Matsushima et al. ( |
2010 | 80F | + | + | + | CS, etanercept, bucillamine, sulfasalazine | CS | Improvement |
Servioli et al. ( |
2011 | 80F | + | − | − | CS, HCQ | Not reported | Not reported |
Kim et al. ( |
2011 | 66M | + | − | + | None | CS | Improvement |
Huys et al. ( |
2012 | 58F | + | + | − | MTX, adalimumab | CS, rituximab, leflunomide, d/c MTX, d/c adalimumab | Improvement |
Duray et al. ( |
2012 | 73M | + | + | − | CS, MTX | CS, CYC | Improvement |
Krysl et al. ( |
2013 | 62M | + | − | − | Chloroquine | CS | Improvement |
Hayashi et al. ( |
2014 | 68M | + | − | − | CS | CS | Incomplete improvement |
Bourgeois et al. ( |
2014 | 70M | + | − | − | Not reported | CS, HCQ, sulfasalazine | Improvement |
Rijkers et al. ( |
2014 | 56F | − | + | − | Not reported | CS | Incomplete improvement |
Roy et al. ( |
2015 | 50F | + | − | − | MTX, sulfasalazine | CS, MMF, d/c MTX | Improvement |
Lu et al. ( |
2015 | 60F | + | + | − | CS, auranofin | CS | Improvement |
Seago et al. ( |
2016 | 66F | + | − | − | Infliximab | CS | Improvement |
Nihat et al. ( |
2016 | 71F | + | + | + | Adalimumab, MTX | CS, CYC, MTX | Improvement |
Magaki et al. ( |
2016 | 37M | + | − | − | None | CS | Improvement |
Matsuda et al. ( |
2016 | 66M | NR | NR | NR | CS, MTX, iguratimod | CS, d/c MTX | Improvement |
Moeyersoons et al. ( |
2017 | 49M | NR | NR | NR | Adalimumab, leflunomide | CS, rituximab, d/c adalimumab, d/c leflunomide | Improvement |
Tsuzaki et al. ( |
2017 | 65M | + | − | − | CS, MTX, etanercept | CS, tocilizumab, d/c etanercept | Improvement |
Degboé et al. ( |
2017 | 59M | + | − | − | MTX | CS, rituximab | Improvement |
Jessee et al. ( |
2017 | 68F | + | − | − | None | CS, MTX | Incomplete improvement |
Choi et al. ( |
2017 | 65F | + | − | + | CS, MTX, leflunomide | CS | Improvement |
Parsons et al. ( |
2018 | 76M | + | − | − | MTX | CS, MTX | Improvement |
Alexander et al. ( |
2018 | 73M | + | − | − | Leflunomide | CS, rituximab | Incomplete improvement |
This report | 2018 | 74M | + | + | − | CS, MTX, HCQ | CS, CYC, d/c MTX | Incomplete improvement |
Although the semiology of the presenting neurological signs and symptoms of our patient (mainly expressive aphasia, right hemiparesis and hypoesthesia) was not suggestive of a clinical seizure, the normalization of the neurological examination following treatment with antiepileptics points toward an underlying epileptic phenomenon. However, multiple EEGs recorded while the patient was symptomatic failed to show epileptiform activity. Alternatively, short unwitnessed seizures may have triggered prolonged waves of cortical spreading depression. Akin to our observations, Chowdhry et al. (
Rheumatoid meningitis may rarely mimic Parkinson's disease (
As was the case with our patient, there is often a significant delay between symptom onset and diagnosis of rheumatoid meningitis. This lag period may be critical for achieving optimal clinical outcomes, and may account for our patient's incomplete recovery, despite aggressive immunosuppressive therapy, and raises the key question as to whether earlier recognition and treatment of the condition would have yielded better outcomes.
Therapeutic management of rheumatoid meningitis remains a major challenge, and the optimal immunosuppressive regimen has yet to emerge. Corticosteroids have been the cornerstone of treatment since cases of rheumatoid meningitis began to be described. The first extensive case series from 1989 described 19 cases (
Cyclophosphamide emerged as the most commonly used immunosuppressive agent likely due to its established use in CNS manifestations of systemic rheumatic diseases. However, recurrences in patients treated with this agent have occurred. One patient received both intravenous (9 months) and oral (2 months) courses yet his disease remained active (
The anti-CD20 monoclonal antibody rituximab has also been used to treat rheumatoid meningitis and may offer a therapeutic alternative to cyclophosphamide. Its first reported use dates back to 2009 (
On the other hand, treatment with TNFα inhibitors might be ineffective. Several case reports mention that rheumatoid meningitis occurred in patients who already were on TNFα inhibitors. Interestingly, anti-TNFα agents have been associated with the development of accelerated nodulosis (
Methotrexate-induced accelerated nodulosis is a known side effect of longstanding treatment for RA and tends to affect small joints (
Rheumatoid meningitis has historically been ascribed a high morbidity and mortality, especially when associated with CNS vasculitis. Debate is still ongoing regarding the optimal therapeutic strategy for this condition. Our review of the literature, focusing on recently published cases, indicates that there has been a definite improvement of morbidity and especially mortality associated with this condition, likely owing to improved diagnostic accuracy and prompt aggressive immunosuppressive treatment initiation. Rituximab appears to be a particularly promising option, as no treatment failure has been observed following its use.
Clinical data in this case report was collected with the consent of the patient. A written informed consent was obtained from the patient for the publication of this case report. The case report is exempt from institutional review board approval.
DP and MW contributed to manuscript preparation and background research. M-CG contributed to pathology interpretation, manuscript preparation, and reviewing. HA, AB, JK, EV, A-LL, and SL contributed to manuscript preparation and reviewing. All authors read and approved the manuscript.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We are grateful to the patient for allowing us to publish this case report.