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 (Figures 1A,B). Cerebrospinal fluid (CSF) analysis showed 6 white blood cells (WBCs), 85% lymphocytes and 15% monocytes, a protein concentration of 0.86 g/L (normal 0.15-0.45 g/L) and a normal glucose content. CSF bacterial and fungal cultures were negative, as were cryptococcal antigen, herpes simplex virus, and syphilis testing. Serum C-reactive protein was markedly elevated at 135 mg/L (normal 0-5 mg/L). Antinuclear antibodies and anti-neutrophil cytoplasmic antibodies were negative. Serologies for human immunodeficiency virus and anti-onconeural antibodies were negative. Methotrexate blood levels were within nontoxic range and immunoglobin G4-subclass titers were normal. Additionally, QuantiFERON-TB testing for Mycobacterium tuberculosis was negative. Serum angiotensin-converting enzyme (ACE) level was mildly elevated (66 U/L), as was beta 2-microglobulin (4.6 mg/L). High-resolution computed tomography (CT) scan of the chest was not suggestive of sarcoidosis.
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 Mycobacterium tuberculosis culture, PCRs for Epstein-Barr virus and cytomegalovirus, ACE level and anti-neuronal cell surface antibodies, all proved negative. A follow-up MRI, 4 weeks after admission, showed progression of the left-sided cortical and leptomeningeal areas of restricted diffusion and enhancement, as well as new right frontoparietal cortical diffusion restriction and leptomeningeal enhancement (Figures 1C,D). A whole-body positron emission tomography scan did not reveal evidence of an underlying malignancy. Further work-up with a bone marrow biopsy showed no evidence of lymphoid neoplasm.
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 (Figure 2A) with acute and chronic inflammation associated with fibrosis and entrapment of the underlying brain parenchyma, which showed evidence of chronic gliosis. The most striking feature was the presence of classical zones of palisading necrobiosis (Figure 2B). The chronic inflammatory aggregates consisted in reactive CD3 positive T cells with fewer number of CD20 positive B lymphocytes, as well as CD68 positive macrophages and CD138 plasma cells with no evidence of light chain restriction (Figures 2C,D). Despite the presence of perivascular leptomeningeal inflammation, no significant vasculitis was present. All the special stains for microorganisms, mycobacteria, and fungal elements were negative. The histopathological findings were consistent with leptomeningeal involvement by nodular rheumatoid meningitis.
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. All antiepileptic drugs, aside from lacosamide, were eventually tapered without clinical or electrographic seizure recurrence. Repeat MRI 3 months after treatment initiation showed complete resolution of previous findings (Figures 1E,F), correlating with normalization of CRP levels. Despite this radiographic improvement, the patient suffered from persistent behavioral and cognitive deficits with intermittent periods of agitation. The neuropsychiatric sequelae remained disabling enough for the patient to eventually be transitioned to a long-term care facility.