Non-infectious encephalopathy with recurrent stroke-like episodes: a case of rheumatoid meningitis

Dear Editor,

We present the case of a 65-year-old man with a 1-year history of recurrent stroke-like episodes, cognitive impairment, and post-traumatic epilepsy. He came to our attention for acute onset of aphasia and transient facial palsy. The emergency CT scan was negative for ischemic/hemorrhagic events, and the CT angiography showed no signs of major vessel occlusion. The electroencephalogram showed no epileptic activity. Brain magnetic resonance imaging showed heterogeneous sylvian and right hemispheric subarachnoid material with associated diffuse pachymeningeal thickening and impregnation. The cerebrospinal fluid (CSF) evaluation showed no signs of infections and augmented protein count, consistent with an inflammatory condition. After an extensive blood workup, a final diagnosis of rheumatoid meningitis was made. In patients with recurrent stroke-like episodes and atypical brain imaging, a possible inflammatory cause should be considered and clinicians should carefully explore patient history of systemic inflammatory signs.

The patient suddenly became aware of speech difficulty around 9:00 in the morning in November 2021. He was in treatment with cardioaspirin and clopidogrel because of a similar episode of slurred speech that occurred in the previous month. Beside DAPT, he had been treated with levetiracetam, allegedly for a post-traumatic epilepsy, and with alprazolam, quetiapine, and amisulpride for depressive-psychotic behavior disorder. He came to our hospital with his wife, who said that the man had a traumatic brain injury after a car accident in December 2020 and subsequent multiple stroke-like episodes during the past year. In effect, in April he presented gait instability and left limb weakness. In June, he presented left leg numbness and weakness, and painful and swollen joints. In October, he was hospitalized once again for gait instability and facial palsy. Each episode was followed by hospitalization in several hospitals, during which various head CT scans were performed without ever documenting acute ischemic lesions.

In the emergency room, the neurological examination demonstrated very mild anomic aphasia. The NIHSS was 1. Head CT scan showed no obvious new-onset ischemic lesions and the CT angiography showed no signs of major vessel occlusion. Given the nature of the symptom and the low-grade NIHSS, fibrinolysis was not performed. The patient was then hospitalized in the Stroke Unit.

During the stay, the man showed inconstant neurological signs, such as hyperreflexia, rigidity, behavioral fluctuations, coordination difficulties, gait instability, and dysarthria. The most marked feature in our patient’s clinical presentation was his cognitive impairment. The Mental Deterioration Battery (MDB) was compatible with cognitive deterioration.

Because of the aforementioned fluctuating clinical features, an electroencephalogram was performed: during the monitoring time, no sign of epileptical activity was recorded, with a frontal intermittent rhythmic delta activity (FIRDA), and a synchronous symmetrical activity in wakefulness on both hemispheres.

During the hospitalization, we repeated an MRI scan that showed heterogeneous sylvian and right hemispheric subarachnoid material with associated diffuse pachymeningeal thickening and impregnation. The images were not typical for post-traumatic findings (Fig. 1).

Fig. 1.

Contrast-enhanced T1 MRI sequence showing meningeal enhancement (1); FLAIR with meningeal contrast enhancement (2, 3)

Since MRI demonstrated pachymeningeal/leptomeningeal phlogistic signs, we performed a lumbar puncture; the cerebrospinal fluid (CSF) evaluation showed a clear, citrine spinal fluid with white blood cell count of 7/μL, red blood cell count of 1/μL, glucose levels of 56 g/dL, and proteins of 131 g/dL. CSF was also tested for common pathogens (virus, bacteria, mycobacteria), showing no signs of infectious conditions.

We were able to rule out infectious causes of pachymeningitis, including mycobacterial and fungal infections, given the blood and CSF workup findings. Differential diagnoses between non-infectious diseases include autoimmune causes of inflammatory meningitis (granulomatosis with polyangiitis, Sjogren disease, neurosarcoidosis, rheumatoid meningitis, IgG4 disease) and malignancies like lymphoma or leptomeningeal carcinomatosis. Paraneoplastic conditions should also be considered within the diagnostic process.

Extensive blood workup was done to rule out coexisting immunological disorders, especially the autoimmune panel and coagulation assessment: the patient tested positive for rheumatoid factor 135 IU/L (< 15), ESR 95 mm, and ACPA 52.6 AU/mL consistent with rheumatoid arthritis diagnosis; he also tested positive for thyroid-associated autoimmune panel. The parameters tested for the coagulation assessment were within normal range. Anticardiolipin antibodies and anti–β-2-glycoprotein antibody levels were within range of normality. These results eliminated antiphospholipid syndrome. Onconeural antibody test results were also negative.

One of the most important diseases, for the similarities with RM, is the immunoglobulin G4 meningitis that typically only involves the dura, with headaches and cranial neuropathies being the most common presenting symptoms. A careful clinical evaluation to look for manifestations like salivary and lacrimal gland, and orbital and retroperitoneal involvement should be pursued to rule out this disease.

A total body CT was performed to exclude malignancies: lungs appeared abnormal, with pleuro-parenchymal thickenings (especially in the apical area as in pleuroparenchymal fibroelastosis) and interstitial thickening. Overall, there were no signs of masses nor malignancies.

Given the positive blood test for rheumatoid arthritis (RA), a rheumatological evaluation was performed. Joint sonography was positive for an aggressive form of arthritis, showing inflammation in minor and major bilateral joints, and signs of tendovaginitis and bursitis in both biceps and shoulders. Therefore, a diagnosis of high-activity RA with systemic involvement was formulated. The pulmonary interstitial disease, seen with the CT scan, and the pachymeningitis, seen with the MRI, were linked to the RA, and a targeted treatment was started.

Meningeal biopsy was not performed because the patient showed a good response to first-line therapies (prednisone 50 mg per diem for 2 weeks, tapering regime, and methotrexate). After a few weeks of treatment, the patient could walk unaided, and spoke fluently and without anomic difficulties. His mental processes were faster and more fluid, and the neuropsychological evaluation showed a marked improvement in all fields. Furthermore, except for the SARS-CoV-2 infection, the man was never hospitalized for neurological acute events.

A CNS complication of rheumatoid arthritis is rheumatoid meningitis [1], a rare but serious manifestation that has a clinical-radiological pattern compatible with that observed in our patient.

It mostly affects people over 50 years old and can cause pachymeningitis, leptomeningitis, or both [2]. It can be patchy or diffuse and usually affects the meninges that surround the brain rather than the spinal cord, and for this reason, its clinical presentation could be variable [3].

Its clinical manifestations were varied and reported heterogeneously, with the most common being transient focal neurological signs. Systemic symptoms are frequently observed like fever, weight loss, malaise, and nausea; we can find episodic headache and neuropsychiatric symptoms too, such as altered mental status, apathy, and depression. In few patients, movement disorders were reported like parkinsonism, gait imbalance, abnormal movements of the extremities, and falls that are not explained by focal signs [4]. Extra-articular RA manifestations include rheumatoid nodules, systemic vasculitis, pleuritis, pericarditis, and scleritis. Finally, other symptoms were visual and hearing loss, and cranial nerve neuropathy.

In conclusion:

1. RA is a possible cause of neurological impairment and clinicians have to consider it when they meet neurological patients with RA.

2. Meningeal biopsy has limited utility in providing definitive pathologic confirmation of RM. A nonspecific meningeal biopsy did not appear to influence treatment or outcome relative to those who did not undergo biopsy, but it exposes the patient to surgical risks. Meningeal biopsy should be strongly considered only in patients with atypical presentation: what is really challenging for the diagnosis is the extensive diagnostic workup [2].

3. Furthermore, with the study of less invasive biomarkers such as CXCL13, ACPA, and RF in the CSF, biopsy could play a limited diagnostic role [5].

Declarations

Conflict of interest

The authors declare no competing interests.