Meningeal rheumatoid nodules in a 55-year-old man presenting with chronic headaches and oculomotor nerve palsy: an uncommon extra-articular manifestation of rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is a multisystem inflammatory disease which can involve many organ systems including the central nervous system (CNS). Though not very common, the results can be severely debilitating. The spectrum of the CNS involvement includes meningitis, encephalitis and occasionally rheumatoid nodules. Its presentation is variable, though very rarely it can present as focal neurological deficits. Imaging can be suggestive, but diagnosis usually requires tissue biopsy. Treatment consists of high-dose steroids and immunosuppressants. We describe the case of a 55-year-old male patient with a history of RA presenting with a third nerve palsy and headache who was found to have rheumatoid nodules on biopsy. CNS involvement in RA should be considered in anyone with rheumatoid arthritis who presents with focal neurological deficits, though infections and space-occupying lesions should also be ruled out.

Background

Rheumatoid arthritis (RA) is a systemic autoimmune condition that typically involves the small joints of the extremities. However, it can involve different organ systems that is termed extra-articular RA. It has been reported to involve the nervous system, both central and peripheral. The involvement of the central nervous system (CNS) has three characteristic neuropathological patterns.¹ It is most commonly in the form of leptomeningitis or encephalitis that can present with headaches, seizures, focal neurological deficits and encephalopathy. Vasculitis is the second pattern and can have different presentations including strokes. The third pattern is rheumatoid nodules in the CNS, and this has been reported the least. These patients are more likely to be asymptomatic, too.¹ These three patterns are not mutually exclusive, and more than one pattern can occur together.

One of the first cases of CNS rheumatoid nodule formation was reported by Steiner and Gelbloom in 1959, and has been rarely reported since then.² This diagnosis requires high level of suspicion and should be considered in any person with RA that presents with neurological manifestations in whom other aetiologies including infectious and oncological have been ruled out. Diagnosis relies on brain imaging and tissue sampling which includes biopsy of the meninges and brain.

We describe a case where a patient with long-standing history of seropositive RA, on prednisone and hydroxycholoroquine presented with a third cranial nerve deficit and chronic headache and was found to have meningeal thickening on imaging. A biopsy revealed the presence of rheumatoid nodules in the meninges. Since very few such cases have been reported, there is no determined clinical course and standard of care treatment. Such patients have previously been treated with corticosteroids and other immunosuppressants with variable outcome.

Case presentation

A 55-year-old male patient with history of seropositive RA chronically on 6 mg of prednisone/day and hydroxychloroquine. He also had a history end-stage renal disease secondary to focal segmental glumerolonephritis on haemodialysis for over 6 years. Other comorbidities included chronic obstructive pulmonary disease, diabetes mellitus type 2 and hypertension. He was having regular follow-up with a rheumatologist and a nephrologist.

The patient presented to his primary care physicians office a few times over a 3-month period for headaches. A CT head was negative at that point. His headaches were thought to be secondary to migraines, and he was treated with medications, with partial relief. However, 3 months after initially noticing the headache, he presented again with acute onset diplopia and ptosis. He was admitted to the hospital for further evaluation and management. Initial evaluation showed a middle-aged man who appeared comfortable. Besides the chronic headache and new onset diplopia and ptosis, he did not have any other active complaints. On examinations, his vital signs were within normal limits. Neurological examination revealed (right pupil dilated and deviated to the right in addition to complete ptosis); however, he did not have any other focal neurological deficits, and mentation was clear. Examination of the other systems showed the presence of chronic lower extremity ulcers and a fistula for haemodialysis in the left arm. He had chronic changes of RA in his wrists without active synovitis. No rheumatoid nodules were identified over his extremities.

Investigations

At presentation, the patient was initially evaluated for a stroke. A CT and CT angiography (CTA) of the head were negative.

MRA of the brain without intravenous showed no evidence of aneurysm or vascular malformation. However, it showed dural thickening that was most prominent along the cerebral convexities, right and left tentorium, and anterior interhemispheric fissure and possibly cavernous sinuses. No acquired intracranial arterial stenosis or occlusion was present. MRI of the orbit and cavernous sinus was then obtained to look for signs of inflammatory changes around the orbits or any other cause for the third nerve palsy. It showed no intraorbital mass. However, it showed dural thickening versus subdural haematomas along the cerebral convexities (figure 1).

Figure 1.

MRI of the brain showed dural thickening (arrow) along the cerebral convexities. (Ax T2 fluid-attenuated inversion recovery (FLAIR) propeller sequence).

Initial baseline labs showed a white cell count of 8.6×10⁹ /L (4–11.0×10⁹ /L), with 72% PMN, haemoglobin of 93 g/L (135–175 g/L), platelet count of 167×10⁹/L (140−400×10⁹/L), sodium of 134 meq/L (135–145 meq/L), potassium of 3.7 meq/L (3.5–5.4 meq/L), creatinine of 4.8 mg/dL (0.50–1.30 mg/dL), blood area nitrogen of 36 mg/dL (5–20 mg/dL), glucose of 90 mg/dL (70–100 (mg/dL) and normal liver function tests. Prior laboratories revealed: rheumatoid factor (RF) 79 U/mL (0–13 U/mL), citric citrullinated peptide IgG Ab >500 (<17 U/mL), C-reactive protein 7.7 mg/dL (<0.5), antineutrophil cytoplasmic antibody negative, antinuclear antibody, negative.

The patient also had a lumber puncture to rule out a CNS infection that showed 17 white cells/mm³ (normal <10) that were 56% neutrophils, 21% lymphocytes, 0 red cell counts. The total protein was 70 mg/dL (20–40 mg /dL), and glucose was 46 mg/dL (40–80 mg/dL). Viral and bacterial cultures and Gram stain was unremarkable. This suggested an infectious aetiology was less likely. A paraneoplastic panel ordered on the cerebrospinal fluid (CSF) studies was also negative. This panel included anti-Hu, anti-Yu, anti-Ri, antiamphiphysin, anti-Ta, anti-Tr and antirecoverin antibodies.

Differential diagnosis

The differential diagnosis for the headache, oculomotor nerve palsy and dural thickening included metastatic disease, infectious process, hypertrophic pachymeningitis in association with RA, neurosarcoidosis and granulomatous infection. All of these differentials were considered.

He had extensive imaging studies, which ruled out a stroke. This included an initial CT head without contrast and CTA. These were negative for any acute findings and were unchanged from prior studies. Subsequently, an MRA was negative, and magnetic resonance venography (MRV) was negative for dural venous thrombosis. MRI brain did show old bilateral cerebellar infarcts, but these were unlikely to be the cause of his symptoms. The only positive finding of significance in all these studies was the presence of dural thickening on MRI brain, most prominent in the cerebral convexities.

Neurosurgery was consulted and the patient underwent a biopsy of the dura and meninges. Grossly the dura appeared markedly thickened. Frozen sections were taken and were negative for malignant process. Microscopic examination revealed fragments of fibrous meningeal tissue with acute and chronic inflammation and areas of granulomatous inflammation with central necrotic debris (figures 2 and 3). Stains were negative for fungal and mycobacterial organisms. These findings in the context of the patient’s clinical history of RA were consistent with rheumatoid nodules.

Figure 2.

Microscopic examination revealed fragments of fibrous meningeal tissue with acute and chronic inflammation and areas of granulomatous inflammation (arrows). These findings were consistent with rheumatoid nodules (30×).

Figure 3.

High-power view (100×)—a high-power view highlights the palisading granulomatous inflammation and central necrobiotic debris. Properly controlled grocott's methamine stain (GMS) and acid fast bacilli (AFB) special stains for fungal and mycobacterial organisms were performed on the specimen and were both negative.

Treatment

The patient developed MRSA sepsis during his hospital stay, most likely from a dialysis catheter. He was treated with intravenous antibiotics and steroids for a while; however, his neurological condition did not improve. It was planned to start rituximab for the patient once his medical condition stabilises; however, he continued to have MRSA bacteraemia, compounding his other chronic medical conditions.

Outcome and follow-up

He developed complications secondary to haemodialysis including recurrent hypotension and fluid overload with pulmonary oedema resulting in hypoxic respiratory failure. He subsequently developed multiorgan failure. With no significant improvement in his medical conditions, he refused all treatment and was discharged to hospice. He passed away shortly after moving to hospice.

Discussion

RA is a multiorgan chronic inflammatory disease that mainly effects the joints but may have extra-articular involvement as well. Rheumatoid nodule formation is a common extra-articular manifestation occurring in up to 20% of patients.³ In most cases, these nodules are located subcutaneously. However, they may occur in many different locations including the pleural linings, lungs and pharynx. Rarely, these nodules may involve the CNS and the meninges.¹ RA nodules involving the CNS may present as headaches, focal neurological deficits, gait disturbances, mood changes, seizures and encephalopathy which can mimic other disease processes.¹ The differentials include strokes, transient ischemic attack (TIA), bacterial or viral meningitis/encephalitis, tumours, intracerebral or subarachnoid haemorrhage (SAH), sarcoidosis and idiopathic hypertrophic pachymeningitis. Most commonly, this presentation occurs in patients with long-standing RA. We performed a comprehensive review of the previous literature and analysed the previously reported cases of rheumatoid nodules found in the meninges.

Review of literature showed only n=13 cases of rheumatoid nodules in the CNS reported since 2000.^4–15 These are presented in table 1. One case was available as an abstract only.¹⁵ There were also cases with evidence of meningitis but no nodules. These were excluded. Analysis of the prior patient revealed that the mean age at presentation was 68.15 years. Nine of the reported cases were in women and three in men. The duration of RA prior to developing meningeal rheumatoid nodules was found to be between 4 and 10 years. The reported neurological presentations were very variable. These included weakness or hemiparesis, acute confusions, short-term memory loss, sensorineural hearing loss and seizures. Half of the patients (n=6) had some degree of hemiparesis with or without hemianaesthesia. This was the most common presentation. Headache was also present in half of the patients (n=6). Two patients present with seizures, and two patients have new onset parkinsonism features at presentation, too. Our patient had presented with chronic headaches and third nerve palsy. However, we could not demonstrate that the nodulosis was directly related to the third nerve palsy. Other differentials for the third nerve palsy in our patient include neuropathy from diabetes or autoimmune causes or raised intracranial pressure from rheumatoid meningitis.

Table 1.

This table depicts the previously reported cases of rheumatoid nodulosis in the brain.

Reference	Age/sex/duration of RA	Neurological symptoms, signs	Neurological	CSF finding	MRI	Treatment prior to presentation	Treatment	Outcome	Pathological finding Nodules/inflammation/vasculitis
Chowdhry et al 4	78/F/10	Headache,	Left hemiparesis	Cell 23/μL with 11% neutrophils, 45% lymphocytes, and 44% monocytes protein 73 mg/dL (normal=14–45 mg/dL) and glucose 60 mg/dL. (CSF) IgG index was elevated to 1.38	Increased T2 signal in the subarachnoid space over the right hemisphere, abnormal leptomeningeal enhancement	CS, MTX, Lef	CS	Recovered	+/+/−
Starosta et al 5	67/M	Sensorineural hearing loss	NA	NA	Pachymeningitis on brain MRI	No	CS	Partial recovery	+/+/−
Starosta et al 5	76/F	Acute confusion	NA	CSF studies were unremarkable	Leptomeningeal enhancement overlying the right cerebral hemisphere on brain MRI	CS, Inflix, MTX	CS, MTX	Partial recovery	+/+/−
Luessi et al 6	64/F	Dysarthria,	Left-sided hemihypaesthesia and impaired coordination	Mononuclear pleocytosis (142 cells/mm3), repeated culture and cytology were negative	Abnormal gadolinium-enhancement in the right frontal meninges with sulcal effacement and areas of hyperintensity in the underlying cortex	MTX, Azulfidine	CS, AZA, CYC, MTX, Inflix	No response	+/+/+
Cianfoni et al 8	74/F	Severe, throbbing headache	Left-side hypoaesthesia and weakness	Lymphocytic cell count (65/mm3; normal <4/mm3), mildly increased protein (43 mg/ dL; normal 20–40 mg/dL), with normal glucose levels	Diffuse thick linear leptomeningeal enhancement was seen	CS, MTX	CS, IT MTX	No response	+/+/−
Matsushima et al 7	80/F		Intermittent weakness and numbness in the right extremities	WCC count (18 cells/ mm3; 93% mononuclear cells), protein level (55 mg/dL), immunoglobulin G index (1.38) and interleukin (IL)−6 level (4.6 pg/mL).	Hyperintense lesions in the cortex of the left parietal lobe and meningeal thickening with abnormal enhancement on the surface of the left parietal lobe	CS, etanercept, sulfasalazine, bucillamine	CS	Recovered	+/+/+
Huys et al 9	58/F	Psychomotor retardation and intermittent headaches	Seizures	WCC count (30/mm3) and proteins (0.56 g/L)	Pachymeningeal and leptomeningeal infiltration with gadolinium enhancement	MTX, adalimumab	CS, rituximab, leflunomide Stopped MTX, adalimumab	Recovered	+/+/−
Duray et al 10	73/M/9 m	Walking difficulties and persistent fever	Normal	91 lymphocytes/mm3, a protein level at 130 mg/dL, and a glucose level at 42 mg/dL for 93 mg/dL in the blood	Normal	CS, MTX	CS, CYC	Recovered	+/+/−
Rijkers et al 11	56/F	Tonic–clonic seizures	–		Frontal lesion of the falx dura with central cysts, bifrontal extensions	–	CS	Partial recovery	+/+/−
Lu et al 12	60/F	Headache, photophobia, mania and delirium, with impaired short-term memory and visual hallucinations, pressured speech, flight of ideas, paranoia, disorganised thoughts, inattention	Poor short-term memory without focal sensory or motor deficits	Two WCCs (lymphocytes), three red cells, normal glucose (58 mg/dL) and normal protein (26 mg/dL)	Pachymeningeal and leptomeningeal enhancement along the left frontal and temporal lobes	CS, auranofin	CS	Recovered	+/+/−
Nihat et al 13	71/F/5	Dysarthria and paraesthesia over the right face and hand. Difficulty walking, tremor of her right arm and headaches	A mild right lower facial weakness and right pronator drift	WCC 50–80, >95% lymphocytes), protein (0.46–0.67 g/L) and glucose (CSF glucose 2.4 mmol/L, serum glucose 5.2 mmol/L, CSF: serum ratio 0.46, normal >0.6).	Leptomeningeal thickening and abnormal gadolinium enhancement over the left frontal lobe	Adalimumab, MTX	CS, CYC, MTX	Recovered	+/+/+
Pellerin/201814	74/M/3	Confusion, apathy, word-finding difficulty, seizures, parkinsonism, decreased attention span, expressive aphasia, postural tremor	Right hemiparesis and hypoaesthesia, shuffling and wide-based gait	6 WCC (85% lymphocytes, 15% mono), protein 86, normal glucose	Scattered restricted diffusion and enhancement within the cortex and leptomeninges	CS, MTX, HCQ	CS, CYC, stopped MTX	Partial recovery	+/+/−
Our case	55/M	Headache	Oculomotor nerve palsy	17 white cells /mm3 (normal <10) 56% neutrophils, 21% lymphocytes, 0 red cells. The total protein was 70 mg/dL (20–40 mg /dL), and glucose was 46 mg/dL (40–80 mg/dL)	Dural thickening along the cerebral convexities, right and left tentorium and anterior interhemispheric fissure	None	Refused	NA	+/+/−

AZA, azathioprine; CSF, cerebrospinal fluid; CYC, cyclophosphamide; HCQ, hydroxychloroquine; MTX, methotrexate; NA, not applicable; RA, rheumatoid arthritis; WCC, white cell count.

Most of the patients had imaging studies in the form of MRI brain that revealed some degree of leptomeningeal enhancement. Only one patient reported by Duray et al had normal MRI findings.¹⁰ CSF studies were reported in 10 of the prior studies. Most of the CSF studies were unremarkable, though five of the patients did have a mildly elevated protein, with one patient having a CSF protein of more than 100 mg/dL (130 mg/dL). Some of the patients had a mildly elevated white cell count (n=6). In most of the cases, this elevated white cell count was predominantly lymphocytes. IgG index was reported to be elevated in two patients.

Microscopic examination of rheumatoid nodules usually show that they are made up of fibrous tissue surrounding a central area of fibrinoid necrosis. Larger nodules may have more than once the centre. The boundary separating the necrotic centre of the nodule and the outer fibrous shell is made up of a structure called a cellular palisade which is characteristic of a rheumatoid nodule. It consists of a densely packed layer of macrophages and fibroblasts which are arranged radially. The outer fibrous layer contains T-cells and plasma cells. All of the patients in our series were diagnosed based on biopsy, with visualisation of the nodules on microscopy. Most of the patients had granulomatous inflammation on biopsy. A few of the patients (n=3) had evidence of vasculitis, too.

All of the patients were treated with corticosteroids in the initial phase. Most of the patients also received another therapeutic agent, too. Six of the patients got methotrexate, with four of these patients responding to therapy and two not responding. One patient was treated intrathecally, too, with a poor response. Four of the patients received cyclophosphamide, and three of these patients had a response. One patient was treated with azathioprine, leflunomide, rituximab and infliximab each. Overall, two of the patients did not respond to therapy. Four patients had a partial recovery, and six patients had a complete recovery.

Learning points.

• Rheumatoid arthritis is a multisystem inflammatory disease which can involve the central nervous system as well.

• The spectrum of the central nervous system involvement and its presentation is variable, very rarely it can present as focal neurological deficits.

• Imaging can be suggestive, but diagnosis usually requires tissue biopsy.

• No standard of care treatment is recommended, but it usually consists of high-dose steroids and other immunosuppressive agents.