Encephalomyelitis associated with rheumatoid arthritis: a case report

Introduction

Rheumatoid arthritis (RA) is a common, chronic, progressive connective tissue disease in which joints are the primary target. Extra-articular manifestations include skin, eye, lungs, and blood vessels [10]. Although the central nervous system (CNS) is rarely involved, a variety of neurological manifestations can occur associated with vasculitis, pachymeningitis, meningitis, opportunistic infection, drug adverse effects, and spinal cord compression [3,4,11,12].
Encephalitis in the course of RA remains a matter of debate. Critics suggest other causes of encephalitis in RA patients, or associate brain damage symptoms with vasculitis. To the best of our knowledge, there is a single clinical report in the literature of encephalitis due to RA. Kitamura et al. [7] described a 57-year-old patient with autoimmune encephalitis (AE) associated with preclinical stage of RA with extensive, symmetric parenchymal changes involving the medial temporal lobes in brain magnetic resonance imaging (MRI) and no autoantibodies to neuronal intracellular or cell-surface antigens in either the serum or cerebrospinal fluid (CSF). In conclusion, the authors suggested that AE can develop as an extra-articular manifestation of RA, in opposi­tion to the published diagnostic criteria of AE, in which rheumatological disorders were listed in the differential diagnosis [5].
The diagnosis of AE associated with RA in the paper of Kitamura et al. [7] was based on clinical, laboratory, and radiological findings. Although, it is of interest whether brain changes correspond with the diagnosis of encephalitis in the neuropathological examination. Here, we present a case of a patient with encephalomyelitis associated with RA confirmed with post-mortem neuropathological findings. To the best of our knowledge, it is the first study with a description of pathological changes in the lite­rature.

Case presentation

A 68-year-old woman presented transient fever, weakness, dizziness, imbalance, nausea, disorientation, and somnolence, which progressed for 2 weeks. She had a history of long-standing, seropositive RA with no extra-articular manifestations controlled by chronic glucocorticosteroid (GKS) therapy, secondary hypoadrenocorticism, hypertension, osteoporosis, stomach ulcers, total hysterectomy with bilateral salpingo-oophorectomy and chemotherapy due to uterine cancer 5 years earlier. In the last few years, she had been hospitalized due to severe electrolyte disturbances several times.
On admission she was confused but able to answer simple questions and perform simple commands, her body temperature and other vital signs were normal, she was dehydrated with no other systemic physical exami­nation abnormalities, no meningeal irritation, and no other focal neurological signs. Routine blood tests revealed hyponatraemia (122 mmol/l, N: 135-145 mmol/l), hypo-osmolality (256 mOsm/kg, N: 270-300 mOsm/kg), leukocytosis (21 cells/μl, N: 4-10 cells/μl), elevated C-reactive protein (CRP) (111 mg/l, N: < 5 mg/l), and elevated erythrocyte sedimentation rate (ESR) (37 mm/h, N: < 20 mm/h). Results of chest radiography and urine analysis were normal. Despite the correction of electrolyte disturbances and decrease of inflammatory parameters after empi­rical antibiotic treatment (cefuroxime), her neurological status slowly worsened with further deterioration of her consciousness level; she became somnolent, responding only to painful stimuli. MRI of the brain and spinal cord revealed an increase of signal intensity on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images with corresponding restricted diffusion involving both cerebral peduncles, pons, medulla oblongata, and cervical spinal cord and mild contrast-enhancement of the right cerebral peduncle (Fig. 1). There were no vascular abnormalities in brain magnetic resonance angiography (MRA). Electroencephalography (EEG) showed diffused, generalized slowing with no evidence of abnormal paroxysmal activity. Computed tomography (CT) of the chest, abdomen, and pelvis revealed no significant abnormalities. Blood testing, including routine blood tests, blood glucose, blood lipids, hepatic, renal, adrenal gland, thyroid function, serology, serum electrolytes, coagulation studies, HIV antibodies, hepatitis B and C, syphilis serology, tumour markers, Borrelia antibodies, autoimmune antibodies (anti-nuclear antibodies – ANA, anti-neutrophil cytoplasmic antibodies – ANCA, rheumatoid factor – RF, cyclic citrullinated peptide – CCP, LA, cardiolipin), neuronal cell surface autoantibodies (anti-NMDA, anti-LGI1, anti-CASPR2, anti-GABAB, anti-AMPA1, anti-AMPA2, anti-DPPX), and onconeural antibodies (anti-Hu, anti-Ri, anti-Yo, anti-MA2, anti-CV2, anti-amphiphysin, anti-GAD56, anti-SOX1, anti-Zic4), were all negative except elevated rheumatoid factor (25.5 IU/ml, N: < 12.5 IU/ml). CSF analysis revealed moderate pleocytosis (68 cells/μl, N: < 5 cells/μl) with mononuclear cell predominance (92%), mildly increased protein level (48 mg/dl, N: < 45 mg/dl), and a normal glucose level. CSF flow cytometry analysis, 14-3-3 protein testing, viral PCRs (varicella-zoster virus, herpes simplex virus, cytomegalovirus, Epstein-Barr virus), and neuronal surface antibodies tests were negative. Results of blood, CSF, and urine bacterial, fungi, and mycobacterium cultures were also negative.
The patient was treated with corticosteroids (methyl­prednisolone, prednisolone), antibiotics (cefta­zi­dime, metronidazole, imipenem/cilastatin), antiviral drugs (aciclovir), and intravenous immunoglobulin (IVIg) with no improvement. During several weeks of hospitalization her general and neurological condi­tion gradually deteriorated; she became unconscious, unresponsive, hypotensive, and finally ventilatory failure. Several serious complications occurred, i.e. urinary tract infection, Clostridium difficile infection, Pseudomonas aeruginosa sepsis, and epileptic seizures. She needed mechanical ventilation, vasopressors, blood transfusions, broad antibiotics therapy, enteral and parenteral nutrition, and antiepileptic drugs. Her follow-up brain MRI did not show significant progression, CSF analysis revealed slightly decreased pleocytosis (42 cells/μl). The patient died after 3 months of hospitalization. A clinical diagnosis of vasculitis due to infection or neoplastic disease was established.
General autopsy revealed right lung haemorrhagic infarct, single renal cysts, mild atherosclerosis, and small articular deformities with no evidence of tumour or systemic vasculitis. The fresh brain weighed 1060 g. Its gross examination disclosed generalized mild atrophy manifested by small brain size, widening of the sulci, narrowing of the gyri, and symmetrical dilation of the lateral ventricles. Small, multiple, subdural, confluent petechial haemorrhage in the occipital cortex and left occipital gyrus, small cavities in the basal ganglia, and minimal atherosclerosis were observed. The cervical spinal cord did not show any abnormalities in macroscopic evaluation. The leptomeninges were clear.
Formalin-fixed, paraffin-embedded tissue sections were stained histologically (haematoxylin and eosin [HE], Mallory’s trichrome, Van Gieson, Gomori trichrome) and immunohistologically with antibodies for GFAP (1 : 500, Bio-Rad, Hercules, USA), CD20 (1 : 100, Leica, Newcastle, UK), CD34 (1 : 50, Dako, Glostrup, Denmark), CD45RO (1 : 500, Leica, Newcastle, UK), CD68 (1 : 250, Cell Marque, Rocklin, USA), and LCA (1 : 75, Cell Marque, Rocklin, USA). In all examined brain and cervical spinal cord structures mild oedema of the cortex and white matter, congestion of small cortical vessels, diffuse microglia and lymphocytic infiltration, and mild inflammation changes of meningeal and parenchymal small vessels (arterioles, capillaries, and to a lesser extent venules) was observed (Figs. 2 and 3). Parenchymal inflammation was most severe in the frontal and temporal lobes and was accompanied by significant neuronal loss, severe cortex and white matter oedema, perineuronal satellitosis, numerous hyaline bodies, diffuse astroglial proliferation, and oligodendrocyte swelling (Fig. 2).
Microglia was sometimes rod-shaped, sometimes forming nodules (Fig. 2A, B). Lymphocytic infiltration was composed of T-cells, particularly seen in the parenchyma, and rarely associated with vessels (Fig. 2C). The vasculitis showed transmural and perivascular lymphocyte T-cell infiltration with fibrous proliferation of the intima and narrowing of the lumen (Fig. 3). More severe inflammatory vascular changes were observed in the brainstem, cerebellum, and cervical spinal cord and corresponded with multiple, small, or single larger foci of ischaemic necrosis in various pathological stages, predominantly in the final stage of macrophage demolition or glial scar formation (Fig. 3). In the pons, larger foci of ischaemic necrosis were visible, surrounded by a glial shaft composed of proliferative, reactive astrocytes and macrophages (Fig. 3C). There was a larger focus of ischaemic necrosis in the phase of glial scar formation with secondary haemorrhagic features in the cortex and white matter of the right occipital lobe (Fig. 3D). Furthermore, slightly expanded perivascular spaces were seen in the basal ganglia and thinning of the ganglion layer with Bergman glia proliferation in the cerebellum.

Discussion

This reported case presented several unique and interesting diagnostic challenges. Lack of autoantibodies against neuronal intracellular antigens, lack of tumour in the general autopsy and whole-body CT scan, no improvement after GKS and IVIg weaken the association with paraneoplastic aetiology. Mild CSF pleocytosis, negative blood and CSF cultures, negative PCR results, and no clinical improvement after treatment with antibiotics and anti-viral drugs indicate against viral or bacterial infection. The persistence and progression of neurological symptoms despite the correction of initial electrolyte disturbances provide evidence against CNS damage due to osmotic demyelination syndrome. Numerous other diseases with a similar clinical course were excluded as part of extensive diagnostics, i.e. Lyme disease, neurosyphilis, antiphospholipid syndrome, and CNS lymphoma. Furthermore, progressive, disseminated neurological symptoms together with multifocal, heterochronous lesions in brain MRI could suggest a diagnosis of ischaemic stroke in the course of rheumatoid vasculitis. Cerebral vasculitis is a rare complication of longstanding, seropositive RA, which may occur as a part of a systemic manifestation of vasculitis or less frequently as an isolated involvement of the brain, and is usually asymptoma­tic with occasional cause of severe, life-threatening progressive and/or diffuse strokes [1,3,4,8,9].
Though, comprehensive radiological and laboratory evaluation were performed, the final diagnosis of encephalomyelitis due to RA was set up on the basis of post-mortem neuropathological examination. We observed numerous, disseminated, hetero­chronous ischaemic lesions predominantly in the brainstem and widespread, diffuse microglia, and T-cell infiltrations with neuronal loss and astrogliosis, most severe in the frontal and temporal lobes. Mild, perivascular lymphocyte T infiltrations involved particularly small and medium-sized vessels and was associated with brainstem ischaemic lesions. No neoplastic or lymphocyte B infiltration was observed. Thus, our findings correspond to other neuropathological descriptions of different kinds of encephalitis. For example, neuronal loss, gliosis, microglial cell activation, and the presence of perivascular and parenchymal infiltrating leukocytes, were reported as neuropathological features of both autoimmune and viral encephalitis [2,13,14]. Interestingly, according to the literature, Behçet disease seems to be the most common autoimmune aetio­logy of encephalitis involving the brainstem [6].
To the best of our knowledge, there is only one clinical description of encephalitis associated with RA in the literature. In the publication of Kitamura et al. [7] a 57-year-old, previously healthy patient had headache, depression, tremor of the hands, and anorexia persisting for 7 months and mild short-term memory loss, postural hand tremors, rigidity in the upper extremities, hyperreflexia, and truncal ataxia in the neurological examination. Laboratory and radiological evaluation revealed elevated CRP, ESR, ANA, RF, CCP, mild mononuclear pleocytosis, mildly elevated protein level in CSF, and symmetric, parenchymal lesions involving the medial temporal lobes in MRI. When joint pain and swelling appeared, the diagnosis of RA was set up, and treatment with methylprednisolone, prednisolone, and methotre­xate was administered with neurological and radiological improvement. In conclusion, the authors suggested AE as the first extra-articular manifestation of preclinical-stage RA. In contrast to the case presented by Kitamura et al. [7], our patient was older (68 years old), had a history of long-standing, seropositive RA controlled by chronic GKS, uterine cancer, and recurrent severe electrolyte disturbances; brain MRI and neurological examination indicated progressive, disseminated brain and spinal cord damage, particularly affecting brainstem, and there was no improvement after GKS treatment. Both patients had negative autoantibodies to paraneoplastic anti-neuronal and neuronal cell surface antigens. Although Kitamura et al. [7] suggest autoimmune aetiology of encephalitis, the aetiology in our case is more complex and includes consequences of CNS damage due to autoimmune parenchymal inflammation together with ischaemic consequences of vasculitis, ventilatory insufficiency, or hypotension. Moreover, elevated serum CCP may reflect disease activity as described Kitamura et al. [7], the normal levels of serum CCP in our patient may suggest previous CNS sensitization for the development of encephalitis. In summary, it seems that encephalitis/encephalomyelitis with both limbic and brainstem predominance can be an extra-articular manifestation of both preclinical or advanced stages of RA. Further research is needed to find out the pathophysiological relations between RA and encephalitis/ encephalomyelitis.
In conclusion, we present the first description of neuropathological changes in a patient with ence­phalomyelitis associated with RA in the literature. Our challenging clinical case underlines that both post-mortem brain examination and brain biopsy may be crucial in establishing the correct diagnosis and undertaking appropriate treatment in unclear cases with features of encephalitis and vasculitis. Thus, encephalomyelitis due to RA remains a controversial entity that needs further research and the establishment of effective diagnostic and treatment guidelines. Clinicians should be aware of encephalomyelitis as a possible CNS manifestation of RA.

Acknowledgments

This work was supported by “Digital Brain – digi­tal collection of the Institute Psychiatry and Neurology” (Project No. POPC.02.03.01-00.0042/18-00).
The project “Digital Brain” is co-funded by the European Union and the Polish budget. The authors are grateful to the First Polish Brain Bank in the Institute Psychiatry and Neurology, Warsaw, Poland.

Disclosure

The authors report no conflict of interest.