Spectrum of central nervous system involvement in rheumatic diseases: pictorial essay

The rheumatic diseases, which include systemic lupus erythematosus, rheumatoid arthritis, Behçet's disease, scleroderma, and ankylosing spondylitis, are characterized by involvement of connective tissue, with multiple manifestations. In those diseases, there can be involvement of the peripheral or central nervous system, and that involvement can be primary, presenting as a major feature of the clinical presentation, or secondary, as an effect of the drugs used in order to control a given disease or its complications. Knowledge of the wide variety of imaging findings is crucial to the diagnosis of a rheumatic disease, especially in the early stages, enabling effective treatment and minimizing disability. This pictorial essay, presenting cases from the records of two tertiary teaching hospitals, encompasses cases of patients diagnosed with rheumatic disease and illustrates the neuroradiological findings on magnetic resonance imaging and computed tomography, in order to emphasize the importance of these methods for properly diagnosing rheumatic diseases.


INTRODUCTION
Rheumatic diseases, including systemic lupus erythematosus, rheumatoid arthritis, Behçet's disease, sclero-derma, and ankylosing spondylitis, are characterized by involvement of the connective tissue of the entire body (1)(2)(3) . In such diseases, involvement of the central nervous system (CNS) or peripheral nervous system can be one of the main characteristics of the clinical picture or can be accompanied by other symptoms. CNS involvement, be it primary or secondary, can occur in the course of rheumatic diseases. The diagnosis depends on the knowledge of a variety of imaging findings, allows effective treatment, and minimizes disability.
This work brings together case files obtained over the last 15 years from the Radiology Departments of the Hospital das Clínicas da Universidade Estadual de Campinas and the Hospital Israelita Albert Einstein. We included patients with a confirmed diagnosis of systemic lupus erythematosus, rheumatoid arthritis, Behçet's disease, scleroderma, or ankylosing spondylitis. The objective was to illustrate neuroradiological findings in magnetic resonance imaging (MRI) and computed tomography (CT), emphasizing the usefulness of both for diagnostic purposes. The study was approved by the research ethics committees of the two institutions.  A B

SYSTEMIC LUPUS ERYTHEMATOSUS
Systemic lupus erythematosus is an autoimmune disease that often involves the CNS, with variable incidence. Neuropsychiatric syndromes are divided into central neurological disorders (aseptic meningitis, cerebrovascular disease, demyelination, headache, benign intracranial hypertension, movement disorders, myelopathy, and epilepsy) and psychiatric disorders (acute confusional state, anxiety disorder, cognitive dysfunction, and affective disorders) (4) . Imaging, especially MRI of the skull, facilitates the diagnosis. MRI is more sensitive than is CT and is considered the gold standard for evaluation of disease progression, and even for investigation. However, there are no specific MRI findings, and in view of the broad spectrum of clinical, biochemical, and pathological manifestations, the radiological findings are pleomorphic (4) .
Cerebral infarctions are common findings, not only in deep regions but also in cortical and subcortical regions. Regional or diffuse cerebral atrophy is common ( Figure  1A). Transient, reversible focal lesions (which can be ac-companied by vasogenic edema) may also be observed in the splenium of the corpus callosum ( Figure 1B). Less commonly, venous sinus thrombosis can be seen, with or without other peripheral thrombotic events, especially in patients with antiphospholipid syndrome.
Reversible posterior encephalopathy is observed, particularly when there is use of a maintenance dose of corticosteroids and hypertensive crisis ( Figure 2). It typically occurs in the parietal-occipital regions (the posterior circulation being most susceptible), although it can occur in the frontal region and basal nuclei, in which case it is accompanied by petechial hemorrhages.
In rare cases, bilateral, symmetric intraparenchymal calcifications are observed, especially in the basal nuclei, case reports citing a probable relationship with vasculopathy (5) . Another unusual form is a demyelinating disease, similar to multiple sclerosis, known as lupoid sclerosis. On MRI, there are findings of demyelinating lesions, including the multifocal white matter lesions seen in multiple sclerosis and vaso-occlusive disease, such as systemic lupus erythematosus.

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Myelitis is one of the most debilitating complications, typically with an MRI pattern of transverse myelitis: a long segment of involvement (height greater than two to three vertebral bodies), involving both halves of the medulla, with a swelling effect (6) .
Another spectrum is neonatal lupus with cardiac and cutaneous anomalies in newborns of mothers with anti-Ro/SSA and anti-La/SSB autoantibodies. In isolation, CNS involvement is rare and is described as transient vasculopathy. One case report in the literature described ischemic infarction secondary to CNS vasculitis (7) . In the present study, we describe the case of a neonate with convulsive seizures after birth and signs of acute ischemia on MRI (Figure 3).

RHEUMATOID ARTHRITIS
Rheumatoid arthritis is the most common inflammatory disease involving the spine and has a predilection for the craniocervical junction. The three main manifestations in the cervical spine are basilar invagination, atlantoaxial instability, and subaxial subluxation. The main finding on MRI is pannus formation around the atlanto-odontoid joint, consisting of inflammatory proliferation of synovial tissue, with a hypointense signal in T1-weighted sequences and a hyperintense signal when there is a long repetition time, accompanied by odontoid erosions, with enhancement after administration of paramagnetic contrast. Subluxations, such as atlanto-occipital subluxation (5% of patients), can lead to spinal canal stenosis and compressive myelopathies (8) . In the present study, we illustrate a case of involvement of the atlanto-occipital joint (Figure 4). Another manifestation in the CNS is rheumatoid meningitis, with involvement of the meninges characterized by sulcal hyperintensity in fluid-attenuated inversion recovery (FLAIR) sequences, together with thickening and enhancement of the leptomeninges and pachymeninges. The diagnosis is confirmed through histopathological analysis, which will show rheumatoid nodules, nonspecific meningeal inflammation or vasculitis (9) .

BEHÇET'S DISEASE
Behçet's disease has vascular, inflammatory, and multisystemic origins. Increasing clinical and imaging evidence suggests that the primary neurological involvement in Behçet's disease can be subclassified into several forms. The most common such form is characterized as

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an inflammatory vascular disease of the CNS with focal or multifocal involvement of the parenchyma, which in most patients presents as a subacute brainstem syndrome accompanied by hemiparesis. Another form, mildly symptomatic and with a better prognosis, can be caused by isolated cerebral venous thrombosis and intracranial hypertension. During the acute phase, Behçet's disease can present hyperintense lesions on contrast-enhanced T2-weighted/FLAIR MRI images. The subthalamic region and brainstem are common sites of involvement, although there can also be involvement of the basal nuclei, cerebral hemispheres, and spinal cord (10) . In the present study, we observed an atypical presentation: a pseudotumor of inflammatory origin caused by Behçet's disease (diagnosis confirmed by stereotactic biopsy with anatomical pathology of gliosis with gemistocytic astrocytes), as depicted in Figure 5. We also describe a patient who developed a dural fistula after venous thrombosis ( Figure 6).

SCLERODERMA
Scleroderma is a rare autoimmune disease characterized by inflammation, vascular injury, and fibrosis. Linear scleroderma includes a spectrum from localized scleroderma to systemic sclerosis.
Linear scleroderma is considered a disease limited to the skin, subcutaneous tissue, and underlying bone. In the craniofacial subtype, there is neurological involvement. Linear scleroderma "en coup de sabre" is a rare subtype of linear scleroderma. In its typical presentation, it affects the frontoparietal region. The "en coup de sabre" lesion is defined as a banded lesion on the frontoparietal scalp and forehead. The associated atrophy of muscle structures, cartilage, and facial bones should raise the hypothesis of Parry-Romberg syndrome, up to 28% of patients with linear scleroderma manifest features of that syndrome, such as slowly progressive unilateral atrophy of the face. CT scans of the skull show narrowing of the external diploic space, cerebral atrophy, subcortical lesions, focal subcortical calcifications, and pachymeningeal abnormalities. Intraparenchymal calcifications involving basil nuclei, the thalamus, and dentate nuclei are more common ipsilateral to the cutaneous lesion, although contralateral involvement can occur. In T2-weighted MRI sequences, there are usually foci of hyperintense signals, mainly in the subcortical white matter but also in the corpus callosum, deep gray nuclei, and brainstem. Cerebral atrophy is subtle and focal, characterized by lack of definition of the cortical-subcortical interface, cortical thickening, and abnormal gyral pattern (11,12) . We illustrate a case of linear scleroderma "en coup de sabre" in combination with Parry-Romberg syndrome (Figure 7).

ANKYLOSING SPONDYLITIS
Ankylosing spondylitis is an inflammatory arthropathy with enthesopathy of the axial skeleton and complications that affect the neuraxis. The most common symptoms are insidious lumbar pain, stiffness and asymmetric peripheral oligoarthritis. Osteoporosis is frequent and the risk of fractures is increased in relation to the general population. Characteristic imaging findings include diffuse osteopenia; bilateral, symmetric sacroiliitis; and calcification of the longitudinal ligaments, syndesmophytes forming the socalled "bamboo spine". Transverse fractures that cross the entire spine, associated with minor trauma, usually in the cervicothoracic or thoracolumbar junction, can occur, resulting in myelopathy and epidural hematoma. MRI shows Romanus and Anderson lesions, which are signal intensity changes in the margins and center of the vertebral bodies, respectively (13) . In the present study, we identified the case of a patient with transverse spine fracture in the lumbar spine after mild trauma, with no previous diagnosis of ankylosing spondylitis (Figure 8).

CONCLUSION
CNS involvement in rheumatic diseases is pleomorphic and nonspecific. However, neuroimaging patterns can affect the diagnosis, in the initial manifestation and in the evaluation of complications.