Central Nervous System Involvement in Systemic Autoimmune Rheumatic Diseases-Diagnosis and Treatment

Abstract

Central nervous system (CNS) involvement in autoimmune rheumatic diseases represents a significant challenge for clinicians across all specialties. While most reviews on the subject focus on neurological manifestations within a specific rheumatic disease, few descriptions shift from neurological clinical syndromes to achieve rheumatological diagnoses. This narrative review aims to synthesize current knowledge on the diagnosis and management of CNS manifestations occurring in the most prevalent rheumatic conditions in adults. We searched the MEDLINE database using the terms "central nervous system", "rheumatic diseases", "systemic lupus erythematosus", "rheumatoid arthritis", "Sjögren syndrome", and "vasculitis". The search strategy included review articles from 2019 to 2024, published in English, Spanish, or Portuguese. We explored the pathophysiological mechanisms linking autoimmunity to CNS pathology, emphasizing the role of syndromic reasoning, autoantibody profiles, and imaging modalities as tools for diagnosis and determination of inflammatory activity. The review also discusses differential diagnoses through a stepwise approach to neurological syndromes, summarized in diagnostic flowcharts, and presents updated treatment options. Although our approach is primarily semiology-based, the complexity of the subject invites future endeavors involving new technologies, such as functional MRI, MR spectroscopy, and nuclear medicine.

Keywords: central nervous system; connective tissue diseases; rheumatic diseases; systemic vasculitis.

Figure 1

Proposed approach for the patient with large-vessel cerebrovascular disease. * Two positive results for lupus anticoagulant, anticardiolipin, or anti-β-2-glycoprotein I, at least 12 weeks apart [9]. † Treat for conventional stroke and monitor for systemic features. Consider primary neurological syndromes (i.e., primary angiitis of the central nervous system). § Attributable to optic neuropathy. ‡ Thoracoabdominal computed tomography or magnetic resonance angiography. ¥ Clinically inflammatory arthritis and erythematous lesions. ¤ Consider reassessing cardiovascular risk factors for ischemic disease. ** By classification criteria, antinuclear antibodies are required for systemic lupus erythematosus diagnosis [24]. If isolated LVCVD is considered (i.e., an abrupt event of clinically significant arterial thrombosis without other inflammatory systemic features), APS is a plausible diagnosis if aPL are present. Consider primary angiitis of the central nervous system if these antibodies are absent. If systemic features are present, the type of systemic involvement can suggest the etiology: (1) peripheral nerve disease leans towards PAN or, rarely, SLE; (2) glomerulonephritis suggests AAV or SLE; (3) optic neuropathy in elderly patients is highly suggestive of GCA, with SLE to be considered in younger patients, especially if skin or joint disease is associated; and (4) if limb or jaw claudication occurs, large-vessel vasculitis is probable, and GCA and TAK should be investigated. Always consider primary atherosclerotic stroke as well, given its higher prevalence compared to autoimmune conditions, even in younger patients. Abbreviations: AAV: antineutrophil cytoplasm antibody (ANCA)-associated vasculitis; ANA: antinuclear antibodies; aPL: antiphospholipid antibodies; APS: antiphospholipid syndrome; Cr: serum creatinine; CRP: C reactive protein; DD: differential diagnosis; ESR: erythrocyte sedimentation rate; GCA: giant cell arteritis; HTN: arterial hypertension; IgG4D: IgG4-related disease; LVCVD: large-vessel cerebrovascular disease; MM: multiple mononeuritis; PAN: polyarteritis nodosa; PN: peripheral neuropathy; SLE: systemic lupus erythematosus; SMNP: sensorimotor polyneuropathy; TAK: Takayasu arteritis; UrP: urinary protein; UrRCC: urinary red cell casts; y: years of age.

Figure 2

Proposed approach for the patient with optic neuropathy and/or inflammatory myelopathy. * Clinically inflammatory arthritis and erythematous lesions. † According to classification criteria, the diagnosis of systemic lupus erythematosus requires the presence of antinuclear antibodies [24]. Consider testing for anti-DNA, anti-Sm, anti-ribosomal P protein, and antiphospholipid antibodies. § The probability of rheumatic conditions is already low, especially if gadolinium-enhanced magnetic resonance shows optic nerve enhancement. Consider ordering anti-aquaporin 4 and anti-myelin oligodendrocyte glycoprotein for differential diagnosis. ¤ This applies specifically to cases of isolated inflammatory myelopathy. In the presence of ocular manifestations, consider consulting with an ophthalmologist, as Behçet’s disease rarely causes optic neuritis but is strongly associated with uveitis [15]. Epidemiologically, GCA is the most common systemic vasculitis in adults, and ON is a hallmark of the disease. Therefore, every elderly patient with acute-onset amaurosis should be evaluated for GCA. In younger patients, SLE and SD should be considered. Among cases of IM, including those with ON, GCA is unlikely, and SLE and SD are the main culprits. BD and AAV are alternative diagnoses, but it is important to note that BD rarely causes ON and more commonly leads to uveitis and retinal vasculitis, which can usually be differentiated through ophthalmologic examination. Abbreviations: AAV: antineutrophil cytoplasm antibody (ANCA)-related vasculitis; BD: Behçet’s disease; CRP: C reactive protein; CTA: computed tomography angiography; ESR: erythrocyte sedimentation rate; GCA: giant cell arteritis; IM: inflammatory myelopathy; ON: optic neuropathy; OSS: ocular staining score (ophthalmic exam with specific dyes with the aim to document and quantify eye surface’s loss of epithelialization); RMA: magnetic resonance angiography; Sch: Schirmer’s test (quantification of lacrimal flow volume by time unit); SD: Sjögren’s disease; SLE: systemic lupus erythematosus; SM: unstimulated sialometry (simple quantification of salivary flow volume by time unit); TAUS: temporal artery ultrasound; y: years of age.

Figure 3

Proposed approach for the patient with aseptic meningitis or hypertrophic pachymeningitis. * The American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) classification criteria include an extensive exclusion criterion, requiring negativity for ANCA, anti-SSA/Ro, anti-SSB/La, anti-DNA, anti-Sm antibodies, and cryoglobulinemia [65]. † We suggest performing contrast-enhanced computed tomography of the thorax (for aseptic meningitis) or the thoracoabdominal region (for hypertrophic pachymeningitis). Because RA is the most prevalent autoimmune rheumatic disease worldwide and AM is well described in this condition, RA should always be considered as a potential final diagnosis. However, SLE, BD, sarcoidosis, and AAV are also possible diagnoses, making it challenging to narrow down AM among rheumatic diseases. Signs of glomerulonephritis and erythematous skin lesions can suggest SLE, while sinus involvement is more indicative of AAV. The eyes should be carefully examined by an ophthalmologist, as uveitis suggests BD, keratoconjunctivitis suggests SD, and scleritis or orbital involvement suggests AAV. Sarcoidosis typically affects the lungs and lymph nodes, which can guide diagnosis. When HP is found, RA, AAV, sarcoidosis, and IgG4D should be considered as potential causes. Pulmonary and mediastinal imaging can help narrow down the diagnoses, as typical patterns may emerge. Abbreviations: AAV: antineutrophil cytoplasm antibody (ANCA)-related vasculitis; ACPA: anti-citrullinated peptide antibodies; AM: aseptic meningitis; ANA: antinuclear antibodies; BD: Behçet’s disease; CT: computed tomography; HP: hypertrophic pachymeningitis; IgG4D: IgG4-related disease; OSS: ocular staining score (ophthalmic exam with specific dyes with the aim to document and quantify the eye surface’s loss of epithelialization); RA: rheumatoid arthritis; Sarc: sarcoidosis; Sch: Schirmer’s test (quantification of lacrimal flow volume by time unit); SD: Sjögren’s disease; SLE: systemic lupus erythematosus; SM: unstimulated sialometry (simple quantification of salivary flow volume by time unit); UrP: urinary protein; UrRCC: urinary red cell casts.