Managing CNS involvement in systemic lupus erythematosus

Epidemiology Systemic lupus erythematosus (SLE) is a systemic connective tissue disease with a broad range of clinical manifestations characterized by inflammatory and immune-mediated pathogenetic mechanisms. Since the first report of stupor and coma in the 19th century, several neuropsychiatric (NP) syndromes have been reported in SLE. The neurologic syndromes secondary to central, peripheral and autonomic nervous system involvement and the psychiatric syndromes observed in patients with lupus fall under the term NP SLE (NPSLE). In 1999, to define the clinical spectrum of NPSLE, an Ad Hoc Committee on behalf of the American College of Rheumatology (ACR) proposed nomenclature and case definition for 19 syndromes (Box 1). For each of these syndromes, diagnostic criteria and an exhaustive list of established exclusions or possible associations were provided in order to help determine the nature of NP event. According to criteria, NPSLE can be attributed to the disease (primary NPSLE) or be a complication of the disease or its treatment (secondary NPSLE), or be completely unrelated to SLE representing an accidentally co-occurring disorder [1]. Since their publication, the ACR classification criteria have been utilized in clinical practice and research. However, high variability in NPSLE prevalence is still recorded varying from 37 to 91% (TaBle 1) [2–6] as a consequence of differences in study populations, misinterpretation and low accuracy of the standardized criteria. In a 6-year prospective study, NPSLE occurred in 95% of childhood-onset SLE patients [7]; 50–60% of NPSLE events occur within the first year after disease onset and 41% of NP events occurring at the time of SLE diagnosis have their onset before [8]. The CNS is more frequently affected than the peripheral nervous system, the latter representing the target of 6–10% of NP events. Therefore, the reported difference in prevalence is mainly due to attribution given to CNS manifestations, especially minor events such as headache, mood disorders and cognitive dysfunction, which represent the most common manifestations of NPSLE. Ainiala et al. performed a population-based study covering an area with 440,000 people and estimated a NPSLE prevalence of 91% among patients suffering from SLE [6]. Assessing the validity of the ACR nomenclature for NPSLE in their cohort of 46 patients and 46 matched controls, the authors found a low specificity (46%) for the proposed criteria. They proposed a revision of the criteria excluding anxiety, headache as well as mild depression, mild cognitive dysfunction (with deficits in less than three domains) and polyneuropathy unconfirmed by electroneurography, which gave rise to a higher degree of specificity (93%) with a 46% detection rate among SLE cases [9]. More recently Hanly et al., in order to determine the prevalence of NPSLE in a multicenter inception cohort of 572 patients at the time of diagnosis (disease duration 5.2 ± 4.2 months), defined a set of decision rules that accounts for the comprehensive list of exclusions and associations in the ACR nomenclature, the revised The occurrence of neuropsychiatric manifestations in systemic lupus erythematosus (NPSLE) represents a diagnostic and therapeutic challenge for patients and clinicians. In this article we briefly discuss new perspectives on the pathogenesis, diagnosis, attribution and outcome of NPSLE. We speculated on the possible role of a rigorous preventive strategy, which takes into account the existence of associated risk factors that are yet to be fully defined, in the management of NPSLE. Finally, we highlight the management options and focus on the established and newly available treatment protocols for the more challenging, in terms of frequency or severity, clinical features of NPSLE.