Blood-brain barrier damage as a risk factor for corticosteroid-induced psychiatric disorders in systemic lupus erythematosus

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Summary

To clarify the incidence of and risk factors for corticosteroid-induced psychiatric disorders (CIPDs) in patients with systemic lupus erythematosus (SLE), we conducted a prospective study of 161 consecutive episodes in 155 inpatients with a SLE flare who were treated with corticosteroids. A subgroup of these patients, those who experienced a total of 22 episodes with current overt central nervous system manifestations of SLE (CNS-SLE), were excluded from follow-up. Results of clinical, laboratory, and neurologic tests (including electroencephalography, magnetic resonance imaging of the brain, and cerebrospinal fluid [CSF] analysis), performed within a week before corticosteroid administration, were assessed with regard to development of CIPDs. Within 8 weeks of corticosteroid administration, a diagnosis of CIPD was made for 14 (10.1%) of 139 episodes in 135 patients with a non-CNS-SLE flare. Using multiple logistic regression analysis, we identified positive Qalbumin (CSF/serum albumin ratio; an indicator of blood-brain barrier [BBB] damage) (odds ratio [OR], 33.3; 95% confidence interval [CI], 3.64–304; p=0.002) and low serum levels of complements (OR, 0.91; 95% CI, 0.83–1.00; p=0.047) as independent risk factors for CIPDs. Positive Qalbumin was detected in 45% (5 of 11) of episodes in which CIPDs developed. Compared with episodes in which no psychiatric events occurred, a higher level of Qalbumin was found in episodes in which CIPDs developed, and an even higher level was noted in episodes with active CNS-SLE (Jonckheere-Terpstra test, p<0.001). Although no causal links have been proven, the results from the present study raise the possibility that BBB damage may be associated with SLE- and corticosteroid-induced behavioral changes.

Introduction

Corticosteroids are the cornerstone of treatment for various inflammatory and immunologically mediated disorders, such as systemic lupus erythematosus (SLE). Despite widespread use, corticosteroid treatment is frequently associated with adverse psychiatric effects, including affective disorders, psychotic disorders, and delirium (Wolkowitz et al., 1997; Patten and Neutel, 2000). SLE is associated with a high incidence of psychiatric manifestations (West, 1994; Ainiala et al., 2001; Brey et al., 2002; Hanly et al., 2004).

It is unknown whether this association is a direct consequence of systemic autoimmunity and inflammation (e.g., entry of immune cells and molecules into the central nervous system [CNS]), an indirect effect (e.g., an epiphenomenon associated with accumulation of toxic metabolites), or a consequence of immunosuppressive therapy with corticosteroids (Kohen et al., 1993; Denburg et al., 1994; Wolkowitz et al., 1997)—because of similar or identical psychopathology (ACR Ad Hoc Committee on Neuropsychiatric Lupus Nomenclature, 1999; Patten and Neutel, 2000) and because no diagnostic gold standard of CNS manifestations of SLE (CNS-SLE) exists (West, 1994; ACR Ad Hoc Committee on Neuropsychiatric Lupus Nomenclature, 1999). Hypoalbuminemia has been demonstrated to be a risk factor for corticosteroid-induced psychiatric disorders (CIPDs) in SLE patients (López-Medrano et al., 2002; Chau and Mok, 2003), but the proposed mechanism remains speculative.

In general, brain damage or disease of any etiology may predispose a person to substance-induced psychiatric disorders such as delirium (Lipowski, 1990). Several abnormal findings associated with CNS involvement in SLE, including abnormal electroencephalographic findings, magnetic resonance images of the brain, and cerebrospinal fluid (CSF) findings, are observed in SLE patients, regardless of whether they exhibit current overt neuropsychiatric symptoms (West, 1994). Although this clinical or subclinical CNS involvement due to SLE might predispose a patient to CIPDs, to our knowledge, no clinical studies from this viewpoint have been reported.

The purpose of the present study was to clarify the incidence of and risk factors for CIPDs in SLE patients, especially with regard to potential CNS involvement in SLE.

Section snippets

Study design

First, to identify the incidence of CIPDs in SLE patients, we prospectively followed for 8 weeks consecutive inpatients with a non-CNS-SLE flare who were treated with corticosteroids. Second, to identify risk factors for CIPDs, we evaluated clinical, laboratory, and neurologic variables within a week before corticosteroid administration and compared them between groups that developed CIPDs and those that did not. Finally, to evaluate potential CNS involvement in SLE in patients developing

Incidence, clinical characteristics, and courses of CIPDs

CIPDs occurred in 14 (10.1%) of 139 episodes in 135 SLE patients without current overt CNS manifestations, as discussed in Section 2. In all 14 events, CIPDs developed within 4 weeks (mean, 12.5 days; range, 2–28 days) of corticosteroid administration. The mean dosage of corticosteroids administered was 51.4 mg/day (range, 40–60 mg/day) or 1.03 mg/kg/day (range, 0.82–1.40 mg/kg/day) as prednisolone. Psychotic disorders occurred in one event (7%), and mood disorders occurred in 13 events (93%),

Discussion

This prospective cohort study had three major findings. First, the incidence of CIPDs, according to the strict definition used, in SLE episodes without overt CNS manifestations was 10.1%. Second, independent risk factors for CIPDs were positive Qalbumin (an indicator of BBB damage) and hypocomplementemia. Third, positive Qalbumin was detected in approximately half the episodes with CIPDs or with active CNS-SLE, although compared with episodes in which no psychiatric events developed, levels of Q

Role of the founding source

The authors report no financial or other relationship relevant to the subjects of this article.

Conflict of interest

None declared.

Acknowledgments

The authors thank Drs. Jun Ishigooka, Naoshi Horikawa, Yasuhiro Katsumata, and Naoyuki Kamatani for helpful comments on the manuscript and Drs. Makihiko Suzuki and Eisuke Inoue for statistical consultation.

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