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Psychiatric manifestations in systemic lupus erythematosus
Autoimmunity Reviews 6 (2007) 421 – 426 www.elsevier.com/locate/autrev
Psychiatric manifestations in systemic lupus erythematosus Ljudmila Stojanovich a,⁎,1 , Gisele Zandman-Goddard b,c,1 , Sanja Pavlovich a , Natasa Sikanich d a
Department of Internal Medicine, “Bezhanijska Kosa” University Medical Center, Belgrade University, Serbia and Montenegro b Department of Medicine C, Wolfson Medical Center, Holon, Israel c Sackler Faculty of Medicine, Tel-Aviv University, Israel d Psychiatry Clinic, Clinical Hospital Center “Dr Dragisa Mishovic”, Serbia and Montenegro Received 7 November 2006; accepted 14 February 2007 Available online 12 March 2007
Abstract Psychiatric abnormalities are common in systemic lupus erythematosus (SLE) with a prevalence of 17% to 75%, reflecting different methods of patient selection and assessment, the different professional orientation of clinicians, and lack of an accepted consensus for diagnosing active neuropsychiatric lupus (NPSLE). The psychiatric syndromes included in the ACR Neuropsychiatric Lupus Nomenclature Committee criteria are cognitive dysfunction, acute confusional state (delirium), anxiety disorder, mood disorder, and psychosis. In SLE patients, identification of psychiatric phenomena and the generation of a differential diagnosis are crucial. Possible mechanisms include vascular injury and pathogenic antibodies. Treatment strategies are based on small case studies. The purpose of this review is to discuss clinical manifestations, pathogenesis and the present therapeutic options in psychiatric lupus. © 2007 Elsevier B.V. All rights reserved. Keywords: Systemic lupus erythematosus; Psychiatric lupus; Cognitive dysfunction; Depression; Psychosis
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Introduction . . . . . . . . . . . . . Psychiatric lupus manifestations . . . 2.1. Cognitive dysfunction . . . . . 2.2. Anxiety, mood, and depressive 2.3. Delirium. . . . . . . . . . . . 2.4. Psychosis . . . . . . . . . . . Autoantibodies in NPSLE . . . . . . Pathogenesis . . . . . . . . . . . . . 4.1. APS Abs . . . . . . . . . . .
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⁎ Corresponding author. “Bezhanijska Kosa” University Medical Center, Bezanijski put b.b. Novi Beograd, Belgrade, 11080, Serbia and Montenegro. Tel.: +381 11 3010 777; fax: +381 11 2606 520. E-mail address: [email protected] (L. Stojanovich). 1 Both authors contributed equally to this work. 1568-9972/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2007.02.007
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4.2. NMDA receptor Abs. . . . . . 5. Treatment of psychiatric manifestations 6. Conclusions . . . . . . . . . . . . . . Take-home messages . . . . . . . . . . . . References . . . . . . . . . . . . . . . . .
. . . . . . . . . . . in patients with SLE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease affecting multiple organ systems, including the skin, joints, kidneys, and nervous system. Neuropsychiatric SLE (NPSLE) is one of the most important manifestations of SLE [1], and includes neurological syndromes of the central, peripheral, and autonomic nervous system, as well as psychiatric disorders. Psychiatric syndromes associated with SLE are diverse in etiology and presentation [2]. These manifestations can be the presenting manifestation of SLE or occur at any time during the disease. Controversy exists concerning the factors responsible for psychiatric manifestations in these patients, which have been attributed to pathophysiology of the disease [3], iatrogenic effects of corticosteroids [4], and psychosocial stressors related to chronic disease [5]. In this review, we will explore the clinical manifestations, pathogenetic mechanisms, classification and possible treatment strategies for psychiatric manifestations of the SLE. 2. Psychiatric lupus manifestations In 1999, the American College of Rheumatology (ACR) committee [1] adopted the terminology of DSMIV for neuropsychiatric lupus syndromes [6] to include cognitive dysfunction, delirium (acute confusional state), anxiety disorder, mood disorder, and psychosis. There is no single diagnostic test that is sensitive or specific for NPSLE. The proper diagnosis depends on the combination of a rheumatologic exam, brain imaging, immunoserological, psychiatric and neuropsychological tests, in the presence of lupus disease activity. Neuropsychological tests are standardized, validated in both research and clinical settings, and analyzed in reference to expected levels of performance expressed as normative data.
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terity and attention/mental flexibility. Within 10 studies, the majority of SLE patients had impairment in 3 or more of the cognitive domains [7]. A recent study on 21 NPSLE patients reported poor performance on verbal and memory tests [8]. In addition, in SLE patients with cognitive dysfunction, anatomical defects defined by brain MRI, functional assessment utilizing SPECT, or MRS (magnetic resonance spectroscopy) that combines anatomic and functional analysis are often found. More severe cognitive dysfunction in SLE patients may be associated with the presence of antiphospholipid syndrome (APS). The persistence of elevated anticardiolipin (aCL) antibodies (Abs) over 1–5 years is linked to a greater and sustained cognitive impairment and may cause long-term subtle deterioration in cognitive function [9,10]. When evaluating the different isotypes, elevated IgG aCL Ab titers are linked to reduced psychomotor speed while elevated IgA aCL Ab titers are linked to reduced conceptual reasoning and executive function [10]. Patients with NPSLE show significantly higher levels of aCL Abs [9]. The incidence of dementia in APS is high in some studies and may contribute to significant morbidity [11]. The association between elevated titers of aCL Abs and a pattern of cognitive dysfunction characterized by difficulties with verbal memory, productivity and speeded output has been replicated in longitudinal studies of cognitive function [7,10–12]. A higher risk of central nervous system (CNS) involvement at the onset of SLE is also associated with higher levels of lupus anticoagulant (LA), aCL-IgG Abs and hypocomplementemia [12]. Among NPSLE patients, prior neuropsychiatric events and APS increase the risk of adverse outcomes [13]. Cognitive dysfunction is not cumulative over time in the majority of SLE patients, and their test performance indicates more or less stable neuropsychological dysfunction [14]. 2.2. Anxiety, mood, and depressive features
2.1. Cognitive dysfunction Cognitive functioning encompasses 5 major areas including general intelligence, verbal learning/memory, visual–spatial skills, psychomotor speed/manual dex-
A significant number of patients with SLE (10.8%– 39.6%) suffer from depression (DPR). Risk factors for DPR include CNS involvement in lupus including direct brain damage, concomitant neuropsychiatric disorders,
L. Stojanovich et al. / Autoimmunity Reviews 6 (2007) 421–426
steroid administration, and the patient's response to the burden of disease [15]. In a study of 71 lupus patients, those with DPR presented higher SLE Disease Activity Indices (SLEDAI) reflecting more severe manifestations or multiple mild involvements. Furthermore, the Systemic Lupus International Collaboration Clinics (SLICC) damage index (measuring accumulated damage) was similar between patients with or without DPR. Patients with higher SLEDAI scores had more severe DPR that remained substantial and associated with disease activity when controlling for history of previous major depressive events, occurrence of life events, and steroid dosage [15]. The problem of acute onset of DPR and psychosis is particularly relevant to the SLE patients and testing for elevated titers of anti-ribosomal P Ab has been demonstrated to be clinically useful by some, but refused by others [16–18]. In SLE patients, careful identification of psychiatric phenomena and generation of a differential diagnosis are crucial. 2.3. Delirium Delirium appears as one of the uncommon psychiatric manifestations of SLE. The severity of delirium seen in SLE patients can vary widely from mild confusion, and mildly disturbed attention and concentration spans to profound disorganization with agitation and hallucinations. DSM-IV [6] differentiates delirium as including impaired perception and attention, with an acute or sub-acute onset (unlike dementia), diurnal fluctuations, and with evidence of a general medical condition. The most common differential diagnostic problem with delirium in the SLE patient is determining whether the delirium is due to exacerbation of the primary disease or CNS infection, metabolic derangement or an adverse effect of corticosteroids. Furthermore, vascular and hemorrhagic sequelae of SLE involvement of the brain include subarachnoid hemorrhage, lupus meningitis, or strokes, all of which can be associated with delirium [20]. In some SLE patients, delirium (encephalopathy) is preceded by DPR and seizures and may be reversible, or it may progress towards coma. Many possible causes including small vessel vasculopathy or vasculitis, leucoencephalopathy, acute disseminated encephalitis, brain edema due to cerebral venous thrombosis, or syndrome of inappropriate diuretic hormone released [19].
pathological nature [6]. During the evaluation of any psychotic patient, organic systemic disease must be considered. SLE psychosis may present by paranoia with visual and auditory hallucinations [20]. Recovery is complete but relapses are not uncommon. The incidence of psychosis in SLE is not easy to estimate reliably because the literature often fails to distinguish psychosis as defined here from delirium and other conditions, and because the distinction from corticosteroid psychosis is difficult. In a prospective study, 3 of 196 SLE patients evaluated consecutively had psychosis [21]. In a large and oftenquoted retrospective study, 11 of 266 patients developed psychosis during a mean follow-up period of at least 90 months [22]. 3. Autoantibodies in NPSLE SLE is exceptional among autoimmune diseases, not only in its multi-system nature, but in its capacity to produce a multitude of Abs. To date, more than 116 Abs have been reported in SLE [23]. In our recent study, 20 Abs (eleven brain-specific Abs and nine systemic Abs) associated with NPSLE were identified in a thorough MEDLINE search [24]. Psychiatric diffuse manifestations were linked with at least 5 different Abs (Tables 1 and 2). Elevated titers of aCL Ab and LA Abs were most reported and found in patients with cognitive impairment, psychosis, depression, seizures, chorea, and migraine. In the setting of known lupus, BRAA was associated with depression and cognitive dysfunction. [25]. There is compelling evidence for the pathogenic Table 1 Psychiatric manifestations and associated Abs NPSLE manifestation
Associated Ab
Cognitive dysfunction
Anti-neuronal Abs Anti-NMDA Abs AGA LCA aCL, LA Anti-Ro Abs Anti-neuronal Abs BRAA Anti-MAP-2 aCL, LA Anti-P Anti-Ro Anti-Sm Abs Anti-NMDA Abs AGA aCL Anti-P Abs AECA
Psychosis
Depression
2.4. Psychosis In the DSM-IV, psychotic events refer to delusions or prominent hallucinations, without insight into their
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Reviewed in Zandman-Goddard et al., [24].
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Table 2 AutoAbs associated with specific psychiatric manifestations a Group
Autoantibody
NP manifestation
Brain-specific
Neuronal
Cognitive dysfunction Psychosis Psychosis
Brain-reactive antigen Ab (BRAA) N-methyl-D-aspartate (NMDA) MAP-2 Ganglioside (AGA) Serum lymphocytotoxic Neurofilament
Systemic
Glial fibrillary acidic protein (GFAP) Cardiolipin (aCL)
LA Endothelial cell (AECA) Nedd5 Ribosomal P (anti-P) Ro (SSA)-serum Sm
Cognitive dysfunction Depression Psychosis Cognitive dysfunction Depression Cognitive dysfunction Diffuse NP manifestations b Organic/major type NP manifestations Dementia Psychosis Depression Cognitive dysfunction Cognitive dysfunction Psychosis Mood disorders NP manifestationsb Psychosis Depression Cognitive dysfunction; psychosis Psychosis
a
Reviewed in Zandman-Goddard et al. [24]. NP manifestations – referred as a group, no specific manifestation stated. b
effect of anti-NMDA Ab on the brain in an experimental lupus model (discussed in Section 4) [26–29]. ACL Abs and LA, were the most widely investigated Abs for various NP manifestations. While the association of aCL Abs and focal neurological disease is well established, aCL Abs were recently found to be associated with cognitive dysfunction [30]. Several studies have confirmed the association of anti-ribosomal P Abs with NP manifestations, predominantly psychosis and depression, while others dispute this correlation [16]. In a recent meta-analysis, anti-P Ab testing had limited diagnostic value for NPSLE, and was not helpful in differentiating among various disease phenotypes [18]. A correlation between Abs against endothelial cells (AECA) with diffuse NP manifestations may indicate a vascular nature of NPSLE [31]. AECA are a group of heterogeneous Abs that react with different endothelial cell antigens. The proportion of AECA-positive sera ranges from 15% to 80% in SLE, and recent data suggest their involvement in endothelial dysfunction and a pathogenic role of AECA in SLE. The same study demonstrates a significant association between AECA
and psychiatric symptoms in SLE patients, a feature not previously reported, implying a role of AECA in the development of NPSLE. 4. Pathogenesis Despite extensive research, the precise mechanisms underlying nervous tissue injury remain poorly understood. Two postulated mechanisms for NPSLE include vascular occlusion (secondary – APS), and injury by pathogenic Abs. 4.1. APS Abs Experimental models show direct evidence for the pathogenicity of aCL Ab in cognitive dysfunction. In one experimental model of APS, female BALB/c mice, immunized with a pathogenic monoclonal aCL Ab, developed hyperactive behavior in an open field, which tests spatial behavior and displayed impaired motor coordination on a rotating bar. The titers of aCL, anti-β2 glycoprotein I Abs, and AECA were elevated in the sera. Thrombotic occlusions of capillaries in combination with mild inflammation were the main findings in mouse brain tissue examination [24,32]. In another experimental model of APS, mice immunized with β2-GPI (that lead to the development of anti-β2-GPI Ab), exhibited hyperactive behavior, as reflected by more frequent rears and a higher number of stairs climbed by the mice at specific time intervals [33]. More direct evidence for the pathogenic potential of aPL was by intracerebroventricular (i.c.v.) administration of immunoglobulin from patients with APS to male C3H that demonstrated binding to the hippocampus and cerebral cortex by immunohistological staining. Mice injected with this IgG performed worse in the water maze than the controls with significant effects attributed to aCL IgG regarding the overall performance of the mice. These results support the hypothesis that aCL Ab that gain access to the CNS may play a direct role in the pathogenesis of the neurological manifestations of APS [34]. In vitro studies and results from a variety of animal models indicate that aCL Abs induce endothelial activation and a prothrombotic state. In addition, LA or aCL Abs have been linked with atherosclerosis, another mechanism that contributes to CNS ischemia [35]. 4.2. NMDA receptor Abs NMDA receptors Abs are present in the CSF and can cause neuronal death in the mouse brain. Mice immunized with NR2 peptide produce anti-DNA Ab. However, mice immunized with anti-NR2 Ab did not
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have immunoglobulin deposition in the brain. This indicates that an intact blood brain barrier protects the brain from autoAb invasion. Hence, by exposing mice to lipopolysaccharide (LPS) causing experimental infection, immunization with anti-NR2 Abs led to deposition in the hippocampal region, the area responsible for memory. Furthermore, injection of lupus serum from a NP patient caused apoptosis of neurons. The same Ab may be responsible for more than one manifestation of NPSLE [26,27]. Despite these intriguing results in an experimental lupus model, recent studies could not verify the correlation of anti-NMDA Ab with cognitive dysfunction in SLE patients at a given point or over time. One clinical study found a correlation with depression [36]. Possible explanations for the discrepancy between the experimental model and the clinical studies could be methodological differences in cognitive testing, Ab measurements, or selection of the study participants. Another option is that the permeability of the BBB, resulting in accelerated access of anti-NR2 Abs to neuronal tissue may have a transient but cumulative effect. Furthermore, a dose-dependent mechanism may explain that exposure to lower levels of anti-NR2 Abs may lead to manifestations of DPR, and higher levels may lead to cognitive dysfunction by causing neuronal death [36]. Possibly, because of the persistence of Abs leads to cognitive dysfunction [35,36]. Thus, the correlation of anti-NR2a Abs with clinical NPSLE remains to be determined. 5. Treatment of psychiatric manifestations in patients with SLE Given the diversity in clinical manifestations, the management is tailored to the specific needs of individual patients. The management of psychiatric lupus manifestations is often frustrating and currently no consensus is available. Counseling and other interventions that assist a person in developing coping skills may be helpful. In the absence of controlled studies, the use of symptomatic therapies, immunosuppressive, anticoagulants and adjunctive psychotropic medication is supported by case series and clinical experience [37]. The present treatment strategies for the various psychiatric manifestations, based on small open trials, include prednisone, cyclophosphamide [38], IVIG [39], together with atypical psychotropic drugs. Selective serotonin reuptake inhibitors (SSRIs) are the first line of treatment for depression in SLE patients because of their safety and tolerability. In unresponsive cases, augmentation and combination strategies may be beneficial [37]. Anticoagulation is warranted in patients with thrombotic disease, particularly in those with the APS [37].
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Treatment of delirium caused by NPSLE is to alter the corticosteroid dosage; a prompt and beneficial effect differentiates delirium caused by NPSLE- or steroidinduced delirium [37]. Acute management of agitation and psychotic symptoms can be achieved with low doses of neuroleptics. 6. Conclusions Psychiatric abnormalities are common accompaniments of SLE. Cognitive dysfunction appears to be more common than previously thought, but its clinical significance and prognostic implications remain unclear. Five different psychiatric syndromes are currently accepted in ACR Neuropsychiatric Lupus Nomenclature Committee criteria consensus: cognitive dysfunction, delirium (acute confusional state), anxiety disorder, mood disorder, and psychosis. The exact role of Abs in the pathogenesis of specific lupus psychiatric manifestations warrants further clarification in prospective studies. Treatment is customized to the psychiatric disorder coupling immunosuppressant and psychotropic modalities. Possibly, establishing a consensus of diagnosis together with an appropriate panel of Abs would be advantageous for the proper management of these patients. Take-home messages abnormalities are common accompani⋅ Psychiatric ments of SLE. Cognitive dysfunction appears to be
⋅ ⋅
more common than previously thought, but its clinical significance and prognostic implications remain unclear. Five different psychiatric syndromes are currently accepted in ACR Neuropsychiatric Lupus Nomenclature Committee criteria consensus: cognitive dysfunction, delirium (acute confusional state), anxiety disorder, mood disorder, and psychosis. The exact role of Abs in the pathogenesis of specific lupus psychiatric manifestations warrants further clarification in prospective studies.
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Psychiatric manifestations in systemic lupus erythematosus Ljudmila Stojanovich a,⁎,1 , Gisele Zandman-Goddard b,c,1 , Sanja Pavlovich a , Natasa Sikanich d a
Department of Internal Medicine, “Bezhanijska Kosa” University Medical Center, Belgrade University, Serbia and Montenegro b Department of Medicine C, Wolfson Medical Center, Holon, Israel c Sackler Faculty of Medicine, Tel-Aviv University, Israel d Psychiatry Clinic, Clinical Hospital Center “Dr Dragisa Mishovic”, Serbia and Montenegro Received 7 November 2006; accepted 14 February 2007 Available online 12 March 2007
Abstract Psychiatric abnormalities are common in systemic lupus erythematosus (SLE) with a prevalence of 17% to 75%, reflecting different methods of patient selection and assessment, the different professional orientation of clinicians, and lack of an accepted consensus for diagnosing active neuropsychiatric lupus (NPSLE). The psychiatric syndromes included in the ACR Neuropsychiatric Lupus Nomenclature Committee criteria are cognitive dysfunction, acute confusional state (delirium), anxiety disorder, mood disorder, and psychosis. In SLE patients, identification of psychiatric phenomena and the generation of a differential diagnosis are crucial. Possible mechanisms include vascular injury and pathogenic antibodies. Treatment strategies are based on small case studies. The purpose of this review is to discuss clinical manifestations, pathogenesis and the present therapeutic options in psychiatric lupus. © 2007 Elsevier B.V. All rights reserved. Keywords: Systemic lupus erythematosus; Psychiatric lupus; Cognitive dysfunction; Depression; Psychosis
Contents 1. 2.
3. 4.
Introduction . . . . . . . . . . . . . Psychiatric lupus manifestations . . . 2.1. Cognitive dysfunction . . . . . 2.2. Anxiety, mood, and depressive 2.3. Delirium. . . . . . . . . . . . 2.4. Psychosis . . . . . . . . . . . Autoantibodies in NPSLE . . . . . . Pathogenesis . . . . . . . . . . . . . 4.1. APS Abs . . . . . . . . . . .
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⁎ Corresponding author. “Bezhanijska Kosa” University Medical Center, Bezanijski put b.b. Novi Beograd, Belgrade, 11080, Serbia and Montenegro. Tel.: +381 11 3010 777; fax: +381 11 2606 520. E-mail address: [email protected] (L. Stojanovich). 1 Both authors contributed equally to this work. 1568-9972/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2007.02.007
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4.2. NMDA receptor Abs. . . . . . 5. Treatment of psychiatric manifestations 6. Conclusions . . . . . . . . . . . . . . Take-home messages . . . . . . . . . . . . References . . . . . . . . . . . . . . . . .
. . . . . . . . . . . in patients with SLE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease affecting multiple organ systems, including the skin, joints, kidneys, and nervous system. Neuropsychiatric SLE (NPSLE) is one of the most important manifestations of SLE [1], and includes neurological syndromes of the central, peripheral, and autonomic nervous system, as well as psychiatric disorders. Psychiatric syndromes associated with SLE are diverse in etiology and presentation [2]. These manifestations can be the presenting manifestation of SLE or occur at any time during the disease. Controversy exists concerning the factors responsible for psychiatric manifestations in these patients, which have been attributed to pathophysiology of the disease [3], iatrogenic effects of corticosteroids [4], and psychosocial stressors related to chronic disease [5]. In this review, we will explore the clinical manifestations, pathogenetic mechanisms, classification and possible treatment strategies for psychiatric manifestations of the SLE. 2. Psychiatric lupus manifestations In 1999, the American College of Rheumatology (ACR) committee [1] adopted the terminology of DSMIV for neuropsychiatric lupus syndromes [6] to include cognitive dysfunction, delirium (acute confusional state), anxiety disorder, mood disorder, and psychosis. There is no single diagnostic test that is sensitive or specific for NPSLE. The proper diagnosis depends on the combination of a rheumatologic exam, brain imaging, immunoserological, psychiatric and neuropsychological tests, in the presence of lupus disease activity. Neuropsychological tests are standardized, validated in both research and clinical settings, and analyzed in reference to expected levels of performance expressed as normative data.
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terity and attention/mental flexibility. Within 10 studies, the majority of SLE patients had impairment in 3 or more of the cognitive domains [7]. A recent study on 21 NPSLE patients reported poor performance on verbal and memory tests [8]. In addition, in SLE patients with cognitive dysfunction, anatomical defects defined by brain MRI, functional assessment utilizing SPECT, or MRS (magnetic resonance spectroscopy) that combines anatomic and functional analysis are often found. More severe cognitive dysfunction in SLE patients may be associated with the presence of antiphospholipid syndrome (APS). The persistence of elevated anticardiolipin (aCL) antibodies (Abs) over 1–5 years is linked to a greater and sustained cognitive impairment and may cause long-term subtle deterioration in cognitive function [9,10]. When evaluating the different isotypes, elevated IgG aCL Ab titers are linked to reduced psychomotor speed while elevated IgA aCL Ab titers are linked to reduced conceptual reasoning and executive function [10]. Patients with NPSLE show significantly higher levels of aCL Abs [9]. The incidence of dementia in APS is high in some studies and may contribute to significant morbidity [11]. The association between elevated titers of aCL Abs and a pattern of cognitive dysfunction characterized by difficulties with verbal memory, productivity and speeded output has been replicated in longitudinal studies of cognitive function [7,10–12]. A higher risk of central nervous system (CNS) involvement at the onset of SLE is also associated with higher levels of lupus anticoagulant (LA), aCL-IgG Abs and hypocomplementemia [12]. Among NPSLE patients, prior neuropsychiatric events and APS increase the risk of adverse outcomes [13]. Cognitive dysfunction is not cumulative over time in the majority of SLE patients, and their test performance indicates more or less stable neuropsychological dysfunction [14]. 2.2. Anxiety, mood, and depressive features
2.1. Cognitive dysfunction Cognitive functioning encompasses 5 major areas including general intelligence, verbal learning/memory, visual–spatial skills, psychomotor speed/manual dex-
A significant number of patients with SLE (10.8%– 39.6%) suffer from depression (DPR). Risk factors for DPR include CNS involvement in lupus including direct brain damage, concomitant neuropsychiatric disorders,
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steroid administration, and the patient's response to the burden of disease [15]. In a study of 71 lupus patients, those with DPR presented higher SLE Disease Activity Indices (SLEDAI) reflecting more severe manifestations or multiple mild involvements. Furthermore, the Systemic Lupus International Collaboration Clinics (SLICC) damage index (measuring accumulated damage) was similar between patients with or without DPR. Patients with higher SLEDAI scores had more severe DPR that remained substantial and associated with disease activity when controlling for history of previous major depressive events, occurrence of life events, and steroid dosage [15]. The problem of acute onset of DPR and psychosis is particularly relevant to the SLE patients and testing for elevated titers of anti-ribosomal P Ab has been demonstrated to be clinically useful by some, but refused by others [16–18]. In SLE patients, careful identification of psychiatric phenomena and generation of a differential diagnosis are crucial. 2.3. Delirium Delirium appears as one of the uncommon psychiatric manifestations of SLE. The severity of delirium seen in SLE patients can vary widely from mild confusion, and mildly disturbed attention and concentration spans to profound disorganization with agitation and hallucinations. DSM-IV [6] differentiates delirium as including impaired perception and attention, with an acute or sub-acute onset (unlike dementia), diurnal fluctuations, and with evidence of a general medical condition. The most common differential diagnostic problem with delirium in the SLE patient is determining whether the delirium is due to exacerbation of the primary disease or CNS infection, metabolic derangement or an adverse effect of corticosteroids. Furthermore, vascular and hemorrhagic sequelae of SLE involvement of the brain include subarachnoid hemorrhage, lupus meningitis, or strokes, all of which can be associated with delirium [20]. In some SLE patients, delirium (encephalopathy) is preceded by DPR and seizures and may be reversible, or it may progress towards coma. Many possible causes including small vessel vasculopathy or vasculitis, leucoencephalopathy, acute disseminated encephalitis, brain edema due to cerebral venous thrombosis, or syndrome of inappropriate diuretic hormone released [19].
pathological nature [6]. During the evaluation of any psychotic patient, organic systemic disease must be considered. SLE psychosis may present by paranoia with visual and auditory hallucinations [20]. Recovery is complete but relapses are not uncommon. The incidence of psychosis in SLE is not easy to estimate reliably because the literature often fails to distinguish psychosis as defined here from delirium and other conditions, and because the distinction from corticosteroid psychosis is difficult. In a prospective study, 3 of 196 SLE patients evaluated consecutively had psychosis [21]. In a large and oftenquoted retrospective study, 11 of 266 patients developed psychosis during a mean follow-up period of at least 90 months [22]. 3. Autoantibodies in NPSLE SLE is exceptional among autoimmune diseases, not only in its multi-system nature, but in its capacity to produce a multitude of Abs. To date, more than 116 Abs have been reported in SLE [23]. In our recent study, 20 Abs (eleven brain-specific Abs and nine systemic Abs) associated with NPSLE were identified in a thorough MEDLINE search [24]. Psychiatric diffuse manifestations were linked with at least 5 different Abs (Tables 1 and 2). Elevated titers of aCL Ab and LA Abs were most reported and found in patients with cognitive impairment, psychosis, depression, seizures, chorea, and migraine. In the setting of known lupus, BRAA was associated with depression and cognitive dysfunction. [25]. There is compelling evidence for the pathogenic Table 1 Psychiatric manifestations and associated Abs NPSLE manifestation
Associated Ab
Cognitive dysfunction
Anti-neuronal Abs Anti-NMDA Abs AGA LCA aCL, LA Anti-Ro Abs Anti-neuronal Abs BRAA Anti-MAP-2 aCL, LA Anti-P Anti-Ro Anti-Sm Abs Anti-NMDA Abs AGA aCL Anti-P Abs AECA
Psychosis
Depression
2.4. Psychosis In the DSM-IV, psychotic events refer to delusions or prominent hallucinations, without insight into their
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Reviewed in Zandman-Goddard et al., [24].
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Table 2 AutoAbs associated with specific psychiatric manifestations a Group
Autoantibody
NP manifestation
Brain-specific
Neuronal
Cognitive dysfunction Psychosis Psychosis
Brain-reactive antigen Ab (BRAA) N-methyl-D-aspartate (NMDA) MAP-2 Ganglioside (AGA) Serum lymphocytotoxic Neurofilament
Systemic
Glial fibrillary acidic protein (GFAP) Cardiolipin (aCL)
LA Endothelial cell (AECA) Nedd5 Ribosomal P (anti-P) Ro (SSA)-serum Sm
Cognitive dysfunction Depression Psychosis Cognitive dysfunction Depression Cognitive dysfunction Diffuse NP manifestations b Organic/major type NP manifestations Dementia Psychosis Depression Cognitive dysfunction Cognitive dysfunction Psychosis Mood disorders NP manifestationsb Psychosis Depression Cognitive dysfunction; psychosis Psychosis
a
Reviewed in Zandman-Goddard et al. [24]. NP manifestations – referred as a group, no specific manifestation stated. b
effect of anti-NMDA Ab on the brain in an experimental lupus model (discussed in Section 4) [26–29]. ACL Abs and LA, were the most widely investigated Abs for various NP manifestations. While the association of aCL Abs and focal neurological disease is well established, aCL Abs were recently found to be associated with cognitive dysfunction [30]. Several studies have confirmed the association of anti-ribosomal P Abs with NP manifestations, predominantly psychosis and depression, while others dispute this correlation [16]. In a recent meta-analysis, anti-P Ab testing had limited diagnostic value for NPSLE, and was not helpful in differentiating among various disease phenotypes [18]. A correlation between Abs against endothelial cells (AECA) with diffuse NP manifestations may indicate a vascular nature of NPSLE [31]. AECA are a group of heterogeneous Abs that react with different endothelial cell antigens. The proportion of AECA-positive sera ranges from 15% to 80% in SLE, and recent data suggest their involvement in endothelial dysfunction and a pathogenic role of AECA in SLE. The same study demonstrates a significant association between AECA
and psychiatric symptoms in SLE patients, a feature not previously reported, implying a role of AECA in the development of NPSLE. 4. Pathogenesis Despite extensive research, the precise mechanisms underlying nervous tissue injury remain poorly understood. Two postulated mechanisms for NPSLE include vascular occlusion (secondary – APS), and injury by pathogenic Abs. 4.1. APS Abs Experimental models show direct evidence for the pathogenicity of aCL Ab in cognitive dysfunction. In one experimental model of APS, female BALB/c mice, immunized with a pathogenic monoclonal aCL Ab, developed hyperactive behavior in an open field, which tests spatial behavior and displayed impaired motor coordination on a rotating bar. The titers of aCL, anti-β2 glycoprotein I Abs, and AECA were elevated in the sera. Thrombotic occlusions of capillaries in combination with mild inflammation were the main findings in mouse brain tissue examination [24,32]. In another experimental model of APS, mice immunized with β2-GPI (that lead to the development of anti-β2-GPI Ab), exhibited hyperactive behavior, as reflected by more frequent rears and a higher number of stairs climbed by the mice at specific time intervals [33]. More direct evidence for the pathogenic potential of aPL was by intracerebroventricular (i.c.v.) administration of immunoglobulin from patients with APS to male C3H that demonstrated binding to the hippocampus and cerebral cortex by immunohistological staining. Mice injected with this IgG performed worse in the water maze than the controls with significant effects attributed to aCL IgG regarding the overall performance of the mice. These results support the hypothesis that aCL Ab that gain access to the CNS may play a direct role in the pathogenesis of the neurological manifestations of APS [34]. In vitro studies and results from a variety of animal models indicate that aCL Abs induce endothelial activation and a prothrombotic state. In addition, LA or aCL Abs have been linked with atherosclerosis, another mechanism that contributes to CNS ischemia [35]. 4.2. NMDA receptor Abs NMDA receptors Abs are present in the CSF and can cause neuronal death in the mouse brain. Mice immunized with NR2 peptide produce anti-DNA Ab. However, mice immunized with anti-NR2 Ab did not
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have immunoglobulin deposition in the brain. This indicates that an intact blood brain barrier protects the brain from autoAb invasion. Hence, by exposing mice to lipopolysaccharide (LPS) causing experimental infection, immunization with anti-NR2 Abs led to deposition in the hippocampal region, the area responsible for memory. Furthermore, injection of lupus serum from a NP patient caused apoptosis of neurons. The same Ab may be responsible for more than one manifestation of NPSLE [26,27]. Despite these intriguing results in an experimental lupus model, recent studies could not verify the correlation of anti-NMDA Ab with cognitive dysfunction in SLE patients at a given point or over time. One clinical study found a correlation with depression [36]. Possible explanations for the discrepancy between the experimental model and the clinical studies could be methodological differences in cognitive testing, Ab measurements, or selection of the study participants. Another option is that the permeability of the BBB, resulting in accelerated access of anti-NR2 Abs to neuronal tissue may have a transient but cumulative effect. Furthermore, a dose-dependent mechanism may explain that exposure to lower levels of anti-NR2 Abs may lead to manifestations of DPR, and higher levels may lead to cognitive dysfunction by causing neuronal death [36]. Possibly, because of the persistence of Abs leads to cognitive dysfunction [35,36]. Thus, the correlation of anti-NR2a Abs with clinical NPSLE remains to be determined. 5. Treatment of psychiatric manifestations in patients with SLE Given the diversity in clinical manifestations, the management is tailored to the specific needs of individual patients. The management of psychiatric lupus manifestations is often frustrating and currently no consensus is available. Counseling and other interventions that assist a person in developing coping skills may be helpful. In the absence of controlled studies, the use of symptomatic therapies, immunosuppressive, anticoagulants and adjunctive psychotropic medication is supported by case series and clinical experience [37]. The present treatment strategies for the various psychiatric manifestations, based on small open trials, include prednisone, cyclophosphamide [38], IVIG [39], together with atypical psychotropic drugs. Selective serotonin reuptake inhibitors (SSRIs) are the first line of treatment for depression in SLE patients because of their safety and tolerability. In unresponsive cases, augmentation and combination strategies may be beneficial [37]. Anticoagulation is warranted in patients with thrombotic disease, particularly in those with the APS [37].
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Treatment of delirium caused by NPSLE is to alter the corticosteroid dosage; a prompt and beneficial effect differentiates delirium caused by NPSLE- or steroidinduced delirium [37]. Acute management of agitation and psychotic symptoms can be achieved with low doses of neuroleptics. 6. Conclusions Psychiatric abnormalities are common accompaniments of SLE. Cognitive dysfunction appears to be more common than previously thought, but its clinical significance and prognostic implications remain unclear. Five different psychiatric syndromes are currently accepted in ACR Neuropsychiatric Lupus Nomenclature Committee criteria consensus: cognitive dysfunction, delirium (acute confusional state), anxiety disorder, mood disorder, and psychosis. The exact role of Abs in the pathogenesis of specific lupus psychiatric manifestations warrants further clarification in prospective studies. Treatment is customized to the psychiatric disorder coupling immunosuppressant and psychotropic modalities. Possibly, establishing a consensus of diagnosis together with an appropriate panel of Abs would be advantageous for the proper management of these patients. Take-home messages abnormalities are common accompani⋅ Psychiatric ments of SLE. Cognitive dysfunction appears to be
⋅ ⋅
more common than previously thought, but its clinical significance and prognostic implications remain unclear. Five different psychiatric syndromes are currently accepted in ACR Neuropsychiatric Lupus Nomenclature Committee criteria consensus: cognitive dysfunction, delirium (acute confusional state), anxiety disorder, mood disorder, and psychosis. The exact role of Abs in the pathogenesis of specific lupus psychiatric manifestations warrants further clarification in prospective studies.
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