Dr. Susan Denburg, PhD
Professor, Psychiatry and Behavioural Sciences
Associate Dean, Academic
Faculty of Health Sciences
McMaster University
Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease of unknown etiology, characterized by damage to tissues and cells resulting directly or indirectly from the action of autoantibodies and/or immune complexes. The clinical manifestations of the disease are varied and determined by the specific antibodies and immune complexes that are present and their respective target organ tissues or cells.
In the context of the Lupus Canada symposium presentation, the primary focus of this brief summary will be one category of these autoantibodies - antiphospholipid antibodies (APLA). APLA, while not exclusive to SLE patients, are present in approximately one third of SLE patients. APLAs are generally classified into two groups: anticardiolipin antibodies (ACLA), and lupus anticoagulants (LAs). APLAs are associated with thrombotic, or clotting events, as well as with recurrent miscarriages. Since SLE is a disease that primarily affects young women, these thrombotic events can produce lifelong illness, particularly when the thrombotic events occur in the central nervous system (CNS).
Nervous system involvement occurs in up to 75% of patients with SLE. Such involvement is frequently termed "neuropsychiatric" (NP), as it reflects both neurologic and psychiatric events (i.e. stroke, seizure, organic brain syndrome, psychosis, depression). More recently, clinical neuropsychology, an approach to studying the functional integrity of the central nervous system, has been applied to the study of neuropsychiatric SLE as it has been found to be sensitive to the presence of nervous system lesions.
Although there is a wide degree of variability in the type of tests administered in SLE research, the common theme in the majority of approaches to neuropsychological assessment (NPA), is that a wide range of functions is assessed, including attention, memory, language, concept formation, visuospatial abilities, executive skills and motor skills. All approaches in wide use have been validated in both research and clinical settings with respect to their utility in identifying the presence of disturbed brain function. NPA can be undertaken in virtually all patients and has the potential to provide objective validation of subjective complaints reported by SLE patients.
Impairment in cognitive function can be a serious complication in SLE patients. Studies of cognitive functioning in SLE have yielded data regarding the prevalence and/or type of cognitive deficit in this patient population. Examination of these different studies, suggests that the cognitive deficits shown by SLE patients are fairly wide-ranging. This diversity in type of cognitive problem is demonstrated in SLE patients with or without overt NP involvement. Problems that have been identified in representative patient samples include attention and concentration, various aspects of verbal and nonverbal memory including working memory, verbal fluency/productivity, visuospatial skills, psychomotor speed, and cognitive flexibility.
Using objective criteria, studies have found a high prevalence of cognitive impairment in 20-55% of SLE patients in general. More importantly, cognitive impairment in such areas as visuospatial skills, verbal and nonverbal memory, and verbal fluency, is seen in 20-40% of SLE patients who have not had a major clinical neuropsychiatric event. This finding cannot be explained on the basis of disease activity, steroid medication, or significant emotional distress and strongly suggests that NPA can detect subclinical nervous system compromise in these patients.
Previous studies of the relationship between anti-brain antibodies and CNS involvement in SLE have defined such involvement on the basis of major neuropsychiatric syndromes. Relatively little attention was paid to subclinical nervous system involvement such as might be indicated by neuropsychological impairment. The relationship between cognitive function, as a marker of nervous system involvement, and various autoantibodies implicated in the disease process of NP-SLE have been assessed by our group.
Pertinent to this symposium, we have reported a significant association between decreased cognitive function and APLAs. In this latter study, 118 adult SLE patients, 33% of whom were LA-positive, underwent cognitive assessment. Within this sample were 75 patients who had never experienced any NP involvement in the course of their disease (never-NP), 29% of whom were LA-positive. LA-positivity was significantly associated with an increased risk of cognitive impairment. Further, the LA-positive group was worse than the LA-negative and community control groups on a range of cognitive functions including tasks involving verbal memory, cognitive flexibility and psychomotor speed. Although the criteria for impaired cognitive area may have differed across studies, other researchers have found either a similar pattern of cognitive deficits in APLA positive SLE patients or worse performance in virtually all areas of function. Therefore, the best available data strongly support a relationship between APLAs and cognitive dysfunction. The associations found in these studies also raise questions regarding the mechanism(s) of cognitive dysfunction in SLE (for example, that ongoing APLA-related microthrombotic events can lead to CNS compromise, manifested as cognitive dysfunction). To date, there is some evidence from objective imaging studies such as CT scan and MRI, which is consistent with this theory; however, longterm follow up data are essential to confirm this relationship.
We have shown through previous research that neuropsychological assessment has proved to be sensitive to the presence of cognitive impairment in patients with SLE, and have uncovered significant impairment even in patients without overt neurologic or psychiatric symptoms. Cognitive impairment, when documented in SLE patients, most likely reflects central nervous system dysfunction. We have also established a neuropsychological test battery which has been shown to be sensitive to the dysfunction associated with APLAs in SLE, with APLA-positive SLE patients having significantly greater impairment in cognitive function compared with APLA-negative SLE patients. APLAs might be only one of several mechanisms underlying the cognitive dysfunction observed in SLE patients. Long-term follow-up studies are essential to assess the predictive value of various risk factors that have been associated with NP involvement (for example, APLA and cognitive dysfunction). The identification of such key factors associated with cognitive improvement or decline and the implications for treatment has become a central focus of the current research work being pursued by the Lupus Research Group at McMaster University.