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Cognitive
Function and Antiphospholipid Antibodies in SLE Patients
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).
Neuropsychiatric Involvement in SLE
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.
Neuropsychological Assessment in SLE
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.
Types of Cognitive Deficit in SLE
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.
Cognitive complications and APLA in SLE
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.
Summary
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.
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