What is Cognitive Dysfunction?

Patients with lupus often experience problems with such intellectual functions as remembering things, articulating thoughts, focusing attention to details, making decisions, or manipulating numbers.  These impairments may range from mild thought disturbances to more severe confusional states.  Even in their mildest forms they can be quite distressing to the patient experiencing them.  They may not interfere significantly with the ability to function normally but still be a source of dissatisfaction in the individual’s work and social interactions.  Because they are difficult to identify objectively, they can be very frustrating for family and friends, and even the treating physician, to deal with.
This impairment in intellectual ability has been termed cognitive dysfunction, and has recently become the focus of much interesting research.  It is now recognized that cognitive dysfunction  is one of the subtler manifestations of “Neuropsychiatric SLE” (NPSLE), that is lupus that affects the nervous system, with manifestations that are either neurologic or psychiatric in nature. Nervous system involvement is common in SLE patients with estimates of occurrence in 25-75% of patients.  It encompasses a variety of clinical syndromes that affect the brain, the spinal cord, or the nerves to the arms and legs; including seizures, strokes, psychosis, neuropathy, movement disorders, and even headaches and MS-like symptoms.
Who is affected?
Cognitive dysfunction has become recognized as a critical manifestation of NPSLE, and more objective criteria have been developed to define the syndrome in a recent academic symposium and workshop sponsored by the American College of Rheumatology. It has been shown in several key research studies to affect a significant portion of lupus patients. It is estimated that approximately 33% of lupus patients who have never had any other signs of NPSLE will have detectable cognitive dysfunction.  Up to 88% of patients who had a prior major neuropsychiatric event show some level of cognitive dysfunction, probably due to residual damage to the nervous system.
How is cognition impaired?
The following key components of cognition that could be impaired in SLE were identified at the ACR symposium,
1) Simple attention—the ability to register and retain information
2) Reasoning—problem solving
3) Executive skills and complex attention—planning, organizing, sequencing information
4) Memory—learning, recall
5) Visual spatial processing—recognizing visual patterns
6) Language—verbal fluency
7) Psychomotor speed—ability to rapidly process and produce written and oral information.
How is Cognitive Dysfunction diagnosed in the SLE patient?
Usually the patient herself will note the first symptoms, or family or friends may note a change in the level of competence of the patient.  If these are reported to the treating physician, he can perform a brief assessment of mental functioning using one of several available mental status exams.  However these tests are often not sensitive enough to detect the milder forms of cognitive dysfunction, If they are positive, they may indicate CNS involvement.
More sophisticated neuropsychological testing may be warranted for patients with more severe complaints of acute deterioration of mental functioning, especially when the screening tests are inconclusive.  It was suggested at the ACR symposium that a standardized battery of tests could be utilized to delineate these defects in a given patient. 
Results from these tests delineate the patient’s strengths and weaknesses and can be compared to a normative group, as well as to the patient’s prior or subsequent performance.  However, these tests must be given by a neuropsychologist who is well trained in administering and interpreting them, and are therefore quite time consuming and expensive and may be impractical in many cases. In an attempt to address this issue, researchers in this area have proposed a more select battery of tests that can be administered in one hour, but still require a neuropsychologist.  Computer assisted testing and scoring is under development for the future and may make this type of assessment more available.
In addition, blood testing for other target organ damage and serological markers of SLE activity should be done in all patients with cognitive dysfunction. Antibody testing for antiphospholipid, antineuronal, and antiribosomal p antibodies can be helpful.  CT scans, MRI, spinal fluid exam, and EEG which may not be diagnostic even in overt cases of NPSLE, are rarely helpful in most patients with cognitive dysfunction.  However, SPECT scanning is a brain imaging technique which offers some future promise.  These scans utilize a radionuclide  marker whose distribution in brain tissue is proportional to blood flow to different areas of the brain.  It is a relatively sensitive test that is often positive in cases of lupus cognitive dysfunction.  However, it’s not always specific, i.e., identical abnormalities can be found in lupus patients who do not have any NPSLE, and even in some normal control patients.
What is the cause of these cognitive deficits in lupus patients? 
 The etiology of cognitive dysfunction in SLE is unknown, but is the focus of ongoing active research.  Looking at the current understanding of the etiology of the broader category of NPSLE may shed some light on this matter. 
There are at least three mechanisms whereby brain tissue is damaged in NPSLE. First, there is blockage of blood supply to brain tissue, either as a direct result of clotting (thrombosis), hemorrhage, vasculitis (inflammation of the vessel wall which causes it to narrow), or vasculopathy (noninflammatory thickening of the blood vessel).  Second, antibodies such as antineuronal or antiribosomal directly damage individual brain cells.  Third, brain cell function is temporarily, but reversibly interrupted, possibly through cytokine release and vasospasm (narrowing of the blood vessels) causing brain cell misfiring.
It is likely that several of these mechanisms play an etiological role in cognitive dysfunction.  One line of research has implicated antiphospholipid antibodies in the pathogenesis of cognitive dysfunction.  These antibodies are usually associated with major NPSLE events, such as stroke, due to clotting intravascularly. It may be that much smaller clots – microthrombi -- related to these antibodies compromise nerve tissue without causing major damage.
It has been noted that lupus patients who have persistently elevated anticardiolipin antibody titers have a higher incidence of deterioration in certain subsets of cognitive function over time.  For example, in one study, SLE patients who had persistently elevated IgG anticardiolipin antibodies had a decline in test scores which measured psychomotor speed over 5 years.  Lupus patients who had persistently elevated IgA anticardiolipin antibodies showed deterioration in scores which measured reasoning and executive ability.  However, changes in overall cognitive status did not deteriorate over time, and were not related to antibody status.  It was only through analysis of individual test scores that this association was found among the different subsets.  In fact, in this study, more patients were impaired overall at baseline than at follow-up five years later.  This suggests that these changes in cognitive function can be quite subtle and, fortunately, may not significantly interfere with and individual’s ability to function at home or at work.
Studies of cognitive function may help predict which patients with lupus are going to have a major NPSLE event such as stroke or seizure disorder. Preliminary studies have shown that lupus patients who have baseline cognitive dysfunction have a higher incidence of developing future major NPSLE events, especially if they have anticardiolipin antibodies.
Treatment Implications
If these studies are substantiated with further research, it may be possible to determine which lupus patients are at risk, and then try therapeutic interventions.  In fact, one group of researchers is undertaking a trial of low dose coumadin anticoagulation for lupus patients with persistent cognitive dysfunction and positive anticardiolipin antibodies, in an attempt to prevent future NPSLE events.  This group has also tried using low dose steroid therapy in patients with persistent cognitive dysfunction and has published some successful initial trials, showing improvement in intellectual function in these lupus patients. Identifying and treating any aggravating medical conditions such as hypertension, infection, or electrolyte disturbances may further improve symptoms. Psychiatric medications are currently used to treat any concomitant depression or anxiety. 
Other Treatment Modalities
Other treatment modalities include supportive psychotherapy which provides specific adjustment and coping skills to deal with symptoms such as depression, stress, fatigue and confusion.  Because stress, anger, anxiety and depression interfere with processing information and other mental activities, addressing these emotions directly can improve overall functioning.  This is accomplished by learning to cope with stress, to retain a positive attitude and to conquer feelings of helplessness.  Some of the specific strategies for cognitive dysfunction include establishing routines to conserve energy and to reduce stress, using organizers and notes, acting deliberately and with concentration to retain information, pacing oneself and prioritizing.  In some cases cognitive rehabilitation may be useful in improving cognitive function with its emphasis on intellectual problem solving, cognitive organization and memory skills. Cognitive rehab also provides education about the brain, methods for information processing and energy conservation techniques. 
Lupus patients should be encouraged by these developments that further breakthroughs in the diagnosis and treatment of NPSLE will occur.