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Disease Registries in the Assessment of Autoimmune Disorders and SLE Cognitive Abnormalities

Interviews with Experts

Melanie J. Harrison, MD
Assistant Attending Physician, Hospital for Special Surgery
Assistant Research Professor of Medicine, Weill Medical College of Cornell University
Assistant Professor of Public Health, Weill Medical College of Cornell University

  1. Registry Content and Aid to Research
  2. Patient Privacy, Ethics, and Institutional Review Boards
  3. Defining Cognition and Cognitive Loss
  4. Diagnosing Cognitive Abnormalities
  5. The Course of Cognitive Dysfunction
  6. Causes and Therapeutic Options
  7. The Kirkland Center for Lupus Research


Stephen A. Paget, MD: My name is Dr. Stephen Paget. I am the Chief of Rheumatology at the Hospital for Special Surgery. It is a pleasure today to introduced Dr. Melanie Harrison, who is one of our Assistant Professors of Clinical Medicine at Hospital for Special Surgery. She has an interest in both clinical epidemiology, coordination of our registries and repositories, and a specific interest in neurocognitive abnormalities in patients with lupus. Dr. Harrison what is a registry and how does it help research?

Registry Content and Aid to Research

Melanie J. Harrison, MD, MS: We have several clinical registries here at the Hospital for Special Surgery, and the registry is a longitudinal, on-going data base, within which we collect and maintain data regarding which patients have which rheumatic diseases. Specifically, we maintain databases on our rheumatoid arthritis population, our lupus population, patients with antiphospholipid antibodies and fibromyalgia, as well as determining whether or not these patients meet classification criteria for each of these diagnoses. We keep track of their signs and symptoms of disease, what medications they may be using, various alternative therapies that they may have tried, as well as things such as psychosocial aspects of the disease and functional status.

We collect this data usually at least once a year. For certain conditions, such as lupus, we might collect the data at least four times a year. For rheumatoid arthritis up to twice a year. From these databases, we are able to (1) identify patients who would be appropriate for other clinical studies; (2) generate our own data from that, which we have collected and therefore draw conclusions; and (3) generate hypotheses based on information that we have collected, which in turn allows us to develop new studies for the future.

Patient Privacy, Ethics, and Institutional Review Boards

Stephen A. Paget, MD: Given the importance of privacy issues today, how do you address both privacy and ethical issues? How do patients feel comfortable giving you information and allowing you to use it?

Melanie J. Harrison, MD, MS: Well first of all, all of the data that we collect and every patient's privacy is maintained by coding each patient's history. So, in other words, once the patient acknowledges that they are going to become part of this data base, we assign a number to them and, with the exception of one single database, every single piece of data is connected to this number. It is an anonymous number, and only we who have been given permission to access this information through institutional review board, which is essentially an ethics review board, will have access to that information.

Second, we don't have access to any information about patients until they themselves give us consent to ask them questions, to access their medical records, and not only do we explain what this means to patients, we make sure that they understand it and we have them sign a consent. Patients are allowed to withdraw from the registries at any time, much like they are allowed to withdraw from any clinical study at any time. Research assistants, as well as all of the other physicians who have access to this information, have to take an ethics exam proving that the understand that the rights to privacy are maintained for all of these patients.

Stephen A. Paget, MD: You are a member of the Hospital for Special Surgery institutional review board. What is the role of that board?

Melanie J. Harrison, MD, MS: The board is responsible for reviewing any and all studies that take place at the institution that have any type of connection to patients - and that includes whether or not we are going to speak to patients directly. It includes whether we are going to review patient records. The institutional review board is responsible for going through not only the protocol of the study being conducted but to also make sure that the people involved understand their responsibilities to maintain the privacy of the patients and to protect the patients so that they are not put in harms way.

Defining Cognition and Cognitive Loss

Stephen A. Paget, MD: Now you have a specific interest in neurologic problems in connective tissue diseases, specifically lupus, and you have a particular interest in cognitive abnormalities. What is a cognitive abnormality and how does a patient and a doctor know that they are dealing with that?

Melanie J. Harrison, MD, MS: Cognition is a very difficult term to interpret or explain. It includes all sorts of processes that go into our intellectual function. It is not just a matter of intelligence, however. It's a matter of receiving information, interpreting it, and even feeding back on it - explaining what it is that you have learned. So it includes things like memory concentration, learning ability and processing ability.

When we look at cognitive abnormalities or when a physician is trying to identify cognitive abnormalities in a patient or a patient is trying to identify cognitive abnormalities in him or herself, it can be very variable. It can be something as simple as not remembering people's names, people whom you've known for a long time, where this is a persistent abnormality - or something as complex as not being able to balance a check book, where the same patient was a CPA years before or even months before.

So in terms of physicians being able to identify it and pick up on it and patients being identify it, a lot of it is patient-dependent. Patients need to voice their concerns, I think, that they have noticed in terms of their ability to remember, to concentrate, to process information, and then the physicians have to have a heightened awareness as to what might be contributing to this. Again, this is similar to the idea that cognition has a lot of processes that go into it, and there are a lot of different things that can contribute to it. So even mild depressive symptoms or pain can cause someone to have mild memory impairment that is not necessarily significant in the long run, although it might be significant and important to that individual.


Defining Cognition and Cognitive Loss

Stephen A. Paget, MD: Physicians and patients know what an evaluation of a glucose level or a sodium level or a rheumatoid factor or an ANA is. How do you measure cognitive abnormalities?

Melanie J. Harrison, MD, MS: Usually, for the purpose of clinical evaluation, not for the purpose of research but for clinical evaluation, one is referred to a neuropsychologist, and that is a psychologist who specializes in the evaluation of cognition. In the process of speaking with the patient, the neuropsychologist identifies particular problems that the patient him- or herself has noted in terms of ever day life. From that, a group of neuropsychological or cognitive function tests are administered. These are usually either verbal tests and/or pen and paper tests, where you either have to copy a pictures, stick pegs in holes, remember lists of various items and reproduce them, match up different diagrams. They are very variable. The batteries usually take a half an hour to an hour and a half and, again, they look at various issues related to cognition such as memory, intelligence, concentration, recall, calculating ability, etc. - all dependent on what the patient him- or herself knows or acknowledges that they are having a problem with.

Stephen A. Paget, MD: Systemic lupus erythematosus is a systemic inflammatory autoimmune disorder. What does it have to do with cognitive abnormalities?

Melanie J. Harrison, MD, MS: One of the groups of manifestations of lupus is a group of neuropsychiatric manifestations. Many of those neuropsychiatric manifestations, anything from seizures to strokes, can lend themselves to cognitive abnormalities. However, cognitive dysfunction often occurs without any of those obvious other neuropsychiatric manifestations. There are all sorts of things that happen to a lupus patient, whether they are flaring or not that can contribute to cognitive dysfunction. Again, these can be mild things, such as depressive symptoms, pain, some of the medications that may take away from someone's memory or ability to concentrate. And then again there are things like antibodies, changes in cytokine levels, other things that are inherent to the actual disease that may, in fact, be contributing to cognitive dysfunction that perhaps in the future we will be able to modify.

The Course of Cognitive Dysfunction

Stephen A. Paget, MD: Tell us about your specific study and how you employ the registries to make that come true.

Melanie J. Harrison, MD, MS: For the last five years, we have been conducting a study of the longitudinal course or the course of cognitive dysfunction over time within lupus patients. Using the registry we identified patients who are seen at the Hospital for Special Surgery, who have been classified as having lupus, who are within a certain age range, and who are not on dialysis because that is another factor that my contribute to fluctuations in cognition. Once we can identify these patients through the registry, in other words once we get their names and their physicians, we ask the physicians if they will ask the patients if they will be willing to participate in this particular study. Once we have that permission, we approach the patients and ask them to come in for a battery of standardized neuropsychological tests that have shown to be effective for the purpose of research in identifying cognitive dysfunction, and then we look at other things such as disease activity and disease damage. Many of these indices have been maintained within the registry, and so those assist us in collecting the data.

Stephen A. Paget, MD: What have you found so far?

Melanie J. Harrison, MD, MS: Well, there are probably three things that we have found so far in our interim analyses.

Number one is that there is tremendous variability both between patients and within patients who have lupus with respect to their cognition. In terms of between patient variability, there can be two patients who have lupus who have nothing in common in terms of their cognitive functioning or dysfunctioning, much like one lupus patient might have arthritis as a prevalent sign and another patient might have a seizure disorder as a prevalent sign. So where as one lupus patient might have a memory problem, another might have a calculation problem.

The second thing that we found out is that patients have kept quiet about this and, as a result, physicians haven't pursued the issue of cognitive dysfunction on a one-on-one basis as much as patients would like. This has become a venue for patients to voice their concerns and, as a result, we have generated a lot of excitement, both on behalf of the patients and physicians, in terms of identifying and looking for some kind of treatment in the process of finding an etiology.

The third thing that we have noticed is that there are two issues that keep coming out - two issues that the patients keep voicing are concerns to them. That is that they have specific difficulties in the area of memory and in the area of what we call executive functioning - that would be organizational thinking, in other words planning a meal, remembering how to get from one place to another, having the forethought to again organize your ideas.

Stephen A. Paget, MD: Again, why do you think those occur?

That remains unclear. As I said before, there are so many different things that may be contributing to cognitive dysfunction. We are looking into specific areas of the brain although, again, considering the between-patient variability in these patterns and even the within-patient variability, that is the variability in which tests are abnormal over time, it is unlikely that there is one particular part of the brain, one aspect of the anatomy, that is abnormal. And so we are looking into other things, such as the generation of antibodies against neuronal tissue, the fluctuations in disease activity, and what that might be associated. In other words, we don't think the disease activity itself is what is causing the cognitive dysfunction but, perhaps, an alteration in the cytokine profiles within those patients during times of flare are altering the brain chemistry if you will.

Causes and Therapeutic Options

Stephen A. Paget, MD: Do these findings stimulate any therapeutic options?

Melanie J. Harrison, MD, MS: For now, no. We are still looking for that particular etiology that we can target in terms of whatever is underlying. However there are certain things that we can do in the interim. We are starting another study where we are trying to develop an educational program for patients. It will actually be a cognitive retraining and rehabilitation program for selected patients, at least to begin with, who have specific memory problems as well as executive dysfunction, and we will attempt to retrain these patients in terms of their ability to function through everyday life.

As far as other things that we can potentially treat, we know that the depressive symptoms, even mild depressive symptoms in lupus patients, might be contributing to what patients perceive as cognitive impairment and actually to cognitive performance. So by treating even mild depressive symptoms, we might be able to improve cognitive function. In much the same way, we know that patients have associated their high steroid doses to cognitive or even mild cognitive impairment or intermittent cognitive impairment that might be severe. As a result, we would encourage patients to be willing to try other medications that might help in terms of some of their other symptoms, as long as it is safe and as long as the physician agrees. So, again, this is a push which we always try for and that is to decrease steroid doses as much as possible.

The Kirkland Center for Lupus Research

Stephen A. Paget, MD: You are a part of the Mary Kirkland Center for Lupus Research. Is there is a specific focus in this area in that center?

Melanie J. Harrison, MD, MS: Absolutely and, in fact, the cognitive retraining program that we are trying to develop and test in terms of its efficacy is bing funded by the Mary Kirkland Center. Besides that, as I mentioned, patients now have a venue for voicing their concerns about this issue, which has raised other concerns of theirs with respect to their quality of life and their ability to maintain not only social function as working individuals and individuals going to school but as social individuals. Again, the issue of quality of life keeps rearing its head and it's not just a matter of being able to get out of a chair. And so we started to look at quality of life, specifically in conjunction with the Kirkland Center, and, again, looking at quality of life with respect to the less tangible aspects of lupus, such as cognitive dysfunction.

Stephen A. Paget, MD: Thank you, Dr. Harrison, very much.

From an interview with Dr. Melanie J. Harrison by Dr. Stephen A. Paget


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