Comments for IOM COMMITTEE ON DEVELOPING A CONSENSUS CASE DEFINITION FOR CMI Beatrice Alexandra Golomb, MD, PhD

I. II. Thank you Dr. Shine and Committee, for heeding our input, and that of the veterans. Administrative note: My name misspelled on the agenda, the correct spelling is Golomb. I ask that this be corrected for the record, and an annotation that I am also an RAC (Research Advisory Committee on Gulf War Veterans Illnesses) member be added. (I note this was annotated for the veteran member of the RAC who spoke.)

III. My credentials to comment include the following: Clinician (internist) with a couple decades experience in primary care, caring for veterans, including Gulf War veterans (GWV). Participated, as the sole civilian, in a high-level DoD mission to the Middle East, directed to fact finding and fact dissemination regarding GWI (1997). (This was as part of my work at RAND.) Authored or coauthored 4 of 8 RAND reports on the relation of exposures to illness in GWV (including the volume on Pyridostigmine bromide mentioned during the meeting, in relation to effects that may occur following withdrawal of PB that may be masked while PB is continued1) Member of RAC since its inception, and served as its first Scientific Director (starting 2002) Published on GWI (including in PNAS 2008, that article has information on the gene environment interaction, about which questions were raised by the Committee2) PI on CDMRP GWI research efforts, completed and underway IV. Recommendations for Case Definition: A. The research case definition should refer to 1990-1 Gulf War participation . Similar symptoms may arise from different causes that may be differentially produced in different settings. For this reason, the definition must not be exclusively symptom based, but require reference to the setting that is distinctive. By way of analogy: A broad CMI (chronic multisymptom illness) definition might include symptoms that would encompass, say, hypothyroidism in a group who were radiation exposed, and vitamin D deficiency in a group on a medication that impairs assimilation (differential for different exposure groups; members in both groups would meet a broad CMI definition) It is true that both conditions may benefit somewhat with treatments like cognitive-behavioral therapy that assists nonspecifically and/or helps in coping. But lumping such conditions arising in these different settings may preclude Identification of the critical mechanisms of each, which in these specific cases has provided Identification of the definitive treatments of each. In contrast, studying them separately may enable elucidation of mechanisms and definitive treatments treatments that might lead them to no longer have chronic multisymptom illness. Once the mechanisms are identified, then it is appropriate to define the condition by mechanism, and determine which persons from other groups are included. In order to preserve this hope, of identification of mechanism and definitive treatment for those affected by Gulf War illness, it is critical that for now, 1990-1 Gulf War service be a requirement for a research case definition. A1. To facilitate VA research incorporating this criterion, I urge the IOM Committee to consider recommending to the VA that coding of veterans by the VA provide for *separate* coding for veterans of the 1990-1 Gulf War.

 Right now, the Gulf War veteran designation by the VA encompasses any veteran deployed to that region during OR AFTER the Gulf War. This dilutes this group with many further individuals who did not share the distinctive suite of exposures of the 1990-1 Gulf War, and is detrimental to use of the otherwise potentially valuable VA database for meaningful research on GWI. B. The case definition for different purposes must be given leeway to differ. First: B1. The case definition for research and for clinical care have different purposes and must not be conflated. a. For initial research to where the priority is maximizing understanding of the condition, to best help veterans in the future, high specificity is vital, in order not to dilute true cases or include, in excess, concurrent conditions that may add variance and extinguish significance for true and potentially important findings. For this reason, the most classical cases should be preferred for first delineating mechanisms and identifying treatments. b. For clinical care, where the priority is patients in the present, high sensitivity is the priority. A decision to exclude those who also have a condition like MS may be appropriate for research, as the mechanisms associated with that condition may add variance and erode power in research; and confusion about the origin of symptoms is possible. But such concurrent conditions are not precluded by GWI, and might even be increased by GW service, so to exclude people from a clinical definition of GWI by such concurrent diagnoses is inappropriate*. For this reason, fewer exclusions of concurrent conditions should be in place and a broader net cast, in order that those who served their nation faithfully, and are suffering as a result, not be inappropriately denied the help that is their due. * A similar case could be made for people who were deployed to a somewhat expanded region, or deployed in a somewhat different time, or who, though symptomatic, possibly even meet expanded, less restrictive symptom criteria. The MS example is just one for-instance. B2. The case definition for different research purposes must also be given leeway to differ in certain respects. c. There may be instances in which it is appropriate to take a subset of the research GWI definition, e.g. defined by exposure or symptom or identified mechanism or objective marker. Regarding exposures, if there is concern that pesticide exposure may induce certain problems or involve certain pathways, then research involving GWI restricted to those with pesticide exposure must be clearly acceptable. Similarly for investigation into treatment of diarrhea in those with GWI, restriction to those cases meeting a GWI definition restricted to those with diarrhea is appropriate. And if there is treatment targeting a mechanism, then restriction to those with GWI who show evidence of a marker linked to that mechanism is reasonable. d. But also, there may be instances in which it is desirable to take a superset, or a set that allows one or more exclusionary conditions. If MS, say, is an exclusionary condition for a typical research GWI definition, studies that include patients who otherwise qualify with GWI but who also have MS may for some purposes be important. GWI does not obviate risk of MS, may complicate MS if present, and may even potentiate its development; so definitions must be conveyed in a fashion that does not preclude study of groups that have GWI, who also have an exclusionary condition. That is, that leeway should be clear. In other cases where a superset is studied, it might be stipulated or recommended that sensitivity analysis confined to those meeting the accepted research case definition should be conducted e. Also as evidence advances, of course, the optimal case definition may be modified, or split. Leeway to allow research to follow the evidence must be incorporated. f. My view is that a research definition for now should include requirement for Gulf War I participation, and high specificity symptom criteria along the lines of those of Dr. Steele but modified to address the further accrual of symptoms with age in all, those with and without GWI

(so, probably requiring more symptoms and possibly splitting symptom domains further and/or differently); and the accrual of health problems affecting many with GWI, so, relaxing some, or allowing leeway for, some among the Kansas exclusion criteria that are among those less likely to complicate the case definition. C. I applaud the notion of conducting analytic research, along similar lines to that previously done by Dr. Steele, to determine what features best capture the excess symptomatology that is distinctive to 1990-1 Gulf War veterans, in their more current manifestations. I urge the Committee to include knowledgeable veterans like Anthony Hardie on a systematic basis throughout your deliberations, to keep the process true to the interests of Gulf War veterans, whom all research in this domain should serve. I urge that their input be taken very seriously. And I second the recommendation, made by nurse and veteran Nichols, to incorporate one or more phases of larger veteran input, and ideally also Gulf War researcher input, before final determinations are made. Responses to Comments A. Comments were made about whether PB crosses the blood brain barrier. I thought it was worth commenting that the BBB is a functional not purely structural construct, and that oxidative stressors including cholinesterase inhibitors (and strongly compounded by the fact that all of the major Gulf exposures are oxidative stressors) themselves have been shown to disrupt the blood brain barrier. B. Comments were made about high rates of depression in GWI as justification for retaining a psychosomatic focus. I want to emphasize that many items on most depression scales are somatic, such as problems with sleep, cognition, fatigue, etc. So Gulf War illness symptoms themselves may qualify people to meet definitions for depression, whether or not they feel depressed at all. Importantly, an analysis from Sweden showed that somatic symptoms in depression can be a relatively specific marker for mitochondrial dysfunction3. We have evidence of significant impairment in mitochondrial function in GWI, in a small case-control study we just completed. C. Comments were made in which the CNS was argued to be the core factor in GWI. I think the CNS is vitally important but I also view this focus as inappropriately narrow. CNS effects come from mechanisms. To illustrate one means by which CNS effects may be secondary, I have long noted the concordance of evidence with mechanisms related to oxidative stress and mitochondrial dysfunction, and have recently completed a pilot study documenting significant differences in mitochondrial mechanisms, which comport with both research findings (in but not restricted to the CNS) and veterans complaints. This is relevant to CNS but also fatigue and muscle and GI and the other domains in that the brain is 2-4% of the body weight, but uses 20% of the oxygen and 50% of the glucose. Brain and muscle are especially vulnerable because they are aerobically demanding post-mitotic organs. (Recall that two of the three veterans who spoke at the outset commented on feeling cold as expected with impaired energy production; classic symptoms, also cited by these veterans, include fatigue, muscle pain, weakness, and cognitive problems; and additional symptoms cited by these veterans of hearing sensitivity, irritability all of which are common symptoms of mitochondrial dysfunction. Note particularly the comment by veteran Angela McLamb, stating she had the feeling like oxygen was cut off from the system. With mitochondrial dysfunction, the effect is the same as oxygen cut off from the system: both lead to inadequate ATP generation resulting in each of the symptoms reported in GWI.) D. Regarding a comment made by a veteran concerning the composition of the Committee, a response was given stipulating that this was not a concern, as people in their capacity as Committee members are

V.

VI.

acting independently. I very much respect that all efforts will be made to ensure this occurs. It merits note, however, that from the standpoint of scientific evidence, while independence is a wonderful ideal, an extensive peer-reviewed literature finds that it is commonly not upheld in practice, with both financial and also intellectual conflict of interest (historically held views, positions or beliefs) influencing stated opinions, receptiveness to scientific findings, and recommendations, in a given climate of evidence. I include just a few examples of citations4-8, but scores are available. There is also an important severaldecades old literature by psychologist Solomon Asch and colleagues showing that people will dismiss the evidence before their eyes to offer opinions conforming to what they hear others say, which I observe to occur routinely in medicine, with inimical implications to clinical recommendations. For reasons like these, the makeup of a Committee can, of course, influence the recommendations that Committee puts forth. This is in no way a criticism of the Committee or its membership, but a recognition of the realities of how physicians and scientists, like other human beings, operate. To my thinking this adds impetus to the recommendation that the Committee offer continued avenues for involvement of affected veterans, as, among all parties, they are the group whose interests may most likely and most strongly align with the ultimate welfare and well-being of those affected by Gulf War illness. VII. Thank you, very much, for your kind attention.

Selected References 1. Golomb B. A Review of the Scientific Literature as it Pertains to Gulf War Illnesses, Vol 2: Pyridostigmine Bromide. Washington, DC: RAND; 1999. 2. Golomb BA. Acetylcholinesterase inhibitors and Gulf War illnesses. Proc Natl Acad Sci U S A 2008;105:4295-300. 3. Gardner A, Boles RG. Symptoms of somatization as a rapid screening tool for mitochondrial dysfunction in depression. Biopsychosoc Med 2008;2:7. 4. Stelfox HT, Chua G, O'Rourke K, Detsky AS. Conflict of interest in the debate over calcium-channel antagonists. N Engl J Med 1998;338:101-6. 5. Wang AT, McCoy CP, Murad MH, Montori VM. Association between industry affiliation and position on cardiovascular risk with rosiglitazone: cross sectional systematic review. BMJ 2010;340:c1344. 6. Barnes DE, Bero LA. Why review articles on the health effects of passive smoking reach different conclusions. Jama 1998;279:1566-70. 7. Ernst E, Resch KL. Reviewer bias against the unconventional? A randomized double-blind study of peer review. Complement Ther Med 1999;7:19-23. 8. Savoie I, Kazanjian A, Bassett K. Do clinical practice guidelines reflect research evidence? J Health Serv Res Policy 2000;5:76-82.