comments - dr. beatrice golomb - iom gulf war illness "cmi" panel

7/28/2019 Comments - Dr. Beatrice Golomb - IOM Gulf War Illness "CMI" Panel.

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Comments forIOM COMMITTEE ON DEVELOPING A CONSENSUS CASE DEFINITION FORCMI

Beatrice Alexandra Golomb, MD, PhD

I. Thank you Dr. Shine and Committee, for heeding our input, and that of the veterans.II. 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 (ResearchAdvisory 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.)Authoredor 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 inPNAS2008, 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 thesetting 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 deficiencyin 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 providedIdentification 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 thoseaffected 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 considerrecommending to the VA that coding of veterans by the VA provide for *separate* coding for veterans of

the 1990-1 Gulf War.


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Right now, the Gulf War veteran designation by the VA encompasses any veteran deployed to thatregion during OR AFTER the Gulf War.

This dilutes this group with many further individuals who did not share the distinctive suite of exposuresof 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 thefuture, high specificity is vital, in order not to dilute true cases or include, inexcess, 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 forfirst delineating mechanisms and identifying treatments.

b. Forclinical care, where the priority is patients in the present, high sensitivity is the priority. Adecision 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, fewerexclusions of concurrent conditions should be in place and a broader net cast, in order that thosewho 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 GWIdefinition, e.g. defined by exposure orsymptom or identified mechanism or objectivemarker. Regarding exposures, if there is concern that pesticide exposure may induce certain

problems or involve certain pathways, then research involving GWI restricted to those withpesticide 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 tothose 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 isreasonable.

d. But also, there may be instances in which it is desirable to take a superset, or a set that allowsone 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, maycomplicate MS if present, and may even potentiate its development; so definitions must beconveyed 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 isstudied, it might be stipulated or recommended that sensitivity analysis confined to those

meeting the accepted research case definition should be conductede. 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 butmodified to address the further accrual of symptoms with age in all, those with and without GWI


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(so, probably requiring more symptoms and possibly splitting symptom domains further and/ordifferently); 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 likelyto complicate the case definition.

C. I applaud the notion of conducting analytic research, along similar lines to that previouslydone by Dr. Steele, to determine what features best capture the excess symptomatology that isdistinctive to 1990-1 Gulf War veterans, in their more current manifestations.

V. I urge the Committee to include knowledgeable veterans like Anthony Hardie on a systematicbasis 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 phasesof larger veteran input, and ideally also Gulf War researcher input, before final determinations are

made.

VI. Responses to CommentsA. 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 todisrupt the blood brain barrier.

B. Comments were made about high rates of depression in GWI as justification for retaininga 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 symptomsthemselves 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 indepression 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 wejust completed.

C. Comments were made in which the CNS was argued to be the core factor in GWI . Ithink 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 oxidativestress 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 withimpaired 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 thesystem. 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 responsewas given stipulating that this was not a concern, as people in their capacity as Committee members are


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comments - dr. beatrice golomb - iom gulf war illness "cmi" panel

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