Office of Public Health & Environmental Hazards

Clinical Experience with Gulf War One Veterans and their Symptoms
J. Wesson Ashford, MD, PhD
Director of California Site War-Related Injuries and Illnesses Study Center (WRIISC) Palo Alto VA Health Care System wes.ashford@va.gov

WRIISC-CA

June 26, 2013

Most Frequent Symptoms, Affected Systems of Veterans from the First Gulf War
Frequency of Symptoms of 53,835 Participants in VA Registry (19921997)

Symptoms
Fatigue Skin rash Headache Muscle and joint pain Loss of memory Shortness of breath Sleep disturbances

Percentage
20.5 18.4 18.0 16.8 14.0 7.9 5.9

Systems
Musculoskeletal and connective tissue Mental disorders Respiratory system Skin and subcutaneous tissue Digestive system Chest pain 25.4 14.7 14.0 13.4 11.1 3.5 SOURCE: Murphy et al., 1999

Results of Iowa Study 3,695 Veterans:

Symptoms, % Prevalence

Fibromyalgia Cognitive Dysfunction Alcohol Abuse Depression Asthma PTSD Sexual Discomfort Chronic fatigue

GW Veterans 19.2 18.7 17.4 17.0 7.2 1.9 1.5 1.3

Non-GW Veterans 9.6 P<.001 7.6 P<.001 12.6 P<.001 10.9 P<.001 4.1 P<.001 0.8 P<.007 1.1 P<.009 0.3 P<.001

Iowa Persian Gulf Study Group, 1997

39 year old male Veteran evaluated at WRIISC-CA February, 2011

Veteran was in good health prior to deployment to Persian Gulf in August, 1990. Veteran flew into Saudi Arabia, deployed within a week to the IRAQ border. Was with the 82 Airborne, in an engineer battalion. During Operation Desert Shield - did mostly training (blowing things up), preparation. - Veteran developed diarrhea within 2 weeks (eating local food - water, fruits, vegetables - vendors would be selling food), which did not last more than 2-3 weeks. Meds included Immodium (does not recall anti-biotics). - Heard chemical weapons alarms go off x 2, put on MOP suit 2-3 times. - Saw SCUD missiles fly overhead, never saw one explode.

During Operation Desert Storm, Veteran supported the infantry blowing things up, disarming mines. Was at the weapons dump at Khamisiyah and was responsible for the destruction of this facility between March 3-10, 1991.
He reports or believes that he was exposed to: o Sand, Smoke from oil-well fires, o Insecticides (DEET, permethrin), Organophosphate nerve agents, Pyridostigmine bromide (PB) o Paints, Solvents, Petroleum fuels and their combustion products, o Anthrax botulinum toxoid vaccinations, Infectious diseases o Psychological and physiological stress o C4, TNT, mines (direct handling). o Was near large radar trucks.

Veteran recalls no other symptoms before returning to the US in April, 1991. On return, Veteran experienced anger, got into fights, irritability, problems with concentration, difficulty with interpersonal relationships (ended relationship with girl-friend from before War), diarrhea and constipation. Veteran avoided social situations and crowds.
Major symptoms subsequently were: > Chronic fatigue > Muscle and joint pain > Headache > Skin rashes first 2 years after return > Sleep disturbances > GI disturbances > Loss of concentration > Forgetfulness, loss of memory Some of these symptoms have been stable (muscle, join pain), but most have gotten progressively worse. Veteran has 4 combat comrades who had similar problems. Veteran has had TBI x 2 times, major - Fort Bragg, parachuting. Knocked unconscious for 5 10 seconds (witnessed). Some dizziness, no other residual.

Findings in Gulf War Veterans with Multi-symptom Conditions

Somatic Medical Symptoms:
pain, fatigue, GI, skin, pulmonary normal x-rays of joints

Neurological
normal MRI scans abnormal SPECT (? Normal PET, autonomic?)

Psychiatric depression, cognitive complaints, sleep issues neuropsychological dysfunction - borderline

WRIISC-CA
Since its creation in 2007, WRIISC-CA has evaluated over 200 complex referrals routed through Central Office from most States West of the Mississippi River (and all States West of the Rockies).
Of these referrals, 42% have been Veterans of the First Gulf War.

The largest single problem in the WRIISC referrals has been PAIN!!

In the WRIISC-CA program, Veterans of GWI had more pain and fatigue than Veterans of prior or later deployments. (note this data from a CPRS analysis of 79 cases, percent adjusted for missing data)

WRIISC CA Analysis of CPRS Data from Cases of 79 Deployed Veterans

WRIISC number of Veterans
Group
N Diag_Pain Diag_Fatique
Pre-GWI
17 12 3 14 11 10 9 12 9 4

WRIISC percentage of Veterans

Pre-GWI GW1 Post-GW1 Type*

GW1
41 33 17 32 21 17 10 27 18 9

Post-GW1
21 16 5 17 14 10 6 13 8 3

71 18 82 65 59 53 71 53 24

80 41 78 51 41 24 66 44 22

76 24 81 67 48 29 62 38 14

1 1 2 2 2 2 3 3 3

Diag_PTSD
Diag_TBI Diag_GI Diag_Derm

Diag_Sleep
Diag_Cog Diag_Pulmonary
*1 = GWI MOST

2 = GWI LESS

3 = AGE-related

FUNDAMENTAL PROBLEMS
Gulf War Illness is considered to exist
(Institute of Medicine, 2009)

There have been many plausible theories for the unique constellation of symptoms that are frequently seen in the Veterans of the First Gulf War, but none has yielded an acceptable explanation There is no clear relation to chronic fatigue syndrome, fibromyalgia, multiple chemical sensitivity, etc.

Idiopathic Small Fiber Neuropathy (an example of a plausible theory)

Caused by diabetes, HIV, Erythromelalgia, postherpetic neuralgia, CRPS, alcoholism, and many other nerve pain conditions Cause is also commonly idiopathic There are no known causes for most cases and most tests do not identify it Peripheral nerve fibers that can be affected include peripheral autonomic neurons (acetylcholine, epinephrine), pain fibers (substance P) (like causalgia) Central small nerve fibers could also be affected (acetylcholine, norepinephrine, serotonin, others)

Plausible biological explanations for GW1 small nerve fiber damage

Peripherally acting Anti-cholinesterase agents (Pyridostigmine bromide -PB, insecticides, DEET, permethryn, flea collar stories, sarin exposure, combinations), could increase the production of the enzyme acetyl-cholinersterase (AChEase). AChEase elevations (after stopping exposure and returning from conflict) could lead to a crisis related to low acetylcholine levels and an increase production of nerve-growth factor (NGF), leading to growth of pain-perception and various autonomic fibers, resulting in a chronic state of hyper-algesia (without evidence of joint or other system damage), along with chronic GI disturbances. (Note that Alzheimer patients who have withdrawn from chronic treatment with a similar agent, donepezil, frequently have precipitous declines. Further NGF treatment of Alzheimer patients led to a hyper-algesic state). Spider Bites toxin, not infectious agent, but a biological toxin that could damage small neurons. High temperatures may increase sensitivity of small neurons (heat-shock proteins). RADAR (radio-frequency injury to neurons has extensive literature, not considered a problem under normal circumstances, but there was a tremendous amount of radar in use in the First Gulf War). Immunological response chronic response to infectious agent attacking small neurons (like Guillan-Barre syndrome) Reaction of body to severe diarrhea or agent that caused severe diarrhea (local fruits, vegetables given to soldiers deployed early, those soldiers deployed later did not seem to get the condition). (Note, some diarrhea could have been an indication of sensitivity to PB tablets.)

Chronic Multi-symptom Illness Gulf War One Type

Complex Exposures Can Affect Large Groups and Lead to a Unique Variety of Conditions, Symptoms and Disorders. In Wars, many Individuals are exposed to a vast array of environmental, physical, and psychological stressors, with each conflict associated with its own unique set of problems (see Strauss, Lancet, 1999). Consider that there are many exposures and other factors that lead combat Veterans to have a higher incidence of a particular variety of symptoms. Those symptoms may result from a multitude of causes. Further, each conflict, having different exposures, may induce a different constellation of symptoms. In all cases, treatments must address the symptoms of the Veterans, minimize their discomfort, and maximize their function.

References
1. Murphy FM, Kang H, Dalager NA, et al.: The health status of Gulf War veterans: lessons learned from the Department of Veterans Affairs Health Registry. Mil Med. 164(5), 327-31 (1999). 2. Iowa Persian Gulf Study Group: Selfreported illness and health status among Gulf War veterans. A population-based study. The Iowa Persian Gulf Study Group. JAMA. 277(3), 238-45 (1997). 3. Straus SE. Bridging the gulf in war syndromes. Lancet. Jan 16;353(9148):162-3 (1999).