MEDICAL GRAND ROUNDS WILLIAM S. WILKE, MD, EDITOR TAKE-HOME POINTS FROM LECTURES BY CLEVELAND CLINIC AND VISITING FACULTY Gulf War syndrome: Proposed causes SHAUN D. FROST, MD TABLE 1 Department of General Internal Medicine, Cleveland Clinic Symptoms often cited • ABSTRACT by Gulf War veterans Many veterans of the Persian Gulf War Fatigue suffer from vague symptoms that have Headache collectively become known as the Gulf Joint pain and stiffness War syndrome. Potential explanations Muscle pain include infectious disease, chemical Rash exposure, and psychological stress. Difficulty remembering or concentrating To date, no single etiology has been Irritability identified to explain Gulf War syndrome Depression conclusively. It may be that multiple Sleep disturbance illnesses with overlapping symptoms and Diarrhea, gas, abdominal cramps causes are responsible. Shortness of breath Cough A 1990 and July 1991 ETWEEN UGUST Choking sensation approximately 700,000 American mil- No single Sinus congestion itary personnel participated in the Persian cause has Gulf crisis. Five years after the war, 5,000 to 80,000 veterans were estimated to suffer from been various poorly characterized symptoms that • HEALTH OF GULF WAR VETERANS conclusively have collectively become known as the Gult War syndrome.1 To date, no single etiology Comparison of postwar mortality rates among identified has been conclusively identified to explain Gulf War participants and nonparticipants these illnesses. has failed to demonstrate a difference in deaths due to disease-related causes. • WAR-RELATED ILLNESS NOT UNIQUE Furthermore, when specifically compared to TO THE PERSIAN GULF EXPERIENCE the general population of the United States, Gulf War veterans have significantly lower Poorly characterized sickness following par- cause-specific standardized mortality ratios.3 ticipation in armed conflicts has been docu- In regard to morbidity, review of mented among veterans of the Vietnam and Department of Defense hospital records for 25 Korean wars, World Wars I and II, and the months following the war found that Gulf War United States Civil War.2 Although the veterans were not at increased risk for unex- symptoms cited are remarkably consistent plained hospitalization during this time period.4 among each veteran group, no unique war- Despite these findings, data from case 5-8 related disease or unifying etiological factor series and population-based surveys SUg. unrelated to psychological stress has been gest that Gulf War veterans more frequently demonstrated. Given this historical prece- suffer from a variety of complaints than non- dent, the report of a post Gulf War syndrome participants. The symptoms most frequently is not surprising. cited are listed in TABLE 1. Despite similar CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 67 • NUMBER 1 JANUARY 2000 13 Downloaded from www.ccjm.org on September 23, 2021. For personal use only. All other uses require permission. MEDICAL GRAND ROUNDS TABLE 2 • INFECTIOUS DISEASE: VISCEROTROPIC LEISHMANIASIS Possible causes of Gulf War syndrome Historically, infectious disease has had a sig- nificant impact on military operations in the Infectious exposure Middle East, with the most common illness- Pathogens endemic to the Middle East es being diarrhea, hepatitis, sandfly fever, Biological warfare agents cutaneous leishmaniasis, and schistosomia- Predeployment vaccination sis.12 In addition to being exposed to endem- Chemical exposure ic pathogens, Gulf War participants were Chemical warfare agents potentially exposed to agents of biological Pyridostigmine used as prophylaxis against warfare. chemical weapons Surprising though is the apparent minimal Pesticides and rodenticides impact on morbidity caused by infection dur- Petroleum products ing the Gulf War. Among 226 non-combat Depleted uranium used in munitions deaths, none were infectious disease-related. Chemical agent resistant paint Furthermore, the disease non-battle injury Desert sand rate was lower than any other major American war. There were no reported cases of cholera, Psychological stress typhoid fever, amoebic dysentery, giardiasis, Posttraumatic stress disorder schistosomiasis, echinococcosis, brucellosis, Depression sandfly fever, anthrax, or botulism. Only a Anxiety handful of cases of cutaneous leishmaniasis, Somatization malaria, Q fever, West Nile fever, meningo- Adjustment reaction coccosis, and hepatitis were reported.13 Despite the paucity of infectious disease during the war, the report of a variant form of Viscerotropic visceral leishmaniasis presenting months to leishmaniasis symptom reporting from several investiga- years after return from the Gulf War has stim- tors, examination of these complaints has ulated interest in a link to Gulf War syn- can present failed to reveal a consistent physical exami- drome.14 This illness (termed viscerotropic years later nation or laboratory abnormality, nor conclu- leishmaniasis) was originally reported in eight sively implicated a distinct exposure, geo- veterans who suffered with vague symptoms graphic risk factor, or demographic except for manifesting up to 2 years after the war's end. the observation that National Guard and Symptoms reported included various combi- reserve personnel are more frequently affect- nations of arthralgia, fever, malaise, abdomi- ed. Exploratory factor analysis9'10 has nal pain, diarrhea, nausea, chronic fatigue, rig- attempted to better characterize these symp- ors, weight loss, coryza, nonproductive cough, toms as a distinct illness, but a confirmatory and headache. Physical examination findings factor analytic model11 failed to support the were waxing and waning in nature and ran a existence of a unique disease. spectrum from none to hepatomegaly, splenomegaly, adenopathy, and abdominal • PROPOSED ETIOLOGIES tenderness. Laboratory findings demonstrated mild anemia and elevated transaminases in Potential explanations for the Gulf War syn- some, but others had no abnormalities. drome can be divided into three categories Definitive diagnosis often required repeated (TABLE 2): microbiologic testing, presumably due to • Infectious disease lower organism burdens in this variant form of • Chemical exposures visceral disease. The potential relationship to • Psychological stress. Gulf War syndrome is intriguing as the pro- The more popular of these hypotheses will be tean nonspecific nature of viscerotropic leish- discussed in further detail. maniasis closely mimics the vague, poorly 14 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 67 • NUMBER 1 JANUARY 2000 Downloaded from www.ccjm.org on September 23, 2021. For personal use only. All other uses require permission. characterized illness of the Gulf War syn- the peripheral pool of chemical weapon avail- drome. It is thus a diagnosis that should be able to enter the central nervous system, entertained in all Gulf War veterans present- increasing the potential to develop OPIDP.15.16 ing with perplexing illness. In an attempt to link the OPIDP hypoth- esis to Gulf War syndrome, exposure of chick- • CHEMICAL EXPOSURE: ens to various combinations of organophos- ORGANOPHOSPHATE INJURY phate chemicals and pyridostigmine in doses likely encountered during the Gulf War Troops may have been exposed to resulted in both clinical and histological evi- organophosphate chemicals in the form of dence of nervous system injury.17 Several pesticides and chemical weapons that were studies have been conducted in humans to released during destruction of Iraqi ammuni- look for objective evidence of neurological tion bunkers. Organophosphates are acetyl- damage among sick veterans. 18~20 Interesting cholinesterase inhibitors that damage the ner- trends suggestive of neurological injury have vous system by two mechanisms: first, an been reported, yet the small sample sizes and acute injury resulting from a functional excess methodological shortcomings of many of of acetylcholine leading to the classic cholin- these experiments limit the ability to draw ergic toxidrome, and second, a delayed, more convincing conclusions. chronic neurotoxic injury known as "organophosphate-induced delayed polyneu- • PSYCHOLOGICAL STRESS ropathy" (OPIDP) resulting from inactivation of the neural tissue enzyme neurotoxic The observation that National Guard and esterase. Classically, OPIDP affects the reserve personnel appear to be more frequent- peripheral nervous system, resulting in pares- ly afflicted may suggest a psychological etiolo- thesias, numbness, and flaccid paralysis. The gy. These people were in general older than spinal cord, brainstem, and subcortex can also regular military personnel, more likely to have be involved, leading to hyperreflexia, bowel had civilian jobs and dependents back home, and bladder incontinence, autonomic dys- and less prepared for combat and therefore Oranophosphate- function, spasticity, fatigue, ataxia, depres- may have been psychologically more suscepti- induced delayed sion, and cognitive impairments. As many of ble to the stresses of war. There is no doubt these symptoms have been observed among that many veterans have suffered psychologi- polyneuropathy Gulf War veterans, it has been suggested that cal illness as evidenced by increased preva- 15 can affect the Gulf War syndrome is a variant of OPIDP. lence of adjustment reactions, depression, anx- The use of pyridostigmine as prophylaxis iety, somatization, alcohol and drug depen- peripheral against possible chemical weapons attack dence, and post-traumatic stress disorder. nervous system,