Cholinergic Autonomic Dysfunction in Veterans With Gulf War Illness:  Confirmation in a Population-Based Sample

Figure 1. Process for selecting the nested case-control sample of Gulf War veterans suitable for the clinical neuroimaging study of Gulf War illness from the population sample of the US Military Health Survey. Nondeployed control subjects included those who were medically deployable personnel in the US military during the Gulf War but who were not deployed to the Kuwaiti theater of operations and did not meet any of the case definitions for Gulf War illness. In the stage 1 and stage 2 boxes, the differences between the total and the sum across its 5 comparative groups are due to subsyndromic subjects or members of special strata.¹⁰ Numbers in the age by sex, race/ethnicity, and officer rank during the war strata in each clinical group are suppressed according to terms of the certificate of confidentiality. The 32 veterans excluded from group misclassification included 31 classified in one of the syndrome groups whose symptoms reported on the survey were not verified by the medical history taken by telephone and 1 classified as a control subject who had omitted symptoms of Gulf War illness on the survey. The 9 excluded for neurological conditions included 5 with a history of traumatic brain injury and 1 each with cerebrovascular disease, Parkinson disease, Guillain-Barré syndrome, and an unspecified chronic disease. The response rate is the American Association for Public Opinion Research response rate 4 and includes in the base the estimated number of eligible cases among those initially selected from the sampling frame to be contacted.¹¹ MR indicates magnetic resonance.

Figure 2. Distribution of values on the Composite Autonomic Symptom Scale (COMPASS) in the control subjects and in the 3 Gulf War illness variant groups. The horizontal bars represent the mean scores. The differences in COMPASS scores across the 4 groups are statistically significant (R² = 0.59, P < .001).

Figure 3. Difference in circadian variation of parasympathetic cardiovagal tone between control subjects and 3 Gulf War illness variant groups, measured by spectral analysis of high-frequency heart rate variability (HRV) in 5-minute epochs every hour from 24-hour Holter monitoring electrocardiography. The control group (black circles) is compared with all cases of Gulf War illness (red diamonds) (A) and with syndrome 1 (green triangles), syndrome 2 (red squares), and syndrome 3 (blue stars) (B). The control group showed the expected low cardiovagal tone during the day and a large increase at night. The syndrome 2 group showed depressed tone throughout the 24-hour period, with no evidence of a nocturnal increase. Syndrome 1 and syndrome 3 showed a blunted, delayed increase at night, and syndrome 3 had elevated tone during the day. The statistical test results of the effects in these graphs are given in Table 4.

Figure 4. Correlation of high-frequency heart rate variability (HRV) at night (A) and during the day (B) with the total Composite Autonomic Severity Score (CASS). Normal R-R intervals from a 24-hour Holter monitor electrocardiogram were analyzed by spectral analysis in a 5-minute epoch each hour. For each participant, the hourly measures of the high-frequency spectral component (0.15 to <0.40 Hz) were averaged across the nighttime hours (12 AM to 5 AM) and across the daytime hours (8 AM to 9 PM), and both measures were log transformed. Measurements on the battery of objective autonomic tests were combined to calculate the CASS, on which higher scores indicate greater autonomic impairment.