Migraine in gulf war illness and chronic fatigue syndrome: prevalence, potential mechanisms, and evaluation

Rakib U Rayhan, Murugan K Ravindran, James N Baraniuk, Rakib U Rayhan, Murugan K Ravindran, James N Baraniuk

Abstract

Objective: To assess the prevalence of headache subtypes in Gulf War Illness (GWI) and Chronic Fatigue Syndrome (CFS) compared to controls.

Background: Approximately, 25% of the military personnel who served in the 1990-1991 Persian Gulf War have developed GWI. Symptoms of GWI and CFS have considerable overlap, including headache complaints. Migraines are reported in CFS. The type and prevalence of headaches in GWI have not been adequately assessed.

Methods: 50 GWI, 39 CFS and 45 controls had structured headache evaluations based on the 2004 International Headache Society criteria. All subjects had history and physical examinations, fatigue and symptom related questionnaires, measurements of systemic hyperalgesia (dolorimetry), and assessments for exclusionary conditions.

Results: Migraines were detected in 64% of GWI (odds ratio = 11.6 [4.1-32.5]) (mean [±95% CI]) and 82% of CFS subjects (odds ratio = 22.5 [7.8-64.8]) compared to only 13% of controls. There was a predominance of females in the CFS compared to GWI and controls. However, migraine status was independent of gender in GWI and CFS groups (x (2) = 2.7; P = 0.101). Measures of fatigue, pain, and other ancillary criteria were comparable between GWI and CFS subjects with and without headache.

Conclusion: The high prevalence of migraine in CFS was confirmed and extended to GWI subjects. GWI and CFS may share dysfunctional central pathophysiological pathways that contribute to migraine and subjective symptoms. The high migraine prevalence warrants the inclusion of a structured headache evaluation in GWI and CFS subjects, and treatment when present.

Keywords: central sensitization; chronic fatigue syndrome; chronic pain; fatigue; fibromyalgia; gulf war illness; migraine; neurolimbic pathway.

Figures

Figure 1
Figure 1
Central sensitization using migraine as a model. (1) Cortical spreading depression (CSD) depolarizes cortical neurons and glia. (2) They release glutamate, K+, H+, metalloproteases, and other agents that dilate pial vessels and activate trigeminal nociceptive nerves. (3) The bifurcated neurons release calcitonin gene related peptide (CGRP) and other vasodilators near dural vessels by the axon response mechanism. Vascular wall stretching activates additional trigeminal nociceptive neurons (4) that have their primary synapse (5) in the upper cervical dorsal horn. (6) Ascending secondary afferents activate the thalamus. (7) Other afferents signal the periaqueductal gray matter. (8) Descending relays to the magnus raphae nucleus activate descending serotonergic neurons to inhibit the primary trigeminal (5 and 6) synapses. (9) Thalamocortical projections stimulate the hypothalamus, somatosensory cortex, amygdala, limbic system, and frontal cortex. (10) Pain, emotion, memory, frontal processing and other inputs converge on the anterior cingulate gyrus (ACC) and (11) interfere with its executive decision-making functions.
Figure 2
Figure 2
CFS symptom severity scores. The severity of fatigue and the 8 ancillary criteria were scored on an anchored ordinal scales from 0 to 4. Controls (blue columns) had significantly lower scores for each item compared to GWI (yellow columns) and CFS (red columns). *P < 0.0000018; ANOVA followed by Tukey's HSD test; error bars depict the mean [±95% CI].
Figure 3
Figure 3
Sum8 and comparison between CFS and GWI subjects based on migraine status. (A) Sum of 8 scores which total the 8 ancillary criteria from the CFS severity score. (B) CFS and GWI subjects were combined to show that migraineurs (n = 64) had higher ratings of headache severity (2.9 [2.7–3.2]) compared to CFS and GWI subjects with no migraines (2.1 [1.6–2.5]; n = 25) and controls (0.88 [0.51–1.3]; n = 45). (C) CFS and GWI subjects with migraines had lower systemic pain thresholds (2.8 [2.4–3.2]) compared to those with no migraines (4.2 [3.4–5.1]) and controls (5.5 [1.6–2.5]). (D) CFS and GWI migraineurs had lower sinus pain thresholds (1.1 [0.9–1.3]) compared to CFS and GWI with no migraines (1.6 [1.3–1.9]) and controls (2.2 [1.8–2.6]). *P ≤ 0.05; ANOVA followed by Tukey's HSD test; error bars depict the mean [±95% CI]. **P ≤ 0.001.

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