Migraine headaches in Chronic Fatigue Syndrome (CFS): Comparison of two prospective cross-sectional studies

Headaches are common complaints in Chronic Fatigue Syndrome (CFS) and fibromyalgia (FM) [1, 2]. However, the characteristics of these headaches are poorly defined with regards to the International Headache Society criteria (IHS) [3].

The CFS case designation requires a 6 month history of persistent, unexplained fatigue that causes significant impairment of activity, plus 4 of 8 associated criteria [1]. These criteria include exertional exhaustion, cognitive and sleep disturbances, and diffuse bodily pain including headaches. Fatigue was verified using a 5 point anchored ordinal scale [4] and the Multidimensional Fatigue Inventory [5]. Disability and impaired quality of life were confirmed using the Medical Outcomes Survey Short Form 36 (SF-36) [6]. Headache severity was assessed by a 5 point ordinal scale [4]. Pain symptoms were compared between groups using the McGill Pain Short Form [7]. Acute and chronic medical, surgical and psychiatric conditions were ruled out by history and physical examinations.

Headaches and other CFS related symptoms overlap with fibromyalgia (FM) criteria. The 1990 American College of Rheumatology (ACR) research definition of FM required 3 months of unexplained, widespread pain plus tenderness to manual thumb pressure at ≥ 11 of 18 traditional tender points [8]. This definition has been replaced by the 2010 FM criteria [9] that emphasize subjective assessments of widespread pain, fatigue, unrefreshing sleep, and cognitive difficulties. The new criteria allow considerable overlap between CFS and FM conditions.

The most prevalent headaches in the general population are tension - type (45%), migraine (12%), sinus (3%), and medication overuse headaches (1 - 2%) [3, 10, 11]. Tension - type (T) headaches are defined by bilateral, pressing or nonpulsatile cephalgia of mild to moderate intensity that may last 30 minutes to 7 days. They are not aggravated by routine physical activity such as walking or stair climbing.

Migraine is diagnosed by having at least 5 episodes lasting 4 to 72 hr with at least 2 of the following criteria: (i) unilateral location; (ii) pulsatile quality; (iii) moderate to severe pain intensity; and (iv) aggravation by physical activities or active avoidance of movement. Either nausea ± emesis, or photophobia and phonophobia must occur. Migraines are subdivided into migraine with aura (MA; 20% to 30% of migraineurs) and migraine without aura (MO) [3, 12, 13]. The focal sensory phenomena of the aura involves either homonymous visual symptoms such as flickering lights, rotating discs, photosensitivity, and loss of vision, or unilateral somatosensory disturbances such as paresthesias or numbness. Symptoms appear gradually over 5 to 20 minutes and last less than 60 minutes. The aura must be detected at least twice. Motor function is not affected. The headache phase of the migraine attack usually begins within 60 minutes after the end of the aura, but sometimes is delayed for several hours. In some cases, pain can be completely absent. Multiple avenues of investigation including brain magnetic resonance imaging (MRI) techniques have associated auras with the concentric expansion of severe and prolonged brain cortex electrical depolarization, neurotransmitter release, vasoconstriction and reactive hyperemia known as cortical spreading depression [14]. Increased pain sensitivity (hyperalgesia) may occur in both MO and MA [15] due to dysfunctional pain regulatory mechanisms during central sensitization [16].

Since 67% of migraine subjects meet CFS criteria [2], we propose that mechanisms of migraine may play roles in CFS pathophysiology. If so, CFS subjects should have elevated rates of migraine headaches compared to control subjects. Mechanisms that differentiate MO from MA may also be present and permit subgroup analysis in CFS.

Two cohorts of CFS [1] and healthy control (HC) subjects were recruited in sequential order (Cohort 1 then Cohort 2) using identical advertisements in the community (e.g. newspapers) and the tertiary medical center (e.g. posters), and information from websites [17, 18]. All subjects gave signed informed consent to take part in this IRB - approved study.

History and physical examinations assessed the CFS case designation criteria. "CFS" was designated by findings of significant, unexplained fatigue lasting at least 6 months plus the presence of at least 4 of 8 ancillary criteria: (i) problems with concentration or memory; (ii) sleep disturbances; (iii) exertional exhaustion that typically developed 24 hr after excessive physical or mental effort; (iv) muscle pain; (v) joint pain; (vi) headaches; (vii) sore throat; and (viii) sore lymph node regions in the cervical, axillary or inguinal areas [1]. These CFS symptoms were scored in nominal fashion as "present" or "absent". In addition, subjects scored the severity of each symptom in the previous 6 months using a 5 point, anchored ordinal scale [4]. Scores were 0 for no symptom, 1 for trivial, 2 for mild, 3 for moderate and 4 for severe complaints. Inclusion of "trivial" allowed subjects to acknowledge complaints that were present but not bothersome enough to warrant treatment or other lifestyle adaptations [19]. Subjects with untreated endocrine, major psychiatric, cardiovascular, infectious (e.g. HIV), neoplastic, and other chronic diseases that may have accounted for fatigue, body pain, headache or other symptoms were excluded.

Cohort 1 was assessed by a series of questionnaires, history and physical examinations. Different combinations of questionnaires were used during their recruitment period. Preliminary results from Cohort 1 suggested an increased prevalence of migraine in CFS compared to HC.

Next, Cohort 2 was recruited. Subjects completed an optimized set of questionnaires and had formalized clinical interviews to diagnose migraine with (MA) and without (MO) aura, and tension - type (T) headaches based on IHS criteria (as outlined in the Introduction) [3]. CFS subjects were classified as CFS+MA, CFS+MO, and CFS+T, respectively. About two - thirds of CFS+MA and CFS+MO subjects had co-morbid tension-type headaches. For statistical convenience, the CFS+T group included 3 subjects with no headaches.

The Multidimensional Fatigue Inventory was used to verify the presence of significant physical, mental, and other fatigue measures [5]. Quality of life (disability) was assessed by the Medical Outcomes Survey Short Form 36 (SF-36) domain scores [6]. Pain complaints were subjectively assessed using the McGill Pain Short Form with its Affective, Sensory and Total Scores [7]. Subjects completed a multisystem complaints questionnaire that evaluated the nominal presence or absence of migraine and tension headaches, musculoskeletal, airway, thoracic, bowel, bladder and other symptoms over the previous 3 months [4].

The frequencies of several symptoms from individual systems were found to be highly correlated with each other in preliminary studies. Therefore, questionnaires were modified to also score the severities of each symptom. The same 0 to 4 point, anchored, ordinal scale was used, and data collected for some Cohort 1 and all Cohort 2 subjects. The severity scores for the selected symptoms were again found to correlate with each other and the Fatigue Severity Score. The sum of severity scores for numbness in the arms and legs, problems with memory, dizziness and balance was calculated and accounted for 32% of the explained variance (R²) between these queries and the Fatigue Score. This sum was defined as the "Neuro-construct" (score range of 0 to 16). A "Cardio-construct" was developed as the sum of scores for rapid heart rate, irregular heart rate, palpitations, and chest pain (range 0 to 16). The explained variance was 30%.

FM was assessed using the 1990 American College of Rheumatology (ACR) research definition. Diagnosis of FM required 3 months of unexplained, widespread pain affecting all 4 quadrants of the body and the axial skeleton, plus tenderness to manual thumb pressure (~4 kg) at ≥ 11 of 18 traditional tender points [8]. Pressure - induced pain thresholds were measured by pushing a strain gauge tipped with a 1cm² rubber tip (dolorimeter) at a rate of 1 kg/sec on the same 18 anatomical sites. The average was the systemic pain threshold (kg). The pressure required to cause pain was also measured over the frontal, ethmoid and maxillary paranasal sinus regions. The average was the sinus pain threshold [20].

Means and 95% confidence intervals were calculated for each variable in the HC and CFS groups [21, 22]. Cohort 1 HC and CFS outcomes were compared using 2-tailed unpaired Student's t-tests with Bonferroni corrections for multiple comparisons (p × 138 comparitors) to identify significant differences. Fisher's Exact tests evaluated differences in proportions [21]. Significance was ascribed to p ≤ 0.05.

The Cohort 2 HC and CFS and headache subtype data were compared by analysis of variance (ANOVA). If significant, variables were compared by 2-tailed unpaired Student's t-tests with Bonferroni corrections. Fisher's Exact tests were used as appropriate.

CFS, FM and headaches were defined by personal history and physical examinations in this study rather than by surveys as reported previously [2, 23, 24]. The headache interview used for Cohort 2 identified the frequencies of migraine subtypes and tension headache in both CFS and HC groups. The self-report questionnaires gave comparable results for Cohorts 1 and 2. However, the questionnaire findings were not accurate when compared to the structured interviews. The interviews provided credibility to the presence of CFS+MA and CFS+T subgroups despite their small sample sizes. The interviews also demonstrated the higher rates of tension headaches in HC, and migraine without aura (MO) in CFS. CFS subjects with tension headaches (CFS+T) tended to have less severe complaints compared to the migraine subtypes. Inclusion of quality of life SF-36 and fatigue (MFI) questionnaires confirmed the disability and spectrum of fatigue manifestations experienced by the CFS groups.

These data verified the high prevalence of migraine pathology in CFS [2]. The ratio of MO to MA was similar to that reported in other migraine groups [10, 12]. We propose that mechanisms of migraine pathophysiology may contribute to other CFS symptoms in addition to headaches. If so, anti - migraine treatments may be beneficial for CFS - related symptoms even in subjects who do not have migraines. This speculation requires prospective evaluation in clinical trials.

Correlates of MO and MA suggested that aura may be associated with distinct phenotypic and pathological alterations. Neuro-construct, Cardio-construct, and McGill Pain Scores were higher in CFS+MA than CFS+MO. These queries relied on self-reported perceptions of dizziness and lightheadedness, peripheral numbness, thoracic sensations, and higher numbers of pain descriptors. It is not clear how these perceptions may be related to the phenomenon of aura. Vertigo has been associated with migraine as vertiginous migraines, but has not been definitively investigated for a relationship to aura [25, 26]. The sensations of abnormal heart beat and palpitations may be related to autonomic dysregulation that is a common feature of CFS [27]. Chest pain was not related to coronary artery disease or angina as determined by history and physical examination, EKG's, and exercise stress tests in a portion of the subjects. Noncardiac chest pain with perceptions of tachycardia and palpitations may be due to esophageal spasms with nutcracker esophagus [28] or costochondritis [29] in CFS.

Conversely, CFS+MO showed trends for an higher prevalence of FM (1990 criteria) [8] and lower systemic and sinus pain thresholds than CFS+MA (Table 5). Additional testing will be required to determine if these measures reach statistical significance when the number of CFS+MA subjects is increased. This potential difference in tenderness (hyperalgesia) and allodynia [23] between CFS+MA and CFS+MO was not apparent when the severities of the pain - related symptoms such as myalgia and arthralgia were compared (Figure 1). The severities of neurocognitive symptoms were also equivalent between CFS+MO and CFS+MA subgroups.

The current study was not designed to correlate triggers of migraine or the presence of an aura with precipitating factors of severe episodes of CFS complaints. Migraine triggers include fasting, premenstrual period hormonal status, lack of sleep, nasal irritants and odors [30]. Similar triggers are associated with acute worsening of CFS complaints. Future studies will be needed to identify correlates and mechanisms of aura, allodynia and hyperalgesia development in CFS migraineurs [16, 20, 23].

The association of migraine with CFS and FM introduces a new perspective for "functional" somatization disorders. We agree with Wessely et al. [31] who stated that the existence of specific functional somatic syndromes is an artifact of medical specialization and different systems - oriented consensus definitions of these illnesses. This attitude is conveyed by the 2010 FM diagnostic criteria that overlap extensively with CFS, and remove the importance of "tender points" [1, 9]. A further stage in the evolution of CFS, FM, irritable bowel syndrome, and other systems - based diagnoses has been proposed by Fink and Schroder with their hypothesis of Bodily Distress Syndrome [32]. A reevaluation of the pathophysiological mechanisms contributing to these seemingly disparate syndromes and individual organic disorders such as migraine may lead to the recognition of common primary pathologic, genetic and environmental diatheses that lead to overlapping and fluctuating patterns of organ - specific complaints.

CFS subjects have a high prevalence of migraine headaches that may be overlooked and undertreated. The proportion with an aura was similar to other migraine groups. CFS+MA was associated with higher severity scores for neural problems such as numbness and dizziness, and alterations of heart beat. The lower pressure - induced pain thresholds and hyperalgesia found in the CFS+MO subgroup was suggestive of nociceptive hyperresponsiveness and central sensitization. Appropriate diagnosis and treatment with triptans may be beneficial for CFS subjects and their complex headaches.

This project was conducted through the Georgetown-Howard Universities Center for Clinical and Translational Science and supported by the National Institutes of Health National Center for Research Resources through Grant 1UL1RR031975; U.S. Public Health Service Award R01 ES015382 from the National Institute of Environmental and Health Science; and the Congressionally Directed Medical Research Program (CDMRP) Award W81XWH-07-1-0618.