Migraine and tension-type headache (TTH) are widespread among the working age population. These diseases reduce work productivity and result economic losses [1, 2]. Chronic headache impairs quality of life and significant financial costs. Until now, the diagnoses of "migraine" and "TTH" are exclusively clinical, and previously developed diagnostic tests are aimed at exclusion of other causes of headache. Searching for biomarkers of migraine and TTH is an urgent scientific issue [10]. Genetic markers of chronic migraine (CM) and chronic TTH will allow differentiation of treatment methods in these patients. There are various symptoms not related to headache during or between migraine and TTH attacks. Vestibular dysfunction (VD), anxiety-phobic disorders, depression, sleep disturbance, myofascial and vertebrogenic pain syndromes are comorbid conditions significantly impairing QOL in patients with primary headache and causing their social maladjustment [3, 4, 5, 6]. Timely identification of comorbidities requires their active diagnosis and subsequent correction for effective therapy of the underlying disease. A differentiated approach to the treatment of patients with CM and TTH considering comorbidities is important.

Despite various available medications, standard therapy turn out to be ineffective in 20% of patients. Effective treatment of CM and TTH requires a special attention because incorrect and ineffective treatment and uncontrolled intake of analgesics are followed by development of drug-induced hypertension. The last one requires more laborious treatment approach [8]. Thus, searching for new methods of treatment of CM and TTH is urgent, especially in case of their combination with drug-induced headache and comorbidities [9].

The objective was to develop the risk criteria of chronic headache and treatment algorithm for CM and TTH considering comorbidities and data of molecular genetic examinations.

Material and methods

Diagnostic algorithm for CM and TTH was applied in 56 patients aged 40 ± 11.7 years. We used the situational anxiety scale, the headache impact test (HIT-6), the express questionnaire for dizziness type [12], the visual analogue scale and the McGill pain questionnaire [14] to assess the systems involved in comorbidities. Neurophysiological examination included vestibulometry with functional tests (Electronystagmograph, Statokin, RF) [13], stabilometry with functional tests ("Stabilan- 01—2", "Ritm" JSC, RF) [15], neuro-orthopedic testing, esthesiometric testing (Esthesiometer E-01, "MPOVT" JSC, RB). Brain MRI was performed to exclude secondary headache (DISCOVERY MR750W 3.0 T MRI scanner, GE, USA). We also carried out molecular genetic examination. Inclusion criterion was headache meeting the criteria of chronic migraine (ICHD-3, 2018).

Statistical analysis was carried out using the STATISTICA 8.0 software. Normality was tested using the Kolmogorov — Smirnov test with the Lilliefors correction and the Shapiro — Wilk test. Quantitative data with abnormal distribution were described as median and interquartile range (Me [25%; 75%]). The Mann — Whitney test (U-test) was used to compare two independent samples for non-parametric data or for different variances of samples with normal distribution. We used the Kruskal — Wallis H-test with Bonferroni correction to compare ≥ 3 independent quantitative samples. Correlation between quantitative parameters and variables was assessed using the chi-square test (χ²) with Yates's correction. The Fisher-Freeman-Halton test (F) was used if the assumptions underlying the chi-square test were failed. The Wilcoxon's test was applied to compare two dependent samples. Differences were considered significant at p-value <0.05).

Results

Forty-three out of 56 patients previously experienced various types of dizziness (Table 1). Benign paroxysmal positional vertigo was found in 35 (81%) out of 43 patients. Vestibulo-vegetative complaints (motion sickness) were significantly more common (n=38, 88%) (χ² = 25.58, p = 0.0001). Combination of several variants of dizziness was noted in 22 (51%) cases (χ² = 10.82, p = 0.0001). Then, we analyzed vestibular function using vestibulometric examination. These data are presented in Table 2.

Table 1. Characteristics of previous paroxysmal vertigo according to the express questionnaire in patients with tension headache

Note. * — p<0.05 according to the χ² test with Yates’ correction.

Table 2. Vestibular function in patients with CM and chronic TTH

Note. * — p<0.05 according to the χ² test with Yates’ correction.

According to vestibulometry data, none patient had spontaneous nystagmus within pain-free period. However, right-sided (n=27, 48%) and left-sided (n=7, 13%) de Klein's test provoked nystagmus (χ² = 32.99, p <0.0001 and χ² = 5.49, p <0.05, respectively). Headache provoked nystagmus in 26 (46%) cases (χ² = 31.31, p <0.0001). We observed high percentage of provocative nystagmus following positional tests, such as the Dix-Hallpike test on the right in 30 (54%) cases and on the left in 5 (9%) cases (χ² = 33.29, p <0.0001 and χ² = 3, 35, p = 0.067, respectively). No asymmetry of vestibulo-ocular and optokinetic reactions was found.

Neuro-orthopedic examination revealed an increased thoracic kyphosis in 11 (20%) cases and its straightening in 12 (21%) patients. Regional cervical spine hypermobility was established in 8 (14%) cases. Functional blockades of cervical spinal motion segment, thoracic segments and transitional spinal zones were detected in all patients. Functional disorders of craniocervical junction mobility (bilateral as a rule) were diagnosed in 39 (69%) patients. Twenty-eight (48%) patients had dysfunction of the temporomandibular joint with restricted mobility or hypermobility, as well deviation of the mandible. All patients had myofascial hypertonicity (MFH) with various pain syndromes. The number of MFH ranged from 3 to 12 per a patient. Active trigger points (1 — 8) were detected in 45 (80%) cases, latent trigger points (1 — 8) — in 54 (96%) patients, only latent trigger points — in 13 (23%) cases. To assess the role of MFH in pain syndrome, we performed their palpation, analyzed the nature of reflective or evoked pain and its changes. in In 23 (41%) patients with active trigger points, localization of reflective and evoked pain during trigger point stimulation corresponded to localization of symptoms of primary headache.

Then, we analyzed pain sensitivity thresholds considering esthesiometry data. Considering significant differences in pain sensitivity thresholds depending on gender, we analyzed these data separately in subgroups of men and women. Examination was performed in 36 females and 20 males with CM and TTH. Control group comprised 25 healthy women and 15 men aged 39.8 ± 9.6 years.

We found decrease of pain sensitivity thresholds in patients with CM and TTH compared to the control group: men — right and left temporal region 0.16 [0.16; 0.20] and 0.16 [0.12; 0.24] mA, respectively, healthy people — 0.22 [0.20; 0.24] and 0.20 [0.12; 0.24] mA; women — right and left temporal region 0.12 [0.12; 0.16] and 0.12 [0.12; 0.20] mA, in healthy people — 0.20 [0.16; 0.22] and 0.20 [0.16; 0.20] mA, respectively. Right and left temporomandibular joints in men — 0.16 [0.12; 0.20] and 0.16 [0.16; 0.20], respectively; healthy people — 0.20 [0.16; 0.20] and 0.20 [0.16; 0.22]; women with migraine — 0.12 [0.12; 0.18] and 0.12 [0.12; 0.16] mA, control group — 0.16 [0.14; 0.24] and 0.20 [0.16; 0.20] mA. Masseter muscles in men — 0.16 [0.16; 0.16] and 0.16 [0.12; 0.20], control group — 0.20 [0.16; 0.24] and 0.20 [0.16; 0.22] mA; women — 0.12 [0.08; 0.20] and 0.14 [0.12; 0.16] mA. These values were less than in healthy people, where pain sensitivity threshold was 0.16 [0.12; 0.20] and 0.16 [0.12; 0.19] mA, respectively; right and left trapezius muscles in men — 0.16 [0.16; 0.20] and 0.16 [0.16; 0.28], control group — 0.20 [0.16; 0.24] and 0.20 [0.12; 0.24] mA, respectively; women — 0.12 [0.12; 0.16] and 0.12 [0.08; 0.20] mA, healthy people — 0.20 [0.20; 0.20] and 0.16 [0.16; 0.20] mA, respectively (p <0.05).

In the main group, thirty-nine (69.6%) patients had previous disorders of statokinetic stability. Comparison of statokinetic stability in Romberg test with open and closed eyes revealed that vision deprivation significantly affects statokinetic stability and reflects insufficient regulation of statokinetic stability following vision deprivation. This led to significant decrease of integral indicator of equilibrium function from 89,46% [79.33; 93.71] to 77.80% [65.82; 85.10] (W, T = 83, Z = 5.756, p <0.0001).

Changes in proprioceptive afferentation also significantly impaired statokinetic stability with decrease of integral indicator of equilibrium function up to 83.26% [73.45; 87.11] (W, T = 522.0, Z = 2.251, p <0.05). Dix-Hallpike tests also significantly affected statokinetic stability. Turning the head to the right significantly deteriorated integral indicator of equilibrium function up to 82.22% [74.15; 92.25] (W, T = 434.0, Z = 2.969, p <0.05). Optokinetic stimulation in horizontal plane significantly reduced integral indicator of equilibrium function due to significant effect on most indicators of statokinetic stability. Integral indicator of equilibrium function decreased up to 83.76% [75.61; 89.23] (W, T = 44, Z = 2.485, p <0.05) after optokinetic stimulation to the right and up to 73.76% [71.41; 82.27] (W, T = 44, Z = 2.485, p <0.05) after optokinetic stimulation to the left.

In this study, we optimized composition of amplification mixture and thermocycling conditions for analysis of polymorphism of genes encoding serotonin transporter protein (SLC6A4), dopamine beta-hydroxylase (DBH), and preprotachykinin (TAC1). Molecular genetic studies were performed to analyze allelic variants and genotypic profiles of 5-HTTLPR and G29A of the gene encoding serotonin transporter protein (SLC6A4); DBH2 and DBH3 of the gene encoding dopamine beta hydroxylase (DBH), as well as rs7793277 and Intron3SNP of the gene encoding preprotachykinin (TAC1).

The following molecular genetic risk factors of chronic TTH were established. Allele A and genotype AA of DBH3 polymorphism of the DBH gene of dopamine beta hydroxylase increase the likelihood of chronic pain by 1.467 and 1.823 times, respectively. Allele G and genotype GG of Intron3SNP polymorphism of the TAC1 gene of preprotachykinin increase the likelihood of chronic pain by 1.991 and 1.395 times, respectively [11].

We also distinguished molecular genetic risk factors of chronic migraine. Allele A and genotype GA of G29A polymorphism of the SLC6A4 gene of serotonin transporter increase the likelihood of chronic pain by 1.393 and 1.235 times, respectively. Genotype AA is an absolute risk factor of chronic course of disease. Allele G and genotype GG of rs7793277 polymorphism of the TAC1 gene of preprotachykinin increase the likelihood of chronic pain by 1.353 and 1.395 times, respectively [11].

We developed an algorithm for choosing the treatment strategy for patients with CM and chronic TTH considering clinical and instrumental data, as well as results of molecular genetic examination:

1. Identification of comorbidities considering anamnestic and neurophysiological data (Table 3).

2. Scoring of molecular-genetic factors of chronic migraine and tension-type headache in accordance with Table 3.

3. Treatment of CM and chronic TTH depending on the influence of comorbidities in accordance with Table 3.

Table 3. Evaluation scale of severity of clinical, instrumental manifestations of comorbidities and molecular genetic data

Treatment algorithm for chronic migraine and chronic headache depending on molecular genetic diagnostic data.

Discussion

Various aspects of pathophysiology of comorbidities and their influence on transition of episodic form to chronic headache are being revised up to the present time. These processes naturally affect general principles of treatment and medical rehabilitation of these patients. Trigger point development results central sensitization. Generator of abnormally enhanced excitation and zone of secondary hyperalgesia occur that contributes to chronic course of disease with development of allodynia. Provocative nystagmus diagnosed during vestibulometry with functional de Klein and Dix-Hallpike tests indicates vascular genesis of latent vestibular dysfunction. The last one is caused by discirculation in vertebral artery system and inner ear under comorbid abnormal afferentation from trigger points in muscles and fibrous tissues of the neck in patients with CM and TTH. Esthesiometric data suggest impairment of sensory perception in patients with CM and TTH that can confirm involvement of peripheral and central sensitization in pathogenesis of CM and chronic TTH. Tension of facial and pericranial muscles is essential in pathogenesis and chronic nature of migraine and TTH, provocation of pain episodes and paroxysmal dizziness. Moreover, MFH and vestibular dysfunction negatively affect patient quality of life in interictal period. Therefore, correction of comorbidities should be one of the most important aspects of therapy for migraine and TTH along with traditional preventive approaches. Polymorphisms in the above-mentioned genes of dopamine and preprotachykinin increase the risk of chronic TTH and migraine by 1.395-1.991 and 1.235-1.395 times, respectively.

Injections of botulinum toxin type A and transcranial magnetic stimulation are perspective for chronic migraine management. However, there is no experience for abobotulinumtoxin A among neurologists in Belarus. Clear indications for selection of patients have not been developed. Introduction of treatment algorithm for patients with CM and chronic TTH into practical healthcare will improve the effectiveness of treatment via a personalized approach to therapy considering comorbidities and molecular genetic data.

The authors declare no conflicts of interest.