Abstract
Multiple sclerosis (MS) is the most common immune-mediated, demyelinating, and degenerative disease of the central nervous system (CNS), primarily affecting young adults and women (2:1 ratio). Despite extensive research, its exact pathophysiology remains unclear. Several environmental risk factors have been associated with increased susceptibility, including low vitamin D levels, Epstein-Barr virus (EBV) infection, smoking, and obesity. Migraine and tension-type headache (TTH) are the most prevalent neurological disorders and among the leading global causes of years lived with disability. According to the Global Burden of Disease, they affect over two billion people worldwide. Given that MS and primary headaches share common demographic risk factors—particularly young age and female sex—numerous studies have explored a possible association between them. However, findings have been inconsistent, largely due to methodological limitations such as retrospective study designs and lack of co ...
Multiple sclerosis (MS) is the most common immune-mediated, demyelinating, and degenerative disease of the central nervous system (CNS), primarily affecting young adults and women (2:1 ratio). Despite extensive research, its exact pathophysiology remains unclear. Several environmental risk factors have been associated with increased susceptibility, including low vitamin D levels, Epstein-Barr virus (EBV) infection, smoking, and obesity. Migraine and tension-type headache (TTH) are the most prevalent neurological disorders and among the leading global causes of years lived with disability. According to the Global Burden of Disease, they affect over two billion people worldwide. Given that MS and primary headaches share common demographic risk factors—particularly young age and female sex—numerous studies have explored a possible association between them. However, findings have been inconsistent, largely due to methodological limitations such as retrospective study designs and lack of control groups. This highlights the need for a well-designed prospective longitudinal study to clarify whether migraine or TTH are more common in individuals with MS. The aim of this dissertation is to investigate whether primary headaches are more prevalent in patients with MS, to analyze their clinical characteristics, and to examine potential associations with brain MRI findings. Initially, a systematic review and meta-analysis of the available literature was conducted, including 23 studies yielding a total of 5,440 patients with MS and 280,958 healthy controls. The prevalence of migraine in individuals with MS was found to be 30%, compared to 19% in healthy controls. Patients with MS were more than twice as likely to experience migraine compared to controls (OR = 2.02, 95% CI = 1.14–3.57). Although this meta-analysis suggests a higher prevalence of migraine in MS, the findings must be interpreted with caution due to methodological limitations of the included studies (retrospective design, lack of control groups).To address these limitations and reliably assess the prevalence of primary headache disorders in MS, a prospective, longitudinal, controlled study was designed. A total of 96 patients with MS and 96 healthy controls were recruited and followed over a two-year period. The types and characteristics of headaches were analyzed and compared between the two groups, along with potential associations with neuroimaging findings. A cross-sectional analysis initially revealed a statistically significant association between migraine and demyelinating lesions in brain regions involved in pain processing and perception, such as the periaqueductal gray matter (OR: 4.7; 95% CI: 1.5–14.59; p=0.008), the thalamus (OR: 7.2; 95% CI: 1.37–37.79; p=0.02), and the cortex (OR: 9.1; 95% CI: 1.53–54.72; p=0.02).Subsequently, a retrospective case-control analysis was conducted to assess the prevalence of primary headaches in both MS patients and controls. Participants were evaluated for headache occurrence during the three months prior to study enrollment, and diagnoses were made using semi-structured headache diaries routinely used in specialized headache clinics at the Eginition University Hospital. The prevalence of primary headaches was significantly higher in MS patients compared to controls (71.9% vs. 43.8%). Specifically, the prevalence of migraine and tension-type headache (TTH) in the MS group was 28.1% and 38.5%, respectively, compared to 8.3% and 28.2% in controls. MS patients were more than four times as likely to be diagnosed with any primary headache (OR = 4.54; 95% CI: 2.28–9.04; p = 1.7 × 10⁻⁵) and over twice as likely to be diagnosed with migraine (OR = 2.21; 95% CI: 1.05–4.62; p < 0.05) or TTH (OR = 2.16; 95% CI: 1.16–4; p < 0.05).Finally, a prospective, controlled longitudinal study was conducted, involving biannual follow-up of participants over two years to accurately document headache prevalence and characteristics. This design addressed key methodological limitations of previous studies (retrospective data collection, absence of control groups, and lack of structured headache diaries) and aimed to draw robust conclusions regarding the prevalence of primary headaches in MS. This prospective analysis confirmed that all primary headaches were significantly more prevalent in MS patients compared to healthy controls (60.14% vs. 41.7%, p=0.014). The prevalence of migraine was 31.3% in the MS group versus 16.7% in controls (p=0.028), while TTH prevalence did not differ significantly (34.4% vs. 29.2%, p=0.535). Furthermore, MS patients were more than twice as likely to develop migraine than controls (OR = 2.3; 95% CI: 1.26–4.21; p = 0.007), and reported more frequent, intense, and prolonged migraine episodes. In conclusion, this dissertation demonstrated that primary headaches—particularly migraine—are significantly more prevalent in individuals with MS than in healthy controls, a finding confirmed through both cross-sectional and prospective controlled methodologies. Additionally, a strong association was observed between migraine and demyelinating lesions in specific brain regions involved in pain processing, suggesting that demyelination and neurodegeneration in these "strategic" areas may underlie the increased prevalence of migraine in MS. These findings underscore the importance of heightened awareness and timely recognition of headache disorders in MS, as well as the need for early intervention to improve patients’ quality of life and long-term outcomes.
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