Повсеместность коморбидной мигрени в множестве склерозов: сосуществуют ли множественный склероз и мигрень?

1. Introduction

Multiple sclerosis (MS) is a chronic inflammatory disease leading to multifocal
neuronal demyelination and axonal damage in the central nervous system (CNS). As
an autoimmune and neurodegenerative condition, MS is a leading cause of
nontraumatic neurological disability in young adults, typically characterized by
symptoms such as visual disturbances, spastic paresis, paresthesia, numbness, and
fatigue. Although MS symptoms can vary, headaches are not considered a typical
manifestation [ 1 ]. Migraine ranks as the second leading cause of disability
worldwide and can be classified based on the presence or absence of aura and
subdivided according to the frequency of headaches. Migraine is a headache
disorder manifesting in attacks lasting 4–72 hours. Typical characteristics of
migraine headache are unilateral location, pulsating quality, moderate-to-severe
intensity, aggravation by routine physical activity, and association with nausea
and/or photophobia and phonophobia. Individuals with chronic migraine experience
headaches occurring on 15 or more days per month for longer than 3 months, with
migraine features present on at least 8 of those days [ 2 ].

A recent comprehensive case-control study by Gklinos et al . [ 3 ]
demonstrated a significant association between multiple sclerosis and both
migraine and tension-type headache, providing robust evidence for increased
prevalence of primary headache disorders in MS patients. A large spectrum of
headache manifestations has been reported as comorbidities in MS, contributing to
additional disability and adversely affecting quality of life [ 4 , 5 ]. Some
studies have shown that migraine commonly presents as an initial symptom in
patients with MS, indicating a potential link between migraine and increased risk
of developing MS [ 6 , 7 ]. However, the current evidence supporting this theory is
limited. It is known that migraine and MS occur within similar demographic groups
and share common background factors, including gender, hormonal status, and
psychological features such as anxiety, depression, and stress. In addition, some
symptoms of migraine and MS may overlap, highlighting the importance of reporting
the duration and nature of symptoms to a healthcare provider. While it is
possible that the two conditions share some underlying mechanisms, current
evidence remains limited. Over time, an increased incidence of headaches,
including migraine, has been observed among patients with MS [ 8 , 9 ]. The
relationship between migraine and MS remains unclear. It is uncertain whether the
association between headaches and MS can be attributed to shared triggers.
Clinical data show that the onset of migraine typically precedes the clinical
diagnosis of MS by several years. The higher prevalence of migraine in MS
patients can be enhanced by disease-modifying treatments [ 10 , 11 ].

Given the potential clinical significance of primary headaches in MS patients
and the geographical variability in migraine prevalence, we propose that routine
clinical screening of primary headaches in this population will facilitate the
development of individualized treatment plans alleviating both the physical and
mental burden of the disease. However, most previous studies have relied on
self-report questionnaires or retrospective surveys, which may lead to symptom
over-interpretation and misclassification. Therefore, the aim of this study was
to assess the prevalence of migraine in MS patients treated with
disease-modifying therapies (DMTs) through direct physician examination and
diagnosis according to standardized criteria, and to compare these findings with
population-based prevalence data from Poland.

2. Materials and methods

A cross-sectional, single-centre, observational study was performed to
investigate the prevalence of comorbidity between migraine and multiple sclerosis
(MS).

The study was conducted in accordance with all relevant institutional and
national guidelines and regulations and was approved by the Bioethical Committee
of the Medical University of Warsaw, Poland (reference number AK-BE/295/2024).
Informed consent was obtained from all participants before enrollment.

Data collection took place over a six-month period in 2024. The participants of
the study were patients enrolled in the National Health Fund’s Therapy Program
for Multiple Sclerosis (MS) at the Outpatient Clinic of Bielanski Hospital,
Warsaw, Poland, as well as MS patients hospitalized in the Neurology Department
of the same hospital. We used convenience sampling—consecutive patients
presenting to the Neurology Outpatient Clinic and hospitalized in the Neurology
Department. This was not a random sample, which represents a study limitation and
may affect result representativeness.

The patients diagnosed with MS prior to the study were included. Patients who
declined to participate in the study were excluded. The inclusion and exclusion
criteria are presented below.

Inclusion Criteria:

- Patients with confirmed diagnosis of multiple sclerosis according to McDonald
2017 criteria;

- Age ≥18 years;

- Ability to provide informed consent for study participation;

- Patients receiving disease-modifying therapies (DMT), including interferon
beta, glatiramer acetate, fingolimod, dimethyl fumarate, teriflunomide,
natalizumab, alemtuzumab, ocrelizumab, as well as treatment-naive patients.

Exclusion Criteria:

- Refusal to participate in the study;

- Secondary headaches related to other neurological conditions (other than MS);

- Medication overuse headaches;

- Active central nervous system infections;

- Severe cognitive impairment preventing interview conduct;

- Headaches related to head trauma within the last 3 months.

All participants were interviewed and examined by physicians experienced in
diagnosing and treating patients with headaches, under the supervision of a
neurologist specializing in headaches.

Every patient (including those who reported experiencing migraine or
migraine-like headaches) was diagnosed for migraine according to the
International Classification of Headache Disorders, 3rd Edition (ICHD-3), by
a physician [ 2 ]. Patients diagnosed with migraine were subsequently assessed to
determine the subtype (episodic or chronic, with or without aura) according to
the ICHD-3 criteria.

Migraine diagnosis was established based on detailed medical history conducted
by experienced neurologists. Patients were asked about headache occurrence during
the last 12 months, with particular attention to characteristics, frequency,
intensity, and accompanying symptoms according to ICHD-3 criteria. For each
headache episode, we assessed: location, pain character, intensity (1–10 scale),
duration, triggering and alleviating factors, and presence of accompanying
symptoms (nausea, vomiting, photophobia, phonophobia). An important limitation of
our study is the lack of prospective headache diary use, which could have
increased the accuracy of migraine diagnosis and reduced recall bias. Future
studies should incorporate prospective headache monitoring using standardized
diaries.

Every participant was directly asked by a physician about their gender, age,
place of living (urban or rural), marital status, parental status, education
level, employment status, and comorbidities. Additional information included the
age at onset of MS symptoms, age at MS diagnosis, type of first symptoms (motor,
sensory, optic, cerebellar, brainstem, spinal cord or multifocal), and the number
of MS relapses in the past 12 months. Moreover, participants were asked about
diagnostic tests performed anytime in their medical history, including brain
magnetic resonance imaging, cerebrospinal fluid analysis, optical coherence
tomography, and visual evoked potentials. Every patient was asked about MS
disease-modifying therapy (type, duration of therapy, previous disease-modifying
therapies). A neurological examination was performed for each participant, and
Expanded Disability Status Scale (EDSS) score was assessed.

Descriptive statistics were used to characterize the study population.
Continuous variables are presented as means ± standard deviations (SD) and
categorical variables as frequencies and percentages. A 95% confidence interval
(CI) for the prevalence of migraine in the MS population was calculated.
Statistical analyses were performed using Statistica (version 13.0, TIBCO
Software Inc., Palo Alto, CA, USA). A p -value < 0.05 was considered
statistically significant.

3. Results

A confidence interval for the proportion of migraine in MS population was 95%
CI: 12.4%–22.8%. A total of 205 MS patients were included in the study (149
women and 56 men), with a mean age of 39.87 ± SD 10.65 years (range: 18 to
72 years) (Fig. 1 ). Among them, 171 patients lived in urban areas, while 34
resided in rural areas. Detailed information about MS relapses in the past year
was collected during patient interviews. All characteristics of the study
population are presented in Table 1 .

Age Distribution of Study Participants. The histogram shows the
age distribution of 205 MS patients, with particular attention to the 18–39
years age group (n = 98) and 40 years or older age group (n = 107), which is
relevant for migraine epidemiology as migraine prevalence peaks in the third and
fourth decades of life.

Table 1. Characteristics of the study population. Characteristic Value Age, yr (mean ± SD) 39.87 ± 10.65 Gender, n (%) Female 149 (72.7%) Male 56 (27.3%) Education Primary 2 (1.0%) Vocational 13 (6.3%) Secondary 49 (24.0%) Higher 141 (68.8%) Residence, n (%) Urban 171 (83.4%) Rural 34 (16.6%) MS phenotype, n (%) RRMS 193 (94.1%) SPMS 2 (1.0%) PPMS 10 (4.9%) MS duration, yr (mean ± SD) 7.72 ± 7.22 EDSS score (mean ± SD) 2.26 ± 1.27 DMT use, n (%) Yes 193 (94.1%) No 12 (5.9%) Relapses (last 12 mon), n (%) 0 152 (74.1%) 1 48 (23.4%) 2 5 (2.4%)
RRMS, relapsing-remitting multiple sclerosis; SPMS, secondary progressive
multiple sclerosis; PPMS, primary progressive multiple sclerosis; DMT,
disease-modifying therapy; EDSS, Expanded Disability Status Scale; SD, standard
deviation; MS, Multiple sclerosis.

Characteristics of the study population.

RRMS, relapsing-remitting multiple sclerosis; SPMS, secondary progressive
multiple sclerosis; PPMS, primary progressive multiple sclerosis; DMT,
disease-modifying therapy; EDSS, Expanded Disability Status Scale; SD, standard
deviation; MS, Multiple sclerosis.

Thirty-six patients (17.56%, 95% CI: 12.4%–22.8%) were diagnosed with
episodic migraine. Among patients aged <40 years (n = 98), 21 (21.4%) had
migraine, compared to 15 patients (14.0%) among those aged ≥40 years (n =
107). Among them, 28 patients had migraine without aura (13.66% of all the
participants, 77.78% of the patients with migraine), while 8 patients had
migraine with aura (3.90% of all the participants, 22.22% of the patients with
migraine). Notably, no patient in the study was diagnosed with chronic migraine.
According to the current MS phenotype classification, all patients were
classified as: RRMS (n = 193), SPMS (n = 2), or PPMS (n = 10). Migraine
characteristics in the study population are presented on Table 2 .

Table 2. Migraine characteristics in the study population. Migraine subtype n (%) Total migraine 36 (17.56) Episodic migraine 36 (100.0) Chronic migraine 0 (0.0) Migraine without aura 28 (77.8) Migraine with aura 8 (22.2)

Migraine characteristics in the study population.

A total of 193 participants were receiving disease modifying therapy (DMT),
while 12 patients remained without chronic immunotherapy. The mean MS duration
was 7.72 ± 7.22 years. The mean EDSS score was 2.26 (range: 1 to 6.5).

We did not find any correlation between the type of MS, the type of DMTs, the
duration of MS, or EDSS score and migraine occurrence.

The medical history of all patients included assessment of relapses within the
year prior to the study. A total of 152 patients had no relapses, 48 patients had
1 relapse, 5 participants had 2 relapses. No participants had more than 2
relapses during this period. The high percentage of patients without relapses in
the past year (74.1%) may reflect the effectiveness of modern disease-modifying
therapies and the fact that most patients were recruited during routine
outpatient visits rather than during hospitalizations for relapses.

Moreover, 29 patients reported a family history of MS, while 176 participants
did not report any familial diagnosis of the condition. No significant evidence
was found supporting a link between the number of relapses, the presence of
migraine, or a family history of MS.

To exclude other pathologies that could affect the prevalence of
migraine in MS patients, we analyzed the occurrence of additional
comorbidities. Among the 205 participants, 116 patients (56.6%) had no comorbid
conditions, while 89 (43.4%) reported at least one. Cardiovascular comorbidities
(including hypertension and heart disease) were present in 35 patients (17.1%).
Specifically, hypertension was noted in 29 patients (14.15%) and heart disease
in 6 patients (2.93%). The most frequent comorbidities were hypertension
(29/205; 14.15%), thyroid diseases (28/205; 13.66%), and depression (22/205;
10.73%). Less common conditions included diabetes mellitus (6/205; 2.93%) and
heart disease (6/205; 2.93%). Additionally, 34 patients (16.59%) reported other
comorbid conditions (Fig. 2 ). No significant correlation between migraine and the
presence of comorbidities was found.

Concomitant diseases among study participants.

4. Discussion

Some literature data suggest that migraine-type headaches occur more frequently
in MS patients than in the general population [ 4 , 5 , 6 ]. Based on these findings, we
estimated the comorbidity of migraine and MS in a Polish population. Our patients
where directly interviewed and examined by physicians. The obtained results
suggest that there is no strong evidence that MS is associated with migraine.
Only 36 (17.6%) out of 205 MS patients were diagnosed with migraine. The limited
number of patients with progressive MS forms (n = 12) does not allow for drawing
definitive conclusions regarding differences in migraine frequency between
different disease phenotypes. A thorough medical history and detailed
neurological examination were necessary to rule out secondary headache syndromes.
Our observations align with the reported prevalence of migraine in the general
population. This is in line with the study of Ashina et al . [ 11 ], which
reported that migraine affects over 1 billion people worldwide, with particularly
high prevalence rates. Based on the results from the 2021 Global Burden of
Disease (GBD) study, 18% of people both in Poland and globally, aged 20 and
older, experience migraine [ 12 , 13 ]. Our findings of 17.56% migraine prevalence
in MS patients closely align with this Polish population estimate. However, we
acknowledge that GBD estimates may have limitations depending on the availability
of country-specific primary data sources, and ideally, comparison should be made
with Polish population-based epidemiological studies when available.

On the other hand, some studies report a lower prevalence of migraine: 14.0%
globally and 16.6% in Central Europe [ 14 ]. Migraine and MS affect similar
demographic groups that share common background, including gender. These
conditions are more prevalent in women and particularly in younger individuals
(in the third and fourth decades of life) [ 15 ]. The mean age of our patients was
39.87 years, with a higher proportion of women than men (149 women vs.
56 men). These factors may contribute to the occurrence of migraine, but the
relationship between migraine and MS remains unclear. Further studies are needed
to confirm any potential associations between these two diseases. Age
stratification of our results revealed interesting patterns. Among patients aged
<40 years, migraine prevalence was 21.4%, while in patients ≥40 years
it was 14.0%. Given the natural course of migraine, which typically declines
with age, the lower prevalence in the older age group likely reflects
underascertainment due to migraine remission rather than true absence of lifetime
migraine history. Therefore, the <40 age group prevalence of 21.4% is more
representative of the cumulative incidence and lifetime prevalence of migraine in
our MS population and should be emphasized in comparisons with general population
data. The overall prevalence of 17.56% in our mixed-age population reflects the
demographic composition of our sample, with a mean age of 39.87 years. Future
should consider age-specific prevalence rates when comparing MS populations to
general population data.

One of the studies based on a meta-analysis suggests that the prevalence of
headache disorders can be higher in MS patients. However, we should underline
that most of the studies included in this meta-analysis were of low-to-moderate
quality due to methodological differences [ 10 ]. Moreover, Mirmosayyeb et
al . [ 15 ] reported that the prevalence of migraine can differ in each continent,
with pooled estimates of 24% in Asia, 43% in Americas, 25% in Europe, and 43%
in Africa. In line with this observation, Fragoso et al . [ 16 ] conducted
a study in which MS patients, who also experienced headaches, were invited to
complete an online survey. Migraine was identified in 54.1% of patients, with
68.3% reporting a moderate-to-high migraine burden. In many studies reporting a
higher prevalence of migraine in a group of MS patients compared to the general
population, data were collected using questionnaires. A meta-analysis performed
by Gklinos et al . [ 10 ] found that migraine is more common in MS patients
than in the general population. However, in only 5 out of 23 studies included in
the meta-analysis, migraine diagnosis was confirmed through a medical interview
conducted by a physician. In relation to these observations, our study ensured
that MS patients were directly diagnosed and examined by physicians experienced
in headache disorders. They did not complete the survey themselves, which
increased the accuracy of migraine diagnosis.

Self-diagnosis can often lead to misclassification, with many patients confusing
migraine with tension-type or migraine-type headache. Moreover, during the
interviews, many patients initially reported experiencing photophobia, but upon
more detailed history taking, they specified that they simply “did not like
looking at light”, which was unrelated to any headache episodes. Similar
misunderstandings are more likely to occur when using questionnaires.

A particularly interesting observation was performed by Gklinos et al .
[ 17 ] The authors were trying to determine if the prevalence of migraine-like
headaches in MS patients is associated with plaques in the brainstem or lesions
in other brain regions. Recent evidence, including the comprehensive
cross-sectional study by Gklinos et al . [ 18 ], has demonstrated a strong
association between periaqueductal gray (PAG) lesions and migraine in MS
patients, providing robust support for anatomical correlates of headache in this
population. This finding was also presented at the recent European Neurological
Congress in Helsinki, highlighting the growing recognition of this important
association. According to ICHD-3, migraine can be diagnosed when other causes of
headache have been excluded. Patients with brainstem plaques may experience
secondary headaches and be misdiagnosed with migraine. This observation requires
further research.

Özer et al . [ 19 ] reported that headache may be the only symptom of
a flare-up in MS patients, with headache and MS relapse occurring concurrently in
23.6% of RRMS patients. It is important to consider if these headaches can be
classified as migraines, which are primary headaches. Comprehensive assessment of
all primary headache types could provide a more complete picture of the
relationship between MS and headache disorders. Headaches occurring during MS
relapses should be classified as secondary headaches associated with the
underlying disease.

The medical history of our patients included relapses at least once in the year
prior to the study enrollment. However, we found no correlation between relapses
and migraine. The reason for that may be that the vast majority of participants
were interviewed and examined during outpatient clinic visits, and experienced no
relapses during that time. Hence, it was not possible to assess headache symptoms
during relapse episodes directly.

To sum up, our results indicating comparable migraine prevalence in MS patients
and the general population require detailed interpretation in the context of
previous studies suggesting higher prevalence. Maybe methodological differences
between studies may significantly influence obtained results. Many previous
studies relied on self-report questionnaires or retrospective surveys, which may
lead to symptom over-interpretation and misclassification of tension-type
headaches as migraine. In our study, each patient was directly examined by
experienced neurologists, which may have increased diagnostic precision.
Moreover, modern disease-modifying therapies for MS may influence headache
frequency and severity. The majority of our patients (94.1%) were receiving DMT,
which could have affected migraine frequency reduction through inflammatory
process control and disease course stabilization. It is also possible that
previous studies included patients with more active MS forms or at different
disease stages, while our group was characterized by relatively stable disease
course (74.1% without relapses in the last year). Our study population was
characterized by relatively stable disease course, with 74.1% of patients
experiencing no relapses in the past year and 94.1% receiving DMTs. This
predominantly stable patient population may have influenced our results in
several ways. Modern DMTs may influence headache frequency through inflammatory
process control and disease course stabilization. Additionally, patients with
more active MS or during relapse periods may have different headache patterns.
Most patients were recruited during routine outpatient visits rather than during
hospitalizations for relapses, which may have affected the observed migraine
prevalence. Finally, cultural, genetic, and environmental differences between
populations may influence migraine prevalence, which may explain discrepancies
between studies conducted in different geographical regions.

5. Study limitations

Our study did not include a control group of healthy individuals matched by age,
sex, and sociodemographic factors. While we compared our results to
well-established general population prevalence data from the Global Burden of
Disease Study and other epidemiological studies, direct comparison with an
examined control group would have strengthened our conclusions. However,
comparison with established population prevalence data is a valid epidemiological
approach widely used in prevalence studies, particularly when population-level
estimates are robust and well-documented.

Our study lacked statistical power for robust association analyses, particularly
for rare comorbidities. No multivariable analysis was performed to adjust for
potential confounders. Therefore, negative findings regarding associations
between migraine and MS characteristics should be interpreted with caution.

Our study did not include detailed MRI (Magnetic Resonance Imaging) analysis in
the context of demyelinating lesion location and burden. Future studies should
investigate the potential relationship between specific MRI lesion locations
(particularly in the periaqueductal gray area, brainstem, and other structures
related to pain processing) and migraine occurrence and severity in MS patients.

Our study has also several important limitations that should be considered when
interpreting the results. First, this is a cross-sectional study with
retrospective headache assessment, which introduces significant recall bias,
particularly in MS patients who may experience cognitive impairment related to
their disease. The retrospective design also does not allow for establishing
robust causal relationships between MS and migraine.

Second, we did not utilize prospective headache diaries for migraine diagnosis,
which could have increased diagnostic accuracy and reduced assessment
subjectivity. Future studies should incorporate prospective symptom monitoring
using standardized tools.

This is a single-center study with convenience sampling of consecutive patients,
which may introduce selection bias and limit the generalizability of results to
the broader MS patient population. The predominantly stable patient population
(74.1% without relapses in past year, 94.1% receiving DMTs) may not be
representative of all MS phenotypes or disease activity states. Differences in
clinical practice, population characteristics, and healthcare accessibility may
influence the obtained results.

Finally, our study did not incorporate standardized migraine severity assessment
scales (such as MIDAS—Migraine Disability Assessment Scale) or their
correlation with MS clinical parameters such as EDSS, disease duration, or
relapse frequency. Future studies should include comprehensive assessment of
migraine’s impact on quality of life and its relationship with MS activity and
progression.

6. Conclusions

Migraine is a common disease both in the general population and in MS patients.
Our study focused exclusively on migraine, not considering other primary
headaches such as tension-type headache. Future studies should encompass a
broader spectrum of primary headaches, as patients may experience different
headache types throughout their lifetime, and their coexistence may complicate
accurate diagnosis. According to our results, migraine does not appear to be less
common in MS patients compared to the general population. However, further
age-stratified and controlled studies are needed to investigate whether migraine
is equally or more common in MS patients, and to explore potential differences
across MS phenotypes and disease activity states. However, further research
involving larger sample sizes and the inclusion of control groups is necessary to
confirm this association.

Acknowledgments

Abbreviations

MS, multiple sclerosis; CNS, central nervous system; ICHD-3, the International
Classification of Headache Disorders, 3rd edition; RRMS, relapsing-remitting
multiple sclerosis; SPMS, secondary progressive multiple sclerosis; PPMS, primary
progressive multiple sclerosis; PRMS, progressive-relapsing multiple sclerosis;
DMT, disease modifying therapy; MIDAS, Migraine Disability Assessment Scale;
EDSS, Expanded Disability Status Scale; CI, confidence interval; PAG,
periaqueductal gray; SD, standard deviations; GBD, Global Burden of Disease; MRI,
Magnetic Resonance Imaging.

Availability of data and materials

The datasets supporting the conclusions of this article are included within the
article. The individual participant data ( e.g. , raw data) can be made
available from the corresponding author on reasonable request, provided it
complies with the ethical approvals and institutional regulations.

Author contributions

ID, PS, KK, NB, JK—Conceptualisation and design of the study. KK, PS, ID,
WD—Writing editing and original draft paper preparation, Analysis and
interpretation of data. PS, NB, PJS—Acquisition of data. ID, JK—Supervision.
All the authors Revising the manuscript critically for important intellectual
content. All the authors approved the manuscript to be published.

Ethics approval and consent to participate

The study was conducted in accordance with all relevant institutional and
national guidelines and regulations and was approved by the Bioethical Committee
of the Medical University of Warsaw, Poland (reference number AK-BE/295/2024).
Informed consent was obtained from all participants before enrollment.

Acknowledgment

The authors would like to acknowledge all participants in the study.

Conflict of interest

The authors declare no conflict of interest.

Funding Statement

This research received no external funding.

References

Associated Data

Data Availability Statement

The datasets supporting the conclusions of this article are included within the
article. The individual participant data ( e.g. , raw data) can be made
available from the corresponding author on reasonable request, provided it
complies with the ethical approvals and institutional regulations.