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A study of migraine characteristics in joint hypermobility syndrome a.k.a.

Ehlers–Danlos syndrome, hypermobility type

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A study of migraine characteristics in joint
hypermobility syndrome a.k.a. Ehlers–
Danlos syndrome, hypermobility type

Francesca Puledda, Alessandro Viganò,

Claudia Celletti, Barbara Petolicchio,
Massimiliano Toscano, Edoardo
Vicenzini, et al.
Neurological Sciences
Official Journal of the Italian
Neurological Society

ISSN 1590-1874

Neurol Sci
DOI 10.1007/s10072-015-2173-6

1 23
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 Author's personal copy
Neurol Sci
DOI 10.1007/s10072-015-2173-6

ORIGINAL ARTICLE

A study of migraine characteristics in joint hypermobility

syndrome a.k.a. Ehlers–Danlos syndrome, hypermobility type
Francesca Puledda1 • Alessandro Viganò1 • Claudia Celletti2 • Barbara Petolicchio1 •

Massimiliano Toscano1 • Edoardo Vicenzini1 • Marco Castori3 • Guido Laudani4 •

Donatella Valente5 • Filippo Camerota2 • Vittorio Di Piero1

Received: 29 December 2014 / Accepted: 13 March 2015

Ó Springer-Verlag Italia 2015

Abstract Joint hypermobility syndrome (JHS) and Eh-
lers–Danlos syndrome, hypermobility type (EDS-HT) are
two clinically overlapping heritable connective tissue dis-
orders strongly associated with musculoskeletal pain, fa-
tigue and headache. Migraine with or without aura is
considered the most common form of headache in JHS/
EDS-HT. In this population of chronically ill patients, we
investigated whether migraine characteristics were differ-
ent from those of a control population of migraine patients.
The study was carried out on 33 selected JHS/EDS-HT
patients, diagnosed according to current criteria. Sixty-six
migraine subjects matching age and gender were con-
secutively selected as controls (MO group) among patients
attending our Headache Clinic. JHS/EDS-HT and MO
were screened for a series of headache characteristics, such
as frequency, intensity, age of onset, level of disability, use
of rescue and prophylactic medications. Differences be-
tween the two groups were tested by using independent
group comparisons. Results showed that in JHS/EDS-HT:
(1) migraine has an earlier onset (12.6 vs 17 years of age;
p = 0.005); (2) the rate of migraine days/month is higher
(15 vs 9.3 days/month; p = 0.01); (3) accompanying
symptoms are usually more frequent; (4) HIT-6 and
MIDAS scores are higher (p = 0.04 and p = 0.03); (5)
efficacy of rescue medication is almost identical, although,
total drug consumption is significantly lower (p \ 0.04).
Joint hypermobility syndrome and Ehlers–Danlos syn-
drome, hypermobility type patients have a more severe
headache syndrome with respect to the MO group, there-
fore demonstrating that migraine has a very high impact on
quality of life in this disease.
Keywords Migraine
Joint hypermobility syndrome

Ehlers–Danlos syndrome hypermobility type

Chronic pain
Background

& Francesca Puledda Ehlers–Danlos syndromes (EDS) are a heterogeneous

fpuledda@hotmail.it group of heritable connective tissue disorders mainly
1
characterized by joint hypermobility, skin hyperextensi-
Department of Neurology and Psychiatry,
bility and tissue fragility. The revised EDS classification
Sapienza University of Rome, Viale dell’Università 30,
00185 Rome, Italy identifies six major types distinguishable on specific diag-
2 nostic criteria (Villefranche criteria), often supported by
Department of Physical Medicine and Rehabilitation,
Sapienza University of Rome, Rome, Italy molecular proofs [1]. EDS, hypermobility type (EDS-HT),
3 formerly known as EDS type III, seems to be the most
Division of Medical Genetics, Department of Molecular
Medicine, Sapienza University of Rome, common type, representing around 90 % of all cases [1].
San Camillo-Forlanini Hospital, Rome, Italy However, its real frequency is unknown, possibly ranging
4
Department of Urology, Sapienza University of Rome, from 1:5000 to 0.75–2 % [2, 3]. In contrast to all other
Rome, Italy major EDS subtypes, the molecular basis of EDS-HT is
5
Department of Pediatrics, Sapienza University of Rome, still unknown, except for a few families with identified
Rome, Italy mutations in TNXB and COL3A1 genes [4].

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Recently, an international group of experts highlighted
the inconsistency of the clinical distinction between EDS-
HT and the apparently more common joint hypermobility
syndrome (JHS) [5], which is diagnosed with a distinct set
of criteria (Brighton criteria) [6]. Such a phenotypic com-
plex is now generally indicated by many authors as JHS/
EDS-HT. This condition is considered an autosomal
dominant trait with incomplete penetrance and variable
expressivity, that predisposes patients to chronic wide-
spread musculoskeletal pain and a wide variety of articular
and extra-articular features linked to a constitutionally
abnormal collagen, with a high disability potential [7, 8].
For unknown reasons, JHS/EDS-HT is markedly more
common in women [9].
Neurological manifestations are common in all EDS
variants, and are mainly represented by neuropathies,
neuromuscular involvement and, more rarely, central ner-
vous system anomalies [10–12]. Overall, chronic pain and
fatigue are the most frequent neurologic complaints en-
countered in these patients, especially in JHS/EDS-HT;
these disorders strongly impact quality of life, possibly
representing the most debilitating features of the syndrome
[13–17]. The mechanisms leading to pain are still largely
obscure, even if neuropathic features have been described
[18]. This implies that the pathophysiology of pain in JHS/
EDS-HT may be more complex than expected, and that
musculoskeletal involvement cannot explain its entire
spectrum.
One of the most common and disabling forms of pain
in JHS/EDS-HT is represented by headache; in a first
description by Jacome, migraine with and without aura
was seen in 11 out of 18 total EDS patients (various
types) [19]. Headache seems to be second only to ar-
ticular pain and shows a prevalence of 32.4 % in EDS-
HT [20]. In particular, migraine seems to have a higher
prevalence in the JHS/EDS-HT population compared to
other forms of headache, as shown in previous studies
[21, 22].
In fact, as Bendik and colleagues [21] have recently
reported, migraine prevalence is up to three times higher in
JHS patients. In their study, 28 patients were compared
with a control population of 232 subjects, and migraine was
shown to be present in 75 % of the JHS population, causing
a marked disability burden.
A very recent review by Martin and Neilson [23] con-
firms that connective tissue disorders, and in particular
JHS/EDS-HT, are strongly associated with migraine
disease.
The main purpose of the present study is to describe
prevalence, frequency and main characteristics of migraine
headache in a population of adult JHS/EDS-HT patients,
and to compare data with a control population of mi-
graineurs attending an outpatient headache clinic.
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Methods
Enrolled subjects
Patients in the JHS/EDS-HT group were selected among
those attending an outpatient multidisciplinary clinic
dedicated to heritable connective tissue disorders. Diag-
nosis was based on the published diagnostic criteria in-
cluding the Villefranche criteria for EDS-HT [1] and the
Brighton criteria for JHS [6, 24] (Tables 1, 2). Patients
were included if they met at least one of these two sets of
criteria.
Table 1 1997 Villefranche criteria for the Ehlers–Danlos syndrome,
hypermobility type [1]
Major criteria
Generalized joint hypermobility
Skin involvement (hyperextensibility and/or smooth, velvety skin)
Minor criteria
Recurring joint dislocations
Chronic joint/limb pain
Positive family history
Diagnosis is made in the presence of at least one of the two major
criteria, in combination with at least one of the three minor criteria
Table 2 1998 Brighton criteria for the joint hypermobility syndrome
[15]
Major criteria
Beighton score of 4/9*
Arthralgia for [3 months in [4 joints
Minor criteria
Beighton score of 1–3
Arthralgia in 1–3 joints
History of joint dislocation
Soft tissue lesions [3
Marfan-like habitus
Skin striae, hyperextensibility, or scarring
Eye signs, lid laxity
History of varicose veins, hernia, visceral prolapse
Other disorders of connective tissue need to be excluded
(Marfan syndrome, Ehlers–Danlos syndrome other than the
hypermobility type)
Diagnosis is made in the presence of either two of the major criteria
or one major and two minor or four minor criteria or two minor
criteria with an independently diagnosed first-degree relative
* The Beighton score is a nine-point evaluation with attribution of one
point in the presence of any of the following: (a) passive apposition of
the thumb to the flexor aspect of the forearm (one point for each
hand); (b) passive dorsiflexion of the fifth finger beyond 90° (one
point for each hand); (c) hyperextension of the elbow beyond 10°
(one point for each arm); (d) hyperextension of the knees beyond 10°
(one point for each leg); (e) forward flexion of the trunk with the
knees extended and the palms resting flat on the floor
 Author's personal copy
Neurol Sci
All JHS/EDS-HT patients were asked to answer the
three-item ID Migraine questionnaire [25, 26] by e-mail, to
screen for the presence of symptoms suggestive of mi-
graine. This test was considered positive for a possible
diagnosis of migraine where at least two of the three items
had a positive response.
All patients positive to ID Migraine subsequently un-
derwent a structured diagnostic interview with a neu-
rologist specialized in headache disorders, and migraine
diagnosis was assigned based on the International Head-
ache Society [27] criteria after completing a semi-struc-
tured diagnostic interview. A full neurological and general
examination was then performed.
As a control group, we subsequently enrolled twice the
number of sex- and aged-matched subjects affected by
migraine and attending our Headache Clinic. All eligible
subjects were selected in a consecutive manner at the first
visit to our center. Controls equally underwent a full di-
agnostic interview, as well as a neurological and general
examination. We excluded from this study patients pre-
senting any specific neurological or chronic disorders, as
well as a previous history of secondary headache. All pa-
tients participating in the study (cases and controls) were
asked to sign a written informed consent form according to
the Declaration of Helsinki.
Interviews and questionnaires
In the neurological diagnostic interview, we examined a
series of headache characteristics, which are described in
Table 3.
Table 3 Screening of main headache characteristics in the diagnostic
interview
Age of headache onset
Localization and type of headache pain
Presence of a positive family history of migraine
Mean attack duration
Mean headache intensity (measured through the Numeric Rating
Scale—NRS)
Presence and type of aura
Presence of chronic migraine
Presence of associated symptoms (photophobia, phonophobia,
osmophobia, nausea and vomiting)
Frequency of migraine (days/month)
Use of prophylactic therapy
Use of rescue migraine medication (NSAIDs, combination
analgesics and triptans)
Number of rescue medication pills taken/month in the last
3 months
Efficacy of rescue therapy (as described in the text)
We studied the efficacy of rescue drugs (both present
and past use), by measuring pain free and pain relief. Pa-
tients were also queried on a subjective basis regarding
their impression as to whether the drug had a positive ac-
tion on their headache or not. Patients were considered
responsive to a specific drug if they referred a subjective
improvement and if they presented a pain relief lower than
1 h or a pain free lower than 2 h. Lastly, to assess the
general consumption of rescue medication as well as to
screen for possible overuse of analgesics, each patient was
asked to indicate the number of pills taken in case of a
migraine attack in the previous 3 months.
All patients and controls were also asked to complete
specific questionnaires, specifically the Migraine Disability
Assessment (MIDAS) [28] and the HIT-6 [29] to assess
headache-related disability. We used the Numeric Rating
Scale (NRS) in JHS/EDS-HT patients to evaluate the
burden and severity of generalized pain due to the under-
lying disease. This is a scale on which patients rate their
current pain intensity from 0 (‘‘no pain’’) to 10 (‘‘worst
possible pain’’), and is one of the most widely used in-
struments for pain evaluation.
Statistical analysis
Data analysis was carried out using STATISTICA version
8 for Windows. Descriptive statistics were used to describe
the sample. The distribution of results of all outcome
variables was checked for normality by the Shapiro–Wilk’s
test. We consequently chose the suited test according to the
parametric vs non-parametric distribution of results. In-
tergroup difference for continuous variables was assessed
by the Mann–Whitney U test (not normal distribution) or
the Independent T test (normal distribution). For catego-
rical data, appropriate n 9 2 contingency tables were
calculated and Chi squared test or Fischer’s exact test
was used, according to parametric distribution and
sample numerosity. Statistical significance was set at a
p value B 0.05.
Results
E-mails including the ID Migraine questionnaire were sent
to a total of 60 JHS/EDS-HT patients; of these, 45 replied.
Two out of 45, however, refused the visit, and dropped out
from the study. In the remaining 43 patients, 33 resulted
positive to a possible migraine diagnosis; while ten patients
were negative to the ID Migraine. In all of the 33 patients,
diagnosis was confirmed by means of the clinical inter-
view. Therefore, the general prevalence of migraine in our
population of JHS/EDS-HT suffering from headache was
76.7 %.
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Table 4 Demographic and JHS/EDS-HT MO

migraine characteristics in the
two groups (values are indicated Total patient number n = 33 n = 66
as mean ± standard deviation)
Female: male ratio 29:4 58:8
Mean age 32.11 ± 11.63 32.39 ± 11.7
Familial migraine history n = 31 (93.4 %) n = 63 (95.5 %)
Quality of pain
Pulsating n = 25 (75.8 %) n = 53 (80.3 %)
Constrictive n = 8 (24.2 %) n = 13 (19.7 %)
Localization of pain
Unilateral n = 12 (36.4 %) n = 25 (37.9 %)
Bilateral n = 12 (36.4 %) n = 26 (39.4 %)
Both n = 9 (27.3 %) n = 15 (22.7 %)
Associated symptoms
Photophobia n = 33 (100 %) [p = 0.05] n = 59 (89.4 %)
Phonophobia n = 26 (78.8 %) n = 62 (94.0 %) [p = 0.02]
Osmophobia n = 18 (54.6 %) [p = 0.2] n = 27 (41.0 %)
Nausea n = 30 (91.0 %) n = 53 (80.3 %)
Vomiting n = 16 (48.5 %) n = 32 (48.5 %)
Aura n = 12 (36.4 %) n = 26 (39.4 %)
Visual n = 12 (36.4 %) n = 22 (33.3 %)
Sensory n = 1 (3.0 %) n = 3 (4.54 %)
Speech n = 1 (3.0 %) n = 1 (1.5 %)
Age of onset 12.6 ± 7.3 [p = 0.005] 17 ± 8.3
Years of disease 18.4 ± 11.4 15.4 ± 10.7
Mean pain intensity 8.5 ± 1.3 8.6 ± 1.2
Mean pain duration 33.8 ± 22.0 36.1 ± 24.2
Mean headache frequency 15.0 ± 11.2 [p = 0.01] 9.3 ± 8.1
Mean MIDAS score 63.2 ± 57.4 [p = 0.03] 40.3 ± 44.7
Mean HIT-6 score 64.3 ± 5.0 [p = 0.04] 60.9 ± 9.1

Demographic and main characteristic of the two
populations are summarized in Table 4, where it can be
seen that basic features of migraine were similar. JHS/
EDS-HT patients presented a series of relevant associated
conditions, listed in Table 5.
A total of 15 JHS/EDS-HT patients (45.45 %) fit the di-
agnosis for chronic migraine according to IHS criteria [27],
while only 13 patients in the control group (19.69 %) met the
criteria. Three patients of the former group and six of the
latter also met the criteria for medication overuse headache.
Headache characteristics
The onset of migraine showed significant differences be-
tween the two groups; in MO patients, it respected that of
large epidemiologic studies [30] and was found to manifest
on average at 17 years of age, while JHS/EDS-HT patients
had a significantly earlier onset (12.1 years of age;
p = 0.005) compared with controls.
While the subjective pain level (measured with the
Numeric Rating Scale) used to describe attacks was not
significantly different between groups, we found a statis-
tically significant difference regarding mean headache
frequency. In fact JHS/EDS-HT patients reported a sig-
nificantly higher average number of migraine days/month
in a 3-month period compared to the MO group (p = 0.01).
Concerning accompanying symptoms, frequency of
nausea and vomiting was the same in the two groups.
However, photophobia and osmophobia were more com-
mon in JHS/EDS-HT with a significant value for the for-
mer, present in 100 % of JHS/EDS-HT patients and 89.4 %
MO patients (p = 0.05). Conversely, phonophobia was
significantly more present in the MO group (94 vs 78.8 %;
p = 0.02).
Rescue and prophylactic headache medication
The use of rescue medication was registered in the two
groups and a distinction was made between the use of
NSAIDs, combination analgesics and triptans (Table 6).
We found that NSAIDs tend to be more used in the
JHS/EDS-HT group (p = 0.07), meaning that most

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Table 5 Associated comorbidities in JHS/EDS-HT patients (ex-
pressed in percentages or number of patients)
Psychiatric diseases
Mood disturbances (36.4 %)
Anxiety with panic attacks (51.2 %)
Bipolar disorder (2 patients)
Psychotic disorder (1 patient)
Gastrointestinal diseases
Gastroesophageal-reflux disease (57.6 %)
Chronic gastritis (30 %)
Hiatal hernia (12.1 %)
Cardiovascular diseases
Orthostatic hypotension (36.4 %)
Postural orthostatic tachycardia syndrome (15.2 %)
Mitral valve prolapse (21.1 %)
Arrhythmias (9.1 %)
Immunological diseases
Raynaud’s phenomenon (18.2 %)
Psoriasis (12.1 %)
ANA positivity (2 patients)
LES (1 patient)
Generic
Multiple medication allergies (27.3 %)
Temporomandibular joint dysfunction (18.2 %)
Inner ear dysfunction (18.2 %)
Allergic asthma (15.2 %)
Urogynecological prolapses and stress incontinence (12.1 %)
Celiac disease (9 %)
hypermobility patients previously tried to control headache
attacks with these drugs. Although efficacy was similar in
the two groups, monthly consumption of NSAIDs in the
past 3 months was significantly higher in the MO group
(p \ 0.001).
A very similar pattern was seen for combination anal-
gesics (codeine ? paracetamol and caffeine ? in-
domethacin ? prochlorperazine were the most common
combinations). In fact, efficacy was almost identical and
JHS/EDS-HT patients reported trying these drugs in the
past more frequently (p \ 0.001) than controls, while MO
group referred assuming a significantly higher number of
combination analgesics immediately prior to the screening
visit (p = 0.006).
Regarding triptans, we found that both groups were gen-
erally not familiar with these drugs, and only a few patients
had used them in the past. These drugs had a lower efficacy in
JHS/EDS-HT patients (p = 0.02) who also consumed a
significantly smaller number of tablets in the past months,
compared to the control migraine group (p = 0.03).
In total, mean drug consumption in the previous
3 months was significantly lower in the JHS/EDS-HT
group (p = 0.04). In general, we also found that JHS/EDS-
HT patients usually prefer to avoid rescue medication when
a migraine attack is present, compared to MO patients
(p = 0.05); when they do, they tend to try different types
of drugs (simple NSAIDs, combinations, triptans) com-
pared to MOs who are generally more ‘‘loyal’’ to the same,
preferred drug (p = 0.02).
There were no statistical differences between present
consumption and efficacy of prophylactic migraine drugs.
More frequently, we found that these belonged to the
category of anti-depressants (mainly amitriptyline) for
JHS/EDS-HT and anticonvulsants (mainly topiramate) for
controls. However, JHS/EDS-HT patients had a sig-
nificantly higher frequency of past prophylactic medication
use (p \ 0.001).
Questionnaires
All hypermobility patients scored significantly higher re-
spect to the MO group, both on MIDAS (p = 0.03) and
HIT-6 questionnaires (p = 0.04). JHS/EDS-HT patients
were also asked to give Numeric Rating Scale values of
generalized and joint pain commonly experienced and as-
sociated with EDS, and the results were also high (NRS
mean value 7.13/10), indicating that these patients suffer
from a condition that causes severe, almost constant, dif-
fuse pain. However, the intensity of generalized pain did
not correlate with the intensity of migraine.
Discussion
The principal finding of this study is that JHS/EDS-HT
patients have a substantially stronger headache syndrome
with respect to normal migraineurs, regarding both head-
ache frequency and its characteristics. In fact these patients
present a higher frequency of migraine days/month, as well
as an earlier onset of the disease, usually in childhood.
Also, specific questionnaires such as MIDAS and HIT-6,
designed to standardize patients’ subjective evaluation of
the disability and the impact of headache in daily life,
showed very high scores in JHS/EDS-HT subjects. These
patients also present more severe accompanying symp-
toms, are more at risk of becoming chronic migraineurs
and are usually not adequately treated for migraine.
In accordance with a previous case–control study con-
ducted by Bendik et al. [21] on 28 JHS patients affected by
headache, we observed in our sample that prevalence of
migraine in JHS/EDS-HT was quite high, much more than
what would be expected in a general population of other-
wise healthy subjects in respect to other forms of primary
headache [31]. We also confirmed the high disability bur-
den of migraine in JHS/EDS-HT and the high sensitivity
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Table 6 General migraine JHS/EDS-HT MO

treatment in the two groups
(values are indicated as Rescue therapy
mean ± standard deviation)
General use of NSAIDs n = 30 (91.0 %) [p = 0.07] n = 50 (75.8 %)
Efficacy of NSAIDs n = 18 (60 %) n = 33 (66 %)
Monthly consumption of NSAIDs n = 3.9 ± 5.6 [p \ 0.001] n = 7.2 ± 5.2
General use of combination analgesics n = 13 (39.4 %) [p \ 0.001] n = 6 (9.1 %)
Efficacy of combination analgesics n = 8 (61.54 %) n = 5 (83.3 %)
Monthly consumption of combination n = 1.5 ± 2.1 [p = 0.006] n = 8.7 ± 6.7
analgesics
General use of triptans n = 4 (12.1 %) n = 10 (15.2 %)
Efficacy of triptans n = 2 (50 %) n = 10 (100 %) [p = 0.02]
Monthly consumption of triptans n = 0.8 ± 1.0 [p = 0.03] n = 3.7 ± 2.7
Total drug consumption 4.24 (total sum 140) [p = 0.04] 6.8 (total sum 449)
Preferred abortive therapy None [p = 0.05] NSAIDs
(none, NSAIDs, combinations, triptans
Prophylactic therapy
Past preventive therapy n = 15 (45.5 %) [p \ 0.001] n = 2 (3 %)
Present preventive therapy n = 2 (6 %) n = 4 (6 %)
Preventive therapies used
B-blockers n=1 n=2
Calcium antagonists n=1 n=1
Anti-depressants n=7 n=3
AEDs n=3
Other (triptophane, magnesium) n=3

and specificity of ID Migraine as a screening tool even in
this rare disease.
The significantly earlier onset of migraine in patients
affected by Ehlers–Danlos syndrome hypermobility type is
an interesting finding and should be integrated in the re-
cently proposed natural history of JHS/EDS-HT, charac-
terized by three apparently distinct phases. A first
‘‘hypermobility’’ phase begins very early and joint insta-
bility and recurrent dislocations are the most characteristic
features. Usually from the second decade of life, the pro-
longed stress to which joints have been exposed possibly
gives rise to a characteristic reduced, rather than enhanced,
mobility. Chronic arthralgias, myalgias and back pain ap-
pear to progressively limit daily activities and define the
second ‘‘pain’’ phase. In the third phase stiffness prevails,
possibly linked to muscular deconditioning and atrophy
[32]. This peculiar disease progression explains the wide
variety of accompanying symptoms and the strong dis-
ability potential that characterizes the joint hypermobility
syndrome. In these patients non-musculoskeletal com-
plaints are in fact very common, together with fatigue,
sleep disturbances and profound asthenia [14, 33] generally
leading to chronic pain [15] and a very poor quality of life
[17, 20].
In this view, the premature commencement of migraine
symptoms is quite remarkable, and of not univocal
interpretation. However, our preliminary findings suggest
that the evolution of head pain progresses irrespective of
musculoskeletal pain. The contribution of migraine to the
resulting disability emerges as relatively independent and
should be investigated and properly treated (and, perhaps,
prevented) as a distinct disease entity.
A large part of our JHS/EDS-HT patients referred that
migraine represented an alarm factor for future pain. For
these patients, migraine was highly intense and disabling
throughout their childhood years (usually from 5 to
10 years old), and followed after a period of several years
by the typical pattern of complete manifestation of the
syndrome, with the trait already described.
Moreover, JHS/EDS-HT patients constitute a heteroge-
neous group of patients, affected by many comorbidities
often associated with other health issues. These data were
strongly confirmed in our study group. However, general-
ized pain did not correlate with the intensity of migraine,
confirming that this represents a separate entity, even in the
context of a syndrome characterized mainly by pain [13].
A possible explanation for these findings is that EDS
could contribute to enhance pain perception through a
mechanism of central sensitization. Pain and sensory inputs
are integrated into the brain neuro-matrix (previously
known as pain matrix or saliency matrix) [34] along with
cortical (cognitive, emotive, attentional, etc.) and

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subcortical mechanisms to generate a univocal conscious
experience (in our case, pain perception). A predisposing
functional alteration of the integration brain mechanism,
possibly due to migraine (i.e., an unbalance between al-
gogenic and analgesic modulation), added to an enhanced
painful inflow, related to EDS condition, could make these
patients more susceptible to pain, causing them to experi-
ence migraine alone earlier in life, and both migraine and
generalized pain later on. This would mean that the two
diseases constitute, in the same patient, different entities
that strongly influence one another, therefore, expressing
their qualities differently than would normally be expected
on the basis of their pathophysiologies alone.
In apparent contrast with these conclusions, JHS/EDS-
HT patients in our study assumed significantly fewer pain
medication/month than the control group, and not because
drugs were considered less efficacious. An exception was
present for triptans, which resulted to be significantly more
efficacious in MO patients, although the sample for this
comparison was quite small. The actual use of triptans was
in fact very low for both JHS/EDS-HT and MO patients,
and this is in line with other epidemiological surveys pre-
viously performed in our country [25, 35].
We believe that most patients in the JHS/EDS-HT group
seemed to be simply more accustomed to pain, as they
directly explained. They also tended to consider headaches
as part of their chronic syndrome, and therefore as hardly
treatable, almost to the point of refusing medication.
Furthermore, a significantly higher number of JHS/EDS-
HT patients had tried previous preventive therapy with
drugs that are, however, specific for chronic pain, and not
considered as first line therapy for migraine (pregabalin,
gabapentin, amitriptyline [36]).
These results seem to indicate that JHS/EDS-HT pa-
tients develop a form of migraine that is stronger and more
disabling from the onset, leading to an early chronicization.
It is, therefore, our belief that these patients deserve an
early diagnosis as well as an aimed, and in many cases
immediate preventive therapy, to reduce the burden of their
disease. In fact we found that given equal terms for age, sex
and years of disease, the percentage of chronic migraine in
the JHS/EDS-HT group was almost twofold compared to
the control group.
It is also evident that these two diseases share not only a
strong comorbidity, but also important epidemiological and
possibly pathogenic features, that must be examined in
depth in further studies. These are, for example, the im-
portance of the genetic basis, the strong female preponder-
ance, the variable expression among different individuals,
the influence of numerous external factors such as stress,
anxiety, underlying diseases and hormonal alterations [7].
Main limitation of the study is the relatively small
number of patients, possibly due to the fact that even if not
precisely rare, JHS/EDS-HT is often underdiagnosed; fur-
thermore, the data we collected were mainly based on self-
report from patients, and this factor could have created a
potential recall bias.
In conclusion, this study shows that migraine has a high
impact on quality of life in JHS/EDS-HT patients. This
condition, although obviously associated with the more
complex underlying syndrome in which the main
manifestation is pain, must, however, always be recognized
separately from other comorbidities and not contemplated
solely as one of the manifestations of the disease. Adequate
migraine therapy is essential in these patients and should
not be delayed, to allow a lower risk of chronicization and
migraine-associated disability.
Acknowledgments The authors would like to kindly thank all pa-
tients that took part in this study.
Conflict of interest The authors have no conflict of interest to de-
clare. This work was supported by the Sapienza University of Rome:
Ateneo Grant Number C26A13C4H9.
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