Spasmophilia comorbidity in fibromyalgia syndrome

L. Bazzichi1, A. Consensi1, A. Rossi2, C. Giacomelli1, F. De Feo1, M. Doveri1, F. Sernissi1,

R. Calabrese3, G. Consoli2, A. Ciapparelli2, L. Dell’Osso2, S. Bombardieri1

1
Department of Internal Medicine, ABSTRACT Introduction
Division of Rheumatology, 2Department of Objectives. To evaluate the role of Fibromyalgia syndrome (FM), is a
Psychiatry, Neurobiology, Pharmacology spasmophilia (SP) in fibromyalgia syn- chronic, generalised pain condition
and Biotechnology, 3Department of
drome (FM). (1) with characteristic tender points on
Neuroscience, University of Pisa, Pisa,
Italy. Methods. Three hundred and fourteen physical examination (regions of the
patients (280 F, 34 M) with a diagno- body that evoke severe pain upon gentle
Laura Bazzichi, MD
Arianna Consensi, Md sis of FM or FM and spasmophilia digital palpation), often accompanied
Alessandra Rossi, PhD (FM+SP) were recruited. Clinical as- by a number of associated symptoms
Camillo Giacomelli, PhD sessment of patients and controls in- such as fatigue, sleep disturbance, head-
Francesca De Feo, PhD cluded the Questionnaires FIQ, HAQ ache, irritable bowel syndrome, tempo-
Marica Doveri, MD and the tender point (TP) count. Life- romandibular joint disorder and mood
Francesca Sernissi, Pharmacist time or ongoing psychiatric aspects disorders (2). It has a high prevalence
Rosanna Calabrese, MD
were evaluated by trained psychiatrists in the general population (2–3%) and
Giorgio Consoli, MD
Antonio Ciapparelli, MD by means of the classic scales: Struc- the condition is more common amongst
Liliana Dell’Osso, MD tured Clinical Interview (SCID) for women than in men, representing in
Stefano Bombardieri, MD, Professor DSM-IV. The following analysis were women 30% of all rheumatic diseases.
Please address correspondence to: evaluated: cytokine (IL1, IL2, IL6, IL8, Moreover, FM may be associated with
Dr Laura Bazzichi, IL10), TNF-α, cortisol, GH, ACTH, other rheumatic diseases (rheumatoid
Divisione di Reumatologia, IGF1, 5HT, intracellular Mg, plasma arthritis, lupus, Sjögren’s syndrome)
Dipartimento di Medicina Interna, calcium p(Ca), PTH, (25(OH)D) and which aggravate the clinical picture.
Università di Pisa, thyroid functionality. Some typical The pathogenesis is still not clear, but
Via Roma 67,
56126 Pisa, Italy.
symptoms were investigated. emerging data suggest a neuro-hormo-
[email protected] Results. Eighty-one patients resulted nal (3) and neuro-transmitter dysregu-
Received on September 21, 2010; accepted
positive for spamophilia (FM+SP), lation (4) and a central sensitisation of
in revised form on December 6, 2010. while 233 resulted negative for spas- the nervous system (5-9) .
Clin Exp Rheumatol 2010; 28 (Suppl. 63):
mophilia (FM). The mean TP number FM is often accompanied by the pres-
S94-S99. resulted higher in the FM group ence of latent tetany or spasmophilia.
© Copyright CLINICAL AND (15.33±3.88) with respect to FM+SP The term spasmophilia was proposed
EXPERIMENTAL RHEUMATOLOGY 2010. (12.88±6.17, p=0.016), while FIQ and in 1874 by Wilhelm Heinrich Erb al-
HAQ did not differ between the two though two French researchers, Dauce
Key words: fibromyalgia, studied groups. in 1831 and Corvisart in 1852, had laid
spasmophilia, latent tetany, FM patients exhibited a higher frequen- the foundations for an independent clas-
psychiatric comorbidity cy of psychiatric disorders with respect sification called “tetany morbid events
to FM+SP patients (72% FM vs. 49% in spontaneous muscle contractions”.
FM+SP, p<0.01). In particular the fre- In the early 1900s, Mac Callum dis-
quency of depression was 65.5% FM covered that the cause of tetany in the
vs. 35% FM+SP (p<0.01). course of hypoparathyroidism was hy-
Conclusions. The presence of spas- pocalcemia, and in 1940 Lerique iden-
mophilia seems to influence psychiat- tified frameworks of neuromuscular
ric comorbidity which was less preva- hyperexcitability that were not hypoc-
lent in FM+SP patients. FM is indeed alcemic defined as “latent tetany”. Fi-
characterised by an abnormal sensory nally, in 1959 Scarlett and De Coucker
processing of pain that seems to result discovered that the spasmophilia nor-
from a combination of interactions be- mocalcaemia could also be secondary
tween neurotransmitters, stress, hor- to hypomagnesaemia (10).
mones and the nervous system; spas- Two types of tetany have been distin-
mophilia would seem to be more linked guished: manifest and latent (spas-
to a dysfunction at the neuromuscular mophilia); the latter requires provoca-
Competing interests: none declared. level. tive tests to be highlighted. The former,

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 Spasmophilia comorbidity in Fibromyalgia / L. Bazzichi et al.

due to hypocalcemia, is relatively rare FM patients were classified according dynia, traumatic event, blurred vision,
and usually postoperative (parathyroid to the 1990 American College of Rheu- sore throat, tachycardia and dyspnea.
tetany), while the mechanism of the matology criteria (ACR criteria) (1). Also disease duration (years) was taken
much more common latent tetany or Exclusionary criteria for patients were into consideration.
spasmophilia involves hyperventila- the presence of any additional rheu- Spasmophilia was evaluated by sur-
tion and magnesium deficiency. Latent matic or neoplastic disease. face electromyography (SEMG) with
tetany particularly affects young wom- The diagnosis of spasmophilia was surface electrodes as reported subse-
en (11). There are many signs of spas- based on clinical and electromyograph- quently in the text.
mophilia, but none is specific, so this ic criteria. At least 4 of the following
pathology is difficult to diagnose (12). symptoms had to be present: cramps Evaluation of psychiatric comorbidity
Chvostek and Trousseau signs are eas- and/or titanic crisis, paresthesia, tachy- Lifetime or ongoing psychiatric aspects
ily evoked to manifest a latent tetany cardia and/or dyspnea, asthenia and were evaluated by trained psychiatrists
(13, 14). Chvostek is a sign of the in- dizziness. Electromyography, carried by means of the classic scales: Struc-
voluntary contraction of facial muscles out on the first interosseus of the hand tured Clinical Interview (SCID) for
caused by light repeated percussions had to be positive. DSM-IV (19).
of the facial nerve immediately ante- All patients were drug-free or had
rior to the external auditory meatus. It a drug wash-out period of at least 2 Analytical measures
is present in 10% of healthy individu- weeks before clinical evaluation and Blood samples were taken early in the
als and is often absent in chronic hy- blood sampling. morning and after an overnight fast.
pocalcemia. Trousseau’s sign consists The Ethics Committee of the Universi- The following analysis were measured:
of triggering a carpo-pedal spasm by ty of Pisa approved the study protocol. thyroid stimulating hormone (TSH),
reducing the blood supply to the hand free thyroxine (FT4), free triiodothyro-
with a tourniquet or sphygmomanom- Evaluation of clinical parameters nine (FT3), antithyroglobulin (TgAb)
eter applied to the forearm for 3 min- Tenderness at tender points was evalu- and antithyroid peroxidase (TPOAb)
utes. The Trousseau sign is also seen in ated in each subject by digital pressure antibodies, routine laboratory chemis-
alkalosis, hypomagnesemia, hypoka- (1). The pain threshold was calculated try (ESR and CRP), cytokine (IL1, IL2,
liemia, and in about 6% of individuals for 18 points, and the tender point (TP) IL6, IL8, IL10), tumour necrosis factor
without any identifiable electrolyte dis- count was determined by the number of α (TNF-α), cortisol, growth hormone
turbances. Latent tetany may become tender points that had a threshold of ≤4 (GH), adreno-cortico-tropic-hormone
overt with the further reduction of ion- kg/cm2. The total fibromyalgic tender (ACTH), insuline-like growth factor
ised calcium after hyperventilation or point score (right + left) was used in (IGF1), serotonin levels (5HT), red
somministration of NaHCO3 or diuret- the statistical analysis. blood cell magnesium (intracellular
ics that cause depletion of calcium. To estimate the impact of fibromyalgia Mg, iMg), plasma calcium p(Ca), par-
Normocalcemic tetany may be defined on the quality of life, all the patients re- athormone (PTH).
as a pathologic state attributable to a ceived a “Fibromyalgia Impact Ques-
deficit of magnesium, and character- tionnaire” consisting of 10 items (15) Myoelectric measurement
ised by signs and symptoms typical as well as the Health Assessment Ques- Electromyography measures the elec-
of neuromuscular excitability (pain- tionnaire (HAQ) (16). The FIQ total trical potentials that are formed in a
ful muscle cramp) and psychosomatic score, which indicates the impact of the muscle during its contraction. The in-
manifestation. disease on life, ranged from 0 (no im- dividual potentials reflect the activity
Because we observed that some of the pact) to 100 (maximum impact). HAQ of a group of motor units in the case of
patients clinically diagnosed as fibro- varies between 0 and 3. Each patient surface electrodes. Compared to more
myalgic in our Division of Rheumatol- was asked if they had frequently suf- established needle electromyography,
ogy presented also spasmophilia the fered from any of the following symp- SEMG provides more comprehensive
aim of the present work is to evaluate toms (17, 18) in the past 12 months: information relating to the muscle
the influence of this comorbidity in fi- fatigue, non-restful sleep, anxiety, (metabolic state) and avoids the risk of
bromyalgia syndrome. depression, irritable bowel syndrome, using needles.
constipation, diarrhoea, fingers turn- Surface electrodes were applied to the
Materials and methods ing blue/white in the cold (Raynaud’s opposing muscle of the thumb, then
Subjects and methods phenomenon), paresthesiae (tingling in using a sphygmomanometer cuff, a
We retrospectively studied a cohort of arms/legs), articular stiffness, muscular pressure greater than 20 mmHg of
314 patients (280 F, 34 M) affected by stiffness, dry eyes, dry mouth, tempo- the patient’s systolic blood pressure
fibromyalgia (FM) or fibromyalgia and romandibular disorders (TMD), mus- was applied to the arm, and the spon-
spasmophilia (FM+SP). The patients cle spasms, tension headache, allergy, taneous activity within 10 minutes of
were recruited and clinically classi- low back pain, restless leg syndrome, ischemia was recorded as well as after
fied at the Division of Rheumatology, gastroesophageal reflux disease, burn- ischemia, and then during hyperpnea
University of Pisa (S. Chiara Hospital). ing/pain with urination, dizziness, allo- for 3 minutes. Surface electromyogra-

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Spasmophilia comorbidity in Fibromyalgia / L. Bazzichi et al.

Table I. Demographic data and clinical characteristics of the patients.

Patients Age Sex Disease duration FIQ HAQ TP

(years)

FM (n=233) 47.52 ± 12.19 210F, 23M 6.8 ± 7.4 59.75 ± 18.68 0.81 ± 0.59 15.33 ± 3.88*

FM+SP (n=81) 44.44 ± 10.75 70F, 11M 7.5 ± 7.0 60.0 ± 9.89 0.91 ± 0.61 12.88 ± 6.17*

(FM: fibromyalgic patients; FM+SP: fibromyalgic patients with spasmophilia comorbidity). Results are expressed as mean±SD.
*Tender point, FM vs. FM+SP; p=0.016 (Mann-Whitney U-test).

phy (SEMG) was considered positive levels did not differ between FM+SP tions resulted lower (FM: 4.35±0.58;
for spasmophilia in the presence of and FM patients, except for TNF-α FM+SP: 3.95±0.56 MEq/L, p=0.0001)
doublets, triplets and multiplets at base- plasma levels with higher results at even if in the normal range.
line and/or after the application of an nearly significant values, in the FM+SP The other laboratory parameters meas-
ischaemic stimulus. group of patients (FM: 14.28±39.34; ured did not differ between the two
Statistical analysis was performed by FM+SP: 23.07±53.88 pg/ml, p=0.06). groups of patients studied.
the non-parametric Mann-Whitney U- FM+SP patients showed the following The percentage of positive AbTPO
test and the Pearson’s chi-square test. concentrations significantly different and AbTg and the values of TSH, fT3
with respect to FM patients: growth hor- and fT4 were similar between FM and
Results mone levels (FM: 2.13±3.20, FM+SP: FM+SP patients (data not shown).
The demographic data and clinical 3.95±4.76 ng/ml, p=0.002) were high- Psychiatric comorbidity, calculated
characteristics of the fibromyalgic pa- er while intracellular Mg concentra- according to the psychiatric evalua-
tients are shown in Table I. All the pa-
tients studied resulted normocalcemic. Table II. Self reported symptoms of patients without spasmophilia (FM) and patients with
Eighty one patients resulted positive fibromyalgia and spasmophilia (FM+SP). Values are expressed in percentages.
for spamophilia (FM+SP), while 233
resulted negative for spasmophilia Patients without Patients p-value
spasmophilia with spasmophilia
(FM). There are no differences in age
(n=233) (n=81)
and disease duration between the two
study groups, while sex ratio (M/F) Fatigue 90 90 0.836
was slightly different between the two Non-restful sleep 69 75 0.414
groups of patients: 1/7 in FM+SP pa- Anxiety 60 61 0.958
tients, 1/9 in FM patients. FIQ and Depression 38 42 0.977
HAQ did not differ between the two Irritable bowel syndrome 67 60 0.943
Constipation 43 37 0.495
studied groups.
Diarrhoea 24 22 0.958
The mean TP number resulted higher
Fingers turn blue/white in the cold 31 22 0.240
in the FM group (15.33±3.88) with re- Paresthesiae 63 65 0.869
spect to FM+SP (12.88±6.17, p=0.016). Articular stiffness 75 81 0.333
Symptoms comparison evidenced Muscular stiffness 77 74 0.783
some differences between FM+SP and Dry eyes 50 43 0.394
FM patients (Table II): restless leg Dry mouth 44 54 0.240
syndrome (59% FM+SP vs. 44% FM), TMD§ 49 53 0.730
and tachycardia (46% FM+SP vs. 31% Muscle spasms 44 55 0.157
FM) were more frequent in FM+SP Tension headache 50 54 0.684
patients with respect to FM patients, Allergy 38 23 0.034*
instead allergies (23% FM+SP vs. 38% Low back pain 58 57 0.972
Restless leg syndrome 44 59 0.049*
FM) resulted less frequent in FM+SP
Gastroesophageal reflux disease 49 57 0.336
patients. Other symptoms more repre-
Burning/pain with urination 23 26 0.641
sented in the FM+SP group of patients, Dizziness 49 45 0.659
even if not reaching significant values, Allodynia 57 49 0.307
were the following: articular stiffness, Traumatic event 42 36 0.520
dry mouth, muscle spams and gastro Blurred vision 41 43 0.917
oesophageal reflux disease. Sore throat 32 35 0.783
We found high levels of IL2 Tachycardia 31 46 0.042*
(10.76±21.40 pg/ml) and IL10 Dyspnea 55 48 0.754
(19.53±31.06 pg/ml) in both the groups
(§TMD: Temporomandibular disorders).
of patients. However, cytokine plasma

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 Spasmophilia comorbidity in Fibromyalgia / L. Bazzichi et al.

tions, was different between the two the studied groups (25, 26). In particu- mately 0.2 mEq/L) in the serum Mg
subgroups and FM patients exhibited lar, IL10 plasma levels in the FM+SP concentration, and increased catecho-
a higher frequency of psychiatric dis- patients resulted higher with respect lamine secretion could be a contribut-
orders with respect to FM+SP patients to FM patients, even if not reaching ing cause of hypomagnesemia in acute
(72% FM vs. 49% FM+SP, p<0.01). In statistic significance. Moreover, TNF- illness and stress (38, 39). In this con-
particular the frequency for depression α plasma levels resulted higher in the text, it would be interesting to know the
was 65.5% in FM patients vs. 35% in FM+SP patients. cathecolamine levels in spasmophilic
FM+SP patients (p<0.01) and panic The possibility that the activation and patients.
disorder was 47.2% in FM patients vs. regulation of the cytokine pattern might GH levels were significantly higher in
39% FM+SP patients. be involved in the genesis of pain and FM+SP patients with respect to FM pa-
hyperalgesia was recently proposed tients, even if in the normal range. Pa-
Discussion (27, 28) based also on the development tients had GH levels <1 ng/ml with the
There are no relevant data in the lit- of the concept of “sickness behaviour” following percentages: FM+SP 38%,
erature that analyse the characteris- (29). In particular it has been suggested FM 54%. It is known that patients with
tics of patients with spasmophilia. In that cytokines may act as a link between fibromyalgia have an abnormal sleep
our study some significant differences the immune and nervous system in FM pattern involving stages 3 and 4 of non-
emerged between the group of patients (25, 30), given the fact that FM patients REM sleep (40). As growth hormone is
affected by fibromyalgia and the group have symptoms similar to sickness be- secreted predominantly during stages 3
of fibromyalgic patients positive for havior. Given our results a role for cy- and 4 of non-REM sleep, it was hypoth-
spasmophilia. tokines might be hypothesized for the esized that fibromyalgia may be associ-
Male sex was slightly more represent- genesis of spasmophilia symptoms. ated with impaired secretion of growth
ed in fibromyalgic patients positive We observed lower intracellular mag- hormones (41). In fact, about one third
for spasmophilia (FM+SP) than in fi- nesium (Mg) levels in spasmophilic of patients with fibromyalgia have low
bromyalgic patients negative for spas- patients, although within the normal IGF-1 levels (42). Furthermore, the
mophilia (FM). range, and this is consistent with the growth hormone is important in main-
There was no difference regarding pathogenesis of spasmophilia. Mg, the taining muscle homeostasis (43), and
the quality of life (FIQ), fatigue, pain second most prevalent intracellular cat- it was theorised that suboptimal levels
and other evaluated symptoms, while ion in the body, plays an important role may be a factor in the impaired reso-
we found a lower mean TP number in in enzyme activity, membrane stability, lution of muscle microtrauma in fibro-
FM+SP patients. Restless leg syndrome and ion transport (31, 32). Mg deficit myalgia (44). We observed that both
and tachycardia were more frequent in may be due to gastrointestinal and re- the group of patients with FM+SP and
FM+SP patients, while allergies were nal mechanisms not efficient for Mg FM referred non-restful sleep with no
less frequent. As far as restless leg syn- conservation (20). Moreover there are difference in incidence. We cannot ex-
drome, there are controversial results in known morbid conditions that produce plain the meaning of higher GH levels
the literature regarding the role of Mg: body Mg loss (diabetes, alcoholism, in patients with spasmophilia, we may
Popoviciu et al. (20) indicated that se- malabsorption) and medications (diu- only hypothesize a role for GH in spas-
rum Mg is low in restless leg syndrome retics, cyclosporine, aminoglycosides, mohilia which should be further inves-
(RLS), and Hornyak (21) and Bartel cisplatin, amphotericin B) which exac- tigated.
(22) found that intravenous Mg in preg- erbate the problem (34). The incidence of autoimmune thyroidi-
nancy was therapeutic to RLS. On the Mg has been shown to inhibit the N- tis in the two studied groups is similar
contrary, Walters (23) did not confirm methyl-D-aspartate (NMDA) receptor and in agreement with literature (45,
these results, finding no statistically (35), activation of which induces the 46). This finding leads us to suppose
difference between RLS patients and release of neurotransmitters, such as that in FM+SP patients, as in FM pa-
controls in either serum or cerebrospi- substance P. A reduction in extracel- tients, it might have a role in worsening
nal fluid Mg. lular Mg lowers the threshold levels of the typical symptoms.
We revealed high values of IL2 and excitatory amino acids (i.e. glutamate) The psychiatric comorbidity of FM pa-
IL10 in both the group of patients stud- necessary to activate this receptor. This tients resulted in agreement with the lit-
ied. In particular 65% of the FM-pa- neurogenic response is followed by the erature (47, 48). Interesting differences
tients and 59% of FM+SP patients had release of proinflammatory cytokines emerged from the comparison between
elevated levels of IL2, 30% of FM pa- (TNF-α, IL-1β, IL-6) by T lymphocytes the two groups: FM patients had a high-
tients and 41% of FM+SP patients had during the first week of dietary depletion er incidence of psychiatric disorders, in
elevated levels of IL10. (36). In fact TNF-α receptor knockout particular of depressive disorders with
Unlike the results found in the litera- in mice reduces adverse effects of Mg respect to spasmophilic patients. In the
ture (24, 25), our study did not reveal deficiency on bone (37). studied FM+SP patients, panic disorder
high values of IL-8 in either FM+SP Exogenous and endogenous catecho- unexpectedly was not representative,
or FM patients, but we confirmed the lamines have been shown experimen- as panic disorder and latent tetany ap-
presence of high levels of IL-10 in both tally to result in a slight drop (approxi- pear to occur concomitantly (49).

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Spasmophilia comorbidity in Fibromyalgia / L. Bazzichi et al.

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