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Coll. Antropol. 37 (2013) 3: 1015–1018
Case Report
Complex Regional Pain Syndrome Type I after
Diphtheria-Tetanus (Di-Te) Vaccination
Ervina Bili}1, Ernest Bili}2, Marija @agar1, Denis ^erimagi}3and Davorka Vranje{1
1University of Zagreb, University Hospital Center, Department of Neurology, Zagreb, Croatia
2University of Zagreb, University Hospital Center, Department of Pediatrics, Zagreb, Croatia
3General Hospital, Department of Neurology, Dubrovnik, Croatia
ABSTRACT
Complex regional pain syndrome type I (CRPS I) is a disorder of one or more extremities characterized by pain, ab-
normal sensitivity (allodynia), swelling, limited range of motion, vasomotor instability, fatigue and emotional distress.
The symptoms may be aggravated by even minor activity or weather change. It is usually provoked by injury, surgery or
injection but in a small proportion of patients CRPS I develops without a clear causative event. There are several litera-
ture reports on CRPS after rubella and hepatitis B vaccination. We present a case of CRPS I affecting the left arm after
diphtheria and tetanus (Di-Te) vaccination in the left deltoid muscle in a young girl having experienced profound emo-
tional stress before the vaccination procedure. History data on previous minor trauma at the site of vaccination or emo-
tional stress may necessitate temporary vaccination delay due to their proneness to impaired local or systemic immune
response and CRPS as a complication of vaccination. If a child or an adult has prominent swelling and severe pain after
vaccination, the diagnosis of CRPS I should be considered and if confirmed, the multidisciplinary treatment should
start as soon as possible.
Key words: complex regional pain syndrome, diphtheria, tetanus, vaccination, adverse effects
Introduction
Complex regional pain syndrome type I (CRPS I) is a
disorder of one or more extremities characterized by
pain, abnormal sensitivity (allodynia), swelling, limited
range of motion, vasomotor instability, fatigue and emo-
tional distress1,2. CRPS may develop following fractures,
limb trauma, infections, soft tissue contusion, tendon
ruptures, myocardial infarction, lesions of central and
peripheral nervous system, but spontaneous onsets have
been also described3–5. Emotional stress may be an im-
portant contributor for CRPS development6–9. The diag-
nosis is based on clinical parameters, as there is no
pathognomonic laboratory test for CRPS I3. The patho-
genesis of CRPS I is unclear and treatment is usually
multidisciplinary combining conservative treatment in-
cluding pharmacotherapy, physical management or psy-
chological approach8,9. Interventional therapies such as
nerve blockade, sympathetic block, spinal cord and pe-
ripheral nerve stimulation, implantable spinal medica-
tion pumps, and chemical or surgical sympathectomy are
still controversial issues but may be helpful10. There are
several case reports of CRPS I following immunization
with different vaccines, but we found no report of CRPS I
development after diphtheria tetanus (Di-Te) vaccina-
tion8,11,12. We present a case of CRPS I affecting the left
arm after Di-Te vaccination in the left deltoid muscle in a
young girl having experienced profound emotional stress
before the vaccination procedure. She described her emo-
tional and physical status before the vaccination as 'ex-
hausted and tired'. The patient also reported sleep dis-
turbance and was worried about her family subsistence
and her own future. The possible sharing mechanism in
all reported cases of CRPS I after immunization is minor
trauma during vaccination. Emotional distress is part of
the full clinical presentation of CRPS I. Our patient had
signs of depression, anxiety and sleep disorder before
vaccination. The emotional state, living conditions (so-
cial and economic), physical and emotional stress may
have also contributed to CRPS I development. Complete
clinical presentation of CRPS I is not frequently reported
as a possible complication following vaccination. It is pos-
1015
Received for publication November 22, 2013
sible that milder forms of CRPS I may be more fre-
quently present but overlooked. If a child or an adult has
prominent swelling and severe pain after vaccination,
the diagnosis of CRPS I should be considered and if con-
firmed, the multidisciplinary treatment should start as
soon as possible.
Case Report
The 18-year-old girl received Di-Te vaccination in the
left deltoid muscle on March 13, 2008. Her past history
did not disclose any previous trauma of the shoulder or
arm, serious disease or atypical reaction to vaccine. She
reported allergy to dust and maggot. Medical history re-
vealed obstructive bronchitis until age 6 and a recent his-
tory of laryngitis treated with antibiotics three weeks be-
fore admission (azithromycin and amoxicillin with clavu-
lanic acid). For a year before the vaccination she was ex-
posed to severe emotional stress caused by poor social
and economic condition in her family and suffered from
sleep disorder.
Only fifteen minutes after vaccine injection, she de-
veloped swelling of the entire left arm, discoloration of
the skin with limited range of motion of the arm and fin-
gers (Figure 1). During the next few hours, she suffered
from severe pain in her left shoulder and forearm, subse-
quently involving the whole left arm. The range of mo-
tion was seriously reduced, and at the end of the same
day she could only move her fingers. At the time of ad-
mission to Department of Neuromuscular Disorders, the
patient was not able to move her left arm, the swelling
was severe and regional pain was graded as 10/10 points
on the pain visual assessment scale. Physical examina-
tion showed discoloration of the skin with slow capillary
refill. The skin was unremarkable at the site of vaccine
injection. Sensation of the arm was normal and there
was no paresthesia or hyperesthesia. All laboratory pa-
rameters were normal (erythrocyte sedimentation rate,
hemoglobin, white blood cell count, biochemistry param-
eters, thyroid hormones, immunological parameters) and
neuroimaging of the head, cervical spine and brachial
plexus revealed no pathologic findings. X-rays and nerve
conduction velocity (NCV) showed no pathologic chan-
ges. The patient had previously responded modestly to
non-steroidal antirheumatics and steroid therapy, so we
decided to administer additional analgesia with opioid
drugs, pregabalin and antidepressants. Upon psychiatric
examination, psychotherapy and pharmacotherapy were
recommended because of the emotional distress and fam-
ily problems. During the 4-week hospital stay, the patient
also underwent physical therapy. Towards the end of hos-
pital stay, all therapeutic approaches yielded encouraging
results, the pain subsided, the range of motion was less
restricted, the swelling was remarkably reduced, and the
patient was optimistic and free from sleep disturbance
(Figure 2). After one year, the patient still suffered less
severe pain, there was no swelling, and her psychological
status was significantly improved. The functional status
of the arm was not fully satisfactory, as there some re-
striction in the range of motion persisted.
Discussion and Conclusion
Di-Te vaccine is composed of diphtheria and tetanus
toxoid with additional agents, i.e. aluminum phosphate,
thiomersalate (preservative), formaldehyde and water.
The term CRPS describes primary clinical characteris-
tics of the disease without defined pathogenesis of the
syndrome. Two forms of CRPS have been defined: type I,
previously called reflex sympathetic dystrophy (RSD)
and type II, previously called causalgia9. The diagnosis of
CRPS I is based exclusively on clinical parameters as
there is no typical laboratory parameter characteristic of
CRPS I13.
It is very important to find out whether a patient with
regional pain and swelling has other clinical parameters
for CRPS I diagnosis. The leading clinical signs for CRPS
I are severe regional pain, allodynia, motor dysfunction,
emotional distress, vasomotor instability and skin color
changes8,9. The pathogenesis of CRPS has not yet been
E. Bili} et al.: CRPS Type I after Di-Te Vaccination, Coll. Antropol. 37 (2013) 3: 1015–1018
1016
Fig. 1. Fifteen minutes after vaccine injection swelling of the arm,
discoloration of the skin with limited range of motion of the arm
and fingers was observed.
Fig. 2. The swelling of the arm was remarkably reduced after
four weeks.
clarified and the view of CRPS indicates that the disor-
der is not caused by just one system or just one mecha-
nism (e.g., sympathetic afferent coupling, adrenorecep-
tor disease, peripheral inflammation, hypoxia, psychoge-
nicity)14,15.
In this case report, we present a young girl with CRPS
I affecting the left arm after Di-Te vaccination in left
deltoid muscle, probably caused by minor trauma on
needle insertion. It is known that CRPS I may be caused
by cumulative trauma, repetitive injury, or even minor
trauma. The severity of physical injury is not related to
the risk of CRPS16. The risk of CRPS may depend on
susceptibility for exaggeration of the underlying disease
mechanism. This is supported by the observation of
abnormal neuroinflammatory responses to triggers in
the unaffected limbs of CRPS patients, such as increased
NO release from peripheral monocytes upon stimulation
with cytokines17 and enhanced axon-reflex vasodilata-
tion upon electrical C-fiber stimulation18. These were
found in unaffected limbs, suggesting that abnormal
responses are innate and do not evolve from the CRPS
itself.
Neural activity in postganglionic noradrenergic fibers
supplying blood vessels induces the release of norepi-
nephrine and possibly other substances, thus causing
vasoconstriction. Excitation of primary afferent fibers
causes vasodilatation in precapillary arterioles and plas-
ma extravasation in postcapillary venules by the release
of substance P and other vasoactive compounds14. Some
of these effects may be mediated by non-neuronal cells
such as mast cells and macrophages (by direct effect or
via cytokines, i.e. TNF alfa, IL-6, IL-1, tryptase). Macro-
phages act as antigen presenting cells and can be acti-
vated by danger/alarm signals from injured cells, such as
those exposed to pathogens, toxins and mechanical da-
mage19.
We found only few reports on CRPS I triggered by
vaccination with various vaccines. All reported cases of
CRPS I after vaccination refer to healthy girls developing
CRPS I after needle vaccination on regular recommen-
ded immunization8,12. Previous lesion of the tissue in-
jected for vaccination or tissue cell damage by viral infec-
tion, along with additional irritation induced by vacci-
nation, may lead to strong macrophage stimulation and
consequentially to the effect described above. In other
words, even a minor trauma such as blow sustained on
physical exercise preceding vaccination may trigger
CRPS in susceptible individuals. Therefore, prior to vac-
cination each individual should be asked about the possi-
ble previous, even minimal trauma in the body area to be
injected. It is of utmost importance in children active in
sports and in preschool children. Our patient was in deep
emotional stress before vaccination, which should be
taken in consideration for the possible role of emotional
stress in modifying normal immune response and in the
pathogenesis of CRPS I.
The pathogenesis of CRPS is multifactorial, and sev-
eral mediators of different disease mechanisms are in-
volved in this complex disorder15. In this case report, we
tried to elucidate some of the possible triggers for CRPS
onset following Di-Te vaccination and the impact of pre-
vious emotional stress on CRPS development. History
data on previous minor trauma at the site of vaccination
(in particular in preschool children and athletes) or emo-
tional stress may necessitate temporary vaccination de-
lay due to their proneness to impaired local or systemic
immune response and CRPS as a complication of vacci-
nation.
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D. ^erimagi}
Department of Neurology, General Hospital, Roka Mi{eti}a 2, 20000 Dubrovnik, Croatia
e-mail: deniscerimagic@yahoo.com
E. Bili} et al.: CRPS Type I after Di-Te Vaccination, Coll. Antropol. 37 (2013) 3: 1015–1018
1017
KOMPLEKSNI REGIONALNI BOLNI SINDROM TIP I NAKON CIJEPLJENJA PROTIV
DIFTERIJE I TETANUSA (DI-TE)
SA@ETAK
Kompleksni regionalni bolni sindrom tip I (CRPS I) je poreme}aj koji zahva}a jedan ili vi{e ekstremiteta, a karak-
terizira se bolovima, smetnjama osjeta (alodinija), oticanjem, ograni~enim opsegom kretnji, vazomotornom nestabil-
no{}u, umorom i emocionalnim distresom. Do pogor{anja ovih simptoma mogu dovesti fizi~ka aktivnost ili promjena
vremenskih prilika. Pojavu ovog sindroma naj~e{}e uzrokuje ozljeda, kirur{ki zahvat ili injekcija, a u manjem broju
slu~ajeva uzrok ostaje nepoznat. U literaturi je opisano nekoliko slu~ajeva pojave CRPS-a nakon cijepljenja protiv ru-
beole i hepatitisa B. Prikazujemo slu~aj pojave CRPS-a tip I na lijevoj ruci, nakon cijepljenja protiv difterije i tetanusa
(Di-Te) u podru~ju lijevog deltoidnog mi{i}a, kod djevoj~ice koja je prije cijepljenja bila pod dubokim emocionalnim
stresom. Anamnesti~ki podaci o ranijoj, ~ak i minimalnoj traumi u podru~ju u kojem se planira aplicirati cjepivo ili
podatak o emocionalnom stresu mogu biti razlog odgode cijepljenja, kako bi se izbjegli lokalni i sustavni imunolo{ki
odgovori te CRPS kao mogu}a komplikacija cijepljenja. Ukoliko dijete ili odrasli pacijent ima izra`en edem ekstremiteta
te intezivnu bol nakon cijepljenja, mora se razmotriti dijagnoza CRPS-a, a ukoliko se ista potvrdi potrebno je {to prije
zapo~eti s multidisciplinarnim lije~enjem.
E. Bili} et al.: CRPS Type I after Di-Te Vaccination, Coll. Antropol. 37 (2013) 3: 1015–1018
1018
