Pseudopheoch omocy oma induced by anxioly ic wi hd awal
Alida Páll MD
1
, Ge gely Becs MD
1
, Annamá ia E dei MD
2
, Lí ia Si a MD
2
, Á pád Czi a
MD
1
, Sándo Ba na MD
3
, Pé e Ko ács MD, DSc
4
, Dénes Páll MD, PhD
4
, Gyö gy P liegle
MD, PhD
5
, Gyö gy Pa agh MD, DSc
1
, Zol án Szabó MD, PhD
1
Di ision o Eme gency Medicine, Ins i u e o In e nal Medicine, Uni e si y o Deb ecen
Medical Cen e , Hunga y
1
Di ision o Endoc inology, Ins i u e o In e nal Medicine, Uni e si y o Deb ecen Medical
Cen e , Hunga y
2
Scanomed Medical Diagnos ic L d, Uni e si y o Deb ecen Medical Cen e , Hunga y
3
Clinical Pha macology Uni , Ins i u e o In e nal Medicine, Uni e si y o Deb ecen Medical
Cen e , Hunga y
4
Di ision o Ra e Diseases, Ins i u e o In e nal Medicine, Uni e si y o Deb ecen Medical
Cen e , Hunga y
5
Co esponding au ho :
Zol án Szabó MD, PhD
Di ision o Eme gency Medicine, Depa men o In e nal Medicine
Uni e si y o Deb ecen Medical Cen e
Hunga y
PO Box 19.
Nagye dei k . 98.
4032 Deb ecen, Hunga y
Phone/Fax: (36)-52-413653
e-mail: [email p o ec ed]
Sho i le: Anxioly ics and pseudopheoch omocy oma
2
Abs ac
Backg ound
Symp oma ic pa oxysmal hype ension wi hou signi ican ly ele a ed ca echolamine
concen a ions and wi h no e idence o an unde lying ad enal umo is known as
pseudopheoch omocy oma.
Me hods
We desc ibe he case o a emale pa ien wi h pa oxysmal hype ensi e c ises accompanied by
headache, e igo, achyca dia, nausea and al e ed men al s a us. P e iously she was ea ed
o a longe pe iod wi h alp azolam due o panic diso de . Causes o seconda y hype ension
we e excluded. Neu ological igge s (in ac anial umo , ce eb al ascula lesions,
hemo hage, and epilepsy) could no be de ec ed.
Resul s
Se ing o he diagnosis o pseudopheoch omocy oma ea men was ini ia ed wi h alpha- and
be a-blocke s esul ing in less common occu ence o he symp oms. Alp azolam was
es a ed a a daily dose o 1 mg. Pa ien ’s clinical condi ion imp o ed apidly and he dosage
o alpha and be a blocke s could be dec eased.
Conclusions
We conclude ha he wi hd awal o an anxioly ic he apeu ic egimen may gene a e
sympa he ic o e d i e esul ing in li e h ea ening pa oxysmal malignan hype ension and
seconda y encephalopa hy. We emphasize ha pseudopheoch omocy oma can be diagnosed
only a e exclusion o he seconda y causes o hype ension. We highligh he impo ance o
psychopha macological app oach o his clinical en i y.
Keywo ds: anxioly ic d ugs, pseudopheoch omocy oma, hype ension, psychopha macology
3
Backg ound
Pseudopheoch omocy oma is a apid onse bunch o symp oms gene a ed by sympa hoad enal
o e d i e [1, 2]. In mos o he cases his clinical synd ome includes pa oxysmal (malignan )
hype ension, emo , palpi a ion, swea ing, ches pain, headache, nausea, dizziness, and
pseudoseizu es [3–5]. The episodes o clinical symp oms and complain s may las om
minu es up o hou s. Impo an ly, he basic di e ence be ween pheoch omocy oma and
pseudopheoch omocy oma is ha in he la e no biochemical and ana omical backg ound can
be cla i ied, howe e e idence o mild o mode a e ca echolamine elease may be p o en
du ing any o he pa oxysms [6–9].
I has been sugges ed ha a numbe o ac o s in e ac
leading o he de elopmen o his clinical condi ion in any one indi idual (Table 1.).
Fu he mo e, he e a e di e ences in he se e i y and clinical cha ac e is ics be ween pa ien s
ha may esul in he di e si y o pseudopheoch omocy oma [10]. In e es ingly, besides he
al eady known clinical causes psychological childhood aumas may also play a ole in he
genesis o his clinical en i y, whe e psycho he apy can e ec i ely elie e symp oms [11].
Fu he mo e, i has o be emphasized ha his condi ion may be seconda y o ce ain d ug
he apies (e.g., sympa homime ic agen s, icyclic an idep essan s, o eboxe ine) all o which
can con ibu e o he appea ance o sympa he ic o e d i e [12–14]. Howe e , i has no been
clea ly elucida ed whe he he modi ica ion o he e mina ion o a o me
psychopha macological he apy may be able o gene a e such se e e symp oms leading o he
diagnosis o pseudopheoch omocy oma [15]. Th oughou ou wo k we aimed o cla i y he
ole o he wi hd awal o he anxioly ic d ug, alp azolam, in he genesis o he cha ac e is ic
clinical ea u es o pseudopheoch omocy oma by p esen ing one o ou pa ien s’ clinical
his o y.
Case p esen a ion
In Janua y 2014, a 55-yea -old Caucasian woman was admi ed o ou Eme gency Uni wi h
pa oxysmal malignan hype ension accompanied by headache, e igo, achyca dia,
lac ima ion, nausea and al e ed men al s a us. He medical his o y included a caesa ean
sec ion (1984), an abdominal su ge y due o mechanical ileus, a lapa oscopic cholecys ec omy
(1995), a gas o-oesophageal e lux and a o al hy oidec omy due o a benign non- oxic
4
mul i-nodula goi e, la e equi ing hy oid ho monal subs i u ion. In 2008, an ele a ed
as ing glucose le el poin ed o an unde lying ype 2 diabe es melli us. Hype ension and
sinus achyca dia was i s diagnosed in 2003. Consequen ly, he pa ien unde wen se e al
examina ions in a ious hospi als bu no unde lying o ganic causes o he complain s could be
de ec ed. Endoc inological diso de s - especially pheoch omocy oma – we e excluded on
se e al occasions. The al e ed men al s a us du ing he hype ensi e c ises aised he
possibili y o neu ological de iciency, bu no signs o in ac anial umo , ce eb al ascula
lesions, hemo hage o e en epilepsy we e de ec able. Mo eo e , ca diac a hy hmias and
ischemic hea disease we e also excluded. E en ually, in 2004, a e nume ous diagnos ic
p ocedu es panic synd ome was diagnosed, he e o e anxioly ic and an idep essan
medica ions we e ini ia ed. Be ween 2004 and 2013 he pa ien was ea ed wi h his
combina ion o psychopha macological agen s. Du ing a ho ough psychia ic ollow-up
pe iod he equency o he pa oxysms d opped no iceably, bu he pa ien seemed o be
addic ed o he psychopha macological egimen so he medica ions we e wi hd awn in
ano he cen e . Du ing he ollowing yea he pa ien did no show any clinical symp oms o
pa oxysmal hype ension. A he ime o he cu en admission o ou clinic he pa ien ’s
medical he apy consis ed o me op olol 100 mg wice daily, esomep azole 40 mg daily,
le o hy oxin 100 µg daily, allopu inol 100 mg daily, and insulin he apy (glulisine insulin
h ee- imes a day and gla gine insulin once a day).
The pa ien p esen ed he sel a he Di ision o Ra e Diseases o u he e iologic
examina ions. Du ing he i s clinical e alua ion a eally se e e a ack could be obse ed.
The pa ien became unconscious, he blood p essu e apidly ose o 230/100 mmHg, wi h a
egula hea a e o 160-180/min (Figu e 1). Mo eo e , ocal muscle wi ching appea ed on
he le ace, and excessi e lac ima ion and lushing could also be obse ed. Because o he
uns able clinical condi ion she was immedia ely admi ed o ou In ensi e Ca e Uni . Be o e
he adminis a ion o addi ional medica ions he pa ien se e e clinical condi ion imp o ed
signi ican ly on i s own. By he end o he pa oxysm he equency o sinus hy hm dec eased
o 90/min and he blood p essu e was also no malized. A e he c isis, no signs o a hy hmia,
o long s anding neu ological de ec s could be obse ed. No o he signi ican clinical
abno mali ies could be ound du ing u he clinical examina ions. A e wa ds du ing he i s
week o hospi alisa ion she had a acks 2-4 imes a day. These pa oxysmal hype ensi e c ises
las ed o 3-5 minu es and hen disappea ed spon aneously wi hou any medical in e en ions.
Be ween he pa oxysms he pa ien did no ha e any complain s. Because o he epea ed
5
a acks a combina ion o alpha- and be a-ad enocep o blocke s was gi en, which was able o
lowe he blood p essu e and he hea a e du ing he pa oxysms, bu no he equency o he
a acks. Hol e elec oca diog aphy eco dings and 12-lead su ace elec oca diog ams
e ealed sudden onse episodes o sinus achyca dia wi hou any signs o u he a ial o
en icula a hy hmias (Figu e 2.). Renal Dopple ul asound examina ion was pe o med o
exclude eno ascula disease. I e ealed physiological blood low in bo h enal a e ies, wi h
no signi ican di e ence ega ding esis i e indices (0.67 s. 0.7, espec i ely). Al hough
p e ious examina ions we e no able o p o e any endoc inological backg ound o he
pa oxysms, a epea ed labo a o y es ing o pheoch omocy oma and ca cinoid was pe o med.
Labo a o y esul s o ou pa ien a e shown in Table 2. An ele a ed se um ch omog anin A
le el appea ed, bu i p o ed o be a alse posi i e esul due o a concomi an p o on-pump
inhibi o (PPI) he apy (a e he emo al o PPI, ch omog anin le el was in he no mal
ange). Su p isingly, an adenoma could be de ec ed in he le ad enal gland du ing compu ed
omog aphy. Due o he epea ed se e e clinical symp oms we we e obliged o s a he
ea men o he pheoch omocy oma, hus, a ca dio-selec i e be a-blocke (bisop olol 5 mg
wice daily) in combina ion wi h an alpha-ad enocep o -blocke (doxazosine 4 mg once daily)
we e ini ia ed. Du ing his ime, u ine concen a ions o 5-hyd oxyindoleace ic acid (5-
HIAA), me aneph ine, no me aneph ine and dopamine we e ound o be no mal. Al hough,
we measu ed sligh ly ele a ed se um concen a ions o no ad enalin and dopamine du ing an
a ack, he le els did no ul ill he c i e ia o pheoch omocy oma (Table 3.). To ensu e he
sa e exclusion o pheoch omocy oma, a
131
I-MIBG scan was also pe o med, which did no
e eal any abno mali ies ela ing o ad enal gland dys unc ion (Figu e 3). Fu he mo e,
hype aldos e onism as a e y a e cause o pa oxysmal hype ension could also be excluded.
Fu he labo a o y es s helped o exclude any ho monal abno mali ies, so he a o emen ioned
ad enal gland adenoma was ega ded as an inciden aloma. Thy oid labo a o y es s showed
he e ec i e ho monal subs i u ion o hypo hy oidism seconda y o he p e ious
hy oidec omy. A e excluding he chances o endoc ine diso de s we ocused on anxioly ic
medica ion. Fo his eason psychia ic examina ion was pe o med and alp azolam was e-
adminis e ed in a daily dose o 1 mg (0.5 mg wice daily). We could demons a e an
immedia e clinical imp o emen , u he mo e, he daily dose o alpha and be a-blocke s could
also be dec eased. Du ing he adminis a ion o alp azolam in a daily dose o 1 mg sleepiness,
a igue occu ed, he e o e we dec eased he daily dose o 0.5 mg. Consequen ly he
pa oxysmal inc ease in blood p essu e eappea ed so u he he apy o 1 mg was necessa y o

6
main ain. A e a ou -week pe iod a he In ensi e Ca e Uni he pa ien was discha ged
hough s ill wi h mild symp oms and wi h an imp o ed quali y o li e. The sys olic and
dias olic blood p essu e and hea a e collec ed a e he discha ge o ou pa ien we e
inse ed o he manusc ip (Table 4).
7
Conclusions
The clinical cons ella ion o pa oxysmal hype ension wi hou a clea unde lying cause and
wi hou p oo o pheoch omocy oma has been in oduced as pseudopheoch omocy oma,
which may lead o se e e disabili y and a wo sening quali y o li e. Impo an ly, his clinical
en i y is cha ac e ized by pa oxysmal episodes o se ious hype ension and concomi an
symp oms due o sympa hoad enal o e d i e, which a e no ela ed o emo ional s ess [16].
Howe e , some pa ien s may expe ience anxie y bu only in eac ion o he dis essing
symp oms and complain s. On he o he hand, panic diso de is cha ac e ized by mild blood
p essu e ele a ion whe e panic and ea a e ine i ably disco e able [17]. Despi e he di e en
p o oking mechanisms hese clinical en i ies bea esemblance o each o he . Un o una ely,
in he case o lacking emo ional dis ess, pa oxysmal hype ension is usually hough o be an
unexplained diso de [1]. Nume ous clinical condi ions may mani es as pa oxysmal
hype ension and should be cla i ied whe e clinically app op ia e. Pa oxysmal hype ension is
mos ly accompanied by achyca dia (palpi a ion) whe e he ac i a ion o sympa hoad enal
sys em is likely o be he unde lying ac o . P e iously, i has been shown ha pa ien s wi h
pseudopheoch omocy oma show be a and alpha-1-ad enocep o hype sensi i i y [6]. The
e ec i e esponse o alpha and be a blocke s also seem o suppo his hypo hesis. Howe e ,
in some ci cums ances hese d ugs a e no e ec i e in he con ol o he symp oms [18]. In
hese pa icula cases psychopha macological he apeu ic app oach may be use ul in he
p e en ion o he pa oxysms and es o ing quali y o li e [19].
P e iously,
a
n idep essan
agen s (desip amine, pa oxe ine) in combina ion wi h anxioly ic d ugs and psycho he apeu ic
in e en ions ha e been shown o be e ec i e in he p e en ion and elimina ion o he a acks
[18]. Impo an ly, he a o emen ioned managemen s a egy may be able o con ol he clinical
symp oms bu he disease i sel is ne e e adica ed. Mo eo e , i is impo an o no e ha
pa oxysmal hype ension and he concomi an symp oms may be seconda y o d ug he apy
which may aise sympa he ic ac i i y. I has no been es ablished whe he he wi hd awal o
an anxioly ic he apy may be able o esul in such se ious consequences. Benzodiazepines
(e.g. alp azolam) a e known o hei anxioly ic, seda i e, hypno ic, eupho ic, an icon ulsan ,
and muscle elaxan e ec s while ac ing on gamma-aminobu y ic acid A (GABA
A
) ecep o s.
The GABA
A
is an iono opic ecep o and ligand-ga ed chlo ide ion channel. I s endogenous
ligand is GABA, which is an inhibi o y neu o ansmi e in he cen al ne ous sys em.
Fu he mo e, i has been shown ha neu onal cholecys okinin (CCK) ecep o s a e also
implica ed in hese mechanisms [20]. The CCK ecep o ac i a ion has been p o en o be
esponsible o con olling ea and panic a acks. Consequen ly, he wi hd awal o he
8
benzodiazepines una guably can lead o he libe a ion o CCK ecep o s om hei inhibi ion.
(Figu e 4.) The concomi an chance o panic a acks a e inc eased, mo eo e al e a ions in
ascula one, sudden inc ease in blood p essu e and li e h ea ening hype ensi e
encephalopa hy a e conside able sequels [21, 22].
In ou wo k we desc ibed he medical his o y o a emale pa ien who was ea ed wi h he
anxioly ic d ug alp azolam o yea s, due o panic diso de . La ely, he anxioly ic he apy was
e mina ed since symp oms had imp o ed and because he dange o addic ion was
conside able. Recen ly, ou pa ien was admi ed o ou cen e due o episodes o se e e,
pa oxysmal hype ension wi h accompanying symp oms e lec ing inc eased sympa he ic
one. Impo an ly, hese clinical signs we e no ini ia ed by ea o emo ional s ess. A e
uling ou all po en ial seconda y unde lying causes ha may ha e con ibu ed o he
wo sening o he clinical s a us, diagnosis o pseudopheoch omocy oma was es ablished.
Conside ing he pa ien ’s se e e symp oms alpha and be a-ad enocep o blocke ea men
we e in oduced, which ha e no been e ec i e enough in he p e en ion o u he
pa oxysms. I was ealized ha he cessa ion o alp azolam ea men migh be esponsible o
he sudden wo sening o he clinical condi ion. Thus, alp azolam he apy was es a ed
esul ing in a apid imp o emen o he symp oms and quali y o li e. The eappea ance o
ele a ed blood p essu e seconda y o he empo a y dec ease in he daily dose o alp azolam
is conside ed o be a posi i e challenge es .
To ou bes knowledge his is he i s pape o epo he possible ole o anxioly ic
wi hd awal in he genesis o pseudopheoch omocy oma. The e o e, we emphasize ha he
e mina ion o an anxioly ic he apeu ic egimen may gene a e se e e sympa he ic
o e shoo ing esul ing in li e h ea ening pa oxysmal malignan hype ension and seconda y
encephalopa hy. We accen ua e ha pseudopheoch omocy oma can be diagnosed only a e
he exclusion o seconda y causes o hype ension. Impo an ly, pheoch omocy oma has o be
sa ely uled ou . Besides he adminis a ion o alpha and be a blocke s, we s ess he
impo ance o psychopha macological and psycho he apeu ic app oach o his clinical en i y.
Lis o abb e ia ions
5-HIAA: 5-hyd oxyindoleace ic acid
CCK : cholecys okinin
GABA: gamma-aminobu y ic acid
131
I-MIBG: iodine-131 me aiodobenzylguanidine
9
PPI: p o on pump inhibi o
Compe ing In e es
All au ho s decla e ha hey ha e no compe ing in e es s.
Au ho s’ con ibu ions
A.P.: She has aken pa in he obse a ion and managemen o he pa ien in he In ensi e
Ca e Uni and has d a ed he manusc ip .
G.B.: He has aken pa in he obse a ion and managemen o he pa ien in he In ensi e
Ca e Uni and has d a ed he manusc ip .
A.E.: She has aken pa in he obse a ion and managemen o he pa ien in he In ensi e
Ca e Uni
L.S: She has pa icipa ed in he obse a ion and managemen o he pa ien .
Á.C.: He has pa icipa ed in he es ablishmen o he diagnosis and he obse a ion o he
pa ien in he Eme gency Room and has d a ed he manusc ip .
S.B.: He has analyzed he adiologic images.
P.K.: He has pa icipa ed in he obse a ion and managemen o he pa ien .
D.P.: He has pa icipa ed in he obse a ion and managemen o he pa ien
Gy.P.: He has pa icipa ed in he obse a ion and managemen o he pa ien .
16
Table 4. Da a on blood p essu e and hea a e ob ained a e he discha ge o ou pa ien
e ealed he lack o eoccu ence o he pa oxysms. BP: blood p essu e, sys: sys olic, dia:
dias olic
Maximum Minimum Mean
BP sys (mmHg) 145 133 140
BP dia (mmHg) 85 79 82
Hea a e (bea s/min) 93 65 74

17
Figu e legend
Figu e 1. Du ing he i s clinical e alua ion o he pa ien a eally se e e a ack could be
obse ed. The pa ien became unconscious, he sys olic blood p essu e apidly ose abo e 230
mmHg. Simila ends we e obse ed du ing he epea ed pa oxysms.
BP: Blood p essu e
Figu e 2. Hol e elec oca diog am e ealed a pa oxysmal sinus achyca dia du ing he a ack.
No o he a ial a hy hmias o li e h ea ening en icula a hy hmias ( en icula achyca dia
and ib illa ion) we e obse ed.
Figu e 3. Fo I-131 MIBG acquisi ion 40 MBq adiopha maceu ical was injec ed. A whole
body (4cm/min) and abdominal SPECT/CT acquisi ion we e pe o med on MEDISO
AnyScan SC sys em 72 hou s a e he injec ion. SPECT pa ame e s we e: 1 min/p ojec ion,
64 iews, ma ix size 64x64. A 16-slice CT was used, wi h 120 mAS and 120 kV abdominal
il e . Fo he SPECT econs uc ion OSEM me hod was pe o med. None o he ad enal
egions showed abno mal ocal up ake.
MIBG: Me aiodobenzylguanidine, SPECT: Single-Pho on Emission Compu ed Tomog aphy, CT:
Compu ed Tomog aphy, OSEM: O de ed Subse Expec a ion Maximiza ion
Figu e 4. The e ec s o benzodiazepines on GABA (gamma-aminobu y ic acid) ecep o and
cholecys okinin (CCK) a e shown.
On one hand binding o GABA molecules o hei si es
igge s he opening o a chlo ide ion-selec i e po e esul ing in he hype pola iza ion o he
cell. On he o he hand benzodiazepines a e likely o an agonize he cholecys okinin-induced
ac i a ion o neu ons.