Medically induced CSF rhinorrhea following treatment of macroprolactinoma: case series and literature review

Abstract

PurposeAlthough several reports have addressed cerebrospinal fluid (CSF) rhinorrhea following dopamine agonist (DA) therapy of macroprolactinomas, further study is warranted for this relatively uncommon entity. Toward this aim, our retrospective series and review of literature further clarifies recommendations in treatment of this rare problem. Methods
We retrospectively reviewed all macroprolactinoma cases in our hospital for a 15-year period. Our systematic search of PubMed identified original articles and reviews of all macroprolactinoma cases with an associated medication-induced CSF leak. ResultsFive patients with drug-induced CSF leak were identified; four of these patients received cabergoline therapy an average of 6 weeks before the onset of rhinorrhea and then underwent surgical repair of the CSF leak. Of 35 published studies included, we identified 60 patients with medication-induced CSF leak. Medical therapy included bromocriptine in 34 patients, cabergoline in 21 patients, and use of both DAs in two patients. Three cases did include complete diagnostic and treatment data. Median time from initiation of the DA treatment to occurrence of rhinorrhea was 6 weeks. For CSF rhinorrhea, 49 patients underwent surgical repair (38 by the transnasal approach) and seven patients were treated nonoperatively. Conclusion
Baseline skull base erosion in macroprolactinomas in combination with subsequent tumor shrinkage induced by DA therapy may result in spontaneous CSF rhinorrhea. Therefore, such patients should be advised about and monitored for this potential setback. Once CSF leak is diagnosed, prompt treatment must be carried out to avoid infectious complications. Transnasal surgery appears the most effective therapeutic approach.

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Pituitary
https://doi.org/10.1007/s11102-018-0907-1
Medically induced CSF rhinorrhea followingtreatment
ofmacroprolactinoma: case series andliterature review
TomášČesák1 · PavelPoczos1,2 · JaroslavAdamkov1 · JiříNáhlovský1 · PetraKašparová3 · FilipGabalec4 ·
PetrČelakovský5 · OndrejChoutka6
© Springer Science+Business Media, LLC, part of Springer Nature 2018
Abstract
Purpose Although several reports have addressed cerebrospinal fluid (CSF) rhinorrhea following dopamine agonist (DA)
therapy of macroprolactinomas, further study is warranted for this relatively uncommon entity. Toward this aim, our retro-
spective series and review of literature further clarifies recommendations in treatment of this rare problem.
Methods We retrospectively reviewed all macroprolactinoma cases in our hospital for a 15-year period. Our systematic
search of PubMed identified original articles and reviews of all macroprolactinoma cases with an associated medication-
induced CSF leak.
Results Five patients with drug-induced CSF leak were identified; four of these patients received cabergoline therapy an
average of 6 weeks before the onset of rhinorrhea and then underwent surgical repair of the CSF leak. Of 35 published stud-
ies included, we identified 60 patients with medication-induced CSF leak. Medical therapy included bromocriptine in 34
patients, cabergoline in 21 patients, and use of both DAs in two patients. Three cases did include complete diagnostic and
treatment data. Median time from initiation of the DA treatment to occurrence of rhinorrhea was 6weeks. For CSF rhinor-
rhea, 49 patients underwent surgical repair (38 by the transnasal approach) and seven patients were treated nonoperatively.
Conclusion Baseline skull base erosion in macroprolactinomas in combination with subsequent tumor shrinkage induced by
DA therapy may result in spontaneous CSF rhinorrhea. Therefore, such patients should be advised about and monitored for
this potential setback. Once CSF leak is diagnosed, prompt treatment must be carried out to avoid infectious complications.
Transnasal surgery appears the most effective therapeutic approach.
Keywords Prolactinoma· Dopamine agonists· Cerebrospinal fluid leak· Rhinorrhea
Introduction
Prolactinoma is the most common pituitary adenoma (40%)
and represents up to 50–60% of all functional pituitary
tumors [1–3]. Prolactinomas are monoclonal in origin.
Specific gene mutations were proved in multiple endocrine
neoplasia (MEN 1) and aryl hydrocarbon-interacting protein
gene (AIP) mutation has been identified in some families
with prolactinoma [4]. Microprolactinomas, smaller than
10mm, are found predominantly in females. Larger prol-
actinomas, macroprolactinomas (> 10mm in diameter), are
more often found in men and younger patients. Giant prolac-
tinomas are a rare subset of macroadenomas, characterized
by large size (> 40mm in diameter) and high aggressiveness
to the adjacent structures including bone [1, 5].
DAs are recommended as the first line treatment [6]. Their
effect on tumor volume, even at low doses, is often impressive
* Pavel Poczos
poczosp@lfhk.cuni.cz
1 Department ofNeurosurgery, University Hospital
Hradec Kralove, Charles University, HradecKralove,
CzechRepublic
2 Department ofAnatomy, Faculty ofMedicine inHradec
Kralove, Charles University, HradecKralove, CzechRepublic
3 The Fingerland Department ofPathology, University
Hospital Hradec Kralove, Charles University,
HradecKralove, CzechRepublic
4 4th Department ofInternal Medicine – Haematology,
University Hospital Hradec Kralove, Charles University,
HradecKralove, CzechRepublic
5 Department ofOtorhinolaryngology andHead andNeck
Surgery, University Hospital Hradec Kralove, Charles
University, HradecKralove, CzechRepublic
6 Saint Alphonsus Neuroscience Institute - Neurosurgery,
Boise, ID, USA

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and persistent [7, 8]. Occasionally, mainly when the adenoma
shows invasive growth and causes skull base erosion, CSF
rhinorrhea may occur during medical therapy [9–16].
To our best knowledge, there has been only one article
with larger case series of patients with DA-induced CSF leak
[13]. We report five patients with invasive macroprolactinoma
treated with CAB, in whom CSF rhinorrhea occurred shortly
after initiation of the treatment. We also performed a review of
the literature and collected all published cases of DA treatment
induced spontaneous CSF rhinorrhea in patients with macro-
prolactinomas. This comprehensive collection of all patients in
literature brings about a clear understanding of this entity and
offers a helpful advice for the management of individual cases.
Subjects andmethods
Patient selection
We analyzed our patients with macroprolactinomas referred
to our department between 2004 and 2018. Only patients
with medically induced CSF rhinorrhea without previous
surgical or radiation therapies were included in this series.
Literature review
This review is based on a systemic search in the PubMed
databases to find any publication presenting patients with
macroprolactinomas who developed CSF leak following
medical treatment. Any patients with spontaneous CSF leak
before drug therapy or postsurgical CSF leak were excluded.
The PubMed database was searched at the end of February
2018 using terms: prolactinoma, dopamine agonists (DA),
cerebrospinal fluid (CSF) leak, rhinorrhea. The literature
review was extended for references cited in these reports.
Analyzed data
Data from our 5 patients and from the literature review were
analyzed to determine patient’s age at presentation of CSF
leak, sex, initial prolactin (PRL) level, type of drugs used
and duration of treatment prior to the onset of rhinorrhea.
The site of the leak in the skull base and definitive CSF leak
treatment method were also recorded. Prolactin level values
were converted to unify all cases in the series to ng/mL by
dividing mIU/L values by 21.2.
Results
Cases series
All five patients in our series were male patients and their
average age was 65years (range 20–76years). Three lesions
were defined as macroprolactinomas and two as giant prolac-
tinomas (Fig.1). The median initial PRL level was 1049ng/
mL [interquartile range (IQR) 4937ng/mL]. Skull base ero-
sion was found in all cases on initial images. Cabergoline
was the only administered DA. CSF rhinorrhea occurred on
average 6.8weeks (median 9 with IQR 4) after initiation of
DA therapy. In one case (patient No. 5) CSF leak stopped
after temporary (2months) withdrawal of medication. Two
patients (No. 3, 4) underwent transnasal surgery with par-
tial tumor removal and concurrent skull base reconstruc-
tion. Two episodes of recurrent CSF rhinorrhea in patient
No. 3 required redo surgical repair. In patient No. 4, partial
resection and repair was complicated by recurrent CSF leak
after discharge. It stopped without another surgical inter-
vention, simply with interruption of CAB therapy that was
then re-initiated 4months later. CSF leak repair without
any tumor removal was performed in patient No. 2. Surger-
ies were performed by means of an endoscopic endonasal
approach. It allowed clear identification of the CSF leak and
its repair. In patient No. 1 the failed initial endoscopic repair
was followed by a second surgery. It consisted of partial
tumor removal and skull base reconstruction through a large
pterional craniotomy. Despite this, a third surgery (a second
endoscopic transnasal approach was required and included
the use of a vascularized pedicled nasoseptal flap [PNSF]).
This was required a month after the transcranial repair due
to recurrence of CSF leak. The pathophysiology of this
particular leak was further eluded to by having the patient
under general anesthesia and direct CSF opening pressure
measurement during the lumbar puncture. The pressure of
more than 300mm H2O persuaded us to insert a temporary
external lumbar drain (LD). Any attempt of clamping of the
LD for several hours was followed by significant increase
of CSF pressure during the following week leading to the
diagnosis of an obvious intracranial hypertension requiring
the insertion of a permanent shunt. This lead to the resolu-
tion of the CSF leak (Table1).
Literature review
We identified 60 patients with prolactinomas who presented
with DA therapy-induced CSF leak in 35 papers published
between the years of 1980 and 2017 (Table2). There were 18
women, 38 men and in four cases the sex was not reported.
In three cases no clinical details were given. The average
age of the female and male population was 44.1years at the
diagnosis [standard deviation (SD) for women 11.34years,
for men 10.71years]. Bromocriptine (BRC) was the therapy
of choice in 34 patients and CAB in monotherapy was pre-
scribed in 21 patients. In two cases the therapy included both
DAs. The median initial prolactin level was 5460ng/mL
(IQR 15,476.5ng/mL). The median time from initiation of

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the DA treatment to the presence of rhinorrhea was 6weeks
(IQR 16 weeks).
The following summary of CSF leak management con-
cerns only the definitive successful treatment method. Bed
rest was ordered as a treatment in 5 patients. Decreased
dosage and withdrawal of DA solved the CSF leak in one
patient. One patient refused any treatment following unsuc-
cessful effect of the decrease of DA. In the remaining 49
cases, operative management was employed. Direct trans-
nasal (microscopic or endoscopic) approach was deployed
in 38 cases in order to repair the CSF fistula and represented
the most common procedure. Of these, one had a previous
DA withdrawal, 7 had a partial tumor removal at the same
time. Craniotomy with tumor removal was performed in 8
patients. Lumbar CSF diversion helped to resolve the CSF
leak in three cases.
Discussion
Patients with extensive and/or invasive macroprolactinomas
represent a subgroup of patients with less common clinical
features of the disease and with a wider range of compli-
cations during their therapy. There are only a few studies
attempting to figure out what enables macroprolactinomas to
be more invasive and resistant to drug therapy. The behavior
Fig. 1 T1 gadolinium enhanced coronal MRI images of each patient
in our series. First row demonstrates each patient at the time of diag-
nosis, while the second row reveals the respective patients’ images
at the time of CSF rhinorrhea onset. Numbers correspond to patients
depicted in Table1
Table 1 Patients with DA induced CSF leak in our series
PT patient, M man, PRL prolactin, CAB cabergoline, CSF cerebrospinal fluid, TN transnasal, CRAN craniotomy, LP lumboperitoneal, DA dopa-
mine agonist
a Multiple repairs were necessary in two patients in this series due to recurrence of CSF leak
PT Age Sex PRL (ng/mL) DAs Time to CSF leak Site of skull base defect Treatment of CSF leaka
#1 20 M 13,970 CAB (1mg 2×/week) 2months Ethmoid, sphenoid, sella TN + CRAN + TN with LP shunt
#2 40 M 1049 CAB (1mg 2×/week) 2weeks Sella TN
#3 65 M 150 CAB (1mg 2×/week) 5weeks Sella TN with debulking + TN + TN
#4 73 M 5135 CAB (0.5mg/day) 2months Sella TN with debulking
#5 76 M 198 CAB (1mg 2×/week) 2months Sella Stop DA

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Table 2 Literature review of DA induced CSF rhinorrhea
Authors (years) References Age Sex PRL (ng/mL) DAs Time to CSF leak Site of skull base
defect
Treatment of CSF
leaka
Acharya etal.
(2010)
[17] NR F NR CAB (dosage NR) NR NR Decreased DA
Afshar and Thomas
(1982)
[18] 28 F 283 BRC (5mg/day) 1week Sella TN
Barlas etal. (1994) [10] 27 F 9500 BRC (10mg/day) 8days Sella Bed rest + bed rest
46 F 310 BRC (5mg/day) 15days Sella Bed rest + TN
54 M 3100 BRC (15mg/day) 1year Sella Stop DA
Baskin and Wilson
(1982)
[19] 27 F 1920 BRC (5mg/day) 2months Sphenoid Stop DA + CRAN
Beckers etal.
(1992)
[20] 58 M 7335 BRC (dosage NR) NR NR TN with debulking
Bronstein etal.
(1989)
[21] 33 M 1700 BRC (10mg/day) 17months Sella TN
52 F 1110 BRC (5mg/day) 16months Sella TN
Cappabianca etal.
(2001)
[11] 39 M 2000 CAB (0.5mg
3×/w)
2months Sella TN
42 M 40,000 CAB (0.5mg
3x/w)
4months Sphenoid TN
53 M 9715 CAB (0.5mg
2×/w)
4months Sella TN
Castro-Castro etal.
(2011)
[22] 56 M 2327 CAB (0.5mg
2×/w)
13days Ethmoid, sella CRAN with debulk-
ing
Chapin etal. (2010) [23] 58 F 12,190 CAB (0.5mg
2×/w)
1week Ethmoid, sella TN
Chattopadhyay
etal. (2005)
[24] 2 patients, no exact data
Clayton etal.
(1985)
[25] 55 F 32,830 BRC (5–30mg/
day)
17days NR LP shunt
de Lacy etal.
(2009)
[14] 42 M 3720 CAB (0.5mg
2x/w)
10months Sella TN
48 M 6603 CAB (0.5mg
2x/w)
10weeks Sella TN
50 F 18,867 CAB (0.5mg
2x/w)
2months Sella TN
64 M 4716 CAB (0.5mg
2x/w)
10weeks Sella TN
Delgrange etal.
(2009)
[26] 1 patient, no exact data
Elgamal etal.
(2001)
[27] 36 M 11,350 BRC (15 later
30mg/day)
2years Sella TN
Eljamel etal.
(1992)
[28] 52 F 20,660 BRC (10mg/day) 4weeks Sphenoid TN + LP shunt
Hewage etal.
(2000)
[29] 42 M 2783 BRC (5mg 2×/
day)
6days Sphenoid, sella TN
Hildebrandt etal.
(1989)
[30] 28 M 6650 BRC (2.5mg 3×/
day)
6months Sphenoid, sella TN
43 F 2000 BRC (50mg long-
acting)
2weeks Sella CRAN
Holness etal.
(1984)
[31] 38 M 3535 BRC (15mg/day) NR Sella CRAN + CRAN
Jouret and Col
(2009)
[32] 43 M 5460 CAB (0.5mg/w) 3weeks Sella TN
Kok etal. (1985) [33] 47 M 636 BRC (15mg/day) 8months Sella Stop + TN

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Table 2 (continued)
Authors (years) References Age Sex PRL (ng/mL) DAs Time to CSF leak Site of skull base
defect
Treatment of CSF
leaka
Landolt etal.
(1982)
[9] 33 M 24,500 BRC dosage 4months Ethmoid, sella,
sphenoid, clivus
Stop + CRAN
39 M 23,000 BRC (15mg/day) 5months Sphenoid, sella TN
60 M 3120 BRC (15mg/day) 3months Sphenoid, sella,
clivus
CRAN
Leong etal. (2000) [34] 24 M 23,584 CAB (0.5mg 2×/
week)
4weeks Sphenoid, sella CRAN
34 M 23,584 BRC (1.25mg/day) 1week Sphenoid stop + TN
39 M 4481 BRC (5mg/day) 6weeks Sphenoid decreased DA + TN
with debulking
47 F 18,867 BRC (5mg 2×/
day)
4months Sella stop DA + stop DA
52 F 18,867 BRC (5mg 2×/
day)
8weeks Ethmoid CRAN + LP shunt
Little etal. (2013) [35] 31 M 5526 CAB 1months Sphenoid TN
Machicado etal.
(2012)
[15] 27 F 13,214 CAB (0.5mg 2×/
week)
3months Sphenoid TN with debulking
Mankahla etal.
(2017)
[16] 39 M 73,246 CAB (0.5mg/
week)
2weeks Sphenoid TN
Nadesapillai etal.
(2004)
[36] 50 M 2028 BRC (2.5mg/day) 3days Sella TN
Nakajima etal.
(1992)
[37] 55 F 18,000 BRC (5mg/day) 3days NR TN with debulking
Netea-Maier etal.
(2006)
[12] 48 M 1367 CAB (0.5mg 2×/
week)
10days Sphenoid, sella decreased
DA + refused op
57 M 18,396 CAB (0.5mg 3×/
week)
10days NR bed rest
65 M 13,207 CAB (0.5mg/day) 8days Sphenoid TN
Padmanabhuni
etal. (2017)
[38] 48 M 4655 CAB (0.25mg 2×/
week)
1week NR TN with debulking
Pascal-Vigneron
etal. (1993)
[39] 62 M 820 BRC (10mg/day) 5.5months Sphenoid TN with debulking
Russell etal.
(1994)
[40] 34 M 11,075 BRC (2.5mg 3×/
day)
3weeks Sella TN + TN
Shrivastava etal.
(2002)
[41] 31 NR 44,600 BRC (1mg/week) 2months NR TN with debulking
Siegel etal. (1996) [42] 44 F 9780 BRC (2.5mg 2×/
day)
6days Sphenoid, sella TN
Suliman etal.
(2007)
[13] 30 M 4717 BRC 6months NR 2 bed rest, 5 TN
36 M 3160 BRC, then CAB 1week NR
39 M 1845 CAB, then BRC 6weeks NR
43 M 16,981 BRC 1months NR
46 M 378 CAB 3months NR
55 F 2544 CAB 7months NR
57 M 1698 BRC 4years NR
Wilson etal. (1983) [43]32 F > 200 BRC (7.5mg/day) 3weeks Sella CRAN + TN
50 M 454 BRC (7.5mg/day) 6weeks Sphenoid, sella TN + CRAN
Ref reference, M male, F female, PRL prolactin, CAB cabergoline, BRC bromocriptine, d day, w week, CSF cerebrospinal fluid, NR not reported,
y year, m month, DA dopamine agonist, TN transnasal, CRAN craniotomy, LP lumboperitoneal
a Multiple repairs were necessary in some cases of this review due to recurrence of CSF leak

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and the pathogenesis of prolactinomas are still unclear [5,
44–47]. Moreover, the relationship between tumor size and
serum PRL level remains controversial. It has been demon-
strated that the preoperative PRL level does not correlate
with tumor size [48].
Results of our literature review confirm that macroprolac-
tinomas are much more frequent in men than women and the
diagnosis is often delayed [1, 5, 49]. Endocrine symptoms
stay unrecognized or neglected by the patients. Neurologic
complications commonly produce the first signs due to mas-
sive extension into the surrounding structures such as the
optic chiasm, the third ventricle, the cavernous sinus, the
temporal lobes, the sphenoid sinus, the clivus or the cribri-
form plate. The Endocrine Society® recommends DA ther-
apy as a first-line treatment to lower PRL levels, decrease
tumor size, and restore gonadal function for patients har-
boring symptomatic prolactin-secreting adenomas. Similarly
to others, they recommend CAB use in preference to other
DA due its higher efficacy in normalizing PRL levels and
higher frequency of pituitary tumor shrinkage [6, 50, 51].
Its superior affinity for dopamine receptor binding sites may
explain the greater efficacy. CAB is also associated with
better treatment compliance then BRC because of the lower
incidence of unpleasant side effects [52, 53]. Furthermore,
CAB decreases tumor size in 90% of patients as opposed to
BRC which decreases tumor size by approximately 50% in
only two-thirds of patients [54–58]. CAB induced notable
tumor shrinkage even in patients who had partial volume
reduction after quinagolide [59]. As far as prolactinomas are
concerned, they are treated medically without histological
diagnosis.
We agree with the opinion that extensive tumor removal
of giant prolactinoma has significant morbidity and mortal-
ity. The majority of surgical series reported postoperative
persistence of hyperprolactinemia and significant tumor
residue. In addition, resection becomes harder following DA
treatment due to the more fibrotic consistency and tumoral
infiltration of anatomical structures surrounding the sella
turcica. Therefore it should be reserved only for very specific
cases, such as those with acute neurological complications
(sudden visual loss), hemorrhage, drug intolerance or resist-
ance [5, 60–63]. Last, but not least, surgical treatment may
be absolutely necessary when CSF leak occurs spontane-
ously or after tumor shrinkage [64, 65].
A clearcut CSF rhinorrhea is a well-recognized compli-
cation of trauma and pituitary surgery [9, 66]. Similar to
our series, the literature review demonstrates that CSF leak
may be an uncommon but serious adverse effect after the
initiation of medical treatment of prolactinomas with DAs
[10, 11, 28, 31, 35]. This phenomenon was first reported in
1979 [67]. Its onset, often misdiagnosed as allergic rhinitis,
can be early within the first few weeks or later after several
months of treatment. Complications such as meningitis,
pneumocephalus, or intracranial abscess may develop;
untreated, these carry a 25–50% mortality rate [68]. Analy-
sis of fluid for beta-2 transferrin is a well-known, specific
method for detecting the presence of CSF [69].
Development ofCSF rhinorrhea
Skull base invasion (mainly of the sellar floor [70]) is a clas-
sic radiographic finding in macroprolactinomas. Lama etal.
described that the potential for developing a CSF fistula is
established when the arachnoid and/or brain parenchyma
have also been violated. Like others [11, 43, 71, 72], we tend
to “blame” the crucial point to tumor shrinkage following
DA treatment. Volume reduction leads to exposure of the
previously created pathological opening in the skull base
that was plugged by tumor itself until then. Those defects
become unplugged and CSF may find its way “outside” the
skull base and subsequently exit the nostril or trickle into
the pharynx. When subarachnoid layer becomes violated,
tissue penetration into the sella occurs and CSF pulsations
may contribute to the erosion of the dura and the sellar floor.
Increased intracranial pressure (ICP) from any cause may
accelerate the process and subsequently hinder the repair
efforts, commonly requiring permanent shunting [73–75].
Rapid shrinkage of prolactinomas may even cause pitui-
tary apoplexy or traction of the optic chiasm and second-
ary visual deterioration in patients with involvement of the
chiasm [49, 76–78].
Last few decades have brought some explications about
the mechanism being involved in the invasiveness of prol-
actinomas. A direct correlation exists between the extent of
tumor infiltration by macrophages, invasiveness and meta-
static potential [79–81]. Factors affecting growth, survival
of the tumor cells and neoangiogenesis are produced by
tumor-associated macrophages [e.g. matrix metalloprotein-
ases (MMPs)] [82]. A subgroup of macrophages secreting
matrix metalloproteinase 9 (MMP-9) and their abundance
may be associated with invasiveness of prolactinomas [80,
83].
Complex alterations in adhesive cell-to-cell interactions
are other possible mechanisms contributing to tumor cell
invasion. E-cadherin represents one of the key molecules
implicated in this process [84]. Invasive prolactinomas
express a significantly reduced amount of e-cadherin, com-
pared with noninvasive ones [85].
Evan-Rams etal.’s study also revealed that the protease-
activated receptor 1 (PAR1) is emerging as a key protein
in the control of cellular invasiveness and tumor progres-
sion [86]. The invasiveness in a range of human tumors
is related also to the up-regulation of PAR1 expression in
tumor cells [87, 88]. However, it is unknown whether PAR1
is associated with an invasive phenotype causing CSF leak
in prolactinomas, or not [13]. Despite invasive features of

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prolactinomas, mitotic rates and immunohistochemistry for
p53 and MIB-1 (Ki67) are often only minimally increased
[89]. Song etal. showed that a higher Ki-67 index indicates
at least a higher recurrence rate. Conversely, a Ki-67 index
< 3% was predictive of a favourable prognosis [90].
CSF leak management
Table2 demonstrates that discontinuation (or reduction) of
DA therapy leading to a cessation of the leak, presumably
by tumor reexpansion, may represent one treatment option.
Patient No.1 from our series was also treated by temporary
withdrawal of DA. Bedrest alone was used in five cases.
Nevertheless, we advocate transnasal surgical repair as the
treatment of choice in the majority of cases. Prior to surgery,
a high-resolution, multiplanar computed tomography [high-
resolution computed tomography (HRCT)] or magnetic reso-
nance imaging cisternography (MRI cisternography) should
be performed to attempt to localize the bone defect. In agree-
ment with other literature sources [91–93], diagnostic nasal
endoscopy alone or after injection of intrathecal fluorescein
is a useful diagnostic adjunct in our practice. Intrathecal
fluorescein was used at our fifth patient during the second
attempt of CSF leak repair. Endoscopic transnasal closure
of the CSF leak was performed in 34% of patients reviewed
in the literature. Earlier, microscopic transnasal techniques
were used. However, from the mid 1990s Cappabianca etal.
[94] significantly contributed to the endoscopic technique
adoption in Europe. The principles of skull base closure
include filling of the dead space (e.g. with fat), meticulous
multilayer-closure with using a buttress for structural sup-
port (e.g. septal bone or cartilage). The vascularized PNSF
now represents the mainstay for repair of large skull base
defects. Its utility is also proven in cases of repeated CSF
leaks in smaller defects [95–98].
A retrospective study of Adams etal. [99] showed on a
total of 107 patients that a use of temporary external LD in
endoscopic CSF leak repair was not associated with reduced
recurrence rates, regardless of leak etiology. Further, it
resulted in a significant increase in hospital length of stay.
We agree with the statement of other authors [97, 100] who
advocate external LD insertion in settings wherein a high-
flow leak is encountered. LD may be very useful in select
cases when PNFS is also applied. A permanent lumboperito-
neal (LP) or ventriculoperitoneal (VP) shunt should be con-
sidered in patients with underlying intracranial hypertension
resulting in persisting CSF leak despite standard surgical
repairs ([101, 102], and patient No. 1 in our series).
Transcranial supratentorial (craniotomy) approaches are
still appropriate in some complex cases but have been largely
replaced by endoscopic endonasal techniques. Partial tumor
removal may be feasible whether the surgery is performed
via the nose or the cranium.
The review reveals that a temporary suspension of DA
therapy at the time of CSF leak was a common practice in
the past that we also utilized in one case, however nowadays
opposing opinions exist. De Lacy etal. recommend against
discontinuing medical therapy in order to avoid recurrence
of tumor [14].
To our knowledge, only one series in the literature [13]
contained more patients with drug induced CSF leak in
prolactinomas.
Suliman etal. reported a 6.1% CSF leak prevalence in 114
patients with prolactinomas treated with DA. They did not
identify any factors to predict the onset of CSF rhinorrhea.
The results of the review suggest that neither the size of the
tumor nor the initial serum PRL appeared to predict the risk
of CSF rhinorrhea. In 2009 De Lacy at al. reported similar
results [14]. Avoiding high DA doses tends to decrease the
probability for complications, such as CSF rhinorrhea and
tumor apoplexy [24].
Our cases and the review literature show that the thera-
peutic approach is mostly individualized in patients with
drug-induced CSF leak. One has to take into consideration
the tumor location, its relationship with the surrounding
anatomical structures, site of the skull base defect, possible
intracranial hypertension, medical discontinuation and last,
but not least, patient’s preference.
We recommend warning patients with macroprolactino-
mas invading the skull base about the possibility of sponta-
neous, DA therapy-induced CSF leak.
Our experience confirms that an appropriately informed
patient upfront better cooperates when complications occur
and require other therapy.
Conclusion
Dopamine agonist induced shrinkage of prolactinoma is a
well-known phenomenon but, in combination with skull
base erosion, may lead to CSF rhinorrhea. Therefore,
patients with such macroprolactinomas should be warned
of this potential setback.
Once CSF rhinorrhea is diagnosed, prompt treatment of
the leak should be initiated and direct surgical repair appears
to be the most effective method by means of a minimally
invasive endoscopic endonasal technique.
Acknowledgements We thank Jan Kremláček for helpful comments
and Peter Poczos for help with graphical editing.
Funding The authors have received no funding.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflicts of
interest.

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