Full text of DOI:10.1007/BF03343840

J. Endocrinol. Invest. 24: 183-187, 2001
CASE REPORT
Cabergoline-induced CSF rhinorrhea in patients with
macroprolactinoma. Report of three cases
P. Cappabianca*, S. Lodrini**, G. Felisati***, C. Peca*, R. Cozzi****, A. Di Sarno*****,
L.M. Cavallo*, S. Giombini**, and A. Colao*****
*Department of Neurosurgery and *****Department of Clinical and Molecular Endocrinology and
Oncology, “Federico II” University, Naples; **Department of Neurosurgery, Istituto Neurologico
“C. Besta”, Milan; ***Department of Otorhinolaryngology, Istituti Clinici di Perfezionamento, University
of Milan; ****Department of Endocrinology, Ospedale Maggiore “Cà Granda”, Milan, Italy
ABSTRACT. Three cases of cerebrospinal fluid
(CSF) leak, in subjects with an invasive macro-
prolactinoma under treatment with cabergoline
(CAB), are reported. The patients underwent sur-
gical treatment by means of an endoscopic en-
donasal transsphenoidal approach, which al-
lowed removal of the lesion and sealing of the
fistula. Many cases of CSF rhinorrhea are de-
scribed in literature after bromocriptine therapy
in invasive prolactinomas, but only one report
has been recently published of such condition af-
ter CAB treatment. The complication is likely due
to the brisk cessation of the so-called “stopper
effect”, i.e. the tumor mechanically blocking the
CSF leak in spite of its previous erosion of the
skull-base, when CAB induces the macropro-
lactinoma shrinkage. Endoscopic transsphenoidal
surgery offers a safe, minimally invasive and ef-
ficient management of this complication, which
allows to regularly perform the following steps of
the therapeutical strategy against the prolacti-
noma.
(J. Endocrinol. Invest. 24: 183-187, 2001)
©2001, Editrice Kurtis
INTRODUCTION
CASE REPORT
Case 1
Prolactinoma is the most frequent type of secret-
ing pituitary tumor. Pharmacological therapy with
dopamine-agonists, bromocriptine (BRC) once and
cabergoline (CAB) recently, is considered the first
treatment option (1-3). The effect of CAB on tumor
volume, even at low doses, is often impressive and
persistent (4, 5). When the adenoma shows inva-
sive growth, skull- base erosion can occur and cere-
brospinal fluid (CSF) leak can represent the clinical
onset (6-8) or it can follow the pharmacological
treatment (9-15). Three cases of CSF fistula induced
by CAB treatment and their repair by means of a
minimally invasive technique, the endoscopic ap-
proach to the sella (16, 17), are described in this
paper.
A 53-year-old man was admitted to the Department
of Neurosurgery of the “Federico II” University of
Naples in May 1999 with a history of severe head-
ache and impotence of two-year duration. General
physical and neurological examinations were nega-
tive. Serum PRL level was 9715 ng/ml (normal val-
ues, nv, <15 ng/ml). Skull X-rays showed extensive
destruction of the skull-base. Computed tomogra-
phy (CT) scan revealed an invasive tumor extending
from the clivus to the ethmoid sinus. Sellar magnet-
ic resonance imaging (MRI) showed a non-homoge-
neous mass in the sellar region with suprasellar, im-
phrasellar and bilateral, parasellar involvement, infil-
trating the clivus. No visual field defect nor involve-
ment of vision was present. He received CAB treat-
ment (0.5 mg twice a week) and was discharged un-
der close scheduled clinical, ophthalmological and
radiological controls. CAB treatment induced stable
normoprolactinemia (2.8 ng/ml) and initial tumor
shrinkage, as assessed by MRI, performed after one
and three months. Four months later the patient de-
veloped a CSF rhinorrhea. Brain and sellar MRI con-
Key-words: Cabergoline, CSF rhinorrhea, endoscopy, pituitary adenoma,
prolactinoma, transsphenoidal surgery.
Correspondence: Dr. Paolo Cappabianca, Departimento di Neuro-
chirurgia, Università “Federico II”, Via Pansini 5, 80131 Naples, Italy.
E-mail: cappabia@unina.it
Accepted July 28, 2000.
183

P. Cappabianca, S. Lodrini, G. Felisati, et al.
firmed tumor shrinkage, mainly of the suprasellar part
of the lesion.
Surgery was performed by means of an endoscop-
ic transsphenoidal approach to the pituitary, which
allowed to make a biopsy of the tumor of fibrous
consistency, to obliterate the fistula and to seal the
pituitary fossa.
Rhinorrhea ceased immediately. At 30-month fol-
low-up the patient is doing well, he is under
dopaminergic medication (CAB) twice a week and
the tumor has furtherly reduced.
Surgical treatment was performed by means of an
endoscopic transsphenoidal approach, which allowed
removal of the tumor, identification of the CSF leak
and a water-tight repair of the sella. Postoperative
course was uneventful, CSF leak ceased. Control MRI
performed 6 months later confirmed the lesion re-
moval and the adequate sellar reconstruction.
The patient is still under CAB treatment (0.5 mg
twice weekly) and prolactin levels are suppressed
(0.86 ng/ml).
Case 3
A 39-year-old male was submitted to CT scan for a
persistent tinnitus and a huge mass of the sellar and
juxta-sellar region was discovered. MRI imaging
confirmed the presence of a midline mass destroy-
ing the sella, reaching upwards to the third ventri-
cle, downwards to the clivus, the right condiloid
process and the epipharinx, forwards to the poste-
rior ethmoid cells and the sphenoid sinus and lat-
erally both the cavernous sinuses. The lesion pre-
sented small hyperproteic and hemorragic areas
and assumed gadolinium non homogeneously (Fig.
1 A and B). Endocrine investigations showed hy-
perprolactinemia (2000 ng/ml) and hypothyroid-hy-
pogonadic features. The patient was put on CAB
(0.5 mg three days a week) with a fall of the PRL be-
low 100 ng/ml in about 2 months. Control MRI
scans revealed a dramatic decrease of tumor vol-
ume, with the sella, the sphenoid and the ethmoid
sinus free of tumor and the development of a sec-
ondary “empty sella” (Fig. 2 A and B). A few days
after this imaging control, profuse CSF rhinorrea
presented, without no neurological and/or oph-
thalmological sign on admission at the Neuro-
surgical Department of the “Carlo Besta” Neuro-
logical Institute of Milan.
Case 2
A 42-year-old male experienced a rapid decrease
of his visual function in September 1997: the oph-
thalmological examination disclosed a bilateral de-
crease of visual acuity (5/10) and a bitemporal
hemianopia. CT and MRI scans showed a huge
neoplasm arising from the sellar region, destroy-
ing the clivus and invading the suprasellar cisterns,
the right temporal fossa and both the cavernous si-
nuses. Endocrine investigations revealed a marked
hyperprolactinemia (about 40.000 ng/ml). CAB
therapy was immediately started at high dosage
(0.5 mg 6 days a week), with a rapid fall of serum
PRL levels to 100 ng/ml. The visual field defect dis-
appeared in three weeks. Two months later a con-
trol MRI of the sellar region showed a marked de-
crease in the volume of the macroprolactinoma;
CAB dosage was then reduced to 0.5 mg three
days a week. In December 1997 the patient noted
a profuse rhinorrhea. Neurological and ophthal-
mological examination, on admission at the Neuro-
surgical Department of the “Carlo Besta” Neuro-
logical Institute of Milan were normal. A CT cis-
ternography showed an arachnoid diverticulum in
the sphenoid sinus.
Surgical treatment, performed by means of an en-
doscopic transsphenoidal approach, permitted tis-
Fig. 1 - A: Post-contrast coronal T1 mag-
netic resonance imaging (MRI). A large
macroadenoma with an intense contrast
enhancement and a central necrotic area.
The lesion involves both the cavernous si-
nus (mainly the left) and presents a
suprasellar portion with marked com-
pression of the chiasm. B: Pre-contrast
sagittal T1 MRI. The same lesion reveal-
ing an antero-superior hemorragic com-
ponent, multiple central necrotic areas
and an upward displacement of the optic
chiasm.
A
B
184

Cabergoline and CSF rhinorrhea
Fig. 2 - A: Post-contrast coronal T1 MRI
after cabergoline treatment. Dramatic
shrinkage of the lesion, with secondary
empty sella; the optic nerves are well
recognizable. B: Post-contrast sagittal
T1 MRI. Secondary empty sella.
A
B
DISCUSSION
sue sampling for histology and closure of the CSF
passage. CSF rhinorrhea ceased, and the post-op-
erative course was uneventful. The patient is still
taking CAB medication (0.5 mg twice a week) and
PRL levels have decreased to 50 ng/ml.
A comprehensive view of the patients’ endocrino-
logical parameters is reported in Table 1.
The “pure” endoscopic transsphenoidal procedure
is carried out without the use of a nasal speculum,
with a diagnostic endoscope used as the unique vi-
sualizing tool. The operation starts with the enlarge-
ment of the sphenoid ostium, avoiding any trauma
to the nasal structures previously met and is per-
formed under a wide view of the sphenoid sinus, of
the sella and of the supra- and parasellar structures,
just progressively pushing the endoscope “inside the
anatomy”. The visualization is excellent, the possibil-
ity of tumor removal is safer and very accurate, the
surgical trauma is almost negligible, no nasal pack-
ing is employed at the end of the operation. The ear-
ly discharge of the patient from the hospital is almost
the rule.
CSF leakage is a potential complication of surgical
and/or conservative management of invasive pro-
lactinomas, sometimes constituting a clinical pre-
sentation of an invasive macroadenoma (6-8, 18-
20), due to its supra- and parasellar development.
We reported three cases of invasive PRL-secreting
pituitary macroadenomas that presented a CSF rhi-
norrhea after medical therapy with CAB. A similar
finding has been recently published (21).
This uncommon complication has also been ob-
served after BRC therapy (9-15), likely caused by
the cessation of the so-called “stopper effect” ex-
erted by the tumor that functions as a “blocker” of
CSF leak (7, 22): the marked shrinkage of the ade-
noma allows the CSF pulsation to act on a sphe-
noid bone and a dura mater already thinned and
eroded by the tumor growth.
For over 20 years BRC has been the standard drug
for prolactinomas, because not only does it inhibit
PRL synthesis and secretion, with normalization of
serum PRL levels in about 80% of cases, but also
Table 1 - Comprehensive view of the patients’ endocrinological parameters.
Case no.
Sex
Age
PRL at diagnosis
(ng/ml)
CAB dose
Period of
treatment
Pre-operative
PRL (ng/ml)
Post-operative
PRL
1
2
M
53
9715
0.5 mg two
days a week
4 months
2.8
Suppression
M
42
40.000
0.5 mg six
days a week
0.5 mg three
days a week
2 months
2 months
100
-
Normalization
50 ng/ml
3
M
39
2000
0.5 mg three
days a week
2 months
100
185

P. Cappabianca, S. Lodrini, G. Felisati, et al.
reduces tumor growth, with tumor shrinkage in
about 75% of cases. However, a subset of patients
(about 20-30%) does not respond satisfactorily to
BRC because of resistance or intolerance (23).
Recently CAB, a selective D2 agonist, became avail-
able. It has the advantage of being administered
at lower doses than BRC, because of its relatively
longer half-life, and does not present relevant side-
effects. It induces stable normoprolactinemia in
83%, and tumor shrinkage in 67-82.3% of the pa-
tients, with disappearance of the tumor mass in
26.1-36.4% in different series (4, 23-27). CAB thus
represents the first line therapy in macroprolacti-
noma-bearing patients, also in those not previous-
ly treated with other dopamine-agonists.
When a CSF fistula appears in the course of the
medical treatment of an invasive macroprolactino-
ma, it is necessary to remove the tumor, if possi-
ble, and to seal the CSF passage way, in order to
stop the rhinorrhea and to permit further adminis-
tration of the CAB medication.
Traditional microscopic transsphenoidal surgery
has been commonly employed for such purpose
over the last decades. The endoscopic closure of
CSF leaks has been advocated by the otolaryngol-
ogists, promoters of functional endoscopic sinus
surgery (FESS) (28), and was used for the first time
in 1981 by Wigand (29). The surgical option that
was used in the present report has been employed
by our groups since 1997 and is the endoscopic
endonasal transsphenoidal approach to the sella
(17). It represents a minimally invasive procedure,
which allows an almost non-traumatic and safe
management of the surgical field, with a very wide
vision of all the surroundings, by means of the
movement of the endoscope at various angles to
explore the cavity. This results in a very deep in-
sight of a distorted anatomy, such as the one faced
in these invasive macroadenomas, with a more re-
liable inspection of the tumor, of the CSF passage
and of the whole surgical area, as compared to the
microscopic procedure, with less operative trauma
(30).
These three cases show that CAB therapy in macro-
prolactinomas is not totally risk-free and has to be
performed under close control in selected centers,
with a multidisciplinary involvement. The probabil-
ity of a CSF rhinorrhea, even if remote, has to be
carefully considered, and the patients should be in-
formed about the possible occurrence of such a
complication. Whether CSF rhinorrhea is similar,
more or less frequent in CAB-treated than in BRC-
treated patients cannot be presently ruled out, due
to the rarity of this complication. Theoretically, the
early and potent shrinking effect of CAB might fa-
cilitate the onset of such complication. Moreover,
only one similar case is now available (21).
The impressive effect of reduction of the lesion un-
der CAB treatment in our cases and the successful
resolution of the CSF leak complication by means of
the endoscopic transsphenoidal approach confirm
and point out the strategy to adopt in this condi-
tion, that is transsphenoidal surgery, followed by
the specific pharmacological treatment.
ACKNOWLEDGMENTS
The authors want to thank Prof. Enrico de Divitiis, Chief of the
Department of Neurosurgery of “Federico II” University of
Naples and Prof. Gaetano Lombardi, Chief of the Department of
Endocrinology of “Federico II” University of Naples, for their
suggestions.
REFERENCES
1. Colao A., Annunziato L., Lombardi G.
Treatment of prolactinomas.
Ann. Med. 1998, 30: 452-459.
2. Webster J., Piscitelli G., Polli A., Ferrari C.I., Ismail I.,
Scanlon M.F.
A comparison of cabergoline and bromocriptine in
the treatment of hyperprolactinemic amenorrhea.
N. Engl. J. Med. 1994, 331: 904-909.
3. Molitch M.E.
Medical treatment of prolactinomas.
Endocrinol. Metab. Clin. North Am. 1999, 28: 143-169.
4. Colao A., Di Sarno A., Landi M.L., Cirillo S.,
Sarnacchiaro F., Facciolli G., Pivonello R., Cataldi
M., Merola B., Annunziato L., Lombardi G.
Long-term and low-dose treatment with cabergo-
line induces macroprolactinoma shrinkage.
J. Clin. Endocrinol. Metab. 1997, 82: 3574-3579.
5. Ferrari C.I., Abs R., Bevan J.S., Brabant G., Ciccarelli
E., Motta T., Mucci M., Muratori M., Musatti L.,
Verbessem G., Scanlon M.F.
Treatment of macroprolactinoma with cabergoline:
a study of 85 patients.
Clin. Endocrinol. (Oxf.) 1997, 46: 409-413.
6. Carroll W.R., Cohen S., Sullivan M.J.
Spontaneous CSF rhinorrhea: an unusual presenta-
tion of a pituitary adenoma.
Otolaryngol. Head Neck Surg. 1991, 104: 380-383.
7. Obana W.G., Hodes J.E., Weinstein P.R., Wilson C.B.
Cerebrospinal fluid rhinorrhea in patients with un-
treated pituitary adenoma: report of two cases.
Surg. Neurol. 1990, 33: 336-340.
8. Spaziante R., Corriero G., Cappabianca P., Russo A.,
Donzelli R., Irace C., Carrabs G.
Rinoliquorrea rivelatrice di un adenoma ipofisario
invasivo associato ad empty sella. Caso clinico.
Quad. Med. Chir. 1987, 3: 1-6.
186

Cabergoline and CSF rhinorrhea
9. Aronoff S.L., Daughaday W.H., Laws E.R. Jr.
Bromocriptine treatment of prolactinomas.
N. Engl. J. Med. 1979, 300: 1391 (letter).
10. Barlas O., Bayindir C., Hepgul K., Can M., Kiris T.,
Sencer E., Unal F., Aral F.
21. Leong K.S., Foy P.M., Swift A.C., Atkin S.L., Hadden
D.R., MacFarlane I.A.
CSF rhinorrhoea following treatment with dopamine
agonists for massive invasive prolactinomas.
Clin. Endocrinol. (Oxf.) 2000, 52: 43-49.
22. Fager C.A.
Bromocriptine-induced cerebrospinal fluid fistula in
patients with macroprolactinomas: report of three
cases and a review of the literature.
Nature and treatment of cerebrospinal fluid rhinor-
rhea in pituitary tumors.
Surg. Clin. North Am. 1973, 53: 283-290.
Surg. Neurol. 1994, 41: 486-489.
23. Pellegrini I., Rasolonjanahary R., Gunz G., Bertrand
P., Delivet S., Jedynak C.P., Kordon C., Peillon F.,
Jaquet P., Enjalbert A.
Resistance to bromocriptine in prolactinomas.
J. Clin. Endocrinol. Metab. 1989, 69: 500-509.
24. Ciccarelli E., Grottoli S., Razzore P., Gaia D.,
Bertagna A., Cirillo S., Cammarota T., Camanni M.,
Camanni F.
11. Baskin D.S., Wilson C.B.
CSF rhinorrhea after bromocriptine for prolacti-
noma.
N. Engl. J. Med. 1982, 306: 178.
12. Bronstein M.D., Musolino N.R., Benabou S.,
Marino R.
Cerebropinal fluid rhinorrhea occurring in long-
term bromocriptine treatment for macroprolacti-
nomas.
Long-term treatment with cabergoline, a new long-
lasting ergoline derivative in idiopathic or tumorous
hyperprolactinemia and outcome of drug-induced
pregnancy.
Surg. Neurol. 1989, 32: 346-349.
13. Hildebrandt G., Zierski J., Christophis P., Laun A.,
Schatz H., Lancranjan I., Klug N.
J. Endocrinol. Invest. 1997, 20: 547-551.
Rhinorrhea following dopamine agonist therapy of
invasive macroprolactinoma.
Acta Neurochir. (Wien) 1989, 96: 107-113.
25. Colao A., Di Sarno A., Landi M.L., Scavuzzo F.,
Cappabianca P., Pivonello R., Volpe R., Di Salle F.,
Cirillo S., Annunziato L., Lombardi G.
14. Holness R.O., Shlossberg A.H., Heffernan L.P.
Cerebrospinal fluid rhinorrhea caused by bromocrip-
tine therapy of prolactinoma.
Neurology 1984, 34: 111-113.
15. Pascal-Vigneron V., Weryha G., Braun M., Morel-
Jean J., Bisset S., Leclère J.
Macroprolactinoma shrinkage during cabergoline
treatment is greater in naive patients than in patients
pre-treated with other dopamine agonists: a prospec-
tive study in 110 patients.
J. Clin. Endocrinol. Metab. 2000, 85: 2247-2252.
26. Colao A., Di Sarno A., Sarnacchiaro F., Ferone D.,
Di Renzo G., Merola B., Annunziato L., Lombardi G.
Prolactinomas resistant to other dopamine agonists
respond to chronic cabergoline treatment.
La rhinorrhée et l’otorrhée: des complications rares
du traitement médical del prolactinomes invasifs.
Ann. Endocrinol. (Paris) 1993, 54: 347-351.
16. Jho H.D., Carrau R.
J. Clin. Endocrinol. Metab. 1997, 83: 876-883.
Endoscopic endonasal transsphenoidal surgery: ex-
perience with 50 patients.
27. Verhelst J., Abs R., Maiter D., van den Bruel A.,
Vandeweghe M., Velkeniers B., Mockel J., Lamberigts
G., Petrossians P., Coremans P., Mahler C., Stevenaert
A., Verlooy J., Raftopoulos C., Beckers A.
J. Neurosurg. 1997, 87: 44-51.
17. Cappabianca P., Alfieri A., de Divitiis E.
Endoscopic endonasal transsphenoidal approach to
the sella: towards functional endoscopic pituitary
surgery (FEPS).
Cabergoline in the treatment of hyperprolactinemia:
a study in 455 patients.
J. Clin. Endocrinol. Metab. 1999, 84: 2518-2522.
Min. Invas. Neurosurg. 1998, 41: 66-73.
28. Kennedy D.W.
18. Rothrock J.F., Laguna J.F., Reynolds A.F.
Rhinorrhea from untreated pituitary adenoma.
Arch. Neurol. 1982, 39: 442-443.
19. Nutkiewicz A., De Feo D.R., Kohut R.I., Fierstien S.
Cerebrospinal fluid rhinorrhea as a presentation of
pituitary adenoma.
Functional endoscopic sinus surgery. Technique.
Arch. Otolaryngol. 1985, 111: 643-649.
29. Wigand M.E.
Transnasal ethmoidectomy under endoscopic control.
Rhinology 1981, 19: 7-15.
30. Cappabianca P., Alfireri A., Colao A., Ferone D.,
Lombardi G., de Divitiis E.
Neurosurgery 1980, 6: 195-197.
20. Spaziante R., de Divitiis E.
Endoscopic endonasal transsphenoidal approach:
an additional reason in support of surgery in the
management of pituitary lesions.
Cerebrospinal fluid rhinorrhea in patients with un-
treated pituitary adenomas.
Surg. Neurol. 1991, 36: 150-151.
Skull Base Surg. 1999, 9: 109-117.
187