CSF RHINORRHEA: AN EARLY COMPLICATION OF DOPAMINE-SENSITIVE MACROPROLACTINOMA

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1 Case Report CSF RHINORRHEA: AN EARLY COMPLICATION OF DOPAMINE-SENSITIVE MACROPROLACTINOMA Amitha Padmanabhuni, MD 1 ; Rachel Hopkins, MD 1 ; Lawrence Chin, MD 2 ; Ruban Dhaliwal, MD, MPH 1 ABSTRACT Objective: Cerebral spinal fluid (CSF) leak is a known surgical complication of invasive macroprolactinomas. Case reports suggest this complication can occur with dopamine agonist treatment alone. Methods: We present clinical features, imaging, and biochemical characteristics of one such case of an invasive macroprolactinoma complicated with early CSF leak. Results: A 35-year-old obese male presented with weight gain of over 100 pounds within the last year and absent morning tumescence. Laboratory evaluation was notable for elevated total prolactin (PRL) (4,655 ng/ml) and low total testosterone (24 ng/dl). Magnetic resonance imaging (MRI) revealed a large pituitary adenoma ( cm) extending into the cavernous and sphenoid sinuses, partially eroding the sphenoid bone. Dopamine agonist, cabergoline 250 µg twice/week was started. After two doses, the patient developed CSF rhinorrhea and was hospitalized. Adenoma was smaller in size ( cm), and total PRL declined to 824 ng/ml. An endoscopic subtotal resection of adenoma with CSF leak repair was performed. Treatment with cabergoline was continued, resulting in complete resolution of CSF leak within a few Submitted for publication June 20, 2016 Accepted for publication October 19, 2016 From the 1 Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, and 2 Department of Neurosurgery, SUNY Upstate Medical University, Syracuse, New York. Address correspondence to Dr. Ruban Dhaliwal, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY dhaliwar@upstate.edu DOI: /EP CR To purchase reprints of this article, please visit: See accompanying article, p days. Two months later, cabergoline dose was increased to 500 µg twice a week as adenoma size remained unchanged. One month later, MRI showed regression of the pituitary tumor with cystic changes. Serum PRL level substantially declined (total PRL, 102 ng/ml). Conclusion: Clinicians should be highly observant of and educate patients about CSF rhinorrhea as potential early consequence of medical therapy of macroprolactinoma to avoid misdiagnosis and fatal sequelae of this complication. (AACE Clinical Case Rep. 2017;3:e294-e298) Abbreviations: CSF = cerebral spinal fluid; DA = dopamine agonist; MRI = magnetic resonance imaging; PRL = prolactin INTRODUCTION Prolactinomas are the most common secretory pituitary tumors (~50%). More than 90% of prolactinomas are microprolactinomas (<1.0 cm size), and only 10% are macroprolactinomas ( 1.0 cm) (1,2). Prolactinomas occur more frequently in women (>70%), mostly in the form of microprolactinoma (female to male ratio, 20:1) (1,3). On the contrary, macroprolactinomas are common in men. The larger tumor size in men presumably results from a diagnostic delay, as menstrual abnormalities are often the presenting symptom in women, thus prompting more timely evaluation. Gender-specific differences in tumor biology may play a role, but this remains unclear (4). Most (~60%) adult men with macroprolactinomas are diagnosed before the age of 40 years, mainly in the fourth decade of life (1). Clinical manifestations at diagnosis in men with macroprolactinoma include visual disturbances and headaches (symptoms related to the compressive effect of tumor). The majority of men with microprolactinomas (~80%) present with symptoms of hypogonadism (5). e294 AACE CLINICAL CASE REPORTS Vol 3 No. 4 Autumn 2017

2 CSF Rhinorrhea in Prolactinoma, AACE Clinical Case Rep. 2017;3(No. 4) e295 Cerebral spinal fluid (CSF) leak is a known complication of invasive macroprolactinoma. It commonly follows surgical manipulation; however, it can also occur with dopamine agonist treatment. Here, we describe a patient with an invasive macroprolactinoma complicated with an early CSF leak within a week of starting low-dose cabergoline and followed by complete regression of the tumor. CASE REPORT A 35-year-old obese male with no significant past medical history presented with weight gain over 100 pounds within the last 1 year. Further history revealed absent morning tumescence for the last 2 years. Physical exam was unremarkable except for obesity and small testicular size (~6 cc). Biochemical evaluation was consistent with the diagnoses of prolactinoma (monomeric prolactin [PRL], 1,719 ng/ml; total PRL, 4,655 ng/ml) and hypogonadotropic hypogonadism (total testosterone, 24 ng/ml, measured by liquid chromatography/mass spectrometry) (Table 1). Patient had no symptoms of diabetes insipidus. Magnetic resonance imaging (MRI) of the brain showed pituitary macroadenoma size cm occupying the pituitary fossa extending into bilateral cavernous sinus and sphenoid sinus (partially eroding the sphenoid bone), posteriorly to the superior portion of clivus, anteriorly to midportion of planum sphenoidale, enveloping bilateral internal carotid artery and abutting the right optic nerve (Fig. 1). Formal testing showed no visual field deficit. Following neurosurgical evaluation, cabergoline 250 µg twice a week was started. After two doses of cabergoline, the patient developed CSF rhinorrhea. Due to the continuous nature and the amount of rhinorrhea, the patient was hospitalized. Computed tomography maxillofacial/ sella showed a heterogeneous multilobulated pituitary fossa mass with bony remodeling of the clivus, focal destruction of the sella, and anterior extension to the sphenoid sinus. Additionally, the mass encased bilateral intracranial internal carotid arteries, and bony erosive changes involved the precavernous segment of left carotid canal. Serum mono- Baseline 8/2014 Table 1 Changes in Important Parameters With Treatment Pre-op (1 week on DA) 9/2014 Post-op (3 weeks on DA) 9/ months on DA 11/ months on DA 12/ months on hcg 07/ months on T 10/ months on T 03/2016 Weight (kg) BMI (kg/m 2 ) Total PRL ( ng/ml) Monomeric PRL ( ng/ml) Total T (300-1,080 ng/dl) Free T ( pg/ml) SHBG (11-80 nmol/l) LH ( mu/ml) FSH ( mu/ml) Estradiol ( pg/ml) ACTH (7-69 pg/ml) Cortisol ( µg/dl) IGF-1 ( ng/ml) TSH ( IU/mL) Free thyroxine ( ng/dl) 4, , < < , <0.5 < < Abbreviations: ACTH = adrenocorticotropic hormone; BMI = body mass index; DA = dopamine agonist (cabergoline); FSH = follicle-stimulating hormone; hcg = human chorionic gonadotropin; IGF-1 = insulin-like growth factor 1; LH = luteinizing hormone; PRL = prolactin; SHBG = sex hormone binding globulin; T = testosterone; TSH = thyroid-stimulating hormone. Normal ranges shown in parentheses.

3 e296 CSF Rhinorrhea in Prolactinoma, AACE Clinical Case Rep. 2017;3(No. 4) A Fig. 1. Magnetic resonance imaging brain on initial evaluation. The lesion is irregular, heterogeneous. The normal pituitary gland is not distinguishable from the lesion. A) Sagittal view, T1 postcontrast showing macroprolactinoma. B) Axial view, T2 images showing bone destruction and adenoma encasing bilateral internal carotid arteries. meric PRL and total PRL levels were 612 and 824 ng/ ml, respectively. Patient underwent endoscopic CSF leak repair. As the tumor was deemed not amenable to resection, minimal debulking was performed. Postoperative MRI with dedicated pituitary protocol done on the same day of surgery still showed a large pituitary tumor, size cm (Fig. 2 A). Cabergoline was continued as initially recommended. CSF leak decreased in the immediate postoperative period, with intermittent mild re-occurrence associated with positional changes over the next few weeks. Histologic findings confirmed the tumor as pituitary adenoma, immunoreactive for PRL (Ki-67, 2 to 4%). Follow-Up Laboratory data after 2 months on 250 µg cabergoline twice/week showed monomeric PRL of 323 ng/ml and A B Fig. 2. Postoperative magnetic resonance imaging (MRI) pituitary. A) Persistent macroprolactinoma on T1 images postcontrast on the immediate postoperative MRI. B) Regression of the tumor and cystic changes on T1 images postcontrast 3 months post-cabergoline. B total PRL of 370 ng/ml. MRI pituitary revealed persistent tumor, size cm. Cabergoline dose was increased to 500 µg twice/week. One month later, MRI showed no discrete mass within the pituitary gland and regression of the extensive tumor, with cystic changes (Fig. 2 B). CSF rhinorrhea completely resolved. Concurrently, monomeric PRL decreased to 90 ng/ml, with a total PRL of 102 ng/ml. Free testosterone level remained very low, at 2 pg/ ml (normal, 8.7 to 25.1 pg/ml), despite near-normal PRL levels. Semen analysis showed azoospermia. Testosterone levels did not respond to human chorionic gonadotropin given over the next 3.5 months (maximum dose, 5,000 units 3 times/week for 2.5 months) (Table 1). Subsequently, testosterone replacement was started, with resultant testosterone level of 321 ng/ml. Two months following testosterone therapy, PRL level mildly increased (51 ng/ml), requiring an increase in cabergoline dose to 1.25 mg weekly (Fig. 3). Follow-up total PRL levels remained in the normal range (2.0 to 18.0 ng/ml), and no further changes were noted in the MRI appearance of the pituitary. DISCUSSION Most prolactinomas are managed medically. Dopamine agonists (DAs) are the first-line treatment, even if the prolactinoma is large and invasive. Cabergoline, an ergot derivative, is a frequently used DA. It is more potent, longer acting, and better tolerated than bromocriptine. Side effects are dose-dependent and commonly include paresthesia and gastrointestinal intolerance. Data suggest that men have more aggressive prolactinomas than women, explaining the lower responsiveness to pharmacotherapy in men (6,7). Cabergoline therapy has been reported to achieve normalization of serum PRL and gonadal function and reduction of tumor volume in more than 50% of patients with macroprolactinomas (5). In a prospective study, PRL levels decreased progressively with cabergoline in both macro- and microprolactinomas (6). At the 24-month follow-up, PRL levels normalized in most macroprolactinomas (75.6%) and microprolactinomas (80%) with cabergoline dose of 1 to 1.5 mg/week. Tumor diameter declined by more than 30% in the maximal diameter in all macroprolactinomas and most microprolactinomas. Surgery for macroprolactinomas usually results in significant tumor debulking, often without normalization of PRL (8). In a study of 92 patients, majority with invasive macroprolactinomas, debulking resulted in PRL normalization and tumor regression in 28 and 19% of the patients, respectively (9). One-third of those treated by combined surgical approach and DA achieved normal PRL and/or complete tumor shrinkage. In another study, no postsurgical remission was observed in patients with invasive macroprolactinoma (10). Only 10% of patients who underwent surgery for an acute complication achieved normal PRL.

4 CSF Rhinorrhea in Prolactinoma, AACE Clinical Case Rep. 2017;3(No. 4) e297 Fig. 3. Changes in serum prolactin. CSF = cerebral spinal fluid. In patients harboring macroprolactinomas, damage frequently occurs in the gonadotrophic axis (73 to 86%). The two presumed causes are: mechanical compression of the gonadotroph cells from the large mass and the inhibitory effect of PRL on gonadotropins (11). While recovery of the gonadotrophic axis has been reported after 6 months of treatment in the majority of patients (both in microprolactinomas and in macroprolactinomas) (6), our experience in this case was not such. In our patient, on cabergoline therapy for approximately 1 year, no improvement was seen in testosterone level, despite near normalization of PRL, rendering the possibility that the damage to the gonadotrophic axis was primarily due to mechanical compression from the tumor. Following testosterone replacement, cabergoline dose had to be increased to maintain PRL in normal range. The Endocrine Society recommends repeat MRI in patients with macroprolactinoma 3 months after starting DA (12). In our patient, MRI was obtained frequently to evaluate mild intermittent CSF leak that continued a few weeks postoperatively. CSF leak is a life-threatening complication associated with a high risk of ascending meningitis. The postulated mechanism of CSF rhinorrhea in this setting is that large and invasive pituitary adenomas frequently invade the sellar floor and infrasellar space and potentially develop a CSF fistula. Any substantial reduction in tumor size leading to unplugging of the eroded area of the skull base can result in CSF leak (13), sometimes referred to as brisk loss of stopper effect (14). CSF rhinorrhea may represent the initial presentation of the prolactinoma or it can follow the pharmacologic treatment. Men have a higher incidence of invasive macroadenomas and complications of nonsurgical rhinorrhea (7,15). There are case reports since 1984 of DA-induced CSF rhinorrhea (16), some indicating its occurrence as early as within the first few weeks after starting DAs to as late as several months into treatment (3,17). Neither clinical, biochemical (baseline PRL levels, rate of PRL decline in response to DA), or imaging characteristics (invasiveness and tumor volume at diagnosis) are helpful in predicting CSF rhinorrhea (15). Literature suggests that cabergoline treatment over 1 year can result in cystic transformation of invasive prolactinoma with tumor shrinkage (18). DA resistance is more frequent in macroprolactinoma with rhinorrhea than those without rhinorrhea (15). In our patient, CSF rhinorrhea occurred after two doses of cabergoline, even though it was the lowest dose (250 µg twice/week). One hypothesis is that increase in intracranial pressure due to patient s significant weight gain (as in pseudotumor cerebri) likely contributed to the early spontaneous CSF leak. Weight loss is often recommended to prevent failure of CSF leak repair (19). This was achieved after testosterone replacement in our patient. Contrary to what the literature suggests, the invasive pituitary tumor in our patient with CSF rhinorrhea was DA sensitive, and lowdose cabergoline was sufficient to achieve recession and cystic changes in a short period of 3 months. CONCLUSION Clinicians should be highly observant of and must educate patients about CSF rhinorrhea as a potential early consequence of medical therapy of macroprolactinoma, even on a low-dose DA, to avoid misdiagnosis and fatal sequelae of this complication. DISCLOSURE The authors have no multiplicity of interest to disclose. REFERENCES 1. Iglesias P, Díez JJ. Macroprolactinoma: a diagnostic and therapeutic update. QJM. 2013;106: Fernandez A, Karavitaki N, Wass JA. Prevalence of pituitary adenomas: a community-based, cross-sectional study in Banbury (Oxfordshire, UK). 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