Raloxifene

Raloxifene

Raloxifene, sold under the brand name Evista among others, is a medication which is used in the prevention and treatment of osteoporosis in postmenopausal women and to reduce the risk of breast cancer in postmenopausal women with osteoporosis or at high risk for breast cancer. It is taken by mouth.


Choudhary et al., evaluated the effect of raloxifene on prolactin levels in addition to dopamine agonist (DA) therapy in patients with prolactinoma.

They conducted a retrospective chart review of 14 patients with prolactinoma on stable dose of DA for 6 months who received raloxifene 60 mg daily as Prolactin (PRL) could not be normalized despite being on fairly high doses of DA. Patients were informed that raloxifene is not FDAapproved for prolactinoma treatment. Prolactin level was measured at 1-6 months after starting raloxifene and at 1-3 months following its discontinuation. Raloxifene was stopped in 8 out of 14 after 2 (1-6) months of treatment as the absolute change in prolactin level was felt to be small. Results The median age and female/male sex ratios were 50 years (range 18-63), 6/8 respectively. The baseline DA dose was 3 mg/week (0.5-7) for cabergoline and 15 mg/day for bromocriptine. 10 patients had an absolute and percentage decrease in prolactin of 8.3 ng/ml (1.5-54.2), and 25.9% (8-55%) from baseline after 1-6 months on raloxifene treatment, respectively. Among 10 patients with a decrease in prolactin level, 2 (20%) achieved prolactin normalization. Two patients had no change in prolactin and two patients had an increase in prolactin level by 22.8 ng/ml and 8.8 ng/ml (47% and 23.6%) respectively.

Raloxifene was associated with 25.9% (8-55%) decrease in prolactin levels in 10/14 (71%) of patients with prolactinoma who were on stable doses of DA including two patients (14%) who achieved normoprolactinemia 1).


Hannen et al., analyzed the effects of fulvestrant and three Selective estrogen receptor modulators (SERMs), bazedoxifene, clomifene, and raloxifene, on pituitary adenomas cell lines AtT20, TtT/GF, and GH3. In cell survival assays, clomifene was shown to be the most potent compound in all three cell lines with IC50 values ranging between 2, 6, and 10 μM, respectively, depending on the cell type. Raloxifene and bazedoxifene were also effective but to a lower extent. Also, all SERMs affected migratory and invasive behavior of pituitary adenoma cells. Mechanistically, treatment of cells with SERMs caused cell apoptosis, as demonstrated by Caspase 3/7 activity and western blot assays. In addition, western blots demonstrate activation of p53 in TtT/GF cells and loss of ERK1/2 activation in AtT20 cells. In contrast, fulvestrant was only effective in GH3 cells. Thus, the general applicability of SERMs for pituitary adenoma cells might be promising in clinical applications for the treatment of pituitary adenomas 2).


The aim of a study was to investigate the ability of a SERM, RLX, to prevent vasospasm in a rabbit model of SAH.

Thirty-four New Zealand white rabbits were allocated into 3 groups randomly. Subarachnoid hemorrhage was induced by injecting autologous blood into the cisterna magna. The treatment groups were as follows: (1) sham operated (no SAH [n = 12]), (2) SAH only (n = 12), and (3) SAH plus RLX (n = 10). Basilar artery lumen areas and arterial wall thickness were measured to assess vasospams in all groups.

There was a statistically significant difference between the mean basilar artery cross-sectional areas and the mean arterial wall thickness measurements of the control and SAH-only groups (P < .05). The difference between the mean basilar artery cross-sectional areas and the mean arterial wall thickness measurements in the RLX-treated group was statistically significant (P < .05). The difference between the SAH group and the SAH + RLX group was also statistically significant (P < .05).

These findings demonstrate that RLX has marked vasodilatatory effect in an experimental model of SAH in rabbits. This observation may have clinical implications suggesting that this SERM drug could be used as possible anti-vasospastic agent in patients without major adverse effects 3).


The effect of raloxifene on cerebral vasospasm following experimental subarachnoid hemorrhage (SAH) was investigated in a rat model. Seven groups of seven rats underwent no SAH, no treatment; SAH only; SAH plus vehicle; SAH plus 3 days intraperitoneal raloxifene treatment; SAH plus 4 days intraperitoneal raloxifene treatment; SAH plus 3 days intrathecal raloxifene treatment; and SAH plus 4 days intrathecal raloxifene treatment. The basilar artery cross-sectional areas were measured at 72 or 96 hours following SAH. The results showed raloxifene decreased SAH-induced cerebral vasospasm in all treatment groups, and suggested no difference between intraperitoneal and intrathecal application, or between 3 days and 4 days of raloxifene treatment. The present study demonstrates that raloxifene is a potential therapeutic agent against cerebral vasospasm after SAH 4).


To directly test whether exogenous 17beta estradiol and raloxifene affect the number of glial cells in brain, C57BL/6NIA female mice aged 20-24 months received bilateral ovariectomy followed by s.c. placement of a 60-day release pellet containing 17beta estradiol (1.7 mg), raloxifene (10 mg), or placebo (cholesterol). After 60 days, numbers of microglia and astrocytes were quantified in dentate gyrus and CA1 regions of the hippocampal formation using immunocytochemistry and design-based stereology. The results show that long-term 17beta estradiol treatment in aged female mice significantly lowered the numbers of astrocytes and microglial cells in dentate gyrus and CA1 regions compared with placebo. After long-term treatment with raloxifene, a similar reduction was observed in numbers of astrocytes and microglial cells in the hippocampal formation. These findings indicate that estrogen and selective estrogen receptor modulators can influence glial-mediated inflammatory pathways and possibly protect against age- and disease-related neuropathology 5).

References

1)

Choudhary C, Hamrahian AH, Bena JF, Recinos P, Kennedy L, Dobri G. THE EFFECT OF RALOXIFENE ON SERUM PROLACTIN LEVEL IN PATIENTS WITH PROLACTINOMA. Endocr Pract. 2019 Mar 13. doi: 10.4158/EP-2018-0321. [Epub ahead of print] PubMed PMID: 30865525.
2)

Hannen R, Steffani M, Voellger B, Carl B, Wang J, Bartsch JW, Nimsky C. Effects of anti-estrogens on cell invasion and survival in pituitary adenoma cells: A systematic study. J Steroid Biochem Mol Biol. 2019 Mar;187:88-96. doi: 10.1016/j.jsbmb.2018.11.005. Epub 2018 Nov 13. PubMed PMID: 30439415.
3)

Gürses L, Seçkin H, Simşek S, Senel OO, Yigitkanli K, Oztürk E, Beşalti O, Belen D, Bavbek M. Effects of raloxifene on cerebral vasospasm after experimental Subarachnoid Hemorrhage in rabbits. Surg Neurol. 2009 Nov;72(5):490-4; discussion 494-5. doi: 10.1016/j.surneu.2008.11.007. Epub 2009 Jan 14. PubMed PMID: 19147193.
4)

Gulsen S, Inci S, Yuruk S, Yasar U, Ozgen T. Effect of raloxifene on cerebral vasospasm following experimental subarachnoid hemorrhage in rats. Neurol Med Chir (Tokyo). 2007 Dec;47(12):537-42; discussion 542. PubMed PMID: 18159137.
5)

Lei DL, Long JM, Hengemihle J, O’Neill J, Manaye KF, Ingram DK, Mouton PR. Effects of estrogen and raloxifene on neuroglia number and morphology in the hippocampus of aged female mice. Neuroscience. 2003;121(3):659-66. PubMed PMID: 14568026.

Pituitary stalk thickening

Pituitary stalk thickening

The diagnosis of lesions determining pituitary stalk thickness is challenging, and the identification of the underlying condition may require a long-term follow-up. Thus, clinicians should readily recognize that, when the diagnosis of central diabetes insipidus has been established, specific MRI sequences should be used in the assessment of the hypothalamic-pituitary region, and whole-brain evaluation is recommended. For clinical practice, a timely diagnosis is advisable to avoid central nervous system damage, pituitary defects and the risk of dissemination of germ cell tumours or organ involvement by LCH. Proper aetiological diagnosis can be achieved via a series of steps that start with careful observation of several neuroimaging predictors and endocrine dysfunction and then progress to more sophisticated and advanced imaging techniques 1).


325 patients with pituitary stalk thickening in the tertiary teaching Ruijin Hospital between January 2012 and February 2018 were enrolled. Basic characteristics and hormonal status were evaluated. Indicators to predict etiology in patients with histological diagnoses were analyzed.

Of the 325 patients, 62.5% were females. Deficiencies in gonadotropin was most common, followed by corticotrophingrowth hormone and thyrotropin. The increase of pituitary stalk width was associated with a risk of central diabetes insipidus (OR=3.57, P<0.001) and with a combination of central diabetes insipidus and anterior pituitary deficiency (OR=2.28, P=0.029). The cut-off pituitary stalk width of 4.75 mm had a sensitivity of 69.2% and a specificity of 71.4% for the presence of central diabetes insipidus together with anterior pituitary deficiency. Six indicators (central diabetes insipidus, patterns of pituitary stalk thickening, pituitary stalk width, neutrophilic granulocyte percentage, serum sodium level and gender were used to develop a model having an accuracy of 95.7% to differentiate neoplastic from inflammatory causes.

Pituitary stalk width could indicate the presence of anterior pituitary dysfunction especially in central diabetes insipidus patients. With the use of a diagnostic model, the neoplastic and inflammatory causes of pituitary stalk thickening could be preliminarily differentiated 2).


CSF-human chorionic gonadotropin (hCG) concentrations that exceed the established reference interval (undetectable values to 0.7 IU/L) in the presence of suprasellar lesions and pituitary stalk thickening must be considered pathological, establishing the need to exclude the presence of germinoma 3).


Diabetes insipidus (DI) associated with a thickened pituitary stalk is a diagnostic challenge in the pediatric population. Langerhans Cell Histiocytosis (LCH) is a rare cause of this entity. A 4-year-old male child presented with central DI of 1-year duration, associated with a thickened pituitary stalk. The etiology for the same remained elusive as the patient had no other manifestation to suggest LCH. A year later, the patient developed a left frontal scalp swelling. Neuroradiology demonstrated multiple punched out osteolytic lesions in both the frontal bones. The infundibulum was thickened and showed post-contrast enhancement. Histology and immunohistochemistry (IHC) of the biopsy specimen confirmed LCH. The child was administered chemotherapy according to LCH protocol, which resulted in 33% reduction in the size of the skull lesions. The DI was controlled with medical management. The present case highlights the need for serial follow-up and magnetic resonance (MR) imaging that led to a diagnosis of LCH 4).

References

1)

Di Iorgi N, Morana G, Maghnie M. Pituitary stalk thickening on MRI: when is the best time to re-scan and how long should we continue re-scanning for? Clin Endocrinol (Oxf). 2015 Oct;83(4):449-55. doi: 10.1111/cen.12769. Epub 2015 Apr 6. PubMed PMID: 25759231.
2)

Ling SY, Zhao ZY, Tao B, Zhao HY, Su TW, Jiang YR, Xie J, Sun QF, Bian LG, Sun K, He NY, Yan FH, Wang WQ, Ning G, Sun LH, Liu JM. PITUITARY STALK THICKENING IN A LARGE COHORT – TOWARDS MORE ACCURATE PREDICATORS OF PITUITARY DYSFUNCTION AND ETIOLOGY. Endocr Pract. 2019 Mar 13. doi: 10.4158/EP-2018-0550. [Epub ahead of print] PubMed PMID: 30865546.
3)

González-Sánchez V, Moreno-Pérez O, Pellicer PS, Sánchez-Ortiga R, Guerra RA, Dot MM, Alfonso AM. Validation of the human chorionic gonadotropin immunoassay in cerebrospinal fluid for the diagnostic work-up of neurohypophyseal germinomas. Ann Clin Biochem. 2011 Sep;48(Pt 5):433-7. doi: 10.1258/acb.2010.010074. PubMed PMID: 21719508.
4)

Redhu R, Nadkarni T, Mahesh R. Diabetes insipidus associated with a thickened pituitary stalk in a case of Langerhans Cell Histiocytosis. J Pediatr Neurosci. 2011 Jan;6(1):62-4. doi: 10.4103/1817-1745.84412. PubMed PMID: 21977093; PubMed Central PMCID: PMC3173920.

Foramen ovale puncture

Foramen ovale puncture

Complications

Although Gasserian ganglion block is an established treatment for trigeminal neuralgia, the foramen ovale cannot always be clearly visualized by classical X-ray radiography.

Cannulation procedures, including those utilizing neuronavigational technology, are occasionally complicated by anatomical variation of the FO, sometimes resulting in miscannulation and subsequent adverse events. The FO, while commonly thought of as oval-shaped, has also been described as “almond,” “banana,” “D shape,” “pear,” and “triangular.” 1).

Advancement of the catheter more than 10 mm from the foramen ovale is likely to damage the internal carotid artery and the abducens nerve at the medial side of the petrolingual ligament. Thermocoagulation of the lateral wall of the cavernous sinus may damage the cranial nerves by heat, giving rise to pareses 2).


Guo et al., described a technique that includes a stereotactic approach in the preoperative plan in cases where the foramen ovale is difficult to access for radiofrequency thermocoagulation of the Gasserian ganglion.

The study included 395 patients for whom three-dimensional computed tomographic reconstruction of the skull base, maxilla, and mandible was conducted before surgery. Accessibility of the foramen ovale was defined using numerical data from the three-dimensional computed tomographic reconstruction images. In those patients for whom accessibility of the foramen ovale was considered difficult, the authors used a stereotactic frame to design an individual operative plan. Adjustments of a single point of data,-that is, a change in X axis, Y axis, or an arc angle-were guided by radiographic fluoroscopy images. After verifying successful cannulation and electroneurophysiology, thermocoagulation targets-especially multiple targets recorded as data on the Z axis of the stereotactic approach-were identified and treated.

There were 24 patients who met the predetermined criteria for having a difficult-to-access foramen ovales-that is, they had at least two contributing factors and/or involvement of division V1 . Twenty-one of the 24 patients required a single satisfactory puncture; three patients required two to three punctures to successfully access the foramen ovale. There were no permanent complications from the procedure.

The authors conclude that this stereotactic approach combined with three-dimensional computed tomographic reconstruction model can improve the accuracy, safety, and efficiency of percutaneous radiofrequency thermocoagulation in patients with trigeminal neuralgia for whom the foramen ovale is difficult to access 3).


Ding et al., assessed the feasibility of accessing the Gasserian ganglion through the FO from a mandibular angle under computed tomography (CT) and neuronavigation guidance.A total of 108 patients with TN were randomly divided into 2 groups (Group G and Group H) using a random number table. In Group H, anterior Hartel approach was used to puncture the FO; whereas in Group G, a percutaneous puncture through a mandibular angle was used to reach the FO. In both groups, procedures were guided by CT imaging and neuronavigation. The success rates, therapeutic effects, complications, and recurrence rates of the 2 groups were compared.The puncture success rates in Group H and Group G were 52/54 (96.30%) and 49/54 (90.74%), respectively (P = 0.24). The 2 procedural failures in Group H were rescued by using submandibular trajectory, and the 5 failures in Group G were successfully reapproached by Hartel method. Therapeutic effects as measured by Barrow Neurological Institute Pain Scale (P = 0.03) and quality of life (QOL) scores (P = 0.04) were significantly better in Group G than those in Group H at 36 months posttreatment. Hematoma developed in 1/54 (1.85%) cases in Group H, and no cases of hematoma were observed in Group G (P = 0.33). In Group H, RFT resulted in injury to the unintended trigeminal nerve branches and motor fibers in 27/52 (51.92%) cases; in Group G, it resulted in the same type of injury in 7/49 cases (14.29%) (P < 0.01). In Group H, the 24- and 36-month recurrence rates were 12/51 (23.53%) and 20/51 (39.22%), respectively; in Group G, these recurrence rates were 7/49 (12.24%) and 9/49 (16.33%, P = 0.03), respectively.CT- and neuronavigation-guided puncture from a mandibular angle through the FO into the Gasserian ganglion can be safely and effectively used to deliver RFT for the treatment of pTN. This method may represent a viable option to treat TN in addition to Hartel approach 4).


The goals of a study of Peris-Celda et al., were to demonstrate the anatomical basis of complications related to FO puncture, and provide anatomical landmarks for improvement of safety, selective lesioning of the trigeminal nerve (TN), and optimal placement of electrodes.

Both sides of 50 dry skulls were studied to obtain the distances from the FO to relevant cranial base references. A total of 36 sides from 18 formalin-fixed specimens were dissected for Meckel cave and TN measurements. The best radiographic projection for FO visualization was assessed in 40 skulls, and the optimal trajectory angles, insertion depths, and topographies of the lesions were evaluated in 17 specimens. In addition, the differences in postoperative pain relief after the radiofrequency procedure among different branches of the TN were statistically assessed in 49 patients to determine if there was any TN branch less efficiently targeted.

Most severe complications during FO puncture are related to incorrect needle placement intracranially or extracranially. The needle should be inserted 25 mm lateral to the oral commissure, forming an approximately 45° angle with the hard palate in the lateral radiographic view, directed 20° medially in the anteroposterior view. Once the needle reaches the FO, it can be advanced by 20 mm, on average, up to the petrous ridge. If the needle/radiofrequency electrode tip remains more than 18 mm away from the midline, injury to the cavernous carotid artery is minimized. Anatomically there is less potential for complications when the needle/radiofrequency electrode is advanced no more than 2 mm away from the clival line in the lateral view, when the needle pierces the medial part of the FO toward the medial part of the trigeminal impression in the petrous ridge, and no more than 4 mm in the lateral part. The 40°/45° inferior transfacial-20° oblique radiographic projection visualized 96.2% of the FOs in dry skulls, and the remainder were not visualized in any other projection of the radiograph. Patients with V1 involvement experienced postoperative pain more frequently than did patients with V2 or V3 involvement. Anatomical targeting of V1 in specimens was more efficiently achieved by inserting the needle in the medial third of the FO; for V2 targeting, in the middle of the FO; and for V3 targeting, in the lateral third of the FO.

Knowledge of the extracranial and intracranial anatomical relationships of the FO is essential to understanding and avoiding complications during FO puncture. These data suggest that better radiographic visualization of the FO can improve lesioning accuracy depending on the part of the FO to be punctured. The angles and safety distances obtained may help the neurosurgeon minimize complications during FO puncture and TN lesioning 5).


Koizuka et al., presented a new method for percutaneous radio-frequency thermocoagulation of the Gasserian ganglion, in which computed tomography (CT) fluoroscopy is used to guide needle placement.

In the present study, 15 patients with trigeminal neuralgia underwent percutaneous radio-frequency thermocoagulation of the Gasserian ganglion guided by high-speed real-time CT fluoroscopy.

RESULTS: Trigeminal neuralgia was improved in all patients after treatment without any severe complications. Moderate dysesthesia occurred in only one case.

CT fluoroscopy-guided percutaneous radio-frequency thermocoagulation of the Gasserian ganglion was safe, quick, and effective for patients with intractable idiopathic trigeminal neuralgia 6).

Videos

References

1)

Zdilla MJ, Fijalkowski KM. The Shape of the Foramen Ovale: A Visualization Aid for Cannulation Procedures. J Craniofac Surg. 2016 Dec 23. doi: 10.1097/SCS.0000000000003325. [Epub ahead of print] PubMed PMID: 28027173.
2)

Kaplan M, Erol FS, Ozveren MF, Topsakal C, Sam B, Tekdemir I. Review of complications due to foramen ovale puncture. J Clin Neurosci. 2007 Jun;14(6):563-8. Epub 2006 Dec 13. PubMed PMID: 17169562.
3)

Guo Z, Wu B, Du C, Cheng M, Tian Y. Stereotactic Approach Combined with 3D CT Reconstruction for Difficult-to-Access Foramen Ovale on Radiofrequency Thermocoagulation of the Gasserian Ganglion for Trigeminal Neuralgia. Pain Med. 2016 Sep;17(9):1704-16. doi: 10.1093/pm/pnv108. Epub 2016 Feb 13. PubMed PMID: 26874883.
4)

Ding W, Chen S, Wang R, Cai J, Cheng Y, Yu L, Li Q, Deng F, Zhu S, Yu W. Percutaneous radiofrequency thermocoagulation for trigeminal neuralgia using neuronavigation-guided puncture from a mandibular angle. Medicine (Baltimore). 2016 Oct;95(40):e4940. PubMed PMID: 27749549; PubMed Central PMCID: PMC5059051.
5)

Peris-Celda M, Graziano F, Russo V, Mericle RA, Ulm AJ. Foramen ovale puncture, lesioning accuracy, and avoiding complications: microsurgical anatomy study with clinical implications. J Neurosurg. 2013 Nov;119(5):1176-93. doi: 10.3171/2013.1.JNS12743. Epub 2013 Apr 19. PubMed PMID: 23600929.
6)

Koizuka S, Saito S, Sekimoto K, Tobe M, Obata H, Koyama Y. Percutaneous radio-frequency thermocoagulation of the Gasserian ganglion guided by high-speed real-time CT fluoroscopy. Neuroradiology. 2009 Sep;51(9):563-6. doi: 10.1007/s00234-009-0541-8. Epub 2009 Jun 5. PubMed PMID: 19499214.
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